BrainStorm Cell Therapeutics released new data on potential biomarkers from its Phase 2 trial investigating NurOwn, the company’s cell therapy for amyotrophic lateral sclerosis (ALS), at the International Symposium on ALS/MND meeting held in Boston last week.
Both these findings and an ongoing Phase 3 trial, now recruiting patients in the U.S., were discussed in greater detail with Ralph Kern, MD, Brainstorm’s chief operating officer and chief medical officer, in an interview to ALS News Today days before the Dec. 8–10 symposium.
NurOwn is an autologous adult stem cell therapy technology that uses a patient’s own stem cells — specifically, bone marrow-derived mesenchymal stem cells (MSC) — and differentiates them into neuron-supporting cells.
Its cells work by secreting nerve-growth factors known to protect existing motor neurons and promote motor neuron growth, with the potential of helping to re-establish nerve-muscle interaction.
In a randomized, placebo-controlled Phase 2 trial (NCT02017912), researchers determined NurOwn’s safety and efficacy after a single combined intramuscular and intrathecal treatment in early-stage ALS patients. Treatment in intrathecal administration is delivered through lumbar puncture directly into the spinal canal, where the cerebrospinal fluid flows, allowing the cells to enter the brain.
In addition to confirming treatment safety, the trial’s primary goal, Phase 2 scientists reported noteworthy signs of efficacy.
“We were able to show improvements in the ALS functional rate scale revised (ALSFRS-R) scores compared to placebo. The changes were most noticeable in the pre-specified subgroup of faster progressors; in other words, people who in the screening period had declined by a higher score,” Kern said.
“That group is about half of the ALS population, and we think that this is a group that has a higher unmet need, because they have a more rapid disease progression,” he added.
Specifically, faster progressors who responded — those with an improvement of at least 1.5 points per month — had favorable changes in both ALSFRS-R bulbar (speech, salivation, and swallowing) and fine motor domains (e.g., handwriting). Some showed a 100 percent improvement over pre-treatment scores, Kern said, adding that the NEALS consortium defines an improvement of 50 percent as “very clinically meaningful.”
NEALS is an academic research group working to define the meaning of ALS research in terms that imply benefit for patients.
Findings included evidence of “neurotrophic factors, such as VEGF and HGF, to be exclusively present, post-treatment,” in patients’ CSF, and “significantly correlated to the decrease in inflammatory factors, such as MCP-1,” Kern said.
The Phase 2 trial, however, failed to detect improvements in breathing capacity — determined by changes in slow vital capacity (SVC) — after a NurOwn transplant, but the “small sample size and the single dose” given may have been a factor, he said.
A Phase 3 study (NCT03280056) is now underway and will enroll about 200 patients, each being given three treatment or placebo doses.
Inflammation, neurons, and possible biomarkers
In diseases like ALS, a treatment’s healing capacity is dependent on its ability to reach affected areas within the brain. These areas are marked by inflammation in ALS — a mechanism that promotes disease progression, but also appears to lay a road map of sorts for NurOwn.
Inflammation may “help the cells target areas of damage, because there is scientific evidence … support[ing] the homing of mesenchymal stem cells to the site of neuronal injury,” Kern reported. “We have shown that NurOwn cells express many chemokine receptors that may drive homing of cells to sites of inflammation.
“They can sense the local environment, respond to it and reduce inflammation.”
These cells also “express a variety of adhesion molecules” that may enhance their ability to penetrate other cells, he added.
In the analyses unveiled at Boston, mechanisms besides the release of neurotrophic factors were seen to possibly mediate NurOwn’s benefits in ALS patients. Specifically, the analyses looked at two that may work as ALS biomarkers: certain microRNAs and an enzyme called chitotriosidase.
Since cells are known to exchange genetic material among themselves, researchers analysed the profile of small RNA molecules — microRNAs — that work to fine-tune the regulation of gene expression and are capable of being secreted and entering nearby cells.
“We know that some of the microRNA material is very relevant to ALS because it, in some cases, is either increased or decreased in ALS,” said Kern.
