In the Pipeline: New Approaches to Vitiligo, Congenital Ichthyosis, and More

An investigational topical isotretinoin formulation from Timber Pharmaceuticals shows benefit in the treatment of congenital ichthyosis (CI), regardless of the subtype. Findings from a sub-analysis of the Phase 2b CONTROL study of TMB-001, presented by Christopher Bunick, MD, PhD at the American Academy of Dermatology (AAD) 2022 Annual Meeting in Boston, show a substantially greater proportion of patients treated with TMB-001 0.05% achieved VIIS-50 and ≥2-grade IGA improvement compared with vehicle, regardless of subtype. Among enrolled patients, 55 percent had ARCI-LI and 45 percent XLRI subtypes.

All patients with XLRI or ARCI-LI who received TMB-001 0.05% and were compliant with treatment achieved VIIS-50 compared to 75 and 17 percent, respectively, of those receiving vehicle. Similarly, all patients with XLRI or ARCI-LI who received TMB-001 0.05% and were compliant with treatment had ≥2-grade improvement in IGA score compared to 25 percent and no patients, respectively, receiving vehicle.

There are no drugs FDA approved specifically to treat congenital ichthyosis, and most patients are managed with topical keratolytics, Dr. Bunick notes. Severe disease may be managed off label with systemic retinoids. Data from the Phase 2A clinical trial, recently published in the Journal of American Academy of Dermatology, showed good efficacy and safety for the topical isotretinoin ointment.

Although the study was double-blind, Dr. Bunick says that many patients reported positive feedback. “I was seeing significant clearance of patients’ skin and improved quality of life. The patients kept telling me, ‘This medicine is changing my life in terms of less scale or the ability to be normal and sleep better with less itch.’”

“One of the reasons that I’m really excited about the topical isotretinoin ointment for congenital ichthyosis is that it’s proving to be very safe, both in the Phase 2a clinical trial and now the Phase 2b clinical trial; there were no major safety signals,” Dr. Bunick observes. “There are no hospitalizations, no deaths, and blood monitoring shows no significant absorption of isotretinoin systemically into the blood.”

“I think it’s important for the dermatology community to realize that, in the phase 2b trial, patients were allowed to cover up to 90 percent of their entire body surface area with the study medication. The medication is not being systemically absorbed, and we’re not seeing systemic side effects. I think that particular aspect of safety is very strongly in favor of this medicine being safe,” he says. “We did see largely local skin reactions, which range from mild to moderate. As a whole, patients tolerated treatment really well with a little bit of mild to moderate redness, itching, and sometimes a little irritation in the area.”

The average body surface area treated in the study was 73.5 percent. “I think that speaks volumes to the efficacy data that we saw, meeting the primary endpoints, and to the safety data that we’ve emphasized. Patients were using isotretinoin over three-fourths of their body with no safety signals identified,” Dr. Bunick observes.

Dr. Bunick notes that features of the novel formulation contribute to both the efficacy and safety seen to date. The patented IPEG delivery system facilitates the delivery of active, stable isotretinoin, “and helps it interact with the skin in a way that’s less irritating and facilitates the medication getting where it needs to go in the skin layers so that it can be efficacious.” Dr. Bunick says. “This is all attributable to the design of the delivery vehicle. Actually, this is an example of personalized medicine, as it was designed to specifically treat congenital ichthyosis patients. That’s a very important fact.”

New 52-week results from the pivotal Phase 3 TRuE-V clinical trial program evaluating Incyte’s topical JAK1/JAK2 inhibitor, ruxolitinib cream (Opzelura), in adolescent and adult patients (age ≥12 years) with nonsegmental vitiligo show that twice daily application with ruxolitinib cream produced clinically meaningful facial and total body repigmentation. A greater proportion of treated patients reached the facial and total body Vitiligo Area Scoring (F-VASI and T-VASI, respectively) endpoints at week 52.

Among patients who applied ruxolitinib cream daily from the start of the trial, approximately 50 percent of patients achieved ≥75% improvement in the facial Vitiligo Area Scoring Index (F-VASI75) at week 52, compared to approximately 30 percent improvement in the F-VASI75 improvement from baseline reported for these patients at Week 24 (previously reported).

Vitiligo affects about 0.5 to two percent of the population and affects all races, ethnicities, genders, and ages—although most patients develop vitiligo by the age of 20—says David Rosmarin, MD, Vice Chair of Research and Education, Department of Dermatology at Tufts Medical Center. He presented the 52-week data in a late-breaking abstract session at the 2022 AAD Annual Meeting in March.

“The impact of vitiligo on patients varies. Some patients want to be accepted as they are and don’t want to be repigmented, and it’s important for us to accept that. There are other patients who want to get their pigment back. For some, it can be devastating; it can affect their relationships with others, their mental health, their relationships and intimacy. Children can be bullied in school or feel like they are stared at. It changes the way people dress to try to cover up the lesions. It can have a very high impact on some patients.”

Dr. Rosmarin says that the potential impact of vitiligo and a lack of any treatments specifically for the disease makes the new findings particularly relevant. “The results confirm what we saw in the Phase 2 study. After 24 weeks of treatment, 30 percent of patients achieve F-VASI75, however, with continued use of the medicine, that number increases to about 50 percent of patients by the year mark. For some patients, they can see a response in the F-VASI75 within the first few months of treatment. In terms of T-VASI, about 50 percent of patients are achieving that endpoint at Week 52. In terms of the Vitiligo Noticeability Scale, where patients describe their vitiligo as either no longer noticeable or a lot less noticeable, that number is around 30-40 percent at the year mark.

