Milnacipran Demonstrated Significant Improvement in Pain and the Core Symptoms of Fibromyalgia Syndrome, Data Show
NEW YORK, Nov. 8Â -- Total daily dosages of milnacipran 100 mg and 200 mg demonstrated statistically significant and clinically meaningful improvements in both pain and other core symptoms associated with fibromyalgia syndrome (FMS), according to Phase III data presented this week at the 2007 American College of Rheumatology meeting in Boston, MA. The therapeutic effects of milnacipran among responders in a six-month study were sustained for up to one year in a double-blind extension trial.
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Although widespread chronic pain is the defining characteristic of FMS, it typically occurs as part of a broader spectrum of symptoms, including fatigue, cognitive dysfunction, and reduced physical function. Milnacipran is the first treatment studied for fibromyalgia whose effectiveness has been evaluated utilizing a composite responder approach which requires, on a patient-by- patient basis, concurrent improvements across multiple FMS domains. As such, composite responder analyses represent a more stringent assessment of therapeutic effect than the evaluation of individual symptoms.
To be considered a responder for the composite "pain of fibromyalgia" endpoint, each patient had to demonstrate concurrent and clinically meaningful improvements in two validated measures: pain and global impression of disease status. In addition to meeting those criteria, responders for the composite "treatment of the fibromyalgia syndrome" endpoint also had to demonstrate improvement in a third validated measure: physical function. The results of two Phase III trials showed that milnacipran demonstrated improvement compared to placebo in treating both the pain of fibromyalgia, as well as the broader syndrome of fibromyalgia. Furthermore, data from a six-month extension study showed that the therapeutic effects of milnacipran were sustained for up to one year of therapy.
"Because patients with fibromyalgia experience a wide array of symptoms that can overlap with other conditions, diagnosis and treatment can be complicated. Currently, many doctors are using multiple medications to treat the various symptoms of fibromyalgia," said Daniel J. Clauw, MD, lead investigator, Chronic Pain and Fatigue Research Center, University of Michigan. "There is a real unmet need for a therapy that not only relieves pain but addresses the functional and physical aspects of the illness that can have a significant impact on a patient's quality of life."
Study Methodology
In two double-blind, placebo-controlled, pivotal Phase III studies (Study MLN-MD-02 and Study FMS-031), the two parallel, primary efficacy assessments consisted of composite responder analyses for the treatment of both fibromyalgia syndrome and the pain of fibromyalgia. Pain composite responders were defined as individuals who achieved both a greater than or equal to 30% reduction in pain compared to baseline as measured by a visual analog scale recorded daily on an electronic patient experience diary, and who rated themselves as "very much improved" or "much improved" on a Patient Global Impression of Change (PGIC) scale. Fibromyalgia syndrome composite responders needed to satisfy the pain composite criteria as well as demonstrate at least a 6-point improvement in their SF-36 physical component summary (SF-36 PCS) score.
In Study MLN-MD-02, 1196 patients were randomized to receive either milnacipran 100 mg/day (n=399), 200 mg/day (n=396) or placebo (n=401) over a three-month period, 67.7% of whom completed the trial.
In Study FMS-031, 888 patients were randomized to receive either milnacipran 100 mg/day (n=224), 200 mg/day (n=441) or placebo (n=223) for six- months, 63.6% of whom completed three-months of treatment, and 57.6% of whom completed the full six-months of double-blind treatment. Results were assessed for all patients at both the three- and six-month visits.
Patients who completed the full six-months of treatment in Study FMS-031 were eligible to enroll in a multi-center, dose-blinded, extension study designed to evaluate durability of response up to one year. A total of 449 patients were either maintained at 200 mg/day (n=209) or re-randomized to 100 mg/day (n=48) or 200 mg/day (n=192) for an additional six months. Efficacy assessments included change in pain, as measured using a paper visual analog scale, and multidimensional symptomatic improvements, as measured using the Fibromyalgia Impact Questionnaire and PGIC.
Data Highlights
Results reported below are based on observed cases, which include only patients who were evaluable at the landmark visit. In study MLN-MD-02, there were 713 evaluable patients for the fibromyalgia syndrome and pain analyses (n=236 for 100 mg, n=215 for 200 mg, and n=262 for placebo).
