110: Phase 1, Single-Center, Randomized, Placebo-Controlled, Partially Blinded, Single Ascending Dose Study on the Effects of Troriluzole on corrected QT in Healthy Subjects

Statement of Purpose, Innovation or Hypothesis: Troriluzole is a novel tripeptide prodrug of riluzole which metabolizes in the body into the active metabolite riluzole. Troriluzole was developed to improve the pharmacokinetics (PK) and therefore the treatment potential, efficacy, and safety of riluzole for use in neurological and neuropsychiatric disorders such as obsessive compulsive disorder (OCD). A Phase 1 study was conducted to assess troriluzole PK and QT prolongation potential in healthy adult participants. Cardiac safety assessments are critical in drug development because some compounds can delay cardiac repolarization, resulting in QT interval prolongation which may cause potentially fatal pro-arrythmias.

Description of Methods & Materials: The objective of this randomized, placebo-controlled, and partially blinded study was to evaluate the effect of a single dose of troriluzole on the Fridericia heart-rate corrected QT interval (QTcF) using concentration-QTc (C-QT) analysis. 72 subjects received single doses of either a therapeutic dose (280 mg) or supratherapeutic doses (560 or 840 mg) of troriluzole, matched placebo, or a positive control (400 mg moxifloxacin). Troriluzole and placebo were administered in a double-blind manner, and moxifloxacin was administered open-label. For the 560 and 840 mg dose groups, sentinel subjects were dosed first, and remaining subjects were dosed after review of initial safety and tolerability data. Assay sensitivity was evaluated by placebo-corrected QTcF analysis using moxifloxacin.

Data & Results: Riluzole C_max geometric means ranged from 358.4 to 1128.5 ng/mL across the single doses, with a maximum concentration of 1363.8 ng/mL at the 840 mg dose. Median riluzole T_max occurred at 2.59, 3.08, and 3.09 hours for the 280, 560, and 840 mg doses, respectively. Moxifloxacin C_max geometric mean was 1720.2 ng/mL, with a median T_max of 2.6 hours following dosing. Based on the C-QT analysis, a QTc effect (ΔΔQTcF) exceeding 10 msec was excluded within the full range of observed riluzole plasma concentrations, up to ~1364 ng/mL (Figure 1). A total of 70 subjects were included in the C-QT analysis, as two subjects were excluded due to the absence of certain electrocardiogram (ECG) results. By-time point analysis of troriluzole showed a small, non-clinically relevant QT shortening within 4 hours post-dose. Least square (LS) mean placebo-corrected ΔQTcF (∆∆QTcF) was negative for troriluzole across most post-dose time points, ranging from -8.1 msec (at 2.5 hours post-dose in the 840 mg dose group) to 2.5 msec (at 1 hour post-dose in the 280 mg dose group), indicating no QT prolongation across the doses. Troriluzole had no clinically relevant effects on any other ECG parameters. After dosing with moxifloxacin, a clear increase of LS mean ΔΔQTcF was observed with a peak value of 14.1 msec (90% confidence interval [CI]: 11.03 to 17.15) at 3 hours post-dose, demonstrating appropriateness as a positive control. All safety events that occurred after administration of troriluzole were mild in severity and resolved by the end of the study.

Interpretation, Conclusion or Significance: There was no clinically meaningful effect on the QTc interval following single troriluzole doses up to 840 mg (3-fold higher than the proposed therapeutic dose for OCD). Overall, this constitutes a negative thorough QT study as described in the ICH E14 clinical guidance.

Disclosures: The study described in this abstract was fully funded by Biohaven Pharmaceuticals, Inc.

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