Botox (botulinum toxin type A) injections have gained a substantial amount of popularity as a temporary wrinkle fix, but the benefits of Botox may be more than skin-deep. Allergan (Irvine, California) is pursuing the use of the therapy to treat headaches and migraines.

The company said it has completed a top-line analysis of its two Phase III trials exploring the use of Botox for the prophylactic treatment of headache in adults suffering from chronic migraine – those who experience migraine attacks 15 or more days every month. According to Allergan, Botox is the first therapy being investigated for this condition, which is estimated to affect up to 3.6 million people in the U.S.

"We are pleased with the top-line results of our Phase III clinical trials, which show that Botox treatment provided benefit to these patients whose lives have been profoundly impacted by this severely debilitating condition," said Scott Whitcup, MD, executive VP of R&D. "It is gratifying to focus our research and development efforts on an indication that addresses such an important unmet medical need."

Based on this early analysis of the two Phase III clinical trials, Allergan says it hopes to file a supplemental biologics license application (sBLA) with the FDA to use Botox in chronic migraine by the middle of next year. The company said it expects to publish full data results mid-2009.

"In our Phase II clinical trials, we looked at various headache populations, including episodic migraine and chronic migraine," Crystal Cienfuegos, an Allergan spokeswoman, told Medical Device Daily in an e-mail response to questions. "Based on the data, we believe that the chronic migraine sufferer would be the headache segment to most likely benefit from Botox treatment, if approved."

This could be good news for Allergan, especially in light of the scrutiny it has faced this year.

In March the company received a subpoena for Botox-related documents from the Department of Justice, U.S. Attorney's Office for the Northern District of Georgia. Allergan said then that it believed the subpoena was in connection to the alleged promotion of Botox as a headache treatment. Allergan said the injection is not FDA-approved for such use and that its policy is to promote its products consistent with FDA-approved labeling (Medical Device Daily, March 5, 2008).

The subpoena came on the heels of the FDA's decision to review both Botox and Myobloc (botulinum toxin type B) made by Solstice Neurosciences (Malvern, Pennsylvania). Disclosure of the investigation concerning the products came just days after the consumer advocacy group Public Citizen (Washington) filed a petition with regulators calling for stricter warnings on Botox and Myobloc (MDD, Jan. 28 and Feb. 11, 2008). The group said it knew of 180 reports of harmful side effects, including 16 deaths, and that these had been reported to the FDA from November 1997 to December 2006. Four of the people who died were younger than 18, Public Citizen said.

Botox is approved in about 60 countries to treat limb spasms in children with cerebral palsy, and it is reported that some doctors in the U.S use it for that purpose. However, a company spokesperson said in February that the company does not market Botox for these applications in the U.S.

Then, adding insult to injury, two law firms – Mark & Associates and McGinnis, Lochridge, Kilgore – filed a civil suit against Allergan in July, alleging negligence in the design, manufacturing and marketing of Botox. The lawsuit claimed, among other things, that the Botox maker continues to promote off-label uses of the drug for patients with cerebral palsy and other uses that are not FDA-approved (MDD, July 11, 2008).

In addition to its cosmetic use, Botox is approved for the treatment of cervical dystonia in adults to decrease the severity of abnormal head position and neck pain associated with cervical dystonia. The drug is also approved to treat severe primary axillary hyperhirosis that is inadequately managed with topical agents.

In both Phase III clinical trials, patients were randomly assigned to treatment with Botox or placebo injections every 12 weeks. The primary analysis was performed at week 24 following two treatment cycles. The two major efficacy measures evaluated in the trials were change from baseline in the number of headache episodes and number of headache days occurring in the 28-day-period preceding week 24. In Allergan's discussions with the FDA concerning the design of the trials, the agency considered number of headache days the preferred efficacy measure for the potential indication, the company noted.

In the first Phase III study, Allergan selected number of headache episodes as the primary endpoint for evaluation, with the number of headache days being the secondary endpoint. Results indicated that although both groups showed a statistically significant improvement from baseline, there was no significant difference in the reduction of number of headache episodes between patients receiving Botox and placebo. However, the study showed a decrease in number of headache days, the FDA's preferred efficacy measure, which was significantly greater in patients receiving the drug compared with those receiving placebo. The decrease in number of migraine/probable migraine days was also found to be significantly greater in patients treated with Botox compared with the placebo group.

Based on the data from the first Phase III trial, the primary endpoint for the second study was changed to number of headache days, with number of headache episodes being a secondary endpoint, before the data were unmasked. In the second Phase III study, the primary endpoint and key secondary endpoints showed statistically significant benefit of Botox treatment over placebo injections, Allergan said. Specifically, patients treated with Botox demonstrated a significantly greater decrease in both number of headache days and number of headache episodes, the company noted. Similar to the first Phase III trial, the second study also showed a decrease in number of migraine/probable migraine days that was significantly greater in the Botox group.

According to Allergan, Botox treatments were well tolerated in patients suffering from chronic migraine in both Phase III trials. Also, in both studies, an evaluation of quality of life revealed an improvement in quality of life among the Botox patients, the company said.

Another migraine treatment being explored is a hand-held magnetic device from Neuralieve (Sunnyvale, California) that could help people whose migraines are accompanied by a set of neurological symptoms called Auras. These symptoms — flickering lights or decreased vision, numbness, or speech disturbances — usually precede a migraine headache and are caused by cortical spreading depression (CSD), a wave of abnormal nerve activity that travels slowly across the cortex. Neuralieve says its transcranial magnetic stimulation device works by creating a focused magnetic pulse that passes non-invasively through the skull, inducing an electric current. The device uses this technology to send signals to disrupt CSD, the company said (MDD, July 1, 2008).

Some companies also are studying the connection between patent foramen ovale (PFO) and migraine. One such company, AGA Medical (Plymouth, Minnesota), is running a trial to evaluate the effectiveness of PFO closure as a treatment for migraine, using its Amplatzer device. One of AGA's primary competitors, NMT Medical (Boston), had a similar trial until it decided to close the study earlier this year, citing enrollment challenges (MDD, Jan. 24, 2008).