Ezogabine Decreases Motor Neuron Excitability in Amyotrophic Lateral Sclerosis

Brian J. Wainger, MD, PhD

Newly published data from a phase 2 randomized controlled trial (NCT02450552) of patients with amyotrophic lateral sclerosis (ALS) demonstrated that treatment with ezogabine decreases cortical and spinal motor neuron (MN) excitability, which may suggest that neurophysiological metrics may be used as a pharmacodynamic biomarker in future clinical trials.

Investigators used change in short-interval intracortical inhibition (SICI; SICI-1 was used in analysis to reflect stronger inhibition from an increase in amplitude) as a primary outcome among 65 patients who were randomized to either placebo (n = 23), 600 mg/day of ezogabine (n = 23), and 900 mg/day of ezogabine (n = 19) for a 10-week study period.

In the 900-mg/day ezogabine group, the SICI-1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12–2.09; P = .009) compared to the placebo group. However, the SICI-1 did not change in the 600-mg/day ezogabine group vs the placebo group (mean ratio, 1.15; 95% CI, 0.87–1.52; P = .31).

"The increase in SICI at 900 mg/day of ezogabine represented approximately 50% of the difference between participants with ALS and healthy control participants, based on reports in the literature and our own recordings of healthy control participants,” the study authors, led by Brian J. Wainger, MD, PhD, assistant professor, neurology and anesthesiology, Harvard Medical School, and physician scientist and principal investigator, Sean M. Healey and AMG Center for ALS, Massachusetts General Hospital, concluded.

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Strong clinical evidence that supported hyperexcitability as a prominent phenotype in both familial and sporadic ALS helped investigators move directly from induced pluripotent stem cell (iPSC) modeling to a clinical trial using neurophysiological metrics of MN excitability as pharmacodynamic biomarkers.

Wainger and colleagues found an increase in the resting motor threshold (RMT) in the 600-mg/day ezogabine group (mean ratio, 4.61; 95% CI, 0.21–9.01; P = .04) but not in the 900-mg/day ezogabine group when compared to placebo (mean ratio, 1.95; 95% CI, –2.64 to 6.54; P = .40).

The motor evoked potential (MEP) amplitudes at moderate (120% of RMT) and stronger (140% and 150% of RMT) stimulation intensities were increased in each active drug group (mean ratio for 120% RMT, 600-mg/day ezogabine group vs placebo: 2.18; 95% CI, 1.49–3.19; P <.001; 900-mg/day ezogabine group vs placebo: 1.99; 95% CI, 1.31–3.02; P = .002).

There was a dose-dependent decrease in strength-duration time constant (SDTC; mean ratio, 600-mg/day ezogabine group vs placebo: 0.93; 95% CI, 0.79–1.10; P = .40; 900-mg/day ezogabine group vs placebo: 0.73; 95% CI, 0.60–0.87; P <.001) and a dose-dependent increase in rheobase (mean ratio, 600-mg/day ezogabine group vs placebo: 1.31: 95% CI, 1.07–1.59; P = .009; 900-mg/day ezogabine group vs placebo: 1.70; 95% CI, 1.36–2.12; P <.001). Notably, these findings were consistent with a reduction in axonal excitability.

Spinal MN axonal hyperexcitability, which has been indicated by SDTC measured using threshold tracking nerve conduction studies (TTNCSs) has been previously found in patients with sporadic and familial ALS, according to the study authors. The additional TTNCS parameters of depolarizing threshold electrotonus, superexcitability, and latency, were all affected with ezogabine treatment.

To further understand the direct connection between compound muscle action potential (CMAP) reduction and disease progression, Wainger and colleagues tested whether the treatment effect on cortical inhibition correlated with the effect on CMAP amplitude. They found that the increased SICI during treatment was correlated with a maintenance of or increase in CMAP amplitude (Spearman rank correlation = 0.34; 95% CI, 0.01–0.61; P = .04).

"Although 2 extreme values showed an unusually large increase in CMAP amplitude, the nonparametric Spearman correlation, based only on rank order, was robust to the effects of such outliers,” Wainger et al concluded.

Doses using identical active and placebo pills for escalation (weeks 1–4), full-dose treatment (weeks 5–8), and weaning (weeks 9–10) followed the timetable and dosing for phase 3 clinical trials of ezogabine in epilepsy. Due to the short 4-week full-dose treatment period, none of the typical measures of disease progression, including the ALS Functional Rating Scale, Revise score, slow vital capacity (SVC) and handheld dynamometry strength, changed in a statistically significant manner.

Permanent drug discontinuation occurred in 30.4% of participants (7 of 23) who received the 600 mg/day dose of ezogabine and 26.3% (5 of 19) in those who received the 900 mg/day dose, compared to 0% in the placebo group. Almost all of the permanent drug discontinuations were associated with adverse events (AEs) as either a primary or secondary reason for discontinuation.

There were 4 serious AEs that occurred after drug initiation. Obtundation occurred in 1 patient in the 900-mg/day dose group and was deemed to have probable association with treatment. The other 3 were single episodes of influenza, pneumonia, and stroke, which were all found in the 600-mg/day group and were not associated with treatment.

"Findings from this trial validate the use of iPSC-based in vitro models for identifying novel disease targets and rapidly repurposing existing drugs for clinical trials,” the study authors concluded.

REFERENCE

Wainger BJ, Macklin EA, Vucic S, et al. Effect of ezogabine on cortical and spinal motor neuron excitability in amyotrophic lateral sclerosis: a randomized clinical trial. JAMA Neurol. Published online November 23, 2020. doi: 10.1001/jamaneurol.2020.4300