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

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

  • Ann Clin Transl Neurol. 2022 Jan;9(1):50-66. doi: 10.1002/acn3.51491.
Jonathan S Katz 1,  Jeffrey D Rothstein 2,  Merit E Cudkowicz 3,  Angela Genge 4,  Björn Oskarsson 5,  Avis B Hains 6,  Chen Chen 6,  Joshua Galanter 6,  Braydon L Burgess 6,  William Cho 6,  Geoffrey A Kerchner 7,  Felix L Yeh 6,  Arundhati Sengupta Ghosh 6,  Sravanthi Cheeti 6,  Logan Brooks 6,  Lee Honigberg 6,  Jessica A Couch 6,  Michael E Rothenberg 6,  Flavia Brunstein 6,  Khema R Sharma 8,  Leonard van den Berg 9,  James D Berry 10,  Jonathan D Glass 11
Affiliations

Affiliations

  • 1 Forbes Norris MDA/ALS Research Center, California Pacific Medical Center, San Francisco, California, USA.
  • 2 Johns Hopkins Hospital, Baltimore, Maryland, USA.
  • 3 Sean M. Healey and AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 4 Montreal Neurological Institute & Hospital, Montreal, QC, Canada.
  • 5 Mayo Clinic, Jacksonville, Florida, USA.
  • 6 Genentech, Inc., South San Francisco, California, USA.
  • 7 F. Hoffmann-La Roche, Ltd., Basel, Switzerland.
  • 8 University of Miami Hospital (CRC), Miami, Florida, USA.
  • 9 UMC Utrecht, Utrecht, The Netherlands.
  • 10 Neurological Clinical Research Institute, Boston, Massachusetts, USA.
  • 11 Emory University School of Medicine, Atlanta, Georgia, USA.
PMID: 35014217 DOI: 10.1002/acn3.51491
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.

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