Ipsen demonstrates leadership position in neurotoxin research with strong presence at TOXINS 2019

Regulatory News:

Ipsen (Euronext: IPN; ADR: IPSEY) today announced that
abobotulinumtoxinA (Dysport^®) and its recombinant botulinum
toxins pipeline are the subject of 50 posters at the 2019 TOXINS
International Conference. Results are presented from basic science (in
vivo, in vitro, ex vivo, in silico), to
clinical (Phase I to IV) and patients and caregivers surveys. Data
highlights include further differentiation of Dysport^® in the
treatment of spasticity and movement disorders¹, results from
the first in-human study of a recombinant neurotoxin (rBoNT-E), real
life data (ULIS-III) as well as a survey with insights from patients and
caregivers on the burden of spasticity (Carenity).

“Our data at TOXINS 2019 further differentiate Dysport^®
in the treatment of spasticity and other movement disorders, and
demonstrate the headway we are making with our innovative pipeline,
including new recombinant botulinum toxins such as our fast-acting
rBoNT-E,” said Alexandre Lebeaut, Executive Vice President, R&D
and Chief Scientific Officer, Ipsen. “We look forward to many
more years of real and significant progress toward our commitment to
improving people’s lives through innovative and effective treatments and
by transforming the treatment paradigm with tailored approaches.”

With Dysport^® (abobotulinumtoxinA), Ipsen offers a single
product to treat a range of therapeutic indications².
Injected at approved doses, the amount of active neurotoxin in Dysport^®
(data³ published in Toxins, in December 2018) may help to
explain the long-lasting symptomatic relief observed in clinical studies
(based on phase 3 trials^4,5) within a well-characterized
safety and tolerability profile. With a long duration of response,
Dysport^® aims at providing an answer to the unmet need of
patients and their families.

Alexandre Lebeaut added: “We are proud and excited to be
presenting these new data at TOXINS 2019 as we continue to build on more
than 30 years of clinical experience with Dysport^®.
We will continue investing in this unique product through research and
novel programs studies to further explore its potential and address
patients’ unmet needs.”

About TOXINS conference

Held every 2 years, TOXINS is a key event for experts – clinicians and
researchers from academia and industry - in the field of neurotoxins and
especially Botulinum toxins. The international congress will take place
in 16-19 January 2019, in Copenhagen, Denmark. The TOXINS 2019
scientific program will feature presentations on the latest developments
in the basic science and clinical applications of neurotoxins.

About spasticity and cervical dystonia

Spasticity is a condition in which there is an abnormal increase in
muscle tone or stiffness in one or more muscles, which might interfere
with movement. Spasticity is usually caused by damage to nerve pathways
in the brain or spinal cord that control muscle movement, and may occur
in association with cerebral palsy, spinal cord injury, multiple
sclerosis, stroke, and brain or head trauma ⁸.

With a prevalence of 4.98/100,000 in Europe, cervical dystonia is the
most common adult-onset focal dystonia, a movement disorder
characterized by involuntary and sustained muscle spasms⁹.
Also known as spasmodic torticollis, cervical dystonia is an idiopathic
chronic condition in which the neck is twisted or deviated.

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 contractions⁶. 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 experience⁷.

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.”

About Ipsen

Ipsen is a global 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
€1.9 billion in 2017, 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 5,400 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.

