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Drug receives fast track designation for lower-risk MDS
The US Food and Drug Administration (FDA) has granted fast track designation to the telomerase inhibitor imetelstat.
The designation is for imetelstat as a potential treatment for adults who have transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes (MDS), do not have 5q deletion, and are refractory or resistant to treatment with an erythropoiesis-stimulating agent (ESA).
Imetelstat was initially developed by Geron Corporation and exclusively licensed to Janssen Biotech, Inc.
Janssen sponsored the application for fast track designation using preliminary data from IMerge, a trial in which researchers are studying transfusion-dependent patients with low- or intermediate-1 risk MDS who have relapsed after or are refractory to treatment with an ESA.
Part 1 of IMerge is a phase 2, single-arm trial. Part 2 is a phase 3, randomized, placebo-controlled trial.
Thirty-two patients have been enrolled in part 1 of IMerge. However, this part of the trial is expanding to enroll approximately 20 additional patients who do not have 5q deletion and are naïve to treatment with a hypomethylating agent and lenalidomide.
The expansion is based on results observed in a subset of the original 32 patients who had not received prior treatment with a hypomethylating agent or lenalidomide and did not have 5q deletion.
As of May 2017, this 13-patient subset showed an increased durability and rate of red blood cell transfusion-independence compared to the overall trial population.
Results in these patients and the rest of the original 32 patients are expected to be presented at an upcoming medical conference.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA. 
The US Food and Drug Administration (FDA) has granted fast track designation to the telomerase inhibitor imetelstat.
The designation is for imetelstat as a potential treatment for adults who have transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes (MDS), do not have 5q deletion, and are refractory or resistant to treatment with an erythropoiesis-stimulating agent (ESA).
Imetelstat was initially developed by Geron Corporation and exclusively licensed to Janssen Biotech, Inc.
Janssen sponsored the application for fast track designation using preliminary data from IMerge, a trial in which researchers are studying transfusion-dependent patients with low- or intermediate-1 risk MDS who have relapsed after or are refractory to treatment with an ESA.
Part 1 of IMerge is a phase 2, single-arm trial. Part 2 is a phase 3, randomized, placebo-controlled trial.
Thirty-two patients have been enrolled in part 1 of IMerge. However, this part of the trial is expanding to enroll approximately 20 additional patients who do not have 5q deletion and are naïve to treatment with a hypomethylating agent and lenalidomide.
The expansion is based on results observed in a subset of the original 32 patients who had not received prior treatment with a hypomethylating agent or lenalidomide and did not have 5q deletion.
As of May 2017, this 13-patient subset showed an increased durability and rate of red blood cell transfusion-independence compared to the overall trial population.
Results in these patients and the rest of the original 32 patients are expected to be presented at an upcoming medical conference.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
The US Food and Drug Administration (FDA) has granted fast track designation to the telomerase inhibitor imetelstat.
The designation is for imetelstat as a potential treatment for adults who have transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes (MDS), do not have 5q deletion, and are refractory or resistant to treatment with an erythropoiesis-stimulating agent (ESA).
Imetelstat was initially developed by Geron Corporation and exclusively licensed to Janssen Biotech, Inc.
Janssen sponsored the application for fast track designation using preliminary data from IMerge, a trial in which researchers are studying transfusion-dependent patients with low- or intermediate-1 risk MDS who have relapsed after or are refractory to treatment with an ESA.
Part 1 of IMerge is a phase 2, single-arm trial. Part 2 is a phase 3, randomized, placebo-controlled trial.
Thirty-two patients have been enrolled in part 1 of IMerge. However, this part of the trial is expanding to enroll approximately 20 additional patients who do not have 5q deletion and are naïve to treatment with a hypomethylating agent and lenalidomide.
The expansion is based on results observed in a subset of the original 32 patients who had not received prior treatment with a hypomethylating agent or lenalidomide and did not have 5q deletion.
As of May 2017, this 13-patient subset showed an increased durability and rate of red blood cell transfusion-independence compared to the overall trial population.
Results in these patients and the rest of the original 32 patients are expected to be presented at an upcoming medical conference.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
FDA approves drug to treat rel/ref MCL
The US Food and Drug Administration (FDA) has granted accelerated approval to the BTK inhibitor acalabrutinib (Calquence, formerly ACP-196).
The drug is now approved to treat adults with mantle cell lymphoma (MCL) who have received at least 1 prior therapy.
The FDA’s accelerated approval pathway is used for drugs intended to treat serious conditions where there is unmet medical need and when said drugs have demonstrated effects that suggest they will provide a clinical benefit to patients.
This means further study is required to verify and describe the anticipated clinical benefits of acalabrutinib, which was approved based on the overall response rate observed in a phase 2 trial.
The company developing acalabrutinib, AstraZeneca Pharmaceuticals LP, is currently conducting the necessary additional research.
The FDA previously granted AstraZeneca priority review, breakthrough therapy, and orphan drug designations for acalabrutinib as a treatment for MCL.
Phase 2 trial
The FDA approved acalabrutinib based on results of the phase 2 ACE-LY-004 trial. This single-arm trial enrolled 124 adults with relapsed or refractory MCL.
According to AstraZeneca, acalabrutinib produced an overall response rate of 80%, with 40% of patients achieving a complete response and 40% experiencing a partial response.
The most common adverse events (AEs) of any grade (occurring in at least 20% of patients) were anemia (46%), thrombocytopenia (44%), headache (39%), neutropenia (36%), diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%).
Dosage reductions due to AEs occurred in 1.6% of patients. Discontinuations due to AEs occurred in 6.5% of patients. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.
According to AstraZeneca, full results from ACE-LY-004 have been submitted for presentation at an upcoming medical meeting.
This will be the first MCL trial data to be presented from the acalabrutinib development program, which includes both monotherapy and combination therapies in hematologic and solid tumor malignancies.
The US Food and Drug Administration (FDA) has granted accelerated approval to the BTK inhibitor acalabrutinib (Calquence, formerly ACP-196).
The drug is now approved to treat adults with mantle cell lymphoma (MCL) who have received at least 1 prior therapy.
The FDA’s accelerated approval pathway is used for drugs intended to treat serious conditions where there is unmet medical need and when said drugs have demonstrated effects that suggest they will provide a clinical benefit to patients.
This means further study is required to verify and describe the anticipated clinical benefits of acalabrutinib, which was approved based on the overall response rate observed in a phase 2 trial.
The company developing acalabrutinib, AstraZeneca Pharmaceuticals LP, is currently conducting the necessary additional research.
The FDA previously granted AstraZeneca priority review, breakthrough therapy, and orphan drug designations for acalabrutinib as a treatment for MCL.
Phase 2 trial
The FDA approved acalabrutinib based on results of the phase 2 ACE-LY-004 trial. This single-arm trial enrolled 124 adults with relapsed or refractory MCL.
According to AstraZeneca, acalabrutinib produced an overall response rate of 80%, with 40% of patients achieving a complete response and 40% experiencing a partial response.
The most common adverse events (AEs) of any grade (occurring in at least 20% of patients) were anemia (46%), thrombocytopenia (44%), headache (39%), neutropenia (36%), diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%).
Dosage reductions due to AEs occurred in 1.6% of patients. Discontinuations due to AEs occurred in 6.5% of patients. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.
According to AstraZeneca, full results from ACE-LY-004 have been submitted for presentation at an upcoming medical meeting.
This will be the first MCL trial data to be presented from the acalabrutinib development program, which includes both monotherapy and combination therapies in hematologic and solid tumor malignancies.
