Safety and efficacy of first-in-man intrathecal injection of human astrocytes (AstroRx®) in ALS patients: phase I/IIa clinical trial results

Abstract

Background: Malfunction of astrocytes is implicated as one of the pathological factors of ALS. Thus, intrathecal injection of healthy astrocytes in ALS can potentially compensate for the diseased astrocytes. AstroRx® is an allogeneic cell-based product, composed of healthy and functional human astrocytes derived from embryonic stem cells. AstroRx® was shown to clear excessive glutamate, reduce oxidative stress, secrete various neuroprotective factors, and act as an immunomodulator. Intrathecal injection of AstroRx® to animal models of ALS slowed disease progression and extended survival. Here we report the result of a first-in-human clinical study evaluating intrathecal injection of AstroRx® in ALS patients.

Methods: We conducted a phase I/IIa, open-label, dose-escalating clinical trial to evaluate the safety, tolerability, and therapeutic effects of intrathecal injection of AstroRx® in patients with ALS. Five patients were injected intrathecally with a single dose of 100 × 10⁶ AstroRx® cells and 5 patients with 250 × 10⁶ cells (low and high dose, respectively). Safety and efficacy assessments were recorded for 3 months pre-treatment (run-in period) and 12 months post-treatment (follow-up period).

Results: A single administration of AstroRx® at either low or high doses was safe and well tolerated. No adverse events (AEs) related to AstroRx® itself were reported. Transient AEs related to the Intrathecal (IT) procedure were all mild to moderate. The study demonstrated a clinically meaningful effect that was maintained over the first 3 months after treatment, as measured by the pre-post slope change in ALSFRS-R. In the 100 × 10⁶ AstroRx® arm, the ALSFRS-R rate of deterioration was attenuated from - 0.88/month pre-treatment to - 0.30/month in the first 3 months post-treatment (p = 0.039). In the 250 × 10⁶ AstroRx® arm, the ALSFRS-R slope decreased from - 1.43/month to - 0.78/month (p = 0.0023). The effect was even more profound in a rapid progressor subgroup of 5 patients. No statistically significant change was measured in muscle strength using hand-held dynamometry and slow vital capacity continued to deteriorate during the study.

Conclusions: Overall, these findings suggest that a single IT administration of AstroRx® to ALS patients at a dose of 100 × 10⁶ or 250 × 10⁶ cells is safe. A signal of beneficial clinical effect was observed for the first 3 months following cell injection. These results support further investigation of repeated intrathecal administrations of AstroRx®, e.g., every 3 months.

Trial registration: NCT03482050.

Keywords: ALS; Astrocytes; Cell therapy; Clinical trial; Intrathecal injection.

Fig. 1

Phase 1/2a study design and study flowchart. A Visit 0 (V0) - screening visit, visit 1 (V1) till visit 4 (V4) presents about 3 months run-in period (pre-treatment), AstroRx injection was performed on V4. V4 till visit V10 is the 6 months follow up time under ASTRO-001 study and additional 6 months follow up was performed under study ASTRO-002 on V10-V12 and by phone call. B Study flow chart of patient allocation, treatment doses of ASTRO-001 and ASTRO-002. V Visit, mo Month, BCV Blood Count Visit, EOS End of Study

Fig. 2

ALSFRS-R slopes analysis in run-in, and 3-, 6- and 12-month follow up after AstroRx® treatment. The change in slopes between pre-treatment slope ("Run-in") and post-treatment slope over 12 months was analyzed by using a repeated mixed model with fit least squares (LS) means (MMRM analysis). Analysis was performed on Cohort A, Cohort B, Cohort A&B as well as on rapid progressors (defined by ALSFRS-R≤1.1/month during run-in). * = P value=0.039 (Run-in vs. 3-month FU, & = P value=0.002 (Run-in vs. 3-month FU) and # = P value <0.001 (Run-in vs. 3-month FU)