Background/Purpose: BHV-1300 is a molecular degrader of extracellular protein (MoDE^TM) in development for the treatment of IgG-driven autoimmune diseases, including rheumatoid arthritis. MoDEs are bifunctional molecules that reduce pathogenic IgG autoantibodies and immune complexes through asialoglycoprotein receptor (ASGPR)-mediated lysosomal degradation in the liver.

TNFα inhibitors and other biologic DMARDs (bDMARDs), the cornerstone of RA therapy, do not achieve sustained remission in a large proportion of patients. The development of neutralizing anti-drug antibodies (ADAs) can reduce the efficacy of these agents. 

Unlike other IgG targeting approaches (i.e. FcRN inhibitors), BHV-1300 can be co-administered with Fc-containing bDMARDs. BHV-1300 has the potential to lower pathogenic autoantibodies, and immune complexes, and to optimize the efficacy of bDMARDs by reducing ADAs.

Methods: Studies were conducted in cynomolgus monkeys to (1) assess the PK of adalimumab when co-administered with BHV-1300 and (2) evaluate the ability of BHV-1300 to remove adalimumab ADAs and restore anti-TNFα activity.

Study 1: 6 groups of cynos (3/group, N=18) received single doses of adalimumab (3 mg/kg SC x1) at various times relative to BHV-1300 (30 mg/kg IV x1). Concentrations of BHV-1300 and adalimumab were determined by LCMS and ELISA, respectively.

Study 2: Cynos received adalimumab (10 mg/kg) in CFA followed by two QW doses of adalimumab in PBS (10 mg/kg). ADA positive cynos were randomized to Groups 1 and 2, and ADA negative cynos were placed in Group 3. Group 2 received active drug (BHV-1300 50 mg/kg IV x1) while Groups 1 and 3 received placebo. After 24 hours, all cynos received adalimumab (3 mg/kg SC x1). Readouts included adalimumab PK, adalimumab’s neutralizing activity of TNF-a, total IgG and PK of BHV-1300.

Results: In Study 1, adalimumab PK, at all timepoints from 6- to 48-hours post-dosing with BHV-1300, was within 20% of historical values. Concentrations of BHV-1300 at 24 hours post-dose showed < 1.5x difference across the 6 groups (see Table 1).

In Study 2, 3/5 cynos in Group 2 had improvement in ADA titers following treatment with BHV-1300 vs. 0/5 untreated ADA-positive cynos. There were significant improvements in adalimumab anti-TNFα activity in BHV-1300 treated ADA+ cynos vs. PBO (Group 2 BHV-1300 vs. Group 1 Vehicle, respectively, Figure 1).  

Conclusion: These data demonstrate BHV-1300 does not adversely affect exposure to adalimumab and that it can reduce neutralizing ADAs. MoDE IgG degraders can be co-administered with bDMARDs in RA. Thus, MoDE degraders offer a unique combinatorial therapeutic approach for difficult to treat RA and other rheumatologic diseases, enabling removal of ADAs, pathogenic autoantibodies, and immune complexes as key differentiated features compared to other approaches.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-igg-degrader-bhv-1300-demonstrates-the-ability-to-remove-anti-bdmard-ada-and-allows-for-co-administration-with-fc-containing-biologics/