Results presented at the International Congress
of Parkinson’s Disease and Movement Disorders (MDS) in Nice,
France, 22-26 September 2019
Regulatory News:
Ipsen (Euronext: IPN; ADR: IPSEY)
today announced first results from the ENGAGE study which reports
that simultaneous treatment with Dysport of both upper and lower
limb spasticity in adult patients along with a Guided
Self-rehabilitation Contract (GSC) – a personalized diary-based
rehabilitation program – improved patients’ voluntary movement as
measured by a composite active range of motion (CXA) outcome.1
Results from the study will be presented at the MDS International
Congress in Nice, France, September 22-26, 2019 as poster #13705
and poster #13711.
ENGAGE is the first study to investigate treatment with Dysport
in patients with spastic hemiparesis in both upper and lower limbs
in combination with GSC. The primary efficacy endpoint of this
international, prospective, single-arm study was the percentage of
patients classified as responders at week six after the second
injection, according to the CXA in the primary treatment target
(PTT) limb.1
Professor Jean-Michel Gracies, Professor and Chair in the
Department of Neurorehabilitation at Hospital Henri Mondor, in
Créteil, France, and the primary investigator for ENGAGE said:
“This study provides insight into treatment strategies that can
improve the outcomes of patients living with spastic paresis,
specifically the role of Guided Self-rehabilitation Contracts
combined with Dysport for the improvement of voluntary movement, an
area of limited data availability. Importantly, stronger active
motion improvements and a longer time to reinjection was seen in
ENGAGE versus previous Dysport studies, which suggests a
synergistic effect of adding a GSC intervention to treatment with
Dysport for patients with UL and LL spasticity.”
Patients in the study received two open-label injection cycles
of Dysport, together with personalized GSC. A total dose of 1,500 U
Dysport was administered across the primary treatment target (PTT)
and non-PTT limbs at each injection cycle. Dosing was determined by
the investigators, providing ≥750 U was administered to the PTT
limb. Results from the study show that 72.1% (98/136; 95% CI: 64.0,
78.9) of patients in the study were classified as responders,
achieving the predefined CXA improvement threshold in the PTT limb
of ≥35° in upper limbs (UL) or ≥5° in the lower limbs (LL).1 These
favorable outcomes were corroborated by the time to reinjection.
Investigators could re-inject Dysport per their clinical judgment.
Mean time to reinjection was 110.1 days (standard deviation: 25.2
days) and median time to reinjection was 106.5 days (range: 78–157
days).1 The time to reinjection recorded in ENGAGE was longer
compared with previous studies in UL and LL which did not include
GSC.1,2,3,4 Safety data were consistent with the known profile of
abobotulinumtoxinA.1
Systemic standardized rehabilitation protocols are not commonly
used in the majority of abobotulinumtoxinA spasticity studies.
Similarly, pivotal studies of Dysport in these patients have
focused on either UL or LL treatment strategies and outcomes;2,3
however, in real-life clinical practice patients can present with
spasticity simultaneously in both the UL and LL.
Importantly, and in contrast to previous pivotal studies of
Dysport, ENGAGE also provided insight into healthcare
professionals’ real-world muscle selection for the administration
of Dysport as it allowed investigators the flexibility of choosing
varied muscle groups in the primary target limb. Prior
pivotal/phase 3 adult UL and LL studies have all previously defined
the target muscle group as elbow, wrist or finger flexors (UL) and
gastrocnemius complex (LL) for primary endpoint.2,3
In ENGAGE, each patient received a personalized GSC tailored to
their individual needs and focused on their PTT limb.1 Patients
were asked to carry out the exercises detailed in the GSC – with a
minimum cumulative 10 minutes of submaximal self-stretch postures
per muscle – on a daily basis throughout the study. Patients kept a
diary of each of the exercises performed and were contacted via
telephone every two weeks to check how the GSC therapy was being
performed and to ensure the diary was being filled out every
day.
Antony Fulford-Smith, Vice President Medical Affairs,
Neurosciences, R&D, at Ipsen said: “Over the last two decades
there has been a shift from patients being recipients of healthcare
to active participants empowered in their own health journey.
Through ENGAGE, we have been able to demonstrate for the first time
the benefit of combining treatment with Dysport with a systematic
rehabilitation protocol, validating the positive impact of
encouraging patients to take an active role in their own treatment.
At Ipsen, we are constantly searching for ways to improve disease
management and comprehensive care with a patient-centred approach.
By using active range of motion as its primary measure, ENGAGE
offers important insights on the potential benefit of using Dysport
with GSC combination therapy in the context of meaningful
functional outcomes for patients.”
About ENGAGE1
ENGAGE is a Phase IIIb/IV (depending on country) international,
prospective, single-arm study designed to assess the influence of
abobotulinumtoxinA (1500 U) administered with GSC on voluntary
movements in the UL and LL in adults with spastic hemiparesis.
