CombinatoRx Announces Top-Line Results from Phase 2b Study of Synavive(TM) (CRx-102) for Knee Osteoarthritis
Investor Conference Call Scheduled for Today at 8:30 am EDT
CAMBRIDGE, Mass.--(BUSINESS WIRE)--
CombinatoRx, Incorporated (NASDAQ: CRXX), today announced
preliminary top-line results from COMET-1 (CRx-102 Osteoarthritis
Multi-center Evaluation Trial), the Company's Phase 2b clinical trial
designed to evaluate the safety and efficacy of Synavive (CRx-102) in
subjects with symptomatic knee osteoarthritis (OA). While there was a
trend in favor of Synavive, and an observed dose-response
relationship, the combination did not demonstrate statistical
significance compared to placebo for WOMAC question #1 measuring pain
while walking on a flat surface (the primary endpoint), nor when
compared to prednisolone alone. Analyses of the full dataset from the
study remain ongoing.
"Encouraging earlier data from both the Phase 2a clinical trials
and molecular mechanism of action led us to have high expectations for
Synavive, and although it is gratifying to see the biology of the
synergy as well as steroid dissociation in this preliminary data, the
results in knee osteoarthritis overall are disappointing. The results
contain some observations that are difficult to reconcile, and we
intend to complete additional analysis of the data in order to further
our understanding of Synavive's biology and determine appropriate next
steps," said Alexis Borisy, President and CEO of CombinatoRx. "While
these outcomes are a setback for the Synavive program, we remain
convinced in the power of the CombinatoRx discovery platform and
approach. We have many valuable assets, including CRx-401, our product
candidate for Type 2 diabetes and CRx-197 for topical dermatology,
both expecting Phase 2a clinical data in the next few months, as well
as programs such as CRx-191 and new emerging programs such as in
B-cell malignancies and a next generation version of Synavive."
Key study results:
Data for the study's primary endpoint, median change in WOMAC
question #1 (ITT) on pain (range from 0-100mm) calculated from
baseline to day 98, are shown in the following table:
WOMAC Pain Subscale (ITT) data, the other widely accepted primary
pain measure based on the normalized sum of WOMAC questions #1-5 on
pain (range from 0-100mm rather than 0-500mm), are shown in the
following table:
WOMAC Stiffness Subscale (ITT) data based on the normalized sum of
WOMAC questions #6-7 on stiffness (range from 0-100mm rather than
0-200mm), are shown in the following table:
WOMAC Physical Function Subscale (ITT) data based on the
normalized sum of WOMAC questions #8-24 on physical function (range
from 0-100mm rather than 0-1,700mm), are shown in the following table:
Synavive was generally well tolerated and there were no serious
adverse events reported. The most commonly reported adverse event was
headache. At 4%, the rate of drop out from headache was evenly
distributed across all active arms, including prednisolone. In
addition, there was no evidence of increased hemoglobin A1c, fasting
plasma glucose or triglycerides in the Synavive arms as compared to
placebo. Systolic blood pressure was increased in the prednisolone
alone arm (a known side effect of glucocorticoids), while the Synavive
combination either reduced blood pressure or increased it to a lesser
degree. Of the 279 patients enrolled, 191 (68%) completed the study.
Primary reasons for discontinuation included adverse event (11%),
subject request (8%) and disease progression/lack of efficacy (6%).
Subject demographics are provided in the table below. Demographics
of the prednisolone arm were somewhat different from the others,
especially when considering gender, race, Body Mass Index (BMI) and OA
beyond target joint.
Subject Placebo Prednisolone Synavive Synavive Synavive
Demographics n=58 (2.7mg) n=54 (2.7/90mg) (2.7/180mg) (2.7/360mg)
n=56 n=54 n=57
----------------------------------------------------------------------
Gender
(female) 64% 56% 66% 61% 67%
----------------------------------------------------------------------
Race
(Caucasian) 72% 93% 84% 89% 86%
----------------------------------------------------------------------
Mean Age 57.8 60.2 yrs 61.1 yrs 59.4 yrs 57.7 yrs
yrs
----------------------------------------------------------------------
Mean BMI 34.6 32.8 33.5 32.4 33.9
----------------------------------------------------------------------
BMI=>40 26% 17% 20% 15% 25%
----------------------------------------------------------------------
OA duration 8.8 yrs 8.4 yrs 10.3 yrs 8.6 yrs 7.1 yrs
(mean)
----------------------------------------------------------------------
OA other than
in target
joint 84% 74% 89% 81% 86%
----------------------------------------------------------------------
Hand OA pain
=> 30mm at
baseline (%) 64% 54% 56% 54% 67%
----------------------------------------------------------------------
Study Design
This clinical trial was a multi-center, randomized, double-blind,
placebo-controlled Phase 2b study evaluating the safety and efficacy
of Synavive in subjects with symptomatic knee osteoarthritis. 279
subjects were enrolled at 57 sites in the United States and Canada.