The US Food and Drug Administration (FDA) has granted accelerated approval to the BTK inhibitor acalabrutinib (Calquence, formerly ACP-196).
The drug is now approved to treat adults with mantle cell lymphoma (MCL) who have received at least 1 prior therapy.
The FDA’s accelerated approval pathway is used for drugs intended to treat serious conditions where there is unmet medical need and when said drugs have demonstrated effects that suggest they will provide a clinical benefit to patients.
This means further study is required to verify and describe the anticipated clinical benefits of acalabrutinib, which was approved based on the overall response rate observed in a phase 2 trial.
The company developing acalabrutinib, AstraZeneca Pharmaceuticals LP, is currently conducting the necessary additional research.
The FDA previously granted AstraZeneca priority review, breakthrough therapy, and orphan drug designations for acalabrutinib as a treatment for MCL.
Phase 2 trial
The FDA approved acalabrutinib based on results of the phase 2 ACE-LY-004 trial. This single-arm trial enrolled 124 adults with relapsed or refractory MCL.
According to AstraZeneca, acalabrutinib produced an overall response rate of 80%, with 40% of patients achieving a complete response and 40% experiencing a partial response.
The most common adverse events (AEs) of any grade (occurring in at least 20% of patients) were anemia (46%), thrombocytopenia (44%), headache (39%), neutropenia (36%), diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%).
Dosage reductions due to AEs occurred in 1.6% of patients. Discontinuations due to AEs occurred in 6.5% of patients. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.
According to AstraZeneca, full results from ACE-LY-004 have been submitted for presentation at an upcoming medical meeting.
This will be the first MCL trial data to be presented from the acalabrutinib development program, which includes both monotherapy and combination therapies in hematologic and solid tumor malignancies.
FDA to rely on foreign authorities’ inspections
The US Food and Drug Administration (FDA) will now recognize 8 European drug regulatory authorities as capable of conducting inspections of manufacturing facilities that meet FDA requirements.
This move is a step toward successful implementation of the amended Pharmaceutical Annex to the 1998 US-European Union (EU) Mutual Recognition Agreement.
This agreement enables US and EU regulators to utilize each other’s good manufacturing practice (GMP) inspections of pharmaceutical manufacturing facilities.
In June, the European Commission determined that the FDA “has the capability, capacity, and procedures in place to carry out GMP inspections at a level equivalent to the EU.”
Now, the FDA has followed suit. The agency said it will rely on inspections of manufacturing facilities conducted by regulatory authorities located in Austria, Croatia, France, Italy, Malta, Spain, Sweden, and the United Kingdom.
“Beginning November 1, we will take the unprecedented and significant step forward in realizing the key benefits of the Mutual Recognition Agreement with our European counterparts in that we will now rely on the inspectional data obtained by these 8 regulatory agencies,” said Dara Corrigan, the FDA’s acting deputy commissioner for global regulatory operations and policy.
“The progress made so far puts us on track to meet our goal of completing all 28 capability assessments in the EU by July 2019.”
The completion of these capability assessments is intended to reduce duplication of drug inspections and allow regulators to devote more resources to other manufacturing facilities in countries where there may be greater risk.
The FDA believes that, ultimately, the prioritization of such inspections will help identify potential drug quality problems more quickly and prevent poor quality drugs from entering the US market.
“At a time in which medical product manufacturing is truly a global enterprise, there is much to be gained by partnering with regulatory counterparts to reduce duplicative efforts and maximize global resources while realizing the greatest bang for our collective inspectional buck,” said FDA Commissioner Scott Gottlieb, MD.
“By partnering with these countries, we can create greater efficiencies and better fulfill our public health goals, relying on the expertise of our colleagues and refocusing our resources on inspections in higher-risk countries.”
The US Food and Drug Administration (FDA) will now recognize 8 European drug regulatory authorities as capable of conducting inspections of manufacturing facilities that meet FDA requirements.
This move is a step toward successful implementation of the amended Pharmaceutical Annex to the 1998 US-European Union (EU) Mutual Recognition Agreement.
This agreement enables US and EU regulators to utilize each other’s good manufacturing practice (GMP) inspections of pharmaceutical manufacturing facilities.
In June, the European Commission determined that the FDA “has the capability, capacity, and procedures in place to carry out GMP inspections at a level equivalent to the EU.”
Now, the FDA has followed suit. The agency said it will rely on inspections of manufacturing facilities conducted by regulatory authorities located in Austria, Croatia, France, Italy, Malta, Spain, Sweden, and the United Kingdom.
“Beginning November 1, we will take the unprecedented and significant step forward in realizing the key benefits of the Mutual Recognition Agreement with our European counterparts in that we will now rely on the inspectional data obtained by these 8 regulatory agencies,” said Dara Corrigan, the FDA’s acting deputy commissioner for global regulatory operations and policy.
“The progress made so far puts us on track to meet our goal of completing all 28 capability assessments in the EU by July 2019.”
The completion of these capability assessments is intended to reduce duplication of drug inspections and allow regulators to devote more resources to other manufacturing facilities in countries where there may be greater risk.
The FDA believes that, ultimately, the prioritization of such inspections will help identify potential drug quality problems more quickly and prevent poor quality drugs from entering the US market.
“At a time in which medical product manufacturing is truly a global enterprise, there is much to be gained by partnering with regulatory counterparts to reduce duplicative efforts and maximize global resources while realizing the greatest bang for our collective inspectional buck,” said FDA Commissioner Scott Gottlieb, MD.
“By partnering with these countries, we can create greater efficiencies and better fulfill our public health goals, relying on the expertise of our colleagues and refocusing our resources on inspections in higher-risk countries.”
The US Food and Drug Administration (FDA) will now recognize 8 European drug regulatory authorities as capable of conducting inspections of manufacturing facilities that meet FDA requirements.
This move is a step toward successful implementation of the amended Pharmaceutical Annex to the 1998 US-European Union (EU) Mutual Recognition Agreement.
This agreement enables US and EU regulators to utilize each other’s good manufacturing practice (GMP) inspections of pharmaceutical manufacturing facilities.
In June, the European Commission determined that the FDA “has the capability, capacity, and procedures in place to carry out GMP inspections at a level equivalent to the EU.”
Now, the FDA has followed suit. The agency said it will rely on inspections of manufacturing facilities conducted by regulatory authorities located in Austria, Croatia, France, Italy, Malta, Spain, Sweden, and the United Kingdom.
“Beginning November 1, we will take the unprecedented and significant step forward in realizing the key benefits of the Mutual Recognition Agreement with our European counterparts in that we will now rely on the inspectional data obtained by these 8 regulatory agencies,” said Dara Corrigan, the FDA’s acting deputy commissioner for global regulatory operations and policy.
“The progress made so far puts us on track to meet our goal of completing all 28 capability assessments in the EU by July 2019.”
The completion of these capability assessments is intended to reduce duplication of drug inspections and allow regulators to devote more resources to other manufacturing facilities in countries where there may be greater risk.
The FDA believes that, ultimately, the prioritization of such inspections will help identify potential drug quality problems more quickly and prevent poor quality drugs from entering the US market.
“At a time in which medical product manufacturing is truly a global enterprise, there is much to be gained by partnering with regulatory counterparts to reduce duplicative efforts and maximize global resources while realizing the greatest bang for our collective inspectional buck,” said FDA Commissioner Scott Gottlieb, MD.
