SS-31

Effects measured: In the highest-dose (0.25 mg/kg/h) cohort, versus placebo, left ventricular end-diastolic volume fell by 18 mL (P=0.009) and end-systolic volume by 14 mL (P=0.005) at end of infusion. Peak plasma levels occurred at end-infusion and were undetectable by 24 hours; the volume changes correlated with peak plasma concentration. Lower doses showed no significant effect.

Side effects: No serious adverse events. Blood pressure and heart rate remained stable across all cohorts.

Sources: Daubert MA, Yow E, Dunn G, et al. Novel Mitochondria-Targeting Peptide in Heart Failure Treatment: A Randomized, Placebo-Controlled Trial of Elamipretide. Circ Heart Fail. 2017;10(12):e004389.

Effects measured: Dose-dependent increase in 6-minute walk distance (P=0.014 for trend). At the highest dose, participants walked 64.5 m farther at day 5 versus 20.4 m for placebo (P=0.053); in the adjusted analysis the improvement was 51.2 m versus 3.0 m for placebo (P=0.0297).

Side effects: No significant differences in safety endpoints between elamipretide and placebo; no increased safety concerns reported.

Sources: Karaa A, Haas R, Goldstein A, Vockley J, Cohen BH, et al. Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy. Neurology. 2018;90(14):e1212-e1221.

Effects measured: Primary endpoint missed: 6-minute walk distance was 398.3 m on elamipretide vs 378.5 m on placebo, a 19.8 m difference (95% CI -2.8 to 42.5; P=0.0833). Secondary, nominally significant signals: less total fatigue (P=0.0006) and less fatigue during activities (P=0.0018) on the PMM Symptom Assessment, plus improvements on Neuro-QoL Fatigue (P=0.0115) and Patient Global Assessment (P=0.0421). Physician Global Assessment, Triple Timed Up and Go, and accelerometry showed no significant change.

Side effects: Injection site reactions were the most common adverse event (80%), mostly mild. No serious adverse events or deaths.

Sources: Karaa A, Haas R, Goldstein A, Vockley J, Cohen BH. A randomized crossover trial of elamipretide in adults with primary mitochondrial myopathy. J Cachexia Sarcopenia Muscle. 2020;11(4):909-918.

Effects measured: Primary endpoint missed: change in LV end-systolic volume from baseline to week 4 did not differ from placebo (4 mg vs placebo difference of means -0.3 mL, 95% CI -4.6 to 4.0, P=0.90; 40 mg vs placebo +2.3 mL, 95% CI -1.9 to 6.5, P=0.28). No significant differences in LVESV or LVEF change between placebo and either dose.

Side effects: Rates of study-drug-related adverse events were similar across all three groups; elamipretide was well tolerated.

Sources: Butler J, Khan MS, Anker SD, et al. Effects of Elamipretide on Left Ventricular Function in Patients With Heart Failure With Reduced Ejection Fraction: The PROGRESS-HF Phase 2 Trial. J Card Fail. 2020;26(5):429-437.

Effects measured: In completers (n=15), best-corrected visual acuity improved by +4.6 letters (P=0.0032) and low-luminance BCVA by +5.4 letters (P=0.0245) from baseline to week 24. Geographic atrophy area still grew (square-root-transformed change +0.14 mm by fundus autofluorescence, +0.13 mm by OCT). This was an uncontrolled open-label phase 1 with safety as the primary endpoint; visual gains were exploratory.

Side effects: All 19 participants had at least one non-ocular adverse event, all mild (73.7%) or moderate (26.3%); no serious adverse events. Two withdrew for adverse events (one conversion to neovascular AMD, one intolerable injection-site reaction).

Sources: Mettu PS, Allingham MJ, Cousins SW. Phase 1 Clinical Trial of Elamipretide in Dry Age-Related Macular Degeneration and Noncentral Geographic Atrophy: ReCLAIM NCGA Study. Ophthalmol Sci. 2022;2(1):100086.

Effects measured: Eight weeks of SS-31 substantially reversed age-related diastolic dysfunction in old mice: the Ea/Aa ratio (early-to-late diastolic mitral annulus velocity) increased and the myocardial performance index decreased toward younger values, both significantly different from saline controls at 8 weeks. SS-31 also normalized the elevated mitochondrial proton leak, reduced mitochondrial ROS in cardiomyocytes, reduced cardiac protein oxidation, and increased phosphorylation of cMyBP-C Ser282. The benefit was independent of titin isoform shift and did not add to mitochondrial-catalase (mCAT) mice, pointing to reduced mitochondrial oxidative stress as the shared mechanism. Specific numeric Ea/Aa and MPI values are reported in the figures rather than the text.

Side effects: No adverse events reported in this study (the comparator was saline-infused old mice).

Sources: Chiao YA, Zhang H, Sweetwyne M, et al. Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice. eLife. 2020;9:e55513.