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

Abstract

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.

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

“…Biofluid bio‐samples for biomarker analysis were obtained in select EAPs (frequency and process varied based on the IP's mechanism of action). While some analyses are still ongoing, results from two protocols have been recently reported 4,5 …”

“…These data can provide valuable pharmacokinetic and pharmacodynamic information to supplement clinical development programs as recently reported. 4,5 As described above, contemporary EAPs funded through the ACT for ALS are expected to produce extensive datasets that can be integrated with those generated by formal clinical trials. These innovative study designs are an exciting new frontier in ALS research.…”

Electrochemical Synthesis of Phthalimidine‐d2 with Heavy Water as Deuterium Source

“…[6] Other deuterium-based drugs have recently been approved, including deucravacitinib as an allosteric inhibitor of tyrosine kinase 2, [7] and RT001 as an investigational treatment for amyotrophic lateral sclerosis. [8] Given these successful precedents on deuterium drugs and the medicinal potential of phthalimidine, it would be highly desirable to develop an efficient synthesis of deuphthalimidine. However, to date, the deuteration of benzylic CÀ H of phthalimidine remains challenging.…”

Keeping expanded access programs in context

“…Further, budgets are often very lean such that a financial loss may be incurred, an issue that will not escape the notice of the institutional business administrators. Some centers have relied on philanthropic support to deflect financial concerns 7 …”

“…Some centers have relied on philanthropic support to deflect financial concerns. 7 In this issue of the Journal, Gelevski and colleagues describe their experience treating 17 ALS patients with IC14, an anti-CD14 monoclonal antibody, via an intermediate size EAP. 8 Their report is an excellent example of the kinds of helpful data that can be collected from an EAP and showcases some best practices for reporting.…”