A total of 160 patients from the Czech Republic, France, the
Russian Federation and the USA were enrolled in the study; the
majority of patients in the study were male and stroke was the
leading cause of acquired brain injury (ABI).
Patients received 2 open-label injection cycles of aboBoNT-A,
together with personalized GSC. Cycles were 12–20 weeks apart
(maximum study duration of 40 weeks). Recruitment was stratified by
country to ensure a 50% (±10%) split of patients with UL or LL as
PTT. A total dose of 1,500 U aboBoNT-A was administered across PTT
and non-PTT limbs at each injection cycle. Dosing was determined by
the investigators, providing ≥750 U was administered to the PTT
limb.
The primary efficacy endpoint was the percentage of patients
classified as responders at Week 6 after the second injection,
according to the CXA, measured by goniometer, in the PTT limb.
Response was defined as an improvement in composite active range of
motion (CXA) of ≥35° or 5° in UL or LL, respectively. CXA of the UL
was calculated as the sum of XA values for elbow flexors, wrist
flexors and extrinsic finger flexors. CXA of the LL was calculated
as the sum of XA values for the soleus and gastrocnemius
muscles.
In the intention-to-treat (ITT) population, overall median (95%
CI) time to first response was 47.0 days (44.0, 62.0), with a
median (95% CI) time to first response in the upper limb (UL) of
54.5 days (44.0, 89.0), and 46.0 days (43.0, 50.0) in the lower
limb (LL). Overall responder rates were 62.0% (95% CI: 50.3, 72.4)
in the UL and 83.1% (95% CI: 72.0, 90.5) in the LL in the modified
ITT population. Responder rates were higher in patients who were
naïve to BoNT for spasticity (78.4%; 95% CI: 62.6, 88.9; N=37)
compared with those who were non-naïve (69.7%; 95% CI: 60.0, 77.9;
N=99). Patients who were naïve to GSC had a lower response rate
(68.7%; 95% CI: 59.0, 77.0; N=99) compared with those who were
non-naïve to GSC (80.6%; 95% CI: 64.7, 90.6; N=36).
About spasticity
Spasticity affects more than an estimated 12 million people
worldwide.6 It is a condition in which certain muscles are
continuously contracted causing stiffness or tightness of the
muscles which can interfere with normal movement, speech and gait.6
Spasticity is usually caused by damage to the portion of the brain
or spinal cord that controls voluntary movement. The damage causes
a change in the balance of signals between the nervous system and
the muscles which leads to increased activity in the muscles.6
There are many causes of spasticity including spinal cord injury,
multiple sclerosis, cerebral palsy, stroke, brain or head trauma
and metabolic diseases.7 Spasticity, is experienced by 34% of
stroke survivors within 18 months following a stroke.8
About Dysport®
Dysport® is an injectable form of a botulinum neurotoxin type A
product, which is a substance derived from Clostridium bacteria
producing BoNT-A that inhibits the effective transmission of nerve
impulses and thereby reduces muscular contractions9. It is supplied
as a lyophilized powder. As of 31 December 2018, Dysport® had
marketing authorization in more than 85 countries and more than 30
years of clinical experience10.
NOTE: Dysport® labels and approved indications may vary from
country to country
INDICATIONS AND IMPORTANT SAFETY INFORMATION
Dysport® is approved for the treatment of adult upper and lower
limb spasticity, paediatric lower limb spasticity and cervical
dystonia (referred to spasmodic torticollis in some markets) in
many international markets. Please refer to national labelling for
details of the locally approved prescribing information in each of
these indications.
Adverse effects resulting from the distribution of the effects
of the toxin to sites remote from the site of administration have
been reported. Patients treated with therapeutic doses may present
with excessive muscle weakness. The risk of occurrence of such
undesirable effects may be reduced by using the lowest effective
dose possible and by not exceeding the maximum recommended dose.
Very rare cases of death, occasionally in the context of dysphagia,
pneumopathy (including but not limited to dyspnoea, respiratory
failure, respiratory arrest) and/or in patients with significant
asthenia have been reported following treatment with botulinum
toxin A or B. Patients with disorders resulting in defective
neuromuscular transmission, difficulty in swallowing or breathing
are more at risk of experiencing these effects. In these patients,
treatment must be administered under the control of a specialist
and only if the benefit of treatment outweighs the risk. Dysport®
should be administered with caution to patients with pre-existing
swallowing or breathing problems as these can worsen following the
distribution of the effect of toxin into the relevant muscles.
