ATLANTA, Nov. 23, 2022 /PRNewswire/ -- UCB (Euronext: UCB), a global biopharmaceutical company, today announced the publication of long-term open-label extension (OLE) study results of FINTEPLA^® (fenfluramine) CIV in Epilepsia. Long-term efficacy and safety findings showed that FINTEPLA, when added to a patient's current anti-epileptic treatment regimen for seizures associated with LGS, was effective in reducing the frequency of multiple seizure types  and was generally well tolerated during a median treatment duration of 364 days.¹ Study participants experienced a sustained reduction in the frequency of motor seizures including those that resulted in a drop or fall like generalized tonic-clonic seizures (GTCS), secondary GTCS, focal to bilateral tonic-clonic, tonic seizures, atonic seizures, and tonic-atonic seizures.¹

LGS is a severe childhood-onset developmental and epileptic encephalopathy characterized by drug-resistant seizures with high morbidity³ as well as serious impairment of neurodevelopmental, cognitive, and motor functions.⁴ LGS has far-reaching effects beyond seizures, including issues with communication, psychiatric symptoms, sleep, behavioral challenges, and mobility.⁵ LGS affects 30,000 to 50,000 people in the U.S.⁶ 

"This long-term safety and efficacy interim analysis of adjunctive FINTEPLA showed that patients with LGS experienced sustained, clinically meaningful reductions in the frequency of seizures associated with a drop, with a particularly robust reduction in the frequency of GTCS, which are associated with sudden unexpected death in epilepsy," said Kelly Knupp, M.D., MSCS, FAES, Associate Professor, Children's Hospital Colorado, and principal investigator of the study. "Given the sustained efficacy and tolerability of FINTEPLA over time, this medication could be an important long-term therapeutic option for patients with LGS, who are highly treatment-resistant, and could be an especially important therapeutic option for LGS patients who experience a high burden of GTCS."

Results of the OLE study showed the median percentage change in monthly frequency of seizures associated with a drop from pre-randomized baseline was -28.6% over the entire OLE (P<0.0001) and -50.5% at month 15 (P<0.0001). Nearly one-third of patients (31.1%) experienced a clinically meaningful 50% or greater reduction in the percentage of seizures associated with a drop, including 11.6% of patients who demonstrated a profound 75% or greater reduction. The median percentage change in the frequency of all motor seizures was 45.9% (P=0.0038).¹ GTCS and tonic seizures were most responsive to LGS treatment with FINTEPLA.¹ Over the entire OLE, the median percentage change in GTCS from pre-randomized baseline was -48.8% (P<0.0001), and, over time, ranged from -56.4% at Month 7-9 (P<0.0001) to -79.1% at Month 13-15 (P<0.0001).¹ The median percentage change in tonic seizures was -35.8% over the entire OLE (P<0.0001) and, over time, ranged from -37.1% at Month 4-6 (P<0.0001) to -62.6% at Month 13-15 (P<0.0001).¹ 

Within the study, the authors note the reason these data are compelling is because GTCS are commonly observed in patients with LGS.¹  Moreover, GTCS may result in bodily injury.^7,8 Sudden unexpected death in epilepsy (SUDEP) is a major concern for people living with LGS, and patients with a history of GTCS have an estimated 10-fold greater risk of SUDEP.^9,10

The OLE study also demonstrated that FINTEPLA was generally well tolerated. The most common treatment-emergent adverse events observed in the OLE were decreased appetite, fatigue, nasopharyngitis, and seizure. The cardiovascular safety in this study further corroborates the FINTEPLA safety profiles; no cases of valvular heart disease or pulmonary arterial hypertension were observed.

"This open label extension provides strong evidence that FINTEPLA is effective in reducing multiple seizure types associated with LGS, particularly more severe generalized seizures for up to 15 months," said Brad Chapman, U.S. Head of Epilepsy and Rare Syndromes, UCB. "We are pleased to be able to offer FINTEPLA to those living with and caring for people with LGS to help reduce the impact of this devastating disease and potentially, improve the quality of life for those living with LGS."

