United States

Ipsen presents 3 late-breaking presentations and 8 abstracts across rare cholestatic liver disease portfolio at AASLD 2024

PARIS, FRANCE, 18 November, 2024 Ipsen (Euronext: IPN; ADR: IPSEY) today announced data at the American Association for the Study of Liver Diseases (AASLD) assessing the long-term efficacy and safety of patients treated with Bylvay^® from two Phase III open-label extension studies: late-breaking abstract (#5045) on PEDFIC 2 in Progressive Familial Intrahepatic Cholestasis (PFIC) and oral presentation ASSERT-EXT (#50) in Alagille syndrome (ALGS). Sustained efficacy data and improvements in height, weight and sleep measures were observed for patients treated with Bylvay for at least 72 weeks in both rare cholestatic diseases.

“We know from our work with patient communities that receiving a diagnosis of PFIC and ALGS can be overwhelming in a patient or caregivers’ life. Disease symptoms like severe itch can have an impact on the whole family,” said Sandra Silvestri, EVP Chief Medical Officer, Ipsen. “Data suggesting Bylvay-treated patients experienced sustained efficacy, and which support the safety and tolerability profile seen in previous clinical trials, are important. Ipsen is committed to being the leader across rare cholestatic liver diseases and we are just getting started.”

PEDFIC 2 Study in PFIC

“These open-label extension data from PEDFIC 2 suggest that the initial reduction in pruritus and in serum bile acid levels achieved following initiation of odevixibat are being sustained into the longer term,” said Dr. Richard J. Thompson, Professor of Molecular Hepatology, King’s College London and principal investigator of the PEDFIC 2 trial. “We are also observing reductions in both pruritus and serum bile acid across a number of PFIC subtypes. This is important information for our understanding of the therapeutic management of our patients living with PFIC.”

PEDFIC 2 was an open-label extension study (n=116; patients from PEDFIC 1 Bylvay and placebo cohorts at week 24, and new Bylvay-naïve patients of any age and PFIC subtype), evaluating the efficacy and safety of Bylvay through 72 weeks (n=83).¹ The data showed a clinically meaningful 1-point reduction in pruritus score at week 72 in 42 percent of patients <18 years old with PFIC 1 and 2 who transitioned to Bylvay at 24 weeks (n=5/12) and 61 percent of patients with any type of PFIC and of any age excluding episodic (n=19/31). Rapid initial pruritus scores achieved by week 4 were sustained for patients who remained on treatment. At 72 weeks, the mean change in serum bile acid (sBA) levels from patients who transition to Bylvay at week 24 (n=15) was –104.00 µmol/L and Bylvay-treated patients (n=43) was -57.97 µmol/L .

Beyond the clinically meaningful and sustained improvements seen in pruritus and sBA levels, height, weight and sleep increases were reported at 72 weeks in Bylvay-treated patients. Most adverse events in Bylvay-treated patients over the duration of the study were reported as mild or moderate. The most common were gastrointestinal (17.2 percent; n=20/116), including diarrhea (12 percent; n=14/116). In two cases, diarrhea led to one treatment interruption and one discontinuation.

Assert-EXT Study in ALGS
“The sustained improvements we’ve seen in Bylvay-treated individuals living with Alagille syndrome are encouraging,” said Dr. Nadia Ovchinsky, Chief, Division of Gastroenterology and Hepatology, Hassenfeld Children’s Hospital at NYU Langone, New York. and principal investigator of the ASSERT trial. “These results not only show the potential to manage symptoms like pruritus, which can be extremely difficult for children and their parents to manage, but we’re also seeing a consistent safety profile over the longer term with sustained tolerability.”

In ASSERT-EXT, the open-label extension study (n=50) evaluating the long-term efficacy and safety of Bylvay in ALGS patients (ages 1-15.9 years) through 72 weeks (n=44), sustained improvements were observed in pruritus and sBA levels through 72 weeks.² At week 72, 93 percent (n=28/30) of patients who received Bylvay throughout the 24 weeks ASSERT trial and 77 percent (n=10/13) of those who transitioned from placebo to Bylvay at week 24 experienced a clinically meaningful ≥1 point reduction in pruritus score. Reductions in sBA levels were also observed in patients treated with Bylvay for 72 weeks showing a mean reduction of 124 µmol/L in those who continuously received Bylvay and a mean reduction of 139 µmol/L in patients who transitioned from placebo to Bylvay. Mean changes from baseline were observed in height (8.2 cm) and weight (2.8 kg) on continuous Bylvay use and for patients who transitioned from placebo to Bylvay, height (10.7 cm) and weight (3.3 kg) mean changes were also reported.

Improvements in sleep were observed from weeks 24 to 72 across all four sleep parameters (n=43), including proportion of days seeing blood due to scratching, proportion of days needing help falling asleep, proportion of days needing soothing and daytime tiredness. Data supports the safety profile in the ASSERT clinical trial for Bylvay. Treatment emergent adverse event (TEAE) occurred in 18 percent (n=6/33) of patients who continuously received Bylvay and 41 percent (n=7/17) of patients who transitioned from placebo to Bylvay. Most adverse events were mild or moderate with diarrhea as the most common TEAE. One TEAE led to discontinuation.

About PFIC and ALGS
PFIC is a group of rare genetic disorders in which bile acids build up in the liver, causing damage, which may result in liver failure. ALGS is also a rare genetic disorder, affecting multiple organs including the liver, heart, skeleton, eyes and kidneys. Without early diagnosis and effective management, people living with PFIC and ALGS may need a liver transplant. Debilitating itch, caused as a result of the serum bile acid build up, is one of the most common symptoms of both PFIC and ALGS, significantly impacting sleep and daily activities and resulting in skin mutilation, loss of sleep, irritability, and poor attention.

Bylvay (odevixibat) posters presented at AASLD

Abstract	Poster or Oral #	Full title	Authors
ASSERT-EXT final results	Oral, Abstract Parallel, ePoster [50] Monday 18 November 11:45–12:00 Human Cholestatic, PBC and other Biliary Disorders in Children and Adults	ASSERT-EXT: Final data from an open-label, Phase 3 study of odevixibat in patients with Alagille syndrome	Nadia Ovchinsky et al.
Hepatic parameters with ODX in PFIC	Poster, Abstract [4277] Monday 18 November 13:00–14:00 Poster Session IV	Effects of odevixibat vs placebo on hepatic biochemical parameters and liver adverse events in patients with PFIC: Data from the PEDFIC 1 study	Tassos Grammatikopoulos et al.
Phase I DDI results	Poster, Abstract [4280] Monday 18 November 13:00–14:00 Poster Session IV	A Phase 1, open-label, fixed-sequence, crossover study to evaluate the interaction of multiple-dose odevixibat with the pharmacokinetics of single-dose combined oral contraceptive steroids in healthy female participants	Florent Mazuir et al.

PEDFIC1/2 OLE final results (LB)	Poster, Abstract [5045] Monday 18 November 13:00–14:00 Poster Session IV	Sustained, long-term efficacy and safety of odevixibat in patients with progressive familial intrahepatic cholestasis: Results from the PEDFIC2 Phase 3, open-label extension study	Richard Thompson et al.

About Bylvay (odevixibat)
Odevixibat is a once-daily non-systemic ileal bile acid transport (IBAT) inhibitor approved under the brand name Bylvay^® in the U.S. as the first drug treatment option for patients 3 months of age and older living with cholestatic pruritus due to progressive familial intrahepatic cholestasis (PFIC). BYLVAY may not be effective in a subgroup of PFIC type 2 patients with specific ABCB11 variants resulting in non-functional or complete absence of the bile salt export pump protein.

Odevixibat was also approved in June 2021 in the E.U. under the brand name Bylvay^®, as the first drug treatment option for all types of PFIC in patients aged 6 months or older. Bylvay has received orphan exclusivity for the treatment of PFIC in the U.S. and E.U.

In June 2023 Bylvay was approved in the U.S. for the treatment of cholestatic pruritus in patients from 12 months of age with Alagille syndrome (ALGS) and received orphan exclusivity for ALGS. In September 2024, odevixibat was approved in the E.U under the brand name Kayfanda^® for the treatment of cholestatic pruritus in ALGS in patients aged 6 months or older.

IMPORTANT SAFETY INFORMATION – U.S.
Warnings and Precautions:

Liver Test Abnormalities
Patients who enrolled in PFIC and ALGS clinical trials had abnormal liver tests at baseline. In clinical trials, treatment-emergent elevations of liver tests or worsening of liver tests relative to baseline values were observed. Most abnormalities included elevations in aspartate aminotransferase (AST), alanine transaminase (ALT) in PFIC and ALGS, and total and direct bilirubin in PFIC clinical trials. No patients permanently discontinued treatment due to liver test abnormalities.

Obtain baseline liver tests and monitor during treatment. Dose reduction or treatment interruption may be required if abnormalities occur. For persistent or recurrent liver test abnormalities, consider treatment discontinuation.

Permanently discontinue Bylvay if a patient progresses to portal hypertension or experiences a hepatic decompensation event.

Diarrhea
Diarrhea occurred in both PFIC and ALGS clinical trials in BYLVAY-treated patients at a rate greater than placebo treated patients. If diarrhea occurs with use of BYLVAY, monitor for dehydration and treat promptly. Treatment interruption or discontinuation may be required for persistent diarrhea with no alternate etiology.

Fat-Soluble Vitamin (FSV) Deficiency
Fat-soluble vitamins (FSV) include vitamin A, D, E, and K. PFIC and ALGS patients can have FSV deficiency at baseline, as part of their disease. BYLVAY may affect absorption of fat-soluble vitamins.

Obtain baseline levels and monitor during treatment, along with any clinical manifestations. Supplement if deficiency is observed. If FSV deficiency persists or worsens despite FSV supplementation, discontinue treatment.

ADVERSE REACTIONS
ALGS: The most common adverse reactions (>5%) are diarrhea, abdominal pain, hematoma, and decreased weight.
PFIC: The most common adverse reactions (>2%) are diarrhea, liver test abnormalities, vomiting, abdominal pain, and fat-soluble vitamin deficiency.

DRUG INTERACTIONS
For patients taking bile acid binding resins, take BYLVAY at least 4 hours before or 4 hours after administering, as bile acid binding resins may bind to and reduce BYLVAY efficacy.

USE IN SPECIFIC POPULATIONS
There are no human data on BYLVAY use in pregnant persons to establish a drug-associated risk of major birth defects, miscarriage, or adverse developmental outcomes. Based on findings from animal reproduction studies, BYLVAY may cause cardiac malformations when a fetus is exposed during pregnancy.

