Optimizing rare disorder trials: a phase 1a/1b randomized study of KL1333 in adults with mitochondrial disease

Abstract

Over the past two decades there has been increased interest in orphan drug development for rare diseases. However, hurdles to clinical trial design for these disorders remain. This phase 1a/1b study addressed several challenges, while evaluating the safety and tolerability of the novel oral molecule KL1333 in healthy volunteers and subjects with primary mitochondrial disease. KL1333 aims to normalize the NAD+:NADH ratio that is critical for ATP production. The trial incorporated innovative design elements with potential translatability to other rare diseases including patient involvement, adaptive design and exploratory objectives, all of which have subsequently informed the protocol of an ongoing phase 2, pivotal efficacy study of KL1333. Results indicate KL1333 is safe and well tolerated, with dose-dependent gastrointestinal side effects, and validate potential novel outcome measures in primary mitochondrial disease including the 30-s Sit to Stand, and the patient-reported fatigue scales. Importantly, the data from the trial support efficacy of KL1333 based on improvements in fatigue and functional strength and endurance. Furthermore, the study highlights the value in using phase 1 studies to capture data that helps optimize later phase efficacy trial design.

Keywords: KL1333; clinical trial; phase 1 trial; primary mitochondrial disease; rare diseases.

Figure 1

Participant flow diagram. PMD = primary mitochondrial disease; QD = once daily; BID = twice daily; TID = three times daily.

Figure 2

Biomarkers and clinical outcome assessments. (A) Lactate:pyruvate ratio analysed at baseline before treatment initiation in healthy volunteers (Parts B and D combined, n = 56) and subjects with PMD (Part C, n = 8). Group differences evaluated with Mann-Whitney test. (B) Correlation between lactate:pyruvate ratio changes from baseline to 0.5 h and total plasma KL1333 concentration following treatment initiation Day 1 in healthy volunteers (Part D, n = 16). (C) Group percentage changes in number of Sit to Stand (STS) repetitions performed during 30 s from baseline (Day −1) to Day 10 following daily oral doses of 50 mg KL1333 (n = 5, one individual could not perform test due to severe myopathy) or placebo (n = 2) and (D) changes in individual number of STS repetitions. (E) Group NeuroQoL Fatigue t-scores changes in patients treated with KL1333 (n = 6) or placebo (n = 2). (F) Time profile of Daily Fatigue Impact Scale (DFIS) mean scores and arithmetic mean total KL1333 pre-dose/Ctrough concentrations in KL1333-treated subjects with PMD (n = 6). (G) Changes in individual NeuroQoL Fatigue t-scores from baseline to follow-up at Day 10 plotted against total KL1333 Ctrough values at Day 10. All bar graphs present medians ± 95% confidence interval (CI). Ctrough = KL1333 concentration immediately before the next dose.

Figure 3

Optimizing clinical trial design in rare disease. Phase 1 trials have the opportunity to play a central role in the therapeutic development for rare diseases, where patient recruitment possibilities are limited.