Background
Kadimastem is a company that is currently testing an “off-the-shelf”, clinical grade astrocyte cell product called AstroRx®. This investigational treatment consists of astrocytes in suspension, derived from human embryonic stem cells. Astrocytes are neighbouring (glial) cells that provide support to motor neurons when healthy. As of July 2023, there has been a single, phase1/2a, open label trial in 10 participants for AstroRx®. Kadimastem announced in March 2023 that it has received IND approval to commence a phase 2a trial for AstroRx® and that this trial will evaluate multiple doses at 3-month intervals.
Trial Design and Results
In February 2023, the results of a phase 1/2a study for AstroRx® were published. The open label trial involved a 3-month monitoring period followed by a single intrathecal injection of AstroRx®. Prior to dosing, all participants began a regimen of immunosuppressant mycophenolate mofetil (MMF) because AstroRx® is not autologous (i.e. not generated from the patient receiving the treatment). Participants were monitored for 6 months after dosing and then could enter a second protocol for an additional 6 months of evaluation. Three cohorts were planned. Cohort B received a dose with a higher concentration of AstroRx® cells than Cohort A. The last group, Cohort C, was intended to receive multiple doses, but was discontinued because of COVID-19 pandemic challenges.
The primary study outcomes were safety and tolerability. Central Nervous System (CNS) imaging was conducted at specified intervals. Secondary outcomes evaluated efficacy, with ALSFRS-R collection as well as measures of strength. Serum biomarkers were analyzed including creatinine, creatine, and neurofilament light (NfL).
During the study, 3 of the 10 participants died, although not attributed by investigators to AstroRx®. Of documented adverse events, the most common was post lumbar puncture headache in 50% of participants. There were also a few mild to moderate adverse events potentially related to the immunosuppressant.
Lab values, ECG, and physical exams showed no clinically significant changes. MRI imaging at 6 months did not show tumours, which had been a concern because embryonic derived cells may contribute to teratomas (a type of tumour).
In both cohorts, at 3-months after administration of AstroRx® there was a statistically significant slowing in the rate of ALSFRS-R decline that reverted to the pre-treatment rate at the 6 and 12 month assessments. However, the rate of SVC decline (a marker of breathing functionality) had a statistically significant acceleration across both cohorts at the 3 and 12-month timepoints which is concerning and should be explored in future studies. Hand-held dynamometry, a measure of strength, trended towards improvement but was not statistically significant. There was no significant effect on NfL within this study.
Summary
Kadimastem has conducted a single dose open label study of AstroRx® in 10 people, of which only 6 were followed up at the one-year timepoint. Within this trial there were multiple protocol modifications due to the COVID-19 pandemic.
The primary focus of the trial was safety and tolerability, although measures of efficacy and biomarkers were evaluated as well. While there were statistically significant reductions in the rate of decline of ALSFRS-R in both cohorts of 5 people at 3 months post treatment, for those participants that followed up at 6 and 12 months, ALSFRS-R, those changes were lost. Additionally, the statistically significant increase in rate of SVC decline seen post treatment is concerning. There is also the question of whether the immunosuppressant, MMT, which was administered in addition to AstroRx® may have effects on the disease course and may be contributing to outcomes either positively or negatively.
The SAC acknowledges the potential ability of healthy astrocytes to provide support to motor neuron health. Given the very small size of the trial and the single-dose treatment of participants with no placebo there is insufficient evidence to determine efficacy of AstroRx® in ALS/MND currently.
A number of messages provided by Kadimastem could raise questions from people affected by ALS/MND. Kadimastem uses the slogan “cells to cure diseases” and their website explains that the goals of AstroRx® treatment include “replacing malfunctioning cells” and “restoring functionality”. Evidence has not been presented showing that AstroRx® could replace malfunctioning cells or restore functionality in humans.
Caution should be taken when interpreting the results so far and should continue until larger, properly controlled clinical trials have been completed.
International Alliance of ALS/MND Associations
March 2024
The original language of communication is English and any translation cannot be guaranteed for accuracy of messaging.