Certain spinal fluid biomarkers may predict responses to NurOwn
Changes observed with neuroinflammation, neurodegeneration, neuroprotection
Treatment with NurOwn (debamestrocel), which BrainStorm Cell Therapeutics is developing for amyotrophic lateral sclerosis (ALS), may bring about changes in biomarkers of inflammation and neurodegeneration that predict clinical outcomes.
The findings come from the Phase 3 trial (NCT03280056) that tested NurOwn against a placebo in 189 adults with rapidly progressing ALS. The trial failed to meet its main goal of slowing disease progression, but showed promise in those with less advanced disease.
“These findings are encouraging and provide preliminary evidence that debamestrocel may be effective in treating ALS. The impact on biomarkers suggests debamestrocel targets inflammation and neurodegeneration,” Chaim Lebovits, president and CEO of BrainStorm, said in a company press release.
The study, “Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes,” was published in Muscle & Nerve. It was funded by BrainStorm.
NurOwn is a cell-based therapy that involves harvesting mesenchymal stem cells from a patient’s bone marrow. These stem cells, which can develop into a variety of cell types, are then grown in a lab to secrete large amounts of neurotrophic factors, or molecules that boost nerve cell heath and survival.
After the modified stem cells are expanded into the millions, they are returned to the patient via an injection into the spinal canal, where they should produce high levels of neurotrophic factors and help slow disease progression.
The previous Phase 3 trial tested the therapy in adults with rapidly progressing ALS, most of whom had advanced disease. An analysis showed that levels of neurofilament light chain (NfL), a biomarker of nerve cell damage, in the spinal fluid were significantly lower after treatment with NurOwn and this reduction was linked to slower disease progression.
NurOwn’s effect on disease biomarkers
To know more about the impact of NurOwn on disease biomarkers, researchers examined 45 biomarkers in spinal fluid samples from 185 of the participants.
Compared with a placebo, NurOwn resulted in significant changes in 16 biomarkers of neuroinflammation, eight biomarkers of neurodegeneration, and nine biomarkers of neuroprotection after 20 weeks.
Similar findings were obtained with the participants with less advanced ALS who saw the greatest clinical benefits with NurOwn, but also in those with more advanced disease, “suggesting debamestrocel remains biologically active regardless of clinical progression,” the researchers wrote. “The results … highlight a pattern across biomarkers relative to placebo, with debamestrocel reducing levels of neuroinflammation (reducing pro-inflammatory biomarkers, and elevating anti-inflammatory biomarkers), lowering markers of neurodegeneration, and elevating neuroprotective biomarkers.”
The researchers identified three biomarkers that seemed to predict clinical responses to NurOwn. For example, lower levels of NfL at the start of the study, that is, its baseline, predicted slower rates of disease progression. Also, the greater the reduction in NfL after NurOwn treatment, the smaller the disease severity progression.
The other two biomarkers were baseline levels of TGF-beta1, which indicated less neuroinflammation, and changes in galectin-1 that indicated greater neuroprotection, both of which also predicted slower disease progression.
“The identification of biomarkers across different pathways could be an indication of the mechanism of action of debamestrocel of balancing the immune response through modulation of inflammation while at the same time preserving the dynamics of the interplay with neurodegenerative processes,” the researchers wrote.
“The publication of these findings is important, because it demonstrates a potential biologic mechanism by which modified mesenchymal stem cells (debamestrocel) may benefit patients with ALS,” said Anthony J. Windebank, MD, a professor of neurology at Mayo Clinic College of Medicine and Science in Rochester, and one of the study authors.
While data from the Phase 3 trial were deemed insufficient to support an approval by the U.S. Food and Drug Administration (FDA), leading BrainStorm to withdraw its application in October, the company plans a Phase 3b trial to test NurOwn in people with less advanced disease.
The two-part trial will enroll about 200 participants whose symptoms started within the last two years. They will receive NurOwn or a placebo for six months along with standard ALS treatments. For the next six months, all will then receive the experimental medication.
The trial’s protocol and planned statistical analyses have been reviewed by the FDA under a special protocol assessment and deemed adequate to support a future regulatory application.
“Biomarkers are becoming an increasingly important part of drug development in ALS,” said Stacy Lindborg, PhD, co-CEO of BrainStorm. “We look forward to confirming these findings in our upcoming Phase 3b trial, which is in planning for the most expeditious path forward to bring NurOwn to people living with ALS.”
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