Novel topical rosacea drug sails through phase III

WAIKOLOA, HAWAII – Ivermectin 1% cream for the treatment of papulopustular rosacea convincingly hit all of its primary efficacy and safety endpoints in two pivotal phase III clinical trials.

The studies included 1,371 subjects randomized in a double-blind fashion 2:1 to 3 months of once-daily topical invermectin 1% or vehicle. These were patients with significant papulopustular rosacea (PPR): In one trial, 75% of patients were rated at baseline as having moderate disease and 25% severe, while in the other study the percentages were 80% and 20%, respectively, Dr. Hilary E. Baldwin reported at the SDEF Hawaii Dermatology Seminar sponsored by the Global Academy for Medical Education/Skin Disease Education Foundation.

The two prespecified coprimary endpoints were treatment success as defined by an Investigator Global Assessment rating of clear or almost clear at 12 weeks, along with reduction in inflammatory lesions from baseline through 12 weeks.

Roughly 40% of topical ivermectin–treated patients met the clear or almost-clear treatment success standard, a rate two- to fourfold greater than in controls in the two trials. The difference between the active treatment group and controls became statistically significant as early as week 4.

In addition, the inflammatory lesion count dropped by an average of more than 20 lesions at 12 weeks in the topical ivermectin–treated patients, an effect more than one-third larger than documented in controls. Here again, the benefit was significant by week 4, according to Dr. Baldwin, a dermatologist at SUNY Downstate Medical Center, Brooklyn.

The incidence of treatment-related dermatologic adverse events was 2.5% in patients on topical ivermectin, compared with 6.3% in controls.

Moreover, in a related single-blind, 9-month safety study involving 910 patients on ivermectin 1% cream once daily and 481 on topical azelaic acid 15% twice daily, the rate of treatment-related dermatologic adverse events was 1.3% in the ivermectin arm, compared with 5.3% with azelaic acid.

Stepping back from these compelling clinical trial data, Dr. Baldwin observed that the exact mechanism of benefit for topical invermectin in PPR has yet to be determined. The medication is certainly acaricidal and is known to kill the demodex mites that reside in the pilosebaceous units of patients with PPR. But it’s tough to think of demodex mites as causative in rosacea because they are also present in the pilosebaceous units of individuals without rosacea.

The latest thinking regarding the pathogenesis of rosacea is that this common chronic inflammatory skin disease is not caused by demodex mites, Propionibacterium acnes, or any other pathogen, she explained. In the current concept, cathelicidin proteins that are present in the epidermis as part of the vanguard of the innate immune system play a key role. When these proteins detect a foreign invader on the skin – bacterial, viral, or fungal – they release toxic enzymes, including cathelicidin LL-37, which kill the offending organism. High levels of LL-37 are proinflammatory, angiogenic, and activate the acquired immune system, effects that would explain the chronic skin redness and telangiectasias of rosacea. The trouble is, demodex is not a foreign invader.

"The innate immune system is not supposed to be triggered by demodex or P. acnes. They’re supposed to be in the follicle. They live there," Dr. Baldwin said.

Why the innate immune system of patients with PPR is apparently alerted by demodex, part of the normal fauna, requires further study, she added.

She anticipates that the full results of the recently completed pivotal phase III trials, sponsored by Galderma, will be published later this year.

SDEF and this news organization are owned by the same parent company.

Dr. Baldwin is on the advisory boards and/or speakers bureaus of Galderma and 10 other pharmaceutical and cosmetics companies.

[email protected]

WAIKOLOA, HAWAII – Ivermectin 1% cream for the treatment of papulopustular rosacea convincingly hit all of its primary efficacy and safety endpoints in two pivotal phase III clinical trials.

The studies included 1,371 subjects randomized in a double-blind fashion 2:1 to 3 months of once-daily topical invermectin 1% or vehicle. These were patients with significant papulopustular rosacea (PPR): In one trial, 75% of patients were rated at baseline as having moderate disease and 25% severe, while in the other study the percentages were 80% and 20%, respectively, Dr. Hilary E. Baldwin reported at the SDEF Hawaii Dermatology Seminar sponsored by the Global Academy for Medical Education/Skin Disease Education Foundation.

The two prespecified coprimary endpoints were treatment success as defined by an Investigator Global Assessment rating of clear or almost clear at 12 weeks, along with reduction in inflammatory lesions from baseline through 12 weeks.

Roughly 40% of topical ivermectin–treated patients met the clear or almost-clear treatment success standard, a rate two- to fourfold greater than in controls in the two trials. The difference between the active treatment group and controls became statistically significant as early as week 4.

In addition, the inflammatory lesion count dropped by an average of more than 20 lesions at 12 weeks in the topical ivermectin–treated patients, an effect more than one-third larger than documented in controls. Here again, the benefit was significant by week 4, according to Dr. Baldwin, a dermatologist at SUNY Downstate Medical Center, Brooklyn.

The incidence of treatment-related dermatologic adverse events was 2.5% in patients on topical ivermectin, compared with 6.3% in controls.

