(upbeat music)
- Hello there, I'm Ralph Kern,
the president and chief medical officer
of BrainStorm Cell Therapeutics.
It's a real privilege today to make a presentation
at the 2020 CIRM grand team meeting.
And look forward to the discussion after the presentation.
we are advancing our cell technology platform,
which is a unique product.
It's unique because it's autologous and convenient.
Our neuron autologous cell therapy uses patient's own cells.
The safety and cell persistence of the autologous product
is an important characteristics.
We use cryopreservation,
which essentially creates an off-the-shelf product
for each patient.
A single bone marrow harvest
creates several years of therapy.
We have a short cycle time
and only seven days from thawing to injection in the clinic.
Our product is also consistent and reliable.
It does not use animal proteins.
There's no xenocontamination, no use of antibiotics.
Genetic modifications or viral vectors
are used in the manufacturing process.
Neuron is culture rescued after thawing,
which creates a hive cell viability and consistent
performance characteristics.
Finally, we use cell potency as a release criteria.
Our platform technology is also unique in that
we have consistent read-through of biologic measures
from in vitro, through animal in vitro testing.
And finally in human biomarker studies.
The three characteristics of our cells
are that of neuroprotection, neurotrophic support
and immunomodulation.
These have been consistently seen
in all of our preclinical work
and also in our phase 2 ALS biomarker studies.
Finally, the consistent safety across clinical trials
and across indications supports platform technology.
Our platform, as you can see is expanding.
Our ALS program is the most advanced and we'll have data
from this study.
At the end of November, we have a progressive MS trial
that's fully enrolled and will be fully dosed
by the end of this year.
And we're looking at advancing our therapeutic pipeline
in Alzheimer's disease and other neurodegenerative diseases
as well.
We have preliminary preclinical work of
MSC-NTF derived exosomes in ARDS,
which is an area of very high interest these days,
given the COVID pandemic.
Our manufacturing process is fast,
consistent, and reproducible.
Cells are derived from the bone marrow
where they're harvested and sent to the manufacturing site
for purification and expansion.
Following this 12-day process,
we cryopreserve an intermediate product,
which creates an off-the-shelf product for each individual,
enabling retreatment for three years or longer.
The cells are then thawed expanded
and induced to differentiate into MSC-NTF cells,
which secrete high levels of neurotrophic factors
and other repair molecules.
And this second step in the process
takes approximately seven days.
Our cells are then loaded into a syringe
in 100 to 125 million cells,
are then administered via intrathecal administration
in a lumbar puncture procedure,
which can be done as an outpatient as well.
And this is a well characterized process
that we have repeated many times in our clinical trials.
And we're very confident that this can be
a practical approach following a successful
commercialization and approval.
The characteristics of the cells are very important.
In addition to a very high purity,
the cells are demonstrated to secrete high levels of
neurotrophic factors, including GDNAF, BDNF, VEGF and HGF.
These are five to 10X changes,
and these contribute to their mechanism of action.
In addition, the cells have known immunomodulatory effects.
They reduce cytokines,
but in addition have also been shown to expand
to regulatory cells.
And this is data from our open label phase 1/2 (A) trials
that were published in JAMA Neurology.
We've shown in vitro that the cells can increase
T regulatory cells.
And you can see on the right when PBMCs are co cultured with
the cellular product that this has been
consistently demonstrated.
So in summary, our cells have three unique characteristics.
One is addressing neuronal degeneration.
We've confirmed this in our phase 2 trial
by an up to 60% reduction in caspase-3 and the CSF
after a single treatment.
The cells also restore neurotrophic support.
That is a consequence of loss of astrocyte function.
And we have demonstrated this by cargo delivery
in our phase 2 trial, and also in our preclinical studies,
both in vitro and in-vivo.
And thirdly, the third axis of treatment
is modifying neuroinflammation, microglial activation.
We've shown consistent immunomodulation
by a reduction of MCP-1, STF-1, and Chitotriosidase.
Our ALS program has a long history.
We initially completed phase 1/2 (A), open-label trials,
where we determined dose and route of administration
that was published in JAMA Neurology as I mentioned.
Following this, we completed a randomized
placebo controlled phase 2 trial involving 48 patients
with a single dose of our treatment, intrathecal.
And this was last year in the journal neurology.
And finally we have completed enrollment and dosing
of a 200-patient phase three trial,
and this will generate top line data by the end of November.
Our phase 2 trial design has a randomization event.
There's a run in period of 12 weeks,
and 48 patients are then randomized three to one
to receive either treatment or placebo
by intrathecal administration.
We collected CSF before and after.
And we followed the patients at monthly intervals
to determine safety tolerability, the functional changes,
including the ALSFRS-R slope, slow vital capacity.
And we pre-specified the fast progressor criteria
where we required that individuals decline by
a minimum of two points in the three month run in period.
The study showed remarkable safety.
There were no treatment related serious adverse events.
There were no dropouts due to SAEs.
And the most common adverse event was
transient mild in severity and related to the procedures.
We measured function as our primary outcome measure.
We used the 48-point ALS functional rating scale,
and this has been well-validated and regulatory approved.
It involves four domains involving respiration,
bulbar function, fine motor function,
and gross motor function.
