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 Nterminal 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.

Loss of Stathmin-2, a hallmark of TDP-43-associated ALS, causes motor neuropathy

“…If the DLK stress response were activated in TDP-43 dysfunctional neurons, it would lead to an even more dramatic loss of STMN2 from the axon. While there has been much interest in DLK as a therapeutic target for ALS, a recent clinical trial of a DLK inhibitor unfortunately failed owing to its poor safety profile ( Katz et al, 2022 ).…”

Loss of Stathmin-2, a hallmark of TDP-43-associated ALS, causes motor neuropathy

“…If the DLK stress response were activated in TDP-43 dysfunctional neurons, it would lead to an even more dramatic loss of STMN2 from the axon. While there has been much interest in DLK as a therapeutic target for ALS, a recent clinical trial of a DLK inhibitor unfortunately failed due to its poor safety profile (Katz et al ., 2022).…”

Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy

“…This finding was reversible, but considered adverse with minimal to no therapeutic window. Genentech also reported ocular findings for 3 in monkey preclinical toxicity studies and in their terminated clinical trial . There was also a report showing importance of DLK in the optic nerve .…”

“…Genentech also reported ocular findings for 3 in monkey preclinical toxicity studies and in their terminated clinical trial. 12 There was also a report showing importance of DLK in the optic nerve. 25 We ultimately decided that 22, and perhaps DLK inhibition in general, is not suitable for chronic dosing unless exposure can be restricted from the eye.…”