Kidney Week

Abstract: SA-PO799

ADX-097, a Tissue-Targeted Complement Inhibitor for the Treatment of Kidney Diseases: Phase 1 Results in Healthy Participants and Model-Informed Phase 2 Dose Selection

Session Information

• C3G, TMA, MGRS, Amyloidosis, and More
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1402 Glomerular Diseases: Clinical, Outcomes, and Therapeutics

Authors

• Jilma, Bernd, Medical University of Vienna, Vienna, Austria

Bernd Jilma, MD

• Vernon, Katherine Anne, Q32 Bio Inc, Waltham, Massachusetts, United States

Katherine Anne Vernon, MBBS, PhD

• Wu, Hong, Q32 Bio Inc, Waltham, Massachusetts, United States

Hong Wu, MD, PhD

• Wawersik, Stefan, Q32 Bio Inc, Waltham, Massachusetts, United States

Stefan Wawersik, PhD

• Rezendes, David, Q32 Bio Inc, Waltham, Massachusetts, United States

David Rezendes

• Faucette, Ryan, Q32 Bio Inc, Waltham, Massachusetts, United States

Ryan Faucette

• Leigh-Pemberton, Richard, Q32 Bio Inc, Waltham, Massachusetts, United States

Richard Leigh-Pemberton, MD

• Hay, Justin L., Certara, Radnor, Pennsylvania, United States

Justin L. Hay, PhD

• Mayer, Christina Lourdes, Semivida Research, LLC, Dallas, Texas, United States

Christina Lourdes Mayer, PharmD, RPh

• Violette, Shelia, Q32 Bio Inc, Waltham, Massachusetts, United States

Shelia Violette, PhD

• Campagna, Jason, Q32 Bio Inc, Waltham, Massachusetts, United States

Jason Campagna, MD, PhD

Background

Alternative complement pathway (AP) activation is implicated in the pathogenesis of various autoimmune renal diseases. ADX-097, a C3d mAb – fH_1-5 fusion protein, was designed to inhibit complement in diseased kidney while avoiding systemic blockade, providing the potential for enhanced activity and safety profile. In preclinical studies, ADX-097 durably inhibited glomerular complement activity and reduced urine protein and sC5b-9 without any impairment of systemic complement. ADX-097 is being evaluated in a Phase 2 renal basket trial in IgA nephropathy, lupus nephritis and complement component 3 glomerulopathy. Here we report results from a Phase 1 study evaluating the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ADX-097.

Methods

A randomized, double-blind, placebo-controlled study of ADX-097 with single ascending and multiple doses was performed in heathy participants. ADX-097 was administered in single dose cohorts IV at 0.1-30 mg/kg, or SC at 3.75 and 10 mg/kg and in one multiple dose cohort of 450 mg SC QW for 5 doses.
Circulating AP activity was measured by Wieslab assay.
An exploratory PK/PD model was used to project a dose that maintains circulating drug concentrations in a target range of 0.3 - 3.2 µg/ml, which is associated with maximal tissue pharmacology in preclinical models.

Results

ADX-097 was well tolerated across all dose levels with no clinically significant drug-related safety findings or ADAs observed.
ADX-097 demonstrated a robust PK/PD relationship with a systemic AP IC₅₀ of 56.3 µg/ml. These data confirmed the in vivo integrity of the fusion protein.
PK/PD simulations projected that 450 mg ADX-097 SC QW can attain circulating concentrations in the target range for maximal tissue pharmacology in preclinical models, with a C_max,ss ~5-fold below the IC₅₀ for systemic AP inhibition.

Conclusion

ADX-097 demonstrated a favorable safety profile and desired PK/PD properties in healthy participants, supporting a Phase 2 dose that is predicted to provide tissue inhibition of complement in glomerular diseases while sparing systemic complement activity.

Funding

• Commercial Support – Q32 Bio Inc