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Mapping melasma management
Melasma has such a high recurrence rate that, once the facial hyperpigmentation has been cleared, it’s best that treatment never entirely stops, Amit G. Pandya, MD, said at the virtual annual meeting of the American Academy of Dermatology.
He recommended alternating between a less-intensive maintenance therapy regimen in the winter months and an acute care regimen in the sunnier summer months. But . And that is largely a matter of location.
Location, location, location
Melasma has a distinctive symmetric bilateral distribution: “Melasma likes the central area of the forehead, whereas the lateral areas of the forehead are more involved in lichen planus pigmentosus. Melanoma likes the area above the eyebrow or under the eyebrow. However, it does not go below the superior orbital rim or above the inferior orbital rim,”said Dr. Pandya, a dermatologist at the Palo Alto Medical Foundation in Sunnyvale, Calif., who is also on the faculty at the University of Texas Southwestern Medical Center, Dallas.
Melasma is common on the bridge of the nose, but usually not along the nasolabial fold, where hyperpigmentation is much more likely to be due to seborrheic dermatitis or drug-induced hyperpigmentation. Melasma doesn’t affect the tip of the nose; that’s more likely a sign of sarcoidosis or drug-induced hyperpigmentation. Melasma is common on the zygomatic prominence, while acanthosis nigricans favors the concave area below the zygomatic prominence. And melasma stays above the mandible; pigmentation below the mandible is more suggestive of poikiloderma of Civatte. Lentigines are scattered broadly across sun-exposed areas of the face. They also tend to be less symmetrical than melasma, the dermatologist continued.
Acute treatment
Dr. Pandya’s acute treatment algorithm begins with topical 4% hydroquinone in patients who’ve never been on it before. A response to the drug, which blocks the tyrosine-to-melanin pathway, takes 4-6 weeks, with maximum effect not seen until 3-6 months or longer. Bluish-grey ochronosis is a rare side effect at the 4% concentration but becomes more common at higher concentrations or when the drug is used in combination therapy.
“Hydroquinone is a workhorse, the oldest and most effective depigmenting agent,” he said.
If the patient hasn’t responded positively by 3 months, Dr. Pandya moves on to daily use of the triple-drug combination of fluocinolone acetonide 0.01%/hydroquinone 4%/tretinoin 0.05% known as Tri-Luma, a kinder, gentler descendant of the 45-year-old Kligman-Willis compounded formula comprised of 0.1% dexamethasone, 5% hydroquinone, and 0.1% tretinoin.
If Tri-Luma also proves ineffective, Dr. Pandya turns to oral tranexamic acid. This is off-label therapy for the drug, a plasmin inhibitor, which is approved for the treatment of menorrhagia. But oral tranexamic acid is widely used for treatment of melasma in East Asia, and Dr. Pandya and others have evaluated it in placebo-controlled clinical trials. His conclusion is that oral tranexamic acid appears to be safe and effective for treatment of melasma.
“The drug is not approved for melasma, it’s approved for menorrhagia, so every doctor has to decide how much risk they want to take. The evidence suggests 500 mg per day is a good dose,” he said.
The collective clinical trials experience with oral tranexamic acid for melasma shows a side effect profile consisting of mild GI upset, headache, and myalgia. While increased thromboembolic risk is a theoretic concern, it hasn’t been an issue in the published studies, which typically exclude patients with a history of thromboembolic disease from enrollment. Patient satisfaction with the oral agent is high, according to Dr. Pandya.
In one randomized, open-label, 40-patient study, oral tranexamic acid plus a triple-combination cream featuring fluocinolone 0.01%, hydroquinone 2%, and tretinoin 0.05%, applied once a day, was significantly more effective and faster-acting than the topical therapy alone. At 8 weeks, the dual-therapy group averaged an 88% improvement in the Melasma Activity and Severity Index (MASI) scores, compared with 55% with the topical therapy alone (Indian J Dermatol. Sep-Oct 2015;60[5]:520).
Cysteamine 5% cream, which is available over the counter as Cyspera but is pricey, showed promising efficacy in a 40-patient, randomized, double-blind trial (J Dermatolog Treat. 2018 Mar;29[2]:182-9). Dr. Pandya said he’s looking forward to seeing further studies.
Chemical peels can be used, but multiple treatment sessions using a superficial peeling agent are required, and even then “the efficacy is usually not profound,” according to Dr. Pandya. Together with two colleagues he recently published a comprehensive systematic review of 113 published studies of all treatments for melasma in nearly 7,000 patients (Am J Clin Dermatol. 2020 Apr;21(2):173-225).
Newer lasers with various pulse lengths, fluences, wave lengths, and treatment frequency show “some promise,” but there have also been published reports of hypopigmentation and rebound hyperpigmentation. The optimal laser regimen remains elusive, he said.
Maintenance therapy
Dr. Pandya usually switches from hydroquinone to a different topical tyrosinase inhibitor for maintenance therapy, such as kojic acid, arbutin, or azelaic acid, all available OTC in many formulations. Alternatively, he might drop down to 2% hydroquinone for the winter months. Another option is triple-combination cream applied two or three times per week. A topical formulation of tranexamic acid is available, but studies of this agent in patients with melasma have yielded mixed results.
“I don’t think topical tranexamic acid is going to harm the patient, but I don’t think the efficacy is as good as with oral tranexamic acid,” he said.
Slap that melasma in irons
A comprehensive melasma management plan requires year-round frequent daily application of a broad spectrum sunscreen. And since it’s now evident that visible-wavelength light can worsen melasma through mechanisms similar to UVA and UVB, which are long recognized as the major drivers of the hyperpigmentation disorder, serious consideration should be given to the use of a tinted broad-spectrum sunscreen or makeup containing more than 3% iron oxide, which blocks visible light. In contrast, zinc oxide does not, Dr. Pandya noted.
In one influential study, aminolevulinic acid was applied on the arms of 20 patients; two sunscreens were applied on areas where the ALA was applied, and on one area, no sunscreen was applied. The minimal phototoxic dose of visible blue light was doubled with application of a broad-spectrum sunscreen containing titanium dioxide, zinc oxide, and 0.2% iron oxide, compared with no sunscreen, but increased 21-fold using a sunscreen containing titanium dioxide, zinc oxide, and 3.2% iron oxide (Dermatol Surg. 2008 Nov;34[11]:1469-76).
Moreover, in a double-blind, randomized trial including 61 patients with melasma, all on background 4% hydroquinone, those assigned to a broad-spectrum sunscreen containing iron oxide had a 78% improvement in MASI scores at 8 weeks, compared with a 62% improvement with a broad-spectrum UV-only sunscreen. Both sunscreens had a sun protection factor of at least 50 (Photodermatol Photoimmunol Photomed. 2014 Feb;30[1]:35-42).
Numerous sunscreen and makeup products containing more than 3% iron oxide are available OTC in various tints. It’s a matter of finding a color that matches the patient’s skin.
Concern has been raised that exposure to the visible blue light emitted by computer screens and cell phones could worsen melasma. Dr. Pandya noted that reassurance on that score was recently provided by French investigators. They measured the intensity of visible light at the wavelengths emitted by computer screens and laptops and determined that it was 100- to 1,000-fold less than sunlight in the same spectrum. They also conducted a prospective, randomized, split-face trial in 12 melasma patients. One side of the face was exposed to the visible blue light at the same wavelengths emitted by device screens, but at far greater intensity. Blinded evaluators found no split-face difference in modified MASI scores.
“These results suggest that at a 20-cm distance, a maximized use of a high-intensity computer screen for 8 hours per day during a 5-day period does not worsen melasma lesions. Although it is very unlikely that similar exposure during a longer period would start to affect melasma lesions, such a possibility cannot be ruled out,” according to the investigators (J Am Acad Dermatol. 2019 Dec 27;S0190-9622(19)33324-9. doi: 10.1016/j.jaad.2019.12.047).
Dr. Pandya reported serving as a consultant to Incyte, Pfizer, Viela Bio, and Villaris.
Melasma has such a high recurrence rate that, once the facial hyperpigmentation has been cleared, it’s best that treatment never entirely stops, Amit G. Pandya, MD, said at the virtual annual meeting of the American Academy of Dermatology.
He recommended alternating between a less-intensive maintenance therapy regimen in the winter months and an acute care regimen in the sunnier summer months. But . And that is largely a matter of location.
Location, location, location
Melasma has a distinctive symmetric bilateral distribution: “Melasma likes the central area of the forehead, whereas the lateral areas of the forehead are more involved in lichen planus pigmentosus. Melanoma likes the area above the eyebrow or under the eyebrow. However, it does not go below the superior orbital rim or above the inferior orbital rim,”said Dr. Pandya, a dermatologist at the Palo Alto Medical Foundation in Sunnyvale, Calif., who is also on the faculty at the University of Texas Southwestern Medical Center, Dallas.
Melasma is common on the bridge of the nose, but usually not along the nasolabial fold, where hyperpigmentation is much more likely to be due to seborrheic dermatitis or drug-induced hyperpigmentation. Melasma doesn’t affect the tip of the nose; that’s more likely a sign of sarcoidosis or drug-induced hyperpigmentation. Melasma is common on the zygomatic prominence, while acanthosis nigricans favors the concave area below the zygomatic prominence. And melasma stays above the mandible; pigmentation below the mandible is more suggestive of poikiloderma of Civatte. Lentigines are scattered broadly across sun-exposed areas of the face. They also tend to be less symmetrical than melasma, the dermatologist continued.
Acute treatment
Dr. Pandya’s acute treatment algorithm begins with topical 4% hydroquinone in patients who’ve never been on it before. A response to the drug, which blocks the tyrosine-to-melanin pathway, takes 4-6 weeks, with maximum effect not seen until 3-6 months or longer. Bluish-grey ochronosis is a rare side effect at the 4% concentration but becomes more common at higher concentrations or when the drug is used in combination therapy.
“Hydroquinone is a workhorse, the oldest and most effective depigmenting agent,” he said.
If the patient hasn’t responded positively by 3 months, Dr. Pandya moves on to daily use of the triple-drug combination of fluocinolone acetonide 0.01%/hydroquinone 4%/tretinoin 0.05% known as Tri-Luma, a kinder, gentler descendant of the 45-year-old Kligman-Willis compounded formula comprised of 0.1% dexamethasone, 5% hydroquinone, and 0.1% tretinoin.
If Tri-Luma also proves ineffective, Dr. Pandya turns to oral tranexamic acid. This is off-label therapy for the drug, a plasmin inhibitor, which is approved for the treatment of menorrhagia. But oral tranexamic acid is widely used for treatment of melasma in East Asia, and Dr. Pandya and others have evaluated it in placebo-controlled clinical trials. His conclusion is that oral tranexamic acid appears to be safe and effective for treatment of melasma.
“The drug is not approved for melasma, it’s approved for menorrhagia, so every doctor has to decide how much risk they want to take. The evidence suggests 500 mg per day is a good dose,” he said.
The collective clinical trials experience with oral tranexamic acid for melasma shows a side effect profile consisting of mild GI upset, headache, and myalgia. While increased thromboembolic risk is a theoretic concern, it hasn’t been an issue in the published studies, which typically exclude patients with a history of thromboembolic disease from enrollment. Patient satisfaction with the oral agent is high, according to Dr. Pandya.
In one randomized, open-label, 40-patient study, oral tranexamic acid plus a triple-combination cream featuring fluocinolone 0.01%, hydroquinone 2%, and tretinoin 0.05%, applied once a day, was significantly more effective and faster-acting than the topical therapy alone. At 8 weeks, the dual-therapy group averaged an 88% improvement in the Melasma Activity and Severity Index (MASI) scores, compared with 55% with the topical therapy alone (Indian J Dermatol. Sep-Oct 2015;60[5]:520).
Cysteamine 5% cream, which is available over the counter as Cyspera but is pricey, showed promising efficacy in a 40-patient, randomized, double-blind trial (J Dermatolog Treat. 2018 Mar;29[2]:182-9). Dr. Pandya said he’s looking forward to seeing further studies.
Chemical peels can be used, but multiple treatment sessions using a superficial peeling agent are required, and even then “the efficacy is usually not profound,” according to Dr. Pandya. Together with two colleagues he recently published a comprehensive systematic review of 113 published studies of all treatments for melasma in nearly 7,000 patients (Am J Clin Dermatol. 2020 Apr;21(2):173-225).
Newer lasers with various pulse lengths, fluences, wave lengths, and treatment frequency show “some promise,” but there have also been published reports of hypopigmentation and rebound hyperpigmentation. The optimal laser regimen remains elusive, he said.
Maintenance therapy
Dr. Pandya usually switches from hydroquinone to a different topical tyrosinase inhibitor for maintenance therapy, such as kojic acid, arbutin, or azelaic acid, all available OTC in many formulations. Alternatively, he might drop down to 2% hydroquinone for the winter months. Another option is triple-combination cream applied two or three times per week. A topical formulation of tranexamic acid is available, but studies of this agent in patients with melasma have yielded mixed results.
“I don’t think topical tranexamic acid is going to harm the patient, but I don’t think the efficacy is as good as with oral tranexamic acid,” he said.
Slap that melasma in irons
A comprehensive melasma management plan requires year-round frequent daily application of a broad spectrum sunscreen. And since it’s now evident that visible-wavelength light can worsen melasma through mechanisms similar to UVA and UVB, which are long recognized as the major drivers of the hyperpigmentation disorder, serious consideration should be given to the use of a tinted broad-spectrum sunscreen or makeup containing more than 3% iron oxide, which blocks visible light. In contrast, zinc oxide does not, Dr. Pandya noted.
In one influential study, aminolevulinic acid was applied on the arms of 20 patients; two sunscreens were applied on areas where the ALA was applied, and on one area, no sunscreen was applied. The minimal phototoxic dose of visible blue light was doubled with application of a broad-spectrum sunscreen containing titanium dioxide, zinc oxide, and 0.2% iron oxide, compared with no sunscreen, but increased 21-fold using a sunscreen containing titanium dioxide, zinc oxide, and 3.2% iron oxide (Dermatol Surg. 2008 Nov;34[11]:1469-76).
Moreover, in a double-blind, randomized trial including 61 patients with melasma, all on background 4% hydroquinone, those assigned to a broad-spectrum sunscreen containing iron oxide had a 78% improvement in MASI scores at 8 weeks, compared with a 62% improvement with a broad-spectrum UV-only sunscreen. Both sunscreens had a sun protection factor of at least 50 (Photodermatol Photoimmunol Photomed. 2014 Feb;30[1]:35-42).
Numerous sunscreen and makeup products containing more than 3% iron oxide are available OTC in various tints. It’s a matter of finding a color that matches the patient’s skin.
Concern has been raised that exposure to the visible blue light emitted by computer screens and cell phones could worsen melasma. Dr. Pandya noted that reassurance on that score was recently provided by French investigators. They measured the intensity of visible light at the wavelengths emitted by computer screens and laptops and determined that it was 100- to 1,000-fold less than sunlight in the same spectrum. They also conducted a prospective, randomized, split-face trial in 12 melasma patients. One side of the face was exposed to the visible blue light at the same wavelengths emitted by device screens, but at far greater intensity. Blinded evaluators found no split-face difference in modified MASI scores.