Moreover, in a related single-blind, 9-month safety study involving 910 patients on ivermectin 1% cream once daily and 481 on topical azelaic acid 15% twice daily, the rate of treatment-related dermatologic adverse events was 1.3% in the ivermectin arm, compared with 5.3% with azelaic acid.

Stepping back from these compelling clinical trial data, Dr. Baldwin observed that the exact mechanism of benefit for topical invermectin in PPR has yet to be determined. The medication is certainly acaricidal and is known to kill the demodex mites that reside in the pilosebaceous units of patients with PPR. But it’s tough to think of demodex mites as causative in rosacea because they are also present in the pilosebaceous units of individuals without rosacea.

The latest thinking regarding the pathogenesis of rosacea is that this common chronic inflammatory skin disease is not caused by demodex mites, Propionibacterium acnes, or any other pathogen, she explained. In the current concept, cathelicidin proteins that are present in the epidermis as part of the vanguard of the innate immune system play a key role. When these proteins detect a foreign invader on the skin – bacterial, viral, or fungal – they release toxic enzymes, including cathelicidin LL-37, which kill the offending organism. High levels of LL-37 are proinflammatory, angiogenic, and activate the acquired immune system, effects that would explain the chronic skin redness and telangiectasias of rosacea. The trouble is, demodex is not a foreign invader.

"The innate immune system is not supposed to be triggered by demodex or P. acnes. They’re supposed to be in the follicle. They live there," Dr. Baldwin said.

Why the innate immune system of patients with PPR is apparently alerted by demodex, part of the normal fauna, requires further study, she added.

She anticipates that the full results of the recently completed pivotal phase III trials, sponsored by Galderma, will be published later this year.

SDEF and this news organization are owned by the same parent company.

Dr. Baldwin is on the advisory boards and/or speakers bureaus of Galderma and 10 other pharmaceutical and cosmetics companies.

[email protected]

WAIKOLOA, HAWAII – Ivermectin 1% cream for the treatment of papulopustular rosacea convincingly hit all of its primary efficacy and safety endpoints in two pivotal phase III clinical trials.

The studies included 1,371 subjects randomized in a double-blind fashion 2:1 to 3 months of once-daily topical invermectin 1% or vehicle. These were patients with significant papulopustular rosacea (PPR): In one trial, 75% of patients were rated at baseline as having moderate disease and 25% severe, while in the other study the percentages were 80% and 20%, respectively, Dr. Hilary E. Baldwin reported at the SDEF Hawaii Dermatology Seminar sponsored by the Global Academy for Medical Education/Skin Disease Education Foundation.

The two prespecified coprimary endpoints were treatment success as defined by an Investigator Global Assessment rating of clear or almost clear at 12 weeks, along with reduction in inflammatory lesions from baseline through 12 weeks.

Roughly 40% of topical ivermectin–treated patients met the clear or almost-clear treatment success standard, a rate two- to fourfold greater than in controls in the two trials. The difference between the active treatment group and controls became statistically significant as early as week 4.

In addition, the inflammatory lesion count dropped by an average of more than 20 lesions at 12 weeks in the topical ivermectin–treated patients, an effect more than one-third larger than documented in controls. Here again, the benefit was significant by week 4, according to Dr. Baldwin, a dermatologist at SUNY Downstate Medical Center, Brooklyn.

The incidence of treatment-related dermatologic adverse events was 2.5% in patients on topical ivermectin, compared with 6.3% in controls.

Moreover, in a related single-blind, 9-month safety study involving 910 patients on ivermectin 1% cream once daily and 481 on topical azelaic acid 15% twice daily, the rate of treatment-related dermatologic adverse events was 1.3% in the ivermectin arm, compared with 5.3% with azelaic acid.

Stepping back from these compelling clinical trial data, Dr. Baldwin observed that the exact mechanism of benefit for topical invermectin in PPR has yet to be determined. The medication is certainly acaricidal and is known to kill the demodex mites that reside in the pilosebaceous units of patients with PPR. But it’s tough to think of demodex mites as causative in rosacea because they are also present in the pilosebaceous units of individuals without rosacea.

The latest thinking regarding the pathogenesis of rosacea is that this common chronic inflammatory skin disease is not caused by demodex mites, Propionibacterium acnes, or any other pathogen, she explained. In the current concept, cathelicidin proteins that are present in the epidermis as part of the vanguard of the innate immune system play a key role. When these proteins detect a foreign invader on the skin – bacterial, viral, or fungal – they release toxic enzymes, including cathelicidin LL-37, which kill the offending organism. High levels of LL-37 are proinflammatory, angiogenic, and activate the acquired immune system, effects that would explain the chronic skin redness and telangiectasias of rosacea. The trouble is, demodex is not a foreign invader.

"The innate immune system is not supposed to be triggered by demodex or P. acnes. They’re supposed to be in the follicle. They live there," Dr. Baldwin said.

Why the innate immune system of patients with PPR is apparently alerted by demodex, part of the normal fauna, requires further study, she added.

She anticipates that the full results of the recently completed pivotal phase III trials, sponsored by Galderma, will be published later this year.

SDEF and this news organization are owned by the same parent company.

Dr. Baldwin is on the advisory boards and/or speakers bureaus of Galderma and 10 other pharmaceutical and cosmetics companies.

[email protected]