A Phase 1 study of GDC-0134, a dual leucine zipper kinase inhibitor, in ALS.

Abstract

OBJECTIVE:

Dual leucine zipper kinase (DLK), which regulates the c-Jun N-terminal kinase pathway involved in axon degeneration and apoptosis following neuronal injury, is a potential therapeutic target in amyotrophic lateral sclerosis (ALS). This first-in-human study investigated safety, tolerability, and pharmacokinetics (PK) of oral GDC-0134, a small-molecule DLK inhibitor. Plasma neurofilament light chain (NFL) levels were explored in GDC-0134-treated ALS patients and DLK conditional knockout (cKO) mice.

METHODS:

The study included placebo-controlled, single and multiple ascending-dose (SAD; MAD) stages, and an open-label safety expansion (OLE) with adaptive dosing for up to 48 weeks.

RESULTS:

Forty-nine patients were enrolled. GDC-0134 (up to 1200 mg daily) was well tolerated in the SAD and MAD stages, with no serious adverse events (SAEs). In the OLE, three study drug-related SAEs occurred: thrombocytopenia, dysesthesia (both Grade 3), and optic ischemic neuropathy (Grade 4); Grade ≤2 sensory neurological AEs led to dose reductions/discontinuations. GDC-0134 exposure was dose-proportional (median half-life = 84 h). Patients showed GDC-0134 exposure-dependent plasma NFL elevations; DLK cKO mice also exhibited plasma NFL compared to wild-type littermates.

INTERPRETATION:

This trial characterized GDC-0134 safety and PK, but no adequately tolerated dose was identified. NFL elevations in GDC-0134-treated patients and DLK cKO mice raised questions about interpretation of biomarkers affected by both disease and on-target drug effects. The safety profile of GDC-0134 was considered unacceptable and led to discontinuation of further drug development for ALS. Further work is necessary to understand relationships between neuroprotective and potentially therapeutic effects of DLK knockout/inhibition and NFL changes in patients with ALS.

• Authors: Jonathan S Katz, Jeffrey D Rothstein, Merit E Cudkowicz, Angela Genge, Björn Oskarsson, Avis B Hains, Chen Chen, Joshua Galanter, Braydon L Burgess, William Cho, Geoffrey A Kerchner, Felix L Yeh, Arundhati Sengupta Ghosh, Sravanthi Cheeti, Logan Brooks, Lee Honigberg, Jessica A Couch, Michael E Rothenberg, Flavia Brunstein, Khema R Sharma, Leonard van den Berg, James D Berry, Jonathan D Glass
• Journal: Annals of clinical and translational neurology (Ann Clin Transl Neurol) Vol. 9 Issue 1 Pg. 50-66 (01 2022) ISSN: 2328-9503 [Electronic] United States
• PMID: 35014217 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 Genentech, Inc. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Chemical References

• Biomarkers
• Neurofilament Proteins
• Protein Kinase Inhibitors
• neurofilament protein L
• MAP Kinase Kinase Kinases
• mitogen-activated protein kinase kinase kinase 12

Topics

• Adult
• Aged
• Amyotrophic Lateral Sclerosis (blood, drug therapy)
• Animals
• Biomarkers (blood)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Humans
• MAP Kinase Kinase Kinases (antagonists & inhibitors, deficiency)
• Male
• Mice
• Mice, Knockout
• Middle Aged
• Neurofilament Proteins (blood)
• Outcome Assessment, Health Care
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)