“These results suggest that at a 20-cm distance, a maximized use of a high-intensity computer screen for 8 hours per day during a 5-day period does not worsen melasma lesions. Although it is very unlikely that similar exposure during a longer period would start to affect melasma lesions, such a possibility cannot be ruled out,” according to the investigators (J Am Acad Dermatol. 2019 Dec 27;S0190-9622(19)33324-9. doi: 10.1016/j.jaad.2019.12.047).
Dr. Pandya reported serving as a consultant to Incyte, Pfizer, Viela Bio, and Villaris.
Melasma has such a high recurrence rate that, once the facial hyperpigmentation has been cleared, it’s best that treatment never entirely stops, Amit G. Pandya, MD, said at the virtual annual meeting of the American Academy of Dermatology.
He recommended alternating between a less-intensive maintenance therapy regimen in the winter months and an acute care regimen in the sunnier summer months. But . And that is largely a matter of location.
Location, location, location
Melasma has a distinctive symmetric bilateral distribution: “Melasma likes the central area of the forehead, whereas the lateral areas of the forehead are more involved in lichen planus pigmentosus. Melanoma likes the area above the eyebrow or under the eyebrow. However, it does not go below the superior orbital rim or above the inferior orbital rim,”said Dr. Pandya, a dermatologist at the Palo Alto Medical Foundation in Sunnyvale, Calif., who is also on the faculty at the University of Texas Southwestern Medical Center, Dallas.
Melasma is common on the bridge of the nose, but usually not along the nasolabial fold, where hyperpigmentation is much more likely to be due to seborrheic dermatitis or drug-induced hyperpigmentation. Melasma doesn’t affect the tip of the nose; that’s more likely a sign of sarcoidosis or drug-induced hyperpigmentation. Melasma is common on the zygomatic prominence, while acanthosis nigricans favors the concave area below the zygomatic prominence. And melasma stays above the mandible; pigmentation below the mandible is more suggestive of poikiloderma of Civatte. Lentigines are scattered broadly across sun-exposed areas of the face. They also tend to be less symmetrical than melasma, the dermatologist continued.
Acute treatment
Dr. Pandya’s acute treatment algorithm begins with topical 4% hydroquinone in patients who’ve never been on it before. A response to the drug, which blocks the tyrosine-to-melanin pathway, takes 4-6 weeks, with maximum effect not seen until 3-6 months or longer. Bluish-grey ochronosis is a rare side effect at the 4% concentration but becomes more common at higher concentrations or when the drug is used in combination therapy.
“Hydroquinone is a workhorse, the oldest and most effective depigmenting agent,” he said.
If the patient hasn’t responded positively by 3 months, Dr. Pandya moves on to daily use of the triple-drug combination of fluocinolone acetonide 0.01%/hydroquinone 4%/tretinoin 0.05% known as Tri-Luma, a kinder, gentler descendant of the 45-year-old Kligman-Willis compounded formula comprised of 0.1% dexamethasone, 5% hydroquinone, and 0.1% tretinoin.
If Tri-Luma also proves ineffective, Dr. Pandya turns to oral tranexamic acid. This is off-label therapy for the drug, a plasmin inhibitor, which is approved for the treatment of menorrhagia. But oral tranexamic acid is widely used for treatment of melasma in East Asia, and Dr. Pandya and others have evaluated it in placebo-controlled clinical trials. His conclusion is that oral tranexamic acid appears to be safe and effective for treatment of melasma.
“The drug is not approved for melasma, it’s approved for menorrhagia, so every doctor has to decide how much risk they want to take. The evidence suggests 500 mg per day is a good dose,” he said.
The collective clinical trials experience with oral tranexamic acid for melasma shows a side effect profile consisting of mild GI upset, headache, and myalgia. While increased thromboembolic risk is a theoretic concern, it hasn’t been an issue in the published studies, which typically exclude patients with a history of thromboembolic disease from enrollment. Patient satisfaction with the oral agent is high, according to Dr. Pandya.
In one randomized, open-label, 40-patient study, oral tranexamic acid plus a triple-combination cream featuring fluocinolone 0.01%, hydroquinone 2%, and tretinoin 0.05%, applied once a day, was significantly more effective and faster-acting than the topical therapy alone. At 8 weeks, the dual-therapy group averaged an 88% improvement in the Melasma Activity and Severity Index (MASI) scores, compared with 55% with the topical therapy alone (Indian J Dermatol. Sep-Oct 2015;60[5]:520).
Cysteamine 5% cream, which is available over the counter as Cyspera but is pricey, showed promising efficacy in a 40-patient, randomized, double-blind trial (J Dermatolog Treat. 2018 Mar;29[2]:182-9). Dr. Pandya said he’s looking forward to seeing further studies.
Chemical peels can be used, but multiple treatment sessions using a superficial peeling agent are required, and even then “the efficacy is usually not profound,” according to Dr. Pandya. Together with two colleagues he recently published a comprehensive systematic review of 113 published studies of all treatments for melasma in nearly 7,000 patients (Am J Clin Dermatol. 2020 Apr;21(2):173-225).
Newer lasers with various pulse lengths, fluences, wave lengths, and treatment frequency show “some promise,” but there have also been published reports of hypopigmentation and rebound hyperpigmentation. The optimal laser regimen remains elusive, he said.
Maintenance therapy
Dr. Pandya usually switches from hydroquinone to a different topical tyrosinase inhibitor for maintenance therapy, such as kojic acid, arbutin, or azelaic acid, all available OTC in many formulations. Alternatively, he might drop down to 2% hydroquinone for the winter months. Another option is triple-combination cream applied two or three times per week. A topical formulation of tranexamic acid is available, but studies of this agent in patients with melasma have yielded mixed results.
“I don’t think topical tranexamic acid is going to harm the patient, but I don’t think the efficacy is as good as with oral tranexamic acid,” he said.
Slap that melasma in irons
A comprehensive melasma management plan requires year-round frequent daily application of a broad spectrum sunscreen. And since it’s now evident that visible-wavelength light can worsen melasma through mechanisms similar to UVA and UVB, which are long recognized as the major drivers of the hyperpigmentation disorder, serious consideration should be given to the use of a tinted broad-spectrum sunscreen or makeup containing more than 3% iron oxide, which blocks visible light. In contrast, zinc oxide does not, Dr. Pandya noted.
In one influential study, aminolevulinic acid was applied on the arms of 20 patients; two sunscreens were applied on areas where the ALA was applied, and on one area, no sunscreen was applied. The minimal phototoxic dose of visible blue light was doubled with application of a broad-spectrum sunscreen containing titanium dioxide, zinc oxide, and 0.2% iron oxide, compared with no sunscreen, but increased 21-fold using a sunscreen containing titanium dioxide, zinc oxide, and 3.2% iron oxide (Dermatol Surg. 2008 Nov;34[11]:1469-76).
Moreover, in a double-blind, randomized trial including 61 patients with melasma, all on background 4% hydroquinone, those assigned to a broad-spectrum sunscreen containing iron oxide had a 78% improvement in MASI scores at 8 weeks, compared with a 62% improvement with a broad-spectrum UV-only sunscreen. Both sunscreens had a sun protection factor of at least 50 (Photodermatol Photoimmunol Photomed. 2014 Feb;30[1]:35-42).
Numerous sunscreen and makeup products containing more than 3% iron oxide are available OTC in various tints. It’s a matter of finding a color that matches the patient’s skin.
Concern has been raised that exposure to the visible blue light emitted by computer screens and cell phones could worsen melasma. Dr. Pandya noted that reassurance on that score was recently provided by French investigators. They measured the intensity of visible light at the wavelengths emitted by computer screens and laptops and determined that it was 100- to 1,000-fold less than sunlight in the same spectrum. They also conducted a prospective, randomized, split-face trial in 12 melasma patients. One side of the face was exposed to the visible blue light at the same wavelengths emitted by device screens, but at far greater intensity. Blinded evaluators found no split-face difference in modified MASI scores.
“These results suggest that at a 20-cm distance, a maximized use of a high-intensity computer screen for 8 hours per day during a 5-day period does not worsen melasma lesions. Although it is very unlikely that similar exposure during a longer period would start to affect melasma lesions, such a possibility cannot be ruled out,” according to the investigators (J Am Acad Dermatol. 2019 Dec 27;S0190-9622(19)33324-9. doi: 10.1016/j.jaad.2019.12.047).
Dr. Pandya reported serving as a consultant to Incyte, Pfizer, Viela Bio, and Villaris.
FROM AAD 20
Novel oral drug improves sunlight tolerance in patients with erythropoietic protoporphyria
in a multicenter, phase 2, randomized trial, Kirstine Belongie, PhD, reported at the virtual annual meeting of the American Academy of Dermatology.
Based upon these favorable phase 2 results, a pivotal phase 3 clinical trial is now underway, added Dr. Belongie of Mitsubishi Tanabe Pharma Development America, in Jersey City, N.J., the study sponsor.
Erythropoietic protoporphyria (EPP) is the most common cutaneous porphyria as well as the most common porphyria of any type in children. It’s a rare but devastating disorder, with an incidence estimated at 1 in 75,000-200,000. It involves acute cutaneous photosensitivity to sunlight, which takes the form of incapacitating burning pain that lasts 3-7 days and is then followed by erythema and edema.
“These phototoxic reactions are extremely painful and cause the patients to have extreme fear of the sun. They do everything they can to avoid the sun. It leads to a highly impaired quality of life that’s restricted to the indoors,” she explained.
Current first-line therapy is sun avoidance, the use of zinc oxide sunblock, and protective clothing. It’s inadequate for most patients. “There is a tremendously high unmet medical need for treatment options, especially in the pediatric population,” Dr. Belongie observed.
Patients with EPP experience prodromal symptoms – tingling, itching, and burning – which serve as a signal to get out of the sun immediately. As demonstrated in the phase 2 trial, dersimelagon prolongs the time to onset of these prodromal symptoms by increasing melanin density in the skin in a dose-dependent fashion.
The phase 2 study included 102 EPP patients, with an average age 40 years, at 9 sites, who were randomized double blind to 16 weeks of dersimelagon at 100 mg or 300 mg once daily or placebo. The goal was to increase their pain-free sunlight exposure time.
The primary endpoint was change from baseline to week 16 in the average daily time to first prodromal symptoms. There was a 20-minute increase with placebo, a 74-minute gain with dersimelagon at 100 mg, and an 83-minute gain with dersimelagon at 300 mg. The difference between active medication and placebo became significant at week 6.
Treatment-emergent adverse events leading to study discontinuation occurred in one patient on dersimelagon at 100 mg/day, five patients on the higher dose, and none on placebo. Dr. Belangie said that the drug was well tolerated, with roughly 90% of adverse events being mild or moderate in severity. The frequency of adverse events was dose-related. The most common were headache, nausea, and diarrhea, occurring in 29%, 46%, and 23%, respectively, of patients on dersimelagon at 300 mg/day, compared with 18%, 12% and 12% of those on placebo.
Consistent with the drug’s mechanism of action, there was also a dose-related increase in hyperpigmentation side effects. New freckles were documented in 15% and 31% of patients on low- and high-dose dersimelagon, skin hyperpigmentation in 9% and 31%, and melanocytic nevi in 12% and 20%.
The ongoing double-blind, international, phase 3 trial includes not only patients with EPP, but also individuals with X-linked porphyria, which has similar clinical symptoms. The trial is double blind for the first 26 weeks, followed by another 26 weeks of open-label treatment.
EPP is an inherited metabolic disorder caused by a genetic mutation resulting in deficient activity of the enzyme ferrochelatase. This leads to accumulation of protoporphyrin IX in erythrocytes, skin, and the liver. The excess protoporphyrin is excreted in bile and can cause hepatobiliary disease. Indeed, up to 5% of patients with EPP develop liver failure.
In October 2019, the Food and Drug Administration approved afamelanotide (Scenesse), also a melanocortin-1 receptor agonist, to increase pain-free light exposure in adults with a history of phototoxic reactions EPP; this was the first FDA-approved treatment for helping EPP patients increase their exposure to light, according to the agency. It is administered as an implant every 2 months.
Dr. Belangie is employed by the study sponsor.
in a multicenter, phase 2, randomized trial, Kirstine Belongie, PhD, reported at the virtual annual meeting of the American Academy of Dermatology.
Based upon these favorable phase 2 results, a pivotal phase 3 clinical trial is now underway, added Dr. Belongie of Mitsubishi Tanabe Pharma Development America, in Jersey City, N.J., the study sponsor.
Erythropoietic protoporphyria (EPP) is the most common cutaneous porphyria as well as the most common porphyria of any type in children. It’s a rare but devastating disorder, with an incidence estimated at 1 in 75,000-200,000. It involves acute cutaneous photosensitivity to sunlight, which takes the form of incapacitating burning pain that lasts 3-7 days and is then followed by erythema and edema.
“These phototoxic reactions are extremely painful and cause the patients to have extreme fear of the sun. They do everything they can to avoid the sun. It leads to a highly impaired quality of life that’s restricted to the indoors,” she explained.
Current first-line therapy is sun avoidance, the use of zinc oxide sunblock, and protective clothing. It’s inadequate for most patients. “There is a tremendously high unmet medical need for treatment options, especially in the pediatric population,” Dr. Belongie observed.
Patients with EPP experience prodromal symptoms – tingling, itching, and burning – which serve as a signal to get out of the sun immediately. As demonstrated in the phase 2 trial, dersimelagon prolongs the time to onset of these prodromal symptoms by increasing melanin density in the skin in a dose-dependent fashion.
The phase 2 study included 102 EPP patients, with an average age 40 years, at 9 sites, who were randomized double blind to 16 weeks of dersimelagon at 100 mg or 300 mg once daily or placebo. The goal was to increase their pain-free sunlight exposure time.
The primary endpoint was change from baseline to week 16 in the average daily time to first prodromal symptoms. There was a 20-minute increase with placebo, a 74-minute gain with dersimelagon at 100 mg, and an 83-minute gain with dersimelagon at 300 mg. The difference between active medication and placebo became significant at week 6.
Treatment-emergent adverse events leading to study discontinuation occurred in one patient on dersimelagon at 100 mg/day, five patients on the higher dose, and none on placebo. Dr. Belangie said that the drug was well tolerated, with roughly 90% of adverse events being mild or moderate in severity. The frequency of adverse events was dose-related. The most common were headache, nausea, and diarrhea, occurring in 29%, 46%, and 23%, respectively, of patients on dersimelagon at 300 mg/day, compared with 18%, 12% and 12% of those on placebo.
Consistent with the drug’s mechanism of action, there was also a dose-related increase in hyperpigmentation side effects. New freckles were documented in 15% and 31% of patients on low- and high-dose dersimelagon, skin hyperpigmentation in 9% and 31%, and melanocytic nevi in 12% and 20%.
The ongoing double-blind, international, phase 3 trial includes not only patients with EPP, but also individuals with X-linked porphyria, which has similar clinical symptoms. The trial is double blind for the first 26 weeks, followed by another 26 weeks of open-label treatment.
