- Published: 06 October 2008
- Written by Editor
CombinatoRx Announces Top-Line Results from Phase 2b Study of Synavive(TM) (CRx-102) for Knee Osteoarthritis
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 Q1 Pain (ITT) Placebo Prednisolone (2.7mg) Synavive (2.7/90mg) Synavive (2.7/180mg) Synavive (2.7/360mg)
Baseline 79.0mm 78.0mm 80.0mm 74.5mm 78.0mm
Day 98 Change -24.5mm -41.0mm -30.0mm -35.5mm -43.0mm
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:
Normalized WOMAC Pain Subscale (ITT) Placebo Prednisolone (2.7mg) Synavive (2.7/90mg) Synavive (2.7/180mg) Synavive (2.7/360mg)
Baseline 75.0mm 75.3mm 74.4mm 62.7mm 74.2mm
Day 98 Change -26.8mm -31.8mm -29.0mm -23.5mm -37.2mm
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:
Normalized WOMAC Stiffness (ITT) Placebo Prednisolone (2.7mg) Synavive (2.7/90mg) Synavive (2.7/180mg) Synavive (2.7/360mg)
Baseline 74.0mm 76.3mm 74.8mm 64.5mm 78.5mm
Day 98 Change -23.0mm -33.3mm -22.5mm -28.3mm -35.0mm p=0.0270*
*Statistical significance compared to placebo
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:
Normalized WOMAC Physical Function (ITT) Placebo Prednisolone (2.7mg) Synavive (2.7/90mg) Synavive (2.7/180mg) Synavive (2.7/360mg)
Baseline 72.4mm 71.0mm 73.1mm 60.7mm 74.8mm
Day 98 Change -22.2mm -30.3mm -27.3mm -17.7mm -30.4mm
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 Demographics Placebo Prednisolone Synavive Synavive Synavive
n=58 (2.7mg) n=54 (2.7/90mg) n=56 (2.7/180mg) n=54 (2.7/360mg) n=57
Gender 64% 56% 66% 61% 67%
(female)
Race 72% 93% 84% 89% 86%
(Caucasian)
Mean Age 57.8 yrs 60.2 yrs 61.1 yrs 59.4 yrs 57.7 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 84% 74% 89% 81% 86%
in target joint
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.
SOURCE: CombinatoRx, Incorporated
CombinatoRx, Incorporated Robert Forrester, 617-301-7100 Executive Vice President, Chief Financial Officer This email address is being protected from spambots. You need JavaScript enabled to view it. or CombinatoRx, Incorporated Gina Nugent, 617-301-7099 VP, Corporate Communications and IR This email address is being protected from spambots. You need JavaScript enabled to view it.
