TY - JOUR
T1 - A Phase 1 study of GDC-0134, a dual leucine zipper kinase inhibitor, in ALS
AU - Katz, Jonathan S.
AU - Rothstein, Jeffrey D.
AU - Cudkowicz, Merit E.
AU - Genge, Angela
AU - Oskarsson, Björn
AU - Hains, Avis B.
AU - Chen, Chen
AU - Galanter, Joshua
AU - Burgess, Braydon L.
AU - Cho, William
AU - Kerchner, Geoffrey A.
AU - Yeh, Felix L.
AU - Ghosh, Arundhati Sengupta
AU - Cheeti, Sravanthi
AU - Brooks, Logan
AU - Honigberg, Lee
AU - Couch, Jessica A.
AU - Rothenberg, Michael E.
AU - Brunstein, Flavia
AU - Sharma, Khema R.
AU - van den Berg, Leonard
AU - Berry, James D.
AU - Glass, Jonathan D.
N1 - Publisher Copyright:
© 2022 Genentech, Inc. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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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U2 - 10.1002/acn3.51491
DO - 10.1002/acn3.51491
M3 - Article
AN - SCOPUS:85122472866
SN - 2328-9503
VL - 9
SP - 50
EP - 66
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
IS - 1
ER -