EPP is an inherited metabolic disorder caused by a genetic mutation resulting in deficient activity of the enzyme ferrochelatase. This leads to accumulation of protoporphyrin IX in erythrocytes, skin, and the liver. The excess protoporphyrin is excreted in bile and can cause hepatobiliary disease. Indeed, up to 5% of patients with EPP develop liver failure.
In October 2019, the Food and Drug Administration approved afamelanotide (Scenesse), also a melanocortin-1 receptor agonist, to increase pain-free light exposure in adults with a history of phototoxic reactions EPP; this was the first FDA-approved treatment for helping EPP patients increase their exposure to light, according to the agency. It is administered as an implant every 2 months.
Dr. Belangie is employed by the study sponsor.
in a multicenter, phase 2, randomized trial, Kirstine Belongie, PhD, reported at the virtual annual meeting of the American Academy of Dermatology.
Based upon these favorable phase 2 results, a pivotal phase 3 clinical trial is now underway, added Dr. Belongie of Mitsubishi Tanabe Pharma Development America, in Jersey City, N.J., the study sponsor.
Erythropoietic protoporphyria (EPP) is the most common cutaneous porphyria as well as the most common porphyria of any type in children. It’s a rare but devastating disorder, with an incidence estimated at 1 in 75,000-200,000. It involves acute cutaneous photosensitivity to sunlight, which takes the form of incapacitating burning pain that lasts 3-7 days and is then followed by erythema and edema.
“These phototoxic reactions are extremely painful and cause the patients to have extreme fear of the sun. They do everything they can to avoid the sun. It leads to a highly impaired quality of life that’s restricted to the indoors,” she explained.
Current first-line therapy is sun avoidance, the use of zinc oxide sunblock, and protective clothing. It’s inadequate for most patients. “There is a tremendously high unmet medical need for treatment options, especially in the pediatric population,” Dr. Belongie observed.
Patients with EPP experience prodromal symptoms – tingling, itching, and burning – which serve as a signal to get out of the sun immediately. As demonstrated in the phase 2 trial, dersimelagon prolongs the time to onset of these prodromal symptoms by increasing melanin density in the skin in a dose-dependent fashion.
The phase 2 study included 102 EPP patients, with an average age 40 years, at 9 sites, who were randomized double blind to 16 weeks of dersimelagon at 100 mg or 300 mg once daily or placebo. The goal was to increase their pain-free sunlight exposure time.
The primary endpoint was change from baseline to week 16 in the average daily time to first prodromal symptoms. There was a 20-minute increase with placebo, a 74-minute gain with dersimelagon at 100 mg, and an 83-minute gain with dersimelagon at 300 mg. The difference between active medication and placebo became significant at week 6.
Treatment-emergent adverse events leading to study discontinuation occurred in one patient on dersimelagon at 100 mg/day, five patients on the higher dose, and none on placebo. Dr. Belangie said that the drug was well tolerated, with roughly 90% of adverse events being mild or moderate in severity. The frequency of adverse events was dose-related. The most common were headache, nausea, and diarrhea, occurring in 29%, 46%, and 23%, respectively, of patients on dersimelagon at 300 mg/day, compared with 18%, 12% and 12% of those on placebo.
Consistent with the drug’s mechanism of action, there was also a dose-related increase in hyperpigmentation side effects. New freckles were documented in 15% and 31% of patients on low- and high-dose dersimelagon, skin hyperpigmentation in 9% and 31%, and melanocytic nevi in 12% and 20%.
The ongoing double-blind, international, phase 3 trial includes not only patients with EPP, but also individuals with X-linked porphyria, which has similar clinical symptoms. The trial is double blind for the first 26 weeks, followed by another 26 weeks of open-label treatment.
EPP is an inherited metabolic disorder caused by a genetic mutation resulting in deficient activity of the enzyme ferrochelatase. This leads to accumulation of protoporphyrin IX in erythrocytes, skin, and the liver. The excess protoporphyrin is excreted in bile and can cause hepatobiliary disease. Indeed, up to 5% of patients with EPP develop liver failure.
In October 2019, the Food and Drug Administration approved afamelanotide (Scenesse), also a melanocortin-1 receptor agonist, to increase pain-free light exposure in adults with a history of phototoxic reactions EPP; this was the first FDA-approved treatment for helping EPP patients increase their exposure to light, according to the agency. It is administered as an implant every 2 months.
Dr. Belangie is employed by the study sponsor.
FROM AAD 2020
Novel botulinum toxin type A earns high marks for forehead lines
, Jeremy B. Green, MD, said at the virtual annual meeting of the American Academy of Dermatology.
When the study is completed, conclusions can be reached about the investigational product’s durability of benefit for treatment of dynamic forehead lines, which are notoriously challenging to treat. However, much is already known about the product’s durability for treatment of glabellar lines, as demonstrated in SAKURA 1 and SAKURA 2, two pivotal, phase 3, multicenter, randomized, double-blind, placebo-controlled trials totaling 609 patients.
In SAKURA 1 and 2, glabellar line severity didn’t return to baseline until a median of 28 and 26 weeks after injection. In contrast, as the study authors noted, the majority of patients whose glabellar lines are treated with the currently available botulinum toxin type A products are no longer responders by 3-4 months after treatment. Since surveys indicate most patients receive repeated injections every 5-6 months, that means they’re walking around with suboptimal results for the last 2-3 months before their next treatment session (Plast Reconstr Surg. 2020 Jan;145[1]:45-58).
This investigational neuromodulator, known as DaxibotulinumtoxinA for Injection, or DAXI, is composed of a highly purified 150-KDa botulinum toxin type A coupled with a proprietary stabilizing peptide. The product is formulated without human serum albumin and, once reconstituted, is stable at room temperature.
Dr. Green, a dermatologist in private practice in Coral Gables, Fla., reported on 61 participants in the phase 2 study, all with moderate or severe forehead lines and glabellar lines as assessed by both investigators and patients on structured scales. The patients’ glabellar lines were treated with 40 U of DAXI at baseline. Then 2 weeks later, their dynamic forehead lines were treated with either 12 U, 18 U, 24 U, or 30 U of DAXI. This sequential treatment recapitulates the approach widely used in clinical practice, he noted.
At baseline, two-thirds of patients had severe forehead lines at maximum eyebrow elevation as determined by Investigator Global Assessment – Forehead Wrinkle Severity and Patient Forehead Wrinkle Severity. The other third of participants had moderate forehead lines.
The primary endpoint was the presence of no or mild forehead lines by investigator assessment 4 weeks after treatment. This was achieved in 86% of patients who received 12 U of DAXI, 87% who recieved 18 U, 94% who received 24 U, and 100% of those who received 30 U.
“There appears to be a dose-dependent response, but this hasn’t yet been statistically analyzed,” Dr. Green said.
By patient assessment, there were no or only mild forehead lines at 4 weeks in 57% of those who received the lowest dose of DAXI, with rates of 80%, 100%, and 93% in those who received 18 U, 24 U, and 30 U.
At week 4, 57% of patients who got 12 U of DAXI pronounced themselves “satisfied” or “very satisfied” with DAXI therapy, as did 73%, 100%, and 93% of those who got the higher doses.
The treatment-related adverse events consisted of a smattering of cases of edema, erythema, or headache, similar to what’s described in the product labeling of all the neuromodulators.
Revance Therapeutics has applied to the Food and Drug Administration for marketing approval of DAXI for the treatment of glabellar lines. A regulatory decision is expected in late November. The company is also developing DAXI for the treatment of variety of neurologic and musculoskeletal conditions, including poststroke upper limb spasticity.
In an interview, Dr. Green said he was favorably impressed with DAXI’s durability for amelioration of forehead lines in the patients he personally treated in the ongoing phase 2 study, although there was no head-to-head comparison with other neuromodulators in the trial. He’s not aware of any planned phase 3 trial aimed at obtaining a forehead line indication.
“Of course, all four of the neuromodulators currently approved in the U.S. have glabellar line indications, but all are also used off-label in other locations, so I would imagine that DAXI will be used similarly if and when it is FDA-approved,” the dermatologist added.
He reported serving as a paid investigator for Revance.
, Jeremy B. Green, MD, said at the virtual annual meeting of the American Academy of Dermatology.
When the study is completed, conclusions can be reached about the investigational product’s durability of benefit for treatment of dynamic forehead lines, which are notoriously challenging to treat. However, much is already known about the product’s durability for treatment of glabellar lines, as demonstrated in SAKURA 1 and SAKURA 2, two pivotal, phase 3, multicenter, randomized, double-blind, placebo-controlled trials totaling 609 patients.
In SAKURA 1 and 2, glabellar line severity didn’t return to baseline until a median of 28 and 26 weeks after injection. In contrast, as the study authors noted, the majority of patients whose glabellar lines are treated with the currently available botulinum toxin type A products are no longer responders by 3-4 months after treatment. Since surveys indicate most patients receive repeated injections every 5-6 months, that means they’re walking around with suboptimal results for the last 2-3 months before their next treatment session (Plast Reconstr Surg. 2020 Jan;145[1]:45-58).
This investigational neuromodulator, known as DaxibotulinumtoxinA for Injection, or DAXI, is composed of a highly purified 150-KDa botulinum toxin type A coupled with a proprietary stabilizing peptide. The product is formulated without human serum albumin and, once reconstituted, is stable at room temperature.
Dr. Green, a dermatologist in private practice in Coral Gables, Fla., reported on 61 participants in the phase 2 study, all with moderate or severe forehead lines and glabellar lines as assessed by both investigators and patients on structured scales. The patients’ glabellar lines were treated with 40 U of DAXI at baseline. Then 2 weeks later, their dynamic forehead lines were treated with either 12 U, 18 U, 24 U, or 30 U of DAXI. This sequential treatment recapitulates the approach widely used in clinical practice, he noted.
At baseline, two-thirds of patients had severe forehead lines at maximum eyebrow elevation as determined by Investigator Global Assessment – Forehead Wrinkle Severity and Patient Forehead Wrinkle Severity. The other third of participants had moderate forehead lines.
The primary endpoint was the presence of no or mild forehead lines by investigator assessment 4 weeks after treatment. This was achieved in 86% of patients who received 12 U of DAXI, 87% who recieved 18 U, 94% who received 24 U, and 100% of those who received 30 U.
“There appears to be a dose-dependent response, but this hasn’t yet been statistically analyzed,” Dr. Green said.
By patient assessment, there were no or only mild forehead lines at 4 weeks in 57% of those who received the lowest dose of DAXI, with rates of 80%, 100%, and 93% in those who received 18 U, 24 U, and 30 U.
At week 4, 57% of patients who got 12 U of DAXI pronounced themselves “satisfied” or “very satisfied” with DAXI therapy, as did 73%, 100%, and 93% of those who got the higher doses.
The treatment-related adverse events consisted of a smattering of cases of edema, erythema, or headache, similar to what’s described in the product labeling of all the neuromodulators.
Revance Therapeutics has applied to the Food and Drug Administration for marketing approval of DAXI for the treatment of glabellar lines. A regulatory decision is expected in late November. The company is also developing DAXI for the treatment of variety of neurologic and musculoskeletal conditions, including poststroke upper limb spasticity.
In an interview, Dr. Green said he was favorably impressed with DAXI’s durability for amelioration of forehead lines in the patients he personally treated in the ongoing phase 2 study, although there was no head-to-head comparison with other neuromodulators in the trial. He’s not aware of any planned phase 3 trial aimed at obtaining a forehead line indication.
“Of course, all four of the neuromodulators currently approved in the U.S. have glabellar line indications, but all are also used off-label in other locations, so I would imagine that DAXI will be used similarly if and when it is FDA-approved,” the dermatologist added.
He reported serving as a paid investigator for Revance.
, Jeremy B. Green, MD, said at the virtual annual meeting of the American Academy of Dermatology.
When the study is completed, conclusions can be reached about the investigational product’s durability of benefit for treatment of dynamic forehead lines, which are notoriously challenging to treat. However, much is already known about the product’s durability for treatment of glabellar lines, as demonstrated in SAKURA 1 and SAKURA 2, two pivotal, phase 3, multicenter, randomized, double-blind, placebo-controlled trials totaling 609 patients.
In SAKURA 1 and 2, glabellar line severity didn’t return to baseline until a median of 28 and 26 weeks after injection. In contrast, as the study authors noted, the majority of patients whose glabellar lines are treated with the currently available botulinum toxin type A products are no longer responders by 3-4 months after treatment. Since surveys indicate most patients receive repeated injections every 5-6 months, that means they’re walking around with suboptimal results for the last 2-3 months before their next treatment session (Plast Reconstr Surg. 2020 Jan;145[1]:45-58).
This investigational neuromodulator, known as DaxibotulinumtoxinA for Injection, or DAXI, is composed of a highly purified 150-KDa botulinum toxin type A coupled with a proprietary stabilizing peptide. The product is formulated without human serum albumin and, once reconstituted, is stable at room temperature.
Dr. Green, a dermatologist in private practice in Coral Gables, Fla., reported on 61 participants in the phase 2 study, all with moderate or severe forehead lines and glabellar lines as assessed by both investigators and patients on structured scales. The patients’ glabellar lines were treated with 40 U of DAXI at baseline. Then 2 weeks later, their dynamic forehead lines were treated with either 12 U, 18 U, 24 U, or 30 U of DAXI. This sequential treatment recapitulates the approach widely used in clinical practice, he noted.
At baseline, two-thirds of patients had severe forehead lines at maximum eyebrow elevation as determined by Investigator Global Assessment – Forehead Wrinkle Severity and Patient Forehead Wrinkle Severity. The other third of participants had moderate forehead lines.
The primary endpoint was the presence of no or mild forehead lines by investigator assessment 4 weeks after treatment. This was achieved in 86% of patients who received 12 U of DAXI, 87% who recieved 18 U, 94% who received 24 U, and 100% of those who received 30 U.
“There appears to be a dose-dependent response, but this hasn’t yet been statistically analyzed,” Dr. Green said.
By patient assessment, there were no or only mild forehead lines at 4 weeks in 57% of those who received the lowest dose of DAXI, with rates of 80%, 100%, and 93% in those who received 18 U, 24 U, and 30 U.
At week 4, 57% of patients who got 12 U of DAXI pronounced themselves “satisfied” or “very satisfied” with DAXI therapy, as did 73%, 100%, and 93% of those who got the higher doses.
The treatment-related adverse events consisted of a smattering of cases of edema, erythema, or headache, similar to what’s described in the product labeling of all the neuromodulators.
Revance Therapeutics has applied to the Food and Drug Administration for marketing approval of DAXI for the treatment of glabellar lines. A regulatory decision is expected in late November. The company is also developing DAXI for the treatment of variety of neurologic and musculoskeletal conditions, including poststroke upper limb spasticity.
In an interview, Dr. Green said he was favorably impressed with DAXI’s durability for amelioration of forehead lines in the patients he personally treated in the ongoing phase 2 study, although there was no head-to-head comparison with other neuromodulators in the trial. He’s not aware of any planned phase 3 trial aimed at obtaining a forehead line indication.
