Injections of stem cells that are induced to secrete neurotrophic factors in patients with amyotrophic lateral sclerosis (ALS) are safe, drugstore well tolerated, and possibly clinically beneficial, results of a small open-label study suggest.
Although the results have to be confirmed with a clinical trial, they are "ground-breaking" and open the door for this line of investigation, author Dimitrios Karussis, MD, PhD, a neuro-immunology expert and professor, Neurology Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, told Medscape Medical News.
"We took one very substantial step forward to finding in the foreseeable future a treatment that may delay progression of the disease, and may even induce some improvement."
For the study, published online January 11 in JAMA Neurology, the researchers used autologous mesenchymal stem cells from bone marrow that were developed by using a technique to enhance production of growth factors, thereby increasing their neuroprotective potential. They also used unique routes of administration: directly into the cerebrospinal fluid (intrathecally [IT]) and intramuscularly (IM).
The first phase 1/2 part of the study randomly assigned 12 patients with probable ALS: 6 to the IT group and 6 to the IM group, in which injections were given in 24 separate sites in the biceps and triceps. One patient in the IM group withdrew consent.
Because an interim analysis showed "very sound efficacy data," the researchers were given the go-ahead to proceed with a second phase 2a study, said Dr Karussis. This part randomly assigned 14 patients with ALS, who received both IT and IM treatment: 4 low doses, 6 mid-doses, and 4 high doses (up to 2 million cells/kg).
One patient in each group was lost to follow-up (1 was a suicide), and 1 in the high-dose group died.
The analysis showed the injections to be safe and well tolerated. Treatment-related adverse events, which mainly included headache, fever, vomiting, leg and back pain, and neck stiffness, were mostly mild and transient and occurred close to the time of cell administration.
There were no significant changes in any laboratory parameter, including blood counts, biochemistry values, renal and hepatic function, thyroid function, and urinalysis measures. MRI did not reveal any significant pathology, such as infection or tumor formation, at the site of the injection.
Although the study was not powered for efficacy, the data provided some indication of clinically meaningful benefit.
In the phase 1/2 part of the study, there was a slower rate of monthly disability progression assessed with the ALS-Functional Rating Scale Revised (ALS-FRS-R) score (from –1.56 to 0.28) and forced vital capacity (FVC) of respiratory function (from –3.5% to –2.3%) at the 6-month follow-up compared with the 3-month run-in period, but only in the IT cohort.
The monthly rate of decline improved more substantially in the phase 2b trial, again in IT-treated patients. The changes were from –1.4 to –0.6 for the ALS-FRS-R score and from –2.6% to 0.86% for FVC. The expected rate of progression is about 1 point in the ALS-FRS-R per month. Continue Reading
"There was a clear benefit of the intrathecal injections," commented Dr Karussis. "If we take the group as a whole, there was more than a 50% improvement in the slope of progression after the treatment compared to before."
Injecting more stem cells did not appear more effective. "When we did an analysis of the different doses, there was no clear trend indicating that there's additional benefit by increasing the dose," said Dr Karussis.
A post hoc analysis of patients receiving IT or IT plus IM treatment (6 patients in the first study and 12 in the second) found a statistically significant improvement in the rate of FVC progression and a trend toward improvement in the rate of ALS-FRS-R score progression that was close to being statistically significant.
Another post hoc analysis in that same subgroup looked at responders, defined as a slope of improvement of at least 25% for ALS-FRS-R score or FVC. Of patients with 3 months of follow-up, 78% were responders; of those with 6 months of follow-up, 87% were responders.
The researchers also saw a trend toward a beneficial effect of using two novel biomarkers: MRI of muscles and measured compound muscle action potentials, which evaluate nerve function using electromyography. This effect was more prominent in the right (injected) arm and in the IM-treated patients.
This trend, said the authors, possibly indicates a localized neurotrophic effect at the transplantation site.
Dr Karussis said the results are exciting, and not just from a statistical or mathematical point of view.
"We observed significant improvement in individual patients and in groups of muscles, which is not always reflected in the numbers. But this is highly unlikely to happen without an intervention, as just a natural course of ALS."
Because the IM injections had only a small local effect, a double-blind, placebo-controlled, multicenter phase 2 clinical trial will investigate only IT stem cell injections. Initial data from that study should be available this summer, said Dr. Karussis.
In a statement, ALS Association Chief Scientist Lucie Bruijn, PhD, MBA, said, "We are encouraged to see that implantation of modified stem cells in this trial was safe for people with ALS. We look forward to learning more about the safety and efficacy of this therapeutic approach, as more trials are performed and results are reported."
The trial was sponsored by Brainstorm Cell Therapeutics. Dr Karussis has disclosed no relevant financial relationships.