Additional results of the OLE found that approximately one-third of investigators (37.6%) and caregivers (35.2%) rated their patients as "Much Improved" or "Very Much Improved" on the Clinical Global Impression of Improvement (CGI-I) scale.¹

FINTEPLA was approved by the U.S. Food and Drug Administration (FDA) for the treatment of LGS in patients 2 years of age and older in March 2022 and for the treatment of Dravet syndrome (DS) in patients 2 years of age and older in June 2020. UCB acquired Zogenix, Inc. and FINTEPLA in March 2022.

Study Design

As of October 19, 2020, 247 eligible patients entered the OLE study after the patients completed participation in the multi-center, double-blind,  parallel-group Phase 3 clinical trial that enrolled children and adults, age 2 to 35 years, with a confirmed LGS diagnosis who were using stable anti-seizure medication regimens at 65 study sites in North America, Europe, and Australia. In that randomized trial, a total of 263 patients were assigned to receive either FINTEPLA 0.7 mg/kg/day (n=87) or FINTEPLA 0.2 mg/kg/day (n=89) or placebo (n=87). After titration (2-week period), patients were maintained on their randomized dose for 12 additional weeks.

A total of 247 eligible patients with LGS who completed that 14-week randomized Phase 3 clinical trial enrolled in the OLE study. Patients were eligible to enroll if they had not experienced any of the following at the end of the Phase 3 clinical trial: clinically meaningful worsening of seizures, clinically significant laboratory findings, or weight loss greater than 15% during the titration and maintenance period that failed to stabilize. The median age of the patients was 14.3 years. All patients were maintained on a stable antiseizure medication regimen of concomitant antiseizure medications during the entire OLE treatment period, and 88.3% received two to four concomitant antiseizure medications.

All patients in the OLE were initially started on FINTEPLA 0.2 mg/kg/day. After one month, they were flexibly titrated to effectiveness and tolerability, up to a maximum of 0.7 mg/kg/day, which were assessed at three-month intervals. They were treated with FINTEPLA for a median treatment duration of 364 days.

The Phase 3 clinical trial and OLE study were both sponsored by Zogenix, Inc., now part of UCB. The trial is still ongoing.

About FINTEPLA ^® (fenfluramine) C-IV

FINTEPLA^® (fenfluramine) oral solution is a prescription medication approved in the U.S., Europe, and in Japan, for the treatment of seizures associated with Dravet syndrome in patients two years of age and older. FINTEPLA is also approved in the U.S. for the treatment of seizures associated with Lennox-Gastaut syndrome.²

In the U.S., FINTEPLA is available through a restricted distribution program, called the FINTEPLA Risk Evaluation and Mitigation Strategy (REMS) Program. Further information is available at www.FinteplaREMS.com or by telephone at 1-877-964-3649.

Please see full Prescribing Information, including Boxed Warning, for additional important information on FINTEPLA.

INDICATIONS AND USAGE²

FINTEPLA is indicated for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) in patients 2 years of age and older.

IMPORTANT SAFETY INFORMATION

BOXED WARNING: VALVULAR HEART DISEASE and PULMONARY ARTERIAL HYPERTENSION

• There is an association between serotonergic drugs with 5-HT2B receptor agonist activity, including fenfluramine (the active ingredient in FINTEPLA), and valvular heart disease and pulmonary arterial hypertension.
• Echocardiogram assessments are required before, during, and after treatment with FINTEPLA.
• FINTEPLA is available only through a restricted program called the FINTEPLA REMS.

CONTRAINDICATIONS

FINTEPLA is contraindicated in patients with hypersensitivity to fenfluramine or any of the excipients in FINTEPLA and with concomitant use, or within 14 days of the administration of monoamine oxidase inhibitors because of an increased risk of serotonin syndrome.

WARNINGS AND PRECAUTIONS

Valvular Heart Disease and Pulmonary Arterial Hypertension (see Boxed Warning): Because of the association between serotonergic drugs with 5–HT2B receptor agonist activity, including fenfluramine (the active ingredient in FINTEPLA), and valvular heart disease (VHD) and pulmonary arterial hypertension (PAH), cardiac monitoring via echocardiogram is required prior to starting treatment, during treatment, and after treatment with FINTEPLA concludes. Cardiac monitoring via echocardiogram can aid in early detection of these conditions. In clinical trials for DS and LGS of up to 3 years in duration, no patient receiving FINTEPLA developed VHD or PAH.

