Accounting for baseline disease covariates, NurOwn-treated participants had reduced neurofilament light values from baseline to week 20 compared with placebo (P <.05).
Recently announced post-hoc data from a phase 3 study (NCT03280056) of NurOwn (BrainStorm Cell Therapeutics), an investigational agent in development for amyotrophic lateral sclerosis (ALS), showed that treatment with the therapy resulted in significant elevation in markers of neuroprotection and decreases in markers of neuroinflammation and neurodegeneration.1,2
The biomarker analysis, which observed 16 pro-inflammatory/anti-inflammatory, 8 neurodegeneration, and 9 neuroprotection biomarkers, were presented at the 2023 ALS and Related Motor Neuron Diseases Gordon Research Conference. Over a 20-week period, in comparison with those on placebo, NurOwn-treated individuals showed a large, significant increase of 369% in vascular endothelial growth factor (VEGF) and an 11% decrease in neurofilament light (NfL), a marker of neuroaxonal damage.
"It's well known that in ALS, accounting for disease characteristics such as site of onset, time from first symptom to treatment and baseline physical function are important to understanding the treatment effect in clinical trials given the great heterogeneity in the disease, which can influence prognosis," Stacy Lindborg, PhD, co-chief executive officer at BrainStorm, said in a statement.1 "The data we presented at the Gordon Research Conference show that it is equally important to examine biomarker data, particularly neurofilament light, which is a predictor of disease progression. Treatment-driven reductions in NfL are associated with better clinical outcomes in ALS."
The NurOwn technology platform is comprised of autologous mesenchymal stromal cells secreting neurotrophic factors cells (MSC-NTF). In the trial, 7 cerebrospinal fluid (CSF) samples were collected by lumbar puncture for all trial participants. Although the study originally failed to meet its primary end point of change, a responder analysis based on ALS Functional Rating Scale-Revised (ALSFRS-R), findings from the post-hoc analysis revealed that those with greater decline in disease progression had higher baseline NfL values (r = -0.33; P = .0064).
On stepwise variable regression model, findings revealed that NfL, a neurodegenerative marker, LAP/TGFß1, an anti-inflammatory biomarker, and change in galectin-1 at week 20, significantly contributed to the production of clinical outcomes with NurOwn treatment. The analysis, which included those with ALSFRS-R items of more than 1 at baseline, also revealed that reductions in NfL were associated with less functional loss following NurOwn treatment (r = -.365). Overall, investigators concluded that this analysis provided further evidence of the importance of NfL as a prognostic and predictive biomarker for ALS.
The impact of NurOwn on Nfl is significant considering the FDA’s decision earlier this year to approve tofersen (Qalsody; Biogen), the first marketed therapy for patients with SOD1 mutation-mediated ALS, based on reductions in the same biomarker. Tofersen was similar to NurOwn in that it failed to meet its primary end point of change in ALSFRS-R in its pivotal phase 3 study. Prior to its approval, a meeting of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted unanimously that NfL may be used as a surrogate biomarker; however, the panel was split on whether data on tofersen’s effect on relevant biomarkers provided enough convincing evidence of the effectiveness of the agent.3,4
A meeting with the FDA’a Cellular, Tissue and Gene Therapies Advisory Committee for NurOwn as a potential treatment for ALS is expected to take place on September 27, 2023, with a PDUFA date set to occur by December 8, 2023. The biologics license application for NurOwn is based on the phase 3 study, in which the agent failed to meet its primary end point, but continued to show significant effects on less severe forms of the disease. In the original analysis, 33% and 28% of patients on NurOwn and placebo, respectively, met the primary end point of change in disease progression of at least 1.25 point on ALSFRS-R.5
In August 2022, the company announced new clinical analyses that strengthened the phase 3 findings, and later submitted the BLA a month later. The prespecified The prespecified analysis of participants with baseline ALSFRS-R scores of at least 35, a less severe population, showed that 35% of those on MSC-NTF had clinical response vs 16% of those on placebo (OR, 2.6; P = .29). Additionally, these participants progressed on average 2 points less on the ALSFRS-R compared with placebo (P = .05), while for participants with more advanced disease, the change from baseline to week 28 was similar between treatment groups (P = .97).6