A person’s own bone marrow stem cells, souped up to pump out neuroprotective molecules, are a safe investigational treatment for amyotrophic lateral sclerosis, according to a paper in the January 11 JAMA Neurology online. The organizers of the 26-person Phase 1/2 study also believe they saw hints that the stem cell therapy slowed disease progression, as Alzforum reported in 2013 (see Apr 2013 conference news). However, with this small, open-label, uncontrolled trial, they cannot prove the treatment worked, said senior author Dimitrios Karussis of the Hebrew University-Hadassah Medical Center in Jerusalem. Researchers are midway through a placebo-controlled, 48-person Phase 2 study, he said, with all participants to complete the trial by May.
Karussis’ treatment protocol modifies mesenchymal stem cells (MSCs) from bone marrow to turn them into nursemaids for the motor neurons that wither and die in ALS. Co-authors at the biotech company BrainStorm Cell Therapeutics in Petach Tikva, Israel, treated each trial participant’s MSCs with three growth factors: basic fibroblast growth factor, platelet-derived growth factor, and heregulin β1. Together, they pushed the MSCs toward a phenotype resembling neural stem cells, Karussis said. The result: The cells started secreting growth factors, including glial-derived neurotrophic factor, nerve growth factor, vascular endothelial growth factor, and hepatocyte growth factor. BrainStorm calls these MSC-NTF cells, or NurOwn cells. Karussis predicts they should support ailing neurons as well as suppress damaging inflammation.
First author Panayiota Petrou of the Hebrew-Hadassah hospital and colleagues initially embarked on a Phase 1/2 study, intending to test the MSC-NTFs for safety in 24 people with ALS. Half of the subjects would receive intramuscular injections, with 1 million cells injected at each of 24 sites in the right biceps and triceps. The other half would get intrathecal infusions directly into the spinal cord at a dose of 1 million stem cells per kilogram of body weight. In a previous study, Karussis’ work suggested that magnetic particles in intrathecally injected MSCs reach several parts of the spinal cord (see Oct 2010 news).
During a planned midterm assessment, after 12 people had received injections, the hospital’s ethics committee expressed satisfaction with the safety data. The only side efects, such as headaches and mild fever, resulted from the lumbar puncture to those who received the intrathecal stem cells. Based on these interim results, the committee allowed the authors to transform their trial into a Phase 2a study, with escalating doses. Each of the following 14 volunteers in the study received both intrathecal and intramuscular injections. Four of those got 1 million cells per kilogram body weight intrathecally, plus 24 intramuscular injections of 1million cells each. Six participants received 1.5 million cells per kilogram body weight plus 36 1-million-cell intramuscular injections. The final four patients got a dose of 2 million cells per kilogram intrathecally plus two 1-million-cell injections intramuscularly. Once again, the treatment was safe for recipients. There was no control group.
The study was too small to prove any efficacy. Still, Petrou and colleagues assessed disease progression in the participants by several means, including the ALS Functional Rating Scale (ALS-FRS), which assesses a person’s ability to perform basic tasks such as speaking or dressing; and forced vital capacity, a measure of exhalation force. They calculated each individual’s rate of decline for three months before and six months after the treatment. For the six people who received only intramuscular stem cells, there was no benefit beyond the injected arm, Karussis said. Thus, the authors combined all recipients of intrathecal stem cells in their analysis.
On the 48-point ALS-FRS, participants declined an average of 1.2 points per month before treatment, compared to 0.6 points per month after receiving stem cells. Forced vital capacity dropped by 5.1 percent per month before treatment and 1.2 percent per month afterwards.
Karussis wondered if those kinds of changes would make a difference to individual patients. A survey of ALS experts indicated that they considered a 20-25 percent or greater downturn in ALS-FRS slope clinically significant (Castrillo-Viguera et al., 2010). Karussis and colleagues labeled their participants “responders” if the slope of either their ALS-FRS scores or forced vital capacity dropped by at least 25 percent after the treatment. By that metric, the majority of his subjects responded to the intrathecal treatment, though without a true placebo group in the study it is difficult to calculate the size of any possible placebo effect. Of the 18 people who completed three months of follow-up, 14 were defined as responders. Out of 15 who completed a six-month follow-up, 13 met the criterion. Other participants did not complete follow-up, or died for reasons unrelated to the treatment.
Clive Svendsen of the Cedars-Sinai Medical Center in Los Angeles said the safety data were solid, but he questioned this individual-level efficacy analysis. “ALS is not a linear disease,” he pointed out, so any single person may have slower or faster periods of progression. All the data show, he said, is that several people’s symptoms worsened at a slower rate than expected, which would happen for some participants in any ALS study regardless of treatment efficacy. He suggested that BrainStorm hyped the possible efficacy of the treatment to attract investors, as argued by financial publisher TheStreet. In response to these comments, Karussis said that he found it illogical to think that the majority of study participants would have their disease slow down after treatment by chance.
Given the open-label nature of the study, Karussis said he cannot rule out a placebo effect, though he doubts that explains the results. He noted that improvements became apparent a couple of months after treatment, beyond when he would expect to see a person report benefit from a placebo. Plus, the lack of benefit in the subjects who received only intramuscular injections supports his belief that the treatments did some good.
Scientists expect evidence of MSC-NTF efficacy, one way or the other, from an ongoing Phase 2 trial in which 36 people will receive a single intrathecal MSC-NTF treatment and 12 a placebo, at Massachusetts General Hospital in Boston, the University of Massachusetts Medical School in Worcester, and the Mayo Clinic in Rochester, Minnesota. “That will be the pivotal trial,” Svendsen said. Hints of efficacy in open-label studies have failed to pan out before, for example with the gene therapy CERE-110 for Alzheimer’s, discontinued in 2015 after a controlled study.
Karussis continues to follow the Phase 1/2 study participants, and said the effects of the stem cell injection seem to wear off after four to six months, with people returning to their pre-treatment rate of decline. Though he has not directly assessed how long MSC-NTFs survive in people, they only last one to four months in animals. In three study participants, the authors provided a second injection, and observed again a slowing of disease progression, Karussis said. He hopes to perform a new study with injections every two months in 24 people.
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