Menstrual Migraine: FrovaŽ
Summary
In May 2006 Vernalis completed further studies aimed at obtaining approval for Frova® for use as a short-term prevention of menstrual migraine, a form of migraine suffered by over 60 per cent of female migraineurs. In the US, this represents approximately 12 million women. None of the triptan class of drugs is currently approved for this indication and Frova®’s long half-life (approximately 26 hours) suggests that it might be an appropriate treatment for this novel application.
The data from the second Phase III efficacy study corroborated the findings from an initial Phase III efficacy study and Vernalis' partner, Endo Pharmaceuticals filed a supplemental New Drug Application (sNDA) with the FDA in July 2006. The Frova® sNDA is supported by data from four clinical studies (two double-blind, placebo-controlled efficacy studies, an open-label safety study and a pharmacokinetic study). The results from three of these studies were reported in prior years. The data from the initial efficacy study was presented to the American Academy of Neurology in April 2003 and published in a peer-reviewed journal (Neurology Report ) in July 2004, with the positive results from the second efficacy study, the last of the four studies, being reported in May 2006.
Vernalis partner, Endo Pharmaceuticals, filed a supplemental New Drug Application (sNDA) with the FDA in July 2006 in order to allow Frova® to be marketed for the short-term prevention of MM. The FDA accepted the filing in September 2006 and issued an Action Letter in September 2007. In that letter FDA identified deficiencies in and asked for additional information to Endo’s sNDA for Frova in the short term prevention of menstrual migraine.
FDA did however acknowledge that both pivotal clinical efficacy trials had met their primary endpoints.
Details of the Action Letter are being fully analysed and then discussed with FDA. Following this discussion with the FDA, Endo and Vernalis will decide upon the appropriate course of action.
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Background
Migraine is thought to affect 15% to 20% of women. According to the American Academy of Neurology, an estimated 50% of these women experience migraines due to the hormonal changes experienced during their menstrual cycle. This is estimated to be a total of 9% (ie. 12 million) of the US female population who may experience Menstrual Migraine.
Menstrual Migraine can be divided into two, firstly Pure Menstrual Migraine (PMM) - with attacks that occur 2 days before until 3 days after onset of menstrual flow and at no other time, and secondly, Menstrually Related Migraine (MRM) - with attacks that occur during menstruation and at other times during the month. Menstrual migraines have been reported to be of a longer duration, more debilitating, more likely to recur and more resistant to treatment than other migraines. According to the National Headache Foundation, migraine is such a pervasive problem that 157 million workdays are lost each year in the US. The per-patient annual costs associated with migraine have been estimated at $6,684 for male and $3,600 for female migraine sufferers. American industry loses an estimated $50 billion annually due to absenteeism and medical costs from headaches, which include migraine.
Current Therapies
The first approach to the management of MM is to identify any obvious trigger factors, such as stress, foods, alcohol or sleep deprivation. However, since the principal factor in MM is believed to be hormonal, this approach often yields limited results. The most common pharmacological approach for the treatment of MM currently is to treat the symptoms of the migraine once it has developed. Hence the treatment of acute MM is currently similar to any other type of acute migraine, notwithstanding the evidence from clinical trials, which suggest that triptans with a short half-life are less effective in the acute treatment of MMs compared to those migraines that occur in the non-menstrual period. Other therapies include NSAIDs, anti-emetics, and analgesic combinations. In terms of the prophylactic management of MM, the treatments used for the prophylaxis of non-menstrual migraine are used, with the addition of hormonal therapy specifically oestrogen, which may be effective. The main prophylactic therapies are Pizotifen, NSAIDs, and Beta/Calcium Channel Blockers. A number of sufferers use non-pharmacological methods to control either the frequency or severity of their migraines, these include – biofeedback, relaxation therapy, hypnosis, meditation, osteopathy, acupuncture, cognitive behavioural training and lifestyle changes such as identifying the possible aggravating factors eg stress, alcohol, coffee, cheese and chocolate.
Some authors suggest that triptans with a longer half-life (such as Frova®) could be beneficial in respect of MM, due to the nature of the migraine attacks – generally longer duration and greater severity, when compared to other migraines.
