Key objectives included assessments of safety, pharmacokinetics, and pharmacodynamic markers of BHV-1300.
MoDETM and TRAPTM degraders represent a novel mechanism for rapid and selective depletion of pathogenic extracellular proteins, such as IgG autoantibodies. Leveraging the liver’s highly effective natural process for removal of senescent proteins, they direct proteins of interest to the hepatocyte lysosomes via the asialoglycoprotein receptor (ASGPR). The degrader platform has the potential to treat various antibody-mediated neurological disorders, including myasthenia gravis, autoimmune encephalopathy, and CIDP. The platform’s lead MoDE BHV-1300 is a bispecific small molecule designed to selectively degrade IgG while preserving humoral immunity by sparing other immunoglobulin isotypes: IgM, IgA, and IgE. Differentiating features from FcRn inhibitors include more robust and rapid IgG lowering, brief PK exposure despite sustained PD effect, potential for reduced immunosuppression, and potential for biologic co-administration.
In Phase 1 clinical development of BHV-1300, healthy participants were administered single or multiple escalating doses of BHV-1300 up to 2000 mg for up to four weeks.
BHV-1300 was safe and well-tolerated with most AEs reported as mild. There were no clinically meaningful increases in AST, ALT, or bilirubin; no clinically meaningful reductions in albumin; and no clinically meaningful increases in cholesterol. BHV-1300 was rapidly eliminated and did not accumulate after weekly dosing, with more than 90% of the molecule being cleared within the first 4 days. BHV-1300 deeply reduced IgG, with median maximal reductions from baseline up to 83% by Day 18, and no clinically significant reduction in IgM, IgA, and IgE relative to baseline.
BHV-1300 was safe and well-tolerated. Robust, rapid, and selective lowering of IgG was observed, highlighting the potential benefit as a treatment in acute and chronic antibody-mediated neurologic diseases. TRAP degraders that exclusively target specific pathogenic antibodies are also in development for the potential treatment of several antibody-mediated neurologic diseases.