While Cassiopea’s Winlevi (clascoterone) is likely to be FDA approved in moderate-to-severe acne, it is at risk of diminishing clinician/patient interest following initially optimistic early uptake, experts said. The market wane could happen if clinical trial data does not match real-world experience, even if early adoption would be driven by its novel antiandrogen mechanism, they said.

Patient compliance to its topical approach would be critical to maintain results, experts added, noting Cassiopea should have been specifically developed for adult females as they are sensitive to its mechanism and are highly compliant.

Analysts and Cassiopea have expressed awareness that many payers will likely cover Winlevi on a nonpreferred tier. This means that prior authorisation, a requirement that a physician obtain approval from your health insurance plan to prescribe a specific medication, would likely be required, and this is a turn-off as the effort to garner evidence can be burdensome for clinicians, experts said. Patient co-payments are also likely, but coupons provided by the company could be used to ease this access barrier, they added.

Even if Winlevi’s pivotal monotherapy data is not overwhelmingly positive, it would still be approvable due to its novel mechanism and awareness that it would be ideal for adult female patients, experts noted. However, Cassiopea CEO Diana Harbort said all acne has hormone elements and available off-label antiandrogenic therapies are not used in men. Severe acne patients and certain moderate acne patients typically need a combination approach, which would boost Winlevi’s real-world efficacy profile, experts said. Winlevi’s nonimpact on hormonal imbalance is a plus for female patients, some noted.
Cassiopea plans to file Winlevi for approval in approximately the next week with an FDA action date of one year later, Harbort said. Winlevi has a $419m peak sales forecast in the US, an analyst report shows. Cassiopea has a $422m market cap.

New mechanism interest; female adult patients should have been targeted

There is clinician interest in new acne mechanisms, as current topical approaches are not very efficacious in the real world, said Dr Steven Feldman, dermatologist, Wake Forest School of Medicine, Winston-Salem, North Carolina and Dr Peter van de Kerkhof, dermatology and venerology chair, Faculty of Medical Sciences, Radboud University, Nijmegen, Netherlands. Winlevi’s antiandrogen approach is a novel acne mechanism, noted van de Kerkhof and Dr Leon Kircik, dermatology clinical associate professor, Icahn School of Medicine, Mount Sinai, New York. With direct-to-consumer advertising campaigns, patients could be inspired to ask their clinicians about Winlevi, added Dr Alan Menter, dermatologist, Texas Dermatology Associates, Dallas.

However, clinician interest could wane if clinical trial data does not match real-world experience, Feldman said. Typical patient noncompliance for a topical approach could be an impediment to matching clinical trial results, where trial patients are highly monitored for compliance, he noted. Acne is also typically a condition found in teenagers, where compliance can be challenging, he added. Winlevi is designed for twice-daily application. However, Cassiopea’s Harbort said moderate-to-severe acne is distressing for teenagers, so they are highly interested in acne clearance. Winlevi’s Phase III program enrolled patients ages nine years and older.

Winlevi’s development pursuit should have targeted adult women, rather than all patients, said Menter and Dr Emil Tanghetti, dermatologist, Center for Dermatology and Laser Surgery, Sacramento, California. In the pivotal program, about 60% of patients were female, as per a July 2018 company presentation. The average age for both trials was around 19 years old, regardless of gender.

In adults, a significant proportion of acne patients are women, Menter noted. Female adults are more compliant than other acne patients, Tanghetti added, noting adult male patients typically prefer oral approaches like generic isotretinoin.

Androgen plays a significant role in adult female acne, Tanghetti and Menter said. Androgen is a weighty contributor to acne flare-ups prior to menstruation, van de Kerkhof added. Uptake in female patients is supported by real-world experience with off-label, antiandrogenic oral spironolactone, Tanghetti said. However, all acne has hormonal elements, and spironolactone is not prescribed for boys and men, Cassiopea’s Harbort said, adding spironolactone has a gynecomastia side-effect.

