Clinical development of PLX-PAD in Critical Limb Ischemia
Two trials of PLX-PAD in Critical Limb Ischemia (CLI) are expected to begin in 2016.
First, our clinical development program for PLX-PAD in CLI was selected for Europe’s Adaptive Pathways pilot project. This unique opportunity provides us with valuable guidance as we prepare the protocol for a Phase II trial to be submitted for conditional marketing authorization.
Also, In December 2015, Japan’s Pharmaceuticals and Medical Devices Agency cleared Pluristem’s protocol for a second trial of PLX-PAD in Critical Limb Ischemia (CLI). Positive results from this 75-patient, randomized, double blind, Phase I/II study are expected to be sufficient to apply for conditional marketing approval in Japan, which would be followed by collection of “real world data” from treated patients once the cell product reaches the market.
Completed CLI trials
We have completed two Phase I clinical trials in a total of 27 patients with Critical Limb Ischemia (Rutherford Categories 4 and 5) who were not suitable candidates for leg revascularization surgery. The data from these trials served as the basis for our successful applications to the Adaptive Pathways pilot project in Europe and to Japan’s accelerated regulatory pathway for regenerative medicine. The objective of both Phase I studies was to evaluate the safety profile, including the immunological profile, associated with the intramuscular administration of PLX‑PAD. Efficacy data were also collected.
A first Phase I, open‑label, dose‑escalation trial was conducted in the United States, evaluating a single administration of 280×106 cells (n=7), or repeated administration of 280×106 cells (two doses given two weeks apart, n=5). PLX‑PAD was administered via multiple intramuscular injections into the affected leg.
A second Phase I, open‑label, dose‑escalation study was conducted in Germany. It assessed 3 doses of PLX‑PAD: 175×106 cells (low dose, n=3), 315×106 cells (intermediate dose, n=6) and 595×106 cells (high dose, n=6). PLX‑PAD was administered via multiple intramuscular injections into the affected leg.
Both studies showed a favorable safety profile of PLX-PAD, with no evidence of immunogenicity or other safety concerns related to our cell therapy. The studies also showed promising findings for amputation-free survival one year after treatment, improvement of tissue perfusion, reduction of ischemic pain at rest, and increased quality of life.
In the U.S. trial, there were no cases of limb amputations or deaths during the 12-month follow‑up period. Based on T‑cell activation ELISPOT and anti‑HLA antibody testing, there was no evidence of PLX‑PAD‑specific humoral or T‑cell allosensitization, which is suggestive of the low immunogenicity of non‑HLA-matched allogenic PLX‑PAD cells.
In the German trial, the safety profile of PLX-PAD was also reassuring. As compared to the U.S. study, the German study included more women, the participants had more severe disease than those in the U.S. trial, and were more likely to be current or past smokers. Amputation free survival (proportion of patients alive with 2 limbs) at 1 year was 73%, as compared to 100% in the U.S. trial. The percentage of amputation free survival in the German trial was still superior to the rates reported in the literature for patients treated with the standard of care. Based on T‑cell activation ELISPOT and anti‑HLA antibody testing, there was no evidence of PLX‑PAD‑specific humoral or T‑cell allosensitization.