Forward Looking Statement

The forward-looking statements, objectives and targets contained herein
are based on the Group’s management strategy, current views and
assumptions. Such statements involve known and unknown risks and
uncertainties that may cause actual results, performance or events to
differ materially from those anticipated herein. All of the above risks
could affect the Group’s future ability to achieve its financial
targets, which were set assuming reasonable macroeconomic conditions
based on the information available today. Use of the words "believes",
"anticipates" and "expects" and similar expressions are intended to
identify forward-looking statements, including the Group’s expectations
regarding future events, including regulatory filings and
determinations. Moreover, the targets described in this document were
prepared without taking into account external growth assumptions and
potential future acquisitions, which may alter these parameters. These
objectives are based on data and assumptions regarded as reasonable by
the Group. These targets depend on conditions or facts likely to happen
in the future, and not exclusively on historical data. Actual results
may depart significantly from these targets given the occurrence of
certain risks and uncertainties, notably the fact that a promising
product in early development phase or clinical trial may end up never
being launched on the market or reaching its commercial targets, notably
for regulatory or competition reasons. The Group must face or might face
competition from generic products that might translate into a loss of
market share. Furthermore, the Research and Development process involves
several stages each of which involves the substantial risk that the
Group may fail to achieve its objectives and be forced to abandon its
efforts with regards to a product in which it has invested significant
sums. Therefore, the Group cannot be certain that favorable results
obtained during pre-clinical trials will be confirmed subsequently
during clinical trials, or that the results of clinical trials will be
sufficient to demonstrate the safe and effective nature of the product
concerned. There can be no guarantees a product will receive the
necessary regulatory approvals or that the product will prove to be
commercially successful. If underlying assumptions prove inaccurate or
risks or uncertainties materialize, actual results may differ materially
from those set forth in the forward-looking statements. Other risks and
uncertainties include but are not limited to, general industry
conditions and competition; general economic factors, including interest
rate and currency exchange rate fluctuations; the impact of
pharmaceutical industry regulation and health care legislation; global
trends toward health care cost containment; technological advances, new
products and patents attained by competitors; challenges inherent in new
product development, including obtaining regulatory approval; the
Group's ability to accurately predict future market conditions;
manufacturing difficulties or delays; financial instability of
international economies and sovereign risk; dependence on the
effectiveness of the Group’s patents and other protections for
innovative products; and the exposure to litigation, including patent
litigation, and/or regulatory actions. The Group also depends on third
parties to develop and market some of its products which could
potentially generate substantial royalties; these partners could behave
in such ways which could cause damage to the Group’s activities and
financial results. The Group cannot be certain that its partners will
fulfil their obligations. It might be unable to obtain any benefit from
those agreements. A default by any of the Group’s partners could
generate lower revenues than expected. Such situations could have a
negative impact on the Group’s business, financial position or
performance. The Group expressly disclaims any obligation or undertaking
to update or revise any forward looking statements, targets or estimates
contained in this press release to reflect any change in events,
conditions, assumptions or circumstances on which any such statements
are based, unless so required by applicable law. The Group’s business is
subject to the risk factors outlined in its registration documents filed
with the French Autorité des Marchés Financiers. The risks and
uncertainties set out are not exhaustive and the reader is advised to
refer to the Group’s 2017 Registration Document available on its website
(www.ipsen.com).

References
1. Field, M. et al. AbobotulinumtoxinA
(Dysport®), OnabotulinumtoxinA (Botox®), and IncobotulinumtoxinA
(Xeomin®) Neurotoxin Content and Potential Implications for Duration of
Response in Patients. Toxins (Basel). 10, 535 (2018).
2.
Ipsen. Dysport SmPC. Electronic Medicines Compendium (2017).
3.
Field, M. et al. AbobotulinumtoxinA (Dysport®),
OnabotulinumtoxinA (Botox®), and IncobotulinumtoxinA (Xeomin®)
Neurotoxin Content and Potential Implications for Duration of Response
in Patients. Toxins (Basel). 1–14 (2018).
doi:10.3390/toxins10120535
4. Gracies, J.-M. et al. Treatment
frequency for long-term efficacy of abobotulinumtoxinA injections : A
phase 3 study in patients with upper limb spasticity following stroke or
traumatic brain injury ISPR8-2543. (2018).
5. Truong, D. et
al. Long-term efficacy and safety of botulinum toxin type A
(Dysport) in cervical dystonia. Parkinsonism Relat. Disord. 16,
316–323 (2010).
6. 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
7. 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).
8. AANS. AANS Website - Spasticity.
9.
Contarino, M. F. et al. Clinical practice: Evidence-based
recommendations for the treatment of cervical dystonia with botulinum
toxin. Front. Neurol. 8, 1–11 (2017).

Abstracts list

I. Dysport^® differentiation

ORAL:
1. Thursday
January 17^th
2019, 17:30 - 18:00
[Poster n° 9.26] AbobotulinumtoxinA
and rehabilitation vs rehabilitation alone in post-stroke spasticity: an
Italian cost-utility analysis (Italy); Lazzaro et al.
Presenting
author: Alessio Baricich (Italy)

