Clascoterone 1% cream (Winlevi, Cassiopea) is a first-in-class topical androgen receptor.
Its efficacy and safety for treating moderate-to-severe acne and reducing noninflammatory and inflammatory lesions was demonstrated in 2 pivotal trials including 1440 patients ages 9 years and older.
Data from an open-label extension study provided evidence of safety during longer-term use.
Studies of clascoterone 1% cream investigated its use as monotherapy, but experts expect it will be used in combination regimens.
The FDA approval of clascoterone 1% cream (Winlevi, Cassiopea) for the topical treatment of acne vulgaris in patients 12 years of age and older gives clinicians a novel tool for managing the large and diverse population of patients who could benefit from hormonal-targeted therapy.
Evidence supporting the regulatory agency’s decision included data from 2 identically designed, phase 3 clinical trials that enrolled patients ages 9 years and older with moderate-to-severe acne (grade 3 or 4 on the 5-point Investigator Global Assessment [IGA] scale). As reported in an article published in JAMA Dermatology1 , the trials met all their primary and secondary efficacy end points by demonstrated superiority of clascoterone 1% cream for getting patients to clear or almost-clear status and reducing the numbers of noninflammatory and inflammatory lesions. In addition, the data from the 12-week studies showed that the new product was safe and well-tolerated across the entire patient population.
“Clascoterone offers us an additional option for treating acne that has a unique mechanism of action in that it is a topical androgen receptor, competing with androgens for binding to the androgen receptor in sebocytes,” said Linda Stein Gold, MD, Director of Dermatology Clinical Research
Henry Ford Health System, Detroit, and Head, Division of Dermatology, Henry Ford Health System, West Bloomfield, Michigan.
“In vitro studies have shown that clascoterone reduces transcription of androgen-responsive genes that drive sebum production and activate inflammatory pathways, including those involved in proinflammatory cytokine synthesis. Through its actions, clascoterone targets more than one acnegenic pathway,” she said.
Dr. Stein Gold was an investigator in the clascoterone pivotal trials and a co-author of the JAMA Dermatology study, as was Adelaide Hebert, MD, Professor and Director of Pediatric Dermatology, McGovern Medical School, UTHealth, Houston. As a board-certified pediatric dermatologist, Dr. Hebert said she is excited that the FDA approved clascoterone cream for pediatric patient use.
She explained, “Lack of approval for use in the pediatric age group is often an obstacle in our ability to treat younger patients most effectively because insurers deny coverage for off-label medications. It is important to note that the pivotal trials included patients as young as 9 years of age and that the reason clascoterone was approved for use in patients ages 12 years and older was the limited number of younger participants, and not because of any evidence of differences in efficacy or safety in the preteen patients.”
She added that she considers topical clascoterone an advance for other reasons as well.
“As a topical androgen receptor inhibitor, clascoterone is truly a first-in-class drug,” she said. “This new topical medication was used safely in non-pregnant females of childbearing age in the clinical trials, and it was very effective in males as well as females. Although we have systemic medications, including spironolactone and oral contraceptives, that could be used as hormonal treatment for acne in females, these agents have not been an option for males. Clascoterone opens up a new pharmacologic arena for younger patients, females, and males with moderate-to-severe acne.”
Pivotal trial summary
The 2 pivotal trials included 1440 patients who were treated at 99 sites in the United States and several Eastern European countries. Eligible patients had to have 30 to 75 inflammatory lesions, 30 to 100 noninflammatory lesions, and to have been on a consistent skin care regimen for at least 1 month that they agreed to continue for the duration of the 12-week study. Patients with nodulocystic acne were excluded.
The total population was comprised of 540 males and 900 females. The vast majority of the study participants (90%) were white, although approximately 30% of patients in 1 study were Fitzpatrick skin type IV-VI; 46% were in the pediatric age range (9 years to 17 years), and the adult subgroup included patients up to 58 years of age. The baseline IGA ratings showed the majority of patients in all 4 treatment groups (82% to 86%) had moderate acne with a mean of approximately 60 noninflammatory lesions and 42 inflammatory lesions.