There is a pregnancy safety study that monitors pregnancy outcomes in women exposed to BYLVAY during pregnancy. Pregnant women exposed to BYLVAY, or their healthcare providers, should report BYLVAY exposure by calling 1-855-463-5127.

To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at +1-855-463-5127, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Indications and Usage U.S.
Bylvay is an ileal bile acid transporter (IBAT) inhibitor indicated for the treatment of cholestatic pruritus in:
Patients 12 months of age and older with Alagille syndrome (ALGS)
Patients 3 months of age and older with progressive familial intrahepatic cholestasis (PFIC)

Limitation of use
Bylvay may not be effective in a subgroup of PFIC type 2 patients with specific ABCB11 variants resulting in non-functional or complete absence of the bile salt export pump protein

Please see full U.S. Prescribing Information.

Indications of use E.U.
Bylvay is indicated for the treatment of progressive familial intrahepatic cholestasis (PFIC) in patients aged 6 months or older. Please see full E.U. Prescribing Information.

Kayfanda is indicated for the treatment of cholestatic pruritus in Alagille syndrome (ALGS) in patients aged 6 months or older. Please see full E.U. Prescribing Information.

ENDS

About PEDFIC 1 and 2
PEDFIC 1 was a 24-week double-blind, randomized, placebo-controlled trial that evaluated the efficacy and tolerability of two doses of odevixibat in reducing pruritus and serum bile acid levels in children with PFIC 1 or 2. PEDFIC 2 is a 72-week open label extension trial, which consisted of children from PEDFIC 1 who received either Bylvay (cohort 1a) or placebo (cohort 1b) and a new cohort (2) of Bylvay-naïve patients of any age and PFIC subtype.

PEDFIC is the largest, global, Phase III trial ever conducted in PFIC. PEDFIC 1 (NCT03566238) was a 24-week double-blind, randomized (1:1:1), placebo-controlled trial that evaluated the efficacy and tolerability of two doses of odevixibat in reducing pruritus and serum bile acid levels in children with PFIC 1 or 2. Participants were randomly allocated to receive placebo (n=20), odevixibat 40 μg/kg (n=23), or odevixibat 120 μg/kg (n=19) once a day. The results were published in The Lancet.³

PEDFIC 2 (NCT03659916), an open-label extension of PEDFIC 1, is a 72-week trial that aimed to evaluate the efficacy and tolerability of odevixibat 120 µg/kg once a day in patients with PFIC. Patients were divided into two cohorts: Cohort 1 (n=56) which consisted of children with PFIC 1 or 2 from PEDFIC 1 who received odevixibat (Cohort 1a: n= 37) or placebo (Cohort 1b: n=19), respectively, and Cohort 2 (n=60) which consisted of newly enrolled, odevixibat-naïve patients of any age and PFIC subtype. Interim results were published in The Journal of Hepatology.⁴

About ASSERT and ASSERT-EXT
ASSERT (NCT04674761) was a 24-week double-blind, randomized, placebo-controlled trial with an open-label long term extension. ASSERT evaluated the safety and efficacy of 120 µg /kg once-daily odevixibat vs placebo for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS). The trial enrolled 52 patients of any age with a genetically confirmed diagnosis of ALGS. The results were published in The Lancet.⁵

In ASSERT-EXT (NCT05035030), ASSERT’s ongoing open-label extension, all trial participants received 120 μg/kg of odevixibat once daily for 72-weeks after the double-blind treatment period completed. In both ASSERT and ASSERT-EXT, the investigators looked for changes in pruritus, serum bile acid concentrations, sleep, and treatment-emergent adverse events.

About Ipsen
We are a global biopharmaceutical company with a focus on bringing transformative medicines to patients in three therapeutic areas: Oncology, Rare Disease and Neuroscience.

Our pipeline is fueled by external innovation and supported by nearly 100 years of development experience and global hubs in the U.S., France and the U.K. Our teams in more than 40 countries and our partnerships around the world enable us to bring medicines to patients in more than 80 countries.

Ipsen is listed in Paris (Euronext: IPN) and in the U.S. through a Sponsored Level I American Depositary Receipt program (ADR: IPSEY). For more information, visit ipsen.com

Ipsen Media contacts

Investors

Nicolas Bogler | + 33 6 52 19 98 92

Media

Jennifer Smith-Parker | + 44 7487 75 71 00 | jennifer.smith-parker.ext@ipsen.com
Rachel Reiff | + 1 908 616 1680 | rachel.reiff@ipsen.com
Anna Gibbins | + 44 7717 80 19 00 | anna.gibbins@ipsen.com

Disclaimers and/or Forward-Looking Statements

Ipsen
The forward-looking statements, objectives and targets contained herein are based on Ipsen’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 Ipsen’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 Ipsen’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 Ipsen. 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 medicine 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. Ipsen must face or might face competition from generic medicine 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 Ipsen may fail to achieve its objectives and be forced to abandon its efforts with regards to a medicine in which it has invested significant sums. Therefore, Ipsen cannot be certain that favorable results obtained during preclinical 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 medicine concerned. There can be no guarantees a medicine will receive the necessary regulatory approvals or that the medicine 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 healthcare legislation; global trends toward healthcare cost containment; technological advances, new medicine and patents attained by competitors; challenges inherent in new-medicine development, including obtaining regulatory approval; Ipsen’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 Ipsen’s patents and other protections for innovative medicines; and the exposure to litigation, including patent litigation, and/or regulatory actions. Ipsen also depends on third parties to develop and market some of its medicines which could potentially generate substantial royalties; these partners could behave in such ways which could cause damage to Ipsen’s activities and financial results. Ipsen 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 Ipsen’s partners could generate lower revenues than expected. Such situations could have a negative impact on Ipsen’s business, financial position or performance. Ipsen 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. Ipsen’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 Ipsen’s latest Universal Registration Document, available on ipsen.com.

References

¹Thompson RJ, et al. Sustained, long-term efficacy and safety of odevixibat in patients with progressive familial intrahepatic cholestasis: Results from the PEDFIC2 phase 3, open-label extension study. Poster Abstract 5045, American Association for the Study of Liver Disease (AASLD). 2024
² Ovchinsky N., et al. ASSERT-EXT: Final data from an open-label, phase 3 study of odevixibat in patients with Alagille syndrome. Oral abstract Parallel ePoster 50. American Association for the Study of Liver Disease (AASLD). 2024
³ Thompson RJ, et al. Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol. 2022. 7:830–842.
⁴ Thompson RJ, et al. Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis 2023. JHEP Rep. 5(8):100782.
⁵ Ovchinsky N., et al. Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT); a phase 3, double-blind, randomized, placebo-controlled trial. Lancet Gastroenterol / Hepatol. 2024 doi.org/10.1016/S2468-1253(24)00074-8.

Attachment

Ipsen PR_Bylvay® (odevixibat) data shows sustained improvement in severe itch and sBA in PFIC and ALGS_181124

Ipsen presents 3 late-breaking presentations and 8 abstracts across rare cholestatic liver disease portfolio at AASLD 2024
Iqirvo approved for use in the U.S. in June 2024, in the E.U. in September 2024 and in the U.K. in October 2024

PARIS, FRANCE, 15 November 2024 Ipsen (Euronext: IPN; ADR: IPSEY) announced today late-breaking data for Iqirvo^® (elafibranor 80 mg tablets) from an interim analysis of the ongoing open-label extension of the Phase III ELATIVE^® study at the American Association for the Study of Liver Disease (AASLD) congress. The late-breaking presentations (Abstract #5041 and Abstract #5042) report on biomarkers of cholestasis, stabilization of surrogate markers of liver fibrosis and moderate-to-severe pruritus data for up to three years in Iqirvo-treated patients. Additionally, exploratory endpoints in fatigue and sleep were evaluated using patient-reported outcomes tools.

“Over three years, Iqirvo data suggest sustained efficacy and support the safety profile of the medicine. Importantly, when patients tell me they are less impacted by itch and fatigue—that matters to me as a physician,” said Dr. Kris Kowdley, Director at The Liver Institute Northwest, Washington and a primary investigator on the ELATIVE study. “Treatment with Iqirvo had an impact on symptoms of pruritus and surrogate markers of fibrosis, which are important findings for people living with PBC.”

“Fatigue is a symptom often reported by people living with PBC and is also very challenging to manage,” said Dr. Mark Swain, Department of Medicine, Cumming School of Medicine, University of Calgary, Canada. “Patients treated with Iqirvo reported improvement in fatigue and sleep, across several patient-reported outcome measures.”

The open-label extension (OLE) included 138 patients who completed the double-blind period of the Phase III ELATIVE^® study¹. This interim analysis was performed after at least one year of treatment with Iqirvo in the OLE (up to three years total). In patients receiving three years of continuous treatment with Iqirvo across the double-blind period and OLE (n=13), 85 percent had a biochemical response (n=11/13; ALP <1.67 x ULN, with ≥ 15% reduction from baseline and total bilirubin ≤ ULN) and 39 percent achieved ALP normalization (n=5/13) at week 156. Surrogate markers of liver fibrosis, liver stiffness measurements (n=23) and enhanced liver fibrosis (ELF™) (n=19) scores, suggest stabilization when measured from baseline to week 130. In patients continuously receiving Iqirvo for up to 156 weeks, pruritus improvements were sustained for patients with moderate or severe pruritus at baseline (n=5).

No new safety findings were observed. The most common treatment-emergent adverse events (>10 percent) occurring more frequently in patients treated with Iqirvo than placebo in the double-blind period of the trial (abdominal pain, diarrhea, nausea and vomiting) were also reported in the OLE.

The impact of Iqirvo on fatigue and sleep were investigated as an exploratory endpoint in the OLE.² Changes in fatigue or sleepiness (including normal sleep) were reviewed from baseline to week 104 looking at the minimal clinically important differences and categorical changes (n=48). Fatigue and sleep improvements for patients treated with Iqirvo were observed at week 104 across three patient-reported outcome (PRO) tools. In patients with moderate-to-severe fatigue or excessive sleepiness at baseline, clinically meaningful improvements were observed after 104 weeks of treatment with Iqirvo in 56 percent (n=18) of patients according to the PRO Measurement Information System (PROMIS) Fatigue Short Form 7a, 50 percent (n=24) of patients according to the fatigue domain of the PBC-40, and 69 percent (n=16) of patients according to the Epworth Sleepiness Scale (ESS). These are interim data and have not been submitted to regulatory agencies. A confirmatory study of Iqirvo is ongoing (NCT06016842).

