Phase 2b program with sonlicromanol in patients with mitochondrial disease due to m.3243A>G mutation

Abstract

Mitochondrial disease incorporates a group of rare conditions with no approved treatment to date, except for Leber hereditary optic neuropathy. Therapeutic options to alleviate the symptoms of mitochondrial disease are urgently needed. Sonlicromanol is a promising candidate, as it positively alters the key metabolic and inflammatory pathways associated with mitochondrial disease. Sonlicromanol is a reductive and oxidative distress modulator, selectively inhibiting microsomal prostaglandin E1 synthase activity. This phase 2b program, aimed at evaluating sonlicromanol in adults with m.3243A>G mutation and primary mitochondrial disease, consisted of a randomized controlled (RCT) study (dose-selection) followed by a 52-week open-label extension study (EXT, long-term tolerability, safety and efficacy of sonlicromanol). Patients were randomized (1:1:1) to receive 100 or 50 mg sonlicromanol or placebo twice daily (bid) for 28 days with a ≥2-week wash-out period between treatments. Patients who completed the RCT study entered the EXT study, wherein they received 100 mg sonlicromanol bid. Overall, 27 patients were randomized (24 RCT patients completed all periods). Fifteen patients entered the EXT, and 12 patients were included in the EXT analysis set. All patients reported good tolerability and favourable safety, with pharmacokinetic results comparable to the earlier phase 2a study. The RCT primary end point [change from placebo in the attentional domain of the cognition score (visual identification; Cogstate IDN)] did not reach statistical significance. Using a categorization of the subject's period baseline a treatment effect over placebo was observed if their baseline was more affected (P = 0.0338). Using this approach, there were signals of improvements over placebo in at least one dose in the Beck Depression Inventory (BDI, P = 0.0143), Cognitive Failure Questionnaire (P = 0.0113) and the depression subscale of the Hospital Anxiety and Depression Scale (P = 0.0256). Statistically and/or clinically meaningful improvements were observed in the patient- and clinician-reported outcome measures at the end of the EXT study [Test of Attentional Performance (TAP) with alarm, P = 0.0102; TAP without alarm, P = 0.0047; BDI somatic, P = 0.0261; BDI total, P = 0.0563; SF12 physical component score, P = 0.0008]. Seven of nine domains of RAND-Short Form-36-like SF-36 pain improved (P = 0.0105). Other promising results were observed in the Neuro-Quality of Life Short Form-Fatigue Scale (P = 0.0036), mini-Balance Evaluation Systems test (P = 0.0009), McGill Pain Questionnaire (P = 0.0105), EuroQol EQ-5D-5L-Visual Analog Scale (P = 0.0213) and EQ-5D-5L-Index (P = 0.0173). Most patients showed improvement in the Five Times Sit-To-Stand Test. Sonlicromanol was well-tolerated and demonstrated a favourable benefit/risk ratio for up to 1 year. Sonlicromanol was efficacious in patients when affected at baseline, as seen across a variety of clinically relevant domains. Long-term treatment showed more pronounced changes from baseline.

Keywords: MELAS; MIDD; m.3243A>G; primary mitochondrial disease; sonlicromanol.

Figure 1

Phase 2b sonlicromanol program design and patient disposition. Patients were screened. The eligible and randomized patients were included in the randomized controlled trial (RCT) and the 52-week extension (EXT) study. The intent-to-treat (ITT) population included all patients who were randomized for this program and had a post-baseline assessment of at least one efficacy parameter. The full analysis set (FAS) population consisted of all the patients who received study medication in this program and had at least one on-treatment efficacy assessment after the first drug intake. The safety population included all the patients who received at least one dose of study medication, irrespective of satisfying other criteria. Adverse effect (AE) 1 = medical device site reaction during treatment period (TP) 1; AE2 = ECG T-wave amplitude decrease in TP2; AE3 = ECG changes after coronavirus disease 2019 (COVID-19) vaccination during TP3. Baseline screening before the EXT revealed three screen failures: eGFR 49 ml/min [exclusion criteria (e.c.) 5b], ECG negative T waves (e.c. 6), Fridericia-corrected QT interval (QTcF) 475 ms (e.c. 6). bid = twice daily.

Figure 2

Efficacy results of the randomized controlled trial. Left: Forest plot of the treatment effects on all randomized controlled trial outcome measures; note that data from the headache and hearing assessments could not be presented in this manner because of data complexity. Treatment effect is the difference between the treatment means divided by the standard error of the difference. For all results, the treatment effect was adjusted so that in all cases a positive value represents an improvement of treatment versus placebo. Light grey indicates 50 mg twice daily (bid); dark grey, 100 mg bid. For the Cogstate visual identification (IDN) test, data from an extreme outlier were excluded. The Newcastle Mitochondrial Disease Adults Scale (NMDAS) score was not considered in this short-duration study. Right: Accompanying change from placebo (CFP) estimates. Significant P-values: ^a0.034; ^b0.035; ^c0.012; ^d0.026; ^e0.014; ^f0.015; ^g0.011; ^h0.034. Grey shading indicates the statistical analysis plan. GCS = Global Composite Score; HADS-A = Hospital Anxiety and Depression Scale-Anxiety; HADS-D = Hospital Anxiety and Depression Scale-Depression; MCS = Mental Component Score; PCS = Physical Component Score; TAP = Test of Attentional Performance; UPSIT = Pennsylvania Smell Identification Test.

Figure 3

Health improvements following 52 weeks of sonlicromanol treatment. (A–D) Left: Individual scores on the indicated measures during the 52 weeks of sonlicromanol treatment. The grey-shaded area depicts the normal ranges. Right: The grey-shaded area shows the threshold greater than the minimal clinically important difference (MCID). The dots represent the change from baseline (CFB) for each patient. The dotted line represents no change. (A) Newcastle Mitochondrial Disease Scale for Adults (NMDAS); (B) Neuro-Quality of Life Short Form-Fatigue (NQF); (C) Five Times Sit-to-Stand Test (5×SST); (D) mini-Balance Evaluation Systems test (mini-BESTest); (E) Patient-reported Global Impression of Change (PGIC); (F) Clinician-scored Global Impression of Change (CGIC). PD = predose.

Figure 4

Dose selection. (A) Individual Beck Depression Inventory (BDI), change from placebo (CFP) and Neuro-Quality of Life Short Form-Fatigue (NQF) values were obtained from outcome measures of the randomized controlled study and showed positive trends toward improvement. They were plotted against the plasma concentration of KH176 (parent compound) for both the 50-mg twice daily (bid) and 100-mg bid doses. The four quadrants of each graph represent positive (top)/negative (bottom) responses and more (right)/less (left) than 2000 ng/ml/h. Numbers denoted in red refer to the percentage of points scored. (B) A correlation between the individual maximum plasma concentration (C_max) and the exposure data for the 50-mg bid and 100-mg bid doses. CFQ = Cognitive Failure Questionnaire.