Zenas BioPharma Eyes Key Lupus and IL-17 Data as Obexelimab FDA Decision Nears

Key Points

• Obexelimab’s FDA decision is approaching: Zenas BioPharma’s application for IgG4-related disease is under review, with a May 27 PDUFA date, while the company also awaits European regulatory review.
• Key lupus data are expected later this quarter: Phase II SunStone results will assess obexelimab in systemic lupus erythematosus using BICLA and SRI-4 endpoints, including a biomarker-positive subgroup that could shape future Phase III design.
• ZB021 is advancing toward proof-of-concept studies: Upcoming Phase I data will focus on safety, tolerability and pharmacokinetics for the oral IL-17AA/AF inhibitor, with Zenas currently prioritizing rheumatology indications over psoriasis for initial development.

Zenas BioPharma NASDAQ: ZBIO outlined development plans for obexelimab in systemic lupus erythematosus (SLE) and ZB021, an investigational oral IL-17AA/AF inhibitor, during an R&D event ahead of clinical data expected later in the quarter.

Founder and Chief Executive Officer Lonnie Moulder said the company’s immediate priority remains a potential approval and launch of obexelimab for IgG4-related disease. The biologics license application is under FDA review with a May 27 PDUFA date, while a marketing authorization application has also been submitted to the European Medicines Agency.

Moulder said Zenas expects top-line results from its Phase II SunStone trial of obexelimab in SLE, as well as pharmacokinetic, safety and tolerability data from the Phase I single-ascending-dose and multiple-ascending-dose study of ZB021, later this quarter. The results are expected to guide program strategy and capital-allocation decisions.

SunStone Trial Targets Lupus Heterogeneity

The SunStone study is a randomized, double-blind, placebo-controlled Phase II trial in patients with active moderate-to-severe SLE. Patients were randomized equally to receive weekly obexelimab or placebo for 24 weeks, with about 95 participants in each arm.

Lisa von Moltke, Zenas’ head of research and development and chief medical officer, said the primary endpoint is the BILAG-based Composite Lupus Assessment, or BICLA, at week 24. The company will also report the SLE Responder Index, known as SRI-4. Both endpoints will be analyzed in the broader study population and in a biomarker-positive subgroup.

The trial’s modified intention-to-treat population includes 160 patients, while the exploratory biomarker population includes 177 patients. Patients enrolled in China could not be included in the biomarker analysis because of challenges involving the processing and use of genetic information, von Moltke said.

The study was designed to detect an approximately 20% difference between obexelimab and placebo at an alpha of 0.10, assuming a 30% placebo response rate. Zenas said changes from an earlier Phase IIa study include a larger trial, subcutaneous dosing, and use of an adjudication committee to evaluate eligibility and outcomes.

Chief Scientific Officer Haley Laken said the biomarker work is based on gene-expression signatures intended to identify patients more likely to respond to B-cell-directed treatment. In a post-hoc analysis from an earlier Xencor-conducted Phase IIa study, 17% of patients in the intention-to-treat population maintained improvement versus placebo at week 32, compared with 52% in a biomarker-positive group. Laken characterized those prior findings as hypothesis-generating.

Zenas plans to assess multiple biomarker-score cutoffs in SunStone, examining the relationship between treatment effect and the proportion of patients classified as biomarker-positive. If supportive, the company could validate a selected biomarker prospectively in a Phase III study, potentially through a biomarker-only or hierarchical design.

ZB021 Phase I Data to Inform Proof-of-Concept Plans

ZB021 is designed to inhibit IL-17AA and IL-17AF, cytokines associated with inflammatory conditions including plaque psoriasis, psoriatic arthritis, axial spondyloarthritis and hidradenitis suppurativa. Laken said ZB021 binds to a central pocket of IL-17AA, preventing receptor binding and signaling. Structural modeling predicts similar binding to IL-17AF.

In preclinical work cited by the company, ZB021 produced an IC50 of 1.5 nanomolar and an IC90 of 6.8 nanomolar in an assay using human keratinocytes. In a rat collagen-induced arthritis model, the candidate showed dose-dependent reductions in clinical score, with activity at 10 milligrams per kilogram once daily comparable with a rat-reactive anti-IL-17 biologic.

Zenas also reported approximately 80% oral bioavailability in non-human primates and said minipig studies showed concentrations in skin, joints and feces that were similar to or higher than plasma levels. The company said the Phase I study in healthy volunteers is intended to establish safety, tolerability and pharmacokinetics for single doses and seven-day once-daily multiple doses.

Laken said Zenas is seeking to achieve average drug concentrations above the IC90 in disease-relevant tissues with once-daily dosing. The company expects to focus its upcoming disclosure on safety, tolerability and pharmacokinetics, including average concentration, or Cavg, relative to the IC90. Pharmacodynamic biomarkers are expected to become more relevant in patient studies because IL-17 is not readily measurable in healthy volunteers.

Potential Focus on Rheumatology Indications

Moulder said Zenas has not made a final decision on the first proof-of-concept indication for ZB021, but the company is strategically focused on rheumatology rather than pursuing psoriasis as an initial registration indication.

Joseph Merola, president of the Rheumatologic Dermatology Society, said IL-17 inhibition is a key treatment mechanism in psoriatic disease, particularly psoriatic arthritis. He said oral therapies could appeal to patients seeking convenience or an alternative to injections, provided they offer an appropriate efficacy and safety profile.

Moulder added that the company expects to present obexelimab open-label extension and vaccine data at the American College of Rheumatology meeting in November. Zenas also expects initial clinical data for its brain-penetrant TYK2 inhibitor, ZB022, and its extended half-life CD19 and FcγRIIb-targeting candidate, ZB014, in 2027.

About Zenas BioPharma (NASDAQ:ZBIO)

Zenas BioPharma, Inc is a clinical-stage biopharmaceutical company focused on developing immune-based therapies for autoimmune diseases and other serious immune-mediated conditions. The company's research is centered on treatments designed to modulate B-cell activity and restore balance to the immune system.

Zenas' lead product candidate is obexelimab, an investigational bifunctional antibody designed to bind CD19 on B cells and Fc gamma receptor IIb. By engaging both targets, obexelimab is intended to inhibit pathogenic B-cell activity without broadly depleting B cells.

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