“By partnering with these countries, we can create greater efficiencies and better fulfill our public health goals, relying on the expertise of our colleagues and refocusing our resources on inspections in higher-risk countries.”
Ibrutinib approved to treat cGVHD in Canada
Health Canada has approved the BTK inhibitor ibrutinib (IMBRUVICA®) for the treatment of patients with steroid-dependent or -refractory chronic graft-versus-host disease (cGVHD).
This is the sixth approval for ibrutinib in Canada.
The drug is approved as monotherapy for patients with previously untreated chronic lymphocytic leukemia (CLL), CLL patients who have received at least 1 prior therapy, patients with Waldenström’s macroglobulinemia, and patients with relapsed or refractory mantle cell lymphoma.
Ibrutinib is also approved for use in combination with bendamustine and rituximab for the treatment of CLL patients who have received at least 1 prior therapy.
Ibrutinib is co-developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics LLC, an AbbVie company. Janssen Inc. markets ibrutinib in Canada.
The approval of ibrutinib to treat cGVHD is based on results of a phase 2 trial, which were presented at the 2016 ASH Annual Meeting.
The trial included 42 patients with a median age of 56 (range, 19 to 74). The most common underlying malignancies that led to patients’ transplants were acute lymphocytic leukemia, acute myeloid leukemia, and CLL.
At baseline, the patients had persistent cGVHD symptoms despite receiving standard treatment with corticosteroids. Most patients’ symptoms included mouth ulcers and skin rashes, and more than 50% had 2 or more organs affected by cGVHD.
The median time since cGVHD diagnosis was 14 months, the median number of prior cGVHD treatments was 2 (range, 1 to 3), and 60% of patients had a Karnofsky performance score of ≤ 80.
Fifty-two percent of patients were receiving ongoing immunosuppressants and systemic corticosteroids at baseline.
Sixty-seven percent of patients responded to treatment with ibrutinib, and 21% had a complete response. In 48% of patients, responses lasted for 5 months or longer. Responses were seen across all organs affected by cGVHD (ie, skin, mouth, gastrointestinal tract, and liver).
The patients’ median steroid dose was reduced over time, from 0.31 mg/kg/day at baseline to 0.14 mg/kg/day at week 48. Five patients were able to completely discontinue corticosteroids while in response.
The most common (≥20%) adverse events (AEs) of all grades were fatigue (57%), bruising (40%), diarrhea (36%), stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), and pneumonia (21%).
Atrial fibrillation (grade 3) occurred in 1 patient (2%). Serious AEs occurred in 52% of patients. The most common serious AEs (2 or more patients) were pneumonia, sepsis (septic shock), cellulitis, headache, and pyrexia.
There were 2 fatal events, a case of pneumonia and a case of pulmonary aspergillosis.
Twenty-four percent of patients discontinued ibrutinib due to AEs. The most common AEs leading to discontinuation were fatigue and pneumonia. AEs leading to dose reductions occurred in 26% of patients.
The recommended dose of ibrutinib for cGVHD is 420 mg (three 140 mg capsules) once daily.
Health Canada has approved the BTK inhibitor ibrutinib (IMBRUVICA®) for the treatment of patients with steroid-dependent or -refractory chronic graft-versus-host disease (cGVHD).
This is the sixth approval for ibrutinib in Canada.
The drug is approved as monotherapy for patients with previously untreated chronic lymphocytic leukemia (CLL), CLL patients who have received at least 1 prior therapy, patients with Waldenström’s macroglobulinemia, and patients with relapsed or refractory mantle cell lymphoma.
Ibrutinib is also approved for use in combination with bendamustine and rituximab for the treatment of CLL patients who have received at least 1 prior therapy.
Ibrutinib is co-developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics LLC, an AbbVie company. Janssen Inc. markets ibrutinib in Canada.
The approval of ibrutinib to treat cGVHD is based on results of a phase 2 trial, which were presented at the 2016 ASH Annual Meeting.
The trial included 42 patients with a median age of 56 (range, 19 to 74). The most common underlying malignancies that led to patients’ transplants were acute lymphocytic leukemia, acute myeloid leukemia, and CLL.
At baseline, the patients had persistent cGVHD symptoms despite receiving standard treatment with corticosteroids. Most patients’ symptoms included mouth ulcers and skin rashes, and more than 50% had 2 or more organs affected by cGVHD.
The median time since cGVHD diagnosis was 14 months, the median number of prior cGVHD treatments was 2 (range, 1 to 3), and 60% of patients had a Karnofsky performance score of ≤ 80.
Fifty-two percent of patients were receiving ongoing immunosuppressants and systemic corticosteroids at baseline.
Sixty-seven percent of patients responded to treatment with ibrutinib, and 21% had a complete response. In 48% of patients, responses lasted for 5 months or longer. Responses were seen across all organs affected by cGVHD (ie, skin, mouth, gastrointestinal tract, and liver).
The patients’ median steroid dose was reduced over time, from 0.31 mg/kg/day at baseline to 0.14 mg/kg/day at week 48. Five patients were able to completely discontinue corticosteroids while in response.
The most common (≥20%) adverse events (AEs) of all grades were fatigue (57%), bruising (40%), diarrhea (36%), stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), and pneumonia (21%).
Atrial fibrillation (grade 3) occurred in 1 patient (2%). Serious AEs occurred in 52% of patients. The most common serious AEs (2 or more patients) were pneumonia, sepsis (septic shock), cellulitis, headache, and pyrexia.
There were 2 fatal events, a case of pneumonia and a case of pulmonary aspergillosis.
Twenty-four percent of patients discontinued ibrutinib due to AEs. The most common AEs leading to discontinuation were fatigue and pneumonia. AEs leading to dose reductions occurred in 26% of patients.
The recommended dose of ibrutinib for cGVHD is 420 mg (three 140 mg capsules) once daily.
Health Canada has approved the BTK inhibitor ibrutinib (IMBRUVICA®) for the treatment of patients with steroid-dependent or -refractory chronic graft-versus-host disease (cGVHD).
This is the sixth approval for ibrutinib in Canada.
The drug is approved as monotherapy for patients with previously untreated chronic lymphocytic leukemia (CLL), CLL patients who have received at least 1 prior therapy, patients with Waldenström’s macroglobulinemia, and patients with relapsed or refractory mantle cell lymphoma.
Ibrutinib is also approved for use in combination with bendamustine and rituximab for the treatment of CLL patients who have received at least 1 prior therapy.
Ibrutinib is co-developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics LLC, an AbbVie company. Janssen Inc. markets ibrutinib in Canada.
The approval of ibrutinib to treat cGVHD is based on results of a phase 2 trial, which were presented at the 2016 ASH Annual Meeting.
The trial included 42 patients with a median age of 56 (range, 19 to 74). The most common underlying malignancies that led to patients’ transplants were acute lymphocytic leukemia, acute myeloid leukemia, and CLL.
At baseline, the patients had persistent cGVHD symptoms despite receiving standard treatment with corticosteroids. Most patients’ symptoms included mouth ulcers and skin rashes, and more than 50% had 2 or more organs affected by cGVHD.
The median time since cGVHD diagnosis was 14 months, the median number of prior cGVHD treatments was 2 (range, 1 to 3), and 60% of patients had a Karnofsky performance score of ≤ 80.
Fifty-two percent of patients were receiving ongoing immunosuppressants and systemic corticosteroids at baseline.
Sixty-seven percent of patients responded to treatment with ibrutinib, and 21% had a complete response. In 48% of patients, responses lasted for 5 months or longer. Responses were seen across all organs affected by cGVHD (ie, skin, mouth, gastrointestinal tract, and liver).