“Of course, all four of the neuromodulators currently approved in the U.S. have glabellar line indications, but all are also used off-label in other locations, so I would imagine that DAXI will be used similarly if and when it is FDA-approved,” the dermatologist added.
He reported serving as a paid investigator for Revance.
FROM AAD 20
Beyond PASI 100: striving for molecular clearance
All PASI 100 responses to psoriasis therapy are not the same, Andrew Blauvelt, MD, declared at the virtual annual meeting of the American Academy of Dermatology.
He presented a first-of-its-kind study that potentially opens the door to a new, more rigorous standard for treatment success in psoriasis: Not simply cleared lesional skin as captured by a Psoriasis Area and Severity Index (PASI) 100 response, but also clearance of residual psoriasis signs and symptoms – as well as what he termed “molecular clearance.”
“We’ve found that clearing skin with drugs utilizing different mechanisms of action may lead to differential consequences for our patients,” observed Dr. Blauvelt, a dermatologist and clinical trialist who is president of the Oregon Medical Research Center, Portland.
A PASI 100 response, traditionally considered an elusive goal for the great majority of patients with severe psoriasis, can now often be achieved using today’s top-tier, high-performance biologics. But Dr. Blauvelt and his coinvestigators are interested in pushing even beyond PASI 100 to a new frontier of therapeutic benefit.
He presented a secondary analysis of the previously reported VOYAGE 1 and 2 head-to-head randomized trials of guselkumab (Tremfya) versus adalimumab (Humira) for treatment of moderate to severe psoriasis. This new analysis, which focused exclusively on PASI 100 responders by week 24, demonstrated that patients with a PASI 100 response to guselkumab, an interleukin (IL)-23 inhibitor, had significantly fewer persistent symptoms and signs of psoriasis than those whose skin clearance was attained using adalimumab, a tumor necrosis factor (TNF) inhibitor.
Moreover,
The analysis included 16 participants in the VOYAGE trials who achieved PASI 100 at week 24 on guselkumab and 5 who did so on adalimumab. At baseline and again at week 24, these individuals completed the Psoriasis Symptoms and Signs Diary (PSSD). Also, biopsies of lesional and nonlesional skin were obtained at baseline and of cleared lesional skin at week 24 for transcriptomic microarray analysis of the expression of many thousands of genes.
Persistent psoriasis symptoms despite cleared skin
The PSSD involves patient ratings of various psoriasis symptoms and signs. Total scores can range from 0 (symptom- and sign-free) up to 100. At week 24, a significantly higher proportion of guselkumab-treated PASI 100 responders had a total PSSD score of zero: 55%, versus 43% in the adalimumab group. This was consistently true across the board for each of the individual signs and symptoms assessed. For example, 61% of the guselkumab group gave themselves a zero for itch, as did 50% of the adalimumab group. Sixty-four percent on guselkumab and 52% on adalimumab reported being free of redness. And 78% of the guselkumab group reported being pain-free, compared with 69% with adalimumab, Dr. Blauvelt reported.
Gene expression analysis
At baseline, more than 2,300 dysregulated genes were identified in lesional skin while functioning normally in nonlesional skin. The great majority of these initially dysregulated genes became normalized in cleared lesional skin in PASI 100 responders at week 24. However, 25 of the genes remained dysregulated in cleared lesional skin, meaning they displayed less than 75% of normal function. Ten of these 25 genes with dysregulated expression at follow-up showed abnormal function in patients with residual symptoms despite cleared skin, but they functioned normally in those without persistent symptoms. This raises the possibility that the residual symptoms of psoriasis were attributable to the abnormal gene functioning, according to Dr. Blauvelt.
Of note, 9 of the 10 dysregulated genes in cleared lesional skin of patients with residual symptoms were present in the adalimumab group; these included two genes localized to the epidermal differentiation complex as well as the psoriasis-specific proline-rich 9 gene known as PRR9, which is induced by IL-17A. In contrast, only four genes, none of which were localized to the epidermal differentiation complex, were insufficiently normalized in the cleared lesional skin of guselkumab-treated PASI-100 responders.
“Nothing like this analysis has ever been done before,” the dermatologist observed. “It’s a pilot study. Perhaps with more data like this, we’ll be using this type of information in clinical practice to go beyond clearing patients’ skin.”
Dr. Blauvelt reported serving as a scientific advisor to and paid clinical investigator for Janssen, which sponsored the study, as well as for roughly two dozen other pharmaceutical companies.
All PASI 100 responses to psoriasis therapy are not the same, Andrew Blauvelt, MD, declared at the virtual annual meeting of the American Academy of Dermatology.
He presented a first-of-its-kind study that potentially opens the door to a new, more rigorous standard for treatment success in psoriasis: Not simply cleared lesional skin as captured by a Psoriasis Area and Severity Index (PASI) 100 response, but also clearance of residual psoriasis signs and symptoms – as well as what he termed “molecular clearance.”
“We’ve found that clearing skin with drugs utilizing different mechanisms of action may lead to differential consequences for our patients,” observed Dr. Blauvelt, a dermatologist and clinical trialist who is president of the Oregon Medical Research Center, Portland.
A PASI 100 response, traditionally considered an elusive goal for the great majority of patients with severe psoriasis, can now often be achieved using today’s top-tier, high-performance biologics. But Dr. Blauvelt and his coinvestigators are interested in pushing even beyond PASI 100 to a new frontier of therapeutic benefit.
He presented a secondary analysis of the previously reported VOYAGE 1 and 2 head-to-head randomized trials of guselkumab (Tremfya) versus adalimumab (Humira) for treatment of moderate to severe psoriasis. This new analysis, which focused exclusively on PASI 100 responders by week 24, demonstrated that patients with a PASI 100 response to guselkumab, an interleukin (IL)-23 inhibitor, had significantly fewer persistent symptoms and signs of psoriasis than those whose skin clearance was attained using adalimumab, a tumor necrosis factor (TNF) inhibitor.
Moreover,
The analysis included 16 participants in the VOYAGE trials who achieved PASI 100 at week 24 on guselkumab and 5 who did so on adalimumab. At baseline and again at week 24, these individuals completed the Psoriasis Symptoms and Signs Diary (PSSD). Also, biopsies of lesional and nonlesional skin were obtained at baseline and of cleared lesional skin at week 24 for transcriptomic microarray analysis of the expression of many thousands of genes.
Persistent psoriasis symptoms despite cleared skin
The PSSD involves patient ratings of various psoriasis symptoms and signs. Total scores can range from 0 (symptom- and sign-free) up to 100. At week 24, a significantly higher proportion of guselkumab-treated PASI 100 responders had a total PSSD score of zero: 55%, versus 43% in the adalimumab group. This was consistently true across the board for each of the individual signs and symptoms assessed. For example, 61% of the guselkumab group gave themselves a zero for itch, as did 50% of the adalimumab group. Sixty-four percent on guselkumab and 52% on adalimumab reported being free of redness. And 78% of the guselkumab group reported being pain-free, compared with 69% with adalimumab, Dr. Blauvelt reported.
Gene expression analysis
At baseline, more than 2,300 dysregulated genes were identified in lesional skin while functioning normally in nonlesional skin. The great majority of these initially dysregulated genes became normalized in cleared lesional skin in PASI 100 responders at week 24. However, 25 of the genes remained dysregulated in cleared lesional skin, meaning they displayed less than 75% of normal function. Ten of these 25 genes with dysregulated expression at follow-up showed abnormal function in patients with residual symptoms despite cleared skin, but they functioned normally in those without persistent symptoms. This raises the possibility that the residual symptoms of psoriasis were attributable to the abnormal gene functioning, according to Dr. Blauvelt.
Of note, 9 of the 10 dysregulated genes in cleared lesional skin of patients with residual symptoms were present in the adalimumab group; these included two genes localized to the epidermal differentiation complex as well as the psoriasis-specific proline-rich 9 gene known as PRR9, which is induced by IL-17A. In contrast, only four genes, none of which were localized to the epidermal differentiation complex, were insufficiently normalized in the cleared lesional skin of guselkumab-treated PASI-100 responders.
“Nothing like this analysis has ever been done before,” the dermatologist observed. “It’s a pilot study. Perhaps with more data like this, we’ll be using this type of information in clinical practice to go beyond clearing patients’ skin.”
Dr. Blauvelt reported serving as a scientific advisor to and paid clinical investigator for Janssen, which sponsored the study, as well as for roughly two dozen other pharmaceutical companies.
All PASI 100 responses to psoriasis therapy are not the same, Andrew Blauvelt, MD, declared at the virtual annual meeting of the American Academy of Dermatology.
He presented a first-of-its-kind study that potentially opens the door to a new, more rigorous standard for treatment success in psoriasis: Not simply cleared lesional skin as captured by a Psoriasis Area and Severity Index (PASI) 100 response, but also clearance of residual psoriasis signs and symptoms – as well as what he termed “molecular clearance.”
“We’ve found that clearing skin with drugs utilizing different mechanisms of action may lead to differential consequences for our patients,” observed Dr. Blauvelt, a dermatologist and clinical trialist who is president of the Oregon Medical Research Center, Portland.
A PASI 100 response, traditionally considered an elusive goal for the great majority of patients with severe psoriasis, can now often be achieved using today’s top-tier, high-performance biologics. But Dr. Blauvelt and his coinvestigators are interested in pushing even beyond PASI 100 to a new frontier of therapeutic benefit.
He presented a secondary analysis of the previously reported VOYAGE 1 and 2 head-to-head randomized trials of guselkumab (Tremfya) versus adalimumab (Humira) for treatment of moderate to severe psoriasis. This new analysis, which focused exclusively on PASI 100 responders by week 24, demonstrated that patients with a PASI 100 response to guselkumab, an interleukin (IL)-23 inhibitor, had significantly fewer persistent symptoms and signs of psoriasis than those whose skin clearance was attained using adalimumab, a tumor necrosis factor (TNF) inhibitor.
Moreover,
The analysis included 16 participants in the VOYAGE trials who achieved PASI 100 at week 24 on guselkumab and 5 who did so on adalimumab. At baseline and again at week 24, these individuals completed the Psoriasis Symptoms and Signs Diary (PSSD). Also, biopsies of lesional and nonlesional skin were obtained at baseline and of cleared lesional skin at week 24 for transcriptomic microarray analysis of the expression of many thousands of genes.
Persistent psoriasis symptoms despite cleared skin
The PSSD involves patient ratings of various psoriasis symptoms and signs. Total scores can range from 0 (symptom- and sign-free) up to 100. At week 24, a significantly higher proportion of guselkumab-treated PASI 100 responders had a total PSSD score of zero: 55%, versus 43% in the adalimumab group. This was consistently true across the board for each of the individual signs and symptoms assessed. For example, 61% of the guselkumab group gave themselves a zero for itch, as did 50% of the adalimumab group. Sixty-four percent on guselkumab and 52% on adalimumab reported being free of redness. And 78% of the guselkumab group reported being pain-free, compared with 69% with adalimumab, Dr. Blauvelt reported.
Gene expression analysis
At baseline, more than 2,300 dysregulated genes were identified in lesional skin while functioning normally in nonlesional skin. The great majority of these initially dysregulated genes became normalized in cleared lesional skin in PASI 100 responders at week 24. However, 25 of the genes remained dysregulated in cleared lesional skin, meaning they displayed less than 75% of normal function. Ten of these 25 genes with dysregulated expression at follow-up showed abnormal function in patients with residual symptoms despite cleared skin, but they functioned normally in those without persistent symptoms. This raises the possibility that the residual symptoms of psoriasis were attributable to the abnormal gene functioning, according to Dr. Blauvelt.
Of note, 9 of the 10 dysregulated genes in cleared lesional skin of patients with residual symptoms were present in the adalimumab group; these included two genes localized to the epidermal differentiation complex as well as the psoriasis-specific proline-rich 9 gene known as PRR9, which is induced by IL-17A. In contrast, only four genes, none of which were localized to the epidermal differentiation complex, were insufficiently normalized in the cleared lesional skin of guselkumab-treated PASI-100 responders.
“Nothing like this analysis has ever been done before,” the dermatologist observed. “It’s a pilot study. Perhaps with more data like this, we’ll be using this type of information in clinical practice to go beyond clearing patients’ skin.”
Dr. Blauvelt reported serving as a scientific advisor to and paid clinical investigator for Janssen, which sponsored the study, as well as for roughly two dozen other pharmaceutical companies.
FROM AAD 20
New topicals for excessive sweating are in sight
Safe and effective of novel agents presented at the virtual annual meeting of the American Academy of Dermatology.
Both investigational topical anticholinergic agents – 5% sofpironium bromide (SPB) gel and 1% glycopyrronium bromide (GPB) cream – met all of the efficacy and safety endpoints required by the Food and Drug Administration.
Primary axillary hyperhidrosis, or symmetrical bilateral excessive armpit sweating, has a prevalence worldwide of 1%-16%, with 5%-6% the most frequently cited numbers. The condition has a strong adverse impact on quality of life. Primary axillary hyperhidrosis is not caused by a disorder of the sweat glands; rather, it’s actually a dysregulation of the autonomic nervous system leading to disproportionate sweating, explained Christoph Abels, MD, PhD, medical director at Dr. August Wolff in Bielefeld, Germany.
“What’s surprising is that more than 50% of patients do not receive appropriate treatment, very likely due to lack of awareness or embarrassment,” he added.
Also, many patients are put off by the systemic side effects of the oral anticholinergic agents, which are the current off-label treatment mainstay for patients with moderate or severe disease, according to Tomoko Fujimoto, MD, PhD, director of Ikebukuro Nishiguchi Fukurou Dermatology, near Tokyo.
Sofpironium bromide gel
Dr. Fujimoto presented the results of a phase 3, double-blind, multicenter, 6-week, vehicle-controlled clinical trial conducted in 281 Japanese patients with moderate to severe primary axillary hyperhidrosis as defined by a baseline score of 3 or 4 on the 4-point Hyperhidrosis Disease Severity Scale (HDSS). Participants were randomized to self-application of 5% SPB gel or its vehicle once daily before bedtime.
Sofpironium bromide blocks the cholinergic response mediated by the M3 muscarinic receptor subtype expressed on eccrine sweat glands, thereby inhibiting sweating. The drug then undergoes breakdown into an inactive metabolite after reaching the blood.
An important aspect of both SPB gel and GPB cream is that these agents are rolled onto the axillae using a dedicated applicator. Patients never touch the medications with their hands, thus avoiding accidental exposure to the mucous membranes. This largely prevents problems with mydriasis and blurred vision as anticholinergic side effects, which has been an issue with glycopyrronium tosylate topical cloth wipes (Qbrexza), the first FDA-approved treatment for primary axillary hyperhidrosis.
The primary endpoint in the Japanese study was at least a 1-point improvement on the HDSS plus at least a 50% reduction in gravimetric sweat production between baseline and week 6. This composite outcome was achieved in 53.9% of patients in the active treatment arm, compared with 36.4% of controls.
The secondary endpoint consisting of a week-6 HDSS score of 1 or 2 – that is, underarm sweating that’s either never noticeable or is tolerable – occurred in 60.3% of the sofpironium bromide group and 47.9% of controls, a between-group difference that achieved statistical significance by week 2, when the rates were 46.8% and 28.2%.
