User login
ACIP backs broader use of MenB vaccination to include adolescents and college students
A recommendation to expand serogroup B meningococcal vaccination to include adolescents and young adults, including college students, was supported by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices, at a meeting on June 24.
The panel voted 14-1 in favor of the following recommendation proposed by ACIP’s meningococcal work group: The serogroup B meningococcal (MenB) vaccine series “may be administered to adolescents and young adults 16 through 23 years of age to provide short-term protection against most strains of serogroup B meningococcal disease,” specifying that 16-18 years is “the preferred age for MenB vaccination.” In reference to the two MenB vaccines now licensed in the United States, the proposal also states that the vaccine be administered as a two- or three-dose series, using the same vaccine product for all doses, with no preference of one product over the other. “Based on available data and expert opinion,” the MenB vaccine used “may be administered concomitantly with other vaccines, indicated for this age, but at a different anatomic site, if feasible.”
The two vaccines licensed by the Food and Drug Administration are Trumenba, a three-dose series marketed by Pfizer, and Bexsero, a two-dose series marketed by GlaxoSmithKline; they are indicated for preventing meningococcal disease caused by Neisseria meningitidis serogroup B in people aged 10-25 years.
The work group’s recommendation is a category B recommendation, so whether the vaccine is recommended is subject to individualized clinical decisions. A university may choose to recommend vaccination for students. In contrast, under a “category A” recommendation, all people in an age- or risk factor–based group would be candidates for immunization. During the discussion before the vote, several panelists raised concerns that while they would not support a category A recommendation at this time, the category B recommendation could create confusion among clinicians and parents about who should get the vaccine and could result in unequal access to the vaccine. One panelist noted that in the past, pediatric practices have not stocked vaccines with a category B recommendation in their offices.
The reasons for choosing the category B recommendation include the current low burden of disease, and the high number of individuals needed to vaccinate to prevent one case or one death of serogroup B disease, explained Jessica MacNeil, an epidemiologist and member of the work group, who is with the CDC’s National Center for Immunization and Respiratory Diseases. Another reason is that the number of cases prevented “may be comparable to the number of serious adverse events” associated with the vaccine, she said.
At the meeting, the panel also voted 15-0 for the statement that children aged 16 though 18 years “without high risk conditions may also be vaccinated” be added to the groups eligible or MenB vaccination in the Vaccines for Children program. The eligible groups currently listed are those aged 10-18 years at increased risk for meningococcal disease “attributable to serogroup B,” which includes those at increased risk because of an outbreak attributed to serogroup B meningococcal disease. These groups were recommended at the last ACIP meeting in February, when the panel recommended MenB vaccination for several groups at increased risk for serogroup B disease, including students during outbreaks at college campuses.
Vaccines with a category B recommendation are covered under Vaccines for Children and the Affordable Care Act.
There was an unprecedented number of public speakers and letters sent to the panel, overwhelmingly in support of broadening the recommendation for vaccination. Many letters were sent from universities or college. Speakers included parents and siblings of young people who had died of meningococcal serogroup B disease, as recently as the fall of 2014, including both college and high school students, and one 20-year-old who was not a college student. One college student whose sister died of meningococcal B disease said it took 6 months for her to get vaccinated, and she eventually was able to get immunized through a travel vaccine clinic. Others said they have gone to Canada to get the vaccine.
Since 2009, there have been seven outbreaks or clusters of serogroup B meningococcal disease reported to the CDC, including two in 2015, for a total of 41 cases. The outbreak at the University of Oregon, Eugene, which started in mid-January, included six cases in students, with one death from meningococcemia in February. In May, the Oregon public health department announced that a 52-year-old man had developed meningococcal disease after visiting his daughter at the university – the seventh confirmed case linked to the outbreak.
ACIP is composed of medical and public health experts who develop recommendations on how to use vaccines to control diseases in the United States.
A recommendation to expand serogroup B meningococcal vaccination to include adolescents and young adults, including college students, was supported by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices, at a meeting on June 24.
The panel voted 14-1 in favor of the following recommendation proposed by ACIP’s meningococcal work group: The serogroup B meningococcal (MenB) vaccine series “may be administered to adolescents and young adults 16 through 23 years of age to provide short-term protection against most strains of serogroup B meningococcal disease,” specifying that 16-18 years is “the preferred age for MenB vaccination.” In reference to the two MenB vaccines now licensed in the United States, the proposal also states that the vaccine be administered as a two- or three-dose series, using the same vaccine product for all doses, with no preference of one product over the other. “Based on available data and expert opinion,” the MenB vaccine used “may be administered concomitantly with other vaccines, indicated for this age, but at a different anatomic site, if feasible.”
The two vaccines licensed by the Food and Drug Administration are Trumenba, a three-dose series marketed by Pfizer, and Bexsero, a two-dose series marketed by GlaxoSmithKline; they are indicated for preventing meningococcal disease caused by Neisseria meningitidis serogroup B in people aged 10-25 years.
The work group’s recommendation is a category B recommendation, so whether the vaccine is recommended is subject to individualized clinical decisions. A university may choose to recommend vaccination for students. In contrast, under a “category A” recommendation, all people in an age- or risk factor–based group would be candidates for immunization. During the discussion before the vote, several panelists raised concerns that while they would not support a category A recommendation at this time, the category B recommendation could create confusion among clinicians and parents about who should get the vaccine and could result in unequal access to the vaccine. One panelist noted that in the past, pediatric practices have not stocked vaccines with a category B recommendation in their offices.
The reasons for choosing the category B recommendation include the current low burden of disease, and the high number of individuals needed to vaccinate to prevent one case or one death of serogroup B disease, explained Jessica MacNeil, an epidemiologist and member of the work group, who is with the CDC’s National Center for Immunization and Respiratory Diseases. Another reason is that the number of cases prevented “may be comparable to the number of serious adverse events” associated with the vaccine, she said.
At the meeting, the panel also voted 15-0 for the statement that children aged 16 though 18 years “without high risk conditions may also be vaccinated” be added to the groups eligible or MenB vaccination in the Vaccines for Children program. The eligible groups currently listed are those aged 10-18 years at increased risk for meningococcal disease “attributable to serogroup B,” which includes those at increased risk because of an outbreak attributed to serogroup B meningococcal disease. These groups were recommended at the last ACIP meeting in February, when the panel recommended MenB vaccination for several groups at increased risk for serogroup B disease, including students during outbreaks at college campuses.
Vaccines with a category B recommendation are covered under Vaccines for Children and the Affordable Care Act.
There was an unprecedented number of public speakers and letters sent to the panel, overwhelmingly in support of broadening the recommendation for vaccination. Many letters were sent from universities or college. Speakers included parents and siblings of young people who had died of meningococcal serogroup B disease, as recently as the fall of 2014, including both college and high school students, and one 20-year-old who was not a college student. One college student whose sister died of meningococcal B disease said it took 6 months for her to get vaccinated, and she eventually was able to get immunized through a travel vaccine clinic. Others said they have gone to Canada to get the vaccine.
Since 2009, there have been seven outbreaks or clusters of serogroup B meningococcal disease reported to the CDC, including two in 2015, for a total of 41 cases. The outbreak at the University of Oregon, Eugene, which started in mid-January, included six cases in students, with one death from meningococcemia in February. In May, the Oregon public health department announced that a 52-year-old man had developed meningococcal disease after visiting his daughter at the university – the seventh confirmed case linked to the outbreak.
ACIP is composed of medical and public health experts who develop recommendations on how to use vaccines to control diseases in the United States.
A recommendation to expand serogroup B meningococcal vaccination to include adolescents and young adults, including college students, was supported by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices, at a meeting on June 24.
The panel voted 14-1 in favor of the following recommendation proposed by ACIP’s meningococcal work group: The serogroup B meningococcal (MenB) vaccine series “may be administered to adolescents and young adults 16 through 23 years of age to provide short-term protection against most strains of serogroup B meningococcal disease,” specifying that 16-18 years is “the preferred age for MenB vaccination.” In reference to the two MenB vaccines now licensed in the United States, the proposal also states that the vaccine be administered as a two- or three-dose series, using the same vaccine product for all doses, with no preference of one product over the other. “Based on available data and expert opinion,” the MenB vaccine used “may be administered concomitantly with other vaccines, indicated for this age, but at a different anatomic site, if feasible.”
The two vaccines licensed by the Food and Drug Administration are Trumenba, a three-dose series marketed by Pfizer, and Bexsero, a two-dose series marketed by GlaxoSmithKline; they are indicated for preventing meningococcal disease caused by Neisseria meningitidis serogroup B in people aged 10-25 years.
The work group’s recommendation is a category B recommendation, so whether the vaccine is recommended is subject to individualized clinical decisions. A university may choose to recommend vaccination for students. In contrast, under a “category A” recommendation, all people in an age- or risk factor–based group would be candidates for immunization. During the discussion before the vote, several panelists raised concerns that while they would not support a category A recommendation at this time, the category B recommendation could create confusion among clinicians and parents about who should get the vaccine and could result in unequal access to the vaccine. One panelist noted that in the past, pediatric practices have not stocked vaccines with a category B recommendation in their offices.
The reasons for choosing the category B recommendation include the current low burden of disease, and the high number of individuals needed to vaccinate to prevent one case or one death of serogroup B disease, explained Jessica MacNeil, an epidemiologist and member of the work group, who is with the CDC’s National Center for Immunization and Respiratory Diseases. Another reason is that the number of cases prevented “may be comparable to the number of serious adverse events” associated with the vaccine, she said.
At the meeting, the panel also voted 15-0 for the statement that children aged 16 though 18 years “without high risk conditions may also be vaccinated” be added to the groups eligible or MenB vaccination in the Vaccines for Children program. The eligible groups currently listed are those aged 10-18 years at increased risk for meningococcal disease “attributable to serogroup B,” which includes those at increased risk because of an outbreak attributed to serogroup B meningococcal disease. These groups were recommended at the last ACIP meeting in February, when the panel recommended MenB vaccination for several groups at increased risk for serogroup B disease, including students during outbreaks at college campuses.
Vaccines with a category B recommendation are covered under Vaccines for Children and the Affordable Care Act.
There was an unprecedented number of public speakers and letters sent to the panel, overwhelmingly in support of broadening the recommendation for vaccination. Many letters were sent from universities or college. Speakers included parents and siblings of young people who had died of meningococcal serogroup B disease, as recently as the fall of 2014, including both college and high school students, and one 20-year-old who was not a college student. One college student whose sister died of meningococcal B disease said it took 6 months for her to get vaccinated, and she eventually was able to get immunized through a travel vaccine clinic. Others said they have gone to Canada to get the vaccine.
Since 2009, there have been seven outbreaks or clusters of serogroup B meningococcal disease reported to the CDC, including two in 2015, for a total of 41 cases. The outbreak at the University of Oregon, Eugene, which started in mid-January, included six cases in students, with one death from meningococcemia in February. In May, the Oregon public health department announced that a 52-year-old man had developed meningococcal disease after visiting his daughter at the university – the seventh confirmed case linked to the outbreak.
ACIP is composed of medical and public health experts who develop recommendations on how to use vaccines to control diseases in the United States.
FROM AN ACIP MEETING
FDA advisors urge physician certification for flibanserin
Without the option of recommending physician certification as a condition for flibanserin approval, the Food and Drug Administration advisory panel vote might have shifted against approval of the drug for treating hypoactive sexual desire disorder in premenopausal women.
At a joint meeting of two FDA advisory panels in June, members of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18-6 that the overall benefit-risk profile of flibanserin supported approval for treating hypoactive sexual desire disorder (HSDD) in premenopausal women, provided that certain risk management options beyond labeling were implemented. If approved by the FDA, flibanserin would be the first drug approved for treating HSDD.
Assurance that prescribers would be fully apprised of the serious risks of hypotension and syncope associated with the drug, exacerbation of those side effects when combined with alcohol or a CYP3A4 inhibitor – and the modest effects over placebo – was cited by several of the panelists who voted in favor of approval.
All of those voting in favor of approval chose the option of supporting approval “only if certain risk management options beyond labeling are implemented.” None of the panelists voted for the option of supporting approval with “labeling alone to manage the risks.”
The conditions include a risk management plan to address serious adverse effects associated with the drug, a requirement for physician certification, and postmarketing studies to further evaluate and monitor the drug’s safety and efficacy.
The risks of hypotension and syncope, and central nervous system depression are also exacerbated by moderate or strong CYP3A4 inhibitors, but the interaction with alcohol was raised as a particularly serious issue because of the high rate of alcohol use and binge drinking among women who would likely be treated with flibanserin, according to FDA reviewers.
The risk of drug interactions can be mitigated with drug interaction screening programs used in health care systems, such as in electronic medical records and pharmacies, while alcohol use is a patient-dependent behavior, is common among women, and therefore more difficult to control, Kimberly Lehrfeld, Pharm.D., a team leader in the division of risk management in the FDA’s office of medication error prevention and analysis, said at the meeting. Several panelists recommended that alcohol use be a contraindication.
Physician certification is among the Elements to Assure Safe Use or ETASU, which along with a medication guide and a communication plan for health care providers, are components of a Risk Evaluation and Mitigation Strategy (REMS), a way to help manage the risks of a drug or biologic while still making it available to patients who need it.
Physician certification is part of the REMS for drugs such as mifepristone (Mifeprex), thalidomide (Thalomid), and natalizumab (Tysabri).
“A risk strategy that gets physicians the information they need to use it properly is going to be key,” said Dr. Robert Silbergleit, who voted for approval.”A REMS strategy is going to be very important because I think that the most likely risks … are going to come from physicians who don’t use the drug properly because they’re not properly educated.”
Dr. Silbergleit, a professor in the department of emergency medicine at the University of Michigan, Ann Arbor, said he was also concerned about the marketing of the drug. “Clinicians may be in the situation where they have to counter direct-to-consumer marketing that could lead to misuse of the drug,” he said at the meeting.
Also voting for approval, Marjorie Shaw Phillips, R.Ph., pharmacy coordinator at Georgia Regents Medical Center in Augusta, said that everyone needs to be aware of the potential safety concerns. But while she does not think pharmacy registration would be beneficial, there is a role for the pharmacist to confirm that it’s an educated provider prescribing the drug and that they’ve discussed the risks with the patient.
She added that it will be important for physicians to set realistic expectations for patients.
“It’s not a magical little pink pill, and there are going to be a whole lot of women with sexual dysfunction for whom there’s no evidence that it’s going to benefit them,” she said at the meeting.
The panel did not specifically recommend pharmacy certification, but pharmacists would have to verify that the prescribing physicians are certified, if the drug is approved, an FDA official said at the meeting.
A decision from the FDA is expected in August. The FDA panelists reported having no relevant financial disclosures.
Sprout Pharmaceuticals, flibanserin’s manufacturer, said in a statement that the company looks forward “to continuing our work with the FDA as it completes its review of our new drug application, including the discussion of a Risks Evaluation and Mitigation Strategy.” If approved, the company plans to market flibanserin as “Addyi.”
Without the option of recommending physician certification as a condition for flibanserin approval, the Food and Drug Administration advisory panel vote might have shifted against approval of the drug for treating hypoactive sexual desire disorder in premenopausal women.
At a joint meeting of two FDA advisory panels in June, members of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18-6 that the overall benefit-risk profile of flibanserin supported approval for treating hypoactive sexual desire disorder (HSDD) in premenopausal women, provided that certain risk management options beyond labeling were implemented. If approved by the FDA, flibanserin would be the first drug approved for treating HSDD.
Assurance that prescribers would be fully apprised of the serious risks of hypotension and syncope associated with the drug, exacerbation of those side effects when combined with alcohol or a CYP3A4 inhibitor – and the modest effects over placebo – was cited by several of the panelists who voted in favor of approval.
All of those voting in favor of approval chose the option of supporting approval “only if certain risk management options beyond labeling are implemented.” None of the panelists voted for the option of supporting approval with “labeling alone to manage the risks.”
The conditions include a risk management plan to address serious adverse effects associated with the drug, a requirement for physician certification, and postmarketing studies to further evaluate and monitor the drug’s safety and efficacy.
The risks of hypotension and syncope, and central nervous system depression are also exacerbated by moderate or strong CYP3A4 inhibitors, but the interaction with alcohol was raised as a particularly serious issue because of the high rate of alcohol use and binge drinking among women who would likely be treated with flibanserin, according to FDA reviewers.
The risk of drug interactions can be mitigated with drug interaction screening programs used in health care systems, such as in electronic medical records and pharmacies, while alcohol use is a patient-dependent behavior, is common among women, and therefore more difficult to control, Kimberly Lehrfeld, Pharm.D., a team leader in the division of risk management in the FDA’s office of medication error prevention and analysis, said at the meeting. Several panelists recommended that alcohol use be a contraindication.