The patients’ median steroid dose was reduced over time, from 0.31 mg/kg/day at baseline to 0.14 mg/kg/day at week 48. Five patients were able to completely discontinue corticosteroids while in response.
The most common (≥20%) adverse events (AEs) of all grades were fatigue (57%), bruising (40%), diarrhea (36%), stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), and pneumonia (21%).
Atrial fibrillation (grade 3) occurred in 1 patient (2%). Serious AEs occurred in 52% of patients. The most common serious AEs (2 or more patients) were pneumonia, sepsis (septic shock), cellulitis, headache, and pyrexia.
There were 2 fatal events, a case of pneumonia and a case of pulmonary aspergillosis.
Twenty-four percent of patients discontinued ibrutinib due to AEs. The most common AEs leading to discontinuation were fatigue and pneumonia. AEs leading to dose reductions occurred in 26% of patients.
The recommended dose of ibrutinib for cGVHD is 420 mg (three 140 mg capsules) once daily.
FDA approves lower dose of rivaroxaban
The US Food and Drug Administration (FDA) has approved use of a 10 mg once-daily dose of the factor Xa inhibitor rivaroxaban (XARELTO®).
This dose is now approved to reduce the risk of recurrent venous thromboembolism (VTE) in patients who have received at least 6 months of standard anticoagulant therapy.
With this approval, the rivaroxaban prescribing information provides instructions for physicians to begin treatment with rivaroxaban at 15 mg, dosed twice daily, for the first 21 days after a VTE occurrence.
On day 22 through at least day 180, the dose decreases to 20 mg once daily. After at least 180 days (6 months), physicians can prescribe 10 mg once daily in patients at continued risk for deep vein thrombosis and/or pulmonary embolism.
The FDA’s approval of a 10 mg once-daily dose of rivaroxaban follows a priority review designation from the FDA and is based on data from the EINSTEIN CHOICE study.
Results from EINSTEIN CHOICE were presented at the American College of Cardiology’s 66th Annual Scientific Session and published in NEJM in March.
Patients enrolled in this phase 3 study had confirmed VTE and were treated initially with standard anticoagulant therapy for 6 to 12 months.
During the study, 3365 patients received rivaroxaban at 10 mg, rivaroxaban at 20 mg, or aspirin at 100 mg once daily for up to 12 months of extended treatment.
Both rivaroxaban doses were superior to aspirin in preventing fatal or non-fatal recurrent VTE, the study’s primary efficacy endpoint.
The rate of recurrent VTE was 1.2% in the 10 mg rivaroxaban arm (hazard ratio [HR]=0.26; 95% CI, 0.14 to 0.47; P<0.001), 1.5% in the 20 mg rivaroxaban arm (HR=0.34; 95% CI, 0.20 to 0.59; P<0.001), and 4.4% in the aspirin arm. Fatal VTE occurred in 0%, 0.2%, and 0.2% of patients, respectively.
The primary safety endpoint was major bleeding as defined by the International Society on Thrombosis and Haemostasis.
The rate of major bleeding was 0.4% for the 10 mg rivaroxaban arm (HR=1.64; 95% CI, 0.39 to 6.84; P=0.50), 0.5% for the 20 mg rivaroxaban arm (HR=2.01; 95% CI, 0.50 to 8.04; P=0.32), and 0.3% for the aspirin arm.
The US Food and Drug Administration (FDA) has approved use of a 10 mg once-daily dose of the factor Xa inhibitor rivaroxaban (XARELTO®).
This dose is now approved to reduce the risk of recurrent venous thromboembolism (VTE) in patients who have received at least 6 months of standard anticoagulant therapy.
With this approval, the rivaroxaban prescribing information provides instructions for physicians to begin treatment with rivaroxaban at 15 mg, dosed twice daily, for the first 21 days after a VTE occurrence.
On day 22 through at least day 180, the dose decreases to 20 mg once daily. After at least 180 days (6 months), physicians can prescribe 10 mg once daily in patients at continued risk for deep vein thrombosis and/or pulmonary embolism.
The FDA’s approval of a 10 mg once-daily dose of rivaroxaban follows a priority review designation from the FDA and is based on data from the EINSTEIN CHOICE study.
Results from EINSTEIN CHOICE were presented at the American College of Cardiology’s 66th Annual Scientific Session and published in NEJM in March.
Patients enrolled in this phase 3 study had confirmed VTE and were treated initially with standard anticoagulant therapy for 6 to 12 months.
During the study, 3365 patients received rivaroxaban at 10 mg, rivaroxaban at 20 mg, or aspirin at 100 mg once daily for up to 12 months of extended treatment.
Both rivaroxaban doses were superior to aspirin in preventing fatal or non-fatal recurrent VTE, the study’s primary efficacy endpoint.
The rate of recurrent VTE was 1.2% in the 10 mg rivaroxaban arm (hazard ratio [HR]=0.26; 95% CI, 0.14 to 0.47; P<0.001), 1.5% in the 20 mg rivaroxaban arm (HR=0.34; 95% CI, 0.20 to 0.59; P<0.001), and 4.4% in the aspirin arm. Fatal VTE occurred in 0%, 0.2%, and 0.2% of patients, respectively.
The primary safety endpoint was major bleeding as defined by the International Society on Thrombosis and Haemostasis.
The rate of major bleeding was 0.4% for the 10 mg rivaroxaban arm (HR=1.64; 95% CI, 0.39 to 6.84; P=0.50), 0.5% for the 20 mg rivaroxaban arm (HR=2.01; 95% CI, 0.50 to 8.04; P=0.32), and 0.3% for the aspirin arm.
The US Food and Drug Administration (FDA) has approved use of a 10 mg once-daily dose of the factor Xa inhibitor rivaroxaban (XARELTO®).
This dose is now approved to reduce the risk of recurrent venous thromboembolism (VTE) in patients who have received at least 6 months of standard anticoagulant therapy.
With this approval, the rivaroxaban prescribing information provides instructions for physicians to begin treatment with rivaroxaban at 15 mg, dosed twice daily, for the first 21 days after a VTE occurrence.
On day 22 through at least day 180, the dose decreases to 20 mg once daily. After at least 180 days (6 months), physicians can prescribe 10 mg once daily in patients at continued risk for deep vein thrombosis and/or pulmonary embolism.
The FDA’s approval of a 10 mg once-daily dose of rivaroxaban follows a priority review designation from the FDA and is based on data from the EINSTEIN CHOICE study.
Results from EINSTEIN CHOICE were presented at the American College of Cardiology’s 66th Annual Scientific Session and published in NEJM in March.
Patients enrolled in this phase 3 study had confirmed VTE and were treated initially with standard anticoagulant therapy for 6 to 12 months.
During the study, 3365 patients received rivaroxaban at 10 mg, rivaroxaban at 20 mg, or aspirin at 100 mg once daily for up to 12 months of extended treatment.
Both rivaroxaban doses were superior to aspirin in preventing fatal or non-fatal recurrent VTE, the study’s primary efficacy endpoint.
The rate of recurrent VTE was 1.2% in the 10 mg rivaroxaban arm (hazard ratio [HR]=0.26; 95% CI, 0.14 to 0.47; P<0.001), 1.5% in the 20 mg rivaroxaban arm (HR=0.34; 95% CI, 0.20 to 0.59; P<0.001), and 4.4% in the aspirin arm. Fatal VTE occurred in 0%, 0.2%, and 0.2% of patients, respectively.
