PHILADELPHIA -- New analyses of phase II trial data indicated that BrainStorm Cell Therapeutics' NurOwn autologous stem cell therapy for amyotrophic lateral sclerosis (ALS) identified caspase-3 as a useful biomarker for treatment response, as well as sheds light on how the therapy works, a researcher said here.
Levels of caspase-3 -- a correlate of apoptosis processes -- in cerebrospinal fluid declined more than 60% in patients showing substantial clinical responses in the phase II trial, compared with reductions of only about 30% in non-responders, said Ralph Kern, MD, MHSc, chief medical officer at BrainStorm.
Moreover, he told attendees at the American Academy of Neurology's annual meeting, "the treatment increased levels of mir-132, which is a very important microRNA that seems to have a neuroprotective effect [and] decreased MCP-1, which is a marker of inflammation and innate immunity."
Kern presented the data during the prestigious .
The intrathecal therapy, based on the patient's own marrow-derived mesenchymal stem cells induced ex vivo to express neurotrophic factors and anti-inflammatory cytokines, is now in a 200-patient phase III trial.
The main phase II data, , found "clear evidence of a clinically meaningful benefit," the company stated at the time. (The treatment also when it was given to an ALS patient outside of a trial protocol, under the recent "Right to Try" law passed by Congress.)
While the phase III trial is underway, BrainStorm is seeking to clarify how the drug actually works and whether biomarkers can be identified that track clinical response.
For purposes of the current study, response was defined as at least a 100% improvement in the slope of ALS Functional Rating Scale-R scores over 12 weeks post-transplant, compared with placebo recipients.
Caspase-3 was a focus because earlier research had implicated it as a driver of motor neuron death in ALS. Indeed, it's been dubbed the in apoptosis, coming in at the end of the cell-death cascade to deliver a final, fatal blow.
Data reported here indicated that, among all active-treated patients, caspase-3 levels declined by roughly 60% (P<0.001 relative to baseline), compared with a non-significant 30% decrease in the placebo group. A similar pattern was seen for CSF MCP-1, an inflammatory mediator frequently elevated in ALS.
"Our feeling is that the treatment may interfere with the cycle of neuronal cell death triggering caspase activation, [and] triggering microglial activation, producing a vicious cycle. We think that treatments that can disrupt this cycle have the potential to modify the clinical course of ALS," Kern said.
Kern said the company hopes to have topline data from the by mid-2020. BrainStorm also recently began a .
Disclosures
The study was funded by BrainStorm Cell Therapeutics. Kern is an company employee. Co-authors disclosed multiple relevant relationships with industry including BrainStorm.
Primary Source
American Academy of Neurology
Kern R, et al "modulation of CSF caspase-3 in MSC-NTF cells (NUROWN®) in a phase 2 ALS study: correlations with CSF biomarkers and clinical response" AAN 2019.