SBT-272, in Phase 1 Trial, Continues to Protect Motor Neurons in Mice

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Stealth BioTherapeutics’ investigational therapy SBT-272 eased inflammation and upper motor neuron degeneration in a mouse model of amyotrophic lateral sclerosis (ALS) associated with the accumulation of toxic TDP-43 protein clumps, the company announced.

Motor neurons are nerve cells that control voluntary movement and progressively die in people with ALS. Upper motor neurons conduct signals from the brain to the spinal cord, and lower motor neurons then make the connection between the spinal cord and the rest of the body.

Notably, SBT-272 was superior to approved ALS treatments at improving upper motor neuron health in the mice and its benefits were associated with better health in mitochondria, the cells’ powerhouses.

“ALS is a devastating progressive neuromuscular disease with a significant unmet medical need,” Reenie McCarthy, Stealth BioTherapeutics’ CEO, said in a press release. “We designed SBT-272 to target mitochondrial dysfunction in the brain, which is known to precede and contribute to several neurodegenerative diseases, including ALS.”

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These preclinical findings were presented at the Keystone Neurodegeneration Symposium held June 5–9 in Keystone, Colorado.

“The new findings … further strengthen the importance of improving mitochondrial health with respect to [TDP-43-related damage] in ALS and lay a strong foundation for the clinical development of SBT-272 for ALS patients,” said Hande Ozdinler, PhD, an associate professor of neurology at Northwestern University Feinberg School of Medicine who was involved in the study.

Motor neuron degeneration in ALS is associated with the toxic buildup and clumping of certain proteins, such as TDP-43 and SOD1, and with mitochondrial dysfunction.

“Upper motor neuron degeneration is an early event in ALS, which is characterized by degeneration of both the upper motor neurons in the brain and the lower motor neurons in the spinal cord,” Ozdinler said.

“Therefore, to build effective treatment strategies for ALS, it is necessary for therapeutics to demonstrate efficacy on upper motor neuron health and function,” Ozdinler added.

SBT-272 is a small molecule designed to improve mitochondrial function by selectively binding to cardiolipin, a fatty molecule located in the inner membrane of these cellular structures — where most of the energy is produced.

By doing that, the therapy is expected to help stabilize the membrane’s structure, thereby reducing mitochondrial oxidative stress and improving energy production.

Oxidative stress is an imbalance between the production of oxygen species (natural byproducts of metabolism) and a cell’s ability to detoxify them, resulting in damage.

Previous preclinical work in an SOD1-associated mouse model showed that SBT-272 lowered levels of a nerve cell damage biomarker, delayed the onset of neurological symptoms in a dose-dependent manner, and prolonged life in male mice.

The therapy was also associated with improvements in mitochondrial structure and movement, and lesser mitochondrial oxidative stress in lab-grown motor neurons with ALS caused by a faulty TDP-43.

SBT-272 was also shown to more efficiently cross the blood-brain barrier — the highly specialized barrier that controls which substances in circulation enter the brain and spinal cord — and to have a better oral bioavailability than its predecessor, Stealth’s elamipretide.

Newly presented data, involving a mouse model of TDP-43-associated ALS, showed that SBT-272 treatment reduced upper motor neuron degeneration and neuroinflammation in the motor cortex, a brain region involved in movement control.

In lab-grown upper motor neurons with ALS features due to a faulty TDP-43, the therapy also significantly improved mitochondrial structural integrity and mobility.

These benefits were associated with a greater outgrowth of nerve fibers (axons), a key indicator of better nerve cell health. Notably, axon outgrowth linked to SBT-272 was superior to that observed with the approved ALS therapies Radicava (edaravone) and Albrioza, also known as AMX0035.

Radicava is available in the U.S. and Canada, while Albrioza has become the most recently approved therapy in Canada and is being reviewed by health authorities in Europe and in the U.S., where a decision is expected in September.

All these findings support further evaluation of SBT-272 as a potential treatment for TDP-43-associated ALS. Stealth also plans to test the therapy in other neurological diseases associated with mitochondrial dysfunction.

After an oral formulation of SBT-272 showed a favorable safety profile in healthy volunteers in a previous Phase 1 clinical trial, under-the-skin injections of the therapy are being tested in another, ongoing Phase 1 study.

“We are encouraged that Dr. Ozdinler’s team has elucidated these signals of neuronal protection, and we look forward to working with the ALS community to progress the clinical development of SBT-272,” McCarthy said.