The primary safety endpoint was major bleeding as defined by the International Society on Thrombosis and Haemostasis.
The rate of major bleeding was 0.4% for the 10 mg rivaroxaban arm (HR=1.64; 95% CI, 0.39 to 6.84; P=0.50), 0.5% for the 20 mg rivaroxaban arm (HR=2.01; 95% CI, 0.50 to 8.04; P=0.32), and 0.3% for the aspirin arm.
Protein may be therapeutic target for MM
Preclinical research suggests the protein BMI-1 may be a therapeutic target for multiple myeloma (MM).
Researchers found that BMI-1 inhibition, with a drug called PTC-209, induced apoptosis in MM cell lines and primary cells.
In addition, PTC-209’s anti-myeloma activity was enhanced by inhibitors targeting EZH2 and BET bromodomains.
The researchers reported these results in Oncotarget.
The team noted that previous studies have suggested epigenetic alterations are involved in the development of MM. They chose to focus the current study on BMI-1 because it’s part of a protein complex involved in epigenetic regulation and could therefore be a potential target for influencing MM development.
“We used the substance PTC-209, which we know inhibits BMI-1, and treated cultivated multiple myeloma cells,” said study author Mohammad Alzrigat, PhD, of Uppsala University in Uppsala, Sweden.
“We used both cell lines that are continuously kept as cultivated cells and cells that were purified from multiple myeloma patients, either newly diagnosed or at relapse. In all cases, we found that [PTC-209] decreased cell survival, which indicates that PTC-209 has an anti-myeloma effect.”
The researchers said PTC-209 demonstrated “potent anti-myeloma activity, reducing the viability of MM cell lines at concentrations ranging up to 1.6 μM over 48 hours of treatment.” INA-6 was the cell line that proved most responsive to PTC-209, and U266-1970 was the least responsive.
The team also found that a 10 μM concentration of PTC-209 reduced the viability of all primary MM cells. This anti-myeloma activity was independent of disease state (whether patients were newly diagnosed or had relapsed disease) and cytogenetic karyotype.
“Our study showed that PTC-209 most likely functions as an anti-myeloma agent by inhibiting the production of BMI-1,” said study author Helena Jernberg-Wiklund, PhD, also of Uppsala University.
“We also saw that when PTC-209 was combined with other substances that inhibit epigenetic alterations, the myeloma cells’ survival was reduced even further compared to when only PTC-209 was used.”
Specifically, the researchers observed synergistic and additive activity when PTC-209 was combined with the EZH2 inhibitor UNC1999 and the BET inhibitor JQ1.
“Our results have both increased our understanding of how epigenetic alterations affect cancer development and shown how inhibiting these mechanisms in combination could potentially be utilized for future treatment of multiple myeloma patients, especially at relapse,” Dr Jernberg-Wiklund said.
Preclinical research suggests the protein BMI-1 may be a therapeutic target for multiple myeloma (MM).
Researchers found that BMI-1 inhibition, with a drug called PTC-209, induced apoptosis in MM cell lines and primary cells.
In addition, PTC-209’s anti-myeloma activity was enhanced by inhibitors targeting EZH2 and BET bromodomains.
The researchers reported these results in Oncotarget.
The team noted that previous studies have suggested epigenetic alterations are involved in the development of MM. They chose to focus the current study on BMI-1 because it’s part of a protein complex involved in epigenetic regulation and could therefore be a potential target for influencing MM development.
“We used the substance PTC-209, which we know inhibits BMI-1, and treated cultivated multiple myeloma cells,” said study author Mohammad Alzrigat, PhD, of Uppsala University in Uppsala, Sweden.
“We used both cell lines that are continuously kept as cultivated cells and cells that were purified from multiple myeloma patients, either newly diagnosed or at relapse. In all cases, we found that [PTC-209] decreased cell survival, which indicates that PTC-209 has an anti-myeloma effect.”
The researchers said PTC-209 demonstrated “potent anti-myeloma activity, reducing the viability of MM cell lines at concentrations ranging up to 1.6 μM over 48 hours of treatment.” INA-6 was the cell line that proved most responsive to PTC-209, and U266-1970 was the least responsive.
The team also found that a 10 μM concentration of PTC-209 reduced the viability of all primary MM cells. This anti-myeloma activity was independent of disease state (whether patients were newly diagnosed or had relapsed disease) and cytogenetic karyotype.
“Our study showed that PTC-209 most likely functions as an anti-myeloma agent by inhibiting the production of BMI-1,” said study author Helena Jernberg-Wiklund, PhD, also of Uppsala University.
“We also saw that when PTC-209 was combined with other substances that inhibit epigenetic alterations, the myeloma cells’ survival was reduced even further compared to when only PTC-209 was used.”
Specifically, the researchers observed synergistic and additive activity when PTC-209 was combined with the EZH2 inhibitor UNC1999 and the BET inhibitor JQ1.
“Our results have both increased our understanding of how epigenetic alterations affect cancer development and shown how inhibiting these mechanisms in combination could potentially be utilized for future treatment of multiple myeloma patients, especially at relapse,” Dr Jernberg-Wiklund said.
Preclinical research suggests the protein BMI-1 may be a therapeutic target for multiple myeloma (MM).
Researchers found that BMI-1 inhibition, with a drug called PTC-209, induced apoptosis in MM cell lines and primary cells.
In addition, PTC-209’s anti-myeloma activity was enhanced by inhibitors targeting EZH2 and BET bromodomains.
The researchers reported these results in Oncotarget.
The team noted that previous studies have suggested epigenetic alterations are involved in the development of MM. They chose to focus the current study on BMI-1 because it’s part of a protein complex involved in epigenetic regulation and could therefore be a potential target for influencing MM development.
“We used the substance PTC-209, which we know inhibits BMI-1, and treated cultivated multiple myeloma cells,” said study author Mohammad Alzrigat, PhD, of Uppsala University in Uppsala, Sweden.
“We used both cell lines that are continuously kept as cultivated cells and cells that were purified from multiple myeloma patients, either newly diagnosed or at relapse. In all cases, we found that [PTC-209] decreased cell survival, which indicates that PTC-209 has an anti-myeloma effect.”
The researchers said PTC-209 demonstrated “potent anti-myeloma activity, reducing the viability of MM cell lines at concentrations ranging up to 1.6 μM over 48 hours of treatment.” INA-6 was the cell line that proved most responsive to PTC-209, and U266-1970 was the least responsive.
The team also found that a 10 μM concentration of PTC-209 reduced the viability of all primary MM cells. This anti-myeloma activity was independent of disease state (whether patients were newly diagnosed or had relapsed disease) and cytogenetic karyotype.
“Our study showed that PTC-209 most likely functions as an anti-myeloma agent by inhibiting the production of BMI-1,” said study author Helena Jernberg-Wiklund, PhD, also of Uppsala University.
“We also saw that when PTC-209 was combined with other substances that inhibit epigenetic alterations, the myeloma cells’ survival was reduced even further compared to when only PTC-209 was used.”
Specifically, the researchers observed synergistic and additive activity when PTC-209 was combined with the EZH2 inhibitor UNC1999 and the BET inhibitor JQ1.
“Our results have both increased our understanding of how epigenetic alterations affect cancer development and shown how inhibiting these mechanisms in combination could potentially be utilized for future treatment of multiple myeloma patients, especially at relapse,” Dr Jernberg-Wiklund said.
Therapy receives rare pediatric disease designation
The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to ATA230 for the treatment of congenital cytomegalovirus (CMV) infection.
