clinical trial testing the use of human spinal cord stem …

Neuralstem is seeking to treat the symptoms of ALS via transplantation of its NSI-566 human spinal cord stem cells (HSSCs) directly into the gray matter of the patients spinal cord. In ALS, motor neurons die, leading to paralysis. In preclinical animal work, Neuralstem cells both made synaptic contact with the host motor neurons and expressed neurotrophic growth factors, which are protective of cells. View published papers here: 1, 2, 3.

Neuralstem initiated the first FDA-approved stem cell trial for ALS in January 2010, at Emory University. This Phase I safety trial, to evaluate the safety of the NSI-566 cells and surgical technique, was designed to enroll up to 18 patients. The Principal Investigator is Eva Feldman, MD, PhD, Director of the A. Alfred Taubman Medical Research Institute, and Director of Research of the ALS Clinic at the University of Michigan Health System. The Site Investigator is Jonathan Glass, MD, Professor of Neurology, Emory School of Medicine and Director of the Emory ALS Center. The trial was awarded an Orphan Drug Designation by the FDA in February 2011.

In humans, Neuralstem expects that the transplanted cells will:

In a review of the safety data from the initial nine patients, Neuralstem cells were deemed to be safe, with no adverse reactions reported believed to be related to cells or surgical technique.

Neuralstem concluded final surgeries in the companys NSI-566/ALS Phase II trial, primarily evaluating safety, in July 2014. After a six month patient follow-up period, this phase of the study concluded in the first quarter of 2015. A larger control NSI-566/ALS Phase II trial is expected to commence in 2016.

Nine-month Phase II and combined Phase I/II NSI-566 ALS data was presented at the American Neurological Association Annual Meeting by Dr. Feldman, in September 2015. The data showed that the intraspinal transplantation of the cells was safe and well-tolerated throughout the escalating doses, reaching a maximum tolerated dose of 16 million cells via 20 bilateral injections. Further, there appeared to be no acceleration in disease progression due to the therapeutic intervention.

Researchers calculated a 95% confidence limit around the slopes of decline of ALSFRSr scores, forced vital capacity (FVC) and grip strength of the ProAct historical database subjects, and evaluated if trial subjects fell within or outside those limits. 73% of Phase II patients, and 79% of combined Phase I and II patients, fell above the upper confidence limit of the ALSFRSr score. 50% of Phase I and II combined, and 40% of Phase II patients' forced vital capacity percent predicted fell above the upper confidence limit, compared to the ProAct database. ALSFRSr scores correlated most strongly with FVC preservation, which was the target of the cervical injections. For grip strength control, researchers used the Ceftriaxone (CEF) study database, since grip strength data was not available in the ProAct database. 67% of Phase I and II combined, and 60% of Phase II patients, all at nine months post-intervention, fell above the 95% upper confidence limit.

The Phase II open-label, dose-escalating trial of NSI-566 evaluated 15 ambulatory patients with ALS, averaging a mean duration of disease of 15.5 months. Participants were divided into five dosing cohorts with three patients in each, who received increasing quantities of cells in the cervical region of the spinal cord via bilateral intraspinal injections ranging from two million to eight million cells. The fifth cohort received an additional eight million cells in the lumbar region. There was no control or placebo group included in the trial. The primary endpoint of the study was the safety of the maximum tolerated dose of stem cell transplantation. Secondary efficacy endpoints included stabilization of ALS Functional Rating Scale-revised (ALSFRSr) scores, and assessment of respiratory functioning, grip strength and muscle strength. Nine of the 15 participants in Phase I and all 15 participants in Phase II were included in the 9-month data. The Phase II trial was approved by the FDA to initiate in April 2013, upon conclusion of the landmark Phase I FDA-approved trial to test the safety of the neural stem cells and transplantation surgery in patients with ALS in February 2013. The National Institutes of Health and ALSA committed to generous grants in funding for the Phase II phase of the study.

The Phase I safety trial enrolled 18 patients. The trial began with 12 late- to mid-stage patients who received a series of injections in the L2-L4 lumbar region. The first six patients were all non-ambulatory with permanent paralysis, and then the trial progressed to six patients who were ambulatory. Neuralstem received approval from the FDA to move into the cervical (upper back) stage of the trial in the fall of 2011. The first of six patients in the cervical cohorts to receive stem cells was treated on November 18, 2011, which marked the first FDA-approved intraspinal surgical transplantation of stem cells into the cervical region. The trial then advanced to the final cervical cohort of three patients. The FDA approved the return of three patients from earlier cohorts to receive cervical transplants, making them the first to receive stem cell transplantation in both the lower and upper parts of their spinal cord. The first of these was treated in June 2012, and received five stem cell injections into the cervical region of the back, for a total of 15 injections, including the ten lower-back injections previously received. The last patient in the Phase I trial was treated in August 2012. The trial was designed as a safety trial to treat 18 patients, and concluded six months after the final surgery.

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