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Abstract: PO1441

A Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of AT1501

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Author

  • Perrin, Steven, Eledon Pharmaceuticals, Irvine, California, United States
Background

CD40L is a costimulatory receptor for CD40 found on T helper cells. Binding of CD40L on T cells to CD40 on antigen presenting cells induces downstream immune and inflammatory responses. Inhibition of CD40L signaling can abolish inflammation, prevent the progression of autoimmunity, and instill transplant tolerance. AT-1501 is a humanized anti CD40L antibody lacking Fc effector function and high affinity binding to CD40L.

Purpose: Execute a phase 1 study of AT-1501 to assess safety, pharmacokinetics, and functional activity.

Methods

The study employed a placebo-controlled, sequential, dose-escalation design. 28 healthy subjects and 4 adults with ALS were enrolled. Five sequential ascending doses of AT1501 (0.5, 1, 2, 4, or 8 mg/kg) or placebo were administered by IV infusion. The primary endpoint was the safety and tolerability of AT1501. The secondary endpoint was to determine plasma pharmacokinetics (PK) and anti-drug antibody (ADA) responses to AT1501. An exploratory endpoint was to examine the ability of AT1501 to block an immune challenge in subjects who received a Keyhole Limpet Hemocyanin (KLH) challenge.

Results

Dose proportionality was achieved over the AT-1501 dose range of 0.5 to 8 mg/kg for Cmax and AUC0-t. The mean AT-1501 t1/2 in healthy volunteers was 18 to 26 days.
AT1501 had a safety profile comparable to placebo and was well tolerated in healthy subjects and subjects with ALS. 54% of subjects treated with AT-1501 had at least 1 TEAE and 62% of subjects treated with placebo had at least 1 TEAE. The most commonly reported TEAEs overall were headache, somnolence, and upper respiratory tract infection. There were no meaningful laboratory abnormalities, vital sign assessments, ECG assessments, or physical examination findings.
Positive ADA responses to AT-1501 were observed in 6 of 30 subjects in the study. There was no dose dependence with respect to the incidence of positive ADA titers. ADA did not appear to affect AT-1501 plasma PK profiles or parameters suggesting they were not neutralizing.
8 mg/kg AT-1501 successfully blocked an immune response to KLH challenge in 2 of the 3 subjects tested.

Conclusion

Our results support further clinical development of AT-1501 for transplantation and autoimmune indications

Funding

  • Commercial Support