NurOwn, Modified Mesenchymal Stem Cells, Show Clinical Benefit in Phase 2 Trial in ALS Patients


BrainStorm Cell Therapeutics Inc. (BCLI) has developed a cell-based product they call “NurOwn.” NurOwn consists of mesenchymal stem cells that have been cultured to secrete a variety of neurotrophic factors (NTFs). These NTFs are a collection of different growth factors that promote the survival of neurons. NurOwn cells were originally developed in the laboratories of Professor Dani Offen and the late Professor Eldad Melamed, at Tel Aviv University. NurOwn cells have been studied extensively and they clearly have the capacity to migrate to damaged areas in the central nervous system (Sadan O, et al., Stem Cells. 2008 Oct;26(10):2542-51), decrease dopamine depletion in a Parkinson’s disease model system (Barhum Y, et al., J Mol Neurosci. 2010 May;41(1):129-37), can promote the survival of photoreceptors in the retina of animals who optic nerves were damaged (Levkovitch-Verbin H, et al., Invest Ophthalmol Vis Sci. 2010 Dec;51(12):6394-400), decrease quinolinic acid toxicity in an animal model of Huntington’s disease (Sadan O, et al., Exp Neurol. 2012 Apr;234(2):417-27), and improve motor function and survival in a genetic model of Huntington’s disease.

On the strength of these experiments, NurOwn cells have also been tested in clinical trials. Because NTF-secreting MSCs (or, MSC-NTF cells) are designed specifically to treat neurodegenerative diseases, most of the clinical trials, to date, have examined of safety and efficacy of MSC-NTFs in patients with neurological disorders. The safety of NurOwn cells was established in a small phase I/II trial with amyotrophic lateral sclerosis (ALS) patients. This was a small study (12 patients), but showed that, at least in this patients population, intrathecal (injected into the central nervous system) and intramuscular administration of MSC-NTF cells in ALS patients with is safe and patients even showed some indications of clinical benefits, but the study was too small to be definitive about the efficacy of these cells.

Now a recently completed randomized, double-blind, placebo-controlled phase 2 study of NurOwn in ALS patients has found that NurOwn is safe and well tolerated and may also confer clinical benefits upon ALS patients.

According to BrainStorm, this phase 2 study achieved its primary objective (safety and tolerability). No deaths were reported in the study and no patients discontinued participation because of an adverse event. All patients in both active treatment and placebo groups experienced at least one treatment-emergent adverse event that tended to be mild-to-moderate in intensity in both groups. Treatment-related adverse events, as determined by a blinded investigator, occurred slightly more frequently in active-treated patients than in placebo-treated patients (97.2 percent vs. 75.0 percent). The largest differences in frequencies were for the localized reactions of injection site pain and back pain, and fever, headache, and joint pain.

However, NurOwn also achieved multiple secondary efficacy endpoints in this trial. NurOwn showed clear evidence of a clinically significant benefit. Most significantly, the response rates were higher for NurOwn-treated subjects compared to placebo at all time points in the 24 weeks during which when the study was conducted.

This clinical trial conducted at three sites in the U.S: Massachusetts General Hospital, UMass Medical School and the Mayo Clinic. 48 patients were randomized to receive NurOwn cells administered via combined intramuscular and intrathecal injection (n= 36), or placebo (n=12). They were followed monthly for approximately three months before treatment and six months following treatment, and were assessed at 2, 4, 8, 12, 16 and 24 weeks.

The primary investigator in this trial, Robert H. Brown of the University of Massachusetts Medical Center and Medical School said, “These exciting findings clearly indicate that it is appropriate to conduct a longer study with repetitive dosing.”

Subjects treated with NurOwn in this trial showed slowing of progression of ALS and no safety concerns. NurOwn-treated patients also displayed increased levels of growth factors in the cerebrospinal fluid and decreased signs of inflammation after two weeks. These are good indicators that the MSC-NTF cells are orchestrating some kind of beneficial biological effect.

Based on these results, new trials are warranted that will examine repeat dosing at 8 to 12 weeks and employ a larger number of subjects.

Bilateral, Multiple, Intraspinal Stem Cell Injections are Safe for ALS


Jonathan Glass, professor of neurology at Emory University in School of Medicine, is the principal investigator of a phase 2 clinical trial that examined the safety of intraspinal injection of human spinal cord–derived neural stem cells in people with amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease.

This clinical trial was not designed to determine whether the treatment was effective, which is odd given that the trial was a phase 2 trial. Glass and his collaborators noted that the transplanted stem cells did not slow down the progression of the disease. However, given that the trial was not designed to detect efficacy, it is difficult to draw any hard-and-fast conclusions.

ALS is a disorder in which the motor neurons of the brain and spinal cord degenerate. Motor neuron degeneration causes progressive loss of muscle control, which includes breathing and swallowing (leading to death). There are no treatments that can stop ALS.

“Though there were two serious complications related to the treatment, the level of acceptable risk for treating patients with ALS, where the prognosis is poor and treatments are limited, is arguably higher than that for more benign disorders,” said Dr. Glass.

In this study, 15 ALS patients who manifested their first signs and symptoms of the disease within two years of the start of the study, were treated at three different university hospitals.

The participants were divided into five treatment groups that received increasing doses of stem cells. This trial was an “open-label” trial, which means that the participants knew they were getting active stem cell treatments.

Participants received bilateral (both sides) injections into the cervical spinal cord between the C3 and C5 regions. The final group received injections into both the lumbar (L2-L4) and cervical cord through two separate surgical procedures.

Vertebral Column regions

The numbers of injections ranged from 10 to 40, and the number of cells injected ranged from two million to 16 million. Because of the large range of injections and stem cells injected, determining the safety of these treatments was probably more important that the efficacy of the treatments.