ATA230 is an allogeneic T-cell immunotherapy targeting antigens expressed by CMV.
Rare pediatric disease designation is granted to drugs that show promise to treat orphan diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 and younger.
The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.
Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, a drug developer with rare pediatric disease designation that receives an approval of a new drug application is eligible for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.
The company developing ATA230 is Atara Biotherapeutics, Inc. The company also received orphan designation for ATA230.
ATA230 trials
ATA230 has been investigated in phase 1 and 2 studies of immunocompromised patients with CMV viremia or disease who are refractory or resistant to antiviral drug treatment in the post-transplant setting.
Researchers reported phase 2 results with ATA230 at the 2016 ASH Annual Meeting.
The data encompassed 15 patients with documented CMV mutations conferring resistance to antiviral therapies. The patients had received a median of 3 prior therapies.
Eleven of the 15 patients (73.3%) responded to ATA230, 6 with complete responses and 5 with partial responses.
At 6 months, the overall survival was 72.7% in responders and 25% in non-responders.
Within the 6 months of follow-up, 1 of the 11 responders died of CMV, and 3 of the 4 non-responders died of CMV.
Adverse events occurred in 6 patients. One grade 3 event and 1 grade 4 event were considered possibly related to ATA230.
The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to ATA230 for the treatment of congenital cytomegalovirus (CMV) infection.
ATA230 is an allogeneic T-cell immunotherapy targeting antigens expressed by CMV.
Rare pediatric disease designation is granted to drugs that show promise to treat orphan diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 and younger.
The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.
Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, a drug developer with rare pediatric disease designation that receives an approval of a new drug application is eligible for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.
The company developing ATA230 is Atara Biotherapeutics, Inc. The company also received orphan designation for ATA230.
ATA230 trials
ATA230 has been investigated in phase 1 and 2 studies of immunocompromised patients with CMV viremia or disease who are refractory or resistant to antiviral drug treatment in the post-transplant setting.
Researchers reported phase 2 results with ATA230 at the 2016 ASH Annual Meeting.
The data encompassed 15 patients with documented CMV mutations conferring resistance to antiviral therapies. The patients had received a median of 3 prior therapies.
Eleven of the 15 patients (73.3%) responded to ATA230, 6 with complete responses and 5 with partial responses.
At 6 months, the overall survival was 72.7% in responders and 25% in non-responders.
Within the 6 months of follow-up, 1 of the 11 responders died of CMV, and 3 of the 4 non-responders died of CMV.
Adverse events occurred in 6 patients. One grade 3 event and 1 grade 4 event were considered possibly related to ATA230.
The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to ATA230 for the treatment of congenital cytomegalovirus (CMV) infection.
ATA230 is an allogeneic T-cell immunotherapy targeting antigens expressed by CMV.
Rare pediatric disease designation is granted to drugs that show promise to treat orphan diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 and younger.
The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.
Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, a drug developer with rare pediatric disease designation that receives an approval of a new drug application is eligible for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.
The company developing ATA230 is Atara Biotherapeutics, Inc. The company also received orphan designation for ATA230.
ATA230 trials
ATA230 has been investigated in phase 1 and 2 studies of immunocompromised patients with CMV viremia or disease who are refractory or resistant to antiviral drug treatment in the post-transplant setting.
Researchers reported phase 2 results with ATA230 at the 2016 ASH Annual Meeting.
The data encompassed 15 patients with documented CMV mutations conferring resistance to antiviral therapies. The patients had received a median of 3 prior therapies.
Eleven of the 15 patients (73.3%) responded to ATA230, 6 with complete responses and 5 with partial responses.
At 6 months, the overall survival was 72.7% in responders and 25% in non-responders.
Within the 6 months of follow-up, 1 of the 11 responders died of CMV, and 3 of the 4 non-responders died of CMV.
Adverse events occurred in 6 patients. One grade 3 event and 1 grade 4 event were considered possibly related to ATA230.
Gene therapy granted breakthrough designation
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to valoctocogene roxaparvovec (formerly BMN 270) for the treatment of patients with hemophilia A.
Valoctocogene roxaparvovec is a recombinant adeno-associated virus vector coding for human coagulation factor VIII (FVIII).
The breakthrough designation is intended to expedite the development and review of valoctocogene roxaparvovec.
The designation entitles BioMarin Pharmaceutical Inc., the company developing valoctocogene roxaparvovec, to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation from the FDA, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The FDA granted breakthrough designation to valoctocogene roxaparvovec based on data from an ongoing phase 1/2 trial. Results from this study were presented at the ISTH 2017 Congress.
The data suggest that valoctocogene roxaparvovec can allow patients with severe hemophilia A to maintain normal FVIII levels for over a year.
The highest dose of valoctocogene roxaparvovec, 6e13 vg/kg, reduced patients’ mean annual FVIII infusions by 94% and their mean annualized bleed rate by 97%, when compared to FVIII prophylaxis.
None of the patients in this study developed FVIII inhibitors. The most common adverse event was alanine aminotransferase (ALT) elevations.
In fact, the increase in ALT levels exceeded a pre-specified threshold, which resulted in the study being placed on hold last year. However, the hold was ultimately lifted. And all patients with ALT increases have either stopped receiving corticosteroids or are being tapered off of them.
BioMarin said it expects to initiate enrollment of a global phase 3 program for valoctocogene roxaparvovec before the end of this year.
The program includes 2 studies of valoctocogene roxaparvovec, one with a 4e13 vg/kg dose and one with a 6e13 vg/kg dose. The studies will each likely include approximately 40 patients.
Valoctocogene roxaparvovec also has orphan designation from the FDA.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to valoctocogene roxaparvovec (formerly BMN 270) for the treatment of patients with hemophilia A.
Valoctocogene roxaparvovec is a recombinant adeno-associated virus vector coding for human coagulation factor VIII (FVIII).
The breakthrough designation is intended to expedite the development and review of valoctocogene roxaparvovec.
The designation entitles BioMarin Pharmaceutical Inc., the company developing valoctocogene roxaparvovec, to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation from the FDA, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The FDA granted breakthrough designation to valoctocogene roxaparvovec based on data from an ongoing phase 1/2 trial. Results from this study were presented at the ISTH 2017 Congress.
The data suggest that valoctocogene roxaparvovec can allow patients with severe hemophilia A to maintain normal FVIII levels for over a year.
The highest dose of valoctocogene roxaparvovec, 6e13 vg/kg, reduced patients’ mean annual FVIII infusions by 94% and their mean annualized bleed rate by 97%, when compared to FVIII prophylaxis.
None of the patients in this study developed FVIII inhibitors. The most common adverse event was alanine aminotransferase (ALT) elevations.
In fact, the increase in ALT levels exceeded a pre-specified threshold, which resulted in the study being placed on hold last year. However, the hold was ultimately lifted. And all patients with ALT increases have either stopped receiving corticosteroids or are being tapered off of them.
BioMarin said it expects to initiate enrollment of a global phase 3 program for valoctocogene roxaparvovec before the end of this year.
The program includes 2 studies of valoctocogene roxaparvovec, one with a 4e13 vg/kg dose and one with a 6e13 vg/kg dose. The studies will each likely include approximately 40 patients.
Valoctocogene roxaparvovec also has orphan designation from the FDA.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to valoctocogene roxaparvovec (formerly BMN 270) for the treatment of patients with hemophilia A.
Valoctocogene roxaparvovec is a recombinant adeno-associated virus vector coding for human coagulation factor VIII (FVIII).