The reduction in total gravimetric weight of axillary sweat from a mean baseline of 227 mg collected over 5 minutes was also significantly greater in the SPB group: a decrease of 157.6 mg, compared with 127.6 mg in controls; a between-group difference that also was significant by week 2. The mean Dermatology Life Quality Index score dropped by 6.8 points in the active-treatment arm from a baseline of 11.3, a significant improvement over the mean 4.5-point drop in controls.
A new 5-point measure of subjective symptoms of primary axillary hyperhidrosis – the Hyperhidrosis Disease Severity Measure–Axilla (HDSM-Ax) – improved by 1.41 points in the SPB group, significantly better than the 0.93 points in vehicle-treated controls. About 48% of patients on SBP experienced at least a 1.5-point reduction on the HDSM-Ax, compared with 26% of controls.
Regarding safety, there was a 2% incidence of application-site itch or scale in the SBP group. Anticholinergic side effects consisted of a single case of mydriasis, another of constipation, and two complaints of thirst, all mild, none resulting in treatment discontinuation. There were no reports of headache or blurred vision.
“These results indicate that the safety risks of sofpironium bromide can be considered small and controllable,” Dr. Fujimoto said. “Moreover, sofpironium bromide is a topical agent that patients can use by themselves, so it is highly convenient, unlike, say, botulinum toxin type A injections.”
Glycopyrronium bromide cream
Following on the heels of a recently published dose-ranging study (Br J Dermatol. 2020 Jan;182[1]:229-231), Dr. Abels presented the 4-week outcomes of a phase 3a, double-blind, randomized, five-country trial of once-daily 1% GPB cream or placebo in 171 patients with moderate or severe primary axillary hyperhidrosis. A phase 3b, open-label, 72-week, long-term safety trial is ongoing in 516 patients.
The primary endpoint of the 4-week trial was the reduction in gravimetric sweat production from day 1 to day 29. A reduction of 50% or more was documented in 57.5% of the patients on GBP and 34.5% of controls. A 75% or greater reduction occurred in 32.2% of the active-treatment group and 16.7% of those on placebo. And a decrease of at least 90% was seen in 23% of patients on topical GBP, compared with 9.5% of controls. All these between-group differences were significant.
The FDA now requires a quality of life measurement as a coprimary endpoint in phase 3 hyperhidrosis studies, and the phase 3 GBP trial also served as the successful validation study for a new patient-reported quality of life instrument designed specifically for this purpose. The new tool, known as the Hyperhydrosis Quality of Life questionnaire (HidroQol), proved much more sensitive than the HDSS or DLQI for evaluating clinical improvement in response to treatment (Br J Dermatol. 2020 Jun 8. doi: 10.1111/bjd.19300).
Initial results from the long-term phase 3b safety study should be available this fall on the first 100 patients followed on topical GBP for 1 year and for 300 followed for 6 months, Dr. Abels said.
Dr. Fujimoto reported serving as a paid consultant to and speaker for Kaken Pharmaceutical, which is developing SBP gel with Brickell Biotech. Dr. Abels is an employee of the company that is developing GPB cream.
Safe and effective of novel agents presented at the virtual annual meeting of the American Academy of Dermatology.
Both investigational topical anticholinergic agents – 5% sofpironium bromide (SPB) gel and 1% glycopyrronium bromide (GPB) cream – met all of the efficacy and safety endpoints required by the Food and Drug Administration.
Primary axillary hyperhidrosis, or symmetrical bilateral excessive armpit sweating, has a prevalence worldwide of 1%-16%, with 5%-6% the most frequently cited numbers. The condition has a strong adverse impact on quality of life. Primary axillary hyperhidrosis is not caused by a disorder of the sweat glands; rather, it’s actually a dysregulation of the autonomic nervous system leading to disproportionate sweating, explained Christoph Abels, MD, PhD, medical director at Dr. August Wolff in Bielefeld, Germany.
“What’s surprising is that more than 50% of patients do not receive appropriate treatment, very likely due to lack of awareness or embarrassment,” he added.
Also, many patients are put off by the systemic side effects of the oral anticholinergic agents, which are the current off-label treatment mainstay for patients with moderate or severe disease, according to Tomoko Fujimoto, MD, PhD, director of Ikebukuro Nishiguchi Fukurou Dermatology, near Tokyo.
Sofpironium bromide gel
Dr. Fujimoto presented the results of a phase 3, double-blind, multicenter, 6-week, vehicle-controlled clinical trial conducted in 281 Japanese patients with moderate to severe primary axillary hyperhidrosis as defined by a baseline score of 3 or 4 on the 4-point Hyperhidrosis Disease Severity Scale (HDSS). Participants were randomized to self-application of 5% SPB gel or its vehicle once daily before bedtime.
Sofpironium bromide blocks the cholinergic response mediated by the M3 muscarinic receptor subtype expressed on eccrine sweat glands, thereby inhibiting sweating. The drug then undergoes breakdown into an inactive metabolite after reaching the blood.
An important aspect of both SPB gel and GPB cream is that these agents are rolled onto the axillae using a dedicated applicator. Patients never touch the medications with their hands, thus avoiding accidental exposure to the mucous membranes. This largely prevents problems with mydriasis and blurred vision as anticholinergic side effects, which has been an issue with glycopyrronium tosylate topical cloth wipes (Qbrexza), the first FDA-approved treatment for primary axillary hyperhidrosis.
The primary endpoint in the Japanese study was at least a 1-point improvement on the HDSS plus at least a 50% reduction in gravimetric sweat production between baseline and week 6. This composite outcome was achieved in 53.9% of patients in the active treatment arm, compared with 36.4% of controls.
The secondary endpoint consisting of a week-6 HDSS score of 1 or 2 – that is, underarm sweating that’s either never noticeable or is tolerable – occurred in 60.3% of the sofpironium bromide group and 47.9% of controls, a between-group difference that achieved statistical significance by week 2, when the rates were 46.8% and 28.2%.
The reduction in total gravimetric weight of axillary sweat from a mean baseline of 227 mg collected over 5 minutes was also significantly greater in the SPB group: a decrease of 157.6 mg, compared with 127.6 mg in controls; a between-group difference that also was significant by week 2. The mean Dermatology Life Quality Index score dropped by 6.8 points in the active-treatment arm from a baseline of 11.3, a significant improvement over the mean 4.5-point drop in controls.
A new 5-point measure of subjective symptoms of primary axillary hyperhidrosis – the Hyperhidrosis Disease Severity Measure–Axilla (HDSM-Ax) – improved by 1.41 points in the SPB group, significantly better than the 0.93 points in vehicle-treated controls. About 48% of patients on SBP experienced at least a 1.5-point reduction on the HDSM-Ax, compared with 26% of controls.
Regarding safety, there was a 2% incidence of application-site itch or scale in the SBP group. Anticholinergic side effects consisted of a single case of mydriasis, another of constipation, and two complaints of thirst, all mild, none resulting in treatment discontinuation. There were no reports of headache or blurred vision.
“These results indicate that the safety risks of sofpironium bromide can be considered small and controllable,” Dr. Fujimoto said. “Moreover, sofpironium bromide is a topical agent that patients can use by themselves, so it is highly convenient, unlike, say, botulinum toxin type A injections.”
Glycopyrronium bromide cream
Following on the heels of a recently published dose-ranging study (Br J Dermatol. 2020 Jan;182[1]:229-231), Dr. Abels presented the 4-week outcomes of a phase 3a, double-blind, randomized, five-country trial of once-daily 1% GPB cream or placebo in 171 patients with moderate or severe primary axillary hyperhidrosis. A phase 3b, open-label, 72-week, long-term safety trial is ongoing in 516 patients.
The primary endpoint of the 4-week trial was the reduction in gravimetric sweat production from day 1 to day 29. A reduction of 50% or more was documented in 57.5% of the patients on GBP and 34.5% of controls. A 75% or greater reduction occurred in 32.2% of the active-treatment group and 16.7% of those on placebo. And a decrease of at least 90% was seen in 23% of patients on topical GBP, compared with 9.5% of controls. All these between-group differences were significant.
The FDA now requires a quality of life measurement as a coprimary endpoint in phase 3 hyperhidrosis studies, and the phase 3 GBP trial also served as the successful validation study for a new patient-reported quality of life instrument designed specifically for this purpose. The new tool, known as the Hyperhydrosis Quality of Life questionnaire (HidroQol), proved much more sensitive than the HDSS or DLQI for evaluating clinical improvement in response to treatment (Br J Dermatol. 2020 Jun 8. doi: 10.1111/bjd.19300).
Initial results from the long-term phase 3b safety study should be available this fall on the first 100 patients followed on topical GBP for 1 year and for 300 followed for 6 months, Dr. Abels said.
Dr. Fujimoto reported serving as a paid consultant to and speaker for Kaken Pharmaceutical, which is developing SBP gel with Brickell Biotech. Dr. Abels is an employee of the company that is developing GPB cream.
Safe and effective of novel agents presented at the virtual annual meeting of the American Academy of Dermatology.
Both investigational topical anticholinergic agents – 5% sofpironium bromide (SPB) gel and 1% glycopyrronium bromide (GPB) cream – met all of the efficacy and safety endpoints required by the Food and Drug Administration.
Primary axillary hyperhidrosis, or symmetrical bilateral excessive armpit sweating, has a prevalence worldwide of 1%-16%, with 5%-6% the most frequently cited numbers. The condition has a strong adverse impact on quality of life. Primary axillary hyperhidrosis is not caused by a disorder of the sweat glands; rather, it’s actually a dysregulation of the autonomic nervous system leading to disproportionate sweating, explained Christoph Abels, MD, PhD, medical director at Dr. August Wolff in Bielefeld, Germany.
“What’s surprising is that more than 50% of patients do not receive appropriate treatment, very likely due to lack of awareness or embarrassment,” he added.
Also, many patients are put off by the systemic side effects of the oral anticholinergic agents, which are the current off-label treatment mainstay for patients with moderate or severe disease, according to Tomoko Fujimoto, MD, PhD, director of Ikebukuro Nishiguchi Fukurou Dermatology, near Tokyo.
Sofpironium bromide gel
Dr. Fujimoto presented the results of a phase 3, double-blind, multicenter, 6-week, vehicle-controlled clinical trial conducted in 281 Japanese patients with moderate to severe primary axillary hyperhidrosis as defined by a baseline score of 3 or 4 on the 4-point Hyperhidrosis Disease Severity Scale (HDSS). Participants were randomized to self-application of 5% SPB gel or its vehicle once daily before bedtime.
Sofpironium bromide blocks the cholinergic response mediated by the M3 muscarinic receptor subtype expressed on eccrine sweat glands, thereby inhibiting sweating. The drug then undergoes breakdown into an inactive metabolite after reaching the blood.
An important aspect of both SPB gel and GPB cream is that these agents are rolled onto the axillae using a dedicated applicator. Patients never touch the medications with their hands, thus avoiding accidental exposure to the mucous membranes. This largely prevents problems with mydriasis and blurred vision as anticholinergic side effects, which has been an issue with glycopyrronium tosylate topical cloth wipes (Qbrexza), the first FDA-approved treatment for primary axillary hyperhidrosis.
The primary endpoint in the Japanese study was at least a 1-point improvement on the HDSS plus at least a 50% reduction in gravimetric sweat production between baseline and week 6. This composite outcome was achieved in 53.9% of patients in the active treatment arm, compared with 36.4% of controls.
The secondary endpoint consisting of a week-6 HDSS score of 1 or 2 – that is, underarm sweating that’s either never noticeable or is tolerable – occurred in 60.3% of the sofpironium bromide group and 47.9% of controls, a between-group difference that achieved statistical significance by week 2, when the rates were 46.8% and 28.2%.
The reduction in total gravimetric weight of axillary sweat from a mean baseline of 227 mg collected over 5 minutes was also significantly greater in the SPB group: a decrease of 157.6 mg, compared with 127.6 mg in controls; a between-group difference that also was significant by week 2. The mean Dermatology Life Quality Index score dropped by 6.8 points in the active-treatment arm from a baseline of 11.3, a significant improvement over the mean 4.5-point drop in controls.
A new 5-point measure of subjective symptoms of primary axillary hyperhidrosis – the Hyperhidrosis Disease Severity Measure–Axilla (HDSM-Ax) – improved by 1.41 points in the SPB group, significantly better than the 0.93 points in vehicle-treated controls. About 48% of patients on SBP experienced at least a 1.5-point reduction on the HDSM-Ax, compared with 26% of controls.
Regarding safety, there was a 2% incidence of application-site itch or scale in the SBP group. Anticholinergic side effects consisted of a single case of mydriasis, another of constipation, and two complaints of thirst, all mild, none resulting in treatment discontinuation. There were no reports of headache or blurred vision.
“These results indicate that the safety risks of sofpironium bromide can be considered small and controllable,” Dr. Fujimoto said. “Moreover, sofpironium bromide is a topical agent that patients can use by themselves, so it is highly convenient, unlike, say, botulinum toxin type A injections.”
Glycopyrronium bromide cream
Following on the heels of a recently published dose-ranging study (Br J Dermatol. 2020 Jan;182[1]:229-231), Dr. Abels presented the 4-week outcomes of a phase 3a, double-blind, randomized, five-country trial of once-daily 1% GPB cream or placebo in 171 patients with moderate or severe primary axillary hyperhidrosis. A phase 3b, open-label, 72-week, long-term safety trial is ongoing in 516 patients.
The primary endpoint of the 4-week trial was the reduction in gravimetric sweat production from day 1 to day 29. A reduction of 50% or more was documented in 57.5% of the patients on GBP and 34.5% of controls. A 75% or greater reduction occurred in 32.2% of the active-treatment group and 16.7% of those on placebo. And a decrease of at least 90% was seen in 23% of patients on topical GBP, compared with 9.5% of controls. All these between-group differences were significant.
The FDA now requires a quality of life measurement as a coprimary endpoint in phase 3 hyperhidrosis studies, and the phase 3 GBP trial also served as the successful validation study for a new patient-reported quality of life instrument designed specifically for this purpose. The new tool, known as the Hyperhydrosis Quality of Life questionnaire (HidroQol), proved much more sensitive than the HDSS or DLQI for evaluating clinical improvement in response to treatment (Br J Dermatol. 2020 Jun 8. doi: 10.1111/bjd.19300).
Initial results from the long-term phase 3b safety study should be available this fall on the first 100 patients followed on topical GBP for 1 year and for 300 followed for 6 months, Dr. Abels said.
Dr. Fujimoto reported serving as a paid consultant to and speaker for Kaken Pharmaceutical, which is developing SBP gel with Brickell Biotech. Dr. Abels is an employee of the company that is developing GPB cream.
FROM AAD 20
Americans getting more sunburns
, for reasons that are unclear, Nicole L. Bolick, MD, reported at the virtual annual meeting of the American Academy of Dermatology.
On the plus side, utilization of indoor tanning plunged in the United States during the same period, a statistic worth celebrating as a public health and legislative success, noted Dr. Bolick, who was at the Harvard T.H. Chan School of Public Health, Boston, when she conducted her study and is now at East Carolina University, Greenville, N.C.