Physician certification is among the Elements to Assure Safe Use or ETASU, which along with a medication guide and a communication plan for health care providers, are components of a Risk Evaluation and Mitigation Strategy (REMS), a way to help manage the risks of a drug or biologic while still making it available to patients who need it.
Physician certification is part of the REMS for drugs such as mifepristone (Mifeprex), thalidomide (Thalomid), and natalizumab (Tysabri).
“A risk strategy that gets physicians the information they need to use it properly is going to be key,” said Dr. Robert Silbergleit, who voted for approval.”A REMS strategy is going to be very important because I think that the most likely risks … are going to come from physicians who don’t use the drug properly because they’re not properly educated.”
Dr. Silbergleit, a professor in the department of emergency medicine at the University of Michigan, Ann Arbor, said he was also concerned about the marketing of the drug. “Clinicians may be in the situation where they have to counter direct-to-consumer marketing that could lead to misuse of the drug,” he said at the meeting.
Also voting for approval, Marjorie Shaw Phillips, R.Ph., pharmacy coordinator at Georgia Regents Medical Center in Augusta, said that everyone needs to be aware of the potential safety concerns. But while she does not think pharmacy registration would be beneficial, there is a role for the pharmacist to confirm that it’s an educated provider prescribing the drug and that they’ve discussed the risks with the patient.
She added that it will be important for physicians to set realistic expectations for patients.
“It’s not a magical little pink pill, and there are going to be a whole lot of women with sexual dysfunction for whom there’s no evidence that it’s going to benefit them,” she said at the meeting.
The panel did not specifically recommend pharmacy certification, but pharmacists would have to verify that the prescribing physicians are certified, if the drug is approved, an FDA official said at the meeting.
A decision from the FDA is expected in August. The FDA panelists reported having no relevant financial disclosures.
Sprout Pharmaceuticals, flibanserin’s manufacturer, said in a statement that the company looks forward “to continuing our work with the FDA as it completes its review of our new drug application, including the discussion of a Risks Evaluation and Mitigation Strategy.” If approved, the company plans to market flibanserin as “Addyi.”
Without the option of recommending physician certification as a condition for flibanserin approval, the Food and Drug Administration advisory panel vote might have shifted against approval of the drug for treating hypoactive sexual desire disorder in premenopausal women.
At a joint meeting of two FDA advisory panels in June, members of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18-6 that the overall benefit-risk profile of flibanserin supported approval for treating hypoactive sexual desire disorder (HSDD) in premenopausal women, provided that certain risk management options beyond labeling were implemented. If approved by the FDA, flibanserin would be the first drug approved for treating HSDD.
Assurance that prescribers would be fully apprised of the serious risks of hypotension and syncope associated with the drug, exacerbation of those side effects when combined with alcohol or a CYP3A4 inhibitor – and the modest effects over placebo – was cited by several of the panelists who voted in favor of approval.
All of those voting in favor of approval chose the option of supporting approval “only if certain risk management options beyond labeling are implemented.” None of the panelists voted for the option of supporting approval with “labeling alone to manage the risks.”
The conditions include a risk management plan to address serious adverse effects associated with the drug, a requirement for physician certification, and postmarketing studies to further evaluate and monitor the drug’s safety and efficacy.
The risks of hypotension and syncope, and central nervous system depression are also exacerbated by moderate or strong CYP3A4 inhibitors, but the interaction with alcohol was raised as a particularly serious issue because of the high rate of alcohol use and binge drinking among women who would likely be treated with flibanserin, according to FDA reviewers.
The risk of drug interactions can be mitigated with drug interaction screening programs used in health care systems, such as in electronic medical records and pharmacies, while alcohol use is a patient-dependent behavior, is common among women, and therefore more difficult to control, Kimberly Lehrfeld, Pharm.D., a team leader in the division of risk management in the FDA’s office of medication error prevention and analysis, said at the meeting. Several panelists recommended that alcohol use be a contraindication.
Physician certification is among the Elements to Assure Safe Use or ETASU, which along with a medication guide and a communication plan for health care providers, are components of a Risk Evaluation and Mitigation Strategy (REMS), a way to help manage the risks of a drug or biologic while still making it available to patients who need it.
Physician certification is part of the REMS for drugs such as mifepristone (Mifeprex), thalidomide (Thalomid), and natalizumab (Tysabri).
“A risk strategy that gets physicians the information they need to use it properly is going to be key,” said Dr. Robert Silbergleit, who voted for approval.”A REMS strategy is going to be very important because I think that the most likely risks … are going to come from physicians who don’t use the drug properly because they’re not properly educated.”
Dr. Silbergleit, a professor in the department of emergency medicine at the University of Michigan, Ann Arbor, said he was also concerned about the marketing of the drug. “Clinicians may be in the situation where they have to counter direct-to-consumer marketing that could lead to misuse of the drug,” he said at the meeting.
Also voting for approval, Marjorie Shaw Phillips, R.Ph., pharmacy coordinator at Georgia Regents Medical Center in Augusta, said that everyone needs to be aware of the potential safety concerns. But while she does not think pharmacy registration would be beneficial, there is a role for the pharmacist to confirm that it’s an educated provider prescribing the drug and that they’ve discussed the risks with the patient.
She added that it will be important for physicians to set realistic expectations for patients.
“It’s not a magical little pink pill, and there are going to be a whole lot of women with sexual dysfunction for whom there’s no evidence that it’s going to benefit them,” she said at the meeting.
The panel did not specifically recommend pharmacy certification, but pharmacists would have to verify that the prescribing physicians are certified, if the drug is approved, an FDA official said at the meeting.
A decision from the FDA is expected in August. The FDA panelists reported having no relevant financial disclosures.
Sprout Pharmaceuticals, flibanserin’s manufacturer, said in a statement that the company looks forward “to continuing our work with the FDA as it completes its review of our new drug application, including the discussion of a Risks Evaluation and Mitigation Strategy.” If approved, the company plans to market flibanserin as “Addyi.”
DDW: New scale measures impact of IBD on sexual function in men
WASHINGTON – Almost 40% of men with inflammatory bowel disease said the disease had a negative effect on their libido and almost 30% said that the disease had prevented them from having sex, in a study that used a new scale designed to evaluate sexual dysfunction in men with IBD, Dr. Aoibhlinn O’Toole reported at the annual Digestive Disease Week.
Dr. O’Toole, an IBD fellow at Beth Israel Deaconess Medical Center, Boston, developed the IBD Sexual Dysfunction Scale (IBDSDS) with her associates at Beth Israel Deaconess and Brigham and Women’s Hospital. The results of the study were based on 175 responses to the IBDSDS questionnaire, which were sent to all the adult male patients treated at the IBD clinics at both medical centers. The IBD-specific tool is now being validated.
Because there has been no IBD-specific scale to measure sexual dysfunction in this group of patients, they developed the IBDSDS and conducted the study to evaluate the prevalence of sexual dysfunction in male patients with IBD and identify factors associated with sexual dysfunction. The process of designing the scale included a literature search of generic questionnaires to identify relevant domains of sexual function and the addition of IBD-specific questions related to the effects of symptoms, medications, and surgery on sexual function.
Despite significant issues that can clearly affect sexuality in this group of patients – including perianal disease and the effect of treatment and symptoms on body image, intimacy, and sexual function – the extent and effects of sexual dysfunction in men with IBD is not well known, Dr. O’Toole pointed out.
The 43 questions in the scale include those that pertain to libido, ejaculation, satisfaction, and body image, as well as elements of two validated screening tools, the International Index of Erectile Function (IIEF), the gold standard screening tool for erectile dysfunction; and the Patient Health Questionnaire 9 (PHQ-9), for depression.
The average age of the 175 respondents was 43 years and the average duration of IBD was 14 years; 57% had Crohn’s disease, 33% had had surgery, 6% had chronic pain, 2% used narcotics, 12% had hypertension, and 4% had diabetes. Almost 90% were in a relationship that “could involve sexual activity” and 2% had not been sexually active in the previous year. In addition, 14% said that they felt that IBD had caused a breakup in an existing relationship, and 21% said they had felt hesitant about starting a new relationship because of IBD.
As for the effects of IBD on sexual function, in the last year, 38% felt that IBD had a negative effect on their libido, 27% said IBD prevented them from having sex, and 18% said that IBD caused problems during sex. In addition, 20% said that IBD made them feel guilty about having sex and 30% said they feared having sex; 2% reported having erectile dysfunction.
The use of erectile-enhancing medications were reported by 23% (prescribed mostly by doctors other than the physician treating the IBD) and 5% were taking testosterone to enhance sexual function. While 78% said they were comfortable speaking about sexual function with their gastroenterologist, only 10% said that their gastroenterologist had initiated a discussion about this topic, Dr. O’Toole said.
Based on other analyses of the results, “we found that impaired sexual function was associated with older age, longer duration of disease, active disease, comorbid depression, presence of an ostomy, and diabetes,” she added.
While the thrombotic risks of testosterone are clear, Dr. O’Toole noted that in patients with IBD, the effects of phosphodiesterase-5 (PDE5) inhibitors like sildenafil (Viagra) on the microcirculation within the gastrointestinal tract and whether the effects of these drugs contribute to microscopic ischemia in the GI tract is unclear, she said. Dr. O’Toole had no relevant financial disclosures.
WASHINGTON – Almost 40% of men with inflammatory bowel disease said the disease had a negative effect on their libido and almost 30% said that the disease had prevented them from having sex, in a study that used a new scale designed to evaluate sexual dysfunction in men with IBD, Dr. Aoibhlinn O’Toole reported at the annual Digestive Disease Week.
Dr. O’Toole, an IBD fellow at Beth Israel Deaconess Medical Center, Boston, developed the IBD Sexual Dysfunction Scale (IBDSDS) with her associates at Beth Israel Deaconess and Brigham and Women’s Hospital. The results of the study were based on 175 responses to the IBDSDS questionnaire, which were sent to all the adult male patients treated at the IBD clinics at both medical centers. The IBD-specific tool is now being validated.
Because there has been no IBD-specific scale to measure sexual dysfunction in this group of patients, they developed the IBDSDS and conducted the study to evaluate the prevalence of sexual dysfunction in male patients with IBD and identify factors associated with sexual dysfunction. The process of designing the scale included a literature search of generic questionnaires to identify relevant domains of sexual function and the addition of IBD-specific questions related to the effects of symptoms, medications, and surgery on sexual function.
Despite significant issues that can clearly affect sexuality in this group of patients – including perianal disease and the effect of treatment and symptoms on body image, intimacy, and sexual function – the extent and effects of sexual dysfunction in men with IBD is not well known, Dr. O’Toole pointed out.
The 43 questions in the scale include those that pertain to libido, ejaculation, satisfaction, and body image, as well as elements of two validated screening tools, the International Index of Erectile Function (IIEF), the gold standard screening tool for erectile dysfunction; and the Patient Health Questionnaire 9 (PHQ-9), for depression.
The average age of the 175 respondents was 43 years and the average duration of IBD was 14 years; 57% had Crohn’s disease, 33% had had surgery, 6% had chronic pain, 2% used narcotics, 12% had hypertension, and 4% had diabetes. Almost 90% were in a relationship that “could involve sexual activity” and 2% had not been sexually active in the previous year. In addition, 14% said that they felt that IBD had caused a breakup in an existing relationship, and 21% said they had felt hesitant about starting a new relationship because of IBD.
As for the effects of IBD on sexual function, in the last year, 38% felt that IBD had a negative effect on their libido, 27% said IBD prevented them from having sex, and 18% said that IBD caused problems during sex. In addition, 20% said that IBD made them feel guilty about having sex and 30% said they feared having sex; 2% reported having erectile dysfunction.
The use of erectile-enhancing medications were reported by 23% (prescribed mostly by doctors other than the physician treating the IBD) and 5% were taking testosterone to enhance sexual function. While 78% said they were comfortable speaking about sexual function with their gastroenterologist, only 10% said that their gastroenterologist had initiated a discussion about this topic, Dr. O’Toole said.
Based on other analyses of the results, “we found that impaired sexual function was associated with older age, longer duration of disease, active disease, comorbid depression, presence of an ostomy, and diabetes,” she added.
While the thrombotic risks of testosterone are clear, Dr. O’Toole noted that in patients with IBD, the effects of phosphodiesterase-5 (PDE5) inhibitors like sildenafil (Viagra) on the microcirculation within the gastrointestinal tract and whether the effects of these drugs contribute to microscopic ischemia in the GI tract is unclear, she said. Dr. O’Toole had no relevant financial disclosures.
WASHINGTON – Almost 40% of men with inflammatory bowel disease said the disease had a negative effect on their libido and almost 30% said that the disease had prevented them from having sex, in a study that used a new scale designed to evaluate sexual dysfunction in men with IBD, Dr. Aoibhlinn O’Toole reported at the annual Digestive Disease Week.
Dr. O’Toole, an IBD fellow at Beth Israel Deaconess Medical Center, Boston, developed the IBD Sexual Dysfunction Scale (IBDSDS) with her associates at Beth Israel Deaconess and Brigham and Women’s Hospital. The results of the study were based on 175 responses to the IBDSDS questionnaire, which were sent to all the adult male patients treated at the IBD clinics at both medical centers. The IBD-specific tool is now being validated.
Because there has been no IBD-specific scale to measure sexual dysfunction in this group of patients, they developed the IBDSDS and conducted the study to evaluate the prevalence of sexual dysfunction in male patients with IBD and identify factors associated with sexual dysfunction. The process of designing the scale included a literature search of generic questionnaires to identify relevant domains of sexual function and the addition of IBD-specific questions related to the effects of symptoms, medications, and surgery on sexual function.
Despite significant issues that can clearly affect sexuality in this group of patients – including perianal disease and the effect of treatment and symptoms on body image, intimacy, and sexual function – the extent and effects of sexual dysfunction in men with IBD is not well known, Dr. O’Toole pointed out.
The 43 questions in the scale include those that pertain to libido, ejaculation, satisfaction, and body image, as well as elements of two validated screening tools, the International Index of Erectile Function (IIEF), the gold standard screening tool for erectile dysfunction; and the Patient Health Questionnaire 9 (PHQ-9), for depression.
The average age of the 175 respondents was 43 years and the average duration of IBD was 14 years; 57% had Crohn’s disease, 33% had had surgery, 6% had chronic pain, 2% used narcotics, 12% had hypertension, and 4% had diabetes. Almost 90% were in a relationship that “could involve sexual activity” and 2% had not been sexually active in the previous year. In addition, 14% said that they felt that IBD had caused a breakup in an existing relationship, and 21% said they had felt hesitant about starting a new relationship because of IBD.
As for the effects of IBD on sexual function, in the last year, 38% felt that IBD had a negative effect on their libido, 27% said IBD prevented them from having sex, and 18% said that IBD caused problems during sex. In addition, 20% said that IBD made them feel guilty about having sex and 30% said they feared having sex; 2% reported having erectile dysfunction.
The use of erectile-enhancing medications were reported by 23% (prescribed mostly by doctors other than the physician treating the IBD) and 5% were taking testosterone to enhance sexual function. While 78% said they were comfortable speaking about sexual function with their gastroenterologist, only 10% said that their gastroenterologist had initiated a discussion about this topic, Dr. O’Toole said.
Based on other analyses of the results, “we found that impaired sexual function was associated with older age, longer duration of disease, active disease, comorbid depression, presence of an ostomy, and diabetes,” she added.
While the thrombotic risks of testosterone are clear, Dr. O’Toole noted that in patients with IBD, the effects of phosphodiesterase-5 (PDE5) inhibitors like sildenafil (Viagra) on the microcirculation within the gastrointestinal tract and whether the effects of these drugs contribute to microscopic ischemia in the GI tract is unclear, she said. Dr. O’Toole had no relevant financial disclosures.
AT DDW 2015
Key clinical point: Once validated, a new scale designed to evaluate sexual dysfunction in men with inflammatory bowel disease could provide a useful tool to evaluate the impact the disease has on sexual function in male patients.
Major finding: The negative effects of IBD on sexual dysfunction in men with the disease, reflected in the responses to the IBD-specific questionnaire, included negative effects on libido in 38% and fear of having sex in 30%.
Data source: Results were based on the responses to the questionnaire from 175 male patients treated at the IBD clinics at two Boston medical centers.
Disclosures: Dr. O’Toole had no relevant financial disclosures.
DDW: Budesonide Improves Dysphagia, Histology, and Endoscopic Findings in EoE
WASHINGTON – Treatment with an oral formulation of budesonide was associated with significant improvements in dysphagia and esophageal eosinophil counts in adolescents and adults with eosinophilic esophagitis, in a study that is also the first to use a recently validated scoring instrument to evaluate medical therapy for this disorder in a randomized trial.
