Article reprint from IN VIVO June 2, 2009
A marketing battle with an unusual twist is brewing between Allergan's popular anti-wrinkle agent Botox and new-to-the-block Dysport, from Ipsen-Medicis. Both sides are citing their REMS (Risk Evaluation and Mitigation Strategy) as a key competitive advantage. Read on...
Article reprint from IN VIVO June 2, 2009
A marketing battle with an unusual twist is brewing between Allergan Inc.'s popular anti-wrinkle agent Botox and Ipsen/Medicis Pharmaceutical Corp.'s new-to-the-block Dysport: both sides are citing their REMS as a key competitive advantage.
The REMS (Risk Evaluation and Mitigation Strategy) program is turning out to be a weapon of choice because it gives each combatant an opportunity to highlight the safety of its product—a potential upside to REMS that industry didn't fully appreciate when the Food and Drug Administration (FDA) began mandating a series of new safety tools slightly more than a year ago.
The FDA began selectively imposing REMS and post-marketing surveillance studies on certain drugs in March 2008, as it was required to do under the FDA Amendments Act of 2007. At the time, no one knew what to expect. Industry's key concern was the extent to which its regulatory burden would increase, and it saw little upside to the new regulations, beyond the potential for faster approvals as regulators grow more comfortable that new drugs will be monitored better and used safely.
The agency has since used its authority fairly liberally to impose REMS on a variety of marketed drugs and new approvals. And industry is learning REMS may offer more than just additional unwanted oversight.
A Chance to Talk Up Safety
Allergan's Botox (botulinum toxin type A), the heavyweight in this battle, is by far the worldwide leader among neuromuscular blocking agents, with more than 83% share. The drug is practically a household name because, while decidedly serious neuromuscular diseases comprise a portion of sales, the bigger opportunity is in aesthetics, where Botox injections are used to temporarily smooth out glabellar lines (wrinkles). In the US, the aesthetic market for botulinum toxins is estimated to be approximately $300 million to $400 million per year. Injections of botulinum type A toxin are the leading non-surgical cosmetic procedure for the past five years, with more than 2.4 million total procedures in 2008.
The botulinum toxin market is poised to change considerably, however, now that in late April the FDA, in quick succession, approved Dysport (botulinum toxin type A) for treatment of cervical dystonia (head-and-neck muscle spasms) and glabellar lines and, a day later, mandated that all botulinum toxin manufacturers develop a REMS for their products and strengthen warnings on their labels—including adding a black box warning. The agency took this action after it received reports that people were using different botulinum toxin products interchangeably and often at the wrong doses. A number of people overdosed, causing severe dysphagia and respiratory depression.
In the US, Ipsen, the mid-sized French biopharma firm that owns Dysport, and the much smaller biotech Medicis have been sharpening their swords. Ipsen will be marketing the drug for neurological disorders and Medicis has licensed rights to market it in the US, Canada, and Japan it for cosmetic and dermatologic applications, although the companies do not plan to co-market. [200620250] A third entrant, Solstice Neurosciences Inc., a specialty biopharmaceutical company, also has Myobloc (botulinum toxin type B) on the market for cervical dystonia.
FDA wants the REMS to emphasize that different botulinum toxin products are not interchangeable. FDA's Cardiovascular and Renal Drugs Products Division Deputy Director Ellis Unger said that the agency is mandating the REMS because "of the potential for serious risk that could occur if botulinium products were substituted for one another."
Of particular concern: dosage strengths, expressed in arbitrary units, are different among the brands. One source of confusion has been that Botox is given in 10 to 20 units for cosmetic applications but competing products require vastly different numbers of units to achieve similar efficacy (Dysport's dose range, for example, starts at 50 units for cosmetic applications and 250 units for therapeutic indications).
The commercial significance of the botulinum toxin REMS will reach well beyond the specifics of the Botox market. It is both an example to watch to see if REMS can be used to distinguish competing therapies in the marketplace—and a potential case study for how competition among biosimilars could evolve in the US.
Like boxers in a ring, the companies have started circulating competing press releases about how the new risk program benefits one over the other. Allergan is playing the REMS as a cake-walk, asking why physicians with decades of experience with Botox would ever consider switching from such a well-established product, while Ipsen and Medicis argue that the REMS provides a unique opportunity to introduce a new product to the market.
For Allergan, the non-interchangeability focus of the REMS is paramount—reinforcing the Botox brand's dominant position in the market. Following the FDA announcement, Allergan released a lengthy press release saying that it would work closely with the agency to update its labeling for Botox and emphasizing that the product is not interchangeable with other botulinum toxin products. During the company's first quarter earning call on May 1, executives honed in on the differentiation between Botox and competitors. "Commercially, we believe that education about non-interchangeability of botulinum products will cause physicians to carefully consider the adoption of Dysport when they have the practical experience of predictable outcomes with Botox, a highly established brand name," said Allergan Chairman and CEO David Pyott.
