Tegoprubart Demonstrates Safety, Target Engagement of ALS Markers in Phase 2 Study

Treatment with tegoprubart resulted in significant reductions of CD40L and CXCL13 levels that occurred after first infusion and sustained throughout the treatment period.

Stanley H. Appel, MD, co-director, Houston Methodist Neurological Institute, and chair, Stanley H. Appel Department of Neurology, Houston Methodist

Stanley H. Appel, MD

Findings from a multicenter, dose-escalating phase 2a study (NCT04322149) evaluating tegoprubart (Eledon Pharmaceuticals), a humanized IgG1 anti-CD40L antibody, showed that the agent is safe and well tolerated in patients with amyotrophic lateral sclerosis (ALS) and met target engagement in a dose-dependent fashion.1

The data, presented at the 2022 Annual NEALS Meeting, held November 1-3 in Clearwater Beach, Florida, expanded on topline findings previously announced in May 2022. All told, tegoprubart, formerly known as AT-1501, met the primary end points of safety and tolerability, with no drug-related serious adverse events (AEs) observed over a 12-week trial. The drug demonstrated target engagement as shown by significant reductions in CD40L and CXCL13 levels.

"Neuroinflammation is a driving force in the pathogenesis and progression of ALS. The ability to suppress inflammatory responses may translate into clinical benefit," Stanley H. Appel, MD, co-director, Houston Methodist Neurological Institute, and chair, Stanley H. Appel Department of Neurology, Houston Methodist, said in a statement following the topline findings.2
"These results reinforce the exciting potential of tegoprubart as a promising therapy for patients with ALS."

Conducted across 13 treatment sites in the US and Canada, the phase 2a study included 54 patients with definite ALS who received 6 intravenous infusions of tegoprubart every 2 weeks at doses of either 1 mg/kg (n = 9), 2 mg/kg (n = 9), 4 mg/kg (n = 18), or 8 mg/kg (n = 18). Patients were no more than 24 months from their diagnosis, and presented to the study with ALS Functional Rating-Revised scores of at least 35 or greater, with an aggregate score of 9 or greater at screening for the dyspnea, orthopnea, and respiratory insufficiency domains.

Throughout the 12-week treatment period, the most frequently seen AEs were fatigue (25/9%), falls (22.2%), and headaches (20.4%, with no thromboembolic AEs observed. In terms of pharmacokinetics (PK), the PK profile was linear and dose proportional, with a half-life around 3 weeks. Additionally, there were a low incidence of anti-drug antibodies—found in less than 5% of the samples—that were all low titer and not associated with altered tegoprubart levels.

Tegoprubart demonstrated dose-dependent target engagement as evidenced by a reduction in circulating levels of CD40L and CXCL13. Across the doses, at least 33% of patients in each group demonstrated at least a 10% reduction in CD40L, the minimum threshold considered to be a meaningful change. For CXCL14, the 1.0 mg/kg represented the lowest amount of patients to show a meaningful change (56%) vs 94% of those in the 8.0 mg/kg group.

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All in all, 20 pro-inflammatory biomarkers demonstrated statistically significant reductions from baseline. Representative biomarkers encompassing of T-cell activation, B-cell activation, and chemotaxis that were altered in a dose-dependent manor by tegoprubart included CXCL10, CXCL9, IgA, IgE, IgM, IL-2R, IL-16, IL-18, tumor necrosis factor alpha (TNFa), and TNFa-R2. While the study was neither primarily designed nor powered to assess the effect of tegoprubart on ALS Functional Rating Scale (ALSFRS), both target engagement and pro-inflammatory biomarker reductions were associated with a trend in the slowing of disease progression as measured by the ALSFRS slope when compared with a cohort form the ALS PRO-ACT database.

"These positive phase 2a topline results demonstrated target engagement and a reduction in key inflammatory biomarkers in patients living with ALS," Merit Cudkowicz, MD, chief of the Department of Neurology, Massachusetts General Hospital, and director, Sean M. Healey & AMG Center for ALS, said in a statement.2 "A key goal for phase 2 trials is confirming that a drug hits the intended targets. These encouraging data support advancing tegoprubart into larger clinical ALS studies."

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REFERENCES
1. Paganoni S, Ladha S, Maragakis S, et al. Tegoprubart (AT-1501) is safe and well-tolerated and reduces inflammation in patients with ALS. Presented at: 2022 Annual NEALS Meeting; November 1-3; Clearwater Beach, FL. Abstract 105
2. Eledon announces positive topline results from phase 2a trial of tegoprubart demonstrating safety, target engagement, and biomarker response in patients living with amyotrophic lateral sclerosis. News release. Eledon Pharmaceuticals. May 31, 2022. Accessed November 2, 2022. https://ir.eledon.com/news-releases/news-release-details/eledon-announces-positive-topline-results-phase-2a-trial
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