Results of the multicenter, double-blind, randomized study comparing treatment with an oral budesonide suspension to placebo for 12 weeks in almost 100 patients with eosinophilic esophagitis (EoE) were reported in two separate presentations at the annual Digestive Disease Week. One of the investigators, Dr. Evan Dellon of the Center for Gastrointestinal Biology and Disease, at the University of North Carolina, Chapel Hill, said that treatment with this “mucoadherent” formulation of the topical steroid was associated with significant improvements in dysphagia symptoms, as measured with the Dysphagia Symptom Questionnaire (DSQ), and a histologic response rate of 39%, vs. 3% among those on placebo.
“The study not only adds to the evidence that topical budesonide is effective for inducing histologic response in subjects with active EoE, but [also] shows for the first time that symptoms of dysphagia, as measured with a validated symptom instrument, improve concordantly with the histologic and endoscopic findings,” Dr. Dellon said in an interview after the meeting. “Moreover, this study shows that a topical steroid formulation designed specifically for EoE, rather than an asthma formulation that is adapted for esophageal use, will likely be a beneficial and potentially preferred clinical treatment option.”
Another study investigator, Dr. Ikuo Hirano, professor of medicine and director of the gastroenterology and hepatology fellowship program at Northwestern University, Chicago, reported that treatment was also associated with significant improvements in the EoE Endoscopic Reference Score, EREFS, which was designed to classify and grade the severity of five major endoscopic features of EoE: edema, rings, exudates, furrows, and stricture formation. This was the first study to use this validated endoscopic scoring instrument in a randomized controlled trial of a medical therapy in patients with EoE, he said at the meeting.
The study was conducted between 2012 and 2014 at 25 U.S. sites, in patients aged 11-40 years with EoE. Baseline demographic and endoscopic characteristics were similar in the two groups. Their mean age was 21-22 years (41% of those on placebo and 35% of those on budesonide were younger than age 18 years) and 69% were male; most patients had edema, all had dysphagia, and 39%-41% had heartburn. Patients were excluded if they had esophageal stricture on screening endoscopy that did not allow passage of a standard adult diagnostic endoscope.
Patients were randomized to treatment with budesonide suspension, at a dose of 2 mg twice a day (51 patients) or a placebo suspension (42 patients). The primary outcomes were a change in the DSQ score from baseline, and the proportion of patients with a histologic response, defined as at least 6 eosinophils per high-power field (eos/hpf) from all biopsies. The final analysis included 87 patients.
At baseline, the mean peak eosinophil counts were 156/hpf among those on budesonide and 130/hpf among those on placebo; after treatment, the mean peak counts dropped to 39/hpf among those on budesonide (a 65% reduction) and to 113/hpf among those on placebo (a 10% reduction), a statistically significant difference (P < .05), said Dr. Dellon, also with the department of medicine at UNC.
From a mean of about 29 in both groups at baseline, DSQ scores dropped by a mean of 14.3 among the treated patients, vs. 7.5 among those on placebo, which was a statistically significant difference (P = .0096). The other primary endpoint, the histologic response rate, was 39% among treated patients, vs. 3% among those on placebo, also a significant difference (P < .0001).
Adverse events were not different between the two groups, and growth velocity among those under age 18 years and cortisol levels were not different between the two groups, he added. There was one case of esophageal candidiasis in a patient on budesonide.
During his presentation, Dr. Hirano said that there were also significant improvements in EREFS scores from baseline in the proximal and distal esophagus among those treated with budesonide, but not among those on placebo. Based on EREFS scores, oral budesonide “resulted in significant improvement in endoscopic features of edema, exudate, rings, [and] furrows, compared to placebo,” but there was no significant change in strictures, another component of the EREFS, in either the treatment or placebo groups. However, patients with high-grade strictures were not enrolled in the study, he added.
After treatment, proximal, distal, and total EREFS scores correlated with peak eosinophil counts, a highly statistically significant finding.
Dr. Hirano said that the primary endpoints used in most EoE clinical trials to date have focused mostly on assessments of symptoms and histopathology, which have limitations. “Symptoms are difficult to quantify and often intermittent [and] they may improve as a result of changes in eating behavior and food avoidance,” he said. Patient-reported outcome instruments have been recently validated, “but have questionable utility in clinical practice” and histology “has shown limited correlation between degree of esophageal eosinophilia and symptom severity [and does not] assess for modeling, an important determinant of overall disease complications,” he added.
The utility of endoscopy in EoE includes the features that are present in vast majority of patients with EoE, and provides a gross assessment of overall disease activity, “both in terms of inflammatory and fibrostenotic features,” he said.
“Endoscopic outcomes are now emerging as clinically relevant endpoints of therapy of trials of eosinophilic esophagitis that supports and complements” symptom and histologic assessments, Dr. Hirano commented, adding that more studies are need to determine the “relative importance of these individual endoscopic features as well as the appropriate utilization of endoscopic parameters in disease management.”
The study was funded by Meritage Pharma, recently acquired by the Shire group of companies. All authors received research funds to conduct the study, and Dr. Hirano disclosed having worked as a consultant for Meritage. Dr. Dellon’s disclosures included receiving grant and research support from Meritage. Shire is developing the oral budesonide suspension formulation as a treatment for adolescents and adults with EoE.
WASHINGTON – Treatment with an oral formulation of budesonide was associated with significant improvements in dysphagia and esophageal eosinophil counts in adolescents and adults with eosinophilic esophagitis, in a study that is also the first to use a recently validated scoring instrument to evaluate medical therapy for this disorder in a randomized trial.
Results of the multicenter, double-blind, randomized study comparing treatment with an oral budesonide suspension to placebo for 12 weeks in almost 100 patients with eosinophilic esophagitis (EoE) were reported in two separate presentations at the annual Digestive Disease Week. One of the investigators, Dr. Evan Dellon of the Center for Gastrointestinal Biology and Disease, at the University of North Carolina, Chapel Hill, said that treatment with this “mucoadherent” formulation of the topical steroid was associated with significant improvements in dysphagia symptoms, as measured with the Dysphagia Symptom Questionnaire (DSQ), and a histologic response rate of 39%, vs. 3% among those on placebo.
“The study not only adds to the evidence that topical budesonide is effective for inducing histologic response in subjects with active EoE, but [also] shows for the first time that symptoms of dysphagia, as measured with a validated symptom instrument, improve concordantly with the histologic and endoscopic findings,” Dr. Dellon said in an interview after the meeting. “Moreover, this study shows that a topical steroid formulation designed specifically for EoE, rather than an asthma formulation that is adapted for esophageal use, will likely be a beneficial and potentially preferred clinical treatment option.”
Another study investigator, Dr. Ikuo Hirano, professor of medicine and director of the gastroenterology and hepatology fellowship program at Northwestern University, Chicago, reported that treatment was also associated with significant improvements in the EoE Endoscopic Reference Score, EREFS, which was designed to classify and grade the severity of five major endoscopic features of EoE: edema, rings, exudates, furrows, and stricture formation. This was the first study to use this validated endoscopic scoring instrument in a randomized controlled trial of a medical therapy in patients with EoE, he said at the meeting.
The study was conducted between 2012 and 2014 at 25 U.S. sites, in patients aged 11-40 years with EoE. Baseline demographic and endoscopic characteristics were similar in the two groups. Their mean age was 21-22 years (41% of those on placebo and 35% of those on budesonide were younger than age 18 years) and 69% were male; most patients had edema, all had dysphagia, and 39%-41% had heartburn. Patients were excluded if they had esophageal stricture on screening endoscopy that did not allow passage of a standard adult diagnostic endoscope.
Patients were randomized to treatment with budesonide suspension, at a dose of 2 mg twice a day (51 patients) or a placebo suspension (42 patients). The primary outcomes were a change in the DSQ score from baseline, and the proportion of patients with a histologic response, defined as at least 6 eosinophils per high-power field (eos/hpf) from all biopsies. The final analysis included 87 patients.
At baseline, the mean peak eosinophil counts were 156/hpf among those on budesonide and 130/hpf among those on placebo; after treatment, the mean peak counts dropped to 39/hpf among those on budesonide (a 65% reduction) and to 113/hpf among those on placebo (a 10% reduction), a statistically significant difference (P < .05), said Dr. Dellon, also with the department of medicine at UNC.
From a mean of about 29 in both groups at baseline, DSQ scores dropped by a mean of 14.3 among the treated patients, vs. 7.5 among those on placebo, which was a statistically significant difference (P = .0096). The other primary endpoint, the histologic response rate, was 39% among treated patients, vs. 3% among those on placebo, also a significant difference (P < .0001).
Adverse events were not different between the two groups, and growth velocity among those under age 18 years and cortisol levels were not different between the two groups, he added. There was one case of esophageal candidiasis in a patient on budesonide.
During his presentation, Dr. Hirano said that there were also significant improvements in EREFS scores from baseline in the proximal and distal esophagus among those treated with budesonide, but not among those on placebo. Based on EREFS scores, oral budesonide “resulted in significant improvement in endoscopic features of edema, exudate, rings, [and] furrows, compared to placebo,” but there was no significant change in strictures, another component of the EREFS, in either the treatment or placebo groups. However, patients with high-grade strictures were not enrolled in the study, he added.
After treatment, proximal, distal, and total EREFS scores correlated with peak eosinophil counts, a highly statistically significant finding.
Dr. Hirano said that the primary endpoints used in most EoE clinical trials to date have focused mostly on assessments of symptoms and histopathology, which have limitations. “Symptoms are difficult to quantify and often intermittent [and] they may improve as a result of changes in eating behavior and food avoidance,” he said. Patient-reported outcome instruments have been recently validated, “but have questionable utility in clinical practice” and histology “has shown limited correlation between degree of esophageal eosinophilia and symptom severity [and does not] assess for modeling, an important determinant of overall disease complications,” he added.
The utility of endoscopy in EoE includes the features that are present in vast majority of patients with EoE, and provides a gross assessment of overall disease activity, “both in terms of inflammatory and fibrostenotic features,” he said.
“Endoscopic outcomes are now emerging as clinically relevant endpoints of therapy of trials of eosinophilic esophagitis that supports and complements” symptom and histologic assessments, Dr. Hirano commented, adding that more studies are need to determine the “relative importance of these individual endoscopic features as well as the appropriate utilization of endoscopic parameters in disease management.”
The study was funded by Meritage Pharma, recently acquired by the Shire group of companies. All authors received research funds to conduct the study, and Dr. Hirano disclosed having worked as a consultant for Meritage. Dr. Dellon’s disclosures included receiving grant and research support from Meritage. Shire is developing the oral budesonide suspension formulation as a treatment for adolescents and adults with EoE.
WASHINGTON – Treatment with an oral formulation of budesonide was associated with significant improvements in dysphagia and esophageal eosinophil counts in adolescents and adults with eosinophilic esophagitis, in a study that is also the first to use a recently validated scoring instrument to evaluate medical therapy for this disorder in a randomized trial.
Results of the multicenter, double-blind, randomized study comparing treatment with an oral budesonide suspension to placebo for 12 weeks in almost 100 patients with eosinophilic esophagitis (EoE) were reported in two separate presentations at the annual Digestive Disease Week. One of the investigators, Dr. Evan Dellon of the Center for Gastrointestinal Biology and Disease, at the University of North Carolina, Chapel Hill, said that treatment with this “mucoadherent” formulation of the topical steroid was associated with significant improvements in dysphagia symptoms, as measured with the Dysphagia Symptom Questionnaire (DSQ), and a histologic response rate of 39%, vs. 3% among those on placebo.
“The study not only adds to the evidence that topical budesonide is effective for inducing histologic response in subjects with active EoE, but [also] shows for the first time that symptoms of dysphagia, as measured with a validated symptom instrument, improve concordantly with the histologic and endoscopic findings,” Dr. Dellon said in an interview after the meeting. “Moreover, this study shows that a topical steroid formulation designed specifically for EoE, rather than an asthma formulation that is adapted for esophageal use, will likely be a beneficial and potentially preferred clinical treatment option.”
Another study investigator, Dr. Ikuo Hirano, professor of medicine and director of the gastroenterology and hepatology fellowship program at Northwestern University, Chicago, reported that treatment was also associated with significant improvements in the EoE Endoscopic Reference Score, EREFS, which was designed to classify and grade the severity of five major endoscopic features of EoE: edema, rings, exudates, furrows, and stricture formation. This was the first study to use this validated endoscopic scoring instrument in a randomized controlled trial of a medical therapy in patients with EoE, he said at the meeting.
The study was conducted between 2012 and 2014 at 25 U.S. sites, in patients aged 11-40 years with EoE. Baseline demographic and endoscopic characteristics were similar in the two groups. Their mean age was 21-22 years (41% of those on placebo and 35% of those on budesonide were younger than age 18 years) and 69% were male; most patients had edema, all had dysphagia, and 39%-41% had heartburn. Patients were excluded if they had esophageal stricture on screening endoscopy that did not allow passage of a standard adult diagnostic endoscope.
Patients were randomized to treatment with budesonide suspension, at a dose of 2 mg twice a day (51 patients) or a placebo suspension (42 patients). The primary outcomes were a change in the DSQ score from baseline, and the proportion of patients with a histologic response, defined as at least 6 eosinophils per high-power field (eos/hpf) from all biopsies. The final analysis included 87 patients.
At baseline, the mean peak eosinophil counts were 156/hpf among those on budesonide and 130/hpf among those on placebo; after treatment, the mean peak counts dropped to 39/hpf among those on budesonide (a 65% reduction) and to 113/hpf among those on placebo (a 10% reduction), a statistically significant difference (P < .05), said Dr. Dellon, also with the department of medicine at UNC.
From a mean of about 29 in both groups at baseline, DSQ scores dropped by a mean of 14.3 among the treated patients, vs. 7.5 among those on placebo, which was a statistically significant difference (P = .0096). The other primary endpoint, the histologic response rate, was 39% among treated patients, vs. 3% among those on placebo, also a significant difference (P < .0001).
Adverse events were not different between the two groups, and growth velocity among those under age 18 years and cortisol levels were not different between the two groups, he added. There was one case of esophageal candidiasis in a patient on budesonide.
During his presentation, Dr. Hirano said that there were also significant improvements in EREFS scores from baseline in the proximal and distal esophagus among those treated with budesonide, but not among those on placebo. Based on EREFS scores, oral budesonide “resulted in significant improvement in endoscopic features of edema, exudate, rings, [and] furrows, compared to placebo,” but there was no significant change in strictures, another component of the EREFS, in either the treatment or placebo groups. However, patients with high-grade strictures were not enrolled in the study, he added.
After treatment, proximal, distal, and total EREFS scores correlated with peak eosinophil counts, a highly statistically significant finding.
Dr. Hirano said that the primary endpoints used in most EoE clinical trials to date have focused mostly on assessments of symptoms and histopathology, which have limitations. “Symptoms are difficult to quantify and often intermittent [and] they may improve as a result of changes in eating behavior and food avoidance,” he said. Patient-reported outcome instruments have been recently validated, “but have questionable utility in clinical practice” and histology “has shown limited correlation between degree of esophageal eosinophilia and symptom severity [and does not] assess for modeling, an important determinant of overall disease complications,” he added.
The utility of endoscopy in EoE includes the features that are present in vast majority of patients with EoE, and provides a gross assessment of overall disease activity, “both in terms of inflammatory and fibrostenotic features,” he said.
“Endoscopic outcomes are now emerging as clinically relevant endpoints of therapy of trials of eosinophilic esophagitis that supports and complements” symptom and histologic assessments, Dr. Hirano commented, adding that more studies are need to determine the “relative importance of these individual endoscopic features as well as the appropriate utilization of endoscopic parameters in disease management.”
The study was funded by Meritage Pharma, recently acquired by the Shire group of companies. All authors received research funds to conduct the study, and Dr. Hirano disclosed having worked as a consultant for Meritage. Dr. Dellon’s disclosures included receiving grant and research support from Meritage. Shire is developing the oral budesonide suspension formulation as a treatment for adolescents and adults with EoE.
AT DDW 2015
DDW: Budesonide improves dysphagia, histology, and endoscopic findings in EoE
WASHINGTON – Treatment with an oral formulation of budesonide was associated with significant improvements in dysphagia and esophageal eosinophil counts in adolescents and adults with eosinophilic esophagitis, in a study that is also the first to use a recently validated scoring instrument to evaluate medical therapy for this disorder in a randomized trial.
Results of the multicenter, double-blind, randomized study comparing treatment with an oral budesonide suspension to placebo for 12 weeks in almost 100 patients with eosinophilic esophagitis (EoE) were reported in two separate presentations at the annual Digestive Disease Week. One of the investigators, Dr. Evan Dellon of the Center for Gastrointestinal Biology and Disease, at the University of North Carolina, Chapel Hill, said that treatment with this “mucoadherent” formulation of the topical steroid was associated with significant improvements in dysphagia symptoms, as measured with the Dysphagia Symptom Questionnaire (DSQ), and a histologic response rate of 39%, vs. 3% among those on placebo.