More good news: Her analysis of data from 67,471 nationally representative participants in the Centers for Disease Control and Prevention’s National Health Information Survey for the years 2005, 2010, and 2015 also demonstrated that the public’s adoption of several key skin cancer prevention behaviors is on the rise, although she added that rates clearly remain suboptimal.
For example, the proportion of Americans who practice sun avoidance climbed from 31.7% in 2005 to 35.5% in 2010, and 36.8% in 2015 in a multivariate logistic regression analysis adjusted for demographics, alcohol use, location, smoking status, education level, health insurance, and family and personal history of skin cancer.
Similarly, the use of sunscreen always or most of the time when outdoors for more than 1 hour on a warm, sunny day rose from an adjusted 31.5% in 2005 to 33.1% in 2010 and to 34.3% in 2015.
Also, sun protective clothing – long pants, hats, and/or long-sleeved shirts – was utilized always or most of the time by 35.9% of respondents in 2005, 38.4% in 2010, and 37.2% in 2015.
In 2005, 19% of Americans reported having a lifetime history of a physician-performed full body skin examination. The prevalence of this secondary skin cancer prevention measure rose to 22.4% in 2010 and remained the same in 2015.
In the 2005 national survey, 14.1% of respondents reported engaging in indoor tanning within the past year. This figure dropped to 6.2% in 2010 and fell further to 4.1% in 2015.
A history of two or more sunburns within the past year was reported by 18.2% of subjects in 2005, by 21.1% in 2010, and by 19.9% in 2015. It’s unclear whether this unwelcome phenomenon is due to inadequate use of sun protection or increased awareness of the link between sun exposure and skin cancer, with a resultant increase in reporting of sunburns. The influence of climate change is another possible explanation worthy of further study, according to Dr. Bolick.
She reported having no financial conflicts regarding her study, conducted free of commercial support.
, for reasons that are unclear, Nicole L. Bolick, MD, reported at the virtual annual meeting of the American Academy of Dermatology.
On the plus side, utilization of indoor tanning plunged in the United States during the same period, a statistic worth celebrating as a public health and legislative success, noted Dr. Bolick, who was at the Harvard T.H. Chan School of Public Health, Boston, when she conducted her study and is now at East Carolina University, Greenville, N.C.
More good news: Her analysis of data from 67,471 nationally representative participants in the Centers for Disease Control and Prevention’s National Health Information Survey for the years 2005, 2010, and 2015 also demonstrated that the public’s adoption of several key skin cancer prevention behaviors is on the rise, although she added that rates clearly remain suboptimal.
For example, the proportion of Americans who practice sun avoidance climbed from 31.7% in 2005 to 35.5% in 2010, and 36.8% in 2015 in a multivariate logistic regression analysis adjusted for demographics, alcohol use, location, smoking status, education level, health insurance, and family and personal history of skin cancer.
Similarly, the use of sunscreen always or most of the time when outdoors for more than 1 hour on a warm, sunny day rose from an adjusted 31.5% in 2005 to 33.1% in 2010 and to 34.3% in 2015.
Also, sun protective clothing – long pants, hats, and/or long-sleeved shirts – was utilized always or most of the time by 35.9% of respondents in 2005, 38.4% in 2010, and 37.2% in 2015.
In 2005, 19% of Americans reported having a lifetime history of a physician-performed full body skin examination. The prevalence of this secondary skin cancer prevention measure rose to 22.4% in 2010 and remained the same in 2015.
In the 2005 national survey, 14.1% of respondents reported engaging in indoor tanning within the past year. This figure dropped to 6.2% in 2010 and fell further to 4.1% in 2015.
A history of two or more sunburns within the past year was reported by 18.2% of subjects in 2005, by 21.1% in 2010, and by 19.9% in 2015. It’s unclear whether this unwelcome phenomenon is due to inadequate use of sun protection or increased awareness of the link between sun exposure and skin cancer, with a resultant increase in reporting of sunburns. The influence of climate change is another possible explanation worthy of further study, according to Dr. Bolick.
She reported having no financial conflicts regarding her study, conducted free of commercial support.
, for reasons that are unclear, Nicole L. Bolick, MD, reported at the virtual annual meeting of the American Academy of Dermatology.
On the plus side, utilization of indoor tanning plunged in the United States during the same period, a statistic worth celebrating as a public health and legislative success, noted Dr. Bolick, who was at the Harvard T.H. Chan School of Public Health, Boston, when she conducted her study and is now at East Carolina University, Greenville, N.C.
More good news: Her analysis of data from 67,471 nationally representative participants in the Centers for Disease Control and Prevention’s National Health Information Survey for the years 2005, 2010, and 2015 also demonstrated that the public’s adoption of several key skin cancer prevention behaviors is on the rise, although she added that rates clearly remain suboptimal.
For example, the proportion of Americans who practice sun avoidance climbed from 31.7% in 2005 to 35.5% in 2010, and 36.8% in 2015 in a multivariate logistic regression analysis adjusted for demographics, alcohol use, location, smoking status, education level, health insurance, and family and personal history of skin cancer.
Similarly, the use of sunscreen always or most of the time when outdoors for more than 1 hour on a warm, sunny day rose from an adjusted 31.5% in 2005 to 33.1% in 2010 and to 34.3% in 2015.
Also, sun protective clothing – long pants, hats, and/or long-sleeved shirts – was utilized always or most of the time by 35.9% of respondents in 2005, 38.4% in 2010, and 37.2% in 2015.
In 2005, 19% of Americans reported having a lifetime history of a physician-performed full body skin examination. The prevalence of this secondary skin cancer prevention measure rose to 22.4% in 2010 and remained the same in 2015.
In the 2005 national survey, 14.1% of respondents reported engaging in indoor tanning within the past year. This figure dropped to 6.2% in 2010 and fell further to 4.1% in 2015.
A history of two or more sunburns within the past year was reported by 18.2% of subjects in 2005, by 21.1% in 2010, and by 19.9% in 2015. It’s unclear whether this unwelcome phenomenon is due to inadequate use of sun protection or increased awareness of the link between sun exposure and skin cancer, with a resultant increase in reporting of sunburns. The influence of climate change is another possible explanation worthy of further study, according to Dr. Bolick.
She reported having no financial conflicts regarding her study, conducted free of commercial support.
FROM AAD 20
Ixekizumab deemed effective for pityriasis rubra pilaris
Teri Greiling, MD, PhD, said at the virtual annual meeting of the American Academy of Dermatology.
The interleukin-17A inhibitor induced long-term remission of pityriasis rubra pilaris (PRP) in 4 of the 11 participants in her open-label, single-arm, 24-week clinical trial of ixekizumab (Taltz) at the Food and Drug Administration–approved dosing for psoriasis. Of 11 patients, 7 experienced at least a 50% reduction in signs and symptoms of the disease. Marked quality-of-life improvements occurred as well, reported Dr. Greiling, a dermatologist at Oregon Health & Science University, Portland.
PRP is a rare papulosquamous disorder that’s challenging to diagnosis and often difficult to treat. Indeed, there is no FDA-approved treatment. The disorder is characterized by widespread follicular keratotic plaques with scale and notable islands of sparing, often with an accompanying waxy yellow palmoplantar keratoderma with fissuring. There are adult- and childhood-onset forms of PRP, as well as sporadic and familial subtypes. Some cases are associated with variants in the CARD14 gene, known to also play a role in familial psoriasis.
Patients with PRP say the disorder has a major adverse impact on their quality of life. Itching and pain are often prominent features.
The 11 study participants, drawn from throughout the United States, were adults with a mean 12-year history of symptoms. All were required to have both clinical and biopsy evidence of PRP. Five had classic adult-onset PRP, five had atypical adult-onset PRP, and one had classic juvenile-onset PRP. All had moderate or severe disease as reflected in a Physician’s Global Assessment score of 3 or 4 on the 0-4 scale. Of the 11, 10 had previously received various systemic therapies for their PRP without success.
Since there is as yet no established PRP severity grading tool, Dr. Greiling applied the principles of the Psoriasis Area and Severity Index (PASI). Participants had a mean baseline PASI score of 24.6, a Dermatology Life Quality Index (DLQI) score of 18, and itch and pain scores of 7 and 6, respectively, on a self-rated 10-point scale.
The primary outcome in the study was change in PASI score at week 24, which was 4 weeks after the final dose of ixekizumab. The mean score improved from 24.8 at week 0 to 9.7 at week 24. Five patients achieved at least a 75% decrease in PASI score, or PASI 75 response, and 2 had a PASI 90 response. The DLQI improved from 18 to 3, and both itch and pain scores dropped to a median of 1. There was no association between response to treatment and PRP clinical subtype.
The four top responders – those with a PASI 89 or better response at week 24 – remained clear or almost clear at week 36, fully 16 weeks after their last dose of ixekizumab. Patients with an intermediate week 24 response – that is, a 50%-85% reduction in PASI score – all relapsed before week 36. The patient with the worst PASI score at both baseline and 24 weeks decided to continue on ixekizumab dosed every 2 weeks independent of the study, rather than at the FDA-approved dosing every 4 weeks for psoriasis, with a resultant drop to a PASI score of 8 at week 36.
To look at mechanism of benefit, Dr. Greiling used quantitative polymerase chain reaction to examine key cytokine expression in the epidermis and dermis. Not surprisingly, IL-17A expression was markedly reduced at both sites, suggesting the importance of the Th17 axis in the pathophysiology of PRP. In contrast, there was no significant change in IL-23 expression.
No serious or unexpected adverse events occurred in the 24-week study.
“In terms of ixekizumab, compared to other treatments, I definitely think it is more effective than any conventional therapies, such as topical steroids, methotrexate, or acitretin,” she said in an interview.
Asked about other biologics, Dr. Greiling said she hasn’t found tumor necrosis factor inhibitors very helpful in her patients with PRP. A formal trial of the IL-17A inhibitor secukinumab (Cosentyx) has been done elsewhere, and although the results haven’t yet been published, her understanding is that the efficacy was similar to her ixekizumab trial.
“I’ve had some of my ixekizumab patients switch to secukinumab, for insurance reasons, though, and had it not be quite as effective, although still helpful,” she said.
Dr. Greiling is now enrolling patients with PRP in a trial of the IL-23 inhibitor guselkumab (Tremfya). It’s her early impression that this may prove to be another therapeutic option.
“I have not yet used brodalumab [Siliq], but I wonder if it would also be helpful, since it seems to have a stronger blockade, working on the IL-17 receptor A,” she said.
She cited two pressing needs that would advance PRP research: the lack of standard criteria for disease diagnosis and the absence of PRP-specific disease measurement tools. “We’re trying to remedy that,” the dermatologist said.
Her study was funded by Eli Lilly. She reported receiving research funding from that company and Janssen.
Teri Greiling, MD, PhD, said at the virtual annual meeting of the American Academy of Dermatology.
The interleukin-17A inhibitor induced long-term remission of pityriasis rubra pilaris (PRP) in 4 of the 11 participants in her open-label, single-arm, 24-week clinical trial of ixekizumab (Taltz) at the Food and Drug Administration–approved dosing for psoriasis. Of 11 patients, 7 experienced at least a 50% reduction in signs and symptoms of the disease. Marked quality-of-life improvements occurred as well, reported Dr. Greiling, a dermatologist at Oregon Health & Science University, Portland.
PRP is a rare papulosquamous disorder that’s challenging to diagnosis and often difficult to treat. Indeed, there is no FDA-approved treatment. The disorder is characterized by widespread follicular keratotic plaques with scale and notable islands of sparing, often with an accompanying waxy yellow palmoplantar keratoderma with fissuring. There are adult- and childhood-onset forms of PRP, as well as sporadic and familial subtypes. Some cases are associated with variants in the CARD14 gene, known to also play a role in familial psoriasis.
Patients with PRP say the disorder has a major adverse impact on their quality of life. Itching and pain are often prominent features.
The 11 study participants, drawn from throughout the United States, were adults with a mean 12-year history of symptoms. All were required to have both clinical and biopsy evidence of PRP. Five had classic adult-onset PRP, five had atypical adult-onset PRP, and one had classic juvenile-onset PRP. All had moderate or severe disease as reflected in a Physician’s Global Assessment score of 3 or 4 on the 0-4 scale. Of the 11, 10 had previously received various systemic therapies for their PRP without success.
Since there is as yet no established PRP severity grading tool, Dr. Greiling applied the principles of the Psoriasis Area and Severity Index (PASI). Participants had a mean baseline PASI score of 24.6, a Dermatology Life Quality Index (DLQI) score of 18, and itch and pain scores of 7 and 6, respectively, on a self-rated 10-point scale.
The primary outcome in the study was change in PASI score at week 24, which was 4 weeks after the final dose of ixekizumab. The mean score improved from 24.8 at week 0 to 9.7 at week 24. Five patients achieved at least a 75% decrease in PASI score, or PASI 75 response, and 2 had a PASI 90 response. The DLQI improved from 18 to 3, and both itch and pain scores dropped to a median of 1. There was no association between response to treatment and PRP clinical subtype.
The four top responders – those with a PASI 89 or better response at week 24 – remained clear or almost clear at week 36, fully 16 weeks after their last dose of ixekizumab. Patients with an intermediate week 24 response – that is, a 50%-85% reduction in PASI score – all relapsed before week 36. The patient with the worst PASI score at both baseline and 24 weeks decided to continue on ixekizumab dosed every 2 weeks independent of the study, rather than at the FDA-approved dosing every 4 weeks for psoriasis, with a resultant drop to a PASI score of 8 at week 36.
To look at mechanism of benefit, Dr. Greiling used quantitative polymerase chain reaction to examine key cytokine expression in the epidermis and dermis. Not surprisingly, IL-17A expression was markedly reduced at both sites, suggesting the importance of the Th17 axis in the pathophysiology of PRP. In contrast, there was no significant change in IL-23 expression.
No serious or unexpected adverse events occurred in the 24-week study.
“In terms of ixekizumab, compared to other treatments, I definitely think it is more effective than any conventional therapies, such as topical steroids, methotrexate, or acitretin,” she said in an interview.
Asked about other biologics, Dr. Greiling said she hasn’t found tumor necrosis factor inhibitors very helpful in her patients with PRP. A formal trial of the IL-17A inhibitor secukinumab (Cosentyx) has been done elsewhere, and although the results haven’t yet been published, her understanding is that the efficacy was similar to her ixekizumab trial.
“I’ve had some of my ixekizumab patients switch to secukinumab, for insurance reasons, though, and had it not be quite as effective, although still helpful,” she said.
Dr. Greiling is now enrolling patients with PRP in a trial of the IL-23 inhibitor guselkumab (Tremfya). It’s her early impression that this may prove to be another therapeutic option.
“I have not yet used brodalumab [Siliq], but I wonder if it would also be helpful, since it seems to have a stronger blockade, working on the IL-17 receptor A,” she said.
She cited two pressing needs that would advance PRP research: the lack of standard criteria for disease diagnosis and the absence of PRP-specific disease measurement tools. “We’re trying to remedy that,” the dermatologist said.
