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** FINTEPLA^=C2=AE=E2=96=BC (fenfluramine) oral solution recommended for ap=
proval in the EU for adjunctive treatment of seizures associated with Lenno=
x-Gastaut syndrome (LGS)
------------------------------------------------------------
=C2=B7 Recommendation based on Phase 3 study data demonstrating safety and =
efficacy in the most difficult to treat seizure types, including drop seizu=
res^1,2=C2=A0 =C2=A0
=C2=B7 LGS is a rare severe form of epilepsy that typically starts during c=
hildhood and persists into adulthood. It is characterized by multiple types=
of drug-resistant seizures with high morbidity^3,4=C2=A0 as well as seriou=
s impairment of neurodevelopmental, cognitive, and motor functions^4
Brussels, Belgium =E2=80=93 19 December 2022 =E2=80=93 07:00 AM CET=E2=80=
=93 UCB, a global biopharmaceutical company, today announced that FINTEPLA^=
=C2=AE=E2=96=BC (fenfluramine) oral solution has been recommended for marke=
ting authorization in the European Union (EU) for the treatment of seizures=
associated with Lennox-Gastaut syndrome (LGS) as an add-on therapy to othe=
r anti-epileptic medicines for patients 2 years of age and older. Fenfluram=
ine is already approved in the US for the treatment of seizures associated =
with Lennox- Gastaut syndrome. In addition, it is also approved for the tre=
atment of seizures associated with Dravet syndrome in the EU*, US, and Japa=
n.^5,6,7
The Committee for Medicinal Products for Human Use (CHMP) of the European M=
edicines Agency based its positive opinion on safety and efficacy data from=
a global, randomized, placebo-controlled Phase 3 clinical trial, in 263 pa=
tients with LGS (aged 2-35 years), that demonstrated adjunctive fenfluramin=
e at a dose of 0.7/mg/kg/day, provided a significantly greater reduction in=
the frequency of drop seizures (p=3D0.001) compared to placebo.^1 The most=
common treatment-emergent adverse events were decreased appetite, somnolen=
ce, fatigue and pyrexia.1 No cases of valvular heart disease or pulmonary a=
rterial hypertension were observed.^1
The CHMP=E2=80=99s positive opinion on fenfluramine will be referred to the=
European Commission (EC), which will deliver a final decision in Q1 2023.=
=C2=A0
=E2=80=9CThis positive CHMP opinion is a significant regulatory milestone t=
owards providing a new treatment option to individuals =E2=80=93 and their =
families =E2=80=93 living with this rare epilepsy in the EU,=E2=80=9D said =
Mike Davis, Head of Global Epilepsy & Rare Syndromes, UCB. =E2=80=9CWe=E2=
=80=99re delighted by this recommendation, highlighting our ongoing commitm=
ent to the LGS community by ensuring we bring differentiated medicines to t=
hose with unmet needs.=E2=80=9D
Additional data supporting the safety and efficacy of fenfluramine in LGS i=
n the open label extension (OLE) part of the study was recently published i=
n Epilepsia showing fenfluramine, when added to a patient=E2=80=99s current=
anti-epileptic treatment regimen for seizures associated with LGS, was eff=
ective in reducing the frequency of multiple seizure types and was generall=
y well tolerated during a median treatment duration of 364 days.^2 Study pa=
rticipants experienced a sustained reduction in the frequency of motor seiz=
ures including those that resulted in a drop or fall (Generalized Tonic-Clo=
nic Seizures (GTCS), secondary GTCS (SGTC; focal to bilateral tonic-clonic)=
, tonic seizures, atonic seizures, and tonic-atonic seizures).^2 In the OLE=
phase, the most common treatment-emergent adverse events were decreased ap=
petite, fatigue, nasopharyngitis and seizure. The cardiovascular safety in =
this study further corroborates the fenfluramine safety profiles observed; =
no cases of valvular heart disease or pulmonary arterial hypertension were =
observed.^ 2
LGS is a severe childhood-onset developmental and epileptic encephalopathy =
(DEE) characterized by multiple types of drug-refractory seizures with high=
morbidity^3,4 as well as serious impairment of neurodevelopmental, cogniti=
ve, and motor functions.^4 LGS affects an estimated 2 in 10,000 people in E=
uropean Union (EU).^8 LGS has far-reaching effects beyond seizures, includi=
ng issues with developmental communication, psychiatric symptoms, sleep, be=
havioural challenges, and mobility.^9 Drop seizures are hallmark features o=
