0009: Pharmacokinetics, Receptor Occupancy, and Pharmacodynamics of Obexelimab Following Intravenous Administration in Adult Healthy Volunteers and in Patients with Rheumatoid Arthritis

Xiaodong Wang, Mark Matijevic, Allen Poma, Shauna Quinn, Minggeng Gao, Lisa Crockett, Jessica Karnes, Keith Wilcoxen and Hua Mu, Zenas BioPharma, Waltham

Background/Purpose: Obexelimab is a novel bifunctional antibody that inhibits B-cell, CD19 expressing plasma cell, and plasmablast activity and is expected to provide clinical benefit across multiple autoimmune disorders. The purpose of this investigation was to evaluate the pharmacokinetics (PK), receptor occupancy (RO), and pharmacodynamics (PD) of obexelimab following intravenous (IV) administration in adult healthy volunteers and in patients with rheumatoid arthritis (RA).

Methods: The PK of obexelimab in healthy volunteers was investigated in a Phase 1, single center, randomized, partially double-blinded, placebo-controlled, single ascending dose (SAD) study. Forty-eight subjects were randomized (3:1) to receive single IV infusions of obexelimab (0.03, 0.1, 0.2, 0.6, 2.0, 5.0, and 10.0 mg/kg) or placebo. Serial blood samples were obtained to at least Day 71 after dosing for determination of serum PK, CD19/FcγRIIb RO, and CD20+ B cell counts.

The PK of obexelimab in RA patients was investigated in a Phase 2a, multi-center, randomized, double-blinded, placebo-controlled study of multiple ascending dose (MAD) (Part A) followed by a cohort expansion (Part B). A total of 57 RA patients were randomized (3:1) to receive ascending IV infusions of obexelimab (0.3, 1.0, 3.0 and 10.0 mg/kg) or placebo every two weeks (Q2W) for 6 doses (Part A), followed by an expansion cohort at 10.0 mg/kg or placebo (randomized 2:1) Q2W for 6 doses (Part B). Serial blood samples were obtained after the first and last (6^th) dose and to Day 169 for determination of serum PK, CD19 RO, and CD20+ B cell counts.

PK parameters were estimated by non-compartmental analysis. CD19 RO, FcγRIIb RO, and CD20+ B cell counts were determined via flow cytometry.

Results: Obexelimab demonstrated similar PK profiles in healthy volunteers and RA patients. Dose proportional PK was observed in both studies.

In the SAD study, faster clearance and shorter half-life was observed at lower dose levels (0.03 to 0.2 mg/kg). At the 4 higher doses (0.6 to 10.0 mg/kg), clearance and half-life were relatively constant (averaged 16.7 ± 3.4 mL/day/kg and 3.6 ± 1.2 days, respectively), consistent with target-mediated drug disposition.

In the MAD study, clearance and half-life were similar across all 4 dose levels and comparable to those from the SAD study. The last dose clearance and half-life averaged 15.2 ± 3.7 mL/day/kg and 3.5 ± 1.1 days, respectively.

In the SAD study, complete CD19 RO was demonstrated on Day 2 at all dose levels. FcγRIIb RO was partially saturated (< 45%) at lower doses up to 2 mg/kg and higher saturation (~70 to 80%) was achieved with 5 and 10 mg/kg doses. Similarly in the MAD study, complete CD19 RO was demonstrated from Day 2 through the end of dosing for the 1.0 to 10.0 mg/kg cohorts. In both studies, the nadir of CD20+ B cells was observed at approximately 50% of baseline values. Recovery of CD19/FcγRIIb RO and CD20+ B cells to 80% of baseline values appeared to be dose dependent.

Conclusion: Obexelimab PK were similar between adult healthy volunteers and RA patients. Robust RO and PD data at the investigated doses from both studies supported further clinical development of obexelimab to treat B-cell mediated autoimmune diseases.

Disclosures: X. Wang, Zenas BioPharma; M. Matijevic, Zenas Biopharma; A. Poma, Zenas BioPharma; S. Quinn, Zenas BioPharma; M. Gao, Zenas Biopharma; L. Crockett, Zenas BioPharma; J. Karnes, Zenas BioPharma; K. Wilcoxen, Zenas BioPharma; H. Mu, Zenas Biopharma.