While characterizing NurOwn, researchers saw that these cells carried a unique set of microRNAs. In the Phase 2 trial, they measured the levels of a group of these microRNAs, linked to neurogenesis and inflammation, in the cerebrospinal fluid of patients before and after a NurOwn infusion, and compared levels to those given placebo patients.
“We saw that the microRNA profile was consistent with how the cells are expected to act in terms of neuronal survival and also reducing inflammation,” Kern said. Importantly, “the microRNA correlated with the outcomes.”
In other words, results suggested that the profile of microRNAs carried by NurOwn cells, if secreted and taken up by neighboring cells, may help to regulate the cells’ gene expression — how they produce other products, like proteins.
“The cell therapy can reprogram cells, and not simply treat cells by releasing neurotrophic factors and reducing inflammation — but potentially altering the genetic makeup of ALS cells,” Kern added.
Measuring levels of certain microRNAs is also a potential dual strategy — by identifying which patients may respond better to the treatment and linking the microRNA profile to disease progression, these microRNAs may work as biomarkers of ALS.
“It could be a tool to select individuals who might respond best, who perhaps need to be treated sooner,” Kern said.
Chitotriosidase, an enzyme involved in inflammation, is known to be excessive in patients with neurodegenerative diseases. In fact, ALS patients were found to carry levels up to 20 times higher in their cerebrospinal fluid than that seen in the general population.
Like microRNAs, chitotriosidase is also a potential biomarker for ALS. But first, the high levels found in Phase 2 patients “need to be validated in Phase 3 in a larger [patient] sample,” Kern said. “I think what we’re seeing so far are important signals that we would like to confirm in Phase 3.”
And it again re-emphasizes NurOwn’s potential benefits, as “reducing chitotriosidase levels shows that it is modifying the inflammatory pathways,” Kern said. Should it also be proven to be a biomarker, measures of “chitotriosidase might identify individuals at risk, or help select patients who would benefit from NurOwn. It may help anticipate disease progression, and it might also be a measure of response to treatment.”
Phase 3 study and beyond
Patients in the Phase 3 study, all within two years of diagnosis but with indications of faster disease progression — noted by an ALSFRS-R of at least 25 at study start and an SVC of greater than or equal to 65 percent predicted (for sex, height and weight) — will be treated every two months to an infusion of NurOwn or placebo to test its safety and efficacy. The study will run through July 2019, with patients evaluated for seven months after a first infusion and given a total of three treatments.
Fast progessors were those who responded best to treatment in Phase 2, Kern said, and “from an ethical perspective, it’s the group that has the greatest unmet need. That’s our thinking around it, and that’s the group that’s being studied in Phase 3.”
Results evaluating NurOwn’s impact on ALS progression should be available in about two years.
“We think it’ll take a year to fully enroll the study, and after that another year, plus or minus a few months, to get top-line data,” Kern said.
Because NurOwn is a cell therapy, not a gene therapy, treatment would need to be given repeatedly. How often is yet to be decided, Kern said, should the trial be a success and the biologics license application (BLA) BrainStorm plans to then file with the U.S. Food and Drug Administration (FDA) be approved.
“It would be continuous treatment, and then the treating physician and patients would then make decisions about how long and how many,” he said. “I think there’s probably room for further refinement … But for the purposes of the scientific study, we have two monthly intervals between treatments.”
The safety of multiple infusions is not of special concern, he added, although that is among primary Phase 3 goals. ALS patients, on a compassionate use basis, have already been given multiple infusions with no safety signals beyond those seen in “the Phase 2 profile,” Kern said.
If the study is successful, NurOwn may be tested in other neurodegenerative diseases.
“I think ALS is the beginning,” he said, mentioning preclinical work already done in diseases like Parkinson’s, Huntington’s, multiple sclerosis and autism — all of which carry their own “challenges” but similar “disease mechanisms.”
“We’re definitely very interested in expanding this adventure to see where this therapy can go,” Kern said. “Obviously, success in ALS would open a lot of people’s eyes to this being a valuable and very promising approach. I think the jury’s still out, and we’re hoping to change that.”