On this episode of the Endpoints, Dr. Steve Perrin, CEO at
ALS TDI answers questions about one of the most talked about clinical trials in
ALS at the moment, Brainstorm Cell Therapeutics’ NurOwn, a proposed
stem-cell-based treatment. The therapy focuses on the cellular support system
around a person with ALS’ motor neurons. It aims to slow disease progression by
replacing the damaged system with an enhanced one.
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), 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 and 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
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 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 3 month lead in process. 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 with some
significant hurdles. The cost of goods associated with manufacturing of
autologous MSC-NTFs from each person is expensive. This may create issues at
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