Promising Cell Therapy Unavailable for ALS Under Right-to-Try

Chaim Lebovits, president and CEO of BrainStorm

Chaim Lebovits

A cellular therapy for patients with neurodegenerative diseases mentioned during discussions of the Right-to-Try (RTT) Act will not be made available outside of a clinical trial due to funding concerns, according to BrainStorm Cell Therapeutics, the company developing the treatment.

The cell therapy, known as NurOwn, consists of mesenchymal stem cells (MSC) harvested from bone marrow aspirate that is manufactured to secrete neurotrophic factors (NTFs). After ex vivo expansion, the autologous cells, which secrete primarily GDNF, brain-derived NTF, VEGF, and hepatocyte growth factor (HGF), are administered in 3 intrathecal transplantations.

A phase III study exploring NurOwn is currently ongoing, with the first patient enrolled in October 2017. The study plans to include 200 participants with rapidly progressing ALS, with a primary outcome measure of safety and efficacy by ALS functional rating scale (ALSFRS-R). Top-line data for the phase III study are anticipated by the end of 2019 (NCT03280056).

Outside of a clinical trial, the treatment is estimated to cost more than $300,000. Under RTT, the patient is required to pay for the treatment, without the assistance of insurance.

"We feel a tremendous sense of urgency and responsibility to provide an ethical, compassionate, and well-reasoned practical response to the demand for NurOwn and have worked tirelessly with patients and other stakeholders to find a solution," Chaim Lebovits, president and CEO of BrainStorm, said in a statement. "As we were unable to identify a practical funding solution, we unfortunately are not in a position to initiate access to NurOwn under RTT at this time."

Phase II findings for the MSC-NTF therapy were initially announced in 2016, with subsequent follow up and biomarker analyses released. The study randomized 48 patients with ALS to receive the MSC-NTF therapy (n = 36) or placebo (n = 12). Most enrolled patients were male (72.9%) and were a mean age of 51.1 years.

There was an improvement in mean ALSFRS-R slope for MSC-NTF compared with placebo, with nearly a 3-point improvement in least square (LS) means with the cell therapy by week 2 post-transplantation compared with a relatively small gain of close to 0.25 in the placebo group. When looking only at rapid progressors, this improvement was more dramatic, at more than a 4-point gain for MSC-NTF compared with a loss of nearly -0.1 for placebo.

In the MSC-NTF group, 50% of patients had a ≥1.5 points improvement in ALSFTS-R at week 2, and 48% continued to have this level of improvement at week 4. Slope changes leveled off for weeks 8 through 16, with 20% of patients having a ≥1.5 gain. In the placebo group, about 35% of patients had a ≥1.5 points improvement at 2 weeks, which declined to 10% at weeks 4 and 8.

For rapid progressors, in the cell therapy arm 80% of patients had ≥1.5 points improvement in ALSFTS-R at week 4 and 50% experienced this level of improvement at week 12. In the placebo group, results were inconsistent, with 20% reporting a ≥1.5-point change at 2 weeks and again at 8 weeks but with no other gains indicated.

There were increases noted in cerebrospinal fluid (CSF) NTFs at 2 weeks’ post treatment with the cell therapy, specifically for VEGF, HGF, and Leukemia inhibitory factor (LIF). These spikes were accompanied by decreases in several inflammatory markers in the CSF, such as MCP-1 and SDF-1.

There were no treatment-related deaths or serious adverse events (AEs) observed in the study. Moreover, no patients discontinued the study due to treatment-related AEs. The most common AEs, which were mostly grade 1 to 2 in severity, for the cell therapy versus placebo, respectively, were headache (80.6% vs 66.7%), back pain (72.2% vs 8.3%), pyrexia (33.3% vs 0%), arthralgia (33.3% vs 0%), injection site pain (27.8% vs 8.3%), and constipation (25% vs 8.3%).

"Stem cells are emerging as a potential viable candidate to treat ALS, and we are very excited to be participating in this important phase III trial," principal investigator of the phase III study Robert Miller, MD, director of the Forbes Norris ALS Research Center at California Pacific Medical Center, said in a statement. "The clinical data from NurOwn have been encouraging, demonstrating clear evidence of clinical benefit and supported by analysis of inflammatory markers and neurotrophic factors in treated patients."

The FDA has granted the MSC-NTF therapy an orphan drug designation and a fast track designation for ALS, which will help speed up development for the cell therapy. In addition to ALS, preclinical work is also focusing on the treatment for multiple sclerosis, Parkinson disease, Huntington disease, autism spectrum disorder, and peripheral nerve injury.