Monitoring: Prior to starting treatment, patients must undergo an echocardiogram to evaluate for VHD and PAH. Echocardiograms should be repeated every 6 months, and once at 3-6 months post treatment with FINTEPLA.

The prescriber must consider the benefits versus the risks of initiating or continuing treatment with FINTEPLA if any of the following signs are observed via echocardiogram: valvular abnormality or new abnormality; VHD indicated by mild or greater aortic regurgitation or moderate or greater mitral regurgitation, with additional characteristics of VHD (eg, valve thickening or restrictive valve motion); PAH indicated by elevated right heart/pulmonary artery pressure (PASP >35mmHg).

FINTEPLA REMS Program (see Boxed Warning): FINTEPLA is available only through a restricted distribution program called the FINTEPLA Risk Evaluation and Mitigation Strategy (REMS) Program. Prescribers must be certified by enrolling in the FINTEPLA REMS. Prescribers must counsel patients receiving FINTEPLA about the risk of valvular heart disease and pulmonary arterial hypertension, how to recognize signs and symptoms of valvular heart disease and pulmonary arterial hypertension, the need for baseline (pretreatment) and periodic cardiac monitoring via echocardiogram during FINTEPLA treatment, and cardiac monitoring after FINTEPLA treatment. Patients must enroll in the FINTEPLA REMS and comply with ongoing monitoring requirements. The pharmacy must be certified by enrolling in the FINTEPLA REMS and must only dispense to patients who are authorized to receive FINTEPLA. Wholesalers and distributors must only distribute to certified pharmacies. Further information is available at www.FinteplaREMS.com or by telephone at 1-877-964-3649.

Decreased Appetite and Decreased Weight: FINTEPLA can cause decreases in appetite and weight. Decreases in weight appear to be dose related. Approximately half of the patients with LGS and most patients with DS resumed the expected measured increases in weight during the open-label extension studies. Weight should be monitored regularly during treatment with FINTEPLA, and dose modifications should be considered if a decrease in weight is observed.

Somnolence, Sedation, and Lethargy: FINTEPLA can cause somnolence, sedation, and lethargy. Other central nervous system (CNS) depressants, including alcohol, could potentiate these effects of FINTEPLA. Prescribers should monitor patients for somnolence and sedation and should advise patients not to drive or operate machinery until they have gained sufficient experience on FINTEPLA to gauge whether it adversely affects their ability to drive or operate machinery.

Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including FINTEPLA, increase the risk of suicidal thoughts or behaviors in patients taking these drugs for any indication. Patients treated with an AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviors, or any unusual changes in mood or behavior.

Anyone considering prescribing FINTEPLA or any other AED must balance the risk of suicidal thoughts or behaviors with the risks of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behaviors. Should suicidal thoughts and behaviors emerge during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Withdrawal of Antiepileptic Drugs: As with most AEDs, FINTEPLA should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. If withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered.

Serotonin Syndrome: Serotonin syndrome, a potentially life-threatening condition, may occur with FINTEPLA, particularly during concomitant administration of FINTEPLA with other serotonergic drugs, including, but not limited to, selective serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), bupropion, triptans, dietary supplements (eg, St. John's Wort, tryptophan), drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors [MAOIs], which are contraindicated with FINTEPLA), dextromethorphan, lithium, tramadol, and antipsychotics with serotonergic agonist activity. Patients should be monitored for the emergence of signs and symptoms of serotonin syndrome, which include mental status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular signs (eg, hyperreflexia, incoordination), and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). If serotonin syndrome is suspected, treatment with FINTEPLA should be stopped immediately and symptomatic treatment should be started.

Increase in Blood Pressure: FINTEPLA can cause an increase in blood pressure. Rare cases of significant elevation in blood pressure, including hypertensive crisis, has been reported in adult patients treated with fenfluramine, including patients without a history of hypertension. In clinical trials for DS and LGS of up to 3 years in duration, no pediatric or adult patient receiving FINTEPLA developed hypertensive crisis. Monitor blood pressure in patients treated with FINTEPLA.

