Background/Purpose:

CD40/CD40L is a cornerstone pathway for both innate and adaptive immune responses and a suitable target for autoimmune diseases including Sjogren’s. BIIB063 is a high affinity MAb, engineered to reduce Fc effector function and avoid half antibody formation in vivo (IgG4P). BIIB063 has the potential to inhibit germinal center formation, immunoglobulin class switching, T cell activation and cytokine release with a potent inhibition of inflammation and autoimmunity. The results of the first in human and the GLP-toxicology findings are presented.

Methods:

In the single ascending dose (SAD) study, 58 healthy volunteers (HV) subjects were assigned to 8 cohorts. Seven cohorts of 4, 6, or 8 subjects were planned to receive increasing single IV doses of BIIB063 (0.003, 0.03, 0.3, 1, 3, 10, and 20 mg/kg) or placebo. One cohort of 8 subjects was planned to receive a single 150 mg SC dose of BIIB063 or placebo. Staggered dosing was used within each cohort to ensure subject safety. Blood samples were analyzed by ELISA for PK and ADA, and flow cytometry for the PD measure of CD40 receptor occupancy (RO). Safety data, including adverse events (AEs) and laboratory tests, were collected. A 26-Week SC and IV Toxicity Study in Cynomolgus Monkeys with a 16-Week Recovery Period was conducted; animals received 10, 30 or 150 mg/kg BIIB063 twice monthly.

Results:

In the SAD study, a total of 29 subjects had been enrolled when the study was voluntarily put on hold due to findings from the ongoing 26-week toxicology study where 4 unscheduled terminations occurred. A thorough investigation revealed Immune complex (IgM-IgG4) deposits in multiple organs of affected animals, consistent with a type 3 hypersensitivity. This reaction occurred in 44% animals irrespective of the dose level and no NOAEL could be established. .

In the SAD, BIIB063 serum concentrations for the lowest two doses (0.003–0.03 mg/kg), were below the LLOQ. BIIB063 Cmax and AUCinf ranged from 3.7 to 22 ug/mL and 100 to 1880 hr*ug/mL following doses of 0.3 and 1 mg/kg, respectively. BIIB063 showed nonlinear PKs and a dose-dependent CD40 RO and RO duration. There was no significant RO of CD40 at dose levels of BIIB063 <0.3 mg/kg, while full CD40 RO was observed at doses of 0.3 and 1 mg/kg. CD40 RO declined within 96 hr for the 0.3mg/kg dose while CD40 RO lasted 8 days for the 1 mg/kg dose. BIIB063 was generally well tolerated.

No ADA was observed in the 0.003-0.03 mg/kg cohorts where serum concentrations of drug were undetectable, while 67% – 100% subjects had positive ADA in the 0.3-1 mg/Kg cohorts. Interestingly, ADA responses were typically detected several weeks after BIIB063 drug clearance, and in the absence of CD40RO. Hence, the potential impact of ADA on PK and PD was undeterminable.

Conclusion:

BIIB063 administered to HV exhibited a PK profile consistent with an IgG4 molecule. Target engagement as measured by CD40 RO was clearly demonstrated and its duration was dose dependent. ADA response was present in the higher doses cohorts in the SAD. The preclinical toxicology findings and the high immunogenicity of BIIB063 led to the voluntary discontinuation of the trial.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/biib063-a-potent-anti-cd40-antagonistic-monoclonal-antibody-mab-lessons-learned-from-an-early-development-program/