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Abstract: SA-PO636

SYNERGY-1: A Phase 1, First-in-Human, Safety, Tolerability, Immunogenicity, Pharmacokinetics, and Pharmacodynamics Study of KP104 in Escalating Single and Multiple Doses

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Wabnitz, Paul, Cancer Research Institute, University of South Australia, Adelaide, South Australia, Australia
  • Gao, Xiang, Kira Pharmaceuticals, Cambridge, Massachusetts, United States
  • Ma, Jay, Kira Pharmaceuticals, Cambridge, Massachusetts, United States
  • Tsui, Ping, Kira Pharmaceuticals, Cambridge, Massachusetts, United States
  • Rabe, Martin, Kira Pharmaceuticals, Cambridge, Massachusetts, United States
  • Fu, Helen N., Kira Pharmaceuticals, Cambridge, Massachusetts, United States
  • He, Chaomei, Kira Pharmaceuticals, Cambridge, Massachusetts, United States
  • Wu, Jingtao, Kira Pharmaceuticals, Cambridge, Massachusetts, United States
  • York, Brian K., Kira Pharmaceuticals, Cambridge, Massachusetts, United States
  • Weng, Christina, Kira Pharmaceuticals, Cambridge, Massachusetts, United States
  • Rankin, Jon, Syneos Health Australia, Sydney, New South Wales, Australia
  • Beddingfield, Frederick C., Kira Pharmaceuticals, Cambridge, Massachusetts, United States
  • Song, Wenru, Kira Pharmaceuticals, Cambridge, Massachusetts, United States
  • Farinola, Nicholas, Cancer Research Institute, University of South Australia, Adelaide, South Australia, Australia
  • Lee, Richard, Kira Pharmaceuticals, Cambridge, Massachusetts, United States
Background

Glomerular diseases (GD), such as IgA nephropathy and complement (C) 3 glomerulopathy which have limited or no approved therapies, are known to be mediated by aberrant C activation. KP104 is a bi-functional C inhibitor fusion protein comprised of humanized anti-C5 monoclonal antibody fused with truncated C factor H. KP104 fusion design inhibits C5-mediated membrane attack complex formation and alternative pathway (AP) activation.

Methods

This is a first-in-human, randomized, double-blind, placebo-controlled, single center study of KP104 in healthy volunteers. Safety, tolerability, anti-drug antibodies (ADA) development, PK, and PD were assessed in single ascending dose (SAD) and multiple ascending dose (MAD) cohorts. At interim analysis, 48 SAD and 8 MAD have completed study assessments. SAD dose levels were 60-1200 mg; MAD was 600 mg IV QW for 5 total doses.

Results

Majority of subjects were Caucasian (81.3% SAD and 62.5% MAD), male (26 SAD and 6 MAD), and mean age was 30.5 and 33.6 years for SAD and MAD, respectively.

No deaths, DLTs, or severe TEAEs were reported. SAD (n=38/48, 79.2%) reported 126 TEAEs in all cohorts. No dose related trend was observed. MAD (n=8/8, 100%) reported 24 TEAEs. Majority of TEAEs were Grade 1 and resolved without treatment.

In SAD cohorts, 3 PD markers, rRBC (AP + terminal pathway [TP]), C3b (AP), and free C5 (TP) all showed substantial inhibition as dose increased. Maximum rRBC, C3b, and free C5 inhibition reached >85%, >90%, and >99.5% (<0.5 µg/mL) respectively, at ≥360 mg and inhibition duration was extended with higher doses. At 1200 mg, inhibition for all 3 PD markers was ≥99%. In the MAD cohort, the 3 PD markers achieved substantial inhibition during entire dosing period.

ADAs were detected in 3 SAD and 4 MAD but did not appear to impact subject safety.

Conclusion

KP104 was safe, well tolerated, and showed proof of mechanism with potent TP and AP inhibition in the SYNERGY-1 study. Complete data will be available at ASN 2022. The data supports planned future clinical trials in C-mediated GD. To our knowledge, KP104 is the first bifunctional biologic demonstrating successful inhibition of both AP and TP.

Funding

  • Commercial Support