POSTERS:
1. [Poster n° 1.16] AbobotulinumtoxinA,
onabutulinumtoxinA and incobotulinumtoxinA neurotoxin content and
activity: potential implications for duration of efficacy in patients;
Field et al.
2. [Poster n° 1.22] AbobotulinumtoxinA (Dysport^®)
shows higher efficacy and longer duration of action in rats with spinal
cord injury-mediated spasticity than in healthy controls; Kalinichev et
al.
3. [Poster n° 3.3] The patients’ perspective on botulinum
neurotoxin A treatment: results of a multinational survey for patients
with spasticity; Bahroo et al.
4. [Poster n° 3.9] Assessment of
upper limb active movement facilitation and neuromuscular plasticity
induced by abobotulinumtoxinA in chronic post-stroke; Chalard et al.
5.
[Poster n° 3.11] Botulinum neurotoxins are used at low doses in the
treatment of spasticity in clinical practice: Results from market
research analysis; de Sainte-Marie et al.
6. [ Poster n° 3.16]
AbobotulinumtoxinA (Dysport^®) improves functional outcomes
after single and repeat dosing in adults and children with spasticity;
Esquenazi et al.
7. [Poster n° 3.22] AbobotulinumtoxinA (Dysport^®),
a long-acting botulinum neurotoxin; Foster et al.
8. [Poster n°
3.51] Management of upper limb spasticity with botulinum toxin A:
Baseline data from the Italian cohort of the upper limb international
spasticity (ULIS)-III Study (Italy); Cosma et al.
9. [Poster n°
3.65] Efficacy of abobotulinumtoxinA for the treatment of hemiparetic
adult patients with lower limb spasticity previously treated with
botulinum toxins; Boyer et al.
10. [Poster n° 3.66] Time to
retreatment with botulinum toxin a in upper limb spasticity management:
upper limb international spasticity (ULIS)-III study interim analysis;
Turner-Stokes et al.
11. [Poster n° 3.68] Fewer injections of
botulinum toxin type A for treatment of spasticity are perceived as
beneficial by both patients and caregivers; Wein et al.
12. [Poster
n° 3.72] First results from the EARLY-BIRD study, a prospective,
non-interventional study to assess effectiveness of abobotulinumtoxinA
(Dysport^®) in post-stroke upper limb spasticity in relation
to timing of treatment (Germany); Wissel et al.
13. [Poster n° 8.1]
Economic benefits of AUL spasticity treatment with Dysport^®
compared to Botox^® or Xeomin^®: Analysis of a
real-life setting in France; Schnitzler et al.
14. [Poster n° 9.10]
AbobotulinumtoxinA time to retreatment across indications; Gracies et al.

II. Leadership in Neurotoxins

ORAL:
1. Thursday
January 17^th
2019, 15:30 – 16:00
[Poster n° 1.14] Botulinum
neurotoxin B engineered for increased receptor affinity has improved
clinical potential; Elliott et al.
Presenting author: Johannes
Krupp (UK)
2. Thursday
January 17^th
2019, 15:30 – 16:00
[Poster n° 1.60] Chimeras of anthrax
toxin and botulinum neurotoxin as novel analgesic proteins; Yang et al.
Presenting
author: Nicole Yang (USA)
3. Thursday
January 17^th
2019, 17:00 – 17:30
[Poster n° 1.7] Mutations in light
chains of botulinum neurotoxin A enable cleavage of human SPAP-23; Binz
et al.
Presenting author: Thomas Binz (Germany)
4.
Friday January 18^th
2019, 15:30 – 16:00
[Poster n° 1.30] Exploring the
effect of various BoNT serotypes in a model of autonomic nervous system
hyperactivity from rodents and humans: paving the way to better
targeting therapeutics in autonomic disorders? Maignel et al.
Presenting
author: Jacquie Maignel (France)
5.
Friday January 18^th
2019, 18:00 – 18:30
[Poster n° 1.42] Development of an
in vitro human neuromuscular junction; Nicoleau et al.
Presenting
author: Camille Nicoleau (France)