“The study not only adds to the evidence that topical budesonide is effective for inducing histologic response in subjects with active EoE, but [also] shows for the first time that symptoms of dysphagia, as measured with a validated symptom instrument, improve concordantly with the histologic and endoscopic findings,” Dr. Dellon said in an interview after the meeting. “Moreover, this study shows that a topical steroid formulation designed specifically for EoE, rather than an asthma formulation that is adapted for esophageal use, will likely be a beneficial and potentially preferred clinical treatment option.”
Another study investigator, Dr. Ikuo Hirano, professor of medicine and director of the gastroenterology and hepatology fellowship program at Northwestern University, Chicago, reported that treatment was also associated with significant improvements in the EoE Endoscopic Reference Score, EREFS, which was designed to classify and grade the severity of five major endoscopic features of EoE: edema, rings, exudates, furrows, and stricture formation. This was the first study to use this validated endoscopic scoring instrument in a randomized controlled trial of a medical therapy in patients with EoE, he said at the meeting.
The study was conducted between 2012 and 2014 at 25 U.S. sites, in patients aged 11-40 years with EoE. Baseline demographic and endoscopic characteristics were similar in the two groups. Their mean age was 21-22 years (41% of those on placebo and 35% of those on budesonide were younger than age 18 years) and 69% were male; most patients had edema, all had dysphagia, and 39%-41% had heartburn. Patients were excluded if they had esophageal stricture on screening endoscopy that did not allow passage of a standard adult diagnostic endoscope.
Patients were randomized to treatment with budesonide suspension, at a dose of 2 mg twice a day (51 patients) or a placebo suspension (42 patients). The primary outcomes were a change in the DSQ score from baseline, and the proportion of patients with a histologic response, defined as at least 6 eosinophils per high-power field (eos/hpf) from all biopsies. The final analysis included 87 patients.
At baseline, the mean peak eosinophil counts were 156/hpf among those on budesonide and 130/hpf among those on placebo; after treatment, the mean peak counts dropped to 39/hpf among those on budesonide (a 65% reduction) and to 113/hpf among those on placebo (a 10% reduction), a statistically significant difference (P < .05), said Dr. Dellon, also with the department of medicine at UNC.
From a mean of about 29 in both groups at baseline, DSQ scores dropped by a mean of 14.3 among the treated patients, vs. 7.5 among those on placebo, which was a statistically significant difference (P = .0096). The other primary endpoint, the histologic response rate, was 39% among treated patients, vs. 3% among those on placebo, also a significant difference (P < .0001).
Adverse events were not different between the two groups, and growth velocity among those under age 18 years and cortisol levels were not different between the two groups, he added. There was one case of esophageal candidiasis in a patient on budesonide.
During his presentation, Dr. Hirano said that there were also significant improvements in EREFS scores from baseline in the proximal and distal esophagus among those treated with budesonide, but not among those on placebo. Based on EREFS scores, oral budesonide “resulted in significant improvement in endoscopic features of edema, exudate, rings, [and] furrows, compared to placebo,” but there was no significant change in strictures, another component of the EREFS, in either the treatment or placebo groups. However, patients with high-grade strictures were not enrolled in the study, he added.
After treatment, proximal, distal, and total EREFS scores correlated with peak eosinophil counts, a highly statistically significant finding.
Dr. Hirano said that the primary endpoints used in most EoE clinical trials to date have focused mostly on assessments of symptoms and histopathology, which have limitations. “Symptoms are difficult to quantify and often intermittent [and] they may improve as a result of changes in eating behavior and food avoidance,” he said. Patient-reported outcome instruments have been recently validated, “but have questionable utility in clinical practice” and histology “has shown limited correlation between degree of esophageal eosinophilia and symptom severity [and does not] assess for modeling, an important determinant of overall disease complications,” he added.
The utility of endoscopy in EoE includes the features that are present in vast majority of patients with EoE, and provides a gross assessment of overall disease activity, “both in terms of inflammatory and fibrostenotic features,” he said.
“Endoscopic outcomes are now emerging as clinically relevant endpoints of therapy of trials of eosinophilic esophagitis that supports and complements” symptom and histologic assessments, Dr. Hirano commented, adding that more studies are need to determine the “relative importance of these individual endoscopic features as well as the appropriate utilization of endoscopic parameters in disease management.”
The study was funded by Meritage Pharma, recently acquired by the Shire group of companies. All authors received research funds to conduct the study, and Dr. Hirano disclosed having worked as a consultant for Meritage. Dr. Dellon’s disclosures included receiving grant and research support from Meritage. Shire is developing the oral budesonide suspension formulation as a treatment for adolescents and adults with EoE.
WASHINGTON – Treatment with an oral formulation of budesonide was associated with significant improvements in dysphagia and esophageal eosinophil counts in adolescents and adults with eosinophilic esophagitis, in a study that is also the first to use a recently validated scoring instrument to evaluate medical therapy for this disorder in a randomized trial.
Results of the multicenter, double-blind, randomized study comparing treatment with an oral budesonide suspension to placebo for 12 weeks in almost 100 patients with eosinophilic esophagitis (EoE) were reported in two separate presentations at the annual Digestive Disease Week. One of the investigators, Dr. Evan Dellon of the Center for Gastrointestinal Biology and Disease, at the University of North Carolina, Chapel Hill, said that treatment with this “mucoadherent” formulation of the topical steroid was associated with significant improvements in dysphagia symptoms, as measured with the Dysphagia Symptom Questionnaire (DSQ), and a histologic response rate of 39%, vs. 3% among those on placebo.
“The study not only adds to the evidence that topical budesonide is effective for inducing histologic response in subjects with active EoE, but [also] shows for the first time that symptoms of dysphagia, as measured with a validated symptom instrument, improve concordantly with the histologic and endoscopic findings,” Dr. Dellon said in an interview after the meeting. “Moreover, this study shows that a topical steroid formulation designed specifically for EoE, rather than an asthma formulation that is adapted for esophageal use, will likely be a beneficial and potentially preferred clinical treatment option.”
Another study investigator, Dr. Ikuo Hirano, professor of medicine and director of the gastroenterology and hepatology fellowship program at Northwestern University, Chicago, reported that treatment was also associated with significant improvements in the EoE Endoscopic Reference Score, EREFS, which was designed to classify and grade the severity of five major endoscopic features of EoE: edema, rings, exudates, furrows, and stricture formation. This was the first study to use this validated endoscopic scoring instrument in a randomized controlled trial of a medical therapy in patients with EoE, he said at the meeting.
The study was conducted between 2012 and 2014 at 25 U.S. sites, in patients aged 11-40 years with EoE. Baseline demographic and endoscopic characteristics were similar in the two groups. Their mean age was 21-22 years (41% of those on placebo and 35% of those on budesonide were younger than age 18 years) and 69% were male; most patients had edema, all had dysphagia, and 39%-41% had heartburn. Patients were excluded if they had esophageal stricture on screening endoscopy that did not allow passage of a standard adult diagnostic endoscope.
Patients were randomized to treatment with budesonide suspension, at a dose of 2 mg twice a day (51 patients) or a placebo suspension (42 patients). The primary outcomes were a change in the DSQ score from baseline, and the proportion of patients with a histologic response, defined as at least 6 eosinophils per high-power field (eos/hpf) from all biopsies. The final analysis included 87 patients.
At baseline, the mean peak eosinophil counts were 156/hpf among those on budesonide and 130/hpf among those on placebo; after treatment, the mean peak counts dropped to 39/hpf among those on budesonide (a 65% reduction) and to 113/hpf among those on placebo (a 10% reduction), a statistically significant difference (P < .05), said Dr. Dellon, also with the department of medicine at UNC.
From a mean of about 29 in both groups at baseline, DSQ scores dropped by a mean of 14.3 among the treated patients, vs. 7.5 among those on placebo, which was a statistically significant difference (P = .0096). The other primary endpoint, the histologic response rate, was 39% among treated patients, vs. 3% among those on placebo, also a significant difference (P < .0001).
Adverse events were not different between the two groups, and growth velocity among those under age 18 years and cortisol levels were not different between the two groups, he added. There was one case of esophageal candidiasis in a patient on budesonide.
During his presentation, Dr. Hirano said that there were also significant improvements in EREFS scores from baseline in the proximal and distal esophagus among those treated with budesonide, but not among those on placebo. Based on EREFS scores, oral budesonide “resulted in significant improvement in endoscopic features of edema, exudate, rings, [and] furrows, compared to placebo,” but there was no significant change in strictures, another component of the EREFS, in either the treatment or placebo groups. However, patients with high-grade strictures were not enrolled in the study, he added.
After treatment, proximal, distal, and total EREFS scores correlated with peak eosinophil counts, a highly statistically significant finding.
Dr. Hirano said that the primary endpoints used in most EoE clinical trials to date have focused mostly on assessments of symptoms and histopathology, which have limitations. “Symptoms are difficult to quantify and often intermittent [and] they may improve as a result of changes in eating behavior and food avoidance,” he said. Patient-reported outcome instruments have been recently validated, “but have questionable utility in clinical practice” and histology “has shown limited correlation between degree of esophageal eosinophilia and symptom severity [and does not] assess for modeling, an important determinant of overall disease complications,” he added.
The utility of endoscopy in EoE includes the features that are present in vast majority of patients with EoE, and provides a gross assessment of overall disease activity, “both in terms of inflammatory and fibrostenotic features,” he said.
“Endoscopic outcomes are now emerging as clinically relevant endpoints of therapy of trials of eosinophilic esophagitis that supports and complements” symptom and histologic assessments, Dr. Hirano commented, adding that more studies are need to determine the “relative importance of these individual endoscopic features as well as the appropriate utilization of endoscopic parameters in disease management.”
The study was funded by Meritage Pharma, recently acquired by the Shire group of companies. All authors received research funds to conduct the study, and Dr. Hirano disclosed having worked as a consultant for Meritage. Dr. Dellon’s disclosures included receiving grant and research support from Meritage. Shire is developing the oral budesonide suspension formulation as a treatment for adolescents and adults with EoE.
WASHINGTON – Treatment with an oral formulation of budesonide was associated with significant improvements in dysphagia and esophageal eosinophil counts in adolescents and adults with eosinophilic esophagitis, in a study that is also the first to use a recently validated scoring instrument to evaluate medical therapy for this disorder in a randomized trial.
Results of the multicenter, double-blind, randomized study comparing treatment with an oral budesonide suspension to placebo for 12 weeks in almost 100 patients with eosinophilic esophagitis (EoE) were reported in two separate presentations at the annual Digestive Disease Week. One of the investigators, Dr. Evan Dellon of the Center for Gastrointestinal Biology and Disease, at the University of North Carolina, Chapel Hill, said that treatment with this “mucoadherent” formulation of the topical steroid was associated with significant improvements in dysphagia symptoms, as measured with the Dysphagia Symptom Questionnaire (DSQ), and a histologic response rate of 39%, vs. 3% among those on placebo.
“The study not only adds to the evidence that topical budesonide is effective for inducing histologic response in subjects with active EoE, but [also] shows for the first time that symptoms of dysphagia, as measured with a validated symptom instrument, improve concordantly with the histologic and endoscopic findings,” Dr. Dellon said in an interview after the meeting. “Moreover, this study shows that a topical steroid formulation designed specifically for EoE, rather than an asthma formulation that is adapted for esophageal use, will likely be a beneficial and potentially preferred clinical treatment option.”
Another study investigator, Dr. Ikuo Hirano, professor of medicine and director of the gastroenterology and hepatology fellowship program at Northwestern University, Chicago, reported that treatment was also associated with significant improvements in the EoE Endoscopic Reference Score, EREFS, which was designed to classify and grade the severity of five major endoscopic features of EoE: edema, rings, exudates, furrows, and stricture formation. This was the first study to use this validated endoscopic scoring instrument in a randomized controlled trial of a medical therapy in patients with EoE, he said at the meeting.
The study was conducted between 2012 and 2014 at 25 U.S. sites, in patients aged 11-40 years with EoE. Baseline demographic and endoscopic characteristics were similar in the two groups. Their mean age was 21-22 years (41% of those on placebo and 35% of those on budesonide were younger than age 18 years) and 69% were male; most patients had edema, all had dysphagia, and 39%-41% had heartburn. Patients were excluded if they had esophageal stricture on screening endoscopy that did not allow passage of a standard adult diagnostic endoscope.
Patients were randomized to treatment with budesonide suspension, at a dose of 2 mg twice a day (51 patients) or a placebo suspension (42 patients). The primary outcomes were a change in the DSQ score from baseline, and the proportion of patients with a histologic response, defined as at least 6 eosinophils per high-power field (eos/hpf) from all biopsies. The final analysis included 87 patients.
At baseline, the mean peak eosinophil counts were 156/hpf among those on budesonide and 130/hpf among those on placebo; after treatment, the mean peak counts dropped to 39/hpf among those on budesonide (a 65% reduction) and to 113/hpf among those on placebo (a 10% reduction), a statistically significant difference (P < .05), said Dr. Dellon, also with the department of medicine at UNC.
From a mean of about 29 in both groups at baseline, DSQ scores dropped by a mean of 14.3 among the treated patients, vs. 7.5 among those on placebo, which was a statistically significant difference (P = .0096). The other primary endpoint, the histologic response rate, was 39% among treated patients, vs. 3% among those on placebo, also a significant difference (P < .0001).
Adverse events were not different between the two groups, and growth velocity among those under age 18 years and cortisol levels were not different between the two groups, he added. There was one case of esophageal candidiasis in a patient on budesonide.
During his presentation, Dr. Hirano said that there were also significant improvements in EREFS scores from baseline in the proximal and distal esophagus among those treated with budesonide, but not among those on placebo. Based on EREFS scores, oral budesonide “resulted in significant improvement in endoscopic features of edema, exudate, rings, [and] furrows, compared to placebo,” but there was no significant change in strictures, another component of the EREFS, in either the treatment or placebo groups. However, patients with high-grade strictures were not enrolled in the study, he added.
After treatment, proximal, distal, and total EREFS scores correlated with peak eosinophil counts, a highly statistically significant finding.
Dr. Hirano said that the primary endpoints used in most EoE clinical trials to date have focused mostly on assessments of symptoms and histopathology, which have limitations. “Symptoms are difficult to quantify and often intermittent [and] they may improve as a result of changes in eating behavior and food avoidance,” he said. Patient-reported outcome instruments have been recently validated, “but have questionable utility in clinical practice” and histology “has shown limited correlation between degree of esophageal eosinophilia and symptom severity [and does not] assess for modeling, an important determinant of overall disease complications,” he added.
The utility of endoscopy in EoE includes the features that are present in vast majority of patients with EoE, and provides a gross assessment of overall disease activity, “both in terms of inflammatory and fibrostenotic features,” he said.
“Endoscopic outcomes are now emerging as clinically relevant endpoints of therapy of trials of eosinophilic esophagitis that supports and complements” symptom and histologic assessments, Dr. Hirano commented, adding that more studies are need to determine the “relative importance of these individual endoscopic features as well as the appropriate utilization of endoscopic parameters in disease management.”
The study was funded by Meritage Pharma, recently acquired by the Shire group of companies. All authors received research funds to conduct the study, and Dr. Hirano disclosed having worked as a consultant for Meritage. Dr. Dellon’s disclosures included receiving grant and research support from Meritage. Shire is developing the oral budesonide suspension formulation as a treatment for adolescents and adults with EoE.
AT DDW 2015
Key clinical point: A mucoadherent oral formulation of budesonide shows promise as an effective treatment for eosinophilic esophagitis (EoE), with a favorable safety profile.
Major finding: Beneficial effects of oral budesonide in a study of adolescents and adults with EoE included a histologic response rate of 39% and significantly improved dysphagia symptoms.
Data source: A randomized, double-blind multicenter U.S. study evaluated the healing effects and response to of oral budesonide vs. placebo in 93 patients with EoE, aged 11-40 years.
Disclosures: The study was funded by Meritage Pharma, recently acquired by the Shire group of companies. All authors received research funds to conduct the study. Dr. Dellon’s disclosures included receiving grant and research support from Meritage. Dr. Hirano disclosed having worked as a consultant for Meritage.
FDA: No changes needed in management of ezogabine’s eye and skin effects
Pigment changes in the retina reported in some patients treated with the antiseizure drug ezogabine do not appear to affect vision, and can be “adequately managed” by following recommendations in the drug’s label, the Food and Drug Administration announced on June 16.
