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August 16, 2012 4:39 pm

Allergan’s Botox, MAP’s Levadex for migraines a near match made in heaven, some caveats exist – experts

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This article is provided to readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market.


Allergan’s (NYSE:AGN) co-promotion agreement with MAP Pharmaceuticals (NASDAQ:MAPP) for the latter’s investigational, orally inhaled migraine drug, Levadex (dihydroergotamine mesylate), mostly complements Allergan’s marketed migraine therapy, Botox (onabotulinumtoxinA), according to neurologists. The drugs treat different migraine categories, so the same set of doctors can be targeted, they noted. Allergan will co-promote Levadex in the US to neurologists and pain specialists.

Nearly one in four US households has a migraine sufferer, according to the Migraine Research Foundation.

This news service previously reported neurologists expect eventual drug approval. MAP has said it plans to refile its New Drug Application this year, after the US Food and Drug Administration (FDA) sent a Complete Response Letter (CRL) requesting additional information on the drug’s chemistry, manufacturing and controls. The agency also requested existing inhaler usability data.

Allergan paid MAP USD 60m up front and will pay up to USD 97m more when certain milestones are reached. The companies will share profits from US sales.

Botox, approved in October 2010 for use in chronic migraines, is intended to be a prophylactic treatment that decreases the overall frequency of migraines, said Dr Egilius Spierings, physician and founder and practicing physician, MedVadis Research, Massachusetts. Levadex is only intended to be used as an abortive treatment for acute or episodic attacks (those occurring less than 15 times a month), he noted.

The usual migraine management is to prescribe Botox and if headaches continue at a relatively high frequency, to add drugs, which could include Levadex, Spierings explained. Specific occurrences when Levadex can be used include menstrual-induced migraines, he said.

Levadex also provides relief late in the headache stage and for “cluster” attacks, said Dr Alan Rapoport, clinical professor of neurology, David Geffen School of Medicine, University of California-Los Angeles. The most prominent feature of cluster headache is immense pain on one side of the head.

Levadex might also be useful in patients who have nausea, vomiting and migraines upon awaking, said Dr Stewart Tepper, professor of neurology, Cleveland Clinic Lerner College of Medicine, Ohio.

Levadex rationale

Levadex is not for use as a prophylactic, since it is a long-acting agent that causes a contraction and narrowing of blood vessels, Spierings said. Hence it should not be used more than once a week on average, and more frequent use can lead to a migraine-rebound cycle, he added. With migraine-rebound cycles, a patient experiences a cycle of migraines cause by the medication itself.

The Levadex label will likely indicate it for abortive treatments with migraines with or without auras, Spierings and Rapoport agreed. Auras are usually visual but can also be sensory, motor or verbal disturbances, according to the Mayo Clinic.

Most chronic migraine sufferers start out as episodic. The progression to constant migraines is associated with medication overuse or a genetic tendency toward progression, Tepper said.

Medication overuse can range from over-the-counter medicines, to combination analgesics and opiates, to triptans, to non-steroidal anti-inflammatory drugs (NSAIDs), Rapoport said. Most physicians would prefer to wean away patients from medication overuse by giving Levadex as needed, Tepper said.

Botox reduces the severity, frequency and duration of chronic migraines and returns them to episodic, Tepper added. Yet even with episodic migraines, many patients require an intermittent treatment, and Excedrin, Advil and triptans often fill that space, he noted.

The physicians concurred Botox and Levadex are not contraindicated so the combined side-effect profiles are not concerning. Levadex, though, will be contraindicated within 24-hour use of triptans, Rapoport noted.

Levadex met all four primary endpoints in its final clinical trial. The study reported a statistically significant improvement in pain relief, freedom from phonophobia (sensitivity to sound), freedom from photophobia (sensitivity to light) and freedom from nausea two hours after dosing, according to the company website. Additional endpoints showed that Levadex provided rapid and sustained pain relief for up to 48 hours after dosing, the company stated.

Co-promotion caveats

The physicians agreed that while the alliance of two migraine products makes sense, it is not “perfect” symmetry.

Spierings noted that there really is “no common ground” between the two medicines from a medical perspective; rather Allergan’s sales reps will be able to target the same medical specialties.

Rapoport noted having sales reps offer both products raises Levadex’s visibility. But there is the possibility Allergan may prefer to tout Botox as the ideal preventative treatment, rendering Levadex unnecessary, he said.

Levadex’s competitors are triptans and injectable dihydroergotamine mesylate, rather than Botox, Tepper noted. But the nuances of Levadex administration and scenarios where it is most appropriate - such as tapering medication overuse with Levadex administration - could mean that it falls into off-label use, he added. Hence, sales reps will have to tread carefully lest they break strict FDA promotional rules.

The MAP spokesperson said discussing both products allows for the physician to understand the care continuum. The Allergan spokesperson did not respond to the physicians’ comments.

Payers will favor triptans over Levadex

Botox is not usually prescribed first-line, the Allergan spokesperson said and declined to comment more.

Rapoport noted that most physicians will likely prescribe triptans and NSAIDs over Levadex initially. If they do not work, then physicians would likely move to Levadex, he noted. Most likely, payers will require generic triptans be prescribed over brand triptans, with Levadex placed on a third tier formulary, Rapoport added.

A payer and reimbursement consultant said if Levadex does not have a clearly defined clinical benefit over existing products, it will likely be relegated to step therapy because of cost-containment strategies from pharmacy benefit managers and payers. He agreed with Rapoport that generics will always be suggested as the first prescription option, followed by physician-preferred brands. If these still fail, physicians could have to validate their Levadex recommendation in writing. It is also possible that the step therapy may not take place but that payers will charge patients significantly higher co-pays if they prefer Levadex, he added.

MAP has not publicly discussed pricing or managed care strategies, the spokesperson said. She declined to comment on whether MAP is engaged in studies that illustrate Levadex’s pharmacoeconomic benefits over competitors, but noted that there are millions of patients who have failed triptan therapies.

In recent financial filings, MAP noted among its competitors is generic sumatriptan. “Although we believe generic sumatriptan could not be substituted for Levadex, generic sumatriptan may be more quickly adopted by health insurers and patients than Levadex,” the filing stated. “Further, we believe that future coverage and reimbursement may be subject to increased restrictions both in the United States and in international markets, pursuant to currently proposed healthcare reforms or otherwise.”

Allergan’s market cap is USD 26.6bn.


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