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Abstract: TH-PO499

Phase 1 Study in Healthy Adults of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ALPN-303, a Dual BAFF/APRIL Antagonist for the Treatment of Autoimmune Glomerulonephritides (GN)

Session Information

Category: Glomerular Diseases

  • 1303 Glomerular Diseases: Clinical‚ Outcomes‚ and Trials

Authors

  • Dillon, Stacey R., Alpine Immune Sciences Inc, Seattle, Washington, United States
  • Harrison, Pille, Alpine Immune Sciences Inc, Seattle, Washington, United States
  • Lickliter, Jason, Nucleus Network Ltd, Melbourne, Victoria, Australia
  • Manjarrez, Kristi L., Alpine Immune Sciences Inc, Seattle, Washington, United States
  • Smith, Alina, Alpine Immune Sciences Inc, Seattle, Washington, United States
  • Lessig, Mary C., Alpine Immune Sciences Inc, Seattle, Washington, United States
  • Sanderson, Russell John, Alpine Immune Sciences Inc, Seattle, Washington, United States
  • Chunyk, Allison G., Alpine Immune Sciences Inc, Seattle, Washington, United States
  • Lewis, Katherine, Alpine Immune Sciences Inc, Seattle, Washington, United States
  • Zayed, Hany, Alpine Immune Sciences Inc, Seattle, Washington, United States
  • Davies, Rupert Hugo, Alpine Immune Sciences Inc, Seattle, Washington, United States
  • Peng, Stanford, Alpine Immune Sciences Inc, Seattle, Washington, United States
Background

Therapeutic agents targeting the B-cell cytokines BAFF and/or APRIL have demonstrated promising clinical potential in autoantibody-related GN such as lupus nephritis (LN) and IgA nephropathy (IgAN), and other B-cell-related diseases such as systemic lupus erythematosus; however, there is still need for more safe and efficacious therapies. ALPN-303 is an Fc fusion protein of an engineered TACI variant TNFRSF domain (vTD) which mediates more potent inhibitory activity than WT TACI-Fc or BAFF- or APRIL-specific antibodies. In preclinical studies, ALPN-303 demonstrated enhanced PK and immunomodulatory properties vs. WT TACI-Fc, which may translate to lower and/or less frequent doses in humans. ALPN-303 also suppressed autoantibodies, renal IgG deposition, and nephritis in mouse models. ALPN-303 may therefore significantly improve clinical outcomes in GN and other B-cell-related diseases.

Methods

In this first-in-human study (NCT05034484), adult HVs are randomized into single ascending dose cohorts of intravenous (IV) or subcutaneous (SC) ALPN-303 or placebo. Subjects are followed to assess safety and PK, circulating immunoglobulins (Ig), and circulating leukocyte populations by flow cytometry.

Results

ALPN-303 has been well tolerated in all cohorts evaluated to date, and overall exhibits dose-related PK and expected PD effects, including dose-related reductions in serum Ig. To date there have been no treatment-related serious adverse events, no infusion-related or injection site reactions, and no adverse trends in safety laboratories. Dose escalation is expected to complete by the time of the meeting; the presentation will include all available safety, PK, and PD data.

Conclusion

ALPN-303 to date demonstrates acceptable safety and tolerability and exhibits PK and PD that appear to differentiate favorably vs WT TACI-Fc. These findings support future clinical development of ALPN-303 in multiple autoantibody-related GN, as well as other B-cell- and/or autoantibody-related diseases.

Funding

  • Commercial Support