While all this news is obviously good for the company, investors are nonetheless less than electrified, and for understandable reasons. Back in 2010, Sanofi SA (ADR) (NYSE:SNY) failed a promising Phase III CLI study for its drug called NV1FGF, even after positive Phase II results that were unfortunately not successfully replicated in the larger pivotal trial. This type of failure happens often, and could be behind why Pluristem’s share price has declined noticeably despite the spate of good news beginning in May 2015.
Sanofi vs Pluristem, Mirror Image Approaches to CLI
What investors should keep in mind though is that the approaches of these two CLI treatments are essentially opposing mirror images of each other in a manner of speaking, meaning the failure of one may not reflect on the other. NV1FGF was a DNA-plasmid delivered shot of an angiogenic growth factor, a gene therapy meant to induce the production of a factor that promotes the production of new blood vessels in affected limbs.
CLI is basically the effect of a clogged cardiovascular system in the legs and feet, and it was theorized by Sanofi and its partners that promoting the growth of new blood vessels would create workarounds to the clogged network of veins and arteries. While Phase II was positive, Phase III unfortunately failed.
Pluristem’s PLX-PAD cells can be seen as the mirror image approach to NV1FGF in the following way. NV1FGF sought to isolate one factor by gene therapy to promote the growth of new blood vessels. The approach makes logical sense, but begins with a complicated procedure involving the identification and isolation of specific genes and delivery of these genes via plasmid DNA into the affected area. The genes must infiltrate cells, take over their machinery, and have them produce this specific factor to promote the genesis of new blood vessels.
PLX-PAD, on the other hand, is nothing but specialized placenta cells grown from actual human placentas. Rather than isolating specific genes to do a narrowly defined job of producing a single known angiogenic factor, infiltrate other cells and have them produce it, placental cells are already designed to promote the growth of new blood vessels by their very nature, and they do not generate an immune response, so need for genetic matching to patients. Nobody knows exactly how they promote new blood vessel growth, only that they do.
After all, it is the cells of the placenta that guide fetal development, which includes growing an entire vascular system from scratch. So while NV1FGF isolates a specific factor by complicated genetic engineering, PLX-PAD takes the far simpler approach of making use of angiogenic growth factors within already functioning placental cells and simply injecting those cells, already equipped with the full machinery to promote angiogenesis.
If we call Sanofi SA (ADR) (NYSE:SNY)’s approach the maximalist-minimalist approach for beginning with complicated engineering to produce a known mechanism of action, Pluristem’s approach would be the minimalist-maximalist approach, beginning with a simple procedure of growing cultured placental cells to induce a complex and generally unknown mechanism of action, but one that is known, from the nature of fetal development and birth itself, to consistently work in growing new blood vessels. Pluristem’s approach in a way lets nature run its course, while Sanofi’s attempted to isolate a specific mechanism from nature and use that to its advantage.
The process of fetal development and the effect that specialized placental cells have on this development not being well understood is, from one perspective, slightly nerve-wracking, especially for Pluristem Therapeutics Inc. (NASDAQ:PSTI) and its investors. On the other hand though, the mysterious nature of these cells may have played a central role in getting Pluristem its $8 million grant in the first place. The grant is specifically designed to fund the trial itself as well as the study of PLX-PAD’s mechanism of action using a battery of immunological, endocrine, and molecular analyses to see what in fact is going on. Whatever this means, it does point to the fact that Europe is very interested in seeing why the initial Phase I trial results for PLX-PAD in CLI were so successful, especially in the U.S. trial.
