Novel Therapies for Hidradenitis Suppurativa Produce Rapid, Deepening Responses

DENVER — Two therapeutic candidates for severe hidradenitis suppurativa (HS) achieved major responses that proved durable in randomized trials reported here.

The IL-17A/F inhibitor sonelokimab achieved at least 75% skin clearance (HiSCR 75) at 40 weeks in 62% of patients enrolled in identical phase III clinical trials. Two different doses of the oral JAK1 inhibitor povorcitinib produced at least 50% clearance (HiSCR 50) in 57-71% of patients after 54 weeks of follow-up in two separate trials.

Both of the agents were well tolerated and associated with low rates of serious and grade ≥3 treatment-emergent adverse events (TEAEs), as reported at the American Academy of Dermatology meeting.

“[Sonelokimab] had a very rapid onset of clinical improvement that continued out to week 40, with really meaningful increases in improvement in both the clinical metrics and measures of quality of life,” said Alexa Kimball, MD, MPH, of Beth Israel Deaconess Medical Center in Boston. “Having a mild or non-impact of HS on most of these patients at week 40, I think really is quite substantially important, especially given that this is a designed assessment for HS patients in particular… . Dosing every 1 month is, of course, convenient for patients.”

Follow-up will continue to week 52.

In the STOP-HS1 and HS2 trials, povorcitinib led to deep responses in a substantial fraction of patients, associated with significantly improved quality of life.

“Povorcitinib demonstrated substantial clinical efficacy through week 54, as up to 29% of patients achieved high score [HiSCR] 100,” said Martina Porter, MD, also of Beth Israel Deaconess Medical Center. “We saw really great responses for inflammatory nodules, abscesses, and draining tunnels [ANdT], and this really led to meaningful improvements in skin pain, fatigue, and quality of life. In terms of complete inflammatory clearance, we also looked at ANdT count of 0 — no abscesses, inflammatory nodules, or draining tunnels at 54 weeks — and up to 20% of patients achieved the endpoint.”

“Both doses of povorcitinib were generally very well tolerated through the 54 weeks of treatment,” she added. “This really does support the potential of povorcitinib for treatment of moderate to severe HS in the future.”

VELA Trials of Sonelokimab

Sonelokimab is a member of a novel biologic class known as a nanobody. In contrast to a conventional monoclonal antibody, a nanobody is a small antigen-binding fragment that has increased binding sensitivity, lower toxicity, and better overall safety.

“This allows us to do some interesting things, such as link two different moieties together [IL-17A and F], coupled to an anti-albumin component, allows for higher persistence in the bloodstream and other places,” said Kimball. “We think that the small characteristics may lead to some advantages in terms of the pharmacodynamics and the penetrance of the medication.”

Treatment with sonelokimab yielded positive results in phase II trials in psoriatic arthritis and plaque psoriasis, as well as HS. Kimball reported findings after 40 weeks of follow-up in the phase III VELA-1 and VELA-2. The trials involved a combined total of 838 adult patients with moderate/severe HS, randomized 2:1 to sonelokimab or placebo. The primary endpoint was HiSCR 75 response rate at 16 weeks. A previous report showed that a third of patients treated with the IL-17 inhibitor met the primary endpoint versus 18-25% for the placebo-treated patients.

The updated analysis after 40 weeks showed that 62% of patients in both trials attained HiSCR 75 responses, and 74-79% of the patients achieved HiSCR 50 responses. Additionally, 36-40% of the patients treated with sonelokimab had HiSCR 90 responses, and about 30% in both trials combined had complete clearance (HiSCR 100). The novel therapy produced substantial improvement across the most common types of HS lesions, including 71-75% reductions in inflammatory nodules, 72-79% for abscesses, and 60-69% for draining tunnels.

The clinical improvement was associated with substantial improvements in quality of life, as more than 60% of patients treated with sonelokimab reported “mild/none” for their severity rating at week 40.

The 52-week safety data continues to be analyzed, but 16-week data showed that serious TEAEs occurred in 2.5% of patients treated with the IL-17 inhibitor. The most common TEAEs associated with sonelokimab were nasopharyngitis (8.6%) and oral candidiasis (7.3%).

In addition to continued follow up in the VELA trials, ongoing studies are evaluating the IL-17 nanobody in a long-term extension of the VELA program, and a separate trial is evaluating the novel agent in adolescents, said Kimball.

STOP-HS1 and 2

In her introduction to the povorcitinib data, Porter repeated a common answer to the question of how JAK inhibitors interfere with HS: “I don’t think we really know that answer, but looking at this data, you can see that [the disease] has a profound response to JAK inhibition.”

The STOP-HS1 and HS2 trials included more than 1,200 adults with moderate/severe HS, randomized to one of two doses of povorcitinib or placebo. The primary endpoint was HiSCR 50 response rate at 12 weeks. As reported last year, the primary analysis showed HiSCR 50 responses in 40-42% of patients treated with either dose of the JAK inhibitor across the two trials.

The updated analysis after 54 weeks showed deepening responses, as the HiSCR 50 rates with povorcitinib increased by about 50% from 12 to 54 weeks for both doses of the JAK inhibitor in both trials. Patients who crossed over to povorcitinib after 12 weeks had rapid responses that deepened over time, including high-threshold responses of HiSCR 75, 90, and 100.

From one- to two-thirds of patients treated with povorcitinib had clinically meaningful improvement in multiple measures of quality of life, said Porter.

Serious TEAEs occurred in 4-6% of povorcitinib-treated patients and grade ≥3 TEAEs in 5-8%. The most frequent TEAEs associated with the JAK inhibitor were acne, nasopharyngitis, and upper respiratory tract infection. Among AEs of special interest, only one major adverse cardiovascular event occurred, eight thromboembolic events, and no malignancies in almost 1,200 patients treated with the drug, including those who crossed over from placebo. Serious and opportunistic infections occurred in 0-2% patients treated with either dose across the two trials.

Please enable JavaScript to view the comments powered by Disqus.