Cerebellar Diseases

SBT-589 showed mitochondrial protection across models of Friedreich's ataxia SBT-589 displayed cardioprotective effects in aggressive mouse model of FA cardiomyopathy Ongoing studies are expected to build on these insights as SBT-589 progresses through developmental stage-gates NEEDHAM, Mass., March 19, 2024 /PRNewswire/ -- Stealth BioTherapeutics Inc. (the "Company" or "Stealth"), a clinical-stage biotechnology company focused on the discovery, development, and commercialization of novel therapies for diseases involving mitochondrial dysfunction, announced today the presentation of new SBT-589 data demonstrating cardioprotective effects across pre-clinical models of Friedreich's ataxia (FA). The data were presented at the Wellcome Trust Conference on Mitochondrial Medicine – Therapeutic Development, held March 18-20, 2024, in Cambridge, England. FA is a chronic disease of metabolic disruption that is typically diagnosed in childhood or adolescence, is inexorably progressive and usually results in premature death from cardiomyopathy or heart failure. There are no approved therapies for the progressive cardiomyopathy, which is linked to severe mitochondrial dysfunction, and is the leading cause of early death in this devastating disease. SBT-589 is a promising novel molecule that acts on mitochondrial pathways essential for cellular health and energy production that are impaired in FA cardiomyopathy. To evaluate the potential of SBT-589 in FA, a series of studies were conducted in FA patient-derived cells, isolated heart mitochondria, and an aggressive mouse model of FA cardiomyopathy. SBT-589 improved bioenergetics in FA patient-derived cells and mitochondria. In an FA mouse model with prominent cardiac hypertrophy and aggressive mortality, mice treated with once-daily SBT-589 displayed significantly reduced cardiac hypertrophy and a delay in the onset of mortality compared to vehicle-treated mice. "Mitochondrial dysfunction is a central contributor to pathology in Friedreich's ataxia, a disease in which heart failure and sudden cardiac events are among the leading causes of mortality," said David A. Brown, Senior Vice President, Discovery. "Mitigating heart disease in FA is central to Stealth's ongoing efforts to improve the lives of individuals with FA. The new findings presented today support continued development of SBT-589 as a potentially disease-modifying therapy to address the unmet need in cardiomyopathy associated with Friedreich's ataxia." The data were presented by Dr. Laura E. Kropp, Senior Manager of Discovery Biology at Stealth, and recipient of the Keith Michael Andrus Cardiac Award from the Friedreich's Ataxia Research Alliance. About Friedreich's Ataxia Friedreich's ataxia is a rare genetic disease affecting an estimated 1 in 50,000 individuals in the United States. The disease is caused by a defect in the frataxin gene resulting in a relative deficiency of frataxin, leading to mitochondrial iron accumulation and oxidative stress. More than 90% of patients with Friedreich's ataxia experience progressive cardiomyopathy which usually becomes fatal by early adulthood and is the leading cause of early mortality. About Stealth BioTherapeutics Stealth BioTherapeutics is a clinical-stage biotechnology company focused on the discovery, development, and commercialization of novel therapies for age-related and rare genetic diseases involving mitochondrial dysfunction. The Company is initiating Phase 3 clinical trials of elamipretide, its lead investigational product candidate, in dry age-related macular degeneration. Elamipretide is also being tested in a fully enrolled Phase 3 clinical trial in primary mitochondrial myopathy, a rare skeletal myopathic disease caused by nuclear DNA mutations, and is the subject of a New Drug Application for Barth syndrome, an ultra-rare cardioskeletal disease. The Company is evaluating its second-generation clinical-stage candidate, SBT-272, for ophthalmic and neurological disease indications. The Company has a deep pipeline of novel mitochondria-targeted compounds under evaluation as therapeutic product candidates. Several of these lead compounds, including SBT-589, have progressed through pre-clinical development stage-gates and toward IND-enabling studies. Investor Contact Kendall Investor Relations Adam Bero, Ph.D. [email protected] [email protected] Media Contact Anna Stallman Communications Anna Stallman [email protected] SOURCE Stealth BioTherapeutics Inc.

