Interim Analysis of an Open-Label, Ascending-Dose, Phase 1 Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Doses of the Subcutaneously Administered Human Monoclonal Antibody Pozelimab in Combination with Single Doses of the Subcutaneously Administered siRNA Cemdisiran in Healthy Volunteers

Introduction. Pozelimab (REGN3918) and cemdisiran (ALN-CC5) are C5 inhibitors under development for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), myasthenia gravis (MG), and other diseases in which tissue damage is mediated by terminal complement pathway activity. Pozelimab is a fully human monoclonal immunoglobulin G4P (IgG4P) antibody directed against C5, and cemdisiran is a synthetic small interfering RNA (siRNA) targeting C5 mRNA. Both agents can be administered via subcutaneous (SC) injection. Pharmacokinetic (PK)/pharmacodynamic (PD) modeling based on observed data from both pozelimab and cemdisiran healthy volunteer studies (NCT03115996, NCT02352493) suggests that, by combining cemdisiran and pozelimab, the dose of both agents may be significantly reduced and the interval for SC dosing of pozelimab may be significantly increased.

Objectives. To provide initial safety and tolerability data for a SC cemdisiran/pozelimab combination approach.

Methods. This is an ongoing phase 1, open-label, parallel-dose cohort combination study (NCT04601844) assessing the safety and tolerability of ascending doses of SC pozelimab in combination with SC cemdisiran when administered on the same day or sequentially, on different days, in healthy subjects.

Cohort Descriptions. Three parallel ascending-dose cohorts, consisting of six subjects each, were selected based on PK/PD modeling using observed data from both pozelimab and cemdisiran non-combination healthy volunteer studies:

• Cohort 1: Cemdisiran low dose SC followed by pozelimab low dose SC, administered on different days

• Cohort 2: Cemdisiran high dose SC followed by pozelimab low dose SC, administered on different days

• Cohort 3: Cemdisiran high dose SC and pozelimab high dose SC, both administered on the same day

Dose regimens were designed to limit the duration of >50% complement inhibition for no longer than 8 weeks, to mitigate risk in the enrolled healthy subjects. An optional additional Cohort 4 was included in the study design and this interim analysis was planned to review safety data to guide the decision regarding whether to enroll this cohort and to inform its dose selection.

Interim Analysis: An interim safety analysis was performed with a data cut-off corresponding to study day 127 for Cohort 1, study day 85 for Cohort 2, and study day 71 for Cohort 3. Eighteen healthy volunteer subjects, nine female and nine male, with a mean age of 36 years (standard deviation 9.5 years), were randomized to one of the three cohorts. Demographic and baseline characteristics were comparable for subjects in each cohort. A total of 47 treatment emergent adverse events (TEAEs) were reported, with comparable distribution across cohorts, all mild to moderate in severity with no severe TEAEs. "Nervous system disorders" was the TEAE System Organ Class with the most subjects for all three cohorts, occurring in 12 (66.7%) of the 18 subjects. "Headache" was the most frequent MedDRA Preferred Term for all three cohorts, occurring in 11 (61.1%) of the 18 subjects. All TEAEs were recovered or recovering at the time of data cut-off, and there were no study drug discontinuations or interruptions of treatment due to TEAEs. There were no serious TEAEs or deaths. There were no clinically meaningful findings or treatment-emergent changes reported on the vital signs or laboratory safety tests.

Conclusions: The combined SC administration of pozelimab and cemdisiran represents a promising approach to achieve therapeutically significant complement inhibition for extended durations.

• An interim safety analysis demonstrated that the combined administration was generally safe and well tolerated.

• Final PK/PD analysis from this healthy volunteer study will allow for assessment of agreement between modeling predictions and observed data, and further inform combination dose regimens for studies in target patient populations.