FDA Allows Phase 2 Trial of NurOwn in Progressive Multiple Sclerosis

Ralph Kern, MD, MHSc

The FDA has accepted an Investigational New Drug (IND) application from BrainStorm Cell Therapeutics for its investigational NurOwn® autologous cell therapy, allowing for the initiation of a phase 2 clinical trial in progressive multiple sclerosis (MS) in the first quarter of 2019.¹

NurOwn® is a novel mesenchymal stem cells (MSCs) therapy whereby the cells are enhanced to secrete neurotrophic factors (NTFs), termed MSC-NTF cells. These MSC-NTF cells can then effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to provoke a desired biological effect and ultimately slow or stabilize disease progression. MSCs are multipotent precursor cells found in many adult tissues, but most commonly harvested from the bone marrow, adipocyte tissue or placenta. MSCs are thought to exert their healing effects through paracrine signaling and communication through cell-cell interactions. BrainStorm’s NurOwn® production process involves harvesting a patient’s own MSCs from their bone marrow and then differentiating the MSCs to secrete high levels of NTFs using their proprietary technology platform.

There are currently no currently FDA-approved autologous cell therapy options for MS. Notably, there is a significant unmet need in progressive MS, where there is only 1 approved treatment. Ultimately, about 50% of the 2.5 million patients with MS worldwide will develop progressive disease.

“We are excited to participate in this phase 2 clinical trial and hope that this innovative cell therapy approach leads to a new treatment option for patients with progressive MS,” said Fred Lublin, MD, the director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center and the Saunders Family Professor of Neurology at Mount Sinai School of Medicine. “We are particularly pleased to see a scientifically rigorous approach to advance the science of stem cell therapeutics.”

Ralph Kern, MD, MHSc, the chief operating officer and chief medical officer of BrainStorm said in November 2018, at the time of the IND submission, that the company believes NurOwn®’s demonstrated safety and efficacy data from its ALS clinical program and the development of neurotrophic factors and other efficacy biomarkers will allow for the expansion of BrainStorm’s cellular therapy pipeline.²

“NurOwn® has the potential to stabilize or improve function by reducing brain inflammation, protecting the brain against ongoing damage, and activating brain repair through the delivery of repair molecules, also known as NTFs,” Kern told NeurologyLive. “This unique approach has the potential to address an important unmet need in progressive MS, for which there are few treatment options.”

Notably, because the differentiated MSCs used with NurOwn® are derived from each patients’ own body, no immunosuppressive therapy is required with the treatment. Kern explained that NurOwn® is delivered by standard lumbar puncture in a labeled, pre-filled syringe, stating that the safety of MSC-NTF cells administered intrathecally has been shown in more than 100 patients with ALS in open-label studies, randomized phase 2 and 3 studies, and in compassionate-treated patients.

“NurOwn® has the potential to become a platform therapy for neurodegenerative disease,” he added.

Kern told NeurologyLive that BrainStorm will provide details of the final study design in Q1 2019, noting that it will include well-validated MS clinical outcomes and biomarkers. He said that the MS clinical trial sites in the United States will also be announced at that time.

Bruce Bebo, PhD, the executive vice president of research at the National MS Society, said in a statement that the society is excited about the launch of early testing and that it looks forward to better understanding the potential benefits and safety of cell-based therapies for MS.

NurOwn® is currently also being assessed in amyotrophic lateral sclerosis (ALS), and after the therapy produced promising phase 2 data, it moved into planning for a randomized, pivotal phase 3 clinical trial. That trial is expected to complete enrollment in mid-2019. The therapy passed an interim safety analysis, which included the first 31 patients, in August 2018.

Prior to the phase 3 pivotal trial in ALS, encouraging findings were demonstrated in a phase 2 trial, especially for patients with rapidly-progressing ALS. The study randomized 48 patients with ALS to receive NurOwn® (n = 36) or placebo (n = 12). Overall, significantly more patients treated with NurOwn® had a ≥1.5-point improvement in ALS functional rating scale score compared with placebo at 4 weeks (P = .02) and 12 weeks (P = .08). There were increases in cerebrospinal fluid NTFs at 2 weeks post treatment, specifically for vascular endothelial growth factor, hepatocyte growth factor, and Leukemia inhibitory factor. The elevated levels of NTFs were accompanied by decreases in inflammatory markers in the cerebrospinal fluid, such as MCP-1 and SDF-1.³

Overall, in the completed phase 2 U.S. study in ALS, ≥100% improvement (disease stabilization or improvement) in post-treatment ALSFRS-R slope (disease progression) as compared to pre-treatment slope (disease progression) was seen in 29% of patients in the MSC-NTF treated group at 12-weeks vs. only 8% in the placebo group. This treatment benefit was sustained in 11% of the MSC-NTF treated group at 24-weeks in the treated group vs. 0% in the placebo group. In rapid-progressors (who declined by ≥ 3 points/month in the 3-month screening period prior to treatment), at week 24, 27% of the MSC-NTF treated group continued to show ≥100% improvement vs. 0% for the placebo group, respectively.

Based on these phase 2 clinical observations, the phase 3 study (NCT03280056) is enrolling ALS rapid-progressors, treating study participants with three repeat doses of autologous MSC-NTF cells (every 2 months), and will evaluate efficacy using an ALSFRS-Revised responder definition. If the phase 3 ALS study is successful, BrainStorm plans to submit a biologics license application (BLA) to the FDA for approval.

REFERENCES

1. FDA Accepts BrainStorm’s NurOwn® IND Application for Progressive Multiple Sclerosis [press release]. New York, NY: BrainStorm Cell Therapeutics Inc; Published December 17, 2018. ir.brainstorm-cell.com/phoenix.zhtml?c=142287&p=RssLanding&cat=news&id=2380832. Accessed December 17, 2018.

2. BrainStorm Cell Therapeutics Announces Submission of IND for NurOwn® in Progressive Multiple Sclerosis [press release]. New York, NY: BrainStorm Cell Therapeutics Inc; Published November 19, 2018. globenewswire.com/news-release/2018/11/19/1653634/0/en/BrainStorm-Cell-Therapeutics-Announces-Submission-of-IND-for-NurOwn-in-Progressive-Multiple-Sclerosis.html. Accessed December 17, 2018.

3. Kern R, Cudkowicz M, Berry J, et al. NurOwn Phase 2 ALS Trial: ALSFRS-R Improvement is Reflected in Subscale Domains. Presented at: 2018 American Academy of Neurology Annual Meeting, Los Angeles, CA, April 21-27, 2018. Abstract S38.002