Update on Clinical Trials

Since our last newsletter, two peer reviewed papers have been published reporting results of clinical trials for spinal cord injury and there have been significant updates on the results of a third ongoing trial.

The SCiStar study: The company Asterias has completed enrollment and dosing in all 5 of its planned SCiStar study Cohorts. This is a Phase 1/2a clinical trial to evaluate safety and potential efficacy for severe cervical spinal cord injury. Readers of Spinal Connections know that the foundation for the Asterias trial was the paper in 2005 by Hans Keirstead at the RIRC (Keirstead, H.S., Bernal, G., Nistor, G., Totoiu, M., Cloutier, F., Sharp, K., and Steward O. Human stem cell derivatives remyelinate and restore locomotion after spinal injury. J. Neurosci., 25, 4694-4705). The clinical trial for oligodendrocyte precursor cells (OPCs) was initially launched by the company Geron and was the first ever trial for human stem cells for spinal cord injury. This trial was terminated for economic reasons and the company Geron folded but the company Asterias re-booted the trial with their product called “AST-OPC1”.

On July 31, 2018 Asterias reported 12 month data for Cohort 3 and 4 updating previous reports on the data from earlier time points. Those of you who have been following this know that there are 5 Cohorts in the trial. Cohort 3 involves 6 subjects with cervical level injuries who are motor complete (AIS-A) who received 20 million cells. Cohort 4 involves 6 subjects with cervical level injuries who are AIS-B who received 20 million cells.

Overall, there continues to be a positive safety profile with no serious adverse effects related to the transplanted cells. Magnetic resonance imaging (MRI) studies at 12 months are consistent with the formation of a tissue matrix at the injury site in 92% (11/12) subjects, suggesting reduction in cavity formation. At 12 months 100% (6/6) subjects in Cohort 3 have recovered at least one motor level on at least one side and one subject recovered two motor levels on one side. For the combined data for Cohorts 2-4, 94% (17/18) subjects recovered at least one motor level on at least one side. Asterias expects to publish 12 month data for the entire study in the first quarter of 2019.

On October 31, 2018, Asterias announced that an independent Data Review Panel recommended moving forward with the clinical development of OPC1. The next step is a meeting with the Food and Drug Administration (FDA) to discuss the path to development and trial design for a controlled Phase 2 clinical trial that could begin in 2020.

Data from the Phase 1/2a clinical trial continues to be promising, but there is a looming hurdle for Asterias in terms of funding to go forward. The larger Phase 2 controlled efficacy trial will cost tens of millions of dollars.

In August, a thoughtful article on the Asterias trial and some of the participants was published in the San Francisco Chronicle by reporter Erin Allday:

https://projects.sfchronicle.com/2018/stem-cells/research/

First-in-Human, Phase I Study of Neural Stem Cell Transplantation for Chronic Spinal Cord Injury:

In June, a peer-reviewed paper was published on the outcome of a Phase I trial involving human spinal cord-derived neural stem cells (NSCs) that are the commercial product of the company Neuralstem Inc.(Curtis et al., 2018, Cell Stem Cell 22, 941-950). NSC’s differ from embryonic stem cell-derived oligodendrocyte precursor cells (OPCs) because the NSCs have not yet become committed to a particular cell type and thus can differentiate into all three of the primary types of cells in the central nervous system (neurons, oligodendrocytes and astrocytes).

The NSC product (NSI-566) was derived from a single post-mortem spinal cord from an 8-week gestational age human fetus. Cells were dissociated from the spinal cord and a single line of cells was expanded under good manufacturing practice (GMP) guidelines to generate a cell bank for clinical use.These cells had previously been tested in a clinical trial for ALS.

Subjects for the trial were individuals with chronic spinal cord injuries, defined as at least one year but no more than 2 years after traumatic SCI. The trial involved four subjects classified as AISA-A, a motor and sensory complete SCI, levels T2-T12 who received injections of NSC into the spinal cord. Each subject received a total of 6 injections of 2 million cells/injection. Injections were placed bilaterally into the remaining tissue lateral to the injury site and within white matter approximately one segment below the injury site. Data are from subjects who were followed for 18-27 months.

All subjects tolerated the procedure well and there were no serious adverse events. Three subjects exhibited one to two levels of neurological improvement in motor and sensory scores, which is considered to be an early sign of potential efficacy. However, there was no improvement in quality of life scores.

Despite these encouraging data, the authors emphasized that this study was designed as a safety trial without statistical power or a control group needed to evaluate any functional change resulting from cell grafting. Nevertheless, the favorable safety profile and hints of potential efficacy could warrant follow-up dose-escalation studies. Also, the study provided additional data supporting the feasibility of the approach of injecting cells into the injured spinal cord.

Perspective on progress:

It’s important to emphasize that it is really a mark of progress that these clinical trials have been carried out. When we launched the RIRC in 1999, there were NO ongoing clinical trials for people living with SCI, and the question was always “when will there be clinical trials”?

At the same time, we need to keep in mind that the treatments being tested today are really first generation. If this was a computer application, you could think of this as version 1.0. The original science documented measurable but modest improvements in motor function in rodents, and the functional gains in people have so far been modest. Building upon these positive beginnings, we can move on to discover better and more effective therapies (version 1.1, 1.2, etc.).

Everything being done today to test new therapies in studies costing millions of dollars began as a new idea for which a small amount of money was needed to get the initial preliminary data. To get version 1.1,1.2 etc. therapies, we need to be able to generate preliminary data to test these new ideas in order to be able to get further funding to develop them. Private donations for the first stage of innovation are the seed from which the gigantic tree grows.