Her study was funded by Eli Lilly. She reported receiving research funding from that company and Janssen.
Teri Greiling, MD, PhD, said at the virtual annual meeting of the American Academy of Dermatology.
The interleukin-17A inhibitor induced long-term remission of pityriasis rubra pilaris (PRP) in 4 of the 11 participants in her open-label, single-arm, 24-week clinical trial of ixekizumab (Taltz) at the Food and Drug Administration–approved dosing for psoriasis. Of 11 patients, 7 experienced at least a 50% reduction in signs and symptoms of the disease. Marked quality-of-life improvements occurred as well, reported Dr. Greiling, a dermatologist at Oregon Health & Science University, Portland.
PRP is a rare papulosquamous disorder that’s challenging to diagnosis and often difficult to treat. Indeed, there is no FDA-approved treatment. The disorder is characterized by widespread follicular keratotic plaques with scale and notable islands of sparing, often with an accompanying waxy yellow palmoplantar keratoderma with fissuring. There are adult- and childhood-onset forms of PRP, as well as sporadic and familial subtypes. Some cases are associated with variants in the CARD14 gene, known to also play a role in familial psoriasis.
Patients with PRP say the disorder has a major adverse impact on their quality of life. Itching and pain are often prominent features.
The 11 study participants, drawn from throughout the United States, were adults with a mean 12-year history of symptoms. All were required to have both clinical and biopsy evidence of PRP. Five had classic adult-onset PRP, five had atypical adult-onset PRP, and one had classic juvenile-onset PRP. All had moderate or severe disease as reflected in a Physician’s Global Assessment score of 3 or 4 on the 0-4 scale. Of the 11, 10 had previously received various systemic therapies for their PRP without success.
Since there is as yet no established PRP severity grading tool, Dr. Greiling applied the principles of the Psoriasis Area and Severity Index (PASI). Participants had a mean baseline PASI score of 24.6, a Dermatology Life Quality Index (DLQI) score of 18, and itch and pain scores of 7 and 6, respectively, on a self-rated 10-point scale.
The primary outcome in the study was change in PASI score at week 24, which was 4 weeks after the final dose of ixekizumab. The mean score improved from 24.8 at week 0 to 9.7 at week 24. Five patients achieved at least a 75% decrease in PASI score, or PASI 75 response, and 2 had a PASI 90 response. The DLQI improved from 18 to 3, and both itch and pain scores dropped to a median of 1. There was no association between response to treatment and PRP clinical subtype.
The four top responders – those with a PASI 89 or better response at week 24 – remained clear or almost clear at week 36, fully 16 weeks after their last dose of ixekizumab. Patients with an intermediate week 24 response – that is, a 50%-85% reduction in PASI score – all relapsed before week 36. The patient with the worst PASI score at both baseline and 24 weeks decided to continue on ixekizumab dosed every 2 weeks independent of the study, rather than at the FDA-approved dosing every 4 weeks for psoriasis, with a resultant drop to a PASI score of 8 at week 36.
To look at mechanism of benefit, Dr. Greiling used quantitative polymerase chain reaction to examine key cytokine expression in the epidermis and dermis. Not surprisingly, IL-17A expression was markedly reduced at both sites, suggesting the importance of the Th17 axis in the pathophysiology of PRP. In contrast, there was no significant change in IL-23 expression.
No serious or unexpected adverse events occurred in the 24-week study.
“In terms of ixekizumab, compared to other treatments, I definitely think it is more effective than any conventional therapies, such as topical steroids, methotrexate, or acitretin,” she said in an interview.
Asked about other biologics, Dr. Greiling said she hasn’t found tumor necrosis factor inhibitors very helpful in her patients with PRP. A formal trial of the IL-17A inhibitor secukinumab (Cosentyx) has been done elsewhere, and although the results haven’t yet been published, her understanding is that the efficacy was similar to her ixekizumab trial.
“I’ve had some of my ixekizumab patients switch to secukinumab, for insurance reasons, though, and had it not be quite as effective, although still helpful,” she said.
Dr. Greiling is now enrolling patients with PRP in a trial of the IL-23 inhibitor guselkumab (Tremfya). It’s her early impression that this may prove to be another therapeutic option.
“I have not yet used brodalumab [Siliq], but I wonder if it would also be helpful, since it seems to have a stronger blockade, working on the IL-17 receptor A,” she said.
She cited two pressing needs that would advance PRP research: the lack of standard criteria for disease diagnosis and the absence of PRP-specific disease measurement tools. “We’re trying to remedy that,” the dermatologist said.
Her study was funded by Eli Lilly. She reported receiving research funding from that company and Janssen.
FROM AAD 2020
IV gentamicin improves epidermolysis bullosa
In a pilot study, , Michelle Hao said at the virtual annual meeting of the American Academy of Dermatology.
Serial skin biopsies and immunofluorescent staining demonstrated the mechanism of benefit: The aminoglycoside promoted creation of new full-length functional collagen fibrils at the dermal-epidermal junction in affected patients, added Ms. Hao, a medical student at the University of Southern California, Los Angeles.
“Glycoside-mediated nonsense suppression therapy may provide a novel, low cost, and readily available treatment for RDEB [recessive dystrophic epidermolysis bullosa] patients harboring nonsense mutations,” she declared.
RDEB is a rare, incurable, life-threatening genetic skin disease which manifests as severe skin fragility and widespread blistering. The disease is caused by mutations in a gene coding for collagen type VII alpha 1 (COL7A1), the building block for the anchoring fibrils responsible for dermal-epidermal adherence. Roughly 30% of COL7A1 mutations are nonsense mutations, which result in truncated, nonfunctional collagen type VII.
Ms. Hao and her senior coinvestigators have previously shown that aminoglycoside antibiotics can override nonsense mutations to produce full-length, functioning protein. Indeed, they demonstrated that topical gentamicin in particular induces formation of new collagen type VII and improves wound closure in RDEB patients with nonsense mutations. However, RDEB skin lesions are so widespread that topical therapy becomes impractical. This was the impetus for the phase 1/2 clinical trial of IV gentamicin.
The open-label study included four patients with RDEB with nonsense mutations. All participants received IV gentamicin at 7.5 mg/kg/day for 2 weeks. Two of the four patients then got additional twice-weekly infusions at the same dose for another 3 months. Skin biopsies were obtained from two prospectively monitored open erosive wound sites and two intact skin sites at baseline and 1 and 3 months after treatment.
The primary endpoint was evidence of new collagen type VII at the dermal-epidermal junction post treatment. At baseline, patients averaged only 2% of the amount present in normal skin. One month post treatment, all four patients showed significant gains in expression of functioning collagen type VII, with levels 30%-130% of what’s present in normal skin. This effect proved durable 3 months post treatment.
At the same visits when biopsies were obtained, participants were assessed regarding wound closure, disease activity as measured using the validated Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI), and quality of life as reflected in Skindex-16 scores. All four patients showed improved wound closure at 1 and 3 months post treatment at the monitored sites, as well as better EBDASI and Skindex-16 Symptoms and Skindex-16 Emotion scores, Ms. Hao continued.
Safety assessments revealed no evidence of oto- or nephrotoxicity in the gentamicin-treated patients. And no one developed autoantibodies to collagen type VII in skin or sera in response to the aminoglycoside-induced creation of new collagen type VII.
Ms. Hao said preliminary analysis of the study data suggests that the more convenient schedule of twice-weekly IV gentamicin was as effective with regard to wound closure as daily infusion therapy.
She reported having no financial conflicts regarding the study, supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the EB Research Partnership, and the EB Research Foundation.
In a pilot study, , Michelle Hao said at the virtual annual meeting of the American Academy of Dermatology.
Serial skin biopsies and immunofluorescent staining demonstrated the mechanism of benefit: The aminoglycoside promoted creation of new full-length functional collagen fibrils at the dermal-epidermal junction in affected patients, added Ms. Hao, a medical student at the University of Southern California, Los Angeles.
“Glycoside-mediated nonsense suppression therapy may provide a novel, low cost, and readily available treatment for RDEB [recessive dystrophic epidermolysis bullosa] patients harboring nonsense mutations,” she declared.
RDEB is a rare, incurable, life-threatening genetic skin disease which manifests as severe skin fragility and widespread blistering. The disease is caused by mutations in a gene coding for collagen type VII alpha 1 (COL7A1), the building block for the anchoring fibrils responsible for dermal-epidermal adherence. Roughly 30% of COL7A1 mutations are nonsense mutations, which result in truncated, nonfunctional collagen type VII.
Ms. Hao and her senior coinvestigators have previously shown that aminoglycoside antibiotics can override nonsense mutations to produce full-length, functioning protein. Indeed, they demonstrated that topical gentamicin in particular induces formation of new collagen type VII and improves wound closure in RDEB patients with nonsense mutations. However, RDEB skin lesions are so widespread that topical therapy becomes impractical. This was the impetus for the phase 1/2 clinical trial of IV gentamicin.
The open-label study included four patients with RDEB with nonsense mutations. All participants received IV gentamicin at 7.5 mg/kg/day for 2 weeks. Two of the four patients then got additional twice-weekly infusions at the same dose for another 3 months. Skin biopsies were obtained from two prospectively monitored open erosive wound sites and two intact skin sites at baseline and 1 and 3 months after treatment.
The primary endpoint was evidence of new collagen type VII at the dermal-epidermal junction post treatment. At baseline, patients averaged only 2% of the amount present in normal skin. One month post treatment, all four patients showed significant gains in expression of functioning collagen type VII, with levels 30%-130% of what’s present in normal skin. This effect proved durable 3 months post treatment.
At the same visits when biopsies were obtained, participants were assessed regarding wound closure, disease activity as measured using the validated Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI), and quality of life as reflected in Skindex-16 scores. All four patients showed improved wound closure at 1 and 3 months post treatment at the monitored sites, as well as better EBDASI and Skindex-16 Symptoms and Skindex-16 Emotion scores, Ms. Hao continued.
Safety assessments revealed no evidence of oto- or nephrotoxicity in the gentamicin-treated patients. And no one developed autoantibodies to collagen type VII in skin or sera in response to the aminoglycoside-induced creation of new collagen type VII.
Ms. Hao said preliminary analysis of the study data suggests that the more convenient schedule of twice-weekly IV gentamicin was as effective with regard to wound closure as daily infusion therapy.
She reported having no financial conflicts regarding the study, supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the EB Research Partnership, and the EB Research Foundation.
In a pilot study, , Michelle Hao said at the virtual annual meeting of the American Academy of Dermatology.
Serial skin biopsies and immunofluorescent staining demonstrated the mechanism of benefit: The aminoglycoside promoted creation of new full-length functional collagen fibrils at the dermal-epidermal junction in affected patients, added Ms. Hao, a medical student at the University of Southern California, Los Angeles.
“Glycoside-mediated nonsense suppression therapy may provide a novel, low cost, and readily available treatment for RDEB [recessive dystrophic epidermolysis bullosa] patients harboring nonsense mutations,” she declared.
RDEB is a rare, incurable, life-threatening genetic skin disease which manifests as severe skin fragility and widespread blistering. The disease is caused by mutations in a gene coding for collagen type VII alpha 1 (COL7A1), the building block for the anchoring fibrils responsible for dermal-epidermal adherence. Roughly 30% of COL7A1 mutations are nonsense mutations, which result in truncated, nonfunctional collagen type VII.
Ms. Hao and her senior coinvestigators have previously shown that aminoglycoside antibiotics can override nonsense mutations to produce full-length, functioning protein. Indeed, they demonstrated that topical gentamicin in particular induces formation of new collagen type VII and improves wound closure in RDEB patients with nonsense mutations. However, RDEB skin lesions are so widespread that topical therapy becomes impractical. This was the impetus for the phase 1/2 clinical trial of IV gentamicin.
The open-label study included four patients with RDEB with nonsense mutations. All participants received IV gentamicin at 7.5 mg/kg/day for 2 weeks. Two of the four patients then got additional twice-weekly infusions at the same dose for another 3 months. Skin biopsies were obtained from two prospectively monitored open erosive wound sites and two intact skin sites at baseline and 1 and 3 months after treatment.
The primary endpoint was evidence of new collagen type VII at the dermal-epidermal junction post treatment. At baseline, patients averaged only 2% of the amount present in normal skin. One month post treatment, all four patients showed significant gains in expression of functioning collagen type VII, with levels 30%-130% of what’s present in normal skin. This effect proved durable 3 months post treatment.
At the same visits when biopsies were obtained, participants were assessed regarding wound closure, disease activity as measured using the validated Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI), and quality of life as reflected in Skindex-16 scores. All four patients showed improved wound closure at 1 and 3 months post treatment at the monitored sites, as well as better EBDASI and Skindex-16 Symptoms and Skindex-16 Emotion scores, Ms. Hao continued.
Safety assessments revealed no evidence of oto- or nephrotoxicity in the gentamicin-treated patients. And no one developed autoantibodies to collagen type VII in skin or sera in response to the aminoglycoside-induced creation of new collagen type VII.
Ms. Hao said preliminary analysis of the study data suggests that the more convenient schedule of twice-weekly IV gentamicin was as effective with regard to wound closure as daily infusion therapy.
She reported having no financial conflicts regarding the study, supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the EB Research Partnership, and the EB Research Foundation.
FROM AAD 2020
Rilzabrutinib shows positive results in phase 2b for pemphigus
accompanied by markedly reduced need for systemic corticosteroids in the phase 2b BELIEVE-PV trial, Dedee F. Murrell, MD, said at the virtual annual meeting of the American Academy of Dermatology.
Moreover, in sharp contrast to the standard first-line treatments for pemphigus – rituximab (Rituxan) and high-dose corticosteroids – the treatment-emergent adverse events that arose with 6 months of rilzabrutinib in BELIEVE-PV were uniformly mild to moderate and transient, added Dr. Murrell, professor of dermatology at the University of New South Wales and head of the department of dermatology at St. George University Hospital, Sydney.
The phase 2b BELIEVE-PV trial was a small, 24-week, open-label study that included six patients with newly diagnosed pemphigus and nine others with relapsing pemphigus. The primary endpoint was control of disease activity, defined as no new lesions appearing and established lesions beginning to heal. This was achieved in 9 of 15 patients (60%) at 4 weeks and in 13 patients by week 12. Meanwhile, the mean daily dose of prednisone fell from 21 mg at baseline to 6 mg at 24 weeks.
The mean score on the Pemphigus Disease Area Index (PDAI) dropped by 79% from a baseline of 15.5. Ten of 15 subjects improved to a PDAI of 0 or 1 – clear or almost clear skin – by week 24. The complete remission rate, defined as an absence of both new and established lesions while on no or a very low dose of prednisone, was 40% at week 24.
Treatment-emergent adverse events consisted of nausea in four patients, dizziness in two, and abdominal distension in two, all of which were grade 1 or 2.
Based upon these favorable results, the pivotal phase 3, double-blind, international PEGASUS trial is underway, led by Dr. Murrell. The trial will enroll 120 pemphigus patients, randomized to rilzabrutinib at 400 mg twice daily or placebo on top of background steroid tapering.
