AEterna Zentaris Partner Keryx Reports a Statistically Significant Benefit in Survival from Updated Results of a Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of Perifosine (KRX-0401) in the Treatment of Advanced Metastatic Colon Cancer
Data Reported at the 2010 ASCO GI Cancers Symposium Demonstrate a Statistically Significant Improvement in Both Time to Tumor Progression and Overall Survival in the Perifosine + Capecitabine Arm Versus Placebo + Capecitabine Arm
QUEBEC CITY, Jan. 25 /PRNewswire-FirstCall/ -- AEterna Zentaris
Inc. (Nasdaq: AEZS; TSX: AEZ) (the "Company"), a late-stage drug
development company specialized in oncology and endocrinology,
today announced that its partner, Keryx Biopharmaceuticals
(NASDAQ:KERX) , presented updated results
yesterday on the clinical activity of perifosine (KRX-0401), the
Company's PI3K/Akt pathway inhibitor for cancer, in combination
with capecitabine (Xeloda(R)) as a treatment for advanced,
metastatic colon cancer. Abstract #447, entitled, "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 colon cancer (mCRC): Updated results", was
presented yesterday in a poster during the 2010 American Society of
Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, held
in Orlando, Florida. Keryx is AEterna Zentaris' partner and
licensee for perifosine in the United States, Canada and Mexico.
Perifosine is also out-licensed to Handok in South Korea while
AEterna Zentaris retains rights for the rest of the world.
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 colon
cancer were randomized to receive capecitabine (a chemotherapy used
in advanced metastatic colon cancer which is marketed by Roche as
Xeloda(R)) at 825 mg/m2 BID (total daily dose of 1,650 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. Of the 38 patients enrolled, 35 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 unevaluable due to toxicity
(days 14, 46) and 1 was unevaluable 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 median
number of prior treatment regimens for all 38 patients was two,
with prior treatment regimens for the P-CAP arm versus CAP arm
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(R), and half treated
with an EGFR antibody:
-------------------------------------------------------------------------
Prior RX P-CAP CAP All Patients
(n equals 20) (n equals 18) (n equals 38)
-------------------------------------------------------------------------
FOLFIRI 18 (90%) 16 (89%) 34 (89%)
-------------------------------------------------------------------------
FOLFOX 15 (75%) 13 (72%) 28 (74%)
-------------------------------------------------------------------------
FOLFIRI & FOLFOX 13 (65%) 12 (67%) 25 (66%)
-------------------------------------------------------------------------
Avastin(R) 15 (75%) 15 (83%) 30 (79%)
-------------------------------------------------------------------------
EGFR Antibody (1) 9 (45%) 10 (56%) 19 (50%)
-------------------------------------------------------------------------
5-FU Refractory
Status 14 (70%) 13 (72%) 27 (71%)
-------------------------------------------------------------------------
Third Line
or greater 18 (90%) 16 (89%) 34 (89%)
-------------------------------------------------------------------------
(1) Prior treatment with Erbitux(R) and/or Vectibix(R)
The primary endpoint of this study was to measure Time to
Progression (TTP). Overall Response Rate (ORR), defined as Complete
Responses (CR) + Partial Responses (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 lasting 12 or more weeks (SD) or better, 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 vs 7% in the CAP arm. The updated efficacy results
for all evaluable patients are as follows:
-------------------------------------------------------------------------
ORR % greater than or equal to SD
CR / PR (min 12 wks)
(Duration of n (%)
Group n Response) p equals 0.036
-------------------------------------------------------------------------
20%
1 CR (34 mos - ongoing)
P-CAP 20 3 PR (21, 19, 11 mos) 15 (75%)
-------------------------------------------------------------------------
7%
CAP 15 1 PR (7 mos) 6 (40%)
-------------------------------------------------------------------------
-------------------------------------------------------------------------
Median TTP Median OS*
Weeks Months
Group p equals 0.0012 p equals 0.0136
-------------------------------------------------------------------------
P-CAP 28 (95% CI (12-48)) 18 (95% CI (10.8-25.7))
-------------------------------------------------------------------------
CAP 11 (95% CI (9-15.9)) 11 (95% CI (5.3-16.9))
-------------------------------------------------------------------------
*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.
NOTE: Kaplan-Meier method used to calculate both TTP and OS. In addition,
TTP and Progression Free Survival (PFS) are identical for all patients in
the study.
Of notable interest, and for the first time presented, were data
showing a highly statistically significant benefit in median OS
(more than doubling) and TTP for the subset of patients who were
refractory to a 5-FU (Fluorouracil) chemotherapy-based treatment
regimen. 5-FU is a core component of the standard of care FOLFIRI
and FOLFOX regimens, and capecitabine is a 5-FU pro-drug. These
results are shown below:
-------------------------------------------------------------------------
greater than or equal to SD
(min 12 wks)
5-FU Ref n (%)
Group n (%) p equals 0.066
-------------------------------------------------------------------------
P-CAP 14 (70%) 1 PR / 8 SD (64%)
-------------------------------------------------------------------------
CAP 11 (73%) 0 PR / 3 SD (27%)
-------------------------------------------------------------------------
-------------------------------------------------------------------------
Median TTP Median OS
Weeks Months
Group p equals 0.0004 p equals 0.0088
-------------------------------------------------------------------------
P-CAP 18 (95% CI (12-36)) 15.3 (95% CI (8.4-26))
-------------------------------------------------------------------------
CAP 10 (95% CI (6.6-11)) 6.8 (95% CI (4.8-11.7))
-------------------------------------------------------------------------
All 38 patients were evaluable for safety. The P-CAP combination
was well-tolerated with Grade 3 and Grade 4 adverse events of
(greater than) 10% incidence for P-CAP arm versus CAP arm as
follows: anemia (15% vs. 0%), fatigue (0% vs. 11%), abdominal pain
(5% vs. 11%) and hand-foot syndrome (30% vs. 0%). Of note,
incidence of Grade 1 and Grade 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 Grade 4 hand-foot syndrome in
the P-CAP arm of 19 weeks.