Glaucoma: Fenfluramine can cause mydriasis and can precipitate angle closure glaucoma. Consider discontinuing treatment with FINTEPLA in patients with acute decreases in visual acuity or ocular pain.

ADVERSE REACTIONS

The most common adverse reactions observed in DS studies (incidence at least 10% and greater than placebo) were decreased appetite; somnolence, sedation, lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue, malaise, asthenia; ataxia, balance disorder, gait disturbance; blood pressure increased; drooling, salivary hypersecretion; pyrexia; upper respiratory tract infection; vomiting; decreased weight; fall; status epilepticus.

The most common adverse reactions observed in the LGS study (incidence at least 10% and greater than placebo) were diarrhea; decreased appetite; fatigue; somnolence; vomiting.

DRUG INTERACTIONS

Strong CYP1A2, CYP2B6, or CYP3A Inducers: Coadministration with strong CYP1A2, CYP2B6, or CYP3A inducers will decrease fenfluramine plasma concentrations. If coadministration of a strong CYP1A2, CYP2B6, or CYP3A inducer with FINTEPLA is necessary, monitor the patient for reduced efficacy and consider increasing the dosage of FINTEPLA as needed. If a strong CYP1A2, CYP2B6, or CYP3A inducer is discontinued during maintenance treatment with FINTEPLA, consider gradual reduction in the FINTEPLA dosage to the dose administered prior to initiating the inducer.

Strong CYP1A2 or CYP2D6 Inhibitors: Coadministration with strong CYP1A2 or CYP2D6 inhibitors will increase fenfluramine plasma concentrations. If FINTEPLA is coadministered with strong CYP1A2 or CYP2D6 inhibitors, the maximum daily dosage of FINTEPLA is 20 mg. If a strong CYP1A2 or CYP2D6 inhibitor is discontinued during maintenance treatment with FINTEPLA, consider gradual increase in the FINTEPLA dosage to the dose recommended without CYP1A2 or CYP2D6 inhibitors. If FINTEPLA is coadministered with stiripentol and a strong CYP1A2 or CYP2D6 inhibitor, the maximum daily dosage of FINTEPLA is 17 mg.

USE IN SPECIFIC POPULATIONS

Administration to patients with hepatic impairment is not recommended.

To report SUSPECTED ADVERSE REACTIONS, contact Zogenix Inc. at 1-866-964-3649 (1-866-Zogenix) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see full Prescribing Information, including Boxed Warning, for additional important information on FINTEPLA.

For further information, contact UCB:
U.S. Brand and Media Relations
Erica Puntel, U.S. Media Relations
T +404 938 5359
Erica.puntel@ucb.com 

Investor Relations
Antje Witte
T +32.2.559.9414
antje.witte@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 solutions to transform the lives of people living with severe diseases of the immune system or of the central nervous system. With approximately 8 600 people in approximately 40 countries, the company generated revenue of € 5.8 billion in 2021. UCB is listed on Euronext Brussels (symbol: UCB). Follow us on Twitter: @UCBUSA.