“People living with PBC tell us just how devastating this disease can be for patients and their families,” said Sandra Silvestri, EVP and Chief Medical Officer, Ipsen. “Data like these continue to provide prescribers with a clear rationale for Iqirvo. As the first-in-class PPAR approved for the treatment of PBC, Iqirvo is on track to be the treatment of choice for patients living with PBC. Ipsen is committed to being a leader the rare liver community can count on.”

About PBC
PBC is a rare, autoimmune, cholestatic liver disease where a build-up of bile and toxins (cholestasis) and chronic inflammation causes irreversible fibrosis (scarring) of the liver and destruction of the bile ducts. Impacting approximately 100,000 people in the U.S.,³ the majority being women, PBC is a lifelong condition that can worsen over time if not effectively treated, may lead to liver transplant and in some cases, premature death. The high symptom burden of PBC can also have an impact on daily life.

Iqirvo (elafibranor) posters presented at AASLD

Poster or Oral #	Full Title	Authors
Poster, Abstract [5041] Monday 18 November 13:00–14:00 Poster Session IV	Long-term efficacy and safety of elafibranor in primary biliary cholangitis: Interim results from the open-label extension of the ELATIVE^® trial up to 3 years	Kris V. Kowdley et al.
Poster, Abstract [5042] Monday 18 November 13:00–14:00 Poster Session IV	Impact of elafibranor on fatigue in patients with primary biliary cholangitis: Interim results from the long-term open-label extension of the ELATIVE^® trial	Mark Swain et al.
Poster, Abstract [4274] Monday 18 November 13:00–14:00 Poster Session IV	Beyond the mean: Exploring the impact of baseline alkaline phosphatase levels on endpoints in primary biliary cholangitis	Cynthia Levy et al.
Oral, Abstract Parallel, ePoster [43] Monday 18 November 11:00–11:15 Human Cholestatic, PBC and other Biliary Disorders in Children and Adults	One-year treatment with elafibranor in the Phase III ELATIVE^® trial improves GLOBE and UK-PBC prognostic scores	Kris V. Kowdley et al.
Poster, Abstract [4292] Monday 18 November 13:00–14:00 Poster Session IV	Use of machine learning (ML) models to stratify response patterns to first-line treatment of primary biliary cholangitis (PBC) with ursodeoxycholic acid (UDCA)	Seema T. Meloni et al.
Poster, Abstract [4349] Monday 18 November 13:00–14:00 Poster Session IV	Elafibranor has no impact on markers of renal function in primary biliary cholangitis: results from the Phase III ELATIVE^® trial	Marcelo Kugelmas et al.
Poster, Abstract [4358] Monday 18 November 13:00–14:00 Poster Session IV	Economic burden of patients with primary biliary cholangitis and experiencing fatigue or pruritus in the United States	Nisreen Shamseddine et al.

About Iqirvo^® (elafibranor) 80 mg tablet
Iqirvo is an oral, once-daily, peroxisome proliferator-activated receptor (PPAR), indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. While the mechanism is not well understood, pharmacological activity that is potentially relevant to Iqirvo therapeutic effects includes inhibition of bile acid synthesis through activation of PPAR-alpha and PPAR-delta. In 2019, Iqirvo was granted Breakthrough Therapy Designation by the U.S Food and Drug Administration (FDA) in adults with PBC who have an inadequate response to ursodeoxycholic acid (UDCA) the existing first-line therapy for PBC. Iqirvo was granted U.S. FDA accelerated approval in June 2024, EU conditional approval by the EMA in September 2024 and UK Medicines and Healthcare products Regulatory Agency (MHRA) approval in October 2024, for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. The FDA and EMA approvals are contingent on the further verification of clinical benefit. Iqirvo is currently in regulatory processes with other authorities. Iqirvo (elafibranor) was developed by GENFIT. Ipsen licensed the exclusive worldwide rights (except China, Hong Kong, Taiwan and Macau) to elafibranor from GENFIT in 2021.

INDICATION
IQIRVO® is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA.

This indication is approved under accelerated approval based on reduction of alkaline phosphatase (ALP). Improvement in survival or prevention of liver decompensation events have not been demonstrated. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Limitations of Use
Use of IQIRVO is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy).

IMPORTANT SAFETY INFORMATION
Myalgia, Myopathy, and Rhabdomyolysis: Rhabdomyolysis resulting in acute kidney injury occurred in one IQIRVO-treated patient who had cirrhosis at baseline and was also taking a stable dose of an HMG-CoA reductase inhibitor (statin). Myalgia or myopathy, with or without CPK elevations, occurred in patients treated with IQIRVO alone or treated concomitantly with a stable dose of an HMG-CoA reductase inhibitor. Assess for myalgia and myopathy prior to IQIRVO initiation. Consider periodic assessment (clinical exam, CPK measurement) during treatment with IQIRVO, especially in those who have signs and symptoms of new onset or worsening of muscle pain or myopathy. Interrupt IQIRVO treatment if there is new onset or worsening of muscle pain, or myopathy, or rhabdomyolysis.

Fractures: Fractures occurred in 6% of IQIRVO-treated patients compared to no placebo-treated patients. Consider the risk of fracture in the care of patients treated with IQIRVO and monitor bone health according to current standards of care.

Adverse Effects on Fetal and Newborn Development: IQIRVO may cause fetal harm when administered during pregnancy. For females of reproductive potential, verify that the patient is not pregnant prior to initiation of therapy. Advise females of reproductive potential to use effective non-hormonal contraceptives or add a barrier method when using systemic hormonal contraceptives during treatment with IQIRVO and for 3 weeks following the last dose of IQIRVO.

Drug-Induced Liver Injury: Drug-induced liver injury occurred in one patient who took IQIRVO 80 mg once daily and two patients who took IQIRVO at 1.5-times the recommended dosage, of which one presented with autoimmune-like hepatitis. The median time to onset of elevation in liver tests was 85 days. Obtain baseline clinical and laboratory assessments at treatment initiation with IQIRVO and monitor thereafter according to routine patient management. Interrupt IQIRVO treatment if liver tests (ALT, AST, total bilirubin [TB], and/or alkaline phosphatase [ALP]) worsen, or the patient develops signs and symptoms consistent with clinical hepatitis (e.g., jaundice, right upper quadrant pain, eosinophilia). Consider permanent discontinuation if liver tests worsen after restarting IQIRVO.

Hypersensitivity Reactions: Hypersensitivity reactions have occurred in a clinical trial with IQIRVO at 1.5-times the recommended dosage. Three patients (0.2%) had rash or unspecified allergic reaction that occurred 2 to 30 days after IQIRVO initiation. Hypersensitivity reactions resolved after discontinuation of IQIRVO and treatment with steroids and/or antihistamines. If a severe hypersensitivity reaction occurs, permanently discontinue IQIRVO. If a mild or moderate hypersensitivity reaction occurs, interrupt IQIRVO and treat promptly. Monitor the patient until signs and symptoms resolve. If a hypersensitivity reaction recurs after IQIRVO rechallenge, then permanently discontinue IQIRVO.

Biliary Obstruction: Avoid use of IQIRVO in patients with complete biliary obstruction. If biliary obstruction is suspected, interrupt IQIRVO and treat as clinically indicated.

Drug-Drug Interactions

IQIRVO may reduce the systemic exposure of progestin and ethinyl estradiol (CYP3A4 substrates), which may lead to contraceptive failure and/or an increase in breakthrough bleeding. Switch to effective non-hormonal contraceptives or add a barrier method when using hormonal contraceptives during treatment with IQIRVO and for at least 3 weeks after last dose.

CPK elevation and/or myalgia occurred in patients on IQIRVO monotherapy. Co-administration of IQIRVO and HMG-CoA reductase inhibitors can increase the risk of myopathy. Monitor for signs and symptoms of muscle injury. Consider periodic assessment (clinical exam, CPK) during treatment. Interrupt IQIRVO treatment if there is new onset or worsening of muscle pain or myopathy.

Co-administration of IQIRVO with rifampin, an inducer of metabolizing enzymes, may reduce the systemic exposure of elafibranor resulting in delayed or suboptimal biochemical response. Monitor the biochemical response (e.g., ALP and bilirubin) when patients initiate rifampin during treatment with IQIRVO.

Bile acid sequestrants may interfere with IQIRVO absorption and systemic exposure, which may reduce efficacy. Administer IQIRVO at least 4 hours before or after a bile acid sequestrant, or at as great an interval as possible.

Use in Special Populations

Pregnancy: Based on data from animal reproduction studies, IQIRVO may cause fetal harm when administered during pregnancy. There are insufficient data from human pregnancies exposed to IQIRVO to allow an assessment of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Report pregnancies to Ipsen Biopharmaceuticals, Inc. adverse event reporting line at 1-855-463-5127 or https://www.ipsen.com/contact-us/.
Lactation: There are no data available on the presence of IQIRVO or its metabolites in human milk, or on effects of the drug on the breastfed infant or the effects on milk production. IQIRVO is not recommended during breastfeeding and for at least 3 weeks following last dose of IQIRVO because the risk to breastfed child cannot be excluded.

Females and Males of Reproductive Potential: IQIRVO may cause fetal harm when administered to pregnant women. Verify the pregnancy status of females of reproductive potential prior to initiating IQIRVO. Advise females of reproductive potential to use effective contraception during treatment with IQIRVO and for 3 weeks after the final dose.

The most common adverse events occurring in ≥10% of patients were weight gain (23%), abdominal pain (11%), nausea (11%), vomiting (11%), and diarrhea (11%).

You are encouraged to report side effects to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Ipsen Biopharmaceuticals, Inc. at 1-855-463-5127.

Please see full Prescribing Information for IQIRVO in the U.S.
Please see full Prescribing Information for IQIRVO in the E.U.

ENDS

About Ipsen
We are a global biopharmaceutical company with a focus on bringing transformative medicines to patients in three therapeutic areas: Oncology, Rare Disease and Neuroscience.

Ipsen is listed in Paris (Euronext: IPN) and in the U.S. through a Sponsored Level I American Depositary Receipt program (ADR: IPSEY). For more information, visit ipsen.com.

