Brainstorm Cell Therapeutics are currently enrolling a phase 3 study which uses mesenchymal stem cells (MSCs), taken from the person with ALS, which are then programmed to secrete neurotrophic factors (NTFs). These are aimed at promoting growth and survival of nerve cells when returned to the person’s spinal cord. MSCs are multipotent bone marrow derived cells that can terminally differentiate into osteocytes (bone), myocytes (muscle), adipocytes (fat), and chondrocytes (cartilage). Research and literature around mesenchymal stem cells in ALS go back more than 10 years.

Preclinical research into the use of MSCs in ALS was first done in mice. MSCs from healthy mice were transplanted into those with the SOD1 transgene. These were shown to delay ALS disease onset, improve survival and increase muscle function (Huang, 2006). Further studies in mice showed a reduction in neuroinflammation (Vercelli, 2008, Sun, 2014) and a dose dependent improvement in motor neuron survival and lifespan when the MSCs were delivered by intrathecal injection.

Based on these preclinical studies and smaller safety trials on stem cells, biotech company Brainstorm began their clinical program in NurOwn. They completed their first Phase 1 safety and tolerability trial of the technology in 2016. This was an open label study conducted at a clinical center in Israel. The treatment was found to be safe and the company began a Phase 2 trial. Fourteen participants were enrolled and there were no serious adverse events associated with treatment. It was reported that the treatment slowed decline in ALSFRS-R score and improved forced vital capacity (FVC).

Brainstorm subsequently executed a placebo-controlled, single dose (IM and IT injection) phase 2 trial NurOwn in 48 people with ALS. The primary endpoint of the study was safety and tolerability with secondary endpoints of change in ALSFRS-R and SVC at 24 weeks post-transplantation. There were no serious adverse events but the trial failed to reach statistically significant changes in ALSFRS-R or forced vital capacity. In a post hoc analysis the investigators divided the study into fast and slow progressors, based on three month pre-enrollment data. In the fast progressing subgroup, NurOwn was found to have a statistically significant impact on slope of ALSFRS at 12 and 24 weeks.

Brainstorm is currently enrolling a Phase 3 clinical trial at 6 sites in the US. It is a randomized, placebo-controlled study, enrolling 200 people with ALS. The trial is attempting to enroll a homogeneous group of participants who must be declining at least 1 ALSFRS-R point per month during the three month lead in period. Participants will receive 3 injections of autologous MSC-NTFs. The study lasts 12 months and the investigators are examining change in slope of ALSFRS from baseline as the primary endpoint.

This is a very exciting, well-designed trial, but it has some significant hurdles. The cost of goods associated with manufacturing of autologous MSC-NTFs from each person is high. This may create issues finding the optimum frequency of dosing, as well as commercialization issues, should it be shown to modify disease progression. Topline data from the Phase 3 trial is expected in 2020. The ALS Therapy Development Institute will report on information from trials as it is released.