In a safety communication, the FDA is advising health care professionals to continue to follow the recommendations in the drug’s prescribing information. The agency is requiring GlaxoSmithKline, which markets ezogabine as Potiga, to conduct a long-term observational study “to further explore any potential long-term consequences of these pigment changes.” The study is expected to provide information on the association between the pigment changes in the retina and skin discoloration. Skin discoloration, which has also been reported in treated patients, “appears to be a cosmetic effect and does not appear to be associated with more serious adverse effects,” the statement said.
These conclusions are based on the FDA’s review of additional reports. The agency also has determined that the 2013 Risk Evaluation and Mitigation Strategy (REMS) for ezogabine does not need to be modified “to ensure that the benefits of Potiga outweigh the risks of retinal and skin pigment changes,” the statement added.
Ezogabine, a potassium channel opener, was approved in 2011 as adjunctive treatment of partial-onset seizures in patients aged 18 years and older “who have responded inadequately to several alternative treatments and for whom the benefits outweigh the risk of retinal abnormalities and potential decline in visual acuity.”
The boxed warning includes a recommendation that patients treated with the drug should undergo systematic visual monitoring by an ophthalmic professional at baseline and every 6 months during treatment, and that the drug should be discontinued if retinal pigment abnormalities or vision changes are detected, “unless no other suitable treatment options are available and the benefits of treatment outweigh the potential risk of vision loss.”
Adverse events associated with ezogabine should be reported to the FDA’s Medwatch program at 800-332-1088, or online.
Pigment changes in the retina reported in some patients treated with the antiseizure drug ezogabine do not appear to affect vision, and can be “adequately managed” by following recommendations in the drug’s label, the Food and Drug Administration announced on June 16.
In a safety communication, the FDA is advising health care professionals to continue to follow the recommendations in the drug’s prescribing information. The agency is requiring GlaxoSmithKline, which markets ezogabine as Potiga, to conduct a long-term observational study “to further explore any potential long-term consequences of these pigment changes.” The study is expected to provide information on the association between the pigment changes in the retina and skin discoloration. Skin discoloration, which has also been reported in treated patients, “appears to be a cosmetic effect and does not appear to be associated with more serious adverse effects,” the statement said.
These conclusions are based on the FDA’s review of additional reports. The agency also has determined that the 2013 Risk Evaluation and Mitigation Strategy (REMS) for ezogabine does not need to be modified “to ensure that the benefits of Potiga outweigh the risks of retinal and skin pigment changes,” the statement added.
Ezogabine, a potassium channel opener, was approved in 2011 as adjunctive treatment of partial-onset seizures in patients aged 18 years and older “who have responded inadequately to several alternative treatments and for whom the benefits outweigh the risk of retinal abnormalities and potential decline in visual acuity.”
The boxed warning includes a recommendation that patients treated with the drug should undergo systematic visual monitoring by an ophthalmic professional at baseline and every 6 months during treatment, and that the drug should be discontinued if retinal pigment abnormalities or vision changes are detected, “unless no other suitable treatment options are available and the benefits of treatment outweigh the potential risk of vision loss.”
Adverse events associated with ezogabine should be reported to the FDA’s Medwatch program at 800-332-1088, or online.
Pigment changes in the retina reported in some patients treated with the antiseizure drug ezogabine do not appear to affect vision, and can be “adequately managed” by following recommendations in the drug’s label, the Food and Drug Administration announced on June 16.
In a safety communication, the FDA is advising health care professionals to continue to follow the recommendations in the drug’s prescribing information. The agency is requiring GlaxoSmithKline, which markets ezogabine as Potiga, to conduct a long-term observational study “to further explore any potential long-term consequences of these pigment changes.” The study is expected to provide information on the association between the pigment changes in the retina and skin discoloration. Skin discoloration, which has also been reported in treated patients, “appears to be a cosmetic effect and does not appear to be associated with more serious adverse effects,” the statement said.
These conclusions are based on the FDA’s review of additional reports. The agency also has determined that the 2013 Risk Evaluation and Mitigation Strategy (REMS) for ezogabine does not need to be modified “to ensure that the benefits of Potiga outweigh the risks of retinal and skin pigment changes,” the statement added.
Ezogabine, a potassium channel opener, was approved in 2011 as adjunctive treatment of partial-onset seizures in patients aged 18 years and older “who have responded inadequately to several alternative treatments and for whom the benefits outweigh the risk of retinal abnormalities and potential decline in visual acuity.”
The boxed warning includes a recommendation that patients treated with the drug should undergo systematic visual monitoring by an ophthalmic professional at baseline and every 6 months during treatment, and that the drug should be discontinued if retinal pigment abnormalities or vision changes are detected, “unless no other suitable treatment options are available and the benefits of treatment outweigh the potential risk of vision loss.”
Adverse events associated with ezogabine should be reported to the FDA’s Medwatch program at 800-332-1088, or online.
FDA panel backs evolocumab for lowering LDL in high-risk patients
GAITHERSBURG, MD. – The benefit-risk profile of the PCSK9 inhibitor evolocumab, injected subcutaneously once or twice a month, supports its approval for treating hypercholesterolemia in certain high-risk populations, a Food and Drug Administration advisory panel has agreed.
At a meeting on June 10, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 15-0 that evolocumab should be approved for treating patients aged 12 years and older and adults with homozygous familial hypercholesterolemia (HoFH), based on its impact on lowering low-density lipoprotein cholesterol (LDL-C) in patients and what is currently known about its safety profile.
In a separate vote on other populations included in the indication proposed by Amgen, the panel voted 11-4 to recommend approval for treating other types of patients but limited it to patients at higher CVD risk and elevated LDL-C levels, particularly those with heterozygous FH. There also was support for approval for other higher-risk patients, such as those at high risk for CVD and high LDL-C levels and those with high LDL-C levels on maximum statin doses, but there was not support for approval for lower-risk groups, such as those with mixed hyperlipidemia.
Amgen has proposed that evolocumab be approved for patients with HoFH, as well as adults with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia.
With these votes, it is likely that evolocumab will be approved this year since the FDA usually follows the recommendations of its advisory panels. Evolocumab and another PCSK9 inhibitor, alirocumab – which the majority of the panel recommended for approval the day before – will be the first in this new class of lipid-lowering agents to be approved in the United States. The recommended doses for adults with primary hyperlipidemia and mixed dyslipidemia are 140 mg every 2 weeks or 420 mg once a month; 420 mg every 2 or 4 weeks is recommended for those with HoFH.
PCSK9 inhibitors are human monoclonal antibodies that bind to proprotein convertase subtilisin kexin type 9 (PCSK9), a serine protease that is involved in the regulation of LDL receptor (LDL-R). Inactivation of PCSK9 results in an increase of LDL-R available to clear LDL-C, reducing LDL-C levels.
The data presented by Amgen include four 12-week, phase III double-blind randomized studies comparing the two doses of evolocumab to placebo and/or ezetimibe in about 3,100 patients. The four studies involved patients with HoFH, patients at high CV risk on background statin therapy, patients on monotherapy with diet as background therapy, and patients intolerant to statins who were on no or low-dose statin. The primary efficacy endpoint was reduction n LDL-C at 10-12 weeks.
Both dosing regimens resulted in significantly lower LDL-C levels from baseline, compared with placebo and ezetimibe. Treatment with the two doses resulted in “consistent, clinically equivalent” LDL-C reductions in patients with primary hyperlipidemia and those with mixed dyslipidemia, with reductions of 55%-75% compared with placebo and 35%-45% compared with ezetimibe. Effects were maintained over 2 years in an open-label extension study in different subgroups, including gender and region, according to Amgen.
In a phase III study of 49 patients with HoFH treated with 420 mg once a month or placebo, evolocumab was associated with LDL-C reductions of about 31%, compared with placebo. In phase II and III studies of almost 5,000 patients who received evolocumab, the overall incidence of adverse events was similar to the comparators, and adverse events in long-term studies were similar to those seen in the initial studies, according to Amgen. To date, no major safety issues have been associated with evolocumab, including in patients with very low LDL-C levels (below 25 mg/dL or 40 mg/dL), compared with levels of 40 mg/dL or greater, according to the company.
Adverse events of interest include neurocognitive events and glycemic changes, recently reported with statins. The incidence of new-onset diabetes was low and similar between those on evolocumab and comparators, although there was a “small imbalance” in glycemic changes in patients on evolocumab, a risk that cannot be ruled out and will be monitored in ongoing studies, including the CV outcomes study, according to Amgen. In phase II and III studies, over a median exposure of about 3 months, the rate of neurocognitive adverse events was low and there was no association between low and very low LDL-C levels and neurocognitive events. Most adverse events were rash and eczema and were mild to moderate.
Although the panel agreed there was no major safety signal of concern in the studies, which was reassuring, the members said that safety issues should continue to be followed and that whether very low levels of LDL-C may be associated with adverse events remained an open question and needed to be studied on a long-term basis, including in the CV outcomes study. The concern was raised that, if LDL-C levels dropped to low levels, some clinicians might reduce or withdraw the statin.
As with alirocumab, the panel was asked to discuss whether the impact on LDL-C with evolocumab was sufficient to demonstrate an effect on clinical outcomes; historically, the FDA has considered reductions in LDL-C sufficient to establish the effectiveness of a lipid-lowering drug and does not require that benefit be shown in a CV outcomes trial before approval, “provided the reduction is sufficiently robust” and the product does not have any safety issues that raise concerns about the benefit-risk profile, according to the FDA. Although several panelists said that, while the drug targets LDL-C via a mechanism that is fairly close to the statin target, which provided more confidence in using LDL-C as a surrogate for CV benefit, they said this question can only be answered definitely with the CV outcomes trial.
The CV outcomes study, the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), has been fully enrolled, with about 27,500 patients, and is expected to be completed no later than 2017, according to Amgen. The study also will provide safety data in more than 5,000 patients with LDL-C levels below 40 mg/dL.
The FDA usually follows the recommendations of its advisory panels. The FDA panelists had no potential conflicts of interest. A decision is expected by Aug. 27. If approved, Amgen plans to market evolocumab as Repatha.
GAITHERSBURG, MD. – The benefit-risk profile of the PCSK9 inhibitor evolocumab, injected subcutaneously once or twice a month, supports its approval for treating hypercholesterolemia in certain high-risk populations, a Food and Drug Administration advisory panel has agreed.
At a meeting on June 10, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 15-0 that evolocumab should be approved for treating patients aged 12 years and older and adults with homozygous familial hypercholesterolemia (HoFH), based on its impact on lowering low-density lipoprotein cholesterol (LDL-C) in patients and what is currently known about its safety profile.
In a separate vote on other populations included in the indication proposed by Amgen, the panel voted 11-4 to recommend approval for treating other types of patients but limited it to patients at higher CVD risk and elevated LDL-C levels, particularly those with heterozygous FH. There also was support for approval for other higher-risk patients, such as those at high risk for CVD and high LDL-C levels and those with high LDL-C levels on maximum statin doses, but there was not support for approval for lower-risk groups, such as those with mixed hyperlipidemia.
Amgen has proposed that evolocumab be approved for patients with HoFH, as well as adults with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia.
With these votes, it is likely that evolocumab will be approved this year since the FDA usually follows the recommendations of its advisory panels. Evolocumab and another PCSK9 inhibitor, alirocumab – which the majority of the panel recommended for approval the day before – will be the first in this new class of lipid-lowering agents to be approved in the United States. The recommended doses for adults with primary hyperlipidemia and mixed dyslipidemia are 140 mg every 2 weeks or 420 mg once a month; 420 mg every 2 or 4 weeks is recommended for those with HoFH.
PCSK9 inhibitors are human monoclonal antibodies that bind to proprotein convertase subtilisin kexin type 9 (PCSK9), a serine protease that is involved in the regulation of LDL receptor (LDL-R). Inactivation of PCSK9 results in an increase of LDL-R available to clear LDL-C, reducing LDL-C levels.
The data presented by Amgen include four 12-week, phase III double-blind randomized studies comparing the two doses of evolocumab to placebo and/or ezetimibe in about 3,100 patients. The four studies involved patients with HoFH, patients at high CV risk on background statin therapy, patients on monotherapy with diet as background therapy, and patients intolerant to statins who were on no or low-dose statin. The primary efficacy endpoint was reduction n LDL-C at 10-12 weeks.
Both dosing regimens resulted in significantly lower LDL-C levels from baseline, compared with placebo and ezetimibe. Treatment with the two doses resulted in “consistent, clinically equivalent” LDL-C reductions in patients with primary hyperlipidemia and those with mixed dyslipidemia, with reductions of 55%-75% compared with placebo and 35%-45% compared with ezetimibe. Effects were maintained over 2 years in an open-label extension study in different subgroups, including gender and region, according to Amgen.
In a phase III study of 49 patients with HoFH treated with 420 mg once a month or placebo, evolocumab was associated with LDL-C reductions of about 31%, compared with placebo. In phase II and III studies of almost 5,000 patients who received evolocumab, the overall incidence of adverse events was similar to the comparators, and adverse events in long-term studies were similar to those seen in the initial studies, according to Amgen. To date, no major safety issues have been associated with evolocumab, including in patients with very low LDL-C levels (below 25 mg/dL or 40 mg/dL), compared with levels of 40 mg/dL or greater, according to the company.
Adverse events of interest include neurocognitive events and glycemic changes, recently reported with statins. The incidence of new-onset diabetes was low and similar between those on evolocumab and comparators, although there was a “small imbalance” in glycemic changes in patients on evolocumab, a risk that cannot be ruled out and will be monitored in ongoing studies, including the CV outcomes study, according to Amgen. In phase II and III studies, over a median exposure of about 3 months, the rate of neurocognitive adverse events was low and there was no association between low and very low LDL-C levels and neurocognitive events. Most adverse events were rash and eczema and were mild to moderate.
Although the panel agreed there was no major safety signal of concern in the studies, which was reassuring, the members said that safety issues should continue to be followed and that whether very low levels of LDL-C may be associated with adverse events remained an open question and needed to be studied on a long-term basis, including in the CV outcomes study. The concern was raised that, if LDL-C levels dropped to low levels, some clinicians might reduce or withdraw the statin.
As with alirocumab, the panel was asked to discuss whether the impact on LDL-C with evolocumab was sufficient to demonstrate an effect on clinical outcomes; historically, the FDA has considered reductions in LDL-C sufficient to establish the effectiveness of a lipid-lowering drug and does not require that benefit be shown in a CV outcomes trial before approval, “provided the reduction is sufficiently robust” and the product does not have any safety issues that raise concerns about the benefit-risk profile, according to the FDA. Although several panelists said that, while the drug targets LDL-C via a mechanism that is fairly close to the statin target, which provided more confidence in using LDL-C as a surrogate for CV benefit, they said this question can only be answered definitely with the CV outcomes trial.
The CV outcomes study, the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), has been fully enrolled, with about 27,500 patients, and is expected to be completed no later than 2017, according to Amgen. The study also will provide safety data in more than 5,000 patients with LDL-C levels below 40 mg/dL.
The FDA usually follows the recommendations of its advisory panels. The FDA panelists had no potential conflicts of interest. A decision is expected by Aug. 27. If approved, Amgen plans to market evolocumab as Repatha.
GAITHERSBURG, MD. – The benefit-risk profile of the PCSK9 inhibitor evolocumab, injected subcutaneously once or twice a month, supports its approval for treating hypercholesterolemia in certain high-risk populations, a Food and Drug Administration advisory panel has agreed.
At a meeting on June 10, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 15-0 that evolocumab should be approved for treating patients aged 12 years and older and adults with homozygous familial hypercholesterolemia (HoFH), based on its impact on lowering low-density lipoprotein cholesterol (LDL-C) in patients and what is currently known about its safety profile.
In a separate vote on other populations included in the indication proposed by Amgen, the panel voted 11-4 to recommend approval for treating other types of patients but limited it to patients at higher CVD risk and elevated LDL-C levels, particularly those with heterozygous FH. There also was support for approval for other higher-risk patients, such as those at high risk for CVD and high LDL-C levels and those with high LDL-C levels on maximum statin doses, but there was not support for approval for lower-risk groups, such as those with mixed hyperlipidemia.
Amgen has proposed that evolocumab be approved for patients with HoFH, as well as adults with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia.
With these votes, it is likely that evolocumab will be approved this year since the FDA usually follows the recommendations of its advisory panels. Evolocumab and another PCSK9 inhibitor, alirocumab – which the majority of the panel recommended for approval the day before – will be the first in this new class of lipid-lowering agents to be approved in the United States. The recommended doses for adults with primary hyperlipidemia and mixed dyslipidemia are 140 mg every 2 weeks or 420 mg once a month; 420 mg every 2 or 4 weeks is recommended for those with HoFH.
PCSK9 inhibitors are human monoclonal antibodies that bind to proprotein convertase subtilisin kexin type 9 (PCSK9), a serine protease that is involved in the regulation of LDL receptor (LDL-R). Inactivation of PCSK9 results in an increase of LDL-R available to clear LDL-C, reducing LDL-C levels.
