Critical Limb Ischemia (CLI)

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Clinical development of PLX-PAD in Critical Limb Ischemia

A phase III study (N=246) in CLI is ongoing in U.S. and Europe

  • Primary Endpoint- time to event (amputation or death); Other measures of efficacy includes AFS, quality of life, TcPO2 and pain score
  • Dosing regimen: two doses of 300 million cells, two months apart (n=164), placebo (n=82)
  • No HLA matching or immunosuppression required
  • Follow-up of 12-36 months increases the study’s power allowing for a smaller trial

Our clinical development program for PLX-PAD in CLI was selected for Europe’s Adaptive Pathways pilot project. This program may allow for an interim analysis of efficacy following data from 50% of the patients (n=123), in support of an application to the EMA for Conditional Marketing Authorization (CMA), a significant opportunity to bring PLX-PAD more quickly to patients suffering from CLI.

The Phase III CLI program (PACE study) has been awarded an $8 million grant from European Union’s Horizon 2020 program, which is its largest Research and Innovation program. The collaborative project includes leading European research institutes and clinical sites, which undertake an extensive scientific program in parallel to the trial, using in-depth immunological, endocrine, and molecular analyses to better understand the mechanism of action of PLX-PAD in CLI.

 For the PACE horizon 2020 website please click here.
The Phase III CLI study was granted Fast Track Designation by the U.S. Food and Drug Administration (FDA).  The FDA’s Fast Track Designation, designed to facilitate the development and expedite the review of drugs to treat serious conditions and unmet medical needs, may increase the possibility for a priority review by the FDA of PLX-PAD cells for the treatment of CLI.

The European Medicines Agency (EMA) has included PLX-PAD in its Adaptive Pathways program which may allow for interim analysis of the study data. Positive results from an interim analysis following treatment of half of the study’s population may lead to early conditional marketing authorization.

In addition, the FDA has cleared the Company’s Expanded Access Program (EAP) for the use of its PLX-PAD cell treatment in patients with CLI. EAP allows the use of an investigational medical product outside of clinical trials and is usually granted in cases where patients are unsuitable for inclusion under the study protocol and the patient’s condition is life-threatening with an unmet medical need. The program Allows for Collection of Real-World Data Alongside the Company’s Ongoing Phase III Study in CLI.

Pivotal (pre-marketing) CLI study in Japan

Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) has accepted PLX-PAD for the treatment of CLI into its accelerated regulatory pathway for regenerative therapies and has agreed on the design of a single study (N=75) that may lead to early conditional marketing approval and reimbursement. 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.

Pluristem signed a binding term sheet with Sosei CVC to establish Joint venture for the clinical development and commercialization of PLX-PAD for CLI in Japan.

Completed CLI trials

We have completed two Phase I/II clinical trials 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 studies was to evaluate the safety profile, including the immunological profile, associated with the intramuscular administration of PLX‑PAD. Efficacy data were also collected.

The first study, 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 study, 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.

For more information regarding CLI press here.