The breakthrough designation is intended to expedite the development and review of valoctocogene roxaparvovec.
The designation entitles BioMarin Pharmaceutical Inc., the company developing valoctocogene roxaparvovec, to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation from the FDA, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The FDA granted breakthrough designation to valoctocogene roxaparvovec based on data from an ongoing phase 1/2 trial. Results from this study were presented at the ISTH 2017 Congress.
The data suggest that valoctocogene roxaparvovec can allow patients with severe hemophilia A to maintain normal FVIII levels for over a year.
The highest dose of valoctocogene roxaparvovec, 6e13 vg/kg, reduced patients’ mean annual FVIII infusions by 94% and their mean annualized bleed rate by 97%, when compared to FVIII prophylaxis.
None of the patients in this study developed FVIII inhibitors. The most common adverse event was alanine aminotransferase (ALT) elevations.
In fact, the increase in ALT levels exceeded a pre-specified threshold, which resulted in the study being placed on hold last year. However, the hold was ultimately lifted. And all patients with ALT increases have either stopped receiving corticosteroids or are being tapered off of them.
BioMarin said it expects to initiate enrollment of a global phase 3 program for valoctocogene roxaparvovec before the end of this year.
The program includes 2 studies of valoctocogene roxaparvovec, one with a 4e13 vg/kg dose and one with a 6e13 vg/kg dose. The studies will each likely include approximately 40 patients.
Valoctocogene roxaparvovec also has orphan designation from the FDA.
Targeting key pathways to eradicate AML
Targeting two pathways simultaneously—one critical for oncogenesis and one essential for cell survival—may be an effective strategy for treating acute myeloid leukemia (AML), according to researchers.
The team studied mouse models of FLT3-ITD AML and found an inhibitor targeting the FLT3 pathway was largely effective against the disease.
However, targeting the BCL-2 pathway as well proved even more effective, completely eliminating AML in most cases.
Fumihiko Ishikawa, MD, PhD, of RIKEN Center for Integrative Medical Sciences in Yokohama, Kanagawa, Japan, and his colleagues described this work in Science Translational Medicine.
The researchers noted that mutations observed in AML patients have also been observed in elderly people without AML. So the team set out to determine which mutations actually contribute to the disease.
The researchers obtained bone marrow or blood samples from patients with FLT3-ITD AML and transplanted different cellular populations from each individual into mice. The team then examined how the cells behaved.
They were surprised to find that cells with similar surface marker profiles behaved differently. Therefore, the team used single-cell genomic sequencing to correlate mutational profiles with malignant potential.
The researchers said their results suggest that FLT3-ITD is “a critical trigger for leukemia initiation,” and it cooperates with accumulated mutations in DNMT3A, TET2, NPM1, and/or WT1.
The team went on to treat the FLT3-ITD AML mice with RK-20449, a FLT3/HCK inhibitor, and they observed “significant responses.”
In fact, RK-20449 eradicated leukemia originating from 5 different patients. The recipient mice experienced complete elimination of AML cells, in spite of the fact that they also carried mutations not directly targeted by RK-20449.
However, the researchers also noted the presence of RK-20449-resistant AML cells in some mice. The team therefore theorized that co-inhibition of an antiapoptotic signal—BCL-2—might remedy this.
So they treated resistant mice with the BCL-2 inhibitor venetoclax as well as RK-20449. The combination produced responses in all mice treated and completely eliminated AML cells in 9 of 12 cases.
“This shows that determining which of the mutations in a diverse landscape are critical in leukemia onset and which of the pathways are critical for therapeutic resistance in leukemia, and simultaneously targeting those pathways, is an encouraging way to treat difficult cancers such as AML,” Dr Ishikawa said.
Targeting two pathways simultaneously—one critical for oncogenesis and one essential for cell survival—may be an effective strategy for treating acute myeloid leukemia (AML), according to researchers.
The team studied mouse models of FLT3-ITD AML and found an inhibitor targeting the FLT3 pathway was largely effective against the disease.
However, targeting the BCL-2 pathway as well proved even more effective, completely eliminating AML in most cases.
Fumihiko Ishikawa, MD, PhD, of RIKEN Center for Integrative Medical Sciences in Yokohama, Kanagawa, Japan, and his colleagues described this work in Science Translational Medicine.
The researchers noted that mutations observed in AML patients have also been observed in elderly people without AML. So the team set out to determine which mutations actually contribute to the disease.
The researchers obtained bone marrow or blood samples from patients with FLT3-ITD AML and transplanted different cellular populations from each individual into mice. The team then examined how the cells behaved.
They were surprised to find that cells with similar surface marker profiles behaved differently. Therefore, the team used single-cell genomic sequencing to correlate mutational profiles with malignant potential.
The researchers said their results suggest that FLT3-ITD is “a critical trigger for leukemia initiation,” and it cooperates with accumulated mutations in DNMT3A, TET2, NPM1, and/or WT1.
The team went on to treat the FLT3-ITD AML mice with RK-20449, a FLT3/HCK inhibitor, and they observed “significant responses.”
In fact, RK-20449 eradicated leukemia originating from 5 different patients. The recipient mice experienced complete elimination of AML cells, in spite of the fact that they also carried mutations not directly targeted by RK-20449.
However, the researchers also noted the presence of RK-20449-resistant AML cells in some mice. The team therefore theorized that co-inhibition of an antiapoptotic signal—BCL-2—might remedy this.
So they treated resistant mice with the BCL-2 inhibitor venetoclax as well as RK-20449. The combination produced responses in all mice treated and completely eliminated AML cells in 9 of 12 cases.
“This shows that determining which of the mutations in a diverse landscape are critical in leukemia onset and which of the pathways are critical for therapeutic resistance in leukemia, and simultaneously targeting those pathways, is an encouraging way to treat difficult cancers such as AML,” Dr Ishikawa said.
Targeting two pathways simultaneously—one critical for oncogenesis and one essential for cell survival—may be an effective strategy for treating acute myeloid leukemia (AML), according to researchers.
The team studied mouse models of FLT3-ITD AML and found an inhibitor targeting the FLT3 pathway was largely effective against the disease.
However, targeting the BCL-2 pathway as well proved even more effective, completely eliminating AML in most cases.
Fumihiko Ishikawa, MD, PhD, of RIKEN Center for Integrative Medical Sciences in Yokohama, Kanagawa, Japan, and his colleagues described this work in Science Translational Medicine.
The researchers noted that mutations observed in AML patients have also been observed in elderly people without AML. So the team set out to determine which mutations actually contribute to the disease.
The researchers obtained bone marrow or blood samples from patients with FLT3-ITD AML and transplanted different cellular populations from each individual into mice. The team then examined how the cells behaved.
They were surprised to find that cells with similar surface marker profiles behaved differently. Therefore, the team used single-cell genomic sequencing to correlate mutational profiles with malignant potential.
The researchers said their results suggest that FLT3-ITD is “a critical trigger for leukemia initiation,” and it cooperates with accumulated mutations in DNMT3A, TET2, NPM1, and/or WT1.
The team went on to treat the FLT3-ITD AML mice with RK-20449, a FLT3/HCK inhibitor, and they observed “significant responses.”
In fact, RK-20449 eradicated leukemia originating from 5 different patients. The recipient mice experienced complete elimination of AML cells, in spite of the fact that they also carried mutations not directly targeted by RK-20449.
However, the researchers also noted the presence of RK-20449-resistant AML cells in some mice. The team therefore theorized that co-inhibition of an antiapoptotic signal—BCL-2—might remedy this.
