Phase 3 Izokibep Study in HS Produces Promising Results

AMSTERDAM — The investigational interleukin (IL)-17A inhibitor izokibep induces clear clinical responses in people with moderate to severe hidradenitis suppurativa (HS) within a few weeks of treatment, according to the results of a randomized controlled phase 3 trial presented at the European Academy of Dermatology and Venereology (EADV) 2024 Congress.
One third of the participants treated with the drug achieved at least a 75% reduction in the HS Clinical Response (HiSCR75) at 12 weeks, which was the primary endpoint in the trial. By comparison, this endpoint was met by 21% of those who received placebo (P < .05).
The percentages of participants who met HiSCR90 and HiSCR100 criteria were also significantly higher in the izokibep group, at respective 25% and 22%, than in the placebo group, at respective 9% and 8%. HiSCR50, however, was achieved by a similar proportion of those in each group (48% for izokibep and 37% for placebo, which was not a significant difference).
High Placebo Response Rate
Providing an independent comment for Medscape Medical News, Hans Christian Ring, MD, PhD, a dermatologist from Bispebjerg Hospital, Copenhagen, Denmark, said: “In the HS community, we certainly appreciate the increasing number of biologic therapies that are currently being investigated among moderate to severe HS.”
With regard to the study, he noted that although the primary endpoint of the trial was met, “the efficacy appears limited, and the placebo response rates appear high.”
However, said Ring: “High placebo response rates are also observed in other recent HS trials for secukinumab, bimekizumab, and adalimumab and may reflect the limitations of HiSCR and the pathogenic complexity of the disease.”
Helping People With ‘a Horrible Disease’
The presenting study investigator Kim Papp, MD, PhD, of Probity Medical Research, in Waterloo, Ontario, Canada, told the audience at the EADV 2024 Congress: “Is there anyone here who I have to remind in the how severely hidradenitis [suppurativa] affects people’s quality of life? I think all of us know that hidradenitis is a horrible disease, and we’re constantly searching for new and improved therapies.”
One hopeful candidate is izokibep, a novel IL-17A inhibitor that is considered a small protein therapeutic because of its relatively small size of just 18.6 kDa, which is about one tenth of the size of a standard monoclonal antibody, Papp said. The drug is designed to selectively inhibit IL-17A with high potency and contains an albumin-blinding domain.
“Albumin has two roles to play. One, it will extend the half-life of the drug. Two, it will allow [izokibep] to be carried or mobilized into the target tissues,” said Papp.
So with a theoretical advantage of greater target tissue penetration over other, larger-molecule IL-17A inhibitors, the aim of the phase 3 study he presented was to see if this made a difference to izokibep’s potential efficacy and safety in people with moderate to severe HS.
Phase 3 Study Details
In the randomized, double-blind, placebo-controlled study, people with HS could be included if they had been diagnosed for 6 months or longer, had two or more HS lesions in 22 distinct anatomic areas (Hurley stage II or III), had a total abscess and inflammatory nodule (AN) count of five or more, and had an inadequate response, intolerance, or contraindication to oral antibiotics.
In all, 258 people were randomized, 129 to a once-weekly subcutaneous injection of izokibep at a dose of 160 mg, and 129 to a once-weekly subcutaneous placebo injection.
“The initial study design was 16 weeks, based upon very early analyses following a previous study,” Papp said. However, “it was thought that the optimal results would actually come earlier. So, the primary endpoints in this study were moved up to 12 weeks.”
Baseline characteristics were well matched between the groups. Overall, the mean age of participants was 37 years, 69% were women, and 70% were White, 19% were Black or African American, 7% were Asian, and 4% were grouped under “other” ethnicity. The mean body mass index was 34, 43% were current smokers, and the mean duration of disease was 10.2 years. About two thirds had Hurley stage II HS, and the rest had Hurley stage II HS. The mean AN count was 12.4, and the mean number of draining tunnels was 2.2.
Other Improvements
Skin pain, quality of life, and AN counts were also significantly improved with izokibep treatment relative to placebo at 12 weeks, although no difference in HS flares were observed:
A three-point or more reduction in a numerical rating scale for skin pain was achieved in 33% of those on izokibep vs 17% of those on placebo (P < .05).
Dermatology Life Quality Index scores were reduced by a mean of 4.9 at 12 weeks from a baseline of 12.3 in the izokibep group and by a mean of 2.7 from a baseline of 11.4 in the placebo group (P < .01).
An AN count of 0, 1, or 2 was achieved in 50% of those on izokibep vs 27% of those given placebo (P < .01).
HS flares occurred in a similar percentage of patients (29% of those on izokibep vs 31% of those on placebo).
Safety Findings
Treatment-emergent adverse events (AEs) were recorded in more izokibep- than placebo-treated patients, at a respective 79% vs 53%. The most common of these were injection-site reactions, occurring in 65% and 8% of patients in each group, respectively. Nearly 5% of those treated discontinued the treatment because of injection site reactions, compared with none of those on placebo.
In both groups, headache was also reported in around 10% and nasopharyngitis in 7% of patients. Fatigue and diarrhea were recorded more often in the izokibep group (5.4% for both AEs) than the placebo group (2.3% for fatigue and 1.6% for diarrhea).
Ring also commented on the safety results for Medscape Medical News and said “it is promising that no candida infections nor IBD [inflammatory bowel disease] are reported. However, it appears surprising that 65% experienced injection-site reactions. This AE is considerable higher than other comparable biologic therapies. Moreover, a high number of headache (10%) is reported, which potentially may lead to discontinuation of the drug.”
Papp had reported that around 81% of those randomly allocated to izokibep and 87% to placebo had completed the trial to 12 weeks. The primary reasons given were withdrawal of consent and being lost to follow-up, however, rather than because of any safety concerns.
The study was funded by Acelyrin. Izokibep is an investigational drug that is also being evaluated in phase 3 studies for psoriasis and other non-dermatological conditions. Papp reported research funding, consultancy, or advisory fees from more than 40 pharmaceutical companies, including Acelyrin. Ring reported research funding from the Kgl Hofbundtmager Aage Bang Foundation, acting as an advisory board member for Novartis, and receipt of speaker fees from LEO Pharma.
Sara Freeman is a freelance medical journalist based in London, England.
 
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