That said, Winlevi could eventually settle into the female adult acne subpopulation postapproval, as seen with Almirall’s topical antibiotic Aczone (dapsone), which was approved for all patients but is mostly prescribed for adult women, Tanghetti said. Aczone was FDA approved in February 2016, garnering $167m sales in 2017, and dropping to $84m in 2018, as per the GlobalData Database.

Prior authorisation is an obstacle to uptake

Payers could place Winlevi in the nonpreferred tier, Cassiopea’s Harbort said. This could mean that a potential uptake challenge is if Winlevi requires prior authorisation, Feldman said. Under prior authorisation, clinicians send photographs and a history of prior topical/oral therapies used by the patient, Menter said. Clinicians typically avoid therapies that require prior authorisation, and would only consider going through this process if it is the last option for patients, Tanghetti said, adding the cost of paperwork processing is not covered by payers or patients.

However, there are no generics for Winlevi, which could make prescribing easy, Kircik said. Cassiopea’s Harbort said prior authorisation is unlikely to be the case for all payers. Also, by the time patients reach dermatologists, they have already gone through multiple treatment regiments, from over-the-counter therapies to those prescribed by general practitioners, she added. Still, payers could be hesitant to cover topical approaches, Feldman said.
Copays could be another barrier to patient access, Feldman said. However, coupons are often used to circumvent this issue, Tanghetti added. Larger companies often package their approved therapies together to improve the reimbursement tier where products are listed, which could be a disadvantage for Cassiopea, as the company does not have other products approved, Menter said. The company is aware of potential market access challenges in acne, and is researching pricing, payer engagement, and coupons, among other options, Harbort said. A high price is not planned to increase patient access, she added.

Underwhelming efficacy data, yet still approvable

That said, Winlevi’s pivotal monotherapy data in all patients is not overwhelmingly positive, said van de Kerkhof, Menter and Tanghetti. Kircik added he had hoped the data would be stronger, as Winlevi has a new mechanism.

The two vehicle-controlled, 12-week Phase III Winlevi trials—708-patient Study 25 (NCT02608450) and 732-patient Study 26 (NCT02608476)—have the same coprimary endpoints, with one being a two-point reduction and Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear). This endpoint was achieved by 16.1% of Winlevi intention-to-treat (ITT) patients versus 7% vehicle-only patients (p=0.0012) in Study 25. In Study 26, this was 18.7% in Winlevi ITT patients and 4.7% with vehicle-only patients (p<0.0001), as per a July 2018 media release.

However, Winlevi’s data is still approvable, Tanghetti said. Winlevi’s approvability is due to the recognition that adult females would be sensitive to its mechanism, van de Kerkhof and Menter said. Cassiopea’s Harbort noted Winlevi could be the first new mechanism approved in acne in nearly 40 years, as the last approved therapy in acne was isotretinoin in 1982.

Although the monotherapy data are underwhelming, Winlevi is unlikely to be used as a monotherapy in the real world as severe patients require multiple approaches, Tanghetti said. Acne is triggered by sebum increase, leading to bacteria colonisation, which causes inflammation. Winlevi can be combined with any therapy that targets any of these three elements, Tanghetti said, adding real-world experience would reveal its ideal combination partner.

In moderate acne patients, it could be a case-by-case basis, where a monotherapy Winlevi approach may be enough in patients with no cystic lesions or inflammatory papules, Menter said. If the patient has skin bumps, called comedones, it could be combined with systemic approaches, Menter added. Cassiopea’s Harbort said Winlevi has the potential to replace antibiotics in polypharmacy due to increased awareness of antibiotic resistance risks.

Winlevi’s topical application advantage means it could circumvent potential adverse events linked with a systemic anti-androgen mechanism, Feldman said. In the one-year, open-label, 609-patient Phase III Study 27 (NCT02682264) investigating safety, no hormonal imbalance was seen in patients. Approximately 18.1% reported treatment-emergent adverse events (TEAEs), with the most frequently reported being nasopharyngitis (2.6%) and upper respiratory tract infection (1.3%), as per a 26 March media release. No hormonal imbalance is a notable benefit for adult female patients, Tanghetti and Menter said.