While an open-label phase 1b trial found that mavodelpar improves functional outcomes in primary mitochondrial myopathy (PMM), a group of rare genetic diseases including thymidine kinase 2 deficiency (TK2d), phase 2b findings failed to do so, according to a recent study published in Scientific Reports.
Participants in the phase 1b trial experienced improvements in 12-minute walking test distance and patient-reported fatigue. However, the phase 2b study demonstrated no evidence of clinical benefit.
Mavodelpar is a selective peroxisome proliferator-activated receptor delta (PPARδ)
agonist that works to regulate genes involved in metabolic processes.
The phase 1b trial included 23 participants who received at least one 100 mg dose of mavodelpar, 17 of whom completed the 12-week study. The investigators terminated the trial prematurely in 2020 due to COVID-19.
Patients experienced a mean 26.4% increase in 12-minute walking test distance, and 94% demonstrated improvements in fatigue at Week 12. Scores on the physical and cognitive subscales of the Modified Fatigue Impact Scale also improved.
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Disease severity, measured by the Newcastle Mitochondrial Disease Adult Scale, did not change significantly, though.
In the 12 participants who underwent muscle biopsy, the investigators observed no significant difference in mitochondrial function after 12 weeks. Participants also experienced non-significant changes in FGF-21 and GDF-15, two markers of mitochondrial disease. On the other hand, molecular pathways related to fatty acid metabolism, inflammation and adipose tissue production were upregulated at 12 weeks.
Moreover, 87% of participants in the phase 1b study experienced a treatment-emergent adverse effect. Constipation and headache were the most common events, each occurring in 17.4% of participants. One individual experienced a serious treatment-emergent adverse event, hematoma (localized bleeding), though the investigators attributed it to muscle biopsy rather than the treatment itself.
Ultimately, investigators discontinued the phase 2b trial after it failed to show mavodelpar was clinically effective. “This outcome highlights the well-recognized challenge in mitochondrial disease drug development, where promising early-phase findings frequently fail to translate into demonstrated clinical efficacy in more rigorous later-phase trials,” the study concluded.
The authors acknowledge several study design limitations including the small sample size and short follow-up period. There is also a possibility of false-positive results, given the large number of endpoints studied.
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