Ipsen contacts

Investors

Nicolas Bogler | + 33 6 52 19 98 92

Media

Jennifer Smith-Parker | + 44 7843 13 77 64 | jennifer.smith-parker.ext@ipsen.com
Rachel Reiff | + 1 908 616 1680 | rachel.reiff@ipsen.com
Anna Gibbins | + 44 7717 80 19 00| anna.gibbins@ipsen.com

Disclaimers and/or Forward-Looking Statements

The forward-looking statements, objectives and targets contained herein are based on Ipsen’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 Ipsen’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 Ipsen’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 Ipsen. 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 medicine 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. Ipsen must face or might face competition from generic medicine 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 Ipsen may fail to achieve its objectives and be forced to abandon its efforts with regards to a medicine in which it has invested significant sums. Therefore, Ipsen cannot be certain that favorable results obtained during preclinical 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 medicine concerned. There can be no guarantees a medicine will receive the necessary regulatory approvals or that the medicine 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 healthcare legislation; global trends toward healthcare cost containment; technological advances, new medicine and patents attained by competitors; challenges inherent in new-medicine development, including obtaining regulatory approval; Ipsen’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 Ipsen’s patents and other protections for innovative medicines; and the exposure to litigation, including patent litigation, and/or regulatory actions. Ipsen also depends on third parties to develop and market some of its medicines which could potentially generate substantial royalties; these partners could behave in such ways which could cause damage to Ipsen’s activities and financial results. Ipsen 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 Ipsen’s partners could generate lower revenues than expected. Such situations could have a negative impact on Ipsen’s business, financial position or performance. Ipsen 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. Ipsen’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 Ipsen’s latest Universal Registration Document, available on ipsen.com.

References

^1.Kowdley. K,. et al. Long term efficacy and safety of elafibranor in primary biliary cholangitis: Interim results from the open-label extension of the ELATIVE^® trial up to 3 years . Poster, Abstract 5041. American Association for the Study of Liver Disease (AASLD).2024
².Swain. M, et al. Impact of elafibranor on fatigue in patients with primary biliary cholangitis: Interim results from the long-term open-label extension of the ELATIVE^® trial . Poster, Abstract 5042. American Association for the Study of Liver Disease (AASLD).2024
³Lu M, Zhou, et al. Fibrotic Liver Disease Consortium Investigators. Increasing Prevalence of Primary Biliary Cholangitis and Reduced Mortality With Treatment. Clin Gastroenterol Hepatol. 2018 Aug;16(8):1342-1350.e1. DOI: 10.1016/j.cgh.2017.12.033.

Attachment

Ipsen PR_Iqirvo® (elafibranor) data shows efficacy and safety for up to 3 years_15112024

Iqirvo^® (elafibranor) 80 mg tablets is the first new medicine approved in nearly a decade for the treatment of the rare liver disease called primary biliary cholangitis
Approval based on positive Phase III ELATIVE trial data
Primary biliary cholangitis impacts approximately 100,000 people in the US and is growing in global prevalence. If inadequately treated, it can cause liver failure
U.S. approval of Iqirvo establishes Ipsen as a leader in the treatment of rare cholestatic liver diseases

PARIS, FRANCE, 10 June 2024 Ipsen (Euronext: IPN; ADR: IPSEY) today announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval for Iqirvo^® (elafibranor) 80 mg tablets for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. Iqirvo may be prescribed immediately in the U.S. for eligible patients.

“For a significant number of people living with PBC, available treatments do not control the condition and may exacerbate symptoms of PBC. Left unmanaged, PBC can progress, leading to liver failure and in some cases, the need for a liver transplant,” said Christelle Huguet, Executive Vice President, Head of Research and Development at Ipsen. “Iqirvo demonstrated statistically significant improvements in biochemical response compared to UDCA alone. Iqirvo is therefore a much-needed treatment option and the first new medicine for PBC in nearly a decade.”

Iqirvo is a first-in-class oral, once-daily peroxisome proliferator-activated receptor (PPAR) agonist. Iqirvo was in-licensed from GENFIT in 2021. The accelerated approval of Iqirvo is based on data from the Phase III ELATIVE trial published in the New England Journal of Medicine¹. The ELATIVE trial demonstrated that 13 times more patients achieved the composite primary endpoint of biochemical response when treated with Iqirvo plus UDCA (n=108) versus placebo plus UDCA (=53) (respectively 51% versus 4% for a 47% treatment difference). ALP is a biochemical marker and is used as a surrogate endpoint in PBC trials. Secondary endpoints showed normalization in ALP levels in only Iqirvo-treated patients (15% for Iqirvo plus UDCA (n=108) versus 0% for placebo plus UDCA (n=53)). Most patients (95%) received study treatment (Iqirvo or placebo) in combination with UDCA.

The most common adverse reactions with Iqirvo reported in ≥10% of study participants were weight gain, abdominal pain, diarrhea, nausea and vomiting. Some study participants treated with Iqirvo experienced myalgia, myopathy and rhabdomyolysis; fractures; adverse effects on fetal and newborn development; drug-induced liver injury; hypersensitivity reactions; or biliary obstruction. See full Important Safety Information below.

“Data from the pivotal Phase III ELATIVE clinical trial demonstrated that Iqirvo is an effective second-line treatment for patients with PBC with favorable benefit and risk data,” said Dr. Kris Kowdley, Director at Liver Institute Northwest, Washington and a primary investigator on the ELATIVE study. “The approval of Iqirvo will allow healthcare providers in the U.S. to address an unmet need with the potential to significantly reduce ALP levels for our patients with PBC.”

PBC is a rare, autoimmune, cholestatic liver disease where a build-up of bile and toxins (cholestasis) and chronic inflammation causes irreversible fibrosis (scarring) of the liver and destruction of the bile ducts. Impacting approximately 100,000 people in the U.S.², the majority being women, PBC is a lifelong condition that can worsen over time if not effectively treated, leading to liver transplant and in some cases, premature death. PBC also affects day-to-day life, with people most commonly experiencing severe fatigue symptoms and debilitating itch (pruritus).

“People living with PBC can feel like the symptoms they experience are dismissed by family members, friends or even their doctors, because they have not experienced something similarly disruptive in their lives. People with PBC may also feel uncertainty around the disease progression and if, or when, their liver health may deteriorate,” said Carol Roberts, Executive President of PBCers, a patient advocacy organization in the U.S. providing support to people living with PBC. “Earlier diagnosis and education about PBC, along with new treatment options are important to meet the current needs of people living with PBC.”

Iqirvo has been submitted to the European Medicines Agency (EMA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), seeking authorization for PBC, with final EMA and MHRA regulatory decisions anticipated in the second half of 2024. The FDA approval of Iqirvo further strengthens Ipsen’s portfolio of treatments for rare cholestatic liver diseases available to patients in the U.S. This includes our FDA approved medicine for the treatment of pruritus in patients three months and older with progressive familial intrahepatic cholestasis (PFIC) and for the treatment of cholestatic pruritus in patients from 12 months of age with Alagille syndrome (ALGS).

IMPORTANT SAFETY INFORMATION

Myalgia, Myopathy, and Rhabdomyolysis: Rhabdomyolysis resulting in acute kidney injury occurred in one IQIRVO-treated patient who had cirrhosis at baseline and was also taking a stable dose of an HMG-CoA reductase inhibitor (statin). Myalgia or myopathy, with or without CPK elevations, occurred in patients treated with IQIRVO alone or treated concomitantly with a stable dose of an HMG-CoA reductase inhibitor. Assess for myalgia and myopathy prior to IQIRVO initiation. Consider periodic assessment (clinical exam, CPK measurement) during treatment with IQIRVO, especially in those who have signs and symptoms of new onset or worsening of muscle pain or myopathy. Interrupt IQIRVO treatment if there is new onset or worsening of muscle pain, or myopathy, or rhabdomyolysis.

Fractures: Fractures occurred in 6% of IQIRVO-treated patients compared to no placebo-treated patients. Consider the risk of fracture in the care of patients treated with IQIRVO and monitor bone health according to current standards of care.

Adverse Effects on Fetal and Newborn Development: IQIRVO may cause fetal harm when administered during pregnancy. For females of reproductive potential, verify that the patient is not pregnant prior to initiation of therapy. Advise females of reproductive potential to use effective non-hormonal contraceptives or add a barrier method when using systemic hormonal contraceptives during treatment with IQIRVO and for 3 weeks following the last dose of IQIRVO.

Drug-Induced Liver Injury: Drug-induced liver injury occurred in one patient who took IQIRVO 80 mg once daily and two patients who took IQIRVO at 1.5-times the recommended dosage, of which one presented with autoimmune-like hepatitis. The median time to onset of elevation in liver tests was 85 days. Obtain baseline clinical, laboratory and imaging assessments at treatment initiation with IQIRVO and monitor thereafter according to routine patient management. Interrupt IQIRVO treatment if liver tests (ALT, AST, total bilirubin [TB], and/or alkaline phosphatase [ALP]) worsen, or the patient develops signs and symptoms consistent with clinical hepatitis (e.g., jaundice, right upper quadrant pain, eosinophilia). Consider permanent discontinuation if liver tests worsen after restarting IQIRVO.

Hypersensitivity Reactions: Hypersensitivity reactions have occurred in a clinical trial with IQIRVO at 1.5-times the recommended dosage. Three patients (0.2%) had rash or unspecified allergic reaction that occurred 2 to 30 days after IQIRVO initiation. Hypersensitivity reactions resolved after discontinuation of IQIRVO and treatment with steroids and/or antihistamines. If a severe hypersensitivity reaction occurs, permanently discontinue IQIRVO. If a mild or moderate hypersensitivity reaction occurs, interrupt IQIRVO and treat promptly. Monitor the patient until signs and symptoms resolve. If a hypersensitivity reaction recurs after IQIRVO rechallenge, then permanently discontinue IQIRVO.

Biliary Obstruction: Avoid use of IQIRVO in patients with complete biliary obstruction. If biliary obstruction is suspected, interrupt IQIRVO and treat as clinically indicated.

Drug-Drug Interactions

Use in Special Populations

Pregnancy: Based on data from animal reproduction studies, IQIRVO may cause fetal harm when administered during pregnancy. There are insufficient data from human pregnancies exposed to IQIRVO to allow an assessment of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Report pregnancies to Ipsen Pharmaceuticals, Inc. Adverse Event reporting line at 1-855-463-5127 or https://www.ipsen.com/contact-us/.

Lactation: There are no data available on the presence of IQIRVO or its metabolites in human milk, or on effects of the drug on the breastfed infant or the effects on milk production. IQIRVO is not recommended during breastfeeding and for at least 3 weeks following last dose of IQIRVO because the risk to breastfed child cannot be excluded.

Females and Males of Reproductive Potential: IQIRVO may cause fetal harm when administered to pregnant women. Verify the pregnancy status of females of reproductive potential prior to initiating IQIRVO. Advise females of reproductive potential to use effective contraception during treatment with IQIRVO and for 3 weeks after the final dose.