GSK said that a regimen of Jemperli (dostarlimab) plus standard chemotherapy reduced the risk of death by 31% versus chemotherapy alone in adults with primary advanced or recurrent endometrial cancer, boosting hopes of expanding the drug’s current label. The company also released new progression-free survival (PFS) data on the PD-1-blocking antibody in combination with the PARP inhibitor Zejula (niraparib).“The results we’ve seen to date comprise the growing body of evidence supporting the role of [Jemperli] as the backbone of our immuno-oncology development programme,” remarked Hesham Abdullah, GSK's global head of oncology R&D.Jemperli gained approval last year in the US and Europe for front-line treatment of advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) based on positive PFS data from Part 1 of the Phase III RUBY trial. The first part of the study also achieved its overall survival (OS) endpoint. Data unveiled on Saturday at the Society of Gynecologic Oncology (SGO) annual meeting on women’s cancer showed that median OS was 44.6 months for Jemperli plus chemotherapy, or 16.4 months longer than for chemotherapy alone. GSK added that in a subgroup of patients with mismatch repair proficient (MMRp)/microsatellite stable (MSS) tumours, Jemperli plus chemotherapy reduced the risk of death by 21%, with median OS in the two arms of 34 months and 27 months, respectively.Meanwhile, Part 2 of the RUBY trial - which is investigating Jemperli plus chemotherapy followed by Jemperli plus Zejula, versus chemotherapy plus placebo followed by placebo – also hit its PFS goal, according to results top-lined last December.Findings presented at the SGO conference showed that the Jemperli/Zejula arm had a 40% lower risk of disease progression or death, with median PFS of 14.5 months, or 6.2 months longer than the comparator group. In the MMRp/MSS population, the Jemperli/Zejula regimen reduced the risk of disease progression or death by 37%, with median PFS of 14.3 months, versus 8.3 months for chemotherapy alone.GSK gained Jemperli – which was developed as part of a collaboration with AnaptysBio - and Zejula via its $5.1-billion purchase of Tesaro in 2019.

Pictured: GSK's headquarters in London/iStock, William Barton GSK on Saturday unveiled new data from its Phase III RUBY program demonstrating better survival outcomes in a wide range of endometrial cancer patients treated with Jemperli (dostarlimab), potentially setting the PD-1 blocker up for a label expansion. Hesham Abdullah, senior vice president and global head of oncology R&D at GSK, said in a statement that RUBY’s findings show that Jemperli-based regimens “could benefit a broader set of patients with endometrial cancer,” adding that the pharma has been amassing a “growing body of evidence supporting the role of dostarlimab-gxly as the backbone” of its immuno-oncology development program. RUBY is a randomized and double-blinded Phase III study comprised of two parts. The first part assessed the efficacy and safety of Jemperli with carboplatin-paclitaxel, followed by maintenance with Jemperli monotherapy, versus carboplatin-paclitaxel with placebo and placebo maintenance therapy. Part two used the same regimen of Jemperli with carboplatin-paclitaxel as an initial treatment, but combined the PD-1 inhibitor with GSK’s PARP inhibitor Zejula (niraparib) for maintenance treatment. The comparator arm received placebo with carboplatin-paclitaxel, followed by placebo. Results from the first part showed that the Jemperli regimen significantly reduced the risk of death by 31% versus the chemotherapy counterpart. Patients in the Jemperli arm likewise had a “clinically meaningful improvement” in overall survival (OS) of 16.4 months. The Jemperli combo was also similarly beneficial in an exploratory analysis of patients with mismatch repair proficient (MMRp)/microsatellite stable (MSS) tumors, cutting their risk of death by 21%. OS in this subpopulation improved by seven months. GSK will regulatory submission in the first half of this year, using data from the first part of RUBY to expand Jemperli’s label to cover the overall endometrial cancer population, according to the pharma’s announcement. Part two evaluated progression-free survival (PFS) and found that patients in the Jemperli-Zejula arm saw a 40% drop in the risk of disease progression or death. These patients also saw a clinically meaningful 6.2-month improvement in median PFS. In MMRp/MMS patients, the combo regimen reduced the risk of death or disease progression by 37% and increased median PFS by six months. GSK previously announced positive PFS findings from part two of Ruby in December 2023, though it did not reveal specific data at the time. Jemperli is a monoclonal antibody that works by targeting and binding the PD-1 receptor and blocking its interaction with corresponding ligands. This mechanism of action disables the cancer cells’ ability to evade the immune system and enhances the body’s anti-cancer immune activity. The monoclonal antibody was first approved in 2021 for the treatment of recurrent or advanced endometrial cancer patients who are mismatch repair deficient. It has since picked up several more approvals, including one for frontline endometrial cancer in August 2023, beating out Merck’s dominant blockbuster treatment Keytruda (pembrolizumab). Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.