| 03 Novembre 2011
The Company's Phase I Trials, Regulated by the FDA & the Paul Ehrlich Institute, Met All Endpoints
HAIFA, ISRAEL, November 3, 2011 – Pluristem Therapeutics, Inc. (NASDAQ:PSTI; TASE:PLTR) today announced positive 12-month data from its Phase I open-label, dose-escalation clinical trials conducted under protocols approved by the Food & Drug Administration (FDA) in the USA and the Paul-Ehrlich-Institute (PEI) in Germany. PLX-PAD cells met all the clinical studies’ protocol endpoints, demonstrating a safe immunologic profile at all dosage levels and found to be potentially effective in treating patients suffering from Critical Limb Ischemia (CLI).
Edwin Horwitz, MD, PhD, Associate Professor of Pediatrics at the Children’s Hospital of Philadelphia, President of the International Society for Cellular Therapy (ISCT), and Chairman of Pluristem’s Scientific Advisory Board will present the 12-month follow-up results at the World Conference on Regenerative Medicine on November 3, 2011 in Leipzig , Germany .
The endpoints of these Phase I trials included data on tumorigenesis, adverse events, immunological reactions, laboratory and ECG findings. The results of these two trials are combined for reporting reasons.
No malignancies were reported and all serum sample levels of tumor markers (PSA, CEA, CA125, AFF and NSE) were within normal range for all patients tested. Monitoring for malignancies was required only in the clinical trial conducted in Germany. It was concluded that treatment with PLX-PAD cells does not induce tumorigenesis.
No clinical evidence of adverse events or toxicities related to the intramuscular (IM) administration of PLX-PAD cells was observed in twenty-six of twenty-seven patients. Only one patient in the US trial experienced a transient local cutaneous inflammation after PLX-PAD was administered. A transient change was noted in the leukocyte and lymphocyte count in the patients, which returned to pre-injection baseline levels within 7 days and without evidence of absolute lymphopenia. No ECG abnormalities were detected during the treatment and monitoring periods.
Additionally, five of the twenty-seven patients received a double dose of PLX-PAD cells from the same placental batch two weeks apart without evidence of adverse events.
Based on the above data it was concluded there were no significant safety issues and PLX-PAD cells can be safely given IM to patients without matching, even if the patients are dosed twice from the same placental source.
Trends Towards Efficacy Based on Amputation Free Survival (AFS):
According to the study protocols, the clinical follow up was completed 3 months after the administration of PLX-PAD cells. During that time statistically significant improvements were noted for the following efficacy parameters (see press release announcement from September 14, 2011):
- Ankle-Brachial Index (ABI) - a measure of blood flow (P=0.033).
- Transcutaneous Oxygen Pressure (TcPO2) - a measure of tissue oxygenation (P=0.05)
- Quality of Life (QoL) - (P< 0.001)
- Visual Analogue Score (VAS) – a measure of pain (P=0.013)
The European Medical Agencies (EMA) and the FDA require the primary endpoint for CLI pivotal clinical trials to be Amputation Free Survival (AFS) rate. AFS data was collected during the Phase I studies and compared with another published CLI trial's data.
From a total of twenty-seven patients, four treatment failures occurred during the observation period of twelve months, which resulted in an AFS rate of 85.2%, as opposed to historical control data of 66.8% for the same time period. This corresponded to an event rate of 14.8%, as opposed to historical control data showing a 33.2% event rate, as outlined in Table 1 below.
Therefore, based on the endpoint of AFS at 12 months, it was concluded there is a trend towards efficacy of PLX-PAD cells in the treatment of CLI.
Table 1: Cumulative Event Rate Comparison
Dr. Horwitz stated: “AFS is the single most important endpoint in CLI clinical trials. Even though these Phase I trials were not controlled studies, the data collected in these trials on AFS indicate significant potential for PLX-PAD cells in treating CLI patients”.
“The safety data from these trials provide strong evidence that supports our business approach of using allogeneic PLX cells for various indications.” said Zami Aberman, Chairman and CEO of Pluristem. “The clinical trials also demonstrated that PLX cells possess superior properties enabling a second, same placental batch dose administration, which will be translated into a logistical advantage when the cells are commercialized. Additionally, the ability to administer our "off-the-shelf" cells in two doses without the need for tissue matching could potentially prolong the therapeutic effect of PLX cells in the treatment of CLI, via a "booster" dose.”
About the Study Protocols
Two Phase I clinical studies were conducted in the USA and Germany in accordance with protocols approved by the FDA and the PEI, respectively. Twenty-seven CLI patients were treated with PLX-PAD cells and followed for 12 months following the administration of the initial doses in the USA and for 24 months in Germany. During the clinical follow up period patients underwent clinical examinations, blood flow measurements, scores for quality of life and pain, ECGs and peripheral blood samples were drawn during their follow up visits for chemistry and immunological analysis.
Twenty-two of the twenty seven patients in the US and Germany received a single course of PLX-PAD cells with either 30 or 50 IM injections above and below the knee of the afflicted limb in a treatment that took, on average, approximately 20 minutes to complete. The remaining five US patients received a double dose of PLX-PAD cells in two courses administered two weeks apart. These five patients received both courses of PLX-PAD cells from the same placental batch. This was done in order to test for a delayed immunological response. Three dosage levels of 200, 300 and 600 million[1] PLX-PAD cells were evaluated. The five patients treated with the double dose of PLX-PAD cells received each a total dose of 600 million PLX-PAD cells.
About the Immunological Data
From an immunological perspective, the administration of PLX-PAD cells stimulated mostly transient non-specific immunological reactions .These reactions were without clinical significance or symptoms. Additionally, IM injections of up to 300 million PLX-PAD cells did not cause any PLX cell-specific response.
In addition, five patients received a double dose of PLX-PAD cells two weeks apart. There was no evidence of immediate clinical toxicity or adverse events and vital signs remained stable in all patients. Additionally, there were no significant changes noted in routine blood counts during the follow up periods. From an immunological perspective, no significant changes were noted in the patients’ lymphocytes including CD3, CD4, and CD8 lymphocyte counts or the CD4/CD8 ratio and in their Natural Killer (NK) cell population. A transient decrease in antigen presenting cells was demonstrated within 24 hours of PLX-PAD administration that returned to pre-PLX-PAD injection levels within one week. This phenomenon may be attributed to the immuno-modulating quality of PLX-PAD cells.