The most common adverse events occurring in ≥10% of patients were weight gain (23%), abdominal pain (11%), nausea (11%), vomiting (11%), and diarrhea (11%).

You are encouraged to report side effects to FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Ipsen Pharmaceuticals at 1-855-463-5127.

Please see full Prescribing Information for IQIRVO.

About Iqirvo

Iqirvo (pronounced EYE-KER-VO) is an oral, once-daily, peroxisome proliferator-activated receptor (PPAR) agonist indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. While the mechanism is not well understood, pharmacological activity that is potentially relevant to Iqirvo therapeutic effects includes inhibition of bile acid synthesis through activation of PPAR-alpha and PPAR-delta. In 2019, Iqirvo was granted Breakthrough Therapy Designation by the U.S Food and Drug Administration (FDA) in adults with PBC who have an inadequate response to ursodeoxycholic acid (UDCA) the existing first-line therapy for PBC. Iqirvo has not received approval by regulatory authorities outside of the U.S. Iqirvo is currently under regulatory review with the European Medicines Agency (EMA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Iqirvo was discovered and developed by GENFIT and Ipsen licensed the exclusive worldwide rights (except China, Hong Kong, Taiwan and Macau) to elafibranor from GENFIT in 2021.

Iqirvo has been granted approval under the FDA accelerated approval program, which allows for approval of medicines that treat serious conditions and fill an unmet medical need based on a surrogate endpoint. Under the program, Ipsen is required to conduct a trial to confirm anticipated clinical benefit. The confirmatory trial for Iqirvo, ELFIDENCE, is ongoing.

Iqirvo is an 80 mg tablet administered orally once daily. To ensure access to Iqirvo for eligible individuals in the U.S., the IPSEN CARES^® patient support program is available as a resource to people living with PBC and their caregivers to provide educational support and address coverage, access and reimbursement questions (1-866-435-5677).

About the Phase III ELATIVE trial

ELATIVE is a multi-center, randomized double-blind, placebo-controlled Phase III clinical trial (n=161) that evaluated the efficacy and safety of Iqirvo 80mg once daily plus UDCA (n=108) versus placebo plus UDCA (n=53). Iqirvo or placebo was administered in combination with UDCA in 95% of patients and as monotherapy in 5% of patients who were unable to tolerate UDCA. The 52-week study was completed by 92% of participants with 97% of those who completed the study continuing in an extension study. The results were published in the New England Journal of Medicine¹.

The ELATIVE trial demonstrated that Iqirvo had a statistically significant treatment benefit with 51% of patients on Iqirvo achieving a biochemical response compared with 4% on the placebo arm, a treatment benefit of 47% (95% CI 32, 57; p<0.0001). Biochemical response was defined as ALP less than 1.67 Upper Limit of Normal (ULN), an ALP decrease of greater than or equal to 15% from baseline and total bilirubin (TB) ≤ ULN at week 52.
ALP normalization at week 52 was a key secondary endpoint with 15% of Iqirvo-treated patients demonstrating normalization versus 0% placebo (p=0.002).
The significant biochemical response to Iqirvo was further supported by data demonstrating reductions from baseline in ALP levels were sustained through week 52 and response was rapid, seen as early as Week 4 in the Iqirvo group.
The most common adverse reactions with Iqirvo reported in ≥10% of study participants were weight gain, abdominal pain, diarrhea, nausea and vomiting.

ENDS

About Ipsen

We are a global biopharmaceutical company with a focus on bringing transformative medicines to patients in three therapeutic areas: Oncology, Rare Disease and Neuroscience.

Ipsen is listed in Paris (Euronext: IPN) and in the U.S. through a Sponsored Level I American Depositary Receipt program (ADR: IPSEY). For more information, visit ipsen.com.

Ipsen contacts

Investors

Craig Marks | + 44 (0)7584 34 91 93
Nicolas Bogler | + 33 6 52 19 98 92

Media

Amy Wolf | + 41 79 576 07 23 | amy.wolf@ipsen.com
Rachel Reiff | + 1 908 616 1680 | rachel.reiff@ipsen.com
Anna Gibbins | + 44 7717 80 19 00| anna.gibbins@ipsen.com

Disclaimers and/or Forward-Looking Statements

Ipsen

References

Kowdley. K.V, et al. Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis. NEJM. 2023. DOI: 10.1056/NEJMoa2306185
Lu M, Zhou, et al. Fibrotic Liver Disease Consortium Investigators. Increasing Prevalence of Primary Biliary Cholangitis and Reduced Mortality With Treatment. Clin Gastroenterol Hepatol. 2018 Aug;16(8):1342-1350.e1. DOI: 10.1016/j.cgh.2017.12.033.

Attachment

Ipsen PR_IQIRVO FDA approval _10062024

New data from the ELATIVE^® Phase III trial show 70% of patients treated with elafibranor achieved composite endpoint of slowing disease progression measured by biochemical response after 78-weeks
Data from the itch domain of the PBC-40 and 5-D Itch questionnaires shows the potential of elafibranor to improve itch-related quality of life in patients with moderate-to-severe pruritus
Significant unmet need remains for new treatment options in primary biliary cholangitis that control disease progression and debilitating symptoms impacting quality of life

PARIS, FRANCE, 5 June 2024 Ipsen (Euronext: IPN; ADR: IPSEY) today announced new late-breaking data at the European Association for the Study of the Liver (EASL) Congress demonstrating the enduring efficacy of elafibranor in managing disease progression after 78 weeks of treatment. In the variable double-blind period of the ELATIVE^® Phase III trial in primary biliary cholangitis (PBC), the potential for elafibranor to improve itch-related quality of life (QoL) as measured by the itch domain of the PBC-40 and the 5-D Itch questionnaire was also demonstrated. Elafibranor is a novel, potential first-in-class, PPAR agonist. It is currently under review by the U.S. Food and Drug Administration, the European Medicines Agency and the UK Medicines and Healthcare Products Regulatory Authority.

“There are a significant proportion of people living with PBC who experience worsening disease and debilitating symptoms despite being on treatment. These long-term data from the Phase III ELATIVE study further demonstrate the potential for elafibranor to provide an effective treatment option for these patients,” said Sandra Silvestri, M.D. Executive Vice President and Chief Medical Officer, Ipsen. “A lack of effective management can lead to advanced forms of the disease where liver transplantation may be the only option. Transplants are not trivial, so we must and can do better to preserve native liver function for people living with PBC.”

Data presented at EASL for patients who had their week-78 double-blind visit (30 patients receiving elafibranor and 13 patients receiving placebo) demonstrated the efficacy of elafibranor was sustained after 78 weeks of treatment with 70% of patients on elafibranor meeting the composite endpoint of biochemical response versus 0% on placebo. Biochemical response was defined as alkaline phosphatase (ALP) <1.67 x upper limit of normal (ULN), an ALP decrease ≥ 15 percent and total bilirubin (TB) ≤ ULN. ALP and bilirubin are important predictors of PBC disease progression. Reductions in levels of both can indicate reduced liver injury and improved liver function. ALP normalization for patients on elafibranor was sustained out to week-78 as well as across other important biomarkers of liver injury, including total bilirubin and gamma glutamyl transferase.¹

New patient-reported outcome data from ELATIVE at week 52 were also presented, demonstrating the potential beneficial effect of elafibranor on itch-related quality of life, including sleep and functioning. Treatment with elafibranor led to greater reductions in 5-D Itch score which comprises five domains (degree, duration, dimension, disability and distribution) versus placebo. A clinically meaningful reduction in the itch domain of PBC-40 for elafibranor versus placebo was also observed, with a greater proportion of patients treated with elafibranor experiencing improvement in itch-related quality of life. These include across measures of severity of itching, sleep disturbance and emotional impact of itching, versus placebo. In the 5-D Itch domain of duration, reduced itching was reported by 58% of patients receiving elafibranor at week 52, compared with 27% on placebo. Additionally, 80% of patients receiving elafibranor improved to no sleep disturbance or only occasional delay, compared with 30% on placebo. The improvements in 5-D Itch and PBC-40 Itch emphasize the potential of elafibranor to reduce both the severity of PBC symptoms and their impact on QoL.²

“When you have a patient with PBC, it’s vital to manage disease progression, to prevent or delay liver damage or failure. You also want to provide relief from distressing symptoms because they can have a very detrimental impact on quality of life,” said Dr. Christopher Bowlus, Professor of Gastroenterology and Hepatology, University of California Davis, U.S. “These new data from ELATIVE provide further evidence that elafibranor has the potential to address the two priority treatment goals by demonstrating longer-term improvements in the prognostic markers of disease progression, as well as potential improvements in pruritus-symptom severity and impacts on the quality of life.”

PBC is a rare, progressive, autoimmune cholestatic liver disease, in which the body attacks and gradually destroys the liver’s small bile ducts.³ If left untreated, bile and toxins can build up, leading to scarring of the liver and eventual liver failure.³^–⁵ Symptoms of PBC can have a substantial impact on a person’s QoL, including fatigue and itching.⁶^,⁷ However, while some people living with PBC may not display symptoms, they remain at risk of disease progression and liver damage, making active disease management vital.⁸

Ipsen also presented new data from its growing rare cholestatic liver disease portfolio at EASL, including data on its treatment for progressive familial intrahepatic cholestasis and Alagille syndrome.

ENDS

About ELATIVE

ELATIVE is a multi-center, randomized, double-blind, placebo-controlled Phase III clinical trial, with an open-label long-term extension (NCT04526665). ELATIVE is evaluating the efficacy and safety of elafibranor 80mg once daily versus placebo for the treatment of patients with PBC with an inadequate response or intolerance to ursodeoxycholic acid (UDCA), the existing first-line therapy for PBC. The trial enrolled 161 patients who were randomized 2:1 to receive elafibranor 80mg once daily or placebo. Patients with an inadequate response to UDCA would continue to receive UDCA in combination with elafibranor or placebo, while patients unable to tolerate UDCA would receive only elafibranor or placebo. Patients continued their assigned treatment after Week 52 until all patients had completed their treatment or for a maximum of 104 weeks. Data was also collected during this period, and additional analyses were conducted with a focus on Week 78.

About Ipsen

We are a global biopharmaceutical company with a focus on bringing transformative medicines to patients in three therapeutic areas: Oncology, Rare Disease and Neuroscience.

Ipsen is listed in Paris (Euronext: IPN) and in the U.S. through a Sponsored Level I American Depositary Receipt program (ADR: IPSEY). For more information, visit ipsen.com.

