Expanded access protocol (EAP) program for access to investigational products for amyotrophic lateral sclerosis (ALS).

INTRODUCTION/AIMS: Expanded access protocols (EAPs) are a Food and Drug Administration (FDA)-regulated pathway for granting access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. There is limited information about the use of EAPs in amyotrophic lateral sclerosis (ALS); the aim of this report is to share the design, operational features, and costs of an EAP program for ALS. METHODS: The program was launched in 2018 at a single center. In alignment with FDA guidance, protocols were designed as individual (single participant) or intermediate size. Inclusion criteria were broad (e.g., no restrictions due to long disease duration or low vital capacity). Safety information was collected in all EAPs. Selected biomarkers were collected in nine of the EAPs. RESULTS: From July 2018 through February 2022, 17 EAPs were submitted for FDA and institutional review board (IRB) approval. The mean time from submission to approval from the FDA and IRB were 24 days and 37 days, respectively. A total of 164 participants were enrolled and, of these, 77 participants were still receiving IP as of February 2022. The mean duration of participation in an EAP was 12.6 mo. No drug-related serious adverse events were reported from any of the EAPs. Average site cost was $613.47 per participant per month, not including IP costs. CONCLUSION: EAPs provide a framework through which access to IP can be safely provided to people with ALS who do not qualify for clinical trials. Site resources are needed to launch and maintain these programs.

Randomized trial of inosine for urate elevation in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Higher urate levels are associated with improved ALS survival in retrospective studies, however whether raising urate levels confers a survival advantage is unknown. In the Safety of Urate Elevation in Amyotrophic Lateral Sclerosis (SURE-ALS) trial, inosine raised serum urate and was safe and well-tolerated. The SURE-ALS2 trial was designed to assess longer term safety. Functional outcomes and a smartphone application were also explored. METHODS: Participants were randomized 2:1 to inosine (n = 14) or placebo (n = 9) for 20 weeks, titrated to serum urate of 7-8 mg/dL. Primary outcomes were safety and tolerability. Functional outcomes were measured with the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). Mobility and ALSFRS-R were also assessed by a smartphone application. RESULTS: During inosine treatment, mean urate ranged 5.68-6.82 mg/dL. Treatment-emergent adverse event (TEAE) incidence was similar between groups (p > .10). Renal TEAEs occurred in three (21%) and hypertension in one (7%) of participants randomized to inosine. Inosine was tolerated in 71% of participants versus placebo 67%. Two participants (14%) in the inosine group experienced TEAEs deemed related to treatment (nephrolithiasis); one was a severe adverse event. Mean ALSFRS-R decline did not differ between groups (p = .69). Change in measured home time was similar between groups. Digital and in-clinic ALSFRS-R correlated well. DISCUSSION: Inosine met pre-specified criteria for safety and tolerability. A functional benefit was not demonstrated in this trial designed for safety and tolerability. Findings suggested potential utility for a smartphone application in ALS clinical and research settings.

An expanded access protocol of RT001 in amyotrophic lateral sclerosis-Initial experience with a lipid peroxidation inhibitor.

INTRODUCTION/AIMS: Lipid peroxidation is thought to play a biologically important role in motor neuron death in amyotrophic lateral sclerosis (ALS). 11,11 Di-deuterated linoleic ethyl ester (RT001) prevents lipid peroxidation in cellular and mitochondrial membranes. Herein we report on the use of RT001 under expanded access (EA). METHODS: We provided RT001 to patients with ALS via EA at a single site. The starting dose was 2.88 g/day, which was increased to to 8.64 g/day as tolerated. Participants were not eligible for alternative clinical trials. Participants were followed for adverse events and pharmacokinetic (PK) parameters were measured approximately 3 months after RT001 initiation. RESULTS: Sixteen participants received RT001 (5.6 ± 1.6 g/day; dose range, 1.92 to 8.64 g/day) for a mean period of 10.8 ± 7.1 months. After 3 months of treatment, PK studies showed that RT001 was absorbed, metabolized, and incorporated into red blood cell membranes at concentrations expected to be therapeutic based on in vitro models. The most common adverse events were gastrointestinal, including diarrhea, which occurred in 25% of the participants, and were considered possibly related to RT001. One participant (6%) discontinued due to an adverse event. Ten serious adverse events occurred: these events were recognized complications of ALS and none were attributed to treatment with RT001. DISCUSSION: RT001 was administered safely to a small group of people living with ALS in the context of an EA protocol. Currently, there is an ongoing randomized, double-blind, controlled study of RT001 in ALS.