The data presented by Amgen include four 12-week, phase III double-blind randomized studies comparing the two doses of evolocumab to placebo and/or ezetimibe in about 3,100 patients. The four studies involved patients with HoFH, patients at high CV risk on background statin therapy, patients on monotherapy with diet as background therapy, and patients intolerant to statins who were on no or low-dose statin. The primary efficacy endpoint was reduction n LDL-C at 10-12 weeks.
Both dosing regimens resulted in significantly lower LDL-C levels from baseline, compared with placebo and ezetimibe. Treatment with the two doses resulted in “consistent, clinically equivalent” LDL-C reductions in patients with primary hyperlipidemia and those with mixed dyslipidemia, with reductions of 55%-75% compared with placebo and 35%-45% compared with ezetimibe. Effects were maintained over 2 years in an open-label extension study in different subgroups, including gender and region, according to Amgen.
In a phase III study of 49 patients with HoFH treated with 420 mg once a month or placebo, evolocumab was associated with LDL-C reductions of about 31%, compared with placebo. In phase II and III studies of almost 5,000 patients who received evolocumab, the overall incidence of adverse events was similar to the comparators, and adverse events in long-term studies were similar to those seen in the initial studies, according to Amgen. To date, no major safety issues have been associated with evolocumab, including in patients with very low LDL-C levels (below 25 mg/dL or 40 mg/dL), compared with levels of 40 mg/dL or greater, according to the company.
Adverse events of interest include neurocognitive events and glycemic changes, recently reported with statins. The incidence of new-onset diabetes was low and similar between those on evolocumab and comparators, although there was a “small imbalance” in glycemic changes in patients on evolocumab, a risk that cannot be ruled out and will be monitored in ongoing studies, including the CV outcomes study, according to Amgen. In phase II and III studies, over a median exposure of about 3 months, the rate of neurocognitive adverse events was low and there was no association between low and very low LDL-C levels and neurocognitive events. Most adverse events were rash and eczema and were mild to moderate.
Although the panel agreed there was no major safety signal of concern in the studies, which was reassuring, the members said that safety issues should continue to be followed and that whether very low levels of LDL-C may be associated with adverse events remained an open question and needed to be studied on a long-term basis, including in the CV outcomes study. The concern was raised that, if LDL-C levels dropped to low levels, some clinicians might reduce or withdraw the statin.
As with alirocumab, the panel was asked to discuss whether the impact on LDL-C with evolocumab was sufficient to demonstrate an effect on clinical outcomes; historically, the FDA has considered reductions in LDL-C sufficient to establish the effectiveness of a lipid-lowering drug and does not require that benefit be shown in a CV outcomes trial before approval, “provided the reduction is sufficiently robust” and the product does not have any safety issues that raise concerns about the benefit-risk profile, according to the FDA. Although several panelists said that, while the drug targets LDL-C via a mechanism that is fairly close to the statin target, which provided more confidence in using LDL-C as a surrogate for CV benefit, they said this question can only be answered definitely with the CV outcomes trial.
The CV outcomes study, the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), has been fully enrolled, with about 27,500 patients, and is expected to be completed no later than 2017, according to Amgen. The study also will provide safety data in more than 5,000 patients with LDL-C levels below 40 mg/dL.
The FDA usually follows the recommendations of its advisory panels. The FDA panelists had no potential conflicts of interest. A decision is expected by Aug. 27. If approved, Amgen plans to market evolocumab as Repatha.
AT AN FDA ADVISORY COMMITTEE MEETING
Panel backs approval of alirocumab, biologic injectable lipid-lowering drug
GAITHERSBURG, MD. – The majority of a Food and Drug Administration Advisory panel has supported the approval of alirocumab, a biologic lipid-lowering drug injected subcutaneously twice a month, as a long-term treatment for hypercholesterolemia, but support for the different patient populations included in the proposed indication varied.
At a meeting on June 9, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-3 that the manufacturer had “sufficiently established that the LDL cholesterol–lowering benefit of alirocumab exceeds its risks,” and to “support approval in one or more patient populations,” the question posed to the panel. However, those voting in favor of approval said the optimal benefit would be in patients with familial hypercholesterolemia; there was also support among some panelists for patients who are truly statin intolerant and those who cannot get to goal on statin therapy alone and are at a high cardiovascular risk.
The proposed indication for the PCSK9-inhibitor is for treating adults with primary hypercholesterolemia (nonfamilial and heterozygous familial) or mixed dyslipidemia, including patients with type 2 diabetes, to reduce LDL cholesterol, total cholesterol, non-HDL cholesterol, apolipoprotein B, triglycerides, and lipoprotein A, and to increase HDL cholesterol and apolipoprotein A-1 (Apo A-1) – either in combination with a statin or as monotherapy, including in patients who cannot tolerate statins. The proposed dose is 75 mg administered subcutaneously every 2 weeks (or a starting dose of 150 mg every 2 weeks for patients who need more than a 60% reduction in LDL-C.
Dr. Brendan Everett, director of the cardiology inpatient service at Brigham and Women’s Hospital, Boston, voted for approval, because of the drug’s potential benefits for patients with heterozygous FH, but added that he would restrict approval to these patients, and did not support approval in other patients, such as those with mixed dyslipidemia.
Alirocumab was compared with placebo or ezetimibe in 10 phase III studies of about 5,100 patients, including those at high CV risk and statin-intolerant patients.
The percent reduction in LDL cholesterol at 24 weeks, from baseline, was the primary endpoint. Summarizing the FDA’s view on the safety and efficacy of alirocumab, Dr. Julie Golden, a medical reviewer in the FDA’s division of metabolism and endocrinology products, said that the agency agrees with the manufacturer, that alirocumab is associated with “substantial and persistent” cholesterol-lowering effects, compared with controls, in all patient populations studied. However, any conclusions about CV benefits are “premature,” she said.
Panelists said that in the studies, there were “weak” safety signals for neurocognitive effects, diabetes, and abnormal liver enzymes, but they were somewhat reassured by the absence of any “highly concerning” adverse events in the studies. Panelists said there was little or no evidence that very low levels of LDL cholesterol are harmful, but that did not provide assurance of safety of very low levels. Several panelists raised the concern that statins may be reduced or stopped in patients whose LDL cholesterol levels dropped to very low levels while on alirocumab, instead of stopping treatment with alirocumab.
Over 20 years, the FDA has accepted reductions in LDL cholesterol as a surrogate for CV risk reduction to support approval of lipid-lowering drugs, but once approved, CV outcomes trials are not required. One of the panelists voting against approval was Dr. Peter Wilson, professor of medicine and public health, Emory University, who said that cardiovascular outcomes data were needed to support approval. “I no longer think we are in an LDL-surrogate era,” he noted.
The alirocumab CV outcomes study – the ODYSSEY Outcomes trial – is enrolling 18,000 patients with recent acute coronary syndrome who are on high intensity statin treatment and are randomized to alirocumab or placebo; MACE is the primary endpoint. The company expects that enrollment in the outcomes study will be completed this year and results will be available in 2017; it will represent 50,000 patient years of experience (vs. 5,000 patient years with the phase III trials) and will include further evaluation of the risks associated with treatment.
The FDA usually follows the recommendations of its advisory panels. The FDA panelists had no potential conflicts of interest.
If approved, Sanofi and Regeneron plan to market alirocumab as Praluent; a decision is expected by July 24th.
On June 10, the panel will review evolocumab, another PCSK9-inhibitor. If approved, these will be the first drugs in this new class of lipid-lowering agents to be approved in the United States. They are human monoclonal antibodies that bind to proprotein convertase subtilisin kexin type 9 (PCSK9), a serine protease that is involved in the regulation of LDL receptor (LDR-R). Inactivation of PCSK9 results in an increase of LDL-R available to clear LDL-C, reducing LDL-C levels.
GAITHERSBURG, MD. – The majority of a Food and Drug Administration Advisory panel has supported the approval of alirocumab, a biologic lipid-lowering drug injected subcutaneously twice a month, as a long-term treatment for hypercholesterolemia, but support for the different patient populations included in the proposed indication varied.
At a meeting on June 9, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-3 that the manufacturer had “sufficiently established that the LDL cholesterol–lowering benefit of alirocumab exceeds its risks,” and to “support approval in one or more patient populations,” the question posed to the panel. However, those voting in favor of approval said the optimal benefit would be in patients with familial hypercholesterolemia; there was also support among some panelists for patients who are truly statin intolerant and those who cannot get to goal on statin therapy alone and are at a high cardiovascular risk.
The proposed indication for the PCSK9-inhibitor is for treating adults with primary hypercholesterolemia (nonfamilial and heterozygous familial) or mixed dyslipidemia, including patients with type 2 diabetes, to reduce LDL cholesterol, total cholesterol, non-HDL cholesterol, apolipoprotein B, triglycerides, and lipoprotein A, and to increase HDL cholesterol and apolipoprotein A-1 (Apo A-1) – either in combination with a statin or as monotherapy, including in patients who cannot tolerate statins. The proposed dose is 75 mg administered subcutaneously every 2 weeks (or a starting dose of 150 mg every 2 weeks for patients who need more than a 60% reduction in LDL-C.
Dr. Brendan Everett, director of the cardiology inpatient service at Brigham and Women’s Hospital, Boston, voted for approval, because of the drug’s potential benefits for patients with heterozygous FH, but added that he would restrict approval to these patients, and did not support approval in other patients, such as those with mixed dyslipidemia.
Alirocumab was compared with placebo or ezetimibe in 10 phase III studies of about 5,100 patients, including those at high CV risk and statin-intolerant patients.
The percent reduction in LDL cholesterol at 24 weeks, from baseline, was the primary endpoint. Summarizing the FDA’s view on the safety and efficacy of alirocumab, Dr. Julie Golden, a medical reviewer in the FDA’s division of metabolism and endocrinology products, said that the agency agrees with the manufacturer, that alirocumab is associated with “substantial and persistent” cholesterol-lowering effects, compared with controls, in all patient populations studied. However, any conclusions about CV benefits are “premature,” she said.
Panelists said that in the studies, there were “weak” safety signals for neurocognitive effects, diabetes, and abnormal liver enzymes, but they were somewhat reassured by the absence of any “highly concerning” adverse events in the studies. Panelists said there was little or no evidence that very low levels of LDL cholesterol are harmful, but that did not provide assurance of safety of very low levels. Several panelists raised the concern that statins may be reduced or stopped in patients whose LDL cholesterol levels dropped to very low levels while on alirocumab, instead of stopping treatment with alirocumab.
Over 20 years, the FDA has accepted reductions in LDL cholesterol as a surrogate for CV risk reduction to support approval of lipid-lowering drugs, but once approved, CV outcomes trials are not required. One of the panelists voting against approval was Dr. Peter Wilson, professor of medicine and public health, Emory University, who said that cardiovascular outcomes data were needed to support approval. “I no longer think we are in an LDL-surrogate era,” he noted.
The alirocumab CV outcomes study – the ODYSSEY Outcomes trial – is enrolling 18,000 patients with recent acute coronary syndrome who are on high intensity statin treatment and are randomized to alirocumab or placebo; MACE is the primary endpoint. The company expects that enrollment in the outcomes study will be completed this year and results will be available in 2017; it will represent 50,000 patient years of experience (vs. 5,000 patient years with the phase III trials) and will include further evaluation of the risks associated with treatment.
The FDA usually follows the recommendations of its advisory panels. The FDA panelists had no potential conflicts of interest.
If approved, Sanofi and Regeneron plan to market alirocumab as Praluent; a decision is expected by July 24th.
On June 10, the panel will review evolocumab, another PCSK9-inhibitor. If approved, these will be the first drugs in this new class of lipid-lowering agents to be approved in the United States. They are human monoclonal antibodies that bind to proprotein convertase subtilisin kexin type 9 (PCSK9), a serine protease that is involved in the regulation of LDL receptor (LDR-R). Inactivation of PCSK9 results in an increase of LDL-R available to clear LDL-C, reducing LDL-C levels.
GAITHERSBURG, MD. – The majority of a Food and Drug Administration Advisory panel has supported the approval of alirocumab, a biologic lipid-lowering drug injected subcutaneously twice a month, as a long-term treatment for hypercholesterolemia, but support for the different patient populations included in the proposed indication varied.
At a meeting on June 9, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-3 that the manufacturer had “sufficiently established that the LDL cholesterol–lowering benefit of alirocumab exceeds its risks,” and to “support approval in one or more patient populations,” the question posed to the panel. However, those voting in favor of approval said the optimal benefit would be in patients with familial hypercholesterolemia; there was also support among some panelists for patients who are truly statin intolerant and those who cannot get to goal on statin therapy alone and are at a high cardiovascular risk.
The proposed indication for the PCSK9-inhibitor is for treating adults with primary hypercholesterolemia (nonfamilial and heterozygous familial) or mixed dyslipidemia, including patients with type 2 diabetes, to reduce LDL cholesterol, total cholesterol, non-HDL cholesterol, apolipoprotein B, triglycerides, and lipoprotein A, and to increase HDL cholesterol and apolipoprotein A-1 (Apo A-1) – either in combination with a statin or as monotherapy, including in patients who cannot tolerate statins. The proposed dose is 75 mg administered subcutaneously every 2 weeks (or a starting dose of 150 mg every 2 weeks for patients who need more than a 60% reduction in LDL-C.
Dr. Brendan Everett, director of the cardiology inpatient service at Brigham and Women’s Hospital, Boston, voted for approval, because of the drug’s potential benefits for patients with heterozygous FH, but added that he would restrict approval to these patients, and did not support approval in other patients, such as those with mixed dyslipidemia.
Alirocumab was compared with placebo or ezetimibe in 10 phase III studies of about 5,100 patients, including those at high CV risk and statin-intolerant patients.
The percent reduction in LDL cholesterol at 24 weeks, from baseline, was the primary endpoint. Summarizing the FDA’s view on the safety and efficacy of alirocumab, Dr. Julie Golden, a medical reviewer in the FDA’s division of metabolism and endocrinology products, said that the agency agrees with the manufacturer, that alirocumab is associated with “substantial and persistent” cholesterol-lowering effects, compared with controls, in all patient populations studied. However, any conclusions about CV benefits are “premature,” she said.
Panelists said that in the studies, there were “weak” safety signals for neurocognitive effects, diabetes, and abnormal liver enzymes, but they were somewhat reassured by the absence of any “highly concerning” adverse events in the studies. Panelists said there was little or no evidence that very low levels of LDL cholesterol are harmful, but that did not provide assurance of safety of very low levels. Several panelists raised the concern that statins may be reduced or stopped in patients whose LDL cholesterol levels dropped to very low levels while on alirocumab, instead of stopping treatment with alirocumab.
Over 20 years, the FDA has accepted reductions in LDL cholesterol as a surrogate for CV risk reduction to support approval of lipid-lowering drugs, but once approved, CV outcomes trials are not required. One of the panelists voting against approval was Dr. Peter Wilson, professor of medicine and public health, Emory University, who said that cardiovascular outcomes data were needed to support approval. “I no longer think we are in an LDL-surrogate era,” he noted.
The alirocumab CV outcomes study – the ODYSSEY Outcomes trial – is enrolling 18,000 patients with recent acute coronary syndrome who are on high intensity statin treatment and are randomized to alirocumab or placebo; MACE is the primary endpoint. The company expects that enrollment in the outcomes study will be completed this year and results will be available in 2017; it will represent 50,000 patient years of experience (vs. 5,000 patient years with the phase III trials) and will include further evaluation of the risks associated with treatment.
The FDA usually follows the recommendations of its advisory panels. The FDA panelists had no potential conflicts of interest.
If approved, Sanofi and Regeneron plan to market alirocumab as Praluent; a decision is expected by July 24th.
On June 10, the panel will review evolocumab, another PCSK9-inhibitor. If approved, these will be the first drugs in this new class of lipid-lowering agents to be approved in the United States. They are human monoclonal antibodies that bind to proprotein convertase subtilisin kexin type 9 (PCSK9), a serine protease that is involved in the regulation of LDL receptor (LDR-R). Inactivation of PCSK9 results in an increase of LDL-R available to clear LDL-C, reducing LDL-C levels.
AT AN FDA ADVISORY COMMITTEE MEETING
FDA panel set to review two biologic lipid-lowering drugs for approval
This week, an expert panel convened by the Food and Drug Administration will vote on whether two biologic lipid-lowering treatments, administered subcutaneously every 2 weeks, should be approved for lowering low-density lipoprotein cholesterol (LDL-C) in different groups of patients.
Alirocumab and evolocumab are human monoclonal antibodies that bind to proprotein convertase subtilisin kexin type 9 (PCSK9), a serine protease that is involved in the regulation of LDL receptor (LDR-R). Inactivation of PCSK9 results in an increase of LDL-R available to clear LDL-C, reducing LDL-C levels. If approved, they will be the first PCSK9 inhibitors, a new class of lipid-lowering agents, to be approved in the United States.