Pyott pulled out the laundry list of Botox's commercial advantages: Botox is a first-to-market brand that "is almost second to none in terms of consumer awareness," he said. He also pointed to high patient satisfaction "with the product's performance based on 20 years of use, the quality of the Botox brand, and the price point relative to other higher-priced aesthetic treatments." Those claims put Botox in an enviable marketing position, but Pyott believes that the REMS is an added level of protection and by highlighting safety issues, it reinforces Botox's first-mover advantage.
"There is a huge advantage of first mover," he added, "because physicians learn how to use a product. This is like learning a language." Because the agency-approved program aims to deflect potential users from substituting competing products for Botox, it also eliminates another of Allergan's concerns: that a botulinum toxin biosimilar will reach the market in the near future and be used as a cheaper substitute for Botox.
Simply put, Pyott said, "The cost of switching [from Botox to Dysport or another competitor] just went up." And not only does the non-interchangeability message hit prescribers, "when some consumers are aware of the fact there is a boxed warning for the category, they're going to be even more thoughtful about products they want to try versus ones they have experience with," he added.
Allergan is also working to counter the Dysport launch with new approvals for Botox. Botox, like Dysport, is currently approved for glabellar lines and cervical dystonia, and it also is approved for strabismus, blepharospasm and primary axillary hyperhidrosis. The drug is under review for spasticity, and Pyott indicated that the REMS agreement could help smooth the approval process. Allergan also is planning to file an sBLA in mid-year for use of Botox in chronic migraine. For Dysport, the REMS provides an opportunity to engage prescribers in a conversation about changing practice—and anything that brings change to a market dominated by the competition is an opportunity to make inroads.
The fight isn't a new match-up and the adversaries aren't complete strangers. Dysport has been approved for nearly two decades in Europe—in some countries it has been on the market longer than Botox—and still Botox enjoys an over 80% market share. Dysport's best chance to snatch market share is to gain the attention of new patients, but the companies acknowledge that the recession does not bode well in the near-term for new patient starts. Pricing could be a tangible factor, as payers don't cover aesthetic medications or procedures. Medicis won't disclose its pricing strategy, but some analysts expect it to sell Dysport at a discount to Botox.
Under any circumstances, Dysport is in a tough position, but the REMS gives the new drug an opening: The Dysport sponsors can spin the REMS as a promotional touch point, using the contact FDA is forcing them to have with clinicians about safety issues to explain how their product differs from its competitors.
Medicis also put the FDA announcement in a positive light. "The REMS for Dysport is designed to help prevent medication errors related to the lack of interchangeability of Dysport with other marketed botulinum toxin products, and ensure that the potential benefits of treatment with Dysport outweigh any potential risk of the spread of toxin effect beyond the injection site," the company said in a press release.
"That's not in any way to say that patients who have been treated with Botox should not be using Dysport for their next treatment," Medicis Chairman and CEO Jonah Shacknai told investors during the company's first quarter earnings call May 7. As an added bonus, Shacknai is as well-suited as anyone in knowing how to find a competitive opening in the context of a new regulatory framework. He got his start in pharma as a Capitol Hill aide responsible for health policy and served on the Commission on the Federal Drug Approval Process and the National Council on Drugs, after which he opened a law firm to represent pharmaceutical industry concerns. To say he has a background in the workings of the regulatory process would be an understatement.
Medicis anticipates shipping Dysport for aesthetic use in the US over the next couple of weeks. It is training roughly 100 aesthetic sales specialists on the product, and plans to expand that number gradually.
None of the bluster is last minute: the sponsors had plenty of notice that a REMS was coming. The April 30 announcement was the end of a lengthy investigation into issues with the botulinum toxin products. In February 2008, the FDA issued an "early communication" describing its review of post-marketing cases from the Adverse Event Reporting System database, which tracks drug safety, and from medical literature of pediatric and adult patients diagnosed with botulism following local injection. The agency's final review found eight cases of botulism in pediatric patients, one that resulted in death. In pediatric post-marketing adverse event case reports, the drug was mostly used to treat muscle spasticity in cerebral palsy, a use that has not been approved by the agency.
The majority of the adult post-marketing case reports occurred following use of the drug for the treatment of spasticity (also an unapproved use) or cervical dystonia; no definitive reports were associated with dermatologic use. Although there were several deaths in adults, FDA said it is not possible to attribute them to the botulinum toxin because the patients also suffered from complications of pre-existing conditions.
While Allergan and Medicis certainly have their commercial strategies in place, it's too early to tell how their messages ultimately will resonate in the marketplace—in short, whether the REMS will actually help to drive sales. Nevertheless other pharma companies would do well to take notes on when the companies began organizing around the possibility of a REMS and where their sparring moves land them in the end.
-Lauren Smith
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