US FDA approves Forest/Cypress's Savella for fibromyalgia - update
This article was originally published in Scrip
The US FDAhas approved Forest Laboratoriesand Cypress Bioscience's SNRI Savella (milnacipran HCl) for the management of fibromyalgia. The companies expect Savella to be available in pharmacies by March.
"The introduction of Savella is important because it is the first drug approved to treat the symptoms of fibromyalgia using a composite responder analysis," said Dr Daniel Clauw, professor of anaesthesiology and medicine (rheumatology) at the University of Michigan. The composite analysis looked at several aspects of fibromyalgia, including pain (visual analogue scale), patient's global assessment (patient global assessment of change) and physical function (short form-36 physical component summary).
Patients were considered to be a responder to Savella only if they demonstrated a clinically significant improvement across all categories. The NDA filing was based on two pivotal Phase III trials involving 2,084 patients which showed that Savella demonstrated clinically significant improvements compared with placebo.
The first study was conducted in 2005 and did not meet its original primary endpoint of a composite response after six months. However, the FDA revised its guidelines, including a provision that products only had to show efficacy at three months rather than six, and patients who withdrew early could be counted as non-responders. Cypress said that after these changes, the study did meet the composite endpoint.
The second trial demonstrated that milnacipran (200mg and 100mg once daily) patients had a significant improvement in the updated composite endpoint, compared with placebo (Scrip Online, January 9th, 2008).
A third study, reported in December, compared Savella 100mg with placebo; patients receiving 100mg of Savella experienced at least a 30% pain reduction from baseline and also rated themselves as "very much improved" or "much improved" based on the patients impression of change (PGIC) visual analogue scale (Scrip Online, December 11th, 2008).
"In older treatments, erosion of efficacy has evolved over time. However, we have data from an extension of the first Phase III and Savella's effect was sustained over a year," said trial investigator Dr Philip Mease, director of the Rheumatology Research Medical Center, Seattle. He reports that the drug is most notable for improving pain, fatigue and patient's clarity of thought.
Fibromyalgia is a chronic condition characterised by widespread musculoskeletal pain and fatigue, for which a cause is still unknown. Higher levels of substance P have been detected in the spinal fluid of patients and it is also thought that suffers have difficulty in modulating pain, which is brought on by a deficiency in noradrenaline.
Savella is a dual-reuptake inhibitor that preferentially blocks the reuptake of noradrenaline with higher potency than serotonin. These two neurotransmitters may play a role in the symptoms of the condition.
Savella will be marketed by Forest and its licensor, Cypress Bioscience. Pierre Fabre, the original developer, sells milnacipran outside the US. The drug has been marketed as an antidepressant in France since 1997. It has since been marketed for the treatment of depression in a number of other countries, including Austria and Israel under the trade name, Ixel, but has not been marketed in the US.
It is also in Phase II trials for co-morbidities in depression. "This approval is crucial for Pierre Fabre laboratories as milnacipran is one of the flagship products of our portfolio," said Dr Jean-Pierre Garnier, chief executive of Pierre Fabre SA.
There are limited therapy options available for fibromyalgia and sufferers have typically turned to pain medication, antidepressants, muscle relaxants, anti-epileptics and sleep medications.
Lilly/Boehringer Ingelheim's antidepressant Cymbalta/Xeristar (duloxetine) and Pfizer's anticonvulsant Lyrica (pregabalin) have been approved to treat the condition in the US. However, there are no approved treatments in the EU. UCBand Jazz Pharmaceuticalshave recently announced positive top-line data from two Phase III trials of their candidate, Xyrem (sodium oxybate), a dopamine antagonist (Scrip Online, November 27th, 2008).
According to Dr Mease there are many promising candidates in the pipeline. "The most comparable drugs are Savella and Cymbalta; they are chemically similar and therefore it would not make sense to take them together," he said. "However, combining one of them with Lyrica may be beneficial; in fact, we are beginning studies to investigate this. "Dr Mease said that it is impossible to tell what the most effective treatment was as there have been no head-to-head studies comparing them.