Ipsen contacts

Investors

Craig Marks | + 44 7584 349 193
Nicolas Bogler | + 33 6 52 19 98 92

Media

Amy Wolf | + 41 79 576 07 23 | amy.wolf@ipsen.com
Anna Gibbins | + 44 7717 801900 | anna.gibbins@ipsen.com

Disclaimers and/or Forward-Looking Statements

References

Bowlus et al. J. Hepatol. 2024 ; 80(S1)S80
Kremer et al. J. Hepatol. 2024; 80(S1)S91
EASL. J Hepatol. 2017; 67(1):145-172.
Younossi ZM, et al. Am J Gastroenterol. 2019; 114(1):48–63.
Galoosian A, et al. J Clin Transl Hepatol. 2020; 8(1), pp. 49-60.
Mells GF, et al. Hepatology. 2013; 58: 273-283.
C Levy, et al. Abstract presented at ISPOR, 7-11 May 2023, Boston.
Prince MI, et al. Gut. 2004; 53(6), pp.865-870.

Attachment

PR_ELATIVE EASL 2024_05062024

PARIS, FRANCE, 2 May 2024 – Ipsen (Euronext: IPN; ADR: IPSEY), a global specialty-driven biopharmaceutical company, announced today the appointment of Keira Driansky as EVP, President of North America, effective May 13, 2024. She will serve on the Executive Leadership Team (ELT) and report directly to Ipsen’s Chief Executive Officer (CEO), David Loew.

“We are thrilled to welcome Keira to Ipsen as our new President of North America as she brings extensive experience in the life sciences industry and a proven track record of leadership to our team,” said David Loew, CEO Ipsen. “As we continue to navigate the complexities of the pharmaceutical landscape, Keira’s strategic vision will be instrumental in guiding our company toward a future of bringing groundbreaking medicines and enhanced outcomes to patients.”

Keira will be joining Ipsen from AstraZeneca, where she spent the last 13 years leading teams across the US, Europe and global functions. Most recently Keira served as Country President of AstraZeneca for Belgium and Luxembourg, where she oversaw 14 launches across various therapeutic areas, leading AZ to become the fastest-growing pharma company in Belgium. Previously, she served as VP, Global Commercial Head for Tagrisso across more than 90 countries. She also spent more than five years in AZ’s US Oncology business leading multiple sales and marketing teams through six launches.  

A former science researcher, Keira brings broad experience across the healthcare industry, from commercial leadership to healthcare investing and business development. She received her MBA from Harvard Business School and an MPhil in Bioscience Enterprise from the University of Cambridge. Keira also conducted breast cancer epidemiology research at the University of Oxford as a Marshall Scholar and conducted biochemistry research at Yale under a Howard Hughes Medical Fellowship.

“I’m excited to join the talented and established team at Ipsen at this time of dynamic growth, with four innovative launches across therapeutic areas, including the latest in first-line pancreatic cancer,” said Keira Driansky. “I look forward to partnering with Ipsen’s employees, customers, and stakeholders across the healthcare ecosystem to deliver breakthrough solutions for some of the most pressing global health challenges of our time.”

Stewart Campbell, who as Ipsen’s President of North America for three years led the acceleration of Ipsen’s growth, will leave Ipsen to pursue other opportunities.

ENDS

About Ipsen

We are a global biopharmaceutical company with a focus on bringing transformative medicines to patients in three therapeutic areas: Oncology, Rare Disease and Neuroscience.

Ipsen is listed in Paris (Euronext: IPN) and in the U.S. through a Sponsored Level I American Depositary Receipt program (ADR: IPSEY). For more information, visit ipsen.com.

Ipsen contacts

Investors

Craig Marks | +44 (0)7584 349 193 | craig.marks@ipsen.com
Nicolas Bogler | +33 6 52 19 98 92 | nicolas.bogler@ipsen.com

Media

Amy Wolf | +41 79 576 07 23 | amy.wolf@ipsen.com
Elizabeth Kalina | +1 857 331 0060| elizabeth.kalina@ipsen.com

Disclaimers and/or Forward-Looking Statements

Attachment

Ipsen PR_Keira Driansky_02052024

Approval based on Phase III NAPOLI 3 clinical trial in which Onivyde^® regimen (NALIRIFOX) demonstrated statistically significant superiority and clinically meaningful improvements in overall survival and progression-free survival versus nab-paclitaxel and gemcitabine ¹
NAPOLI 3 represents the first positive Phase III trial in first-line metastatic pancreatic adenocarcinoma (mPDAC) to demonstrate superior overall survival versus the currently approved regimen of nab-paclitaxel and gemcitabine¹
Onivyde is the only FDA-approved treatment regimen to demonstrate efficacy in two Phase III trials across lines of therapy in mPDAC^1,²

PARIS, FRANCE, 13 February 2024 – Ipsen (Euronext: IPN; ADR: IPSEY) announced today that the U.S. Food and Drug Administration (FDA) has approved the supplemental new drug application for Onivyde^® (irinotecan liposome injection) plus oxaliplatin, fluorouracil and leucovorin (NALIRIFOX) as a first-line treatment in adults living with metastatic pancreatic adenocarcinoma (mPDAC). This is the second approval for an Onivyde regimen in mPDAC, following the FDA’s approval in 2015 of Onivyde plus fluorouracil and leucovorin following disease progression with gemcitabine-based therapy.

“The results from the Phase III NAPOLI 3 trial represent the first positive data for an investigational regimen in first-line metastatic pancreatic adenocarcinoma versus the currently approved nab-paclitaxel and gemcitabine regimen,” said Christelle Huguet, EVP and Head of Research and Development, Ipsen. “With today’s approval, this Onivyde (NALIRIFOX) regimen can now offer a potential new standard-of-care treatment option with proven survival benefits for people living with metastatic pancreatic adenocarcinoma in the U.S.”

Pancreatic adenocarcinoma (PDAC) is the most common type of cancer that forms in the pancreas, with more than 60,000 people diagnosed in the U.S. each year and nearly 500,000 people globally.³^,⁴ Since there are no specific symptoms in the early stages, PDAC is often detected late and after the disease has spread to other parts of the body (metastatic or stage IV).⁵ Characterized as a complex cancer due to rapid tumor progression, limited genetic targets and multiple resistance mechanisms,⁶ mPDAC has a poor prognosis with fewer than 20% of people surviving longer than one year.⁴^,⁵ Overall, pancreatic cancer has the lowest five-year survival rate of all cancer types globally and in the U.S.⁴^,⁵

“Metastatic pancreatic adenocarcinoma is a difficult disease to manage with very few available treatment options. Given the reality of this aggressive form of cancer and the complexity of the disease, every advance in the treatment landscape represents a meaningful improvement in patient outcomes.” said Dr. Zev Wainberg, Professor of Medicine and Co-Director of the UCLA GI Oncology Program. “The approval of this Onivyde regimen is an important milestone for people living with mPDAC, their families and healthcare providers, with the NAPOLI 3 trial having demonstrated survival benefits versus a current standard of care treatment option.”

“We are pleased that the U.S. Food and Drug Administration has issued this new approval of the NALIRIFOX regimen. With each new approved treatment, there is more hope for those who will be diagnosed in the future and people currently living with pancreatic cancer may have more time with their loved ones,” said Julie Fleshman, JD, MBA, President and CEO of Pancreatic Cancer Action Network (PanCAN), a patient advocacy organization committed to providing evidence-based information and resources to patients and caregivers, along with advancing research to improve patient outcomes. “We are thankful to the patients who participated in this clinical trial as they play a crucial role in advancing treatments for pancreatic cancer.”

NAPOLI 3 data

The FDA approval was based on efficacy and safety data from NAPOLI 3, a randomized, open-label, Phase III pivotal trial that enrolled 770 people living with mPDAC between the ages of 20 and 85 without prior treatment across 187 trial site locations in 18 countries. The study, which met the primary and secondary endpoints, was presented as a late-breaking presentation at the ASCO Gastrointestinal conference 2023 and subsequently published in The Lancet.^1,⁷Additionally, NALIRIFOX was recognized by the National Comprehensive Cancer Network^® (NCCN) guidelines* and recommended as a preferred, Category 1 treatment option in first-line metastatic disease and as a preferred option in first-line locally advanced disease.⁸

The study demonstrated NALIRIFOX (n=383) provided a statistically significant improvement in median overall survival (mOS) of 11.1 months (95% confidence interval (CI) (10.0, 12.1)) compared to 9.2 months (95% CI (8.3, 10.6)) in nab-paclitaxel and gemcitabine treated patients (n=387); (hazard ratio (HR) 0.84 [95% CI 0.71–0.99]; p=0.0403).⁹
NALIRIFOX regimen also demonstrated a statistically significant improvement in median progression-free survival (mPFS) of 7.4 months (95% CI (6.0, 7.7)) versus 5.6 months (95% CI (5.3, 5.8)) for nab-paclitaxel and gemcitabine treated patients (HR 0.70 [95% CI 0.59–0.85]; p=0.0001).⁹
The objective response rate was 41.8% (36.8%-46.9%; 95% CI) for patients treated with the NALIRIFOX regimen versus 36.2% (31.4%-41.2%; 95% CI) for patients treated with nab-paclitaxel and gemcitabine.⁹
The safety profile of the Onivyde regimen was manageable and consistent with the profiles of the treatment components, with the potential of serious adverse events of fatal neutropenic fever and severe diarrhea. The most common Grade 3/4 treatment-emergent adverse events were diarrhea, fatigue, nausea, vomiting, decreased appetite, abdominal pain, mucosal inflammation, constipation and decreased weight.⁹ In NAPOLI 3, Grade 3 and 4 diarrhea (early and late-onset) occurred in 20% receiving NALIRIFOX. In the clinical trial, diarrhea was managed following institutional guidelines and appropriate antidiarrheal medications.⁹

*NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

ENDS

About Onivyde (irinotecan liposome injection)

Onivyde is a cancer medicine that blocks an enzyme called topoisomerase I, which is involved in copying cell DNA needed to make new cells. By blocking the enzyme, cancer cells are prevented from multiplying and eventually die. In Onivyde, irinotecan is enclosed in tiny fat particles called ‘liposomes’, which accumulate in the tumor and release slowly over time. Onivyde is administered via intravenous infusion over 90 minutes every two weeks, with recommendations on dosing modifications. Onivyde may be prescribed immediately in the U.S. for eligible people living with mPDAC who are treatment naïve or following gemcitabine-based therapy.

