Stealth BioTherapeutics’ SBT-589 Shows Cardioprotective Effects in Preclinical Models of Friedreich Ataxia


Recent preclinical findings revealed SBT-589's potential to treat cardiomyopathy in Friedreich ataxia by targeting mitochondrial dysfunction.

Laura E. Kropp, PhD, MPH, senior manager of discovery biology at Stealth BioTherapeutics

Laura E. Kropp, PhD, MPH

Credit: LinkedIn

New data on SBT-589 (Stealth BioTherapeutics) presented at the 2024 Wellcome Trust Conference on Mitochondrial Medicine – Therapeutic Development, held March 18-20, in Cambridge, England, demonstrated cardioprotective effects across preclinical models of Friedreich ataxia (FA).1,2 These findings support further development of SBT-589, a novel molecule that can act on mitochondrial pathways that are impaired, and suggest the compound could be a disease-modifying therapy in FA cardiomyopathy.

All told, mice treated with once-daily SBT-589 displayed significantly reduced cardiac hypertrophy and a delay in the onset of mortality compared with vehicle-treated mice. Notably, investigators observed that the compound improved bioenergetics in FA patient-derived cells and mitochondria. In previous research, findings showed that SBT-589 had the ability to bypass dysfunctional complex I and lower redox stress, which led to the hypothesis that the compound might show beneficial effects across models of FA.

Top Clinical Takeaways

  • SBT-589, a novel molecule, exhibited promising cardioprotective effects in preclinical models of Friedreich ataxia.
  • The compound improved bioenergetics in patient-derived cells and mitochondria, suggesting its potential as a disease-modifying therapy.
  • Mitigating heart disease in FA is an important focus for research efforts, given its significant contribution to mortality in this condition.

“Our major finding was that the novel compound, SBT-589, improved metrics of adverse cardiac growth (hypertrophy) in a highly aggressive mouse model of FA cardiomyopathy. Transgenic FA mice showed increased left ventricular mass (normalized to body weight) and increased left ventricular wall thickness compared with control mice. We found that 3 weeks of daily SBT-589 treatment prevented cardiac hypertrophy,” lead author Laura E. Kropp, PhD, MPH, senior manager of discovery biology at Stealth BioTherapeutics, told NeurologyLive®.

“We also observed a delay in the onset of mortality in mice treated with SBT-589 by approximately 20 days (notable as mice usually live ~75 days). These data suggest that SBT-589 exerts cardioprotective effects, with potential implications on mortality/morbidity. Given the severity of disease in this FA cardiomyopathy model, our results are exciting and highlight the promise of this compound for further development," Kropp added.

READ MORE: First Patient Dosed in Phase 2 Open Label Extension Study of Nomlabofusp for Friedreich Ataxia

Investigators conducted a new series of studies in FA patient-derived cells, isolated heart mitochondria, and an aggressive mouse model of FA cardiomyopathy, to assess the protective effects of SBT-589 on various aspects of mitochondrial function. Using high-resolution respirometry, investigators observed that SBT-589 restored oxygen consumption rates to near baseline following chemical inhibition of complex I and declined mitochondrial reactive oxygen species emission. Additionally, SBT-589 enhanced cell viability and lowered markers of lipid peroxidation after treatment with redox stressors.

"We also found that SBT-589 was efficacious in mitochondrial and cellular models of FA. In FA, mitochondrial dysfunction caused by deficiency in frataxin is central to disease pathology,” Kropp said. “We showed that, in isolated mitochondria, SBT-589 can reduce emission of reactive oxygen species, which can contribute to cardiovascular pathology. In FA patient-derived cells, we demonstrated that SBT-589 can address major pathways in FA disease progression as it can both ‘bypass’ deficiencies in complex I of the electron transport chain to improve bioenergetics and ameliorate iron-mediated cell death. These data confirm that SBT-589 works by improving mitochondrial health.”

Authors used the cardiac MCK-Cre conditional knockout mouse, a model with prominent cardiac hypertrophy and an aggressive mortality rate, in parallel studies. SBT-589 was dosed daily by subcutaneous injection (60mg/kg) beginning at 4 weeks of age until the animals succumbed to the disease. Investigators noted that they performed an echocardiogram at baseline, 4 weeks of age, and 7 weeks of age.

Additional findings showed that SBT-589 significantly reduced various parameters of cardiac hypertrophy following 3 weeks of the daily dosing. Findings showed that SBT-589 delayed the onset of mortality by 20 days compared with vehicle control, which authors wrote as a notable observation in a model since it typically does not live past 80 days.

“There are currently no therapies that directly address the heart disease in FA, which is a leading cause of death. Our results suggest that SBT-589 could slow progression of cardiomyopathy,” Kropp added. “We are currently finishing up the next round of studies examining the potential of SBT-589 and expect to gain deeper insights into the cardioprotective effects. Thus far, SBT-589 is also progressing successfully through developmental stage gates, bringing it closer to potential testing human trials. Our team has a shared passion for the therapeutic potential of targeting mitochondria, with the hopes of improving the lives of individuals living with FA.”

1. Stealth BioTherapeutics Presents Data of Novel Compound, SBT-589, in Friedreich’s Ataxia Cardiac Models at the Wellcome Trust Mitochondrial Medicine Conference. News Release. Stealth BioTherapeutics. Published March 19, 2024. Accessed May 1, 2024.
2. Kropp LE, Handler A, Zariwala H, et al. Effects of the novel therapeutic SBT-589 across models of Friedreich’s ataxia. Presented at: 2024 Wellcome Trust Conference on Mitochondrial Medicine – Therapeutic Development; March 18-20, 2024, in Cambridge, England.
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