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.

Figure 1

Study design. (A) In the SAD, in each cohort, patients were re‐randomized for each dosing period; all patients received GDC‐0134 at one or more periods. Patients from the SAD could participate in the MAD if no safety or tolerability concerns arose in the SAD and if at least 1 month had elapsed since their last dose. The OLE included patients who continued directly from the MAD, previously enrolled SAD or MAD patients, and treatment‐naive patients. The OLE was designed to enable adaptive dosing based on the MAD; however, patients were required to remain at their initial dose level for at least 12 weeks before escalating. One dose escalation to 600 mg BID was offered in OLE after MAD M5 was completed; some but not all patients escalated. Due to subsequent safety/tolerability concerns, the highest allowable OLE dose was reduced to 800 mg QD shortly after escalation. *Not all patients escalated to 600 mg BID, and patients may have received doses below 800 mg QD before the study was paused. **After the pause, one patient resumed dosing at 400 mg QD for 11 days. (B) Study flow and treatment discontinuations. ^aSeventy‐nine patients were enrolled and evaluated across the SAD, MAD and OLE. Patients appear in the summary for each stage in which they participated. In total, 49 unique patients were enrolled in the study (7 patients from SAD also participated in the MAD; 23 patients from SAD and/or MAD participated in the OLE). ^bSingle ascending doses of GDC‐0134 were explored in a serial fashion; each patient within a SAD cohort received a single dose of GDC‐0134 or placebo on up to 4 occasions. ^cDoses assigned at OLE entry and the number of patients who received each dose throughout the OLE are indicated, along with the median (range) duration of dosing. ^dPatients who entered the OLE from MAD‐M5 began dosing at 1200 mg QD and later switched to 600 mg BID, whereas patients who enrolled in the OLE after review of MAD‐M5 data began dosing at 600 mg BID (OLE‐M5a). NFL, neurofilament light chain; SAD, single ascending dose; MAD, multiple ascending does; OLE, open‐label safety expansion; QD, once daily; BID, twice daily.

Figure 2

GDC‐0134 pharmacokinetics. Mean (+SD) plasma concentration‐time profiles of GDC‐0134 over (A) 24 h and (B) 168 h following a single dose of GDC‐0134 in the SAD stage. (C) Mean (+SD) steady‐state plasma concentration‐time profiles of GDC‐0134 following multiple doses of GDC‐0134 in the MAD stage. SAD, single ascending dose; MAD, multiple ascending does; SD, standard deviation; QD, once daily.

Figure 3

NFL. (A) Plasma NFL changes from baseline in the first 12 weeks of the OLE by dose level and grouped by patient (top panels) or binned by treatment duration (bottom panels). (B) Data points from panel (A) plotted versus average GDC‐0134 concentration (μmol/L) at the time of NFL observation. All available data over the first 12 weeks of OLE (Day 85) until dose reduction or discontinuation are shown. MAD data are included for patients who entered the OLE without an interruption in GDC‐0134 treatment. In (A), dotted lines represent the approximate 99% CI of variance attributable to technical and biological factors. CIs were calculated from longitudinal analysis of timepoints in the SAD/MAD when patients were not receiving study drug, and the influence of treatment was believed to be negligible. Baseline is an average of both screening and Day 1 predose samples. Boxplots represent the median and IQRs; whiskers represent the range to a maximum of 1.5× the IQR. The number of patients evaluated at each timepoint is indicated above the boxplots. In (B), gray shading represents the 95% CI of the Lowess curve. (C) Plasma NFL levels (median +/− IQR) in WT (+/+) mice compared to DLK cKO heterozygous (−/+) and DLK cKO homozygous (−/−) mice. NFL, neurofilament light; CI, confidence interval; OLE, open‐label safety expansion; MAD, multiple ascending does; SAD, single ascending dose; IQR, interquartile range; DLK, dual leucine zipper kinase; cKO, conditional knock out; WT, wild‐type; HET, heterozygotes; QD, once daily; BID, twice daily.