Development of milnacipran for fibromyalgia hits a snag

October 04, 2005

Oct 4, 2005

New York, NY - The development of milnacipran, a nontricyclic antidepressant, for use in the treatment of fibromyalgia hit a snag last week when a preliminary analysis of data from a key phase 3 trial failed to reach statistical significance [ 1 ]. However, the companies developing the product for this indication, Cypress Biosciences and Forest Laboratories, say they are continuing with other phase 3 studies and will reevaluate development plans in the next few months as further analyses are performed. Meanwhile, results from a successful phase 2 study have been published in the October 2005 issue of Journal of Rheumatology [ 2 ], positioning the drug as an agent with efficacy similar to the tricyclic antidepressants but without their many potential side effects.

Milnacipran (Ixel), originally developed by Pierre Fabre Medicament, is already marketed for depression in many countries, but not in the US; it has been used by an estimated three million people in the six years it has been available. Cypress licensed the product in 2001 and joined up with Forest in 2004 to develop and market milnacipran for fibromyalgia for the US market. Both studies discussed below are part of this program and are company-funded.


Dual reuptake inhibitor

Milnacipran is described as the first in a new class of antidepressants, agents that act as both norepinephrine (noradrenaline) and serotonin reuptake inhibitors (NSRIs); duloxetine also belongs to this class. In addition, the classic tricyclic antidepressants also act in this manner, blocking the reuptake of both neurotransmitters. However, milnacipran is unique in its preference for norepinephrine reuptake inhibition, say the researchers reporting the phase 2 study. The group comprises several researchers from Cypress, as well as several academic researchers, and the senior author is Dr Daniel Clauw (Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor).

Of all the drugs that have been tried in fibromyalgia, the tricyclic antidepressants have the most evidence of treatment efficacy, and they form the cornerstone of most treatment paradigms, the researchers comment. It appears that inhibition of both neurotransmitters is needed, as studies in fibromyalgia with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine have shown they are not effective pain medications, they add. However, the tricyclics have many potential side effects, some of which stem from their activity on other systems, eg, histaminergic and muscarinic activities. Milnacipran doesn't have these other activities and thus lacks many side effects of the tricyclics, the group explains.

The phase 2 study they report showed statistically significant improvement in pain, as well as improvements in global well-being, fatigue, and other domains. The fibromyalgia patients were subdivided into those who also had comorbid depression and those without, and both groups responded equally well to milnacipran; however, the group with depression had considerably higher placebo response rates, so the overall efficacy was significantly greater in the nondepressed group, the researchers comment. This is consistent with what has been seen with the tricyclics, they comment, in that the analgesic effects are somewhat or largely independent of the antidepressant effects. The drug was generally well tolerated, especially with twice-daily dosing; the majority of adverse effects were rated as mild or moderate, and no serious adverse events were reported. Patients who discontinued the drug due to adverse events (14.4% overall) complained of headache, gastrointestinal complaints, orthostatic dizziness, exacerbation of hypertension, depression, lethargy, increased sweating, and hot flashes.


Results not statistically significant

However, in the announcement last week, Cypress and Forest said that preliminary top-line results from a pivotal phase 3 study involving 888 fibromyalgia patients did not achieve statistical significance at the p<0.05 level. The primary end point was a composite response rate of pain as measured by the Patient Experience Diary (PED) and overall impression of well-being as measured by the Patient Global Impression of Change (PGIC). Using the last-observation carry-forward analysis, for patients receiving 200-mg milnacipran per day, the p value was 0.058. This is "supportive of continued development of milnacipran as a treatment for fibromyalgia," the companies comment. They also note that in another analysis, based on the FDA-recommended baseline-observation carry-forward approach, the p value was 0.048. They add, however, that while this yields a statistically significant result, "the FDA may not accept this as a registration study." The magnitude of effect observed at three months was maintained at six months, indicating a durable response, and the drug was generally well tolerated. The most common adverse events leading to withdrawal among the milnacipran-treated patients were nausea (6%), increase in heart rate (2%), headache (2%), and depression (2%).

In a webcast to investors, Cypress chair and CEO Dr Jay Kanzler said that the data so far are "strongly supportive of efficacy of milnacipran in fibromyalgia" although the study having failed to reach statistical significance does not qualify for approval. It may be that another study will be needed, he added, but he emphasized that the company remains committed "to be the first to the market with a drug for fibromyalgia."

At present, there are no drugs approved for use in the treatment of fibromyalgia. Another contender in the race to reach the market is pregabalin (Lyrica, Pfizer), recently launched for use in neuropathic pain, and one study has also shown promising results with pramipexole (Mirapex, Boehringer Ingelheim), a dopamine agonist marketed for Parkinson's disease, as previously reported on rheuma wire .

Sources

1. Forest Laboratories Inc and Cypress Bioscience Inc. Forest Laboratories Inc and Cypress Bioscience Inc announce results     of Phase III study for milnacipran as a treatment for fibromyalgia [press release]. September 28, 2005. Available at:     http://www.cypressbio.com/news/releases/20050928.pdf.

2. Gendreau RM, Thorn MD, Gendreau JF, et al. Efficacy of milnacipran in patients with fibromyalgia. J Rheumatol 2005;     32:1975-1985.

 

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