Phase I (safety) and Phase II (dosage) clinical trials are not expected to determine efficacy, which is ordinarily the subject of Phase III trials. And usually, efficacy suggestions in earlier trials are rarely discussed. In the case of the March 7, 2014 Annals of Neurology Intraspinal neural stem cell transplantation in amyotrophic lateral sclerosis: Phase I trial outcomes, the authors clearly define both the existence and causes of apparent efficacy that are both revealing and promising.
As stated by Eva Feldman, MD, PhD, Director of the A. Alfred Taubman Medical Research Institute, Director of Research of the ALS Clinic at the University of Michigan Health System and principal investigator for the NSI-566/ALS trial, "Pre-surgical disease progression rates for the various functional outcome measures were calculated to create slopes for each patient, so that we could determine if post-surgical data points, at 6, 9, 12 and 15 months, improved relative to predicted points. We also did analyses to determine which, if any, functional outcome assessments most closely correlated with the overall ALSFRS-R scores. Comparison of the outcome data to predicted outcome points in group E (patients who received both lumbar and cervical injections) revealed improvements in a significant number of measures at 6, 9, 12 and 15 months post-surgery. Overall, 50% of the patients in the trial showed improvement across multiple clinical measures at the same time points. We also found that a measure of grip strength correlated most closely with the overall ALSFRS-R scores.
We (also) conducted an analysis to identify the most biologically active period of the injected cells for the patients receiving both lumbar and cervical injections. This analysis reveals that the maximal periods of benefit correlate with the two surgical interventions. Importantly, as the 'bell-shaped curve' associated with each intervention is likely due to disease progression, increasing the total cell dose, and applying multiple applications of these stem cells, may increase both the length and magnitude of the potential benefit. We are of course exploring this very dosing regimen in our ongoing Phase II trial."
Karl Johe, PhD, Neuralstem's Chairman of the Board and Chief Scientific Officer, stated, "This peer-reviewed article is the first such report of cervical and dual-targeted intraspinal transplantation of neural stem cells in ALS subjects. We believe our cells offer a means to replace lost cells, provide neurotrophic support, and improve the diseased microenvironment. This study demonstrates these factors, and that the cells and the novel surgical route of administration are safe and well-tolerated. Our ability to directly inject cells into the cervical regions of the spinal cord represents a significant advance in the field of cell therapy.
Richard Garr, Neuralstem's CEO, states, "The initial patient so widely known of who demonstrated great efficacy in the early stages of the Phase I trial is no longer unique. Others have now shown equal or greater benefit from the trials--primarily those who had the highest number of cells injected, who had both lumbar and cervical injections and who were recently diagnosed when initially operated upon." As these (probable) conditions of improved performance are refined and continued in the remainder of the Phase II/IIA trials, it may be a reasonable expectation that more patients volunteering for the Phase III trial, beginning as early as February, 2015 will accrue similar benefit while contributing to the advancement of ALS/MND science. This is very encouraging data.
Under the collective aegis of Drs. Feldman, Boulis, Glass, Rutkove, Cudkowicz, et al, there is clear leadership of clinicians who are experienced and attuned to the nuances of patient condition and behavior as they relate to clinical trial participation. Both the investigators and Neuralstem have shown conservatism and patient safety as their foremost goals.