f LGS, particularly tonic seizures. Convulsive seizures (eg, generalized to=
nic-clonic [GTC] seizures) are also commonly observed and usually occur in =
later stages of LGS but sometimes may precede core seizure types. In additi=
on to being associated with bodily injury and hospitalizations, GTC seizure=
s are a primary risk factor of sudden unexpected death in epilepsy (SUDEP).=
Patients with GTC seizures have an approximately 10-fold greater risk for =
SUDEP than patients with other seizure types.^5
About fenfluramine C-IV in EU
*Fintepla is indicated for the treatment of seizures associated with Dravet=
syndrome as an add-on therapy to other anti-epileptic medicines for patien=
ts 2 years of age and older. Fenfluramine is a serotonin releasing agent, a=
nd thereby stimulates multiple 5-HT receptor sub-types through the release =
of serotonin. Fenfluramine may reduce seizures by acting as an agonist at s=
pecific serotonin receptors in the brain, including the 5-HT1D, 5-HT2A, and=
5-HT2C receptors, and also by acting on the sigma-1 receptor.^5
Fenfluramine oral solution is available under a controlled access program f=
or Dravet Syndrome to ensure regular cardiac monitoring and to mitigate pot=
ential off-label use for weight management.
Please refer to Summary of Product Characteristics (https://www.ema.europa.=
eu/en/documents/product-information/fintepla-epar-product-information_en.pd=
f) (SmPC) before prescribing.=C2=A0
=E2=96=BCThis medicinal product is subject to additional monitoring. This w=
ill allow quick identification of new safety information. Healthcare profes=
sionals are asked to report any suspected adverse reactions.
FINTEPLA^=C2=AE is a registered trademark of the UCB Group of Companies.
Key Safety Information about FINTEPLA^=C2=AE=E2=96=BC in EU^5
Aortic or mitral valvular heart disease and pulmonary arterial hypertension
Because of reported cases of valvular heart disease that may have been caus=
ed by fenfluramine at higher doses used to treat adult obesity, cardiac mon=
itoring must be performed using echocardiography. In the controlled clinica=
l studies of fenfluramine for the treatment of Dravet syndrome, no valvular=
heart disease was observed. Prior to starting treatment, patients must und=
ergo an echocardiogram to establish a baseline prior to initiating treatmen=
t and exclude any pre-existing valvular heart disease or pulmonary hyperten=
sion. Echocardiogram monitoring should be conducted every 6 months for the =
first 2 years and annually thereafter. If an echocardiogram indicates patho=
logical valvular changes, a follow-up echocardiogram should be considered a=
t an earlier timeframe to evaluate whether the abnormality is persistent. I=
f pathological abnormalities on the echocardiogram are observed, it is reco=
mmended to evaluate the benefit versus risk of continuing fenfluramine trea=
tment with the prescriber, caregiver, and cardiologist. If treatment is sto=
pped because of aortic or mitral valvular heart disease, appropriate monito=
ring and follow-up should be provided in accordance with local guidelines f=
or the treatment of aortic or mitral valvular heart disease. With past use =
in higher doses to treat adult obesity, fenfluramine was reported to be ass=
ociated with pulmonary arterial hypertension. Pulmonary arterial hypertensi=
on was not observed in the clinical programme, but because of the low incid=
ence of this disease, the clinical trial experience with fenfluramine is in=
adequate to determine if fenfluramine increases the risk for pulmonary arte=
rial hypertension in patients with Dravet syndrome. If echocardiogram findi=
ngs are suggestive of pulmonary arterial hypertension, a repeat echocardiog=
ram should be performed as soon as possible and within 3 months to confirm =
these findings. If the echocardiogram finding is confirmed suggestive of an=
increased probability of pulmonary arterial hypertension defined as =E2=80=
=9Cintermediate probability=E2=80=9D by the 2015 European Society of Cardio=
logy (ESC) and the European Respiratory Society (ERS) Guidelines, it should=
lead to a benefit-risk evaluation of continuation of Fintepla by the presc=
riber, carer, and cardiologist. If the echocardiogram finding, after confir=
mation, suggests of a high probability of pulmonary arterial hypertension, =
as defined by the 2015 ESC and ERS Guidelines, it is recommended fenflurami=
ne treatment should be stopped.
