Alopecia Areata Clinical Trials Paving the Way for Treatment Innovations
Interest in alopecia areata has skyrocketed since the 94th Academy Awards ceremony, during which stand-up comedian Chris Rock was slapped in response to a joke about the disorder. The increased interest in alopecia areata comes at a time when the space is undergoing exciting changes, from ongoing clinical trials to the potential of new treatment paradigms, says Dr Emma Guttman-Yassky, system chair of dermatology and immunology at the Icahn School of Medicine at Mount Sinai in New York.
“It’s a hopeful time for patients,” Guttman-Yassky adds.
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By GlobalDataAccording to the GlobalData Clinical Trials database, there are 19 industry-sponsored, ongoing Phase I–III trials in alopecia areata, with an additional eight trials planned. In the coming months, the space is also expecting a jump in its treatment options, with the likely entry of Janus kinase (JAK) inhibitors. The potential of anti-programmed cell death protein 1 (PD-1) monoclonal antibodies, a standard in cancer treatment, is also under investigation.
These investigations are inspired by dermatologists utilising off-label drugs that target the inflammatory pathway in alopecia areata patients, leading to clinical trials, says Dr Wilma Bergfeld, senior dermatologist, Cleveland Clinic, Ohio. The exploration of these approaches started with positive efficacy signals in hard-to-treat adults, but the goal is to use them in more patients, such as younger patients and even those with multiple diseases triggered by inflammatory issues like atopic dermatitis, she adds.
Recruitment straightforward for alopecia areata clinical trials
Enrolment in alopecia areata trials is swift as patients have dramatic symptoms that make them highly engaged in looking for better therapeutic options, notes Dr Brett King, associate professor of dermatology, Yale University School of Medicine, New Haven, Connecticut. Guttman-Yassky adds severe patients can consider steroid injections, which are painful, required every month, and unreliable in terms of efficacy. This is not ideal in alopecia areata where the root cause is systemic inflammation with many potential spots requiring injections, she explains.
While there are not many challenges in running alopecia areata trials, there are some, Bergfeld says. One is the addition of quality of life and suicidal ideation evaluations, which, while important, extends a trial participant’s clinical trial site visit for longer. This is on top of the usual photography, blood work, and electrocardiogram checks, she notes. Also, trials that require patients to be off active therapy for one month or longer, and some studies excluding patients who have had any prior biologics, can make recruitment a bit tougher, she says. However, sponsors have started to ease these relatively rigorous criteria.
JAK race in alopecia areata
There are three key oral JAK inhibitor players in alopecia areata: Eli Lilly’s Olumiant (baricitinib), Pfizer’s ritlecitinib, and Concert Pharmaceuticals’ CTP-543 (deuruxolitinib). Currently, all eyes are on the first two, as they already have positive Phase III data.
Concert completed the recruitment of its Phase III alopecia areata program in January, with data from the first trial (NCT04518995) expected in Q2 and data from the second trial (NCT04797650) expected in Q3. A Concert spokesperson says, assuming Phase III program success, it intends to move as rapidly as possible to file to the FDA in the first half of 2023. Other companies in this article did not respond to a comment request.
In the two frontrunner JAK inhibitors with Phase III data, Olumiant and ritlecitinib, have shown overall similar data so far, King says. With Olumiant, the estimated percentage of patients with a Severity of Alopecia Tool (SALT) score of 20 or less at week 36 was 38.8% and 35.9% in the 4mg dose in two separate Phase III trials (NCT03570749; NCT03899259). In the Phase IIb/III ritlecitinib trial (NCT03732807), a significantly greater proportion of patients in the 30mg or 50mg arm had 20% or less scalp hair loss after 24 weeks versus placebo.
Teasing the JAK difference
Due to Olumiant and ritlecitinib’s similar efficacy profiles, clinician choice will come down to which dose would get approved, King says. The higher dose is needed to reach maximum effect, he adds. In the lower 2mg Olumiant dose in the two Phase III trials, 22.8% and 19.4% patients had a SALT score of 20 or less at week 36.
If both doses are approved for both drugs, it will then come down to safety, King adds. In Europe and Japan, Olumiant is already approved for moderate-to-severe atopic dermatitis in both doses. Therefore, Olumiant has real-world safety data that could make clinicians choose Olumiant over ritlecitinib, King noted. However, with ritlecitinib only targeting JAK3 and Olumiant and deuruxolitinib targeting JAK 1 and 2, there is the potential for the former to have a safety edge. “The general rule is that the more specific [a treatment is], the better for safety,” Guttman-Yassky notes.
Still, there seems to be a safety class effect among JAK inhibitors, Bergfeld says. The most common side effects are increased risk of upper respiratory tract infection, tuberculosis, and viral hepatitis, among others, she notes. There are also boxed warnings linked to JAK inhibitors, including for thrombosis event risk, she adds. However, more information on safety is ideal, as these drugs are potentially lifelong therapies, she notes.
Questions remain about what would happen to JAK inhibitor efficacy once treatment is stopped, paused, or if the dose is tapered down, King notes. It is possible that less severe symptoms may return, but details are needed regarding capacity and how differently this may play out between JAK inhibitors, he explains, adding: “We may not have a complete view of efficacy just yet.”
Anti-PD-1 in alopecia areata?
AnaptysBio is offering a different mechanism in this space, as it is investigating its anti-PD-1 monoclonal antibody rosnilimab in a placebo-controlled Phase II trial (NCT05205070). The 45-patient study recruited its first patient in December 2021, with a primary completion date expected in January 2023. It has a primary endpoint of SALT score changes up to 24 weeks.
Monoclonal antibodies are intriguing because they can induce alopecia when used in treating cancer, Guttman-Yassky notes. However, in alopecia areata patients, they could potentially be an agonist that induces hair growth, she says. The hypothesis is that enhancing PD-1 signaling could suppress T-cell-driven human inflammatory diseases.
Preclinical data has focused on inflammation and inhibition of patient immune cells. In a Phase I trial recruiting healthy volunteers, the study collected data on dosing and impact on PD-1, among others. Guttman-Yassky notes that while there is interest in this mechanism, there is still limited data to map out its efficacy potential and limitations in patients.
There is the risk that the anti-PD1 mechanism may not apply to all patients, as JAK is a major pathway in comparison, Bergfeld says. As such, it might come down to patient selection, she notes. The Phase II’s ClinicalTrials.gov page does not specifically mention any screening requirements relevant to rosenlimab’s mechanism.
Update: On June 13, the FDA approved Olumiant to treat adult patients with severe alopecia areata.
