Keryx Reports Final Results of a Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of KRX-0401 (Perifosine) in the Treatment of Advanced Metastatic Colorectal Cancer

NEW YORK, June 8 /PRNewswire-FirstCall/ -- Keryx Biopharmaceuticals, Inc. (Nasdaq: KERX) today reported final results on the clinical activity of KRX-0401 (perifosine), the Company's oral anti-cancer agent that inhibits Akt activation in the phosphoinositide 3-kinase (PI3K) pathway, in combination with capecitabine (Xeloda®) as a treatment for advanced, metastatic colorectal cancer.  Abstract #3531, entitled, "Final results of a randomized phase II study of perifosine in combination with capecitabine (P-CAP) versus capecitabine plus placebo (CAP) in patients with second- or third-line metastatic colorectal cancer (mCRC)," is being presented today in a poster discussion held during the 46th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

STUDY DESIGN:

In this randomized, double-blind, placebo-controlled study conducted at 11 centers across the United States, heavily pre-treated patients with second- or third-line metastatic colorectal cancer were randomized to receive capecitabine (a chemotherapy used in advanced metastatic colorectal cancer which is marketed by Roche as Xeloda®) at 825 mg/m2 BID (total daily dose of 1650 mg/m2) on days 1 – 14 every 21 days plus either perifosine or placebo at 50 mg daily.  The study enrolled a total of 38 patients, 34 of which were third-line or greater. Median age of patients was 65 (32-83); 61% of the patients were male. Of the 38 patients enrolled, 35 patients were evaluable for response (20 patients on the perifosine + capecitabine arm and 15 patients on the placebo + capecitabine arm).  Three patients on the placebo + capecitabine arm were not evaluable for response (2 patients were inevaluable due to toxicity (days 14, 46) and 1 was inevaluable due to a new malignancy on day 6).  All patients in the perifosine + capecitabine arm were evaluable for response.

The patients in the study were heavily pre-treated, with the arms well-balanced in terms of prior treatment regimens. The prior treatment regimens for all 38 patients are shown in the table below.  Notably, all of the patients (with the exception of one CAP arm patient) had been treated with FOLFIRI and/or FOLFOX, almost 80% treated with Avastin®, and half treated with an EGFR antibody:

The primary endpoint of this study was to measure Time to Progression (TTP).  Overall Response Rate (ORR), defined as Complete Response (CR) + Partial Response (PR) by RECIST, and Overall Survival (OS) were measured as secondary endpoints.  

STUDY RESULTS:

The P-CAP arm demonstrated a statistically significant advantage for TTP and OS, as well as for the percentage of patients achieving Stable Disease (SD) or better lasting 12 or more weeks, as compared to the CAP arm.  The P-CAP arm demonstrated a greater than 60% improvement in OS, a more than doubling of median TTP, and almost a doubling of the percentage of patients achieving SD or better.  In addition, the ORR was 20% (including one CR, and durable responses) in the P-CAP arm versus 7% in the CAP arm.  

The final efficacy results are as follows:

ALL EVALUABLE PATIENTS (n=35):

*Survival is calculated from date of randomization until the date of death from any cause, whether or not additional therapies were received after removal from treatment.

Of notable interest were the patients who were previously refractory to a 5-FU based regimen.  The P-CAP arm again demonstrated a statistically significant increase in both TTP and OS compared to the CAP arm.  The final data is illustrated below:

5-FU REFRACTORY PATIENTS (n=25):

All 38 patients were evaluable for safety.  The P-CAP combination was well-tolerated with Grade 3 and 4 adverse events of > 10% incidence for the P-CAP arm versus CAP arm as follows: hand-foot syndrome (30% vs. 0%), anemia (15% vs. 0%), fatigue (0% vs. 11%) and abdominal pain (5% vs. 11%).  Of note, incidence of Grade 1 and 2 hand-foot syndrome was similar in both the P-CAP and CAP arms (25% vs. 22%, respectively).  Hand-foot syndrome is a reported adverse event with capecitabine monotherapy.  Patients who remained on treatment longer in the Phase 2 study had a greater chance to develop hand-foot syndrome as illustrated by a median time to onset of Grade 3 and 4 hand-foot syndrome in the P-CAP arm of 19 weeks.  

Based on the Phase 2 data, a Phase 3 randomized double-blind trial comparing perifosine + capecitabine vs. placebo + capecitabine in patients with advanced refractory colorectal cancer (X-PECT trial), under Special Protocol Assessment (SPA) from the FDA, is open and enrolling patients at multiple centers throughout the US.  

Commenting on the data, Dr. Johanna Bendell, Director of GI Oncology Research at Sarah Cannon Research Institute in Nashville, TN, stated, "As the final randomized Phase 2 data confirmed the promising activity of perifosine plus capecitabine compared to placebo plus capecitabine, I believe the ongoing X-PECT trial will soon provide us an answer as to the role of perifosine in the treatment of patients with refractory colorectal cancer."  Dr. Bendell is the Principal Investigator for the Phase 3 X-PECT trial.

