Making it the first and only botulinum toxin in the UK to be approved for the treatment of paediatric spasticity in both upper and lower limbs
The first botulinum toxin approval in paediatric upper limb spasticity in Europe in over a decade
6 January 2020 — Ipsen (Euronext: IPN; ADR: IPSEY) today announced that the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) has granted a licence update for Dysport® for the symptomatic treatment of focal spasticity of upper limbs in paediatric cerebral palsy (CP) patients, two years of age or older.
Spasticity in children is most commonly associated with CP.[i] Approximately 17 million people worldwide are diagnosed with CP,[ii] with an estimated 1 in 400 babies born with cerebral palsy in the UK,[iii] 75-91% of whom will have a specific type known as spastic CP.[iv] For these children, spasticity affects movement and motor skills, hindering their ability to move in a coordinated and purposeful way, which can consequently impact on their ability to participate in everyday activities.1,2
“Therapeutic options such as botulinum toxin type A are an important part of the multidisciplinary approach for treating spasticity,” said Alison Smith, Consultant Paediatric Neuro-physiotherapist, NPP Neuro Group, UK, “they work by interrupting the muscle contraction and thereby reducing stiffness related to spasticity helping children with cerebral palsy to not only improve physical functioning but also achieve their goals which can improve their mental and emotional wellbeing. Having a therapeutic option approved for both upper and lower limb indications creates a real benefit for the patient as it allows a holistic treatment approach for any patients with multi-focal spasticity.”
This approval was based on the Phase III study demonstrating that Dysport® reduced spasticity symptoms in children aged two years and older being treated for upper limb spasticity due to CP, as measured by the Modified Ashworth Scale (MAS), which is the standard scale for assessing muscle resistance associated with spasticity.[v],6 The safety profile was consistent with that seen in the approved indications for paediatric CP lower limb spasticity after repeated injections and no new safety concerns were identified.[vi]
Asad Mohsin Ali, UK & Ireland General Manager, Ipsen said “Today’s approval is an important advancement for children in the UK living with cerebral palsy, who can now benefit from long-lasting symptom relief between their botulinum toxin A injections. As a father myself, I am proud that Ipsen is the first company in the UK to have obtained this approval that may help children lead as normal a life as possible.”
Effective treatment of spasticity requires a highly specialised, multidisciplinary approach including physiotherapy and occupational therapy to reduce overactivity and the risk of permanent muscle shortening, thus promoting functional activity and helping to allow the child to participate in their daily activities.[vii]
For further information, please contact:
Lydia Jenkins, Communications Manager UK & Ireland, Ipsen
T: +44 7736 616028
Sophie Cremin, 90TEN
T: +44 7732 692815
About Paediatric Cerebral Palsy Spasticity
Spasticity is abnormal and involuntary muscle stiffness, or overactivity (contractions) in a group of muscles,[viii] which causes them to have increased tone, leading to stiffness or tightness.[ix] Cerebral palsy (CP) is the leading cause of childhood disability affecting function and development, and the most frequent cause of spasticity in children.1 Approximately 17 million people worldwide are diagnosed with CP,2 with an estimated 1 in 400 babies born in the UK have a type of CP,3 approximately 75-91% of whom will develop spastic cerebral palsy.4
Upper limb spasticity in children is a condition that causes muscle spasms in the elbow, wrist, and finger muscles.[x] Lower limb spasticity is a condition that causes increased muscle stiffness in the calf, which can prevent the ankle from flexing as needed and causes the foot to be pointed down and in.[xi] Upper limb is the most common form of spasticity and is a significant source of disability particularly in children where impaired muscle growth can lead to abnormal posturing and deformities causing pain and difficulties performing daily tasks such as washing.[xii],[xiii]
About the Phase III Pivotal Study