During the nine months of follow-up, patients were assessed for side effects from the intraspinal injections and progression of the disease, according to the functional rating scale. Most of the side effects were related to temporary pain associated with surgery and to medications that suppress the immune system.

Two people developed serious complications related to the treatment. One patient developed spinal cord swelling that caused pain, sensory loss and partial paralysis, and another patient developed central pain syndrome; a neurological condition caused by damage to or dysfunction of the central nervous system (CNS), which includes the brain, brainstem, and spinal cord. This syndrome can be caused by stroke, multiple sclerosis, tumors, epilepsy, brain or spinal cord trauma, or Parkinson’s disease.

The participants’ functioning was compared to three historical control groups, and there was no difference in how fast the disease progressed between those
who received stem cells and those who did not. This is a significant finding because injecting cells into the spinal cord might actually accelerate the progression of the disease. However, this study seemed to show that 10-40 injections into the spinal do not affect the progression of ALS.

However, Glass cautioned that no conclusions can be draw about effectiveness of the treatment from such a small, non-blinded, non-placebo-controlled study.

“This study was not designed, nor was it large enough, to determine the effectiveness of slowing or stopping the progression of ALS. The importance of this study is that it will allow us to move forward to a larger trial specifically designed to test whether transplantation of human stem cells into the spinal cord will be a positive treatment for patients with ALS,” Dr. Glass said.

These results were published in Jonathan D. Glass et al., “Transplantation of spinal cord–derived neural stem cells for ALS: Analysis of phase 1 and 2 trials,” Neurology, June 2016 DOI:10.1212/WNL.0000000000002889.

BrainStorm Cell Therapeutics Will Conduct Phase 2 Clinical Trial on ALS Patients with Their NurOwn® Cells


The biotechnology company BrainStorm Cell Therapeutics Inc. has developed an autologous stem cell therapy for several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS, also known as Lou Gehrig’s disease), Multiple Sclerosis (MS) and Parkinson’s Disease (PD). BrainStorm has designed a proprietary product called NurOwn™ that is made from the patient’s own bone marrow mesenchymal stem cells (BM-MSCs). Essentially, the patient’s BM-MSCs are isolated, purified, and cultured in a specialized culture system that drives the BM-MSCs to differentiate into nerve-like cells that Neurotrophic Factors (NTF). These NTFs have the capacity to keep nerve cells alive and prevent moribund cells from dying.

Figure taken from http://www.brainstorm-cell.com/index.php/science-technology/nurown%E2%84%A2
Figure taken from http://www.brainstorm-cell.com/index.php/science-technology/nurown%E2%84%A2. 

By transplanting NurOwn cells back into the patient at or near the site of neural damage, in the spine and/or muscles, it could potentially delay or even roll back damage from neurodegeneration. NurOwn cells have proven their efficacy in animal experiments (e.g., STEM CELLS 2008;26:2542–2551), and in a few small clinical trials.

In one case, a 75-year-old man who suffered from ALS and myasthenia gravis (the immune system attacks your own receptors for acetylcholine at the neuromuscular junction, which prevents the muscle contraction), was treated with NurOwn cells, and experienced the following improvement 1 month later.

Figure copying (a test of visuospatial function) of the patient, before and 1 month after the first enhanced (neurotrophic factors producing) mesenchymal stem cell (MSC‐NTF) transplantation.
Figure copying (a test of visuospatial function) of the patient, before and 1 month after the first enhanced (neurotrophic factors producing) mesenchymal stem cell (MSC‐NTF) transplantation.

This is only a case study and involves only one patient, which is the absolute lowest-quality evidence you can have in medicine.  Therefore, this study is suggestive that NurOwn cells can help ALS patients improve.

Now BrainStorm Cell Therapeutics has entered into a collaborative agreement with Hadassah Medical Center in Jerusalem, Israel, to conduct a Phase 2 clinical trial to test the ability of NurOwn cells to treatment patients with Amyotrophic Lateral Sclerosis (ALS).

This clinical trial is not BrainStorm’s first rodeo, since they have conducted two other clinical trials in collaboration with Hadassah Medical Center. BrainStorm hopes that the results of this clinical trial will provide guidance in preparing a Phase 3 clinical trial that will test their NurOwn® stem cell based therapy in patients suffering from ALS.

In this trial, BrainStorm plans to enroll up to 24 ALS patients, all of whom will receive three consecutive stem cell transplantations of their own BM-MSCs that have been genetically engineered to secrete NFTs. The goal of this trial is to establish the safety and efficacy of a treatment regimen that includes multiple doses of stem cells. Because this trial includes human subjects, it must be approved by Hadassah’s Helsinki Committee and the Israeli Ministry of Health before the study can commence.

Professor Dimitrios Karussis, MD, PhD, Head of the Unit of Neuroimmunology and Cell Therapies at Hadassah’s Department of Neurology, who served as Principal Investigator in Brainstorm’s prior ALS studies, will serve as the Principal Investigator for this trial.

“NurOwn has generated promising clinical data in ALS and has the potential to offer a new approach for the treatment of patients afflicted with this disease,” stated Professor Karussis. “We are excited to be collaborating with BrainStorm to advance this product to the next phase of development and the application of stem cell therapies in similar neurological diseases in general.”

“Evaluating multiple doses with NurOwn is an important next step in our efforts to understand the treatment effect of this investigative medicine,” stated Chaim Lebovits, CEO of Brainstorm. “We are pleased to continue our partnership with Hadassah Medical Center, which has long maintained a reputation for excellence in the treatment of neurological disorders.”