Aspiration has occurred in rare cases and is a risk when treating
patients who have a chronic respiratory disorder. Dysport® should
only be used with caution and under close medical supervision in
patients with clinical or sub-clinical evidence of marked defective
neuro-muscular transmission (e.g. myasthenia gravis). Such patients
may have an increased sensitivity to agents such as Dysport®, which
may result in excessive muscle weakness. Caution should be
exercised when treating adult patients, especially the elderly,
with focal spasticity affecting the lower limbs, who may be at
increased risk of fall. In placebo controlled clinical studies
where patients were treated for lower limb spasticity, 6.3% and
3.7% of patients experienced a fall in the Dysport® and placebo
groups, respectively. The recommended posology and frequency of
administration for Dysport® must not be exceeded. Patients and
their care-givers must be warned of the necessity to seek immediate
medical treatment in case of problems with swallowing, speech or
respiratory problems. For the treatment of spasticity in children,
Dysport® should only be used in children 2 years of age or over. As
with any intramuscular injection, Dysport® should only be used
where strictly necessary in patients with prolonged bleeding times,
or infection/inflammation at the proposed site(s) of injection.
Dysport® should only be used to treat a single patient, during a
single session. Any unused product remaining should be disposed of
in accordance with Special Precautions for Disposal and Handling.
Specific precautions must be taken during the preparation and
administration of the product and the inactivation and disposal of
any unused reconstituted solution. This product contains a small
amount of human albumin. The risk of transmission of viral
infection cannot be excluded with absolute certainty following the
use of human blood or blood products.”
For full prescribing information, see SmPC for Dysport (300
units) Powder and Dysport (500 units) Powder.
About Ipsen
Ipsen is a global specialty-driven biopharmaceutical group
focused on innovation and specialty care. The group develops and
commercializes innovative medicines in three key therapeutic areas
– Oncology, Neuroscience and Rare Diseases. Its commitment to
Oncology is exemplified through its growing portfolio of key
therapies for prostate cancer, neuroendocrine tumors, renal cell
carcinoma and pancreatic cancer. Ipsen also has a well-established
Consumer Healthcare business. With total sales over €2.2 billion in
2018, Ipsen sells more than 20 drugs in over 115 countries, with a
direct commercial presence in more than 30 countries. Ipsen’s
R&D is focused on its innovative and differentiated
technological platforms located in the heart of the leading
biotechnological and life sciences hubs (Paris-Saclay, France;
Oxford, UK; Cambridge, US). The Group has about 5,700 employees
worldwide. Ipsen is listed in Paris (Euronext: IPN) and in the
United States through a Sponsored Level I American Depositary
Receipt program (ADR: IPSEY). For more information on Ipsen, visit
www.ipsen.com.
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1 Gracies, J.M., et al. Concomitant treatment of spastic paresis
in both upper and lower limbs with abobotulinumtoxinA combined with
a prescribed guided self-rehabilitation contract; effect on active
range of motion from the single-arm open-label ENGAGE study. Poster
presented at International Congress of Parkinson’s Disease and
Movement Disorders (MDS) 2019. Poster #1371.
2 Gracies, J.M., et al. Efficacy and safety of
abobotulinumtoxinA in spastic lower limb: Randomized trial and
extension. Neurology 2017;89(22):2245-53. Available at:
https://n.neurology.org/content/89/22/2245.long. Accessed July
2019.
3 Gracies, J.M., et al. Effects of repeated abobotulinumtoxinA
injections in upper limb spasticity. Muscle Nerve
2018;57(2):245–54. Available at:
https://onlinelibrary.wiley.com/doi/full/10.1002/mus.25721.
Accessed July 2019.
4 Gracies, J.M., et al. Safety and efficacy of
abobotulinumtoxinA for hemiparesis in adults with upper limb
spasticity after stroke or traumatic brain injury: a double-blind
randomized controlled trial. Lancet Neurol. 2015;14(10):992-1001.
Available at:
https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(15)00216-1/fulltext.
Accessed July 2019.
5 Gracies, J.M., et al. Guided Self-rehabilitation Contracts
combined with simultaneous injections of abobotulinumtoxinA into
upper and lower limbs in spastic hemiparesis: baseline data from
the ENGAGE study. Poster presented at International Congress of
Parkinson’s Disease and Movement Disorders (MDS) 2019. Poster
#1370.
6 American Association of Neurological Surgeons. Spasticity.
Available at:
https://www.aans.org/Patients/Neurosurgical-Conditions-and-Treatments/Spasticity.
Accessed July 2019.
7 National Institute of Neurological Disorders and Stroke.
Spasticity Information Page. Available at:
https://www.ninds.nih.gov/disorders/all-disorders/spasticity-information-page.
Accessed July 2019.
8 Chih-Lin Kuo, C.-H., Hu, G.-C. Post-stroke Spasticity: A
Review of Epidemiology, Pathophysiology, and Treatments. Int. J.
Gerontol. 2018;12(4):280-284. Available at:
https://www.sciencedirect.com/science/article/pii/S1873959818300073.
Accessed July 2019.
9. 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
10. Jitpimolmard, S., Tiamkao, S. & Laopaiboon, M. 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).
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Christian Marcoux, M.Sc. SVP, Global Communications +33 (0) 1 58
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Investor Relations Manager +33 (0)1 58 33 51 04
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