In study FMS-031, at the three-month visit there were 549 evaluable patients for the syndrome analysis (n=134 for 100 mg, n=259 for 200 mg, and n=156 for placebo), and 553 evaluable patients for the pain analysis (n=135 for 100 mg, n=260 for 200 mg, and n=158 for placebo). At the six-month visit there were 488 evaluable patients for the fibromyalgia syndrome analysis (n=120 for 100 mg, n=229 for 200 mg, and n=139 for placebo), and 491 evaluable patients for the fibromyalgia pain analysis (n=121 for 100 mg, n=230 for 200 mg, and n=140 for placebo).
Composite responder rates for fibromyalgia syndrome (pain, PGIC, and SF-36 PCS)
   -- A statistically significant number of patients treated with milnacipran
      during Study MLN-MD-02 met the composite syndrome responder criteria
      (25% and 26% for the milnacipran 100 mg and 200 mg groups,
      respectively) compared to patients treated with placebo (13%).
   -- A statistically significant number of patients treated with milnacipran
      during Study FMS-031 also met the composite syndrome responder criteria
      at three months (33% and 33% for the milnacipran 100 mg and 200 mg
      groups, respectively) compared to patients treated with placebo (17%).
      Statistically significant differences were also observed at the six-
      month visit: 33% and 32% of patients met responder criteria for the
      milnacipran 100 mg and 200 mg groups, respectively, compared to 19% of
      patients in the placebo group.
   Composite responder rates for fibromyalgia pain (pain and PGIC)
   -- A statistically significant number of patients treated with milnacipran
      during Study MLN-MD-02 met the composite pain responder criteria (39%
      and 46% in the milnacipran 100 mg and 200 mg groups, respectively)
      compared to patients treated with placebo (25%).
   -- A statistically significant number of patients treated with milnacipran
      during Study FMS-031 also met the composite pain responder criteria at
      three months (45% and 45% in the milnacipran 100 mg and 200 mg groups,
      respectively) compared to patients treated with placebo (27%).
      Statistically significant differences were also observed at the six-
      month visit: 44% and 45% of patients met the composite pain responder
      criteria in the milnacipran 100 mg and 200 mg groups, respectively,
      compared to 28% of patients in placebo group.
Tolerability
Milnacipran was generally well-tolerated, with the majority of adverse events (AEs) reported being mild to moderate in nature.
   -- The most common treatment emergent AEs during the placebo-controlled
      clinical trials included nausea (37% vs. 20% placebo), headache (18%
      vs. 14% placebo), constipation (16% vs. 4% placebo), hot flushes (12%
      vs. 2% placebo), hyperhidrosis (9% vs. 2 % placebo), vomiting (7% vs.
      2%), palpitations (7% vs. 2%), heart rate increase (6% vs. 1% placebo),
      dry mouth (5% vs. 2%) and hypertension (5% vs. 2%).
   -- Milnacipran did not cause weight gain.
Development Plans
On September 28, 2005, Forest and Cypress reported that preliminary top- line results from Study FMS-031 did not achieve statistical significance. Subsequently, the Food and Drug Administration (FDA) revised its guidelines for approval of FMS therapies and agreed to allow the Companies to re-assess the data based on an updated analysis approach, which included a change from LOCF (last observation carried forward) to BOCF (baseline observation carried forward) analysis as well as other changes in the use of primary endpoints for efficacy evaluation. Using the revised analyses, a daily dose of 200 mg milnacipran produced statistically significant differences compared to placebo for both the fibromyalgia syndrome and pain of fibromyalgia composite endpoints. Also, compared to placebo, a daily dose of 100 mg milnacipran produced a statistically significant difference on the fibromyalgia syndrome composite endpoint and trended toward significance on the pain of fibromyalgia composite endpoint (p= .056). These data will be included as part of the New Drug Application (NDA) for milnacipran for the treatment of FMS, planned for submission around the end of 2007.
The Companies will review these data and the status of the milnacipran development timeline during an investor call on Thursday, November 8, 10:00 - 11:00 AM ET. To participate in the call, please use the following URL: http://phx.corporate-ir.net/phoenix.zhtml?p=irol- eventDetails&c=83198&eventID=1686016. (Due to the length of the link, please copy and paste into your browser.)
The webcast can also be accessed from both the Forest and Cypress corporate websites: www.cypressbio.com or www.frx.com.
