番茄社区

NEW ORLEANS -- A trio of novel therapies produced clinically significant improvements in 40% to 70% of patients with moderate to severe hidradenitis suppurativa (HS), according to data reported here.

Izokibep, a novel interleukin (IL)-17A inhibitor, led to an at least 50% improvement at 12 weeks in 21 of 30 patients, including an "unprecedented" 100% response in a third of patients. The multitargeted monoclonal antibody eltrekibart led to 50% responses (Hidradenitis Suppurative Clinical Response 50, HiSCR50) in two-thirds of patients in a small placebo-controlled trial. Long-term follow-up in two randomized trials of the IL-17A and F inhibitor bimekizumab (Bimzelx) showed that response rates continued to increase out to 1 year and that patients who switched from placebo to active drug did as well as those randomized to bimekizumab.

The design of izokibep offers several potential advantages over other HS therapies, including enhanced potency, improved tissue penetration, and extended plasma half-life, along with a well-tolerated safety profile, said Kim Papp, MD, PhD, of Probity Medical Research in Waterloo, Ontario, Canada, at the American Academy of Dermatology annual meeting.

"We achieved unprecedented responses with no additional safety signals, and the evidence is certainly compelling to support progressing this drug into phase III development, which is what's happening," said Papp.

The molecular design of izokibep addresses a key limitation of other therapies used to treat HS. For reasons that are not entirely understood, drug exposure in HS is lower as compared to use of the same drug in other types of inflammatory conditions.

In its 2015 approval of adalimumab (Humira) for HS, the FDA pointed out the lower tissue concentration observed in patients with HS versus those with psoriasis, said Papp. A from an early trial of bimekizumab in HS noted lower-than-expected circulating drug levels.

In contrast to other anti-IL-17A drugs, izokibep simultaneously binds to both protein subunits, resulting in higher affinity and potency. The antibody is one-tenth the size a typical monoclonal antibody, enabling greater tissue concentration. Attachment to the albumin-binding domain results in a longer half-life, said Papp.

Izokibep

With what they believed to be a better-designed drug, investigators evaluated izokibep's safety and efficacy in a phase IIb open-label trial. The primary objective was to determine whether the drug had clinical attributes that made further evaluation in a phase III trial worthwhile.

The study involved 30 patients who had a mean age of 38. Almost half of the cohort was Black, and women accounted for 70%. The patients had a mean abscess/inflammatory nodule count of 7.0, and two-thirds had Hurley stage II severity.

The analysis showed an HiSCR50 response rate of 71% at 12 weeks. Perhaps more important, 57% of the patients had HiSCR75 responses, 38% met HiSCR90 response criteria, and 33% had complete clearance (HiSCR100). An HiSCR50 response is fairly standard for clinical trials in HS, so the high rates of HiSCR75, 90, and 100 are particularly meaningful, as patients with high disease burden may still have substantial residual disease with an HiSCR50 response, Papp noted.

The most common treatment-emergent adverse event (TEAE) was injection-site reaction (40%). Additionally, five patients had injection-site pruritus, four had erythema, and three had swelling at the injection site. Moderator Andrew Blauvelt, MD, of the Oregon Medical Research Center in Portland, wondered whether izokibep's molecular construct might have been a contributing factor.

"I don't think we really understand the injection-site reactions," said Papp. "To be honest, overall, the injection-site reactions are not problematic."

Eltrekibart

Eltrekibart (LY3041658) is a septa-specific monoclonal antibody to the chemokine receptors CXCR1 and CXCR2, meaning the molecule binds all seven ligands of the targets, said Seth Forman, MD, of ForCare Clinical Research in Tampa, Florida. CXCR1 and 2 are involved in neutrophil migration to sites of inflammation, a in HS pathogenesis.

Forman reported findings from a phase II placebo-controlled trial of patients with moderate or severe HS (HS duration ≥6 months; at least two distinct anatomical regions, at least one of which was Hurley II or II status; and total abscess/inflammatory node count of at least 4.0). Patients were randomized 2:1 to eltrekibart or placebo, and the primary endpoint was the percentage of patients attaining HiSCR50 response at week 16. All patients received eltrekibart maintenance therapy during follow-up to 36 weeks.

Investigators performed two comparative analyses. One analysis directly compared outcomes between the eltrekibart and placebo arms. A second prespecified analysis compared results with eltrekibart versus placebo results augmented by historical data from published studies.

Analysis of the week-16 response data showed that 65.6% of the eltrekibart group achieved HiSCR50 responses versus 41.4% of the placebo group and 32.3% for the augmented placebo results. Forman said their analyses included a 61.9% Bayesian posterior probability of a ≥30% difference in favor of eltrekibart and the augmented placebo results.

The mean abscess/nodule count decreased by 6.8 with eltrekibart but remained the same with placebo.

During the maintenance phase, the HiSCR50 response rate at 36 weeks increased to 81.9% among patients randomized to eltrekibart during the double-blind phase of the trial.

TEAEs were generally mild or moderate in severity, said Forman. One patient in the eltrekibart group discontinued because of adverse events during randomized treatment, and one discontinued during the maintenance phase. The most common TEAEs were infection (including COVID-19), constipation, diarrhea, skin disorders, and musculoskeletal disorders/arthralgia. More notable, said Forman, was the absence of several types of adverse events, including thromboembolic events, herpes simplex infection, and declines in hemoglobin.

"Neutralizing seven distinct CXCR1 and CXCR2 ligands with a septa-specific monoclonal antibody is a promising therapeutic strategy for HS and potentially other neutrophil-predominant disorders," Forman said.

Bimekizumab

Two phase III randomized trials, and , showed HiSCR50 response rates of 45% to 54% by week 16 in patients randomized to receive bimekizumab every 2 or 4 weeks. Patients allocated to bimekizumab received maintenance treatment to 48 weeks, and patients in the placebo groups switched to bimekizumab. The trials involved a combined total of 1,014 patients with moderate/severe HS.

In both trials, patients who received rescue antibiotics or who discontinued treatment were considered non-responders. Data analysis with multiple imputations for non-response (mNRI) showed 48-week HiSCR50 response rates of 53% to 61% with bimekizumab in BE HEARD I and 61% to 64% in BE HEARD II. Corresponding rates for patients who switched from placebo to bimekizumab at 16 weeks were 45% and 68%, reported Alexa Kimball, MD, MPH, of Beth Israel Deaconess Medical Center in Boston.

The observed rates of HiSCR50 response with bimekizumab at 48 weeks ranged from 77% to 80% in BE HEARD I and 76% to 82% in BE HEARD II. Rates for the placebo-switch groups were 66% and 74% in BE HEARD I and II, respectively.

Investigators performed the same analyses for HiSCR75 response rates. With mNRI, the 48-week rates with bimekizumab ranged from 41% to 47% in BE HEARD I and from 47% to 54% in BE HEARD II. Corresponding rates for the placebo-switch groups were 40% and 60%. Observed rates at 48 weeks with bimekizumab ranged from 56% to 64% and from 58% to 71% in BE HEARD I and II, respectively. HiSCR75 rates for the placebo-switch groups were 57% and 67%.

Collectively, the data suggested that dosing every 2 weeks "edged out" 4-week dosing strategies, said Kimball. Bimekizumab was generally well tolerated, and no new safety signals emerged from weeks 16 to 48.

"The improvement [with bimekizumab] takes place fairly early and then slows down a little but continues to improve over a long period of time," she added. "That's very consistent with my clinical experience with these types of agents."