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). 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
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.