Dysport® was evaluated in a Phase III, randomised, double-blind, low-dose controlled, multicentre study that included a total of 210 children treated, aged two to 17 years, for upper limb spasticity.14 Patients with a MAS of Grade 2 or greater at the primary targeted muscle groups (PTMG) were enrolled and received doses of Dysport® at 8 Units/kg (n=70), 16 Units/kg (n=70) or 2 Units/kg (n=70) injected into the PTMG (elbow flexors: brachialis and brachioradialis or wrist flexors: flexor carpi radialis, and flexor carpi ulnaris).[xiv],[xv] After the initial treatment, up to three further treatments of Dysport® could be administered at planned doses of either 8 Units/kg or 16 Units/kg, or titrated up or down according to investigator judgement.15 Primary endpoint was mean change in MAS score from baseline to week 6 in Primary Targeted Muscle Group (elbow flexors or wrist flexors); secondary endpoints were mean Physician Global Assessment (PGA) score and Goal Attainment Scale (GAS) score at week 6.15 Spasticity improvements were also assessed using the Tardieu scale as a tertiary endpoint.15 Safety assessments were also carried out.6
Dysport® showed statistically significant improvements from baseline in MAS in the PTMG at Week 6, the primary endpoint, with doses of 8 Units/kg and 16 Units/kg compared to low dose Dysport® (2 Units/kg) (-2.0, -2.3 and -1.6, respectively).6 A total of 208 patients were included in this assessment as part of the modified intent to treat (mITT) population.6 Dysport® 16 Units/kg received a mean +2.0 Physician Global Assessment (PGA) score, though there was no statistically significant difference in mean PGA (2.0, 2.0 and 1.8, respectively) or mean Goal Attainment Scale (GAS) (52.6, 52.6 and 52.1, respectively between groups).6 The majority of subjects treated with Dysport were retreated by Week 28 (62.3% in the Dysport 8 U/kg group and 61.4% in the Dysport 16 U/kg group), though more than 24% of subjects in both treatment groups had not yet required retreatment by Week 34.6 The safety assessments, which were also carried out, found that the safety profile was consistent with that seen in the approved indications for paediatric CP lower limb spasticity after repeated injections and no new safety concerns were identified.6
About Dysport®
A copy of the summary of product characteristics for Dysport® can be found at: https://www.medicines.org.uk/emc/product/7261/smpc
Dysport® is an injectable botulinum neurotoxin type A (BoNT-A), which is a substance derived from Clostridium bacteria that inhibits the effective transmission of nerve impulses and thereby reduces muscular contractions.[xvi] It is supplied as a lyophilised powder.
Dysport® was first approved in the UK in 1990 for the treatment of blepharospasm and hemifacial spasm and is licenced in more than 85 countries for various therapeutic indication.[xvii]
Dysport® is indicated for symptomatic treatment of focal spasticity of:6
- Upper limbs in adults
- Lower limbs in adults affecting the ankle joint due to stroke or traumatic brain injury (TBI)
- Dynamic equinus foot deformity in ambulant paediatric cerebral palsy patients, two years of age or older
- Upper limbs in paediatric cerebral palsy patients, two years of age or older
Dysport® is indicated in adults for symptomatic treatment of:6
- Spasmodic torticollis
- Blepharospasm
- Hemifacial spasm
- Severe primary hyperhidrosis of the axillae, which does not respond to topical treatment with antiperspirants or antihidrotics
Dysport® should only be administered by appropriately trained physicians. For the treatment of focal spasticity, Dysport® can also be administered by healthcare professionals having received appropriate training and qualification in accordance with national guidelines (e.g. Royal College of Physicians).[xviii]
Ipsen co-developed Dysport® in partnership with the UK Government bodies, specifically the Centre for Applied Microbiology and Research[xix] and provides continued value through a quarterly royalty to Public Health England which totalled more than £30m in 2018.[xx]
Ipsen in the UK
Our team in the UK is a core part of Ipsen’s global biopharmaceutical business and are driven by the belief that patients don’t have time to wait. We have a biotech mindset coupled with pharmaceutical capabilities and have invested in a robust business presence in the UK that spans the early stages of R&D (Abingdon, Oxford) through to in-house manufacturing (Wrexham, Wales) so we can effectively deliver on our promise to UK patients. As part of this investment in the heart of UK life sciences, we employ over 800 people across our three UK sites, including our commercial headquarters in Bath Road, Slough.
