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The Allergan product was granted Priority Review for upper limb spasticity and is expected to be decided on in the second quarter of 2019, while the lower limb indication will have its evaluation by the fourth quarter.
C. David Nicholson, PhD
The FDA has accepted supplemental Biologics License Applications (sBLA) for onabotulinumtoxinA (Botox, Allergan) for the treatment of pediatric patients aged 2 years and older with upper and lower limb spasticity.1
The sBLAs are supported by data from 4 phase 3 studies—one in upper limb and one in lower limb compared to placebo (upper, NCT01603602; lower, NCT01603641), and one each in open-label fashion (upper, NCT01603615; lower, NCT01603641)—evaluating the safety and efficacy of onabotulinumtoxinA in more than 600 pediatric patients with spasticity.
The upper limb spasticity indication application has been granted a Priority Review designation and will be assigned a Prescription Drug User Fee Act (PDUFA) action date for the second quarter of 2019, while the lower limb indication will undergo the standard 10-month review process and claim an action date in the fourth quarter of 2019.
"The FDA's acceptance of Allergan's supplemental biologics license applications is a monumental milestone on our journey to bring new treatment options to pediatric patients with upper and lower limb spasticity," said C. David Nicholson, PhD, the Chief Research and Development Officer at Allergan. "Botox has been used in a variety of therapeutic areas for the past 30 years since FDA approval of blepharospasm and strabismus, and we remain steadfast in our commitment to investing in research that explores the potential benefits of Botox in treating patients across an array of therapeutic areas."
While the data from the 4 phase 3 trials has yet to be shared by Allergan, there is evidence of botulinum toxin formulations showing efficacy in treating spasticity. Currently, abobotulinumtoxinA (Dysport, Ispen) is the only FDA-approved therapy for the treatment of lower limb spasticity in pediatric patients. Upper limb spasticity in these patients lacks an approved therapy.
A 2016 review in Seminars in Plastic Surgery by Aloysia L. Schwabe, MD, noted that “there is an abundance of research supporting clinical effectiveness” of botulinum neurotoxin formulations in pediatric patients with spasticity notwithstanding the lack of labeling for the population.2 Notably though, in her review, Schwabe pointed out that while these medicines share similar mechanisms of action, they lack bioequivalence and have differing adverse event (AEs) profiles.
“With a diverse patient population with differing clinical presentations, identifying who benefits most from various interventions at specific times of development is of utmost importance,” she wrote.
In a 2006 etrospective chart review in the Journal of Child Neurology by Edward M. Goldstein, MD, it was found that high-dose administration (≥ 15 U/kg or ≥800 U total) of onabotulinumtoxinA is a safe treatment for children with spasticity. In reviewing 94 children (mean dose, 34.1 U or 19.1 U/kg) and 14 young adults (mean dose, 927.3 U or 15.2 U/kg) who received a total of 119 injections over a 2-year period, AEs were reported by only 2.8% (n = 3) of patients and included single instances of rash and enuresis. One 13-year-old patient reported a single serious AE, a mild case of generalized botulism. That patient had been dosed with 23 U/kg onabotulinumtoxinA.3
The most common cause of focal spasticity in pediatric patients is cerebral palsy, occurring in an estimated 2.5 per 1,000 live births globally. Almost every patient with cerebral palsy has impaired motor function, while spasticity affects up to 91% of patients.
"Pediatric spasticity is a significant concern and can negatively impact a child's development and quality of life, interfering with everyday activities such as walking, dressing and playing," said Heakyung Kim, M.D., Pediatric Rehabilitation Medicine at Columbia University Medical Center/New York Presbyterian Hospital. "Spasticity management in pediatrics is critical while children are growing and adaptable. Considering the negative effects of long-term spasticity, it is important to provide continuum of care throughout childhood into adulthood. The positive results for Botox for the treatment of pediatric upper and lower limb spasticity are promising as we look to address unmet and ongoing needs in children and adolescents."
1. FDA Accepts Supplemental Biologics License Applications (sBLAs) for BOTOX® (onabotulinumtoxinA) for Pediatric Patients with Upper and Lower Limb Spasticity [press release]. Dublin, Ireland: Allergan; Published March 7, 2019. prnewswire.com/news-releases/fda-accepts-supplemental-biologics-license-applications-sblas-for-botox-onabotulinumtoxina-for-pediatric-patients-with-upper-and-lower-limb-spasticity-300807192.html. Accessed March 7, 2019.
2. Schwabe AL. Botulinum toxin in the treatment of pediatric upper limb spasticity. Semin Plast Surg. 2016;30(1):24-28. doi: 10.1055/s-0036-1571302.
3. Goldstein E M. Safety of high-dose botulinum toxin type A therapy for the treatment of pediatric spasticity. J Child Neurol. 2006;21(3):189-192. doi: 10.2310/7010.2006.00041.