HEALEY-ALS Platform Trial Undergoes Amendments for ALS Therapy NUZ-001

As it gears up to test its novel therapeutic NUZ-001, Neurizon Therapeutics announced an update to the HEALEY-ALS Platform trial’s master protocol, with changes that include longer trial duration, modified inclusion criteria, and a more patient-centric approach to the study. In the same update, the company also reported positive secondary end point data from its phase 1 MEND study of NUZ-001, with the agent demonstrating significant effects on slow vital capacity (SVC), a notable assessment for patients with amyotrophic lateral sclerosis (ALS).¹

The platform trial, a prominent, double-blind, first-of-its-kind study, essentially tests numerous novel therapeutics in development for ALS while using the same placebo-controlled cohort to improve trial efficiency and reduce the number of patients on placebo. In the new update, the randomized controlled trial (RCT) period was extended from 24 to 36 weeks to allow for longer evaluation of treatment effects and increase the power to detect positive treatment outcomes, especially for therapies that take longer to show effects.

The master protocol's inclusion criteria were updated to shorten the time since symptom onset from 36 to 24 months, focusing on fast progressors. Additionally, peripheral blood mononuclear cell (PBMC) collection was incorporated for future induced pluripotent stem cell generation, and patient-centric variables were refined to support a more streamlined and flexible visit schedule. Through these changes, Neurizon believes there will be lower risk and greater opportunity for clinically meaningful outcome with NUZ-001, which hopes to join the platform trial in the second half of this year.

"Following a comprehensive review of the data from the first 5 completed regimens, HEALEY has implemented improvements to the HEALEY Master Protocol to maximize the potential for a positive outcome,” Michael Thurn, managing director and chief executive officer at Neurizon, said in a statement.¹ “We were excited to learn about the strong correlation between reducing the respiratory function decline rate in patients treated with NUZ-001 and overall functional decline as measured by ALSFRS-R. Having supporting positive secondary endpoints greatly increases the likelihood of receiving accelerated approval."

NUZ-001, developed by Neurizon Therapeutics, operates by inhibiting the aggregation of TAR DNA-binding protein 43 (TDP-43), a pathological hallmark of ALS. In addition to the updated master protocol, the company announced positive data from a comparative analysis of the phase 1 MEND study, which featured 12 patients on the drug against 35 matched controls from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.

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All told, results showed a –1.51 vital capacity (VC) percent predicted (PP) points per month for those on the investigational agent vs –2.93 VC PP per month for untreated matched controls (difference, 1.42; P = .058), leading to a 48% slowing favoring NUZ-001. Notably, these findings correlate closely with the 39% slowing on the ALS Functional Rating Scale-Revised rate of decline seen in these patients, announced in early 2024. Based on these findings, SVC has been chosen as a secondary end point for NUZ-001’s platform trial entry, with change in ALSFRS-R and survival as the primary outcomes.²

In November 2024, Neurizon announced positive results from a preclinical study of NUZ-001, with data highlighting the agent’s ability to improve the electrophysiological dysfunction of TDP-43 M337V mutated motor neurons. All told, use of NUZ-001 and NUZ-001 Sulfone, its major active metabolite, led to significant and dose-dependent reductions in TDP-43 aggregation by 50% and 55%, respectively. In an additional preclinical study, NUZ-001 and NUZ-001 Sulfone rescued the electrical activity of TDP-43 M337V motor neurons, by increasing bursting and network burst activity, and reducing inter-burst intervals to wild type motor neuron activity levels.

Despite its initial promise, several of the regimens included in HEALEY-ALS have not panned out thus far. Earlier this year, it was reported that two drugs, fosigotifator (Calico Life Sciences) and DNL343 (Denali Therapeutics), failed to meet their primary end point of overall function and survival in the study. Fosigotifator targets eIF2B, a guanine nucleotide factor that is essential for protein synthesis and a key regulatory of the integrated stress response. DNL343, a similarly built agent, is designed to activate eIF2B and thereby restore protein synthesis, disperse TDP-43 aggregates, and improve neuronal survival.^3,4

REFERENCES
1. HEALEY ALS Platform Trial Preparation Shows Positive Respiratory Outcome of NUZ-001. News release. Neurizon. March 24, 2025. Accessed March 24, 2025. https://www.biotechnewswire.ai/202503242623/healey-als-platform-trial-preparation-shows-positive-respiratory-outcome-of-nuz-001.html
2. Press release: Neurizon's NUZ-001 Reduces Aggregation of Key ALS Disease Target TDP-43 in Preclinical Study. News release. Neurizon. November 19, 2024. Accessed March 24, 2025. https://www.ncardia.com/insights/news/press-release-neurizons-nuz-001-reduces-aggregation-of-key-als-disease-target-tdp-42-in-preclinical-study
3. Denali Therapeutics Announces Topline Results for Regimen G Evaluating eIF2B Agonist DNL343 in the Phase 2/3 HEALEY ALS Platform Trial. News release. January 6, 2025. Accessed March 24, 2025. https://www.globenewswire.com/news-release/2025/01/06/3005002/0/en/Denali-Therapeutics-Announces-Topline-Results-for-Regimen-G-Evaluating-eIF2B-Agonist-DNL343-in-the-Phase-2-3-HEALEY-ALS-Platform-Trial.html
4. Sean M. Healey & AMG Center Announces Update in ALS Platform Trial with Fosigotifator. News release. Sean M. Healey & AMG Center for ALS. January 6, 2025. Accessed March 24, 2025. https://www.massgeneral.org/neurology/als/news/healeyamg-announces-platform-trial-update-fosigotifator