To support access to Onivyde for eligible individuals in the U.S., Ipsen Cares patient support program is available as a resource to people living with mPDAC and their caregivers to provide educational support and address coverage, access and reimbursement questions (1-866-435-5677).

Onivyde is currently approved in most major markets including the U.S., Europe and Asia in combination with fluorouracil (FU) and leucovorin (LV) for the treatment of adult patients with metastatic pancreatic adenocarcinoma after disease progression following gemcitabine-based therapy. Onivyde is not indicated as a single agent for the treatment of adult patients with metastatic pancreatic adenocarcinoma.

In 2020, the FDA granted Ipsen Fast Track designation for Onivyde as a first-line combination treatment for mPDAC. The FDA’s Fast Track program facilitates the development and expedites the review of medicines that treat serious conditions and have the potential to address an unmet medical need.

Ipsen has exclusive commercialization rights for the current and potential future indications for Onivyde in the U.S. Servier, an independent international pharmaceutical company with an international presence in 150 countries, is responsible for the commercialization of Onivyde outside of the U.S. and Taiwan. PharmaEngine is a commercial stage oncology company headquartered in Taipei and is responsible for the commercialization of Onivyde in Taiwan.

About PDAC

PDAC is the most common type of cancer that forms in the pancreas, with more than 60,000 people diagnosed in the U.S. each year and nearly 500,000 people globally.³^,⁴ Since there are no specific symptoms in the early stages, PDAC is often detected late and after the disease has spread to other parts of the body (metastatic or stage IV).⁵ Weight loss, abdominal pain and jaundice are the most common symptoms, making PDAC difficult to detect.¹⁰ Despite significant advances in cancer treatments since the 1970s, no treatment options for PDAC significantly extend life.⁵ Currently, fewer than 20% of people diagnosed with PDAC survive longer than one year and, overall, pancreatic cancer has the lowest five-year survival rate of all cancer types globally and in the U.S.³^,⁴

About the NAPOLI 3 trial¹

NAPOLI 3 is a randomized, open-label Phase III trial of an investigational Onivyde treatment regimen (NALIRIFOX) in patients who have not previously received chemotherapy for mPDAC. NAPOLI 3 enrolled 770 patients across 187 trial site locations in 18 countries across Europe, North America, South America, Asia, and Australia. Patients were randomized to receive Onivyde plus oxaliplatin, fluorouracil and leucovorin (NALIRIFOX regimen; n=383) twice in a month (days 1 and 15 of 28-day cycle) compared to an injection of nab-paclitaxel and gemcitabine (n=387) administered three times a month (days 1, 8, 15 of a 28-day cycle).

About Ipsen

We are a global biopharmaceutical company with a focus on bringing transformative medicines to patients in three therapeutic areas: Oncology, Rare Disease and Neuroscience.

Ipsen is listed in Paris (Euronext: IPN) and in the U.S. through a Sponsored Level I American Depositary Receipt program (ADR: IPSEY). For more information, visit ipsen.com.

U.S. IMPORTANT SAFETY INFORMATION

Indications

ONIVYDE^®(irinotecan liposome injection) is indicated, in combination with oxaliplatin, fluorouracil, and leucovorin for the first-line treatment of adult patients with metastatic pancreatic adenocarcinoma.
ONIVYDE is indicated, in combination with fluorouracil, and leucovorin, for the treatment of adult patients with metastatic pancreatic adenocarcinoma after disease progression following gemcitabine-based therapy.

Limitations of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic pancreatic adenocarcinoma.

WARNING: SEVERE Neutropenia and SEVERE DIARRHEA

Neutropenia

Severe and life-threatening neutropenia, including fatal neutropenic sepsis and fatal neutropenic fever, has occurred in patients receiving ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin and in combination with fluorouracil and leucovorin. Withhold ONIVYDE for absolute neutrophil count below 1500/mm³or neutropenic fever. Monitor blood cell counts periodically during treatment.

Diarrhea

Severe and life-threatening diarrhea has occurred in patients receiving ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin and in combination with fluorouracil and leucovorin. Do not administer ONIVYDE to patients with bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2-4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity.

CONTRAINDICATIONS

ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction or anaphylaxis to ONIVYDE or irinotecan HCl.

WARNINGS AND PRECAUTIONS

Severe Neutropenia: See Boxed WARNING. In NAPOLI 3, Grade 3 and 4 neutropenia occurred in 26% of patients receiving ONIVYDE in combination with oxaliplatin, fluorouracil, and leucovorin (NALIRIFOX) and fatal neutropenic fever in 0.3% of patients. In NAPOLI 3, the incidence of Grade 3 or 4 neutropenia was similar among Asian patients [6 of 20 (30%)] compared to White patients [76 of 289 (26%)]. Neutropenic fever/neutropenic sepsis was reported in 5% of Asian patients (1 of 20) compared to 2.3% of White patients (7 of 306). In NAPOLI-1, Grade 3 and 4 neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil and leucovorin (ONIVYDE/FU/LV). Neutropenic sepsis occurred in 3% and fatal neutropenic sepsis in 0.8%. In NAPOLI-1, the incidence of Grade 3 or 4 neutropenia was higher among Asian patients [18 of 33 (55%)] compared to White patients [13 of 73 (18%)]. Neutropenic fever/neutropenic sepsis was reported in 6% of Asian patients compared to 1% of White patients.

Severe Diarrhea: See Boxed WARNING. In NAPOLI 3, Grade 3 and 4 diarrhea (early-onset [within 24 hours of chemotherapy] and late-onset [more than 24 hours following chemotherapy]) occurred in 20% receiving NALIRIFOX. In NAPOLI-1, Grade 3 or 4 diarrhea occurred in 13% receiving ONIVYDE/FU/LV. The incidence of Grade 3 or 4 late-onset diarrhea was 9% in patients receiving ONIVYDE/FU/LV. The incidence of Grade 3 or 4 early-onset diarrhea was 3% in patients receiving ONIVYDE/FU/LV. To reduce the risk of severe diarrhea, patients should stop lactose-containing products, eat a low-fat diet, and maintain hydration during treatment with ONIVYDE. Withhold ONIVYDE for Grade 2-4 diarrhea. Local institutional guidelines should be followed for the treatment of diarrhea that does not improve within 48 hours and may include the addition of diphenoxylate hydrochloride plus atropine sulfate or octreotide. Following recovery to Grade 1 diarrhea, resume ONIVYDE at a reduced dose.

Interstitial Lung Disease (ILD): Irinotecan HCl can cause severe and fatal ILD. Withhold ONIVYDE in patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation. Discontinue ONIVYDE in patients with a confirmed diagnosis of ILD.

Severe Hypersensitivity Reaction: Irinotecan, including ONIVYDE, can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction.

Embryo-Fetal Toxicity: ONIVYDE can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and for 7 months after the last dose of ONIVYDE treatment.

ADVERSE REACTIONS FOR NALIRIFOX

The most common adverse reactions (≥20% with a difference between arms of ≥5% for all grades or ≥2% for Grades 3 or 4 compared to nab-paclitaxel and gemcitabine) of NALIRIFOX were diarrhea (72%), fatigue (62%), nausea (59%), neutropenia (48%), vomiting (40%), decreased appetite (37%), abdominal pain (35%), hypokalemia (32%), mucosal inflammation (28%), constipation (25%) and weight decreased (22%).
Permanent discontinuation of ONIVYDE due to an adverse reaction occurred in 17% of patients. Adverse reactions that resulted in permanent discontinuation of ONIVYDE in ≥1% of patients included neutropenia, thrombocytopenia, diarrhea, fatigue, infections and cerebrovascular accident.
Dosage reduction of ONIVYDE due to an adverse reaction occurred in 52% of patients. Adverse reactions that required dosage reduction in ≥1% of patients included anemia, decreased appetite, diarrhea, fatigue, febrile neutropenia, hypokalemia, liver function test abnormalities, nausea, mucosal inflammation, neutropenia, peripheral neuropathy, vomiting, thrombocytopenia and weight decreased.
Dosage interruptions of ONIVYDE due to an adverse reaction occurred in 1.9% of patients. Adverse reactions that required dosage interruption in ≥0.5% of patients included hypersensitivity and infusion related reaction.
The most common laboratory abnormalities (≥10% Grade 3 or 4) were decreased neutrophils (26%), decreased potassium (22%), decreased lymphocytes (11%) and decreased hemoglobin (10%).

ADVERSE REACTIONS FOR ONIVYDE/5-FU/LV

The most common adverse reactions (≥20%) were diarrhea (59%), fatigue/asthenia (56%), vomiting (52%), nausea (51%), decreased appetite (44%), stomatitis (32%), and pyrexia (23%).
Adverse reactions led to permanent discontinuation of ONIVYDE in 11% of patients receiving ONIVYDE/5-FU/LV; The most frequent adverse reactions resulting in discontinuation of ONIVYDE were diarrhea, vomiting, and sepsis.
Dose reductions of ONIVYDE for adverse reactions occurred in 33% of patients receiving ONIVYDE/5-FU/LV; the most frequent adverse reactions requiring dose reductions were neutropenia, diarrhea, nausea, and anemia.
ONIVYDE was withheld or delayed for adverse reactions in 62% of patients receiving ONIVYDE/5-FU/LV; the most frequent adverse reactions requiring interruption or delays were neutropenia, diarrhea, fatigue, vomiting, and thrombocytopenia.
The most common laboratory abnormalities (≥10% Grade 3 or 4) were lymphopenia and neutropenia.

Postmarketing Experience: Immune system disorders: Hypersensitivity (including anaphylactic reaction and angioedema)

DRUG INTERACTIONS

Avoid the use of strong CYP3A4 inducers, if possible, and substitute non-enzyme inducing therapies ≥2 weeks prior to initiation of ONIVYDE.
Avoid the use of strong CYP3A4 or UGT1A1 inhibitors, if possible, and discontinue strong CYP3A4 inhibitors ≥1 week prior to starting therapy.

USE IN SPECIFIC POPULATIONS

Pregnancy and Reproductive Potential: See WARNINGS & PRECAUTIONS. Advise males with female partners of reproductive potential to use condoms during and for 4 months after the last dose of ONIVYDE treatment.
Lactation: Advise nursing women not to breastfeed during and for 1 month after the last dose of ONIVYDE treatment.

To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at 1-855-463-5127 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see full Prescribing Information, including Boxed WARNING for ONIVYDE.