Our business focuses on oncology, neurosciences and rare diseases, to create innovative therapies in areas of high unmet medical need. In the UK we already provide treatments for a range of conditions, including renal cell carcinoma and neuroendocrine tumours, where there are limited treatment options available for patients. In addition to the eight treatments we have already made available to patients in the UK, our team is continuing to research, develop and commercialise new assets to urgently address the needs of patients who are still waiting.
[1] Shamsoddini, Alireza et al. Management of spasticity in children with cerebral palsy. Iran J Pediatr. 2014; 24(4) 345-51.
[2] Cerebral Palsy Foundation. Key Facts. Available at: https://www.yourcpf.org/statistics/. Last accessed: January 2020.
[3] CerebralPalsy.org.uk. We support people who are affected by Cerebral Palsy. Available at: https://www.cerebralpalsy.org.uk/ Last accessed: January 2020.
[4] Cerebral Palsy Sport. Key facts and statistics. Available at: http://www.cpsport.org/resources/cerebral-palsy-key-facts-and-statistics/. Last accessed: January 2020.
[5] Craven, B., Morris, A. Modified Ashworth scale reliability for measurement of lower extremity spasticity among patients with SCI. Spinal Cord. 2010; 48: 207–213.
[6] SmPC Dysport 500 Units. 175.1_DYS500_UK.
[7] Hoare, B. Rationale for using botulinum toxin A as an adjunct to upper limb rehabilitation in children with cerebral palsy.
J Child Neurol. 2014; 29(8):1066-76.
[8] The Hillingdon hospitals NHS Foundation Trust. Patient information leaflet. Spasticity and its management. Available at: https://www.thh.nhs.uk/documents/_Patients/PatientLeaflets/Alderbourne/Spasticity_and_its_management.pdf. Last accessed: January 2020.
[9] Physical effects of stroke. Stroke Association. Available at: www.stroke.org.uk. Last accessed: January 2020.
[10] Lynn Bar-On., et al. Spasticity and Its Contribution to Hypertonia in Cerebral Palsy. Biomed Res Int. 2015; 317-47
[11] Pirazzini, M., Rossetto, O., Eleopra, R. & Montecucco, C. Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology
Pharmacol. Rev. 200–235 (2017). doi:10.1124/pr.116.012658
[12] Santos CA et al. Upper limb function evaluation scales for individuals with cerebral palsy: a systematic review. J Phys Ther Sci 2015; 27(5): 1617-20.
[13] Colver A, Fairhurst C and Pharoah PO. Cerebral palsy. Lancet 2014; 383(9924): 1240-9.
[14] Data on File. DYS-UK-003853. Last accessed: January 2020.
[15] Data on File. DYS-UK-003847. Last accessed: January 2020.
[16] Jitpimolmard S., et al. Long term results of botulinum toxin type A (Dysport) in the treatment of hemifacial spasm: a report of 175 cases. J Neurol Neurosurg Psychiatry 1998;64(6):751-757.
[17] Ipsen. Our Science: Neuroscience. Available at: https://d1bml1vmyeu9v2.cloudfront.net/our-science/neuroscience/. Last accessed: January 2020.
[18] Spasticity in adults: management using botulinum toxin. National guidelines 2018. Royal College of Physicians. Available at: https://www.rcplondon.ac.uk/guidelines-policy/spasticity-adults-management-using-botulinum-toxin. Last accessed: January 2020.
[19] Erbguth FJ., From poison to remedy: The chequered history of botulinum toxin. J Neural Transm 2007;115: 559-65
[20] Data on File. DYS-UK-003296. Last accessed: January 2020.