Commenting on the data, Dr. Cathy Eng, Associate Medical
Director for Colorectal Cancer at MD Anderson Cancer Center in
Houston, Texas, stated, "This randomized Phase 2 trial demonstrates
the very promising activity of perifosine (an oral AKT pathway
inhibitor) for response, PFS, and OS in the care of previously
treated, advanced colorectal cancer. Akt is downstream from the
EGFR receptor and may have a role also in KRAS mutant tumor types.
Preclinical data suggest that the Akt pathway inhibitors may be of
benefit not only with chemotherapy but also in combination with
other biologic agents. Perifosine is definitely worthy of further
analysis and should be pursued in a Phase 3 trial in this
indication."
Dr. Paulo Hoff, Professor of Medicine and Chairman of Medical
Oncology at the University of Sao Paulo, Brazil and the lead
investigator for the capecitabine (Xeloda(R)) Phase 3 approval
study stated, "The data we see in this study for the capecitabine
alone group is very much in line with expectation and, therefore,
the combination data of perifosine plus capecitabine appears very
compelling. It seems that the inhibition of Akt and other pathways
by perifosine modulates the activity of capecitabine. What is of
particular interest to me is the TTP and OS data for the 5-FU
refractory patients, which holds great promise and I urge the
Company to move forward into Phase 3."
Juergen Engel, Ph.D., President and CEO at AEterna Zentaris
stated, "This is a very positive development to begin the Year
2010. We now have a lot of options to create value for our
shareholders with our late-stage compounds in oncology, perifosine
and AEZS-108, as well as in endocrinology with AEZS-130, thanks to
the successful collaboration with our partner Keryx and the
continuous interest of dedicated investigators. We now look forward
to the further development of perifosine."
A copy of the abstract is available upon request. 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 146,100 people will be 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(R)), irinotecan
(Camptosar(R)), oxaliplatin (Eloxatin(R)), bevacizumab
(Avastin(R)), cetuximab (Erbitux(R)), and panitumumab
(Vectibix(R)). 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(R), a VEGF monoclonal antibody inhibitor, is
commonly administered together with FOLFIRI and FOLFOX. Typically,
patients who fail FOLFIRI and/or FOLFOX (+ Avastin(R)) and who are
considered EGFR-positive (non-mutated, wild-type KRAS status),
receive the EGFR monoclonal antibody inhibitors Erbitux(R) or
Vectibix(R). However, patients who continue to progress beyond
these treatments have a poor prognosis.
About Perifosine (KRX-0401)
Perifosine is a novel oral anticancer agent that modulates
several key signal transduction pathways, including Akt, MAPK, and
JNK that have been shown to be critical for the survival of cancer
cells. Perifosine has demonstrated both safety and clinical
efficacy in several tumor types, both as a single agent and in
combination with novel therapies. Perifosine is currently in a
Phase 3 trial, under Special Protocol Assessment (SPA), in multiple
myeloma for which it has received Orphan Drug and Fast Track
designations from the FDA in this indication. Perifosine is also in
Phase 2 clinical trials for several other tumor types.
About AEterna Zentaris Inc.
AEterna Zentaris Inc. is a late-stage drug development company
specialized in oncology and endocrinology. News releases and
additional information are available at www.aezsinc.com.
Forward-Looking Statements
This press release contains forward-looking statements made
pursuant to the safe harbor provisions of the U.S. Securities
Litigation Reform Act of 1995. Forward-looking statements involve
known and unknown risks and uncertainties, which could cause the
Company's actual results to differ materially from those in the
forward-looking statements. Such risks and uncertainties include,
among others, the availability of funds and resources to pursue
R&D projects, the successful and timely completion of clinical
studies, the ability of the Company to take advantage of business
opportunities in the pharmaceutical industry, uncertainties related
to the regulatory process and general changes in economic
conditions. Investors should consult the Company's quarterly and
annual filings with the Canadian and U.S. securities commissions
for additional information on risks and uncertainties relating to
the forward-looking statements. Investors are cautioned not to rely
on these forward-looking statements. The Company does not undertake
to update these forward-looking statements. We disclaim any
obligation to update any such factors or to publicly announce the
result of any revisions to any of the forward-looking statements
contained herein to reflect future results, events or developments
except if we are required by a governmental authority or applicable
law.
Source: AETERNA ZENTARIS INC.
CONTACT: Investor Relations: Dennis Turpin, SVP and CFO, (418)
652-8525,
ext. 242, dturpin@aezsinc.com; Media
Relations: Paul Burroughs, Director of
Communications, (418) 652-8525, ext. 406, pburroughs@aezsinc.com
Posted: January 2010