“The key points here are that we’re seeing patients have continued benefit with continued use of the medication. In fact, at Week 52, they probably still haven’t yet plateaued. We’re also seeing very good color matching in terms of the photos that we’re capturing. And these are all meaningful responses to patients.”

Dr. Rosmarin notes the “remarkable” consistency of the data at 52 weeks compared to the Phase 2 study. “When we look at the Phase 2 study, it showed about 30 percent of patients achieving the F-VASI75 at Week 24 and 50 percent around at week 52. We see the same results, basically, in both larger Phase 3 studies. We see a similar result in the crossover arm—patients who were originally given the vehicle and then given the medicine after 24 weeks of not being on active treatment,” he says. “In terms of subgroup analysis that was done on the Phase 3 program, patients of all ages, races, genders, duration of disease can still respond to the medicine. Even patients who had vitiligo for more than 50 years can still respond well to ruxolitinib cream. I think that’s an important point.”

Data show a favorable safety profile and good tolerability for ruxolitinib cream, Dr. Rosmarin notes, with low rates of application site burning reported. “We know that other medicines, such as calcineurin inhibitors, can cause some burning for patients; this medicine seems to be very well tolerated. There is about a six percent rate of application site acne, and that’s a class effect from JAK inhibitors. Labs were checked throughout the study and we didn’t see any clinically meaningful changes,” he says.

Ruxolitinib cream is under FDA review for the treatment of adolescent and adult patients with vitiligo (age ≥12 years) with a PDUFA target action date of July 18, 2022. If the drug is approved, clinicians will need to establish maintenance regimens. “Once patients achieve adequate repigmentation and meet their goals, we don’t know what will be the best dosing regimen yet. Will they need to use the medicine, for instance, twice a week to maintain the response? That’s still something that needs to be explored.”

There may also be a role for combination approaches. “The Phase 3 program only looked at ruxolitinib cream monotherapy. For many patients, that’s a convenient option. However, it is completely possible that combining ruxolitinib cream with other options like phototherapy in particular may be synergistic. In the Phase 2 program, patients were allowed to use light treatment voluntarily in the third part of that study, and we did see continued responses with the use of light in combination with ruxolitinib cream.”

With a lack of multiple, high quality randomized controlled trials in vitiligo, “It’s been hard to give patients complete guidance on what their chances are of repigmenting in areas like the face and the body,” Dr. Rosmarin says. “We now have that information based on this great randomized controlled Phase 3 program. We’re seeing that ruxolitinib cream works really well for face as well as body.”

Data Updates from the Dermatology Pipeline

Olumiant (baricitinib) from Eli Lilly: Produced significant scalp, eyelash, and eyebrow hair regrowth at 52 weeks; nearly 75 percent of those who responded to Olumiant 4mg achieved 90 percent scalp coverage.

FDA has granted priority review for Olumiant as a potential first-in-disease medicine for severe alopecia areata.

The 52-week pooled findings, presented at the AAD Annual Meeting, demonstrate continued improvement in scalp, eyebrows, and eyelash hair regrowth from 36-week results published recently in the New England Journal of Medicine.

Among patients who took Olumiant 4mg, 39 percent achieved significant scalp hair regrowth, defined as a SALT score ≤20, or 80 percent or more scalp hair coverage; 74.1% also achieved a SALT score ≤10, or 90 percent hair coverage, at 52 weeks.

Effisayil (Spesolimab) from Boehringer Ingelheim: Clears skin pustules in patients with generalized pustular psoriasis (GPP) flares within the first week after treatment; benefits are sustained over 12 weeks.

FDA has accepted a Biologics License Application (BLA) and granted Priority Review for spesolimab for the treatment of GPP flares.

Spesolimab, a novel, humanized, selective antibody that blocks the activation of the interleukin-36 receptor (IL-36R). According to data presented at the 2022 AAD Annual Meeting in Boston, 84.4 percent of patients who received spesolimab had no visible pustules at 12-weeks; 81.3 percent had clear/almost clear skin.

The Effisayil 1 trial, recently published in The New England Journal of Medicine, showed significant clearance of skin pustules in patients with GPP flares within the first week after treatment with spesolimab versus placebo.

Rapid skin clearance observed in the first week following treatment with spesolimab was generally consistent across patient subgroups, including age, gender, ethnicity, and IL-36 gene mutation status.

Dupixent (dupilumab) from Sanofi-Regeneron: Significantly reduced itch and skin lesions compared to placebo in adults with uncontrolled prurigo nodularis (PN).

Findings presented at the AAD 2022 Annual Meeting are the first from a Phase 3 trial demonstrating that targeting key drivers of type 2 inflammation, IL-4 and IL-13, with dupilumab significantly improved itch and skin lesions in PN.

The randomized, placebo-controlled PRIME2 trial met its primary and all key secondary endpoints; 37 percent of Dupixent patients experienced a clinically meaningful reduction in itch from baseline compared to 22 percent of placebo patients at week 12. Nearly three times as many Dupixent patients experienced a clinically meaningful reduction in itch from baseline at week 24: 58 percent of Dupixent patients compared to 20 percent of placebo patients.

Nearly three times as many Dupixent patients achieved clear or almost clear skin at week 24: 45 percent of Dupixent patients compared to 16 percent of placebo patients.

Safety results were generally consistent with the known safety profile of Dupixent in its approved dermatology indications.