The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee will review alirocumab, developed by Sanofi and Regeneron, on June 9, and will review evolocumab, developed by Amgen, on June 10.
The votes on whether the data on the drugs support approval will be based on whether the LDL-C–lowering benefits of the drugs exceed their risks, since lipid-lowering drugs are currently approved using the LDL-C endpoint as a surrogate for cardiovascular benefit, “provided the reduction is sufficiently robust and the product (or its class) does not have safety issues that raise concern that risk exceeds benefit,” according to the FDA draft questions.
For each drug separately, however, the FDA also is asking the panel to discuss whether their LDL-C–lowering effects are “sufficient to substitute for demonstrating its effect on clinical outcomes,” such as a evidence from a cardiovascular outcome trial.
Promising CV outcomes data are available for both drugs, but CV outcomes trials have not been completed and those data are not addressed in the questions.
Alirocumab
The Sanofi/Regeneron briefing document proposes that alirocumab be approved before the results of the ongoing 18,000-patient CV outcomes study – the ODYSSEY Outcomes trial – are available, and that approval “at this time is based on the unmet needs of patients for additional LDL-C lowering, the demonstration of substantial LDL-C lowering by alirocumab, and an acceptable safety profile.” Patients enrolled in the ODYSSEY Outcomes study have recent acute coronary syndrome, are on high intensity statin treatment, and are randomized to alirocumab or placebo.
Two different dose regimens of alirocumab have been studied in 10 multicenter phase III studies – the ODYSSEY program – which include five 12- to 18-month placebo-controlled studies in about 3,500 patients and five 6- to 24-month studies comparing alirocumab with ezetimibe in about 1,800 patients, which evaluated the percent change in LDL-C at 24 months as the primary endpoint.
The FDA’s briefing document posted before the meeting states that, in studies, alirocumab “demonstrated early and sustained LDL-C lowering from baseline across patient populations, regardless of background lipid-modifying therapies, and is generally well-tolerated.” Treatment was associated with reductions of LDL-C ranging from 36% to 61% from baseline, and differences of 39%-62%, compared with placebo – which were statistically significant – and differences of 24%-36%, compared with ezetimibe. Differences over ezetimibe were statistically significant in all but one of the five studies using ezetimibe as the comparator.
The rate of serious adverse events among those who received alirocumab in placebo-controlled studies were similar to placebo (about 14%) but were slightly higher, compared with ezetimibe (13.1% vs. 11.2%). Rash and pruritus were the most common adverse events associated with alirocumab.
Compared with fewer than 1% of those on controls, about 20% of those treated with alirocumab had at least one LDL-C value that dropped below 15 mg/dL and about 40% had one value that dropped below 25 mg/dL. So far, a review of adverse events “divided by levels of LDL-C achieved did not demonstrate a safety signal,” but patients have not been treated long enough to determine what “if any, adverse effects of prolonged exposure to very low levels of LDL-C will be,” according to the FDA briefing document.
The proposed indication for alirocumab is for treating adults with primary hypercholesterolemia (nonfamilial and heterozygous familial) or mixed dyslipidemia, including patients with type 2 diabetes, to reduce LDL-C, total cholesterol, non–high-density lipoprotein C, apolipoprotein B, triglycerides, and lipoprotein (a) [Lp(a)], and to increase HDL cholesterol and apolipoprotein A-1(Apo A-1). It is proposed for use in combination with a statin, with or without another lipid-modifying therapy, and as monotherapy, or as add-on to other nonstatin lipid-modifying therapy, including in patients who cannot tolerate statins. The proposed dose is 75 mg administered subcutaneously every 2 weeks (or a starting dose of 150 mg every 2 weeks for patients who need more than a 60% reduction in LDL-C).
Evolocumab
This month, Amgen expects to complete enrollment of FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a CV outcomes study of about 27,500 patients, which started in 2013 and should end by 2017. This also will provide safety data in more than 5,000 patients with LDL-C levels below 40 mg/dL, according to Amgen’s briefing documents posted on the FDA website before the meeting.
The Amgen data include four 12-week double-blind randomized studies comparing evolocumab to placebo or ezetimibe in about 3,100 patients. Both dosing regimens resulted in significantly lower LDL-C levels from baseline, compared with placebo and ezetimibe.
In studies of over 6,000 patients with primary hyperlipidemia or mixed dyslipidemia, evolocumab resulted in LDL-C reductions of 55%-75% compared with placebo, and 35%-45% compared with ezetimibe, according to Amgen. In studies of patients with homozygous familial hypercholesterolemia (HoFH), treatment was associated with LDL-C reductions of about 30%, compared with placebo. To date, no safety risk has been identified with low LDL-C levels in patients with levels that dropped below 25 mg/dL or 40 mg/dL, compared with levels of 40 mg/dL or greater, according to the company.
The proposed indication for evolocumab includes treatment of adults with hyperlipidemia or mixed dyslipidemia. Treatment would be in combination with a statin or a statin with other lipid-lowering therapies, or alone, or in combination with other lipid-lowering therapies in patients who are statin intolerant, or alone or in combination with other lipid-lowering therapies in patients for whom a statin is not considered clinically appropriate. It also is being reviewed for treatment of patients with HoFH who are aged 12 years and older in combination with other lipid-lowering therapies. The recommended doses for adults with primary hyperlipidemia and mixed dyslipidemia are 140 mg every 2 weeks or 420 mg once a month; 420 mg every 2 or 4 weeks is recommended for those with HoFH.
If approved, Sanofi and Regeneron plan to market alirocumab as Praluent and Amgen plans to market evolocumab as Repatha.
This week, an expert panel convened by the Food and Drug Administration will vote on whether two biologic lipid-lowering treatments, administered subcutaneously every 2 weeks, should be approved for lowering low-density lipoprotein cholesterol (LDL-C) in different groups of patients.
Alirocumab and evolocumab are human monoclonal antibodies that bind to proprotein convertase subtilisin kexin type 9 (PCSK9), a serine protease that is involved in the regulation of LDL receptor (LDR-R). Inactivation of PCSK9 results in an increase of LDL-R available to clear LDL-C, reducing LDL-C levels. If approved, they will be the first PCSK9 inhibitors, a new class of lipid-lowering agents, to be approved in the United States.
The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee will review alirocumab, developed by Sanofi and Regeneron, on June 9, and will review evolocumab, developed by Amgen, on June 10.
The votes on whether the data on the drugs support approval will be based on whether the LDL-C–lowering benefits of the drugs exceed their risks, since lipid-lowering drugs are currently approved using the LDL-C endpoint as a surrogate for cardiovascular benefit, “provided the reduction is sufficiently robust and the product (or its class) does not have safety issues that raise concern that risk exceeds benefit,” according to the FDA draft questions.
For each drug separately, however, the FDA also is asking the panel to discuss whether their LDL-C–lowering effects are “sufficient to substitute for demonstrating its effect on clinical outcomes,” such as a evidence from a cardiovascular outcome trial.
Promising CV outcomes data are available for both drugs, but CV outcomes trials have not been completed and those data are not addressed in the questions.
Alirocumab
The Sanofi/Regeneron briefing document proposes that alirocumab be approved before the results of the ongoing 18,000-patient CV outcomes study – the ODYSSEY Outcomes trial – are available, and that approval “at this time is based on the unmet needs of patients for additional LDL-C lowering, the demonstration of substantial LDL-C lowering by alirocumab, and an acceptable safety profile.” Patients enrolled in the ODYSSEY Outcomes study have recent acute coronary syndrome, are on high intensity statin treatment, and are randomized to alirocumab or placebo.
Two different dose regimens of alirocumab have been studied in 10 multicenter phase III studies – the ODYSSEY program – which include five 12- to 18-month placebo-controlled studies in about 3,500 patients and five 6- to 24-month studies comparing alirocumab with ezetimibe in about 1,800 patients, which evaluated the percent change in LDL-C at 24 months as the primary endpoint.
The FDA’s briefing document posted before the meeting states that, in studies, alirocumab “demonstrated early and sustained LDL-C lowering from baseline across patient populations, regardless of background lipid-modifying therapies, and is generally well-tolerated.” Treatment was associated with reductions of LDL-C ranging from 36% to 61% from baseline, and differences of 39%-62%, compared with placebo – which were statistically significant – and differences of 24%-36%, compared with ezetimibe. Differences over ezetimibe were statistically significant in all but one of the five studies using ezetimibe as the comparator.
The rate of serious adverse events among those who received alirocumab in placebo-controlled studies were similar to placebo (about 14%) but were slightly higher, compared with ezetimibe (13.1% vs. 11.2%). Rash and pruritus were the most common adverse events associated with alirocumab.
Compared with fewer than 1% of those on controls, about 20% of those treated with alirocumab had at least one LDL-C value that dropped below 15 mg/dL and about 40% had one value that dropped below 25 mg/dL. So far, a review of adverse events “divided by levels of LDL-C achieved did not demonstrate a safety signal,” but patients have not been treated long enough to determine what “if any, adverse effects of prolonged exposure to very low levels of LDL-C will be,” according to the FDA briefing document.
The proposed indication for alirocumab is for treating adults with primary hypercholesterolemia (nonfamilial and heterozygous familial) or mixed dyslipidemia, including patients with type 2 diabetes, to reduce LDL-C, total cholesterol, non–high-density lipoprotein C, apolipoprotein B, triglycerides, and lipoprotein (a) [Lp(a)], and to increase HDL cholesterol and apolipoprotein A-1(Apo A-1). It is proposed for use in combination with a statin, with or without another lipid-modifying therapy, and as monotherapy, or as add-on to other nonstatin lipid-modifying therapy, including in patients who cannot tolerate statins. The proposed dose is 75 mg administered subcutaneously every 2 weeks (or a starting dose of 150 mg every 2 weeks for patients who need more than a 60% reduction in LDL-C).
Evolocumab
This month, Amgen expects to complete enrollment of FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a CV outcomes study of about 27,500 patients, which started in 2013 and should end by 2017. This also will provide safety data in more than 5,000 patients with LDL-C levels below 40 mg/dL, according to Amgen’s briefing documents posted on the FDA website before the meeting.
The Amgen data include four 12-week double-blind randomized studies comparing evolocumab to placebo or ezetimibe in about 3,100 patients. Both dosing regimens resulted in significantly lower LDL-C levels from baseline, compared with placebo and ezetimibe.
In studies of over 6,000 patients with primary hyperlipidemia or mixed dyslipidemia, evolocumab resulted in LDL-C reductions of 55%-75% compared with placebo, and 35%-45% compared with ezetimibe, according to Amgen. In studies of patients with homozygous familial hypercholesterolemia (HoFH), treatment was associated with LDL-C reductions of about 30%, compared with placebo. To date, no safety risk has been identified with low LDL-C levels in patients with levels that dropped below 25 mg/dL or 40 mg/dL, compared with levels of 40 mg/dL or greater, according to the company.
The proposed indication for evolocumab includes treatment of adults with hyperlipidemia or mixed dyslipidemia. Treatment would be in combination with a statin or a statin with other lipid-lowering therapies, or alone, or in combination with other lipid-lowering therapies in patients who are statin intolerant, or alone or in combination with other lipid-lowering therapies in patients for whom a statin is not considered clinically appropriate. It also is being reviewed for treatment of patients with HoFH who are aged 12 years and older in combination with other lipid-lowering therapies. The recommended doses for adults with primary hyperlipidemia and mixed dyslipidemia are 140 mg every 2 weeks or 420 mg once a month; 420 mg every 2 or 4 weeks is recommended for those with HoFH.
If approved, Sanofi and Regeneron plan to market alirocumab as Praluent and Amgen plans to market evolocumab as Repatha.
This week, an expert panel convened by the Food and Drug Administration will vote on whether two biologic lipid-lowering treatments, administered subcutaneously every 2 weeks, should be approved for lowering low-density lipoprotein cholesterol (LDL-C) in different groups of patients.
Alirocumab and evolocumab are human monoclonal antibodies that bind to proprotein convertase subtilisin kexin type 9 (PCSK9), a serine protease that is involved in the regulation of LDL receptor (LDR-R). Inactivation of PCSK9 results in an increase of LDL-R available to clear LDL-C, reducing LDL-C levels. If approved, they will be the first PCSK9 inhibitors, a new class of lipid-lowering agents, to be approved in the United States.
The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee will review alirocumab, developed by Sanofi and Regeneron, on June 9, and will review evolocumab, developed by Amgen, on June 10.
The votes on whether the data on the drugs support approval will be based on whether the LDL-C–lowering benefits of the drugs exceed their risks, since lipid-lowering drugs are currently approved using the LDL-C endpoint as a surrogate for cardiovascular benefit, “provided the reduction is sufficiently robust and the product (or its class) does not have safety issues that raise concern that risk exceeds benefit,” according to the FDA draft questions.
For each drug separately, however, the FDA also is asking the panel to discuss whether their LDL-C–lowering effects are “sufficient to substitute for demonstrating its effect on clinical outcomes,” such as a evidence from a cardiovascular outcome trial.
Promising CV outcomes data are available for both drugs, but CV outcomes trials have not been completed and those data are not addressed in the questions.
Alirocumab
The Sanofi/Regeneron briefing document proposes that alirocumab be approved before the results of the ongoing 18,000-patient CV outcomes study – the ODYSSEY Outcomes trial – are available, and that approval “at this time is based on the unmet needs of patients for additional LDL-C lowering, the demonstration of substantial LDL-C lowering by alirocumab, and an acceptable safety profile.” Patients enrolled in the ODYSSEY Outcomes study have recent acute coronary syndrome, are on high intensity statin treatment, and are randomized to alirocumab or placebo.
Two different dose regimens of alirocumab have been studied in 10 multicenter phase III studies – the ODYSSEY program – which include five 12- to 18-month placebo-controlled studies in about 3,500 patients and five 6- to 24-month studies comparing alirocumab with ezetimibe in about 1,800 patients, which evaluated the percent change in LDL-C at 24 months as the primary endpoint.
The FDA’s briefing document posted before the meeting states that, in studies, alirocumab “demonstrated early and sustained LDL-C lowering from baseline across patient populations, regardless of background lipid-modifying therapies, and is generally well-tolerated.” Treatment was associated with reductions of LDL-C ranging from 36% to 61% from baseline, and differences of 39%-62%, compared with placebo – which were statistically significant – and differences of 24%-36%, compared with ezetimibe. Differences over ezetimibe were statistically significant in all but one of the five studies using ezetimibe as the comparator.
The rate of serious adverse events among those who received alirocumab in placebo-controlled studies were similar to placebo (about 14%) but were slightly higher, compared with ezetimibe (13.1% vs. 11.2%). Rash and pruritus were the most common adverse events associated with alirocumab.
Compared with fewer than 1% of those on controls, about 20% of those treated with alirocumab had at least one LDL-C value that dropped below 15 mg/dL and about 40% had one value that dropped below 25 mg/dL. So far, a review of adverse events “divided by levels of LDL-C achieved did not demonstrate a safety signal,” but patients have not been treated long enough to determine what “if any, adverse effects of prolonged exposure to very low levels of LDL-C will be,” according to the FDA briefing document.
The proposed indication for alirocumab is for treating adults with primary hypercholesterolemia (nonfamilial and heterozygous familial) or mixed dyslipidemia, including patients with type 2 diabetes, to reduce LDL-C, total cholesterol, non–high-density lipoprotein C, apolipoprotein B, triglycerides, and lipoprotein (a) [Lp(a)], and to increase HDL cholesterol and apolipoprotein A-1(Apo A-1). It is proposed for use in combination with a statin, with or without another lipid-modifying therapy, and as monotherapy, or as add-on to other nonstatin lipid-modifying therapy, including in patients who cannot tolerate statins. The proposed dose is 75 mg administered subcutaneously every 2 weeks (or a starting dose of 150 mg every 2 weeks for patients who need more than a 60% reduction in LDL-C).
Evolocumab
This month, Amgen expects to complete enrollment of FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a CV outcomes study of about 27,500 patients, which started in 2013 and should end by 2017. This also will provide safety data in more than 5,000 patients with LDL-C levels below 40 mg/dL, according to Amgen’s briefing documents posted on the FDA website before the meeting.
The Amgen data include four 12-week double-blind randomized studies comparing evolocumab to placebo or ezetimibe in about 3,100 patients. Both dosing regimens resulted in significantly lower LDL-C levels from baseline, compared with placebo and ezetimibe.
