Earlier this month, Ipsen’s Dysport (abotulinumtoxinA) was approved for the treatment of lower limb spasticity in pediatric patients over two years old, making it the first, and currently the only, FDA-approved botulinum toxin product for treatment in children with lower limb spasticity associated with cerebral palsy. Ipsen is one of three companies, including Allergan and Merz GmbH, which market botulinum toxin-based injectables for therapeutic and aesthetic uses.
You may be more familiar with the blockbuster wrinkle reducer Botox. While Allergan's Botox is the most widely-known—and successful— each company has attempted to carve out its own niche in specific target markets. Ipsen is hoping that the latest indication for Dysport will set it up to compete with Botox in a more meaningful way.
Privately-held Merz has focused most of its marketing efforts for Xeomin (incobotulinumtoxinA) in Europe. However, Ipsen is expanding beyond its French roots and aggressively expanding its presence in the U.S., while remaining true to its longstanding focus on pediatric therapeutics.
"What we’re most excited about is that we now have an approval for this indication for a population that is underserved and still has tremendous unmet medical needs," says David Cox, Ipsen's VP of medical & regulatory affairs.
The competitive landscape
Allergan and Merz each have an ongoing clinical study evaluating the use of their product in treatment of lower limb spasticty in children with cerebral palsy. Allergan’s Phase 3 study was initiated in July 2012, with an expected completion date of May 2017. Merz’s study, XEMEC, is a comparative study evaluating Xeomin versus Botox in this population. XEMEC is focused on children between the ages of 2 and 12, with a planned completion date of December 2016.
Allergan’s Botox was approved for its first indication in 1989 for an aesthetic application. Since then, the company has racked up numerous therapeutic approvals for Botox, including treatment of migraine, cervical dystonia, upper and lower limb spasticity in adults and overactive bladder (OAB), amongst others.
For the second quarter of 2016, Botox generated roughly $780 million in revenues, including $323 million on the cosmetic side and $381 million on the therapeutic side. Allergan has seen a lot of growth on the therapeutic side mainly in the areas of migraine and OAB, where it continues to focus its marketing efforts.
Merz’s earnings are not disclosed; however, Xeomin has only three FDA approvals, including blepharospasm, cervical dystonia and adult upper limb spasticity.
Last year Ipsen saw global sales of Dysport increase 9.7% to €279.5 million ($315.2 million), driven mainly by performance on the cosmetic side in the Russian, Brazilian, Mexican and Australian markets. However, given the latest approval in the U.S., the company is hoping to see increased sales in the pediatric therapeutic market, allowing it to take on the giant that is Botox.
Spasticity as a defining feature of cerebral palsy
Prevalence estimates vary widely, but in the U.S. about 500,000 children are living with cerebral palsy. According to Cox, roughly 77% of all patients with cerebral palsy have some type of spasticity and require treatment for it. In the case of lower limb spasticity, botulinum toxin treatments are used to reduce muscle tone (which is exaggerated in patients with cerebral palsy), and improve function and gait.
For some time, adults with spasticity have had approved treatment options for spasticity. Botox is approved for upper and lower limb spasticity, and Xeomin is approved for upper limb spasticity—both in adults only. Dysport was approved for treatment of upper limb spasticity in adults in July 2015. However, gaining approval for lower limb spasticity in the pediatric population has been challenging due to dosing issues.
"For this type of medicine, we really wanted to know how long this medicine was going to work, and at which doses. We needed to know when to re-treat, because we want the kids to need as few injections as possible," Cox explained.
These issues were carefully evaluated in Ipsen’s randomized, placebo-controlled clinical trial involving 235 pediatric patients with cerebral palsy and dynamic eqinus foot deformity. In this global study, investigators evaluated the effects of three different doses of Dysport using the Modified Ashworth Scale (MAS) as a primary endpoint, and the Physician’s Global Assessment as a secondary endpoint. In addition, the team used the Tardieu scale, which assesses changes in range of motion. The study was published in Pediatrics in January.
After four weeks, there were statistically significant improvements across the board, with a high level of tolerability and significantly improved function. The researchers also determined that pediatric patients treated with the doses studied would not need to be re-treated for 16 to 22 weeks.
"This is the largest study of its kind, and it’s a landmark study," Cox said. "We were able to validate dosing in a pediatric population in the context of a Phase 3, registration-quality study."
Potential dangers of off-label use in children
While off-label use in this population hasn't been uncommon, it poses its own set of risks. Instead of definitive evidence, physicians have often relied on experience and available guidance to determine how much to dose. Dosing in this population can be especially challenging because of children’s low weight, combined with the fact that treating spasticity requires much higher dosing than using botulinum toxin for getting rid of wrinkles.
The medical literature is full of case studies showing that Botox injections have helped children with cerebral palsy walk for the first time and function in a way that their parents never thought possible. However, there are also numerous reports of children who have been overdosed with botulinum toxin, including a seven-year-old girl from Texas, whose parents attributed her death from respiratory failure in 2007 to Botox after she received a series of injections to treat lower-limb spasticity.
Ipsen is hoping to change this trend with its first-to-market treatment.
Keeping these warnings and tragedies in mind, Ipsen is putting a strong focus on the patients. "Now that we have completed this landmark trial and been approved for this indication, we can partner with the community. We can also communicate clearly with medical professionals and payers, and provide education," said Cox.