In our phase 2 trial we looked at a change
in rate of disease progression determined at 24 weeks.
In our phase 3 study,
we'll be looking at a responder definition,
and looking at the change in ALSFRS slope at 28 weeks.
This is an example of the data that we've obtained
in our phase 2 trial and showing how we analyze
the outcomes.
As you can see on the top in a treated patient.
This individual had a rate of decline
prior to treatment of minus 1.08 points per month.
After treatment, the rate of decline decreased
and was 0.4 points per month.
This individual would be considered a responder
and you can see
if they had continued on the same trajectory,
the outcome would be very different.
A patient who received placebo
is illustrated on the bottom.
You can see in the run in period,
the slope was minus 0.57.
After treatment it was,
it continued maybe a little bit worse,
but this would be a nonresponder.
And we can measure both the change in slope.
We can measure the slope after treatment,
and we can also measure score changes after baseline,
as outcome measures.
In our phase 2 trial, you can see that the slope change.
In other words, the positive change in the treated
individuals which are in the blue bars,
shows that there is a change
in the rate of disease progression, a positive direction.
Placebo patients didn't show this.
When we looked at the total group,
we saw an immediate effect.
In the rapid progressor group it was longer
and a greater magnitude.
When we looked at a responder definition
of a one and a half point per month improvement
in this rate of disease progression,
we saw that there was an improvement
in the overall population, but this was accentuated
in the rapid progressor group again defined,
by those who had two points per month
declined in the three months running period.
And based on this data, we proceeded to a biomarker analysis
that to provide additional support
for our clinical observations.
What we were able to show in our phase 2 trial was that
we were able to deliver cargo and this included VEGF,
HGF, LIF and other biomarkers.
You can see that the placebo group on the bottom
did not show any cargo delivery.
We then asked a second question.
In addition to cargo delivery,
can we affect pharmacodynamic biomarkers?
In this case, inflammatory biomarkers.
We were able to show that after a single treatment,
two weeks later, we were able to reduce MCP-1 levels
in the CSF by 40% with no effect with placebo.
We also showed a reduction of STF-1 Alpha
by 22% of reduction of caspase-3 by up to 60%.
And we then asked a third question which is,
in addition to cargo delivery
and reduction in a pharmacodynamic biomarker,
could we correlate these characteristics together?
And the answer is yes.
On the top you can see that there's a correlation
between the MCP-1 levels on the x-axis post-treatment
and the VEGF cargo delivery on the y-axis.
Showing that there's a correlation
between a cargo delivery and pharmacodynamic biomarkers.
On the bottom we asked the next question which is,
is there a correlation between the
pharmacodynamic biomarker of MCP-1 on the x-axis
and the improvement scores on the y-axis,
which correlate to those graphs that I'd shown you earlier.
And the answer to that was yes.
That those who had lower MCP-1 levels post treatment
had greater improvement scores
or changes in rate of disease progression after treatment.
So this was very encouraging.
It led us to design a well powered phase 3 trial,
which has a randomization event
following an initial run in period.
We have a bone marrow aspiration in the run in period
where the product is acquired
and then individuals are then randomized one-to-one
to receive treatment or placebo.
Unlike phase 2, this involves three treatments.
And also the inclusion criteria specifies
that individuals must be fast progressors.
So individuals must have declined by three points or more
in the three months run in period.
The study is 28 weeks in duration.
There's monthly assessments.
In spite of the COVID pandemic,
we were able to continue treatments
throughout the hospital restrictions.
And I'm very happy to say that the study
is fully enrolled and fully dosed.
And we have a few remaining assessments
leading to top line data by the end of November.
What are we looking for in this study?
We're looking at efficacy.
In other words, the change in function
as measured by the ALS functional rating scale.
Obviously we're looking at safety.
Slow vital capacity,
which is a functional measure of breathing,
survival, both in terms of tracheostomy free survival
and mortality will be measured
as well as seven serial biomarker assessments of CSF
and plasma.
And this study, I may say has one of the most robust
collections of biomarkers of any clinical trial
that we're aware of.
And we believe that the combination of the very careful
clinical assessments and correlation of those
clinical assessments with biomarker values will help
confirm the value of this treatment in ALS.
I must say that we are fortunate to have great partners
in addition to CIRM,
and I wanna recognize the funding that we've received
and the support we've received all along
from the California Institute for Regenerative Medicine.
We want to also call out the city of hope
and Dana-Farber Cancer Institute,
which have been wonderful partners to us
in terms of manufacturing and product support.
I also wanna call out attention to the treatment centers
and universities that we're very privileged to work with,
including University of Massachusetts,
Massachusetts General Hospital,
the Mayo Clinic in Rochester, Minnesota, UC Irvine,
Cedar Sinai, and Sutter Health or CPMC in San Francisco.
Without the collaboration of CIRM,
our manufacturing sites and these wonderful centers.
I don't think we would be having this discussion today.
And we really want to acknowledge that support.
With that I thank you for your attention today.
I'm very happy that we've been able to complete the study
in our timelines and we expect top line data
By the end of November.
We appreciate the support
and we'd love to take any questions
during the Q&A session with you that follows.
Thank you very much.