There is also a tacit acknowledgment in the industry that the ALSFRS-R (revised) scale needs to evolve.
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The story of BrainStorm Cell Therapeutics’ NurOwn is a portrait of the inherent challenges in developing an effective treatment for one of humanity’s most elusive diseases, amyotrophic lateral sclerosis (ALS). It is also a cautionary tale for other therapeutic hopefuls in the space.
NurOwn is a platform comprised of autologous mesenchymal stem cells (MSCs) and neurotrophic factors (NTFs). The MSC-NTF cells are used to deliver multiple NTFs as well as immunomodulatory cytokines to sites of damage, producing a biological effect that may slow or stabilize the progression of diseases such as ALS and multiple sclerosis (MS). The approach borrows its inspiration from the field of oncology.
“We’re standing on the shoulders of giants because we’re following a very successful set of products that have been made for cancer. The success of the CAR-T world has really created an opportunity for us to use the same model to create cellular therapy for patients,” said BrainStorm president and chief medical officer, Dr. Ralph Kern.
In February, the U.S. Food and Drug Administration (FDA) found that high-level data from the phase III trial of NurOwn in ALS was not sufficient to support a Biologics License Application (BLA).
While the trial hit the primary treatment response endpoint, with 34.7% achieving an improvement of 1.5 points per month, the placebo response of 27.7% exceeded those of others observed in contemporary ALS trials.
When looking only at a pre-specified subgroup of patients with early-stage disease based on an ALS Functional Rating Scale - Revised (ALSFRS-R) baseline score of 35, however, NurOwn shined, demonstrating a meaningful response across all primary and secondary endpoints. In this cohort, 34.6% of NurOwn recipients received a clinically significant response versus only 15.6% in the placebo group.
Outcry from the ALS community was swift.
When trial participant, Phil Green, began treatment with NurOwn in May 2019, his ALSFRS score was 33, where it remained through three stem cell transplants until March 2020, seven months following the last treatment. A little more than a year later, Green’s score has fallen swiftly to 27.
“What if I would have continued with NurOwn? Would I still be at 33 today? The difference in those six points is me being able to get up and downstairs and walk without any assistance. I have not been upstairs in my house in almost a year,” Green said.
Green told BioSpace that he was very disappointed in the FDA’s request for more data to prove NurOwn’s benefit.
“The data showed that a subgroup of trial participants had a significant treatment effect. We really need to take a different approach in ALS to evaluate therapeutic efficacy. ALS is a terminal disease with no FDA-approved disease-modifying treatments. If a therapy shows that it helps some people with ALS, that is a huge win for our disease,” he said. “In the case of NurOwn, it seemed to be most effective in people that were earlier in their disease progression with an ALSFRS-R of 35 or more. Who has an ALSFRS-R higher than 35? Nearly everyone that just received a diagnosis of ALS!”
The study also highlighted the question of biomarkers in ALS research, as NurOwn was found to significantly increase neurotrophic factors and cause a reduction in both neuroinflammatory and neurodegenerative biomarkers.
While the value of biomarkers is well established in oncology, the relationship between clinical and biological evidence in the neurodegenerative disease space is still in its infancy.
“We showed really quite impressive changes in various biomarkers, and we equally saw some very exciting changes in the clinical endpoints. But right now, that relationship to the point where you would have an approval has not been established in ALS, or really in any neurodegenerative disease,” said BrainStorm EVP and Head of Global Clinical Research, Stacy Lindborg, Ph.D.
There is also a tacit acknowledgment in the industry that the ALSFRS-R (revised) scale needs to evolve. Implicit in the ‘R’ is the reality that science still does not have a complete understanding of the disease pattern behind ALS.
The NurOwn trial may have exposed the limitations near the bottom of the scale. While BrainStorm had anticipated a baseline number of around 35 on the scale, it ended up with one around 30.
“Depending on which patients participate in a trial, one can be more affected by it or less affected. I think it’s safe to say that we enrolled a group of ALS patients in our trial that were more advanced than traditional ALS clinical trials. As a consequence, I think we saw the limitations of the scale a little bit more than other trials in terms of the rate of progression,” said Kern.
Clene Nanomedicine, Inc., which is developing a nanotherapeutic, CNM-Au8, aimed at reversing neurodegeneration by enhancing naturally occurring cellular metabolism, took this complexity to heart when designing its ALS trials.
“We’re not that concerned about the ALSFRS scale. In fact, that’s one of the reasons why we wanted to do a mix of endpoints. We maybe took a little bit of learning from BrainStorm’s experience on the design of our own studies. We’re looking at collectively at MUNIX, which is not usually done in this country because it’s not reimbursed, but it is done ex-US,” said Clene president and CEO, Rob Etherington.
Clene is simultaneously investigating CNM-Au8 in an Australian RESCUE Phase II study, and the Phase III Healey ALS Platform Trial. The primary endpoint in the RESCUE trial is the Motor Unit Number Index (MUNIX), while the Healey trial counts ALSFRS-R as its primary measurement. Vital capacity is a secondary endpoint in both studies.
“So these two studies kind of dovetail together, and the data in Clene’s case is going to emerge from both of them within a matter of months. Taken together, it will be very exciting to see if we can improve neurological function with the oral administration of a nanocatalyst such as our CNM-Au8,” said Etherington.
If BrainStorm chooses to take another stab at applying for a BLA based on the pre-specified cohort, precedent could be on the company’s side.
RADICAVA® (edaravone), developed by Mitsubishi Tanabe, was approved by the FDA on May 5, 2017, becoming the first new ALS treatment to be approved in 22 years. But Radicava’s path to the market was anything but straightforward.
“[ALS] is heterogeneous, and sometimes it’s really important, even when a drug doesn’t work in everybody, to look at if there’s a subset that might have benefited. I’d say we learned that lesson from a different drug, a marketed drug now for ALS called Radicava where the first trial was also negative in everybody, but a subset of people responded. Those were early fast progressors, and when they repeated the studies just in that group, it was positive and that led to marketing. So it is really important to look at all the data, and especially for a fatal illness like ALS, to make sure you’re not missing a group that might have responded” said Dr. Merit Cudkowicz, director of the Healey & AMG Center for ALS who was also an investigator on the NurOwn trial.
NurOwn recently scored a win in another neurodegenerative disease, displaying promising topline results in a phase II study assessing neurologic function, cognition and biomarkers. BrainStorm has not yet announced a phase III trial.
“Similar to our ALS data, we’re currently reviewing it with MS experts and the leadership of the advocacy community. We want to get their feedback and reflection on our data first,” said Kern. “During that process, we’ll obviously have a better feel for the data. We’ll know what feels right and what is right. It’ll come to us soon.”