POSTERS:
1. [Poster n° 1.2] Building the landscape:
Stability profile of botulinum neurotoxins; Barata et al.
2.
[Poster n° 1.3] Computational tools for the design, characterisation and
optimisation of recombinant botulinum neurotoxins for therapeutic
applications; Barata & Bunting.
3. [Poster n° 1.4] Recombinant
expression and characterisation of a botulinum neurotoxin serotype X
chimera; Beard et al.
4. [Poster n° 1.8] New modified recombinant
botulinum neurotoxin type F with enhanced potency; Burgina et al.
5.
[Poster n° 1.10] Pharmacodynamic characterisation of a new recombinant
serotype E botulinum toxin using electromyography in the monkey; Cornet
et al.
6. [Poster n° 1.12] Potency comparison in in vitro, ex vivo
and in vivo assays of commercially available botulinum neurotoxin
serotypes A1, B1 and F1; Donald et al.
7. [Poster n° 1.17]
Development of a cell-based assay to replace LD50 for botulinum
neurotoxin A1; Fonfria et al.
8. [Poster n° 1.18] Phage assisted
continuous evolution of botulinum neurotoxin light chains generates
novel light chains with modified SNARE cleavage specificity; Foster et
al.
9. [Poster n° 1.27] Engineering fluorescently-labelled
botulinum neurotoxins and derivatives to image their trafficking in
neuronal and non-neuronal cells; Loss and Elliott.
10. [Poster n°
1.33] How to safely manufacture nature’s most potent toxins; Marks.
11.
[Poster n° 1.34] Distribution of botulinum toxin receptors and targets
in different rat tissues; Martin et al.
12. [Poster n° 1.35]
Evaluation of the fate of different fragments of SNAP25 in the injected
muscle with BoNT/A or BoNT/E over a 30-day or a 75-day period in the
rat; Martin et al.
13. [Poster n° 1.41] Assessment of multiple
hiPSC-derived models for botulinum neurotoxin testing; Nicoleau et al.
14.
[Poster n° 1.43] Translational Value of hiSPC-Derived Models for
Botulinum Neurotoxin Research; Nicoleau et al.
15. [Poster n° 1.47]
Outcomes of the first-in-human study with a recombinant botulinum toxin
E (rBoNT-E): safety and pharmacodynamic profile of rBoNT-E compared with
abobotulinumtoxinA (Dysport^®); Pons et al.
16. [Poster
n° 1.53] Comparative Botulinum Neurotoxin Type-A Activity in the EndoPep
Assay – Formulation Effects; van der Schans et al.
17. [Poster n°
1.61] Genome-wide siRNA screen identification of genes in regulation of
BoNT/A trafficking in a sensitized human neuronal stem cell line; Yeo et
al.
18. [Poster n° 9.13] Predictive models using fusion methods to
estimate pharmacodynamic properties of a recombinant botulinum toxin E
in humans; Laugerotte et al.

III. Commitment to patients

POSTERS:
1. [Poster n° 1.6] Results from the INPUT survey:
Training impact on usage of botulinum neurotoxin-A for cervical dystonia
and spastic paresis management; Bhidayasiri et al.
2. [Poster n°
1.15] AbobotulinumtoxinA (Dysport^®) shows efficacy in a model
of MRMT-1-induced cancer pain in the rat; Favre-Guilmard et al [Poster
n° 2.6] How satisfied are cervical dystonia patients after 3 years of
botulinum toxin treatment? Colosimo et al.
3. [Poster n° 2.7]
AbobotulinumtoxinA using 2mL dilution maintains durable functional
improvements across multiple treatment cycles (US); Dashtipour et al.
4.
[Poster n° 2.25] Factors predicting Long-term patient satisfaction with
botulinum toxin treatment in cervical dystonia; Misra et al.
5.
[Poster n° 3.55] Burden of spasticity among patients and caregivers:
results of a multinational survey; Patel et al.
6. [Poster n° 5.2]
Rationale and design for a phase II trial of abobotulinumtoxinA (Dysport^®)
in the management of vulvodynia; Goldstein et al.
7. [Poster n°
6.3] Systematic literature review examining the efficacy of
abobotulinumtoxinA in aesthetic indications; Cohen et al.
8.
[Poster n° 6.5] Dosing of abobotulinumtoxinA for long-term treatment of
glabellar lines: Injection practices from the APPEAL non-interventional
study; Gubanova et al.
9. [Poster n° 6.14] Systematic literature
review examining patient and investigator satisfaction with
abobotulinumtoxinA treatment in aesthetic indications; Redaelli et al.
10.
[Poster n° 9.3] Rationale and design for a Phase II trial of
abobotulinumtoxinA (Dysport^®) in the management of hallux
valgus; Armstrong et al.
11. [Poster n° 9.11] Improvement of
Cervical Dystonia and Spastic Paresis Management: Assessment of 5 Years
of the Innovative International Educational Program Ixcellence Network;
Jacinto et al.

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