Forward looking statements

This press release contains forward-looking statements including, without limitation, statements containing the words "believes", "anticipates", "expects", "intends", "plans", "seeks", "estimates", "may", "will", "continue" and similar expressions. These forward-looking statements are based on current plans, estimates and beliefs of management. All statements, other than statements of historical facts, are statements that could be deemed forward-looking statements, including but not limited to, the ability of UCB to successfully integrate the operations of Zogenix as planned or at all, estimates of revenues, operating margins, capital expenditures, cash, other financial information, expected legal, arbitration, political, regulatory or clinical results or practices and other such estimates and results. By their nature, such forward-looking statements are not guarantees of future performance and are subject to known and unknown risks, uncertainties and assumptions which might cause the actual results, financial condition, performance or achievements of UCB, or industry results, to differ materially from those that may be expressed or implied by such forward-looking statements contained in this press release. Important factors that could result in such differences include: the global spread and impact of COVID-19, changes in general economic, business and competitive conditions, the inability to obtain necessary regulatory approvals or to obtain them on acceptable terms or within expected timing, costs associated with research and development, changes in the prospects for products in the pipeline or under development by UCB, effects of future judicial decisions or governmental investigations, safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, product liability claims, challenges to patent protection for products or product candidates, competition from other products including biosimilars, changes in laws or regulations, exchange rate fluctuations, changes or uncertainties in tax laws or the administration of such laws, and hiring and retention of its employees. There is no guarantee that new product candidates will be discovered or identified in the pipeline, or that new indications for existing products will be developed and approved. Movement from concept to commercial product is uncertain; preclinical results do not guarantee safety and efficacy of product candidates in humans. So far, the complexity of the human body cannot be reproduced in computer models, cell culture systems or animal models. The length of the timing to complete clinical trials and to get regulatory approval for product marketing has varied in the past and UCB expects similar unpredictability going forward. Products or potential products which are the subject of partnerships, joint ventures or licensing collaborations may be subject to disputes between the partners or may prove to be not as safe, effective or commercially successful as UCB may have believed at the start of such partnership. UCB' efforts to acquire other products or companies and to integrate the operations of such acquired companies may not be as successful as UCB may have believed at the moment of acquisition. Also, UCB or others could discover safety, side effects or manufacturing problems with its products and/or devices after they are marketed. The discovery of significant problems with a product similar to one of UCB's products that implicate an entire class of products may have a material adverse effect on sales of the entire class of affected products. Moreover, sales may be impacted by international and domestic trends toward managed care and health care cost containment, including pricing pressure, political and public scrutiny, customer and prescriber patterns or practices, and the reimbursement policies imposed by third-party payers as well as legislation affecting biopharmaceutical pricing and reimbursement activities and outcomes. Finally, a breakdown, cyberattack or information security breach could compromise the confidentiality, integrity and availability of UCB's data and systems.

Given these uncertainties, you should not place undue reliance on any of such forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labelling in any market, or at any particular time, nor can there be any guarantee that such products will be or will continue to be commercially successful in the future.

UCB is providing this information, including forward-looking statements, only as of the date of this press release and expressly disclaims any duty to update any information contained in this press release, either to confirm the actual results or to report or reflect any change in its forward-looking statements with regard thereto or any change in events, conditions or circumstances on which any such statement is based, unless such statement is required pursuant to applicable laws and regulations.

Additionally, information contained in this document shall not constitute an offer to sell or the solicitation of an offer to buy any securities, nor shall there be any offer, solicitation or sale of securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of such jurisdiction.

References

1. Knupp K, Scheffer I, Ceuleman B, et al. Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox-Gastaut syndrome: interim analysis of an open-label extension study. Epilepsia. 2022;00:1–13.
2. FINTEPLA^® (fenfluramine) oral solution CIV. U.S. Prescribing Information. March 2022.
3. Strzelczyk A, Schubert-Bast S. Expanding the treatment landscape for Lennox-Gastaut Syndrome: current and future strategies. CNS Drugs. 2021;35(1):61-83.
4. Arzimanoglou A, French J, Blume WT, et al. Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology. Lancet Neurol. 2009;8(1):82-93.
5. LGS Foundation. LGS characteristics and major concerns survey. https://www.lgsfoundation.org/wp-content/uploads/2021/08/2019-PFDD-Caregiver-Survey-1.pdf. Accessed March 2022.
6. Data on file, Zogenix, Inc. 2021.
7. Cross JH, Auvin S, Falip M, Striano P, Arzimanoglou A. Expert opinion on the management of Lennox-Gastaut syndrome: treatment algorithms and practical considerations. Front Neurol.2017;8:505.
8. Gastaut H, Roger J, Soulayrol R, et al. Childhood epileptic encephalopathy with diffuse slow spike-waves (otherwise known as "petit mal variant") or Lennox syndrome. Epilepsia. 1966;7(2):139-179.
9. Sveinsson O, Andersson T, Mattsson P, Carlsson S, Tomson T. Clinical risk factors in SUDEP: a nationwide population-based case-control study. Neurology. 2020;94(4):e419-e429.
10. Cross JH, Galer BS, Gil-Nagel A, et al. Impact of fenfluramine on the expected SUDEP mortality rates in patients with Dravet syndrome. Seizure. 2021;93:154-159.

FINTEPLA^® is a registered trademark of the UCB Group of Companies.
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