Trial reportAnnals of clinical and translational neurology2022
A Phase 1 study of GDC-0134, a dual leucine zipper kinase inhibitor, in ALS.
Trial report in Annals of clinical and translational neurology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
22 citing papers in PubMed, 36 citations in OpenAlex.
- Targeting TDP-43 in sporadic amyotrophic lateral sclerosis.Journal of neurology · 2026Review
- Novel neuroprotective strategy based on inhibition of acute axonal palmitoylation of dual leucine-zipper kinase.Neural regeneration research · 2026Article
- Targeting druggable kinases in neuropathic pain.npj drug discovery · 2026Review
- Use of blood-based neurofilament light chain as an endpoint in clinical trials of neurodegenerative conditions: a scoping review.Journal of neurology · 2026Article
- Article
- Combinatorial chemistry identifies additional compounds that selectively inhibit DLK-dependent retrograde signaling while minimally affecting other axonal roles of DLK.Scientific reports · 2026Article
- Pyruvate kinase deficiency links metabolic perturbations to neurodegeneration and axonal protection.Molecular metabolism · 2025Article
- Inhibiting acute, axonal DLK palmitoylation is neuroprotective and avoids deleterious effects of cell-wide DLK inhibition.Nature communications · 2025Article
- The transcriptional response of cortical neurons to concussion reveals divergent fates after injury.Nature communications · 2025Article
- DLK-dependent axonal mitochondrial fission drives degeneration after axotomy.Nature communications · 2024Article
- Remyelination protects neurons from DLK-mediated neurodegeneration.Nature communications · 2024Article
- The transcriptional response of cortical neurons to concussion reveals divergent fates after injury.bioRxiv : the preprint server for biology · 2024Article
- Recruitment, regulation, and release: Control of signaling enzyme localization and function by reversible S-acylation.The Journal of biological chemistry · 2024Review
- Remyelination protects neurons from DLK-mediated neurodegeneration.bioRxiv : the preprint server for biology · 2024Article
- DLK-dependent axonal mitochondrial fission drives degeneration following axotomy.bioRxiv : the preprint server for biology · 2024Article
- Review
- Biomarker Qualification for Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: Theory and Practice.Annals of neurology · 2024Review
- Targeting synapse function and loss for treatment of neurodegenerative diseases.Nature reviews. Drug discovery · 2024Review
- Promoting regeneration while blocking cell death preserves motor neuron function in a model of ALS.Brain : a journal of neurology · 2023Article
- Emerging Therapies and Novel Targets for TDP-43 Proteinopathy in ALS/FTD.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2022Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
23 authors at 10 institutions in 4 countries.
Funding
Abstract
objectiveDual 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.
methodsThe 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.
resultsForty-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.
interpretationThis 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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.