The trial was a standard flare design where patients with active
disease needed to demonstrate an increase in knee pain as determined
by the WOMAC question #1 (related to pain while walking on a flat
surface) upon withdrawal of their NSAID/COXIB therapy to be eligible.
In the study, patients were randomized to three different doses of
Synavive (2.7mg prednisolone and 360mg, 180mg or 90mg of
dipyridamole), 2.7mg of prednisolone alone or placebo. Patients were
dosed for a total of 14 weeks (98 days) including an initial two-week
dipyridamole titration phase. The primary endpoint of this study to
assess the efficacy of Synavive compared to placebo was the change in
WOMAC question #1 calculated from baseline to day 98. Secondary
endpoints included the full WOMAC pain, stiffness, physical function
parameters and patient global assessment scores.
Patients who completed the 14-week core study were eligible to
participate in a one-year extension study designed to investigate the
long-term safety and durability of response for Synavive.
About Osteoarthritis
Osteoarthritis is the most common degenerative joint disease and a
frequent cause of physical disability among older adults. According to
the Arthritis Foundation, more than 21 million people in the United
States suffer from the disease. Osteoarthritis affects the hands,
lower back, neck, and weight-bearing joints such as the knees, hips,
and foot joints. Symptoms of osteoarthritis range from stiffness and
intermittent mild pain to severe joint pain and impaired biomechanical
function. Although there is no cure for most forms of osteoarthritis,
various therapies can help patients manage symptoms such as
non-steroidal anti-inflammatory drugs, COX-2 inhibitors, local
analgesics, intra-articular corticosteroid injection and surgery.
About Synavive
Synavive is a novel dissociated glucocorticoid product candidate
designed to enhance the anti-inflammatory benefits of glucocorticoids,
without associated side effects. Synavive contains the cardiovascular
agent dipyridamole and a very low dose of the glucocorticoid
prednisolone and is being developed in a uniquely engineered
formulation. Synavive is thought to act through a novel multi-target
mechanism of action in which dipyridamole synergistically and
selectively amplifies prednisolone's anti-inflammatory and
immunomodulatory activities by inhibiting key cell mediators of
inflammation. In prior proof-of-concept clinical trials, Synavive
demonstrated a powerful anti-inflammatory effect and rapid onset of
action in patients with osteoarthritis and rheumatoid arthritis and
was generally well-tolerated. Synavive is in Phase 2 clinical
development for the treatment of immuno-inflammatory conditions.
Conference Call Information:
CombinatoRx will host a conference call to discuss the COMET-1
results today on Monday, October 6, 2008 at 8:30 a.m. EDT. To access
the call, please dial 866-761-0748 or 617-614-2706 (international)
five minutes prior to the start time and provide the passcode
90757256. A replay of the call will be available from 10:30 a.m. EDT
on October 6, 2008 until October 20, 2008. To access the replay,
please dial 866-286-8010 (domestic) or 617-801-6888 (international),
and provide the passcode 55161275. A live audio webcast of the call
will also be available on the "Investors" section of the company's
website, www.combinatorx.com. An archived audio webcast will be
available on the CombinatoRx website approximately two hours after the
event and will be archived for 14 days.
About CombinatoRx:
CombinatoRx, Incorporated (CRXX) is pioneering the new field of
synergistic combination pharmaceuticals and has a broad product
portfolio in Phase 2 clinical development. Going beyond traditional
combinations, CombinatoRx creates product candidates with novel
mechanisms of action striking at the biological complexities of human
disease. The lead programs in the CombinatoRx portfolio are advancing
into later stage clinical trials based on the strength of multiple
positive Phase 2a results. This portfolio is internally generated from
the CombinatoRx proprietary drug discovery technology which provides a
renewable and previously untapped source of novel drug candidates. The
Company was founded in 2000 and is located in Cambridge,
Massachusetts. To learn more about CombinatoRx, please visit
www.combinatorx.com.
Forward-Looking Statement:
This press release contains forward-looking statements within the
meaning of the Private Securities Litigation Reform Act of 1995
concerning CombinatoRx, its Synavive product candidate and its
clinical potential, its other product candidates and its drug
discovery technology. These forward-looking statements about future
expectations, plans and prospects of CombinatoRx and its product
candidates, including Synavive involve significant risks,
uncertainties and assumptions, including risks related to the
Company's ability to obtain additional financing or funding for its
research and development activities, the unproven nature of the
Company's drug discovery technology, potential difficulty and delays
in obtaining regulatory approval for the sale and marketing of
Synavive and its other product candidates, the Company's ability to
initiate and successfully complete clinical trials of Synavive and its
other product candidates and those other risks that can be found in
the "Risk Factors" section of the CombinatoRx Annual Report on Form
10-K on file with the Securities and Exchange Commission and the other
reports that CombinatoRx periodically files with the Securities and
Exchange Commission. Actual results may differ materially from those
CombinatoRx contemplated by these forward-looking statements.
CombinatoRx does not undertake to update any of these forward-looking
statements to reflect a change in its views or events or circumstances
that occur after the date of this release.
(c) 2008 CombinatoRx, Incorporated. All rights reserved.