Dr. Cathy Eng, Associate Medical Director for Colorectal Cancer at MD Anderson Cancer Center in Houston, Texas, and co-investigator in the X-PECT trial stated, "The data from the randomized Phase 2 trial continues to demonstrate the promising activity of perifosine (an oral Akt pathway inhibitor) for response, PFS, and OS in the care of previously treated, advanced colorectal cancer.  We look forward to collaborating in the X-PECT trial."

Ron Bentsur, Chief Executive Officer of Keryx, commented "We are pleased by the final data, showing the promising activity of the perifosine + capecitabine combination in this very advanced colorectal cancer patient population.  We believe that our Phase 3 study, in agreement with the FDA under SPA, has been designed to confirm the activity observed in this randomized Phase 2 trial."

A copy of the poster is available via request to Keryx.

Perifosine is also currently in a Phase 3 trial, under Special Protocol Assessment (SPA), for the treatment of relapsed/refractory multiple myeloma.

KRX-0401 (perifosine) is in-licensed by Keryx from Aeterna Zentaris Inc. (Nasdaq: AEZS; TSX: AEZ) in the United States, Canada and Mexico.

About Colorectal Cancer

According to the American Cancer Society, colorectal cancer is the third most common form of cancer diagnosed in the United States. It is estimated that over 146,000 people were diagnosed with some form of colorectal cancer with over 49,000 patients dying from colorectal cancer in 2009.  Surgery is often the main treatment for early stage colorectal cancer.  When colorectal cancer metastasizes (spreads to other parts of the body such as the liver) chemotherapy is commonly used.  Treatment of patients with recurrent or advanced colorectal cancer depends on the location of the disease. Chemotherapy regimens (i.e. FOLFOX or FOLFIRI either with or without bevacizumab) have been shown to increase survival rates with some stages of colorectal cancer.  Currently, there are seven approved drugs for patients with metastatic colorectal cancer: 5-fluorouracil (5-FU), capecitabine (Xeloda®), irinotecan (Camptosar®), oxaliplatin (Eloxatin®), bevacizumab (Avastin®), cetuximab (Erbitux®) , and panitumumab (Vectibix®). Depending on the stage of the cancer, two or more of these types of treatment may be combined at the same time or used after one another.  For example, FOLFOX combines 5-FU, leucovorin and oxaliplatin and FOLFIRI combines 5-FU, leucovorin and irinotecan.  Avastin®, a VEGF monoclonal antibody inhibitor, is commonly administered together with FOLFIRI and FOLFOX.  Typically, patients who fail FOLFIRI and/or FOLFOX (+ Avastin) and who are considered EGFR-positive (non-mutated, wild-type KRAS status), receive the EGFR monoclonal antibody inhibitors Erbitux® or Vectibix®.  However, patients who continue to progress beyond these treatments have a poor prognosis.

ABOUT KERYX BIOPHARMACEUTICALS, INC.

Keryx Biopharmaceuticals is focused on the acquisition, development and commercialization of medically important pharmaceutical products for the treatment of life-threatening diseases, including cancer and renal disease. Keryx is developing KRX-0401 (perifosine), a novel, potentially first-in-class, oral anti-cancer agent that inhibits Akt activation in the phosphoinositide 3-kinase (PI3K) pathway, and also affects a number of other key signal transduction pathways, including the JNK pathway, all of which are pathways associated with programmed cell death, cell growth, cell differentiation and cell survival. KRX-0401 has demonstrated both safety and clinical efficacy in several tumor types, both as a single agent and in combination with novel therapies. KRX-0401 is currently in Phase 3 clinical development for both refractory advanced colorectal cancer and multiple myeloma, and in Phase 1 and 2 clinical development for several other tumor types. Each of the KRX-0401 Phase 3 programs are being conducted under Special Protocol Assessment (SPA) agreements with the FDA. Keryx is also developing Zerenex(TM) (ferric citrate), an oral, iron-based compound that has the capacity to bind to phosphate and form non-absorbable complexes. The Phase 3 clinical program of Zerenex in the treatment for hyperphosphatemia (elevated phosphate levels) in patients with end-stage renal disease is being conducted pursuant to an SPA agreement with the FDA. Keryx is headquartered in New York City.

Cautionary Statement

Some of the statements included in this press release, particularly those anticipating future clinical trials and business prospects for KRX-0401 (perifosine), may be forward-looking statements that involve a number of risks and uncertainties. For those statements, we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995. Among the factors that could cause our actual results to differ materially are the following: our ability to successfully and cost-effectively complete clinical trials for KRX-0401; the risk that the data (both safety and efficacy) from ongoing clinical trials will not coincide with the data analyses from prior pre-clinical and clinical trials previously reported by the Company; and other risk factors identified from time to time in our reports filed with the Securities and Exchange Commission. Any forward-looking statements set forth in this press release speak only as of the date of this press release. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. This press release and prior releases are available at http://www.keryx.com. The information found on our website is not incorporated by reference into this press release and is included for reference purposes only.

SOURCE Keryx Biopharmaceuticals, Inc.

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