Incyte Ready To Go For Approval Of Topical Ruxolitinib In Atopic Dermatitis
Executive Summary
With positive data from two Phase III trials, Incyte hopes to file an NDA this year for topical Jakafi in mild-to-moderate AD.
Incyte Corp. hopes to file the topical formulation of its JAK1/2 inhibitor ruxolitinib for mild-to-moderate atopic dermatitis by the end of 2020 now that the candidate has met the primary endpoint in a pair of Phase III studies. But at least one analyst questions whether the drug would be better positioned in such a competitive therapeutic space if the company had studied it against topical corticosteroids.
Incyte announced in January that topical ruxolitinib met a primary endpoint of investigator’s global assessment in one Phase III study; the candidate is a different formulation of Incyte’s oral Jakafi, which is approved to treat polycythemia vera, myelofibrosis and acute graft-versus-host disease. The Delaware-based firm revealed on 19 February that ruxolitinib cream met the primary endpoint in the second TRuE-AD pivotal study and provided topline efficacy data from both studies. (Also see "Atopic Dermatitis: Ruxolitinib And Baricitinib Spearheading New Therapies" - Scrip, 30 Jan, 2020.)
Both pivotal trials used a vehicle control – a version of the topical cream without the active pharmaceutical ingredient. Credit Suisse has criticized Incyte’s strategy in these studies, saying a demonstration of relative efficacy compared to the current standard of care for mild-to-moderate AD, topical corticosteroids, might be more useful for dermatologists.
Competing In AD
Atopic dermatitis is becoming a crowded space, dominated currently by Sanofi/Regeneron Pharmaceuticals Inc.’s Dupixent (dupilumab), an injectable interleukin-4 (IL-4)/IL-13 blocker. During its quarterly earnings call on 6 February, Sanofi reported that Dupixent revenues grew 135% year-over-year, to €679m (about $733m) during the fourth quarter of 2019. (Also see "Sanofi Highlights MS Asset After Solid Q4" - Scrip, 6 Feb, 2020.)
At the pharma’s capital markets day in December, Sanofi CEO Paul Hudson said Dupixent would prevail in the AD competition against a coming wave of oral JAK inhibitors and monoclonal antibodies that block IL-13 or IL-31. (Also see "Sanofi CEO Hudson Delivers An Ambitious Turnaround Agenda" - Scrip, 10 Dec, 2019.)
However, topical ruxolitinib is intended to treat a less-severe segment of the AD population. Lee noted that Dupixent is intended primarily for patients with severe AD and that in clinical trials of Dupixent, patients typically had eczema on 50% or more of their bodies – compared to 30% or less in the TRuE-AD studies. Patients with mild-to-moderate AD are better suited for topical therapy, he said.
Credit Suisse analyst Evan Seigerman called the data positive in a 19 February note, but said the second Phase III study’s good results were largely expected. While topical ruxolitinib is intended for mild-to-moderate AD patients and Dupixent is indicated for moderate-to-severe patients, he predicted that Incyte would not make much headway in the overlapping moderate disease patients. He expects an indication for AD could bring in $300m for Incyte by 2025, but that an ongoing Phase III study of the topical formulation in vitiligo is the bigger market opportunity. Those data are expected in 2021.
“While we could see some overlap in the moderate population, we believe [ruxolitinib and Dupixent] are different (mechanistically and route of administration) and are likely to target different populations,” Seigerman wrote. A key opinion leader in dermatology told Credit Suisse she does not expect novel entrants in the atopic dermatitis space to provide much challenge to Dupixent in the near-term.
Taking a more positive view of the data and Incyte’s opportunity in AD is SVB Leerink analyst Andrew Berens, who said the data “expands [the] revenue opportunity” for the Jakafi franchise.
“The success in the AD pivotal trials is a validation of the opportunity for topical Jakafi in dermatology indications, representing a sizable expansion market for legacy Jakafi API,” Berens wrote in a 19 February note. He predicts a new drug application (NDA) filing with the US Food and Drug Administration before the end of 2020, pending 44-week safety data from the two studies, and expects a launch in 2021 and peak sales of $1.1bn in atopic dermatitis.
What The Trials Showed
The Phase III studies enrolled almost 1,250 patients ages 12 and older who have been diagnosed with AD for at least two years, are candidates for topical therapy, have an Investigator’s Global Assessment (IGA) score of 2 to 3 at baseline and eczema on between 3% and 20% of their body surface area, excluding the scalp.
Statistical significance on the IGA treatment success endpoint is defined as an IGA score of zero (clear) or one (almost clear) with an additional requirement for at least a two-point improvement from baseline. In TRuE-AD2, first reported in January, the 0.75mg dose of topical ruxolitinib met that endpoint in 39% of patients while the 1.5mg dose hit the mark in 51.3% of patients (p<0.0001 for both doses). For vehicle, 7.6% of patients met the endpoint.
In TRuE-AD1, 50% of patients getting the 0.75mg dose of ruxolitinib met the primary endpoint, while 53.8% who got the 1.5mg dose did so (p<0.0001 for both doses). For the vehicle arm, 15.1% met the primary endpoint.
Incyte VP, inflammation & autoimmunity, Jim Lee said in an interview that the variance in vehicle response is not that unusual in a study of a topical therapy for a dermatologic indication. “From a clinical trial perspective, you do get variability in responses – these are two separate studies that were done, so it could just be related to the inherent variability often observed in clinical trials,” he said, adding that Incyte is only starting a deeper dive into the datasets.
“If you take a look at all of the previous studies done with topical therapies in atopic dermatitis, there is a bit of variability in the vehicle response rate,” Lee continued. “It’s not truly a placebo rate, this is a skin disease and it can respond to emollients. The vehicle is actually the cream without the active drug, so we always anticipate some response in that arm – it’s a real response. Then, the real question is what do you get when you add the active drug.”
Lee said Incyte tested ruxolitinib against vehicle in its Phase III program because that is what the US FDA prefers to see.
Top-line data from the two studies revealed that both doses of ruxolitinib met a secondary endpoint of at least a 75% improvement from baseline in eczema severity area index (EASI) score, and demonstrated statistical significance for itch reduction as measured by Itch Numerical Rating Scale. Lee said it is too early to say whether Incyte will seek labeling claims based on those data in its NDA. He also said it is possible the company could seek approval of both doses tested in Phase III or just one of the doses.