Stealth Biotherapeutics’ SBT-272 Earns Orphan Drug Status

Decision based on interim results from a Phase 1 study

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by Jacob Harney |

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The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to Stealth Biotherapeutics’ investigational therapy SBT-272 for the treatment of amyotrophic lateral sclerosis (ALS).

Aimed at speeding the development of new treatments for rare, life-threatening diseases, orphan drug status offers regulatory support and certain financial incentives during clinical development, as well as seven years of marketing exclusivity if the treatment receives regulatory approval.

The designation comes as Stealth announced positive interim results from a Phase 1 study of SBT-272, which demonstrated that the doses selected for future clinical testing are expected to reach therapeutic concentrations in the brain.

Delivered as under-the-skin injections, the selected doses also appear generally safe and well-tolerated, although final safety analyses are ongoing.

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“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,” Reenie McCarthy, Stealth CEO, said in a press release.

“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,” McCarthy added.

ALS is marked by the progressive degeneration of motor neurons, which are the nerve cells that communicate with muscle fibers to control movement. This includes upper motor neurons — those that travel from the brain to the spinal cord — and lower motor neurons, which carry signals from the spinal cord to the muscles.

Dysfunction of mitochondria — the cellular organelles that produce most of cells’ energy — is observed early in ALS and is thought to contribute to motor neuron death.

SBT-272 is a small molecule that aims to improve mitochondrial function by selectively binding to cardiolipin, a fatty molecule located on the inner membrane of mitochondria. In doing so, SBT-272 is expected to stabilize that membrane, thereby improving energy production and preventing oxidative stress, which is a type of cellular damage thought to drive nerve cell death in ALS.

Preclinical studies demonstrated that SBT-272 delayed the onset of neurological symptoms, prolonged lifespan, and lowered levels of a biomarker of nerve damage in a mouse model of SOD1-associated ALS. The toxic buildup of the SOD1 protein is linked to some ALS cases.

Moreover, the treatment was associated with improved mitochondrial structure in cell cultures of motor neurons affected by toxic TDP-43 buildup, another protein linked to ALS.

More recently, Stealth Biotherapeutics announced that SBT-272 reduced upper motor neuron degeneration and inflammation in the motor cortex — a brain region involved in movement control — in a TDP-43 ALS model.

Signs of improved nerve health also were observed with the treatment, which were superior to that observed with approved ALS therapies Radicava (edaravone) and Relyvrio (sodium phenylbutyrate and taurursodiol), also known as Albrioza or AMX0035.

“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,” said Hande Ozdinler, PhD, associate professor of neurology at the Northwestern University’s Feinberg School of Medicine.

Conference presentation

These preclinical results were presented at the recent Northeast Amyotrophic Lateral Sclerosis conference held in Clearwater, Florida.

A previous Phase 1 study showed that an oral formulation of SBT-272 was safe in healthy volunteers. The ongoing Phase 1 study now is testing an under-the-skin formulation.

“There appears to be compelling support for the therapeutic potential of targeting mitochondria in ALS and the ongoing clinical development of SBT-272,” Ozdinler said.

Stealth reports that SBT-272 demonstrates a greater ability to enter the brain than elamipretide, another of Stealth’s mitochondria-targeted treatments, making it a promising option for neurological diseases marked by mitochondrial dysfunction like ALS.