In studies of over 6,000 patients with primary hyperlipidemia or mixed dyslipidemia, evolocumab resulted in LDL-C reductions of 55%-75% compared with placebo, and 35%-45% compared with ezetimibe, according to Amgen. In studies of patients with homozygous familial hypercholesterolemia (HoFH), treatment was associated with LDL-C reductions of about 30%, compared with placebo. To date, no safety risk has been identified with low LDL-C levels in patients with levels that dropped below 25 mg/dL or 40 mg/dL, compared with levels of 40 mg/dL or greater, according to the company.
The proposed indication for evolocumab includes treatment of adults with hyperlipidemia or mixed dyslipidemia. Treatment would be in combination with a statin or a statin with other lipid-lowering therapies, or alone, or in combination with other lipid-lowering therapies in patients who are statin intolerant, or alone or in combination with other lipid-lowering therapies in patients for whom a statin is not considered clinically appropriate. It also is being reviewed for treatment of patients with HoFH who are aged 12 years and older in combination with other lipid-lowering therapies. The recommended doses for adults with primary hyperlipidemia and mixed dyslipidemia are 140 mg every 2 weeks or 420 mg once a month; 420 mg every 2 or 4 weeks is recommended for those with HoFH.
If approved, Sanofi and Regeneron plan to market alirocumab as Praluent and Amgen plans to market evolocumab as Repatha.
FDA panel supports approval of flibanserin for hypoactive sexual desire
SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel has supported the approval of flibanserin, an oral, centrally-acting, non-hormonal drug taken once a day for treating hypoactive sexual desire disorder in premenopausal women.
But the panel also recommended some conditions, including a risk management plan to address serious adverse effects associated with the drug, a requirement for physician certification, and postmarketing studies to further evaluate and monitor the drug’s safety and efficacy. At a joint meeting of two FDA advisory panels on June 4 members of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18 to 6 that the overall benefit-risk profile of flibanserin supported approval for treating hypoactive sexual desire disorder (HSDD) in premenopausal women, provided that certain risk management options beyond labeling were implemented.
No panelist voted for the option of approval with labeling alone to manage the risks of the drug. The main safety issues raised by the FDA were the risks of hypotension and syncope – effects associated with the drug alone and exacerbated by alcohol and by co-administration with CYPA34 inhibitors.
Those in favor of approval said that the drug had only a modest beneficial effect in a controlled, limited population, but cited the unmet need for a treatment for HSDD. They strongly supported certification of prescribers to assure the drug is used to treat the appropriate patients and that patients are fully counseled about the potential risks.
Several panelists said that alcohol should be contraindicated in women taking the drug and that an alcohol interaction study should be conducted in women only. The manufacturer, Sprout Pharmaceuticals, conducted such a study but enrolled 23 men and only two women.
Flibanserin is a “post-synaptic 5-HT1A agonist 5-HT2A antagonist,” a non-hormonal treatment with sedating effects; the recommended dose is 100 mg taken every day at bedtime. It is mainly metabolized by CYP3A4.
In three phase III 24-week North American studies, women treated with flibanserin experienced significant improvements in the number of satisfying sexual events (SSEs) per month and sexual desire from baseline. The three studies enrolled premenopausal women whose mean age was 36 years. Most women were white, ten percent were black, and 8% were Hispanic. They met the DSM-IV criteria for HSDD for at least 6 months and were in a stable, monogamous relationship with a sexually functional partner for at least 1 year (mean was 11 years). Flibanserin was given to 1,227 study participants, while 1,238 received placebo.
Oral contraceptives, weak CYP3A4 inhibitors, were allowed in the three studies, but other CYP3A4 inhibitors, including fluticasone and grapefruit, were among the exclusion criteria. Perimenopausal or postmenopasual women were excluded.
In all three studies, the change from baseline in the number of satisfying sexual events (SSEs) was a primary endpoint. In the most recent trial, the mean change in SSEs from baseline was 1.5 SSEs per month among those on placebo, versus 2.5 among those on the drug.
In the two earlier studies, the mean increases were 1.6 and 1.9 SSEs among those on flibanserin, versus 0.8 and 1.1 respectively, among those on placebo.
In the first two studies, the primary endpoint that evaluated the treatment effect on sexual desire was “eDiary Desire,” a measure of the most intense level of desire during the previous 24 hours.
In the most recent study, the mean change from baseline to week 24 in the desire domain of the Female Sexual Function Index (FSFI-Desire) over 28 days was a co-primary endpoint (it was a secondary endpoint in the first two studies). In the first two studies flibanserin did not have a significant effect over placebo on the second primary endpoint, sexual desire, as measured by the eDiary Desire measurement, but the effect on a secondary endpoint, measured by FSFI-Desire, was statistically significant.
In the third pivotal study there were significant improvements associated with treatment over placebo in the FSFI-Desire endpoint.
One panelist voting in favor of approval, Dr. Walid Gellad, co-director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, said that if this were the seventh drug for the indication, “this would be a very different discussion.” But it is clear than many women suffer with HSDD, and there are many women who can benefit from flibanserin, although “the benefits are modest...maybe less than modest,” he added.
The risk of syncope, while rare and not associated with any deaths in the study, is a serious safety issue because it occurs unexpectedly and can be accentuated by other factors, he added.
Since the studies were conducted in a select patient population, a Risk Evaluation and Mitigation Strategy (REMS) was needed, he said, with prescriber certification to make sure it is prescribed to appropriate patients, who are those as close as possible to the patients enrolled in the study.
Since 2009, when Boehringer Ingelheim submitted the drug for approval, the FDA has declined twice to approve flibanserin. Reasons for the first decision not to approve included inadequate evidence that it was effective and the need for more information on its effects when used with other drugs and alcohol.
In 2013, it was resubmitted for approval by the new manufacturer, Sprout Pharmaceuticals, with another phase III study and other data, but it was not approved by the FDA for reasons that included numerically small treatment differences compared with placebo that did not outweigh safety concerns, according to the agency. The company appealed this decision, which was denied, and then conducted an additional study and filed for approval again.
During the open public hearing, numerous representatives of health organizations and women with HSDD cited the critical need for an FDA-approved option for women with the disorder, who currently have a multitude of unapproved, unproven, and questionable products marketed for this use.
Speakers opposing approval cited the small magnitude in improvements (at best, 8 more SSEs a year), which were not outweighed by the risks, and other issues, including the inclusion of only two women in the alcohol interaction study, the likelihood of off-label use in postmenopausal women, and the possibility that the drug could result in a significant number of syncope cases.
The FDA usually follows the recommendations of its advisory panels. Panelists were cleared of potential conflicts of interest related to the topic of the meeting. The FDA is expected to make a decision by August 2015.
SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel has supported the approval of flibanserin, an oral, centrally-acting, non-hormonal drug taken once a day for treating hypoactive sexual desire disorder in premenopausal women.
But the panel also recommended some conditions, including a risk management plan to address serious adverse effects associated with the drug, a requirement for physician certification, and postmarketing studies to further evaluate and monitor the drug’s safety and efficacy. At a joint meeting of two FDA advisory panels on June 4 members of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18 to 6 that the overall benefit-risk profile of flibanserin supported approval for treating hypoactive sexual desire disorder (HSDD) in premenopausal women, provided that certain risk management options beyond labeling were implemented.
No panelist voted for the option of approval with labeling alone to manage the risks of the drug. The main safety issues raised by the FDA were the risks of hypotension and syncope – effects associated with the drug alone and exacerbated by alcohol and by co-administration with CYPA34 inhibitors.
Those in favor of approval said that the drug had only a modest beneficial effect in a controlled, limited population, but cited the unmet need for a treatment for HSDD. They strongly supported certification of prescribers to assure the drug is used to treat the appropriate patients and that patients are fully counseled about the potential risks.
Several panelists said that alcohol should be contraindicated in women taking the drug and that an alcohol interaction study should be conducted in women only. The manufacturer, Sprout Pharmaceuticals, conducted such a study but enrolled 23 men and only two women.
Flibanserin is a “post-synaptic 5-HT1A agonist 5-HT2A antagonist,” a non-hormonal treatment with sedating effects; the recommended dose is 100 mg taken every day at bedtime. It is mainly metabolized by CYP3A4.
In three phase III 24-week North American studies, women treated with flibanserin experienced significant improvements in the number of satisfying sexual events (SSEs) per month and sexual desire from baseline. The three studies enrolled premenopausal women whose mean age was 36 years. Most women were white, ten percent were black, and 8% were Hispanic. They met the DSM-IV criteria for HSDD for at least 6 months and were in a stable, monogamous relationship with a sexually functional partner for at least 1 year (mean was 11 years). Flibanserin was given to 1,227 study participants, while 1,238 received placebo.
Oral contraceptives, weak CYP3A4 inhibitors, were allowed in the three studies, but other CYP3A4 inhibitors, including fluticasone and grapefruit, were among the exclusion criteria. Perimenopausal or postmenopasual women were excluded.
In all three studies, the change from baseline in the number of satisfying sexual events (SSEs) was a primary endpoint. In the most recent trial, the mean change in SSEs from baseline was 1.5 SSEs per month among those on placebo, versus 2.5 among those on the drug.
In the two earlier studies, the mean increases were 1.6 and 1.9 SSEs among those on flibanserin, versus 0.8 and 1.1 respectively, among those on placebo.
In the first two studies, the primary endpoint that evaluated the treatment effect on sexual desire was “eDiary Desire,” a measure of the most intense level of desire during the previous 24 hours.
In the most recent study, the mean change from baseline to week 24 in the desire domain of the Female Sexual Function Index (FSFI-Desire) over 28 days was a co-primary endpoint (it was a secondary endpoint in the first two studies). In the first two studies flibanserin did not have a significant effect over placebo on the second primary endpoint, sexual desire, as measured by the eDiary Desire measurement, but the effect on a secondary endpoint, measured by FSFI-Desire, was statistically significant.
In the third pivotal study there were significant improvements associated with treatment over placebo in the FSFI-Desire endpoint.
One panelist voting in favor of approval, Dr. Walid Gellad, co-director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, said that if this were the seventh drug for the indication, “this would be a very different discussion.” But it is clear than many women suffer with HSDD, and there are many women who can benefit from flibanserin, although “the benefits are modest...maybe less than modest,” he added.
The risk of syncope, while rare and not associated with any deaths in the study, is a serious safety issue because it occurs unexpectedly and can be accentuated by other factors, he added.
Since the studies were conducted in a select patient population, a Risk Evaluation and Mitigation Strategy (REMS) was needed, he said, with prescriber certification to make sure it is prescribed to appropriate patients, who are those as close as possible to the patients enrolled in the study.
Since 2009, when Boehringer Ingelheim submitted the drug for approval, the FDA has declined twice to approve flibanserin. Reasons for the first decision not to approve included inadequate evidence that it was effective and the need for more information on its effects when used with other drugs and alcohol.
In 2013, it was resubmitted for approval by the new manufacturer, Sprout Pharmaceuticals, with another phase III study and other data, but it was not approved by the FDA for reasons that included numerically small treatment differences compared with placebo that did not outweigh safety concerns, according to the agency. The company appealed this decision, which was denied, and then conducted an additional study and filed for approval again.
During the open public hearing, numerous representatives of health organizations and women with HSDD cited the critical need for an FDA-approved option for women with the disorder, who currently have a multitude of unapproved, unproven, and questionable products marketed for this use.
Speakers opposing approval cited the small magnitude in improvements (at best, 8 more SSEs a year), which were not outweighed by the risks, and other issues, including the inclusion of only two women in the alcohol interaction study, the likelihood of off-label use in postmenopausal women, and the possibility that the drug could result in a significant number of syncope cases.
The FDA usually follows the recommendations of its advisory panels. Panelists were cleared of potential conflicts of interest related to the topic of the meeting. The FDA is expected to make a decision by August 2015.
SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel has supported the approval of flibanserin, an oral, centrally-acting, non-hormonal drug taken once a day for treating hypoactive sexual desire disorder in premenopausal women.
But the panel also recommended some conditions, including a risk management plan to address serious adverse effects associated with the drug, a requirement for physician certification, and postmarketing studies to further evaluate and monitor the drug’s safety and efficacy. At a joint meeting of two FDA advisory panels on June 4 members of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18 to 6 that the overall benefit-risk profile of flibanserin supported approval for treating hypoactive sexual desire disorder (HSDD) in premenopausal women, provided that certain risk management options beyond labeling were implemented.
No panelist voted for the option of approval with labeling alone to manage the risks of the drug. The main safety issues raised by the FDA were the risks of hypotension and syncope – effects associated with the drug alone and exacerbated by alcohol and by co-administration with CYPA34 inhibitors.
Those in favor of approval said that the drug had only a modest beneficial effect in a controlled, limited population, but cited the unmet need for a treatment for HSDD. They strongly supported certification of prescribers to assure the drug is used to treat the appropriate patients and that patients are fully counseled about the potential risks.
Several panelists said that alcohol should be contraindicated in women taking the drug and that an alcohol interaction study should be conducted in women only. The manufacturer, Sprout Pharmaceuticals, conducted such a study but enrolled 23 men and only two women.
Flibanserin is a “post-synaptic 5-HT1A agonist 5-HT2A antagonist,” a non-hormonal treatment with sedating effects; the recommended dose is 100 mg taken every day at bedtime. It is mainly metabolized by CYP3A4.
In three phase III 24-week North American studies, women treated with flibanserin experienced significant improvements in the number of satisfying sexual events (SSEs) per month and sexual desire from baseline. The three studies enrolled premenopausal women whose mean age was 36 years. Most women were white, ten percent were black, and 8% were Hispanic. They met the DSM-IV criteria for HSDD for at least 6 months and were in a stable, monogamous relationship with a sexually functional partner for at least 1 year (mean was 11 years). Flibanserin was given to 1,227 study participants, while 1,238 received placebo.
Oral contraceptives, weak CYP3A4 inhibitors, were allowed in the three studies, but other CYP3A4 inhibitors, including fluticasone and grapefruit, were among the exclusion criteria. Perimenopausal or postmenopasual women were excluded.
In all three studies, the change from baseline in the number of satisfying sexual events (SSEs) was a primary endpoint. In the most recent trial, the mean change in SSEs from baseline was 1.5 SSEs per month among those on placebo, versus 2.5 among those on the drug.
In the two earlier studies, the mean increases were 1.6 and 1.9 SSEs among those on flibanserin, versus 0.8 and 1.1 respectively, among those on placebo.
In the first two studies, the primary endpoint that evaluated the treatment effect on sexual desire was “eDiary Desire,” a measure of the most intense level of desire during the previous 24 hours.
In the most recent study, the mean change from baseline to week 24 in the desire domain of the Female Sexual Function Index (FSFI-Desire) over 28 days was a co-primary endpoint (it was a secondary endpoint in the first two studies). In the first two studies flibanserin did not have a significant effect over placebo on the second primary endpoint, sexual desire, as measured by the eDiary Desire measurement, but the effect on a secondary endpoint, measured by FSFI-Desire, was statistically significant.
In the third pivotal study there were significant improvements associated with treatment over placebo in the FSFI-Desire endpoint.
One panelist voting in favor of approval, Dr. Walid Gellad, co-director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, said that if this were the seventh drug for the indication, “this would be a very different discussion.” But it is clear than many women suffer with HSDD, and there are many women who can benefit from flibanserin, although “the benefits are modest...maybe less than modest,” he added.
The risk of syncope, while rare and not associated with any deaths in the study, is a serious safety issue because it occurs unexpectedly and can be accentuated by other factors, he added.
Since the studies were conducted in a select patient population, a Risk Evaluation and Mitigation Strategy (REMS) was needed, he said, with prescriber certification to make sure it is prescribed to appropriate patients, who are those as close as possible to the patients enrolled in the study.
Since 2009, when Boehringer Ingelheim submitted the drug for approval, the FDA has declined twice to approve flibanserin. Reasons for the first decision not to approve included inadequate evidence that it was effective and the need for more information on its effects when used with other drugs and alcohol.
In 2013, it was resubmitted for approval by the new manufacturer, Sprout Pharmaceuticals, with another phase III study and other data, but it was not approved by the FDA for reasons that included numerically small treatment differences compared with placebo that did not outweigh safety concerns, according to the agency. The company appealed this decision, which was denied, and then conducted an additional study and filed for approval again.
During the open public hearing, numerous representatives of health organizations and women with HSDD cited the critical need for an FDA-approved option for women with the disorder, who currently have a multitude of unapproved, unproven, and questionable products marketed for this use.
Speakers opposing approval cited the small magnitude in improvements (at best, 8 more SSEs a year), which were not outweighed by the risks, and other issues, including the inclusion of only two women in the alcohol interaction study, the likelihood of off-label use in postmenopausal women, and the possibility that the drug could result in a significant number of syncope cases.
The FDA usually follows the recommendations of its advisory panels. Panelists were cleared of potential conflicts of interest related to the topic of the meeting. The FDA is expected to make a decision by August 2015.
AT AN FDA ADVISORY COMMITTEE MEETING