Patients were instructed to apply 1 g of their assigned study medication to the face twice daily, and they returned for scheduled follow-up visits at 4-week intervals. The protocols followed the FDA’s industry guidelines for establishing effectiveness of drugs intended to treat acne vulgaris and assessed 3 coprimary efficacy endpoints: 1) proportion of patients achieving treatment success at week 12, defined as an IGA rating of clear to almost-clear (score of 0 or 1) and a ≥2-point reduction from baseline; 2) absolute change from baseline in noninflammatory lesion count at week 12; and 3) inflammatory lesion count at week 12.
The treatment success rates in the 2 studies were 18.4% and 20.3% for the clascoterone groups and 9.0% and 6.5% for the vehicle-treated patients. Clascoterone reduced noninflammatory and inflammatory lesion counts by approximately 30% and 45%, respectively, compared with reductions of approximately 16%-22% and 30%-36.5%, respectively, in the control groups.
Treatment compliance was also assessed by weighing the returned study product tubes. The data showed that the majority of patients in both the clascoterone and control groups (almost 90%) were compliant with using their assigned treatment as defined by achieving ≥80% of expected application at each follow-up visit.
No safety issues occurred with the use of clascoterone cream during the 12-week treatment period of the pivotal trials. Local skin reactions, including erythema, scaling, dryness, and pruritus, occurred at similar rates in the clascoterone and vehicle treatment groups. Across the 2 studies, only 13 adverse events were considered related to use of clascoterone cream, and application site dryness was the only 1 of the 13 that occurred in more than a single patient (n = 2).
None of the 13 adverse events considered related to topical clascoterone was judged to be severe, but 5 patients withdrew from the study because of an adverse event (all rated mild) as did 13 patients using vehicle cream. There were no systemic adverse events.
Experience with clascoterone in an open-label, long-term extension study enrolling patients who had completed a pivotal trial reaffirmed the safety and tolerability of the topical agent2. A total of 347 patients completed the 9-month extension trial, of whom 179 had used clascoterone for 12 weeks in a pivotal trial. No new safety signals emerged with ongoing use of clascoterone, and the overall frequency of treatment-related adverse events remained low. A total of 19 adverse events occurred that were considered related to clascoterone, but none was serious and most were mild.
“We are in a new era of clinical trials in dermatology when medication safety during extended periods of use is being examined up front. This is important for drugs used to treat acne and other conditions that require ongoing management,” said Dr. Hebert.
“The fact that there was a lack of any new or serious adverse events that would deter longer-term use of topical clascoterone further establishes that this new drug provides an opportunity for treating acne in a way we have not had available before.”
Adoption into clinical care
Clascoterone was studied only as monotherapy in the premarketing clinical trials and in a predominantly white patient population. Therefore, data from further studies and outcomes from clinical experience are needed to determine its best use in clinical practice. Dr. Stein Gold said she suspects that it may complement other treatment modalities.
Dr. Hebert also believes that clascoterone cream will be used in combination with other acne therapies.
“With the exception of oral isotretinoin, the standard of care for managing acne involves a multimodal approach, and that is especially true in the population with moderate-to-severe disease that was the focus of the clascoterone trials. Success in clearing acne in these patients almost always requires use of more than one medication,” she said.
References
- Hebert A, Thiboutot D, Stein Gold L, et al. Efficacy and safety of topical clascoterone Cream, 1%, for treatment in patients with facial acne: two phase 3 randomized clinical trials. JAMA Dermatol. 2020;156(6):1-10.
- Eichenfield L, Hebert A, Gold LS, et al. Open-label, long-term extension study to evaluate the safety of clascoterone (CB-03-01) cream, 1% twice daily, in patients with acne vulgaris. J Am Acad Dermatol. 2020;83(2):477-485.
Disclosures
Dr. Hebert was a study investigator and serves as a consultant to Cassiopea and has received honoraria and fees. She is an advisor or consultant for Allergan, Almirall, Galderma, and Ortho Dermatologics.
Dr Stein Gold was a study investigator and a compensated (ie, honoraria, personal fees) advisor to Cassiopea. She has also received personal fees for advisory, speaking, consulting, research, and/or other ties with Almirall, Foamix, Galderma Laboratories, Novartis, Sol-Gel, and Sun Pharmaceuticals.