Decreased appetite and weight loss=C2=A0
Fenfluramine can cause decreased appetite and weight loss. An additive effe=
ct on decreased appetite can occur when fenfluramine is combined with other=
anti-epileptic medicines, for example stiripentol. The decrease in weight =
appears to be dose related. Most subjects resumed weight gain over time whi=
le continuing treatment. The patient's weight should be monitored. A benefi=
t risk evaluation should be undertaken prior to commencing treatment with f=
enfluramine in patients with a history of anorexia nervosa or bulimia nervo=
sa.
Fintepla controlled access programme
A controlled access programme has been created to 1) prevent off-label use =
in weight management in obese patients and 2) confirm that prescribing phys=
icians have been informed of the need for periodic cardiac monitoring in pa=
tients taking Fintepla.=C2=A0
Somnolence
Fenfluramine can cause somnolence. Other central nervous system depressants=
, including alcohol, could potentiate the somnolence effect of fenfluramine=
.
Suicidal behaviour and ideation=C2=A0
Suicidal behaviour and ideation have been reported in patients treated with=
anti-epileptic medicines in several indications. A meta-analysis of random=
ised placebo-controlled trials with anti-epileptic medicines that did not i=
nclude fenfluramine has shown a small increased risk of suicidal behaviour =
and ideation. The mechanism of this risk is not known, and the available da=
ta do not exclude the possibility of an increased risk for fenfluramine. Pa=
tients and caregivers of patients should be advised to seek medical advice =
should any signs of suicidal behaviour and ideation emerge.
Serotonin syndrome
As with other serotonergic agents, serotonin syndrome, a potentially life-t=
hreatening condition, may occur with fenfluramine treatment, particularly w=
ith concomitant use of other serotonergic agents (including SSRIs, SNRIs, t=
ricyclic antidepressants, or triptans); with agents that impair metabolism =
of serotonin such as MAOIs; or with antipsychotics that may affect the sero=
tonergic neurotransmitter systems. Serotonin syndrome symptoms may include =
mental status changes (eg, agitation, hallucinations, coma), autonomic inst=
ability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscul=
ar aberrations (eg, hyperreflexia, incoordination), and/or gastrointestinal=
symptoms (eg, nausea, vomiting, diarrhoea). If concomitant treatment with =
fenfluramine and other serotonergic agents that may affect the serotonergic=
systems is clinically warranted, careful observation of the patient is adv=
ised, particularly during treatment initiation and dose increases.
Increased seizure frequency
As with other anti-epileptic medicines, a clinically relevant increase in s=
eizure frequency may occur during treatment with fenfluramine, which may re=
quire adjustment in the dose of fenfluramine and/or concomitant anti-epilep=
tic medicines, or discontinuation of fenfluramine, should the benefit-risk =
be negative.=C2=A0
Cyproheptadine=C2=A0
Cyproheptadine is a potent serotonin receptor antagonist and may therefore =
decrease the efficacy of fenfluramine. If cyproheptadine is added to treatm=
ent with fenfluramine, patients should be monitored for worsening of seizur=
es. If fenfluramine treatment is initiated in a patient taking cyproheptadi=
ne, fenfluramine=E2=80=99s efficacy may be reduced.
Glaucoma
Fenfluramine can cause mydriasis and can precipitate angle closure glaucoma=
. Discontinue therapy in patients with acute decreases in visual acuity. Co=
nsider discontinuation if there is ocular pain and another cause cannot be =
determined.
Strong CYP1A2 or CYP2B6 inducers
Co-administration with strong CYP1A2 inducers or CYP2B6 inducers may decrea=
se fenfluramine plasma concentrations. An increase in fenfluramine dosage s=
hould be considered when co-administered with a strong CYP1A2 or CYP2B6 ind=
ucer; the maximum daily dose should not be exceeded.