So they treated resistant mice with the BCL-2 inhibitor venetoclax as well as RK-20449. The combination produced responses in all mice treated and completely eliminated AML cells in 9 of 12 cases.
“This shows that determining which of the mutations in a diverse landscape are critical in leukemia onset and which of the pathways are critical for therapeutic resistance in leukemia, and simultaneously targeting those pathways, is an encouraging way to treat difficult cancers such as AML,” Dr Ishikawa said.
FDA approves IV formulation of drug for CINV
The US Food and Drug Administration (FDA) has approved an intravenous (IV) formulation of rolapitant (VARUBI®) for the same indication as the oral formulation.
This means IV rolapitant is now FDA-approved for use in combination with other antiemetic agents to prevent delayed nausea and vomiting associated with initial and repeat courses of emetogenic chemotherapy in adults with cancer.
TESARO Inc., makers of rolapitant, said the US commercial launch of IV rolapitant is planned for November.
Rolapitant is a selective and competitive antagonist of human substance P/neurokinin 1 receptors, which play an important role in the delayed phase of chemotherapy-induced nausea and vomiting (CINV).
IV rolapitant features a ready-to-use, single-dose vial for administration. It does not require refrigerated storage or mixing.
The recommended dose of IV rolapitant is 166.5 mg, administered over 30 minutes. The drug is to be administered up to 2 hours before chemotherapy administration in combination with a 5-HT3 receptor antagonist and dexamethasone.
The full prescribing information for IV rolapitant is available at www.varubirx.com.
Bioequivalence trial
Results from a bioequivalence trial suggest the IV and oral formulations of rolapitant are comparable.
The study was conducted in healthy volunteers. Subjects were randomized to receive a single dose of IV rolapitant at 166.5 mg administered over 30 minutes (n=61) or oral rolapitant at 180 mg (n=62).
The primary endpoint was bioequivalence, and the 166.5 mg IV infusion of rolapitant met bioequivalence criteria.
Researchers said the safety profile of IV rolapitant was largely consistent with that of oral rolapitant, although infusion-site reactions were observed with the IV formulation. These included the sensation of warmth, abdominal pain, dizziness, and paresthesia.
These results were recently published in The Journal of Clinical Pharmacology.
Oral rolapitant trials
Two phase 3 trials showed that oral rolapitant, in combination with a 5-HT3 receptor antagonist and dexamethasone, was well tolerated and more effective than active control in preventing CINV after highly emetogenic chemotherapy.
Results from these trials (NCT01499849 and NCT01500213) were published in a single article in The Lancet Oncology.
A third phase 3 trial showed that oral rolapitant, in combination with a 5-HT3 receptor antagonist and dexamethasone, was well tolerated and more effective than active control in preventing CINV after moderately emetogenic chemotherapy.
Results from this trial (NCT01500226) were also published in The Lancet Oncology.
The US Food and Drug Administration (FDA) has approved an intravenous (IV) formulation of rolapitant (VARUBI®) for the same indication as the oral formulation.
This means IV rolapitant is now FDA-approved for use in combination with other antiemetic agents to prevent delayed nausea and vomiting associated with initial and repeat courses of emetogenic chemotherapy in adults with cancer.
TESARO Inc., makers of rolapitant, said the US commercial launch of IV rolapitant is planned for November.
Rolapitant is a selective and competitive antagonist of human substance P/neurokinin 1 receptors, which play an important role in the delayed phase of chemotherapy-induced nausea and vomiting (CINV).
IV rolapitant features a ready-to-use, single-dose vial for administration. It does not require refrigerated storage or mixing.
The recommended dose of IV rolapitant is 166.5 mg, administered over 30 minutes. The drug is to be administered up to 2 hours before chemotherapy administration in combination with a 5-HT3 receptor antagonist and dexamethasone.
The full prescribing information for IV rolapitant is available at www.varubirx.com.
Bioequivalence trial
Results from a bioequivalence trial suggest the IV and oral formulations of rolapitant are comparable.
The study was conducted in healthy volunteers. Subjects were randomized to receive a single dose of IV rolapitant at 166.5 mg administered over 30 minutes (n=61) or oral rolapitant at 180 mg (n=62).
The primary endpoint was bioequivalence, and the 166.5 mg IV infusion of rolapitant met bioequivalence criteria.
Researchers said the safety profile of IV rolapitant was largely consistent with that of oral rolapitant, although infusion-site reactions were observed with the IV formulation. These included the sensation of warmth, abdominal pain, dizziness, and paresthesia.
These results were recently published in The Journal of Clinical Pharmacology.
Oral rolapitant trials
Two phase 3 trials showed that oral rolapitant, in combination with a 5-HT3 receptor antagonist and dexamethasone, was well tolerated and more effective than active control in preventing CINV after highly emetogenic chemotherapy.
Results from these trials (NCT01499849 and NCT01500213) were published in a single article in The Lancet Oncology.
A third phase 3 trial showed that oral rolapitant, in combination with a 5-HT3 receptor antagonist and dexamethasone, was well tolerated and more effective than active control in preventing CINV after moderately emetogenic chemotherapy.
Results from this trial (NCT01500226) were also published in The Lancet Oncology.
The US Food and Drug Administration (FDA) has approved an intravenous (IV) formulation of rolapitant (VARUBI®) for the same indication as the oral formulation.
This means IV rolapitant is now FDA-approved for use in combination with other antiemetic agents to prevent delayed nausea and vomiting associated with initial and repeat courses of emetogenic chemotherapy in adults with cancer.
TESARO Inc., makers of rolapitant, said the US commercial launch of IV rolapitant is planned for November.
Rolapitant is a selective and competitive antagonist of human substance P/neurokinin 1 receptors, which play an important role in the delayed phase of chemotherapy-induced nausea and vomiting (CINV).
IV rolapitant features a ready-to-use, single-dose vial for administration. It does not require refrigerated storage or mixing.
The recommended dose of IV rolapitant is 166.5 mg, administered over 30 minutes. The drug is to be administered up to 2 hours before chemotherapy administration in combination with a 5-HT3 receptor antagonist and dexamethasone.
The full prescribing information for IV rolapitant is available at www.varubirx.com.
Bioequivalence trial
Results from a bioequivalence trial suggest the IV and oral formulations of rolapitant are comparable.
The study was conducted in healthy volunteers. Subjects were randomized to receive a single dose of IV rolapitant at 166.5 mg administered over 30 minutes (n=61) or oral rolapitant at 180 mg (n=62).
The primary endpoint was bioequivalence, and the 166.5 mg IV infusion of rolapitant met bioequivalence criteria.
Researchers said the safety profile of IV rolapitant was largely consistent with that of oral rolapitant, although infusion-site reactions were observed with the IV formulation. These included the sensation of warmth, abdominal pain, dizziness, and paresthesia.
These results were recently published in The Journal of Clinical Pharmacology.
Oral rolapitant trials
Two phase 3 trials showed that oral rolapitant, in combination with a 5-HT3 receptor antagonist and dexamethasone, was well tolerated and more effective than active control in preventing CINV after highly emetogenic chemotherapy.
Results from these trials (NCT01499849 and NCT01500213) were published in a single article in The Lancet Oncology.
A third phase 3 trial showed that oral rolapitant, in combination with a 5-HT3 receptor antagonist and dexamethasone, was well tolerated and more effective than active control in preventing CINV after moderately emetogenic chemotherapy.
Results from this trial (NCT01500226) were also published in The Lancet Oncology.