Milnacipran | Proof of Concept Trials

Development Status | Phase II Results | Phase III Trials

Results of Phase III Trials

Background

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.

Results of First Phase III Trial (FMS-031)

In this study, 888 patients were randomized to receive either milnacipran 100 mg (n=224), 200mg (n=441) or placebo (n=223) daily for six months, 512 of whom completed the full six-month of double-blind treatment (128 100 mg, 239 200 mg, and 145 placebo). Results were assessed for all patients at both the three- and six-month visit.  The results of this trial were announced in

September 2005.  

Primary efficacy assessments consisted of composite responder analyses for the treatment of both fibromyalgia syndrome and pain of fibromyalgia.  Pain composite responders were defined as individuals who achieved both a >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” (1) or “Much Improved” (2) on a 7-point 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 (PCS) score.

Secondary endpoints included statistically significant improvements in self reports of pain (24-hour recall PED pain scores), patient global impression of change (PGIC scores), physical function (as measured by SF-36 PCS and mental component summary; MCS) and Fibromyalgia Impact Questionnaire (FIQ) total score.

Using the FDA-preferred method of data imputation, Baseline Observation Carried Forward (BOCF), milnacipran was found to be efficacious in treating both the pain of fibromyalgia at the 200mg daily dose, as well as the broader syndrome of fibromyalgia at both the 100mg and 200mg daily doses:

Milnacipran was well-tolerated with most AEs classified as mild or moderate in severity. The two most commonly reported adverse events (AEs) among all patients were nausea (milnacipran 100 mg/day, 33%; milnacipran 200 mg/day, 40%; placebo, 21%) and headache (milnacipran 100 mg/day, 16.0%; milnacipran 200 mg/day, 18%; placebo, 12%).

Results of Second Phase III Trial (MLN-MD-02)

In this study, 1196 patients were randomized to receive either milnacipran 100 mg (n=399), 200 mg (n=396) or placebo (n=401) daily over a 3-month period.  The results of this trial were announced in May 2007. Primary efficacy assessments consisted of composite responder analyses for the treatment of both fibromyalgia syndrome and pain of fibromyalgia.  Pain composite responders were defined as individuals who achieved both a >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” (1) or “Much Improved” (2) on a 7-point 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 PCS score.

Secondary endpoints included statistically significant improvements in self reports of pain (24-hour recall PED pain scores), patient global impression of change (PGIC scores), physical function (as measured by SF-36 PCS and MCS scores) and Fibromyalgia Impact Questionnaire (FIQ) total score.

Using the FDA’s preferred method of data imputation, BOCF, milnacipran was found to be efficacious in treating both the pain and syndrome of fibromyalgia at the 100mg and 200mg daily doses:

Milnacipran was well-tolerated with approximately 90% of AEs classified as mild or moderate in severity. Overall premature discontinuation rates (all causes including adverse event related) were 35% for patients receiving 200mg per day of milnacipran, 34% for patients receiving 100mg per day of milnacipran and 28% for patients receiving placebo.  The most commonly reported adverse events (AEs) among all patients were nausea (milnacipran 100 mg/day, 34%; milnacipran 200 mg/day, 38%; placebo, 19%) and headache (milnacipran 100 mg/day, 18%; milnacipran 200 mg/day, 18%; placebo, 15%).

Ongoing Phase III Trials

We have an ongoing Phase III study that was initiated in the first quarter of 2006. We expect to enroll approximately 1000 patients into this trial. It is a 3-month study and its analysis plan is consistent with our second phase III study, with the difference being that it is a 2-arm study. We expect to announce top-line results in the second half of 2008. In addition to this research, a fourth phase III trial is being conducted in Europe by Pierre Fabre (this study was designed in collaboration with Cypress and Forest).

Future Development Plans

In February 2008, we announced that the U.S. Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for milnacipran for the treatment of fibromyalgia. With a standard 10-month review timeline, the FDA Prescription Drug User Fee Act (PDUFA) target action date is the end of October 2008.