Excipients
This medicinal product contains sodium ethyl para-hydroxybenzoate (E 215) a=
nd sodium methyl para hydroxybenzoate (E 219) which may cause allergic reac=
tions (possibly delayed). It also contains sulfur dioxide (E 220) which may=
rarely cause severe hypersensitivity reactions and bronchospasm. Patients =
with rare glucose-galactose malabsorption should not take this medicinal pr=
oduct. This medicinal product contains less than 1 mmol sodium (23 mg) per =
the maximum daily dose of 12 mL, that is to say essentially =E2=80=98sodium=
-free=E2=80=99. This medicinal product contains glucose which may be harmfu=
l to the teeth.
For further safety information and full prescribing information visit: Fint=
epla, INN-fenfluramine (europa.eu) (https://www.ema.europa.eu/en/documents/=
product-information/fintepla-epar-product-information_en.pdf)
For further information, contact UCB:=C2=A0
Investor Relations=C2=A0=C2=A0 =C2=A0=C2=A0=C2=A0
Antje Witte
T +32.2.559.9414
antje.witte@ucb.com
Julien Bayet
T: +32 2 559 9580
julien.bayet@ucb.com
=C2=A0Global Communications
Nick Francis
T+44 7769 307745
nick.francis@ucb.com
About UCB
UCB, Brussels, Belgium (www.ucb.com) is a global biopharmaceutical company =
focused on the discovery and development of innovative medicines and soluti=
ons to transform the lives of people living with severe diseases of the imm=
une system or of the central nervous system. With approximately 8 600 peopl=
e in approximately 40 countries, the company generated revenue of =E2=82=AC=
5.8 billion in 2021. UCB is listed on Euronext Brussels (symbol: UCB). Fol=
low us on Twitter: @UCB_news
References:
=C2=A0
1. Knupp K, Scheffer I, Ceulemans B, et al. Efficacy and safety of fenflura=
mine for the treatment of seizures associated with Lennox-Gastaut syndrome.=
A Randomized Clinical Trial. JAMA Neurol. 2022;79(6):554-564
=C2=A0
2. Knupp K, Scheffer I, Ceulemans B, et al. Fenfluramine provides clinicall=
y meaningful reduction in frequency of drop seizures in patients with Lenno=
x-Gastaut syndrome: interim analysis of an open-label extension study. Epil=
epsia. 2022; doi: 10.1111/epi.17431
3. Strzelczyk A, Schubert-Bast S. Expanding the Treatment Landscape for Len=
nox-Gastaut Syndrome: Current and Future Strategies. CNS Drugs. 2021;35(1):=
61-83.
4. Specchio, N, Wirrell, EC, Scheffer, IE, Nabbout, R, Riney, K, Samia, P, =
et al. International League Against Epilepsy classification and definition =
of epilepsy syndromes with onset in childhood: Position paper by the ILAE T=
ask Force on Nosology and Definitions. Epilepsia. 2022;63:1398=E2=80=93 144=
2.
5. Fintepla EMA SmPC https://www.ema.europa.eu/en/documents/product-informa=
tion/fintepla-epar-product-information_en.pdf Accessed December 2022
6. Fintepla US PI https://www.ucb-usa.com/fintepla-prescribing-information.=
pdf Accessed December 2022
7. Fintepla Japan PI. September 2022. =E3=83=95=E3=82=A3=E3=83=B3=E3=83=86=
=E3=83=97=E3=83=A9=E5=86=85=E7=94=A8=E6=B6=B22.2mg/mL (pmda.go.jp). Accesse=
d December 2022
8. EMA. EU/3/17/1855 : Orphan designation for the treatment of Lennox-Gasta=
ut syndrome https://www.ema.europa.eu/en/medicines/human/orphan-designation=
s/eu3171855#:~:text=3DAt%20the%20time%20of%20designation,is%205%20people%20=
in%2010%2C000. Accessed December 2022
9. LGS Foundation. LGS Characteristics and Major Concerns Survey. https://w=
ww.lgsfoundation.org/wp-content/uploads/2021/08/2019-PFDD-Caregiver-Survey-=
1.pdf. Accessed December 2022.
GenericFile
CHMP opinion LGS - Media Release For Source Clear (https://mb.cision.com/Pu=
blic/18595/3686694/984de483b40e087f.pdf)
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