Eledon’s Antibody, Tegoprubart, Shows Promise in ALS Phase 2 Trial
Eledon Pharmaceuticals’ investigational antibody-based therapy, tegoprubart, safely and effectively reduces levels of inflammatory biomarkers in adults with amyotrophic lateral sclerosis (ALS), according to top-line data from a Phase 2a clinical trial.
Exploratory findings suggested that lower levels of inflammatory biomarkers and whether tegoprubart’s target is significantly reduced, called target engagement, were associated with slower disease progression, further highlighting the therapy’s potential benefits in ALS.
“Neuroinflammation is a driving force in the [development] and progression of ALS. The ability to suppress inflammatory responses may translate into clinical benefit,” Stanley H. Appel, MD, co-director of the Houston Methodist Neurological Institute, one of the trial’s participating sites, said in a press release. Appel is also chair of the Stanley H. Appel department of neurology at Houston Methodist.
The results “demonstrated target engagement and a reduction in key inflammatory biomarkers in patients living with ALS,” said Merit Cudkowicz, MD, the chief of the neurology department and the director of MGH’s Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital.
“These encouraging data support advancing tegoprubart into larger clinical ALS studies,” said Cudkowicz, who is also the Julieanne Dorn professor of neurology at Harvard Medical School.
Eledon now plans to publish the trial’s data in a peer reviewed journal and work with the ALS patient community and health authorities to determine the best design for the next trial, according to the company’s recent webcast.
Tegoprubart is a lab-made antibody initially developed by the ALS Therapy Development Institute (ALS TDI) with support from the ALS Association, ALS ONE, and ALS Finding a Cure. It was brought into trials by Anelixis Therapeutics, ALS TDI’s for-profit subsidiary that’s now part of Eledon.
Administered directly into the bloodstream, the therapy is designed to suppress neuroinflammation by preventing two molecules at the surface of several types of immune cells — CD40 ligand (CD40L) and CD40 receptor — from interacting.
CD40L’s binding to its receptor on immune cells is known to boost pro-inflammatory responses, including those leading to autoimmunity and neuroinflammation. Previous research has shown that CD40-CD40L signaling between immune cells is increased in 56% of ALS patients, and levels of CD40L in circulation are associated with rate of disease progression.
By targeting CD40L, tegoprubart promotes a shift in immune T-cells from a pro-inflammatory status to a more immunosuppressive role that dampens immune responses, according to Eledon. As such, the therapy has the potential to halt damaging inflammation associated with ALS and other inflammatory conditions.
Preclinical data showed tegoprubart reduced inflammation and motor neuron death, significantly delaying disease onset and extending the survival of animal models of ALS — further supporting the critical role of neuroinflammation in ALS progression.
Motor neurons are the specialized nerve cells that control voluntary movement and that progressively die in people with ALS.
Based on these promising findings, the therapy received orphan drug designation in the U.S. for ALS, which is meant to expedite its clinical development and regulatory review.
Single ascending doses of tegoprubart were deemed safe and well tolerated in healthy volunteers and ALS patients in a previous Phase 1 trial. The therapy also showed favorable pharmacokinetics, or movement into, through, and out of the body.
The Phase 2a trial (NCT04322149) evaluated the safety, tolerability, and pharmacodynamics (effects on the body) of four doses of the therapy — 1, 2, 4, and 8 mg/kg — in 54 adult ALS patients diagnosed in the previous two years. Participants, enrolled at sites in the U.S. and Canada, received six infusions into the vein, given every other week for 12 weeks, or about three months.
The trial’s secondary measures included target engagement and changes in inflammatory biomarkers.
Monthly changes in disease progression rate, as measured with the ALS Functional Rating System-Revised (ALSFRS-R) scale, were also assessed as an exploratory goal. These were compared to disease progression of a control group of patients from the ALS PRO-ACT database, the largest ALS clinical trial dataset to date.
Newly announced top-line results showed that tegoprubart was generally safe and well tolerated at all doses, with treatment-related side effects reported in 35.2% of patients. None were serious or severe.
Rates of side effects were well distributed across dose groups and only two patients in the lower dose groups discontinued treatment due to them. Antibodies against the therapy also were detected in less than 5% of samples and did not affect therapy levels.
Tegoprubart’s higher doses (4 and 8 mg/kg) showed effective target engagement, based on significant reductions in levels of CD40L and CXCL13, biomarkers of immune T- and B-cell function.
Before starting the medication, patients exhibited a pro-inflammatory ALS signature comprised of 32 different inflammatory biomarkers. However, treatment led to dose-dependent, significant reductions in the levels of up to 23 of these biomarkers, including TNF-alpha, MCP1, EN-RAGE, and C-Reactive Protein. Maximum declines in these biomarkers were seen after about one month of treatment.
Both effective target engagement (defined as at least a 10% drop in CXCL13 levels) and high responses (at least a 10% reduction in 75% or more of inflammatory biomarkers) were associated with slower disease progression, when compared with the external control group.
High responders in the two high-dose groups showed the slowest disease progression, which was 31.3% slower than that reported in the control group.
These findings “reinforce the exciting potential of tegoprubart as a promising therapy for patients with ALS,” Appel said.
David-Alexandre C. Gros, MD, Eledon’s CEO, praised the support for tegoprubart among ALS patients and their families.
“There would be no tegoprubart without the resolve of so many ALS patients and their families who supported the early drug discovery efforts for tegoprubart, and who continue to champion the scientific advancement of ALS research,” Gros said. “Our new data are helping elucidate the role of inflammation in ALS. We look forward to presenting and reporting additional data from this and from our other clinical trials later this year.”
Tegoprubart is also being evaluated as a potential treatment for other inflammation-related conditions in clinical trials. According to the webcast, the company has plans to develop a new formulation of tegoprubart that can be administered through under-the-skin injections.