Trials and Tribulations: Update on Stem Cell Trials for Spinal Cord Injury
Recent news for stem cell trials for spinal cord injury is decidedly mixed. On the one hand, the trials have proceeded without any reports of serious adverse effects, and there have been encouraging reports of improvements. On the other, it’s sad to report that the “Pathway” trial by the company Stem Cells Inc. has been terminated and the company announced it would wind down its operations. Also, another company sponsoring a stem cell trial for SCI (Neuralstem) announced a strategic reorganization to re-focus its priorities on small molecule therapies.
As background, most readers of “Spinal Connections” know there have been 3 ongoing trials of stem cell therapies for spinal cord injury. The first to be launched was the trial of oligodendrocyte precursor cells (OPCs) by the c company Geron. The OPC trial was based on research by Hans Keirstead at the RIRC. Geron discontinued the trial but it was re-launched by the company Asterias. Next was the trial by the company “Stem Cells Inc,” which began in Switzerland, and was later extended to the United States and Canada. This trial involved transplantation of neural stem cells (NSCs) that differentiate into nerve cells, and glial cells. The foundation for the trial was research by Aileen Anderson and Brian Cummings at the RIRC. A third trial was launched by the company “Neuralstem” and is being run out of the University of California San Diego. This is an extension to spinal cord injury of an approach initially tested for amyotrophic lateral sclerosis (ALS). This trial involves a different type of proprietary neural stem cell. The OPC product of Asterias is derived by differentiating human embryonic stem cells (HESCs), whereas both of the NSC products were originally derived from cells harvested from aborted human fetuses.
The Asterias “SCiStar” trial-OPCs: In the Phase 1 clinical trial launched by Geron, five patients with neurologically complete, thoracic spinal cord injury received two million AST-OPC1 cells at the spinal cord injury site 7-14 days post-injury. Based on the lack of serious adverse events in this safety trial, Asterias launched the SCiStar trial, which will test three sequential escalating doses of “AST-OPC1” cells (20 million cells in the final cohort). Subjects are individuals who have suffered SCI at cervical level 5-7 and are neurologically complete (Asia A). Subjects will receive OPC transplants 14 to 30 days post-injury and will be followed by neurological exams and imaging procedures. A news release in October, 2015 announced a positive safety profile and absence of serious adverse events for the first 3 subjects who received the low dose, so the next cohort of 5 subjects will receive 10 million cells. According to the press release, the first patient who received OPCs at Shepherd Center in Atlanta exhibited neurological improvement from ASIA Impairment Scale (AIS) A to an AIS C at the 3 month assessment.
The Stem Cells Inc “Pathway Study”, NSCs: This was a trial involving the company’s proprietary human NSC line “HuCNS-SC®” for subjects with cervical SCI. Things seemed to be going well for this trial earlier in the spring of 2016. At the 2016 American Spinal Injury Association (ASIA) annual meeting in Philadelphia in April, Dr. Stephen Huhn, Chief Medical Officer and VP of Clinical Research at Stem Cells Inc. gave an update. The 6-month results from Cohort I (6 subjects) revealed improved muscle strength in 5/6 subjects, improved dexterity and fine motor skill in 4/6 patients and no serious side effects. On this basis, Cohort II had been launched, which was to be a randomized, single-blinded study of 40 AIS-B subjects. By late May, 11 subjects had received transplants in Cohort II.
But then suddenly on May 31 Stem Cells Inc. announced that it would terminate the study and close out operations. The 6,9, and 12-month results from Cohort I revealed encouraging patterns of improvements, but the effect was smaller at the 12 month time point. Because of this, the Company conducted an interim analysis of data from Cohort II. There were differences in motor strength that favored the treatment group, but the effect size was small and the company concluded that the study would be unlikely to achieve the primary endpoint objective.
For perspective regarding the issue of “effect size”, it’s important to emphasize the difference between preclinical studies in animals and human clinical trials. In most studies with animals, scientists make every effort to be sure that injuries are comparable and everything except the treatment is similar between groups. This practice of “minimizing variability” is so that it is possible to detect treatment effects. The problem is that human SCIs are highly variable, so if “effect size” is small, it’s harder to achieve a statistically significant result in a clinical trial.
Of course there is major disappointment that the “Pathway” trial is terminated. There will be a lot to learn from the Stem Cells Inc. experience, both in terms of the science and the economics of developing therapies for SCI. This is another practical lesson that limited financial resources make it difficult for small companies to continue when it becomes clear that the path to a therapy is longer than expected.
Neuralstem NSI-566/cSCI: The trial by Neuralstem is a phase I trial in which 5 subjects received six injections in, or around, the injury site, using the same cells and similar procedure as the company’s ALS trials. Subjects also receive physical therapy and immunosuppressive therapy. The 5th subject received the cells in July 2015. At the time of this writing, there are no updates on the results of the Neuralstem trial except that there have been no reports of adverse events.
However, on May 20, 2016 Neuralstem announced a “Plan of reorganization to further align business with strategic intent”. According to the press release: “The company's refocused strategy emphasizes its commitment to prioritize the small molecule platform, undertake business development efforts to secure alternative funding and partnerships for its stem cell assets.... Accordingly, the corporate reorganization includes a workforce reduction across all divisions that will result in significantly lower operating expenses while retaining the expertise needed to implement the company's refocused strategy”. It remains to be seen how this reorganization will affect any further trials of Neuralstem’s product for spinal cord injury.