Clinical Studies
Initial efficacy study: In October 2002, positive study data were first presented from a study of more than 500 menstrual migraine sufferers in the U.S., suggesting that six days treatment per month with Frova® (beginning two days prior to the anticipated onset of menstrual migraine) was effective in preventing migraine headaches triggered by menstruation. The study was a crossover design covering three menstrual cycles in which patients were administered each of placebo, once-daily and twice-daily dosing with Frova® for one month. The data demonstrated a highly statistically significant improvement in the numbers of patients who were headache-free during their menstrual cycles for both once and twice-daily dose regimens of Frova® compared to placebo (p ‹ 0.0001). These data were published in a leading journal, Neurology (2004, 63: 261-269). Read the Neurology Report.
Safety study: In December 2005, data were announced from a long-term safety study that investigated the higher dose regimen from the initial efficacy study. Female patients were administered Frova® for six days each month (2 x 2.5 mg twice-daily on day one, and 2.5 mg twice-daily for five days) covering their menstrual cycles. The study results indicated that Frova® was well-tolerated when used as a six-day dosing regimen for up to 12 menstrual periods as preventive therapy for MM. Importantly, more than 300 patients received 12 months of treatment, exceeding the study objective of treating 100 patients for 12 menstrual cycles.
Second efficacy study: In May 2006, Vernalis announced positve data from a second Phase III efficacy study in a difficult to treat menstrual migraine poplulation. Patients in the study were treated for three peri-menstrual periods (PMPs) and the primary endpoint was the number of menstrual migraine-free PMPs. Both once and twice-daily dose regimens of Frova® demonstrated efficacy, with statistical significance compared to placebo (p<0.01 and p<0.001 respectively). In addition, both dose regimens achieved statistical significance in other measures of effectiveness. These secondary endpoints included increased number of PMPs with one or no days of mild headache, reduction in headache intensity and a reduction in the use of rescue medication. There were no serious adverse events attributed to Frova®. The frequency of other adverse events was similar across both active treatment arms and placebo.
To be eligible for entry into this study, patients had to have previously been exposed to non-triptan therapy (i.e. NSAIDs - non-steroidal anti-inflammatory drugs) for the treatment of menstrual migraine episodes and had to have responded inadequately to acute triptan therapy. Prior to randomisation all patients had to experience an MM during a one-month cycle.
The following posters were presented at the annual meeting of the American Headache Society (AHS) in Chicago on 9th June 2007.
| Poster | |
|---|---|
|
Safety and Tolerability of Short-term Frovatriptan for Prevention of Menstrual Migraine in Double-blind Placebo-controlled Clinical Trials |
(133 KB) |
|
Characteristics of Patients With Inadequate Responses to Acute Triptan Treatment for Menstrual Migraine |
(164 KB) |
|
Open-Label Safety, Tolerability, and Effectiveness of Short-term Frovatripitan Treatment for the Prevention of Menstrual Migraine |
(147 KB) |
|
Prevention of Difficult-to-Treat Menstrual Migraine Using a 6-Day Regimen of Frovatriptan: A Second Double-blind, Randomized, Placebo-controlled Trial |
(164 KB) |
Regulatory Status
At present none of the triptans to date are labelled for the preventative treatment of either migraine generally or MM specifically.
Vernalis partner, Endo Pharmaceuticals, filed an sNDA with the FDA in July 2006 in order to allow Frova® to be marketed for the short-term prevention of MM. The FDA accepted the filing in September 2006 and issued an Action Letter in September 2007. In that letter FDA identified deficiencies in and asked for additional information to Endo’s sNDA for Frova in the short term prevention of menstrual migraine.
FDA did however acknowledge that both pivotal clinical efficacy trials had met their primary endpoints.
Details of the Action Letter are being fully analyzed and then discussed with FDA. Following this discussion with the FDA, Endo and Vernalis will decide upon the appropriate course of action.
In 2H 2007, Vernalis’ European partner, Menarini, plans to submit an application to extend the current indication to include prevention of menstrual migraine throughout Europe under the mutual recognition procedure with France acting as the reference member state. If successful it would lead to an extension of the existing indication for acute treatment in 25 EU countries.