August 31, 2022

Steve Perrin, Ph.D., ALS Therapy Development Institute

Amyotrophic Lateral Sclerosis (ALS) is a debilitating neurological disorder characterized by motor neuron degeneration that is always fatal. In 2016, the ALS Research Program (ALSRP) funded a Therapeutic Development Award to Dr. Steve Perrin at the ALS Therapy Development Institute (ALS TDI) titled, �Anti-CD40 Ligand Therapy for Slowing Progression and Extending Life in Amyotrophic Lateral Sclerosis� targeting immune cell activation and protecting nerve cells against progression of ALS. At that time, ALS TDI had discovered that subtly modulating the immune system with an antibody targeting a protein called CD40 Ligand (CD40L) is protective in a mouse model of ALS. Disease progression in the mice treated with the antibody was slower and the animals lived longer than usual. ALS TDI then discovered that the elements of the immune system that are targeted with this antibody are also disrupted in people living with ALS. Because of these discoveries, ALS TDI moved forward with development of a new antibody drug, AT1501, to target CD40L in patients with ALS. This was a real challenge as antibody drugs that had previously targeted CD40L in humans were toxic and caused potentially fatal blood clots.

With support from their FY16 ALSRP award, Dr. Perrin and ALS TDI team showed that, in non-human primates, the newly developed AT1501 did not cause platelets to clot, and it was safe enough to move into human phase 1 ALS clinical trials. In April 2018, in response to the successful ALSRP award, as well as further development efforts by ALS TDI, the Food and Drug Administration granted Orphan Drug Designation and Investigational New Drug approval of AT1501.

AT1501, now named Tegoprubart, was advanced through early clinical trials by Anelixis Therapeutics, a for-profit clinical-stage development company. Anelixis successfully completed phase 1 trials of Tegoprubart in 2019. Then in May 2022, Eledon Pharmaceuticals announced their results from the phase 2a trial, an open-label, dose-escalating, safety, and biomarker study of Tegoprubart. The endpoints of the study were safety and tolerability and changes in pro-inflammatory biomarkers. Tegoprubart was well-tolerated, with no drug-related serious adverse events. Pro-inflammatory biomarker reduction was associated with a non-significant trend toward slowing disease progression as measured by the Revised ALS Functional Rating Scale. According to Dr. Perrin, seeing a lead candidate from his research team reach people with ALS is a good sign that we are moving closer to ensuring patients living with ALS can get the treatment they need. Of the ALSRP's support in this drug's pathway from bench to bedside, Dr. Fernando G. Vieira, M.D., ALS TDI's chief executive officer/chief scientific officer, noted that ALS TDI had previously discovered CD40L's possible implication in ALS and invented Tegoprubart to target the pathway.

�The ALSRP supported critical work that was necessary to turn that invention into a medicine that could be tested in people with ALS,� Dr. Vieira said.

The team hopes Tegoprubart proves to be the first of multiple effective treatments for ALS invented at ALS TDI.

Links:

Public and Technical Abstracts: Anti-CD40 Ligand Therapy for Slowing Progression and Extending Life in Amyotrophic Lateral Sclerosis

https://www.pr.com/press-release/862530

https://www.als.net/tegoprubart/

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