Rilzabrutinib is also in earlier-stage clinical trials for the treatment of immune thrombocytopenia.
Dr. Murrell reported serving as a consultant to Principia Biopharma, sponsor of the BELIEVE-PV and PEGASUS trials, and has received institutional research grants from numerous pharmaceutical companies.
SOURCE: Murrell DF. AAD 2020 LBCT.
accompanied by markedly reduced need for systemic corticosteroids in the phase 2b BELIEVE-PV trial, Dedee F. Murrell, MD, said at the virtual annual meeting of the American Academy of Dermatology.
Moreover, in sharp contrast to the standard first-line treatments for pemphigus – rituximab (Rituxan) and high-dose corticosteroids – the treatment-emergent adverse events that arose with 6 months of rilzabrutinib in BELIEVE-PV were uniformly mild to moderate and transient, added Dr. Murrell, professor of dermatology at the University of New South Wales and head of the department of dermatology at St. George University Hospital, Sydney.
The phase 2b BELIEVE-PV trial was a small, 24-week, open-label study that included six patients with newly diagnosed pemphigus and nine others with relapsing pemphigus. The primary endpoint was control of disease activity, defined as no new lesions appearing and established lesions beginning to heal. This was achieved in 9 of 15 patients (60%) at 4 weeks and in 13 patients by week 12. Meanwhile, the mean daily dose of prednisone fell from 21 mg at baseline to 6 mg at 24 weeks.
The mean score on the Pemphigus Disease Area Index (PDAI) dropped by 79% from a baseline of 15.5. Ten of 15 subjects improved to a PDAI of 0 or 1 – clear or almost clear skin – by week 24. The complete remission rate, defined as an absence of both new and established lesions while on no or a very low dose of prednisone, was 40% at week 24.
Treatment-emergent adverse events consisted of nausea in four patients, dizziness in two, and abdominal distension in two, all of which were grade 1 or 2.
Based upon these favorable results, the pivotal phase 3, double-blind, international PEGASUS trial is underway, led by Dr. Murrell. The trial will enroll 120 pemphigus patients, randomized to rilzabrutinib at 400 mg twice daily or placebo on top of background steroid tapering.
Rilzabrutinib is also in earlier-stage clinical trials for the treatment of immune thrombocytopenia.
Dr. Murrell reported serving as a consultant to Principia Biopharma, sponsor of the BELIEVE-PV and PEGASUS trials, and has received institutional research grants from numerous pharmaceutical companies.
SOURCE: Murrell DF. AAD 2020 LBCT.
accompanied by markedly reduced need for systemic corticosteroids in the phase 2b BELIEVE-PV trial, Dedee F. Murrell, MD, said at the virtual annual meeting of the American Academy of Dermatology.
Moreover, in sharp contrast to the standard first-line treatments for pemphigus – rituximab (Rituxan) and high-dose corticosteroids – the treatment-emergent adverse events that arose with 6 months of rilzabrutinib in BELIEVE-PV were uniformly mild to moderate and transient, added Dr. Murrell, professor of dermatology at the University of New South Wales and head of the department of dermatology at St. George University Hospital, Sydney.
The phase 2b BELIEVE-PV trial was a small, 24-week, open-label study that included six patients with newly diagnosed pemphigus and nine others with relapsing pemphigus. The primary endpoint was control of disease activity, defined as no new lesions appearing and established lesions beginning to heal. This was achieved in 9 of 15 patients (60%) at 4 weeks and in 13 patients by week 12. Meanwhile, the mean daily dose of prednisone fell from 21 mg at baseline to 6 mg at 24 weeks.
The mean score on the Pemphigus Disease Area Index (PDAI) dropped by 79% from a baseline of 15.5. Ten of 15 subjects improved to a PDAI of 0 or 1 – clear or almost clear skin – by week 24. The complete remission rate, defined as an absence of both new and established lesions while on no or a very low dose of prednisone, was 40% at week 24.
Treatment-emergent adverse events consisted of nausea in four patients, dizziness in two, and abdominal distension in two, all of which were grade 1 or 2.
Based upon these favorable results, the pivotal phase 3, double-blind, international PEGASUS trial is underway, led by Dr. Murrell. The trial will enroll 120 pemphigus patients, randomized to rilzabrutinib at 400 mg twice daily or placebo on top of background steroid tapering.
Rilzabrutinib is also in earlier-stage clinical trials for the treatment of immune thrombocytopenia.
Dr. Murrell reported serving as a consultant to Principia Biopharma, sponsor of the BELIEVE-PV and PEGASUS trials, and has received institutional research grants from numerous pharmaceutical companies.
SOURCE: Murrell DF. AAD 2020 LBCT.
FROM AAD 20
COVID-19 pandemic dictates reconsideration of pemphigus therapy
The Dedee F. Murrell, MD, said at the virtual annual meeting of the American Academy of Dermatology.
Together with physicians from the Mayo Clinic, Alexandria (Egypt) University, and Tehran (Iran) University, she recently published updated expert guidance for treatment of this severe, potentially fatal mucocutaneous autoimmune blistering disease, in a letter to the editor in the Journal of the American Academy of Dermatology. She presented some of the key recommendations at AAD 2020.
First off, rituximab (Rituxan), the only Food and Drug Administration–approved medication for moderate to severe pemphigus vulgaris and a biologic considered first-line therapy prepandemic, is ill-advised during the COVID-19 era. Its mechanism of benefit is through B-cell depletion. This is an irreversible effect, and reconstitution of B-cell immunity takes 6-12 months. The absence of this immunologic protection for such a long time poses potentially serious problems for pemphigus patients who become infected with SARS-CoV-2.
Also, the opportunity to administer intravenous infusions of the biologic becomes unpredictable during pandemic surges, when limitations on nonemergent medical care may be necessary, noted Dr. Murrell, professor of dermatology at the University of New South Wales and head of dermatology at St. George University Hospital, both in Sydney.
“We have taken the approach of postponing rituximab infusions temporarily, with the aim of delaying peak patient immunosuppression during peak COVID-19 incidence to reduce the risk of adverse outcomes,” Dr. Murrell and coauthors wrote in the letter (J Am Acad Dermatol. 2020 Jun;82[6]:e235-6).
The other traditional go-to therapy for pemphigus is corticosteroids. They’re effective, fast acting, and relatively inexpensive. But their nonselective immunosuppressive action boosts infection risk in general, and more specifically it increases the risk of developing severe forms of COVID-19 should a patient become infected with SARS-CoV-2.
“A basic therapeutic principle with particular importance during the pandemic is that glucocorticoids and steroid-sparing immunosuppressive agents, such as azathioprine and mycophenolate mofetil, should be tapered to the lowest effective dose. In active COVID-19 infection, immunosuppressive steroid-sparing medications should be discontinued when possible, although glucocorticoid cessation often cannot be considered due to risk for adrenal insufficiency,” the authors continued.
“Effective as adjuvant treatment in both pemphigus and COVID-19,intravenous immunoglobulin supports immunity and therefore may be useful in this setting,” they wrote. It’s not immunosuppressive, and, they noted, there’s good-quality evidence from a Japanese randomized, double-blind, controlled trial that a 5-day course of intravenous immunoglobulin is effective therapy for pemphigus (J Am Acad Dermatol. 2009 Apr;60[4]:595-603).
Moreover, intravenous immunoglobulin is also reportedly effective in severe COVID-19 (Open Forum Infect Dis. 2020 Mar 21. doi: 10.1093/ofid/ofaa102.).
Another option is to consider enrolling a patient with moderate or severe pemphigus vulgaris or foliaceus in the ongoing pivotal phase 3, international, double-blind, placebo-controlled PEGASUS trial of rilzabrutinib, a promising oral reversible Bruton tyrosine kinase inhibitor. The medication has a short half-life and a self-limited immunomodulatory effect. Moreover, the trial is set up for remote patient visits on an outpatient basis via teledermatology, so the 65-week study can continue despite the pandemic. Both newly diagnosed and relapsing patients are eligible for the trial, headed by Dr. Murrell. At AAD 2020 she reported encouraging results from a phase 2b trial of rilzabrutinib.
She is a consultant to Principia Biopharma, sponsor of the PEGASUS trial, and has received institutional research grants from numerous pharmaceutical companies.
The Dedee F. Murrell, MD, said at the virtual annual meeting of the American Academy of Dermatology.
Together with physicians from the Mayo Clinic, Alexandria (Egypt) University, and Tehran (Iran) University, she recently published updated expert guidance for treatment of this severe, potentially fatal mucocutaneous autoimmune blistering disease, in a letter to the editor in the Journal of the American Academy of Dermatology. She presented some of the key recommendations at AAD 2020.
First off, rituximab (Rituxan), the only Food and Drug Administration–approved medication for moderate to severe pemphigus vulgaris and a biologic considered first-line therapy prepandemic, is ill-advised during the COVID-19 era. Its mechanism of benefit is through B-cell depletion. This is an irreversible effect, and reconstitution of B-cell immunity takes 6-12 months. The absence of this immunologic protection for such a long time poses potentially serious problems for pemphigus patients who become infected with SARS-CoV-2.
Also, the opportunity to administer intravenous infusions of the biologic becomes unpredictable during pandemic surges, when limitations on nonemergent medical care may be necessary, noted Dr. Murrell, professor of dermatology at the University of New South Wales and head of dermatology at St. George University Hospital, both in Sydney.
“We have taken the approach of postponing rituximab infusions temporarily, with the aim of delaying peak patient immunosuppression during peak COVID-19 incidence to reduce the risk of adverse outcomes,” Dr. Murrell and coauthors wrote in the letter (J Am Acad Dermatol. 2020 Jun;82[6]:e235-6).
The other traditional go-to therapy for pemphigus is corticosteroids. They’re effective, fast acting, and relatively inexpensive. But their nonselective immunosuppressive action boosts infection risk in general, and more specifically it increases the risk of developing severe forms of COVID-19 should a patient become infected with SARS-CoV-2.
“A basic therapeutic principle with particular importance during the pandemic is that glucocorticoids and steroid-sparing immunosuppressive agents, such as azathioprine and mycophenolate mofetil, should be tapered to the lowest effective dose. In active COVID-19 infection, immunosuppressive steroid-sparing medications should be discontinued when possible, although glucocorticoid cessation often cannot be considered due to risk for adrenal insufficiency,” the authors continued.
“Effective as adjuvant treatment in both pemphigus and COVID-19,intravenous immunoglobulin supports immunity and therefore may be useful in this setting,” they wrote. It’s not immunosuppressive, and, they noted, there’s good-quality evidence from a Japanese randomized, double-blind, controlled trial that a 5-day course of intravenous immunoglobulin is effective therapy for pemphigus (J Am Acad Dermatol. 2009 Apr;60[4]:595-603).
Moreover, intravenous immunoglobulin is also reportedly effective in severe COVID-19 (Open Forum Infect Dis. 2020 Mar 21. doi: 10.1093/ofid/ofaa102.).
Another option is to consider enrolling a patient with moderate or severe pemphigus vulgaris or foliaceus in the ongoing pivotal phase 3, international, double-blind, placebo-controlled PEGASUS trial of rilzabrutinib, a promising oral reversible Bruton tyrosine kinase inhibitor. The medication has a short half-life and a self-limited immunomodulatory effect. Moreover, the trial is set up for remote patient visits on an outpatient basis via teledermatology, so the 65-week study can continue despite the pandemic. Both newly diagnosed and relapsing patients are eligible for the trial, headed by Dr. Murrell. At AAD 2020 she reported encouraging results from a phase 2b trial of rilzabrutinib.
She is a consultant to Principia Biopharma, sponsor of the PEGASUS trial, and has received institutional research grants from numerous pharmaceutical companies.
The Dedee F. Murrell, MD, said at the virtual annual meeting of the American Academy of Dermatology.
Together with physicians from the Mayo Clinic, Alexandria (Egypt) University, and Tehran (Iran) University, she recently published updated expert guidance for treatment of this severe, potentially fatal mucocutaneous autoimmune blistering disease, in a letter to the editor in the Journal of the American Academy of Dermatology. She presented some of the key recommendations at AAD 2020.
First off, rituximab (Rituxan), the only Food and Drug Administration–approved medication for moderate to severe pemphigus vulgaris and a biologic considered first-line therapy prepandemic, is ill-advised during the COVID-19 era. Its mechanism of benefit is through B-cell depletion. This is an irreversible effect, and reconstitution of B-cell immunity takes 6-12 months. The absence of this immunologic protection for such a long time poses potentially serious problems for pemphigus patients who become infected with SARS-CoV-2.
Also, the opportunity to administer intravenous infusions of the biologic becomes unpredictable during pandemic surges, when limitations on nonemergent medical care may be necessary, noted Dr. Murrell, professor of dermatology at the University of New South Wales and head of dermatology at St. George University Hospital, both in Sydney.
“We have taken the approach of postponing rituximab infusions temporarily, with the aim of delaying peak patient immunosuppression during peak COVID-19 incidence to reduce the risk of adverse outcomes,” Dr. Murrell and coauthors wrote in the letter (J Am Acad Dermatol. 2020 Jun;82[6]:e235-6).
The other traditional go-to therapy for pemphigus is corticosteroids. They’re effective, fast acting, and relatively inexpensive. But their nonselective immunosuppressive action boosts infection risk in general, and more specifically it increases the risk of developing severe forms of COVID-19 should a patient become infected with SARS-CoV-2.
“A basic therapeutic principle with particular importance during the pandemic is that glucocorticoids and steroid-sparing immunosuppressive agents, such as azathioprine and mycophenolate mofetil, should be tapered to the lowest effective dose. In active COVID-19 infection, immunosuppressive steroid-sparing medications should be discontinued when possible, although glucocorticoid cessation often cannot be considered due to risk for adrenal insufficiency,” the authors continued.
“Effective as adjuvant treatment in both pemphigus and COVID-19,intravenous immunoglobulin supports immunity and therefore may be useful in this setting,” they wrote. It’s not immunosuppressive, and, they noted, there’s good-quality evidence from a Japanese randomized, double-blind, controlled trial that a 5-day course of intravenous immunoglobulin is effective therapy for pemphigus (J Am Acad Dermatol. 2009 Apr;60[4]:595-603).
Moreover, intravenous immunoglobulin is also reportedly effective in severe COVID-19 (Open Forum Infect Dis. 2020 Mar 21. doi: 10.1093/ofid/ofaa102.).
Another option is to consider enrolling a patient with moderate or severe pemphigus vulgaris or foliaceus in the ongoing pivotal phase 3, international, double-blind, placebo-controlled PEGASUS trial of rilzabrutinib, a promising oral reversible Bruton tyrosine kinase inhibitor. The medication has a short half-life and a self-limited immunomodulatory effect. Moreover, the trial is set up for remote patient visits on an outpatient basis via teledermatology, so the 65-week study can continue despite the pandemic. Both newly diagnosed and relapsing patients are eligible for the trial, headed by Dr. Murrell. At AAD 2020 she reported encouraging results from a phase 2b trial of rilzabrutinib.
She is a consultant to Principia Biopharma, sponsor of the PEGASUS trial, and has received institutional research grants from numerous pharmaceutical companies.
FROM AAD 20