SBT-272 Shows Neuroprotective Impacts in ALS Mouse Models of TDP-43 Pathology

Hande Ozdinler, PhD

Findings from a mouse model study of amyotrophic lateral sclerosis (ALS) presented at the 2022 Northeast Amyotrophic Lateral Sclerosis (NEALS) Meeting, held November 1-3, in Clearwater Beach, Florida, showed that treatment with SBT-272 (Stealth BioTherapeutics) resulted in neuroprotection of upper motor neurons (UMNs) that are diseased with TDP-43 pathology.¹

In vivo administration of SBT-272, a small molecule agent that targets the cardiolipin-rich inner mitochondrial membrane, led to UMN retention (SBT-272 1.0 mg/kg/day: 51.40 [±0.93]; 5 mg/kg/day: 49.93 [±1.76]; vehicle: 29.58 [±1.32]; P <.0001). Using TMRE flow cytometry, investigators also observed that SBT-272 significantly reduced microglia (ionized calcium binding adaptor molecule 1: SBT-272 1 mg/kg/day: 9.13 [±0.57]; 5 mg/kg/day: 13.27 [±2.03]; vehicle: 37.08 [±3.73]; P < 0.0001) and astrogliosis (glial fibrillary acidic protein: SBT-272 1 mg/kg/day: 20.07 [±1.85]; 5 mg/kg/day: 24 [± 4.1]; Vehicle: 59.75 [±7.31]; P < 0.0001).

"The preclinical data demonstrate that SBT-272 improves the stability and function of mitochondria in upper motor neurons that are diseased with TDP-43 pathology. This also provides neuroprotection and reduces neuroinflammation in the motor cortex of a TDP-43 model of ALS," Hande Ozdinler, PhD, associate professor of neurology, Feinberg School of Medicine, Northwestern University, said in a statement.² "There appears to be compelling support for the therapeutic potential of targeting mitochondria in ALS and the ongoing clinical development of SBT-272."

SBT-272 recently was granted orphan drug designation by the FDA as a treatment for ALS. To study the effect of UMN axonal outgrowth and branching, investigators collected data on motor cortexes from prp-hTDP-43A315T and UeGFP litter mates that were dosed with either SBT-272 via intraperitoneal injection or vehicle. Immunohistology was performed on perfused brains to determine loss of GFP+ UMN, count of activated microglia and activated astrogliosis in the motor cortex.

Overall, treatment with SBT-272 resulted in improved mitochrondria membrane potential and axonal outgrowth of TDP-43 in vitro. Although the mice were cultured and treated with SBT-272 with add-on edaravone (Radicava; MT Pharma) and recently approved AMX0035 (Relyvrio; Amylyx Pharmaceuticals), the agent was superior to the 2 therapies on axonal growth outcome. Additionally, the investigators reported good correspondence between in vitro and in vivo potencies of SBT-2272 in the well-characterized TDP-43 model of ALS.

In an announcement, Reenie McCarthy, chief executive officer, Stealth BioTherapeutics, said, "We are pleased to receive orphan drug designation from FDA for SBT-272 for the treatment of ALS, underscoring the urgent need for innovative new therapies for this devastating disease. We are encouraged by the clinical profile of SBT-272 observed to date and look forward to evaluating its therapeutic potential in ALS and other neurodegenerative diseases of mitochondrial dysfunction."

The company also presented interim results from a phase 1 study of SBT-272 in healthy volunteers. The 2-part study included a single-ascending dose phase that evaluated the agent in doses ranging from 5 to 60 mg, as well as a multiple-ascending dose design, which included 3 groups of SBT-272 who received once daily doses of either 20, 40, or 60 mg, for 7 days. Each part included a smaller group of individuals on placebo.

All told, the phase 1 interim findings showed that SBT-272 had a clinical pharmacokinectic profile consistent with non-clinical allometric scaling predictions, as well as a consistent safety profile. Injection site reactions, although mild-to-moderate and generally resolved by 4-hours post-dose, were the most commonly reported adverse event in the 5-40 mg dose range. In the 60 mg groups, injection site reactions severity increased relative to lower doses. At the conclusion of the presentation, the authors wrote that the agent is planned to go into clinical studies of patients with ALS.

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REFERENCES
1. Gautam M, Genc B, Gunay A, et al. SBT-272 improved mitochondria structure and function and preserved upper motor neurons with TDP-43 pathology. Presented at: 2022 Annual NEALS Meeting; November 1-3; Clearwater Beach, FL. Abstract 58
2. Stealth BioTherapeutics announces SBT-272 data updates and orphan drug designation for the treatment of amyotrophic lateral sclerosis (ALS). News release. Stealth BioTherapeutics. November 1, 2022. Accessed November 1, 2022. https://www.prnewswire.com/news-releases/stealth-biotherapeutics-announces-sbt-272-data-updates-and-orphan-drug-designation-for-the-treatment-of-amyotrophic-lateral-sclerosis-als-301663981.html
3. Zariwala H, Wakefield J, Abbruscato A. Translational pharmacology of SBT-272, a novel mitochrondria-targeted drug for ALS. Presented at: 2022 Annual NEALS Meeting; November 1-3; Clearwater Beach, FL. Abstract 122