About Milnacipran
Milnacipran is a unique dual-reuptake inhibitor, which preferentially blocks the reuptake of norepinephrine with higher potency than serotonin, two neurotransmitters known to play an essential role in regulating pain and mood. It has been approved for the treatment of depression in over 32 countries, with real-world commercial experience outside the U.S. spanning more than 10 years and 20 million patient-months. Milnacipran is being developed for fibromyalgia in the United States market jointly by Forest and its licensor, Cypress Biosciences, Inc. Milnacipran was originally developed by and is sold outside of the U.S. by Pierre Fabre Medicament.
About Fibromyalgia
FMS is a chronic and debilitating condition characterized by widespread pain and stiffness throughout the body, accompanied by severe fatigue, insomnia and mood symptoms. According to the American College of Rheumatology, FMS is estimated to affect over six million people in the United States. FMS is most often diagnosed in the primary care setting and, in addition, is the second most commonly diagnosed condition in rheumatology clinics in the United States after osteoarthritis. Despite the high prevalence and severity of this syndrome, there are limited treatment options specifically approved for FMS in the United States or elsewhere, and the addressable patient population is not yet well established.
About Cypress
Cypress is committed to being an innovator and leader in providing products for the treatment of patients with Fibromyalgia Syndrome. As part of its business development strategy, the company evaluates a number of Proof of Concept stage opportunities that leverage its repurposing experience and innovative approach to clinical trial design and regulatory strategy, and intend to continue to do this on an ongoing basis. The company continues to evaluate various other potential strategic transactions, including the potential acquisition of products, product candidates, technologies and companies.
For more information about Cypress, please visit Cypress' website at www.cypressbio.com.
This press release, as well as Cypress' SEC filings and website at http://www.cypressbio.com, contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 including statements about the potential of milnacipran to treat fibromyalgia syndrome and our planned NDA filing for milnacipran. Actual results could vary materially from those described as a result of a number of factors, including those set forth in Cypress' Annual Report on Form 10-K, the most recent Quarterly Report on Form 10-Q and any subsequent SEC filings and including, but not limited to, that more detailed analysis of the trial results may not be favorable or may lead to different conclusions; the FDA may not accept our first Phase III clinical trial as one of the two pivotal trials required for NDA approval, that upon further reflection that we may determine not to submit an NDA around the end of 2007 and even if we do submit the NDA, that it may not be accepted or not approved by the FDA, that we may not be able to protect our milnacipran patent portfolio and that milnacipran may never be approved as a drug by the FDA.
About Forest Laboratories and Its Products
Forest Laboratories (www.frx.com) is a US-based pharmaceutical company dedicated to identifying, developing and delivering products that make a positive difference in peoples' lives. Forest Laboratories' growing product line includes Lexapro(R) (escitalopram oxalate), an SSRI indicated for adults for the initial and maintenance treatment of major depressive disorder and generalized anxiety disorder; Namenda(R) (memantine HCl), an N-methyl D- aspartate (NMDA)-receptor antagonist indicated for the treatment of moderate to severe Alzheimer's disease; and Campral(R)* (acamprosate calcium), indicated in combination with psychosocial support for the maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation. In addition to our growing product line, Forest also co-promotes the Daiichi Sankyo, Inc. products Benicar(R)* (olmesartan medoxomil), an angiotensin receptor blocker, Benicar HCT(R)* (olmesartan medoxomil-hydrochlorothiazide), an angiotensin receptor blocker and diuretic combination product, and AZOR(TM)* (amlodipine and olmesartan medoxomil) a calcium channel blocker and angiotensin receptor blocker combination product, all indicated for the treatment of hypertension.
*Azor is a trademark of Daiichi Sankyo, Inc.; Benicar and Benicar HCT are registered trademarks of Daiichi Sankyo, Inc.; and Campral is a registered trademark of Merck Sante s.a.s., subsidiary of Merck KGaA, Darmstadt, Germany.
Except for the historical information contained herein, this release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. These statements involve a number of risks and uncertainties, including the difficulty of predicting FDA approvals, the acceptance and demand for new pharmaceutical products, the impact of competitive products and pricing, the timely development and launch of new products, and the risk factors listed from time to time in the Forest Laboratories' SEC reports, including the Company's Annual Report on Form 10-K for the fiscal year ended March 31, 2007, and on Form 10-Q for the period ended June 30, 2007.