Ipsen contacts
Email: corporate.communications@ipsen.com

Investors

Craig Marks | + 44 7584 349 193

Media

Joanna Parish | + 44 7840 023 741

Rachel Reiff | +1 908 616 1680

Disclaimers and/or Forward-Looking Statements

References

¹ Wainberg et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet. 2023 Oct 7;402(10409):1272-1281.
² Wang-Gillam et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2015. DOI: https://doi.org/10.1016/S0140-6736(15)00986-1
³ American Cancer Society – Cancer Facts and Figures 2024. Available : https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2024/2024-cancer-facts-and-figures-acs.pdf
⁴ https://www.cancer.net/cancer-types/pancreatic-cancer/statistics
⁵ Orth, M., Metzger, P., Gerum, S. et al. Pancreatic ductal adenocarcinoma: biological hallmarks, current status, and future perspectives of combined modality treatment approaches. Radiat Oncol 14, 141 (2019). https://doi.org/10.1186/s13014-019-1345-6
⁶ Sarantis et al. Pancreatic ductal adenocarcinoma: Treatment hurdles, tumor microenvironment and immunotherapy. World J Gastrointest Oncol. 2020 Feb 15; 12(2): 173–181. DOI: 10.4251/wjgo.v12.i2.173
⁷ Wainberg, Z.A et al. NAPOLI-3: A Randomized, Open-label Phase 3 Study of Liposomal Irinotecan + 5-fluorouracil/leucovorin + Oxaliplatin (NALIRIFOX) versus Nab-paclitaxel + Gemcitabine in Treatment-naïve Patients with Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC). Presented at ASCO Gastrointestinal Cancers Symposium, 2023, January 19-21; San Francisco, California.
⁸ https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455
⁹ FDA U.S. Prescribing Information. https://d2rkmuse97gwnh.cloudfront.net/a88aa6d6-3ca0-4362-a711-d53c45ae33ff/68b50c8f-8577-4904-950d-d82fa1f91417/68b50c8f-8577-4904-950d-d82fa1f91417_source__v.pdf
¹⁰ www.cancer.org/cancer/types/pancreatic-cancer/detection-diagnosis-staging/signs-and-symptoms

Attachment

Ipsen PR_Onivyde FDA approval_13022024

New Drug Application granted priority review with PDUFA date set for June 10, 2024
European Medicines Agency (EMA) has also validated the Marketing Authorization Application (MAA) for elafibranor
Investigational elafibranor is the first novel second-line treatment for primary biliary cholangitis (PBC) to be filed in E.U. and U.S. in nearly a decade

PARIS, FRANCE, 07 December 2023 – Ipsen (Euronext: IPN; ADR: IPSEY) and GENFIT (Nasdaq and Euronext: GNFT) today announced that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for investigational elafibranor. An oral, once-daily dual peroxisome activated receptor alpha/delta (PPAR α,δ) agonist, investigational elafibranor could potentially be the first novel second-line treatment for the rare, cholestatic liver disease, PBC, in nearly a decade. The target FDA PDUFA date under priority review is June 10, 2024.

The European Medicines Agency (EMA) has also validated Ipsen’s Marketing Authorization Application (MAA) for elafibranor and the review of the submission to the EMA’s Committee for Medicinal Products for Human Use (CHMP) began on 26 October 2023. Furthermore, a third simultaneous regulatory filing of elafibranor has been validated for review by the UK Medicines and Healthcare products Regulatory Agency (MHRA).

“We are delighted to have achieved simultaneous filings for elafibranor, which is in line with our ambition to be able to bring a new and much needed medicine to as many people living with PBC as rapidly as possible,” said Christelle Huguet, EVP and Head of Research & Development, Ipsen. “This is a condition where many patients are living with worsening disease and debilitating symptoms despite being on treatment. Elafibranor, if approved, has the potential to change the management of this challenging condition for people living with PBC, offering a new second line treatment choice, where the number of effective options are currently limited.”

PBC is a rare, progressive, autoimmune cholestatic liver disease¹ in which bile ducts in the liver are gradually destroyed.² The damage to bile ducts can inhibit the liver’s ability to rid the body of toxins, and can lead to scarring of liver tissue, known as cirrhosis.^1,2,3 Common symptoms of PBC include fatigue and pruritus (itch), which can be severely debilitating.⁴ Untreated, PBC can lead to liver failure, or in some cases death.¹It primarily affects women, with nine women diagnosed for every man.³ A significant proportion of people living with PBC do not benefit from existing therapies.^5,6,7

“These simultaneous regulatory submission acceptances are another important step in the elafibranor journey. We are pleased to be partnering with Ipsen, who we know has a good understanding of the rare-disease regulatory process,” said Pascal Prigent, Chief Executive Officer of GENFIT. “We know they share the same goal as GENFIT, to bring a new, much needed treatment option to people living with PBC as fast as possible; we look forward to elafibranor’s progress through the regulatory review processes.”

ENDS

Elafibranor

Elafibranor is an oral, once-daily, dual peroxisome activated receptor (PPAR) alpha/delta (α,δ) agonist, currently under investigation as a treatment for patients with PBC, a rare cholestatic liver disease. Elafibranor, through activation of PPAR α,δ targets multiple cell types and biological processes involved in the pathophysiology of PBC, including cholestasis (impairment of bile flow in the liver), bile toxicity, inflammation and fibrosis and bile acid output. In 2019, elafibranor was granted a Breakthrough Therapy Designation by the U.S Food and Drug Administration in adults with PBC who have an inadequate response to ursodeoxycholic acid (UDCA) the existing first-line therapy for PBC. Elafibranor has not received approval by regulatory authorities anywhere in the world.

ELATIVE

ELATIVE is a multi-center, randomized, double-blind, placebo-controlled Phase III clinical trial, with an open-label long-term extension (NCT04526665). ELATIVE evaluated the efficacy and safety of elafibranor 80mg once daily versus placebo for the treatment of patients with PBC with an inadequate response or intolerance to UDCA. The trial enrolled 161 patients who were randomized 2:1 to receive either elafibranor 80mg once daily or placebo. Patients with an inadequate response to UDCA would continue to receive UDCA in combination with elafibranor or placebo, while patients unable to tolerate UDCA would receive only elafibranor or placebo. Data confirmed the potential for elafibranor to be an effective new treatment option for PBC, with 13 times more patients achieving a biochemical response, suggesting an improvement in disease progression, when treated with elafibranor compared with patients on placebo: 47% placebo-adjusted difference, elafibranor 80mg (51%) compared with placebo (4%) (P<0.001).⁸

Reductions in levels of alkaline phosphatase (ALP) were rapid, seen as early as Week 4 in the elafibranor group, and were sustained through Week 52, with a decrease in ALP of 41% on elafibranor compared with placebo.⁸ ALP and bilirubin are important predictors of PBC disease progression. ELATIVE also investigated the effect of treatment with elafibranor on pruritus (severe itch), a significant symptom burden amongst people living with PBC. Findings from the secondary endpoint using the PBC Worst Itch NRS score, showed a reduction in pruritis for elafibranor, which was not statistically significant. Data reported from two separate patient-reported outcome measures demonstrated reductions in moderate to severe pruritus, which favored elafibranor versus placebo.⁸ Elafibranor was well-tolerated in the trial and has a well-documented safety profile. Adverse events occurring in >10% of patients and more frequently on elafibranor versus placebo included abdominal pain, diarrhea, nausea, and vomiting.⁸

Ipsen
We are a global biopharmaceutical company with a focus on bringing transformative medicines to patients in three therapeutic areas: Oncology, Rare Disease and Neuroscience.

Ipsen is listed in Paris (Euronext: IPN) and in the U.S. through a Sponsored Level I American Depositary Receipt program (ADR: IPSEY). For more information, visit ipsen.com.

GENFIT
GENFIT is a late-stage biopharmaceutical company dedicated to improving the lives of patients with rare and life-threatening liver diseases characterized by high unmet medical needs. GENFIT is a pioneer in liver disease research and development with a rich history and strong scientific heritage spanning more than two decades. Today, GENFIT has a growing and diversified pipeline with programs at various development stages. The Company’s area of focus is Acute on Chronic Liver Failure (ACLF). Its ACLF franchise consists of five assets in development: VS-01, NTZ, SRT-015, CLM-022 and VS-02-HE. These are all based on differentiated mechanisms of action leveraging complementary pathways. Other assets target other life-threatening disease indications such as cholangiocarcinoma (CCA) and Urea Cycle Disorders (UCD)/Organic Acidemias (OA). GENFIT’s track record in bringing early-stage assets with high potential to late development and pre-commercialization stages is highlighted in the successful 52-week Phase 3 ELATIVE® trial evaluating elafibranor in PBC. Beyond therapeutics, GENFIT’s pipeline also includes a diagnostic franchise focused on MASH (previously known as NASH) and ammonia. GENFIT has facilities in Lille and Paris (France), Zurich (Switzerland) and Cambridge, MA (USA). GENFIT is a publicly traded company listed on the Nasdaq Global Select Market and on compartment B of Euronext’s regulated market in Paris (Nasdaq and Euronext: GNFT). In 2021, IPSEN became one of GENFIT’s largest shareholders and holds 8% of the company’s share capital. For more information, visit www.genfit.com

Ipsen contacts

Investors

Craig Marks | + 44 (0)7584 34 91 93 | craig.marks@ipsen.com

Nicolas Bogler | + 33 6 52 19 98 92 | nicolas.bogler@ipsen.com

Media

Amy Wolf | + 41 79 576 07 23 | amy.wolf@ipsen.com

Ioana Piscociu | + 33 6 69 09 12 96 | Ioana.piscociu@ipsen.com

Anna Gibbins | + 44 7717 80 19 00| anna.gibbins@ipsen.com

GENFIT contacts

Investors

GENFIT Investors | + 33 3 20 16 40 00 | investors@genfit.com

Media

Stephanie Boyer | + 33 3 20 16 40 00 | stephanie.boyer@genfit.com

Ipsen Forward-Looking Statements

GENFIT Forward-Looking Statements

This press release contains certain forward-looking statements, including those within the meaning of the Private Securities Litigation Reform Act of 1995 with respect to GENFIT, including, but not limited to statements about the potential of elafibranor as a safe and effective second-line treatment for PBC, the opportunity to manage the disease progression and the potential of elafibranor to improve pruritus, reduce cholestatic injury and improve liver function. The use of certain words, including “believe”, “potential,” “expect”, “target”, “may” and “will” and similar expressions, is intended to identify forward-looking statements. Although the Company believes its expectations are based on the current expectations and reasonable assumptions of the Company’s management, these forward-looking statements are subject to numerous known and unknown risks and uncertainties, which could cause actual results to differ materially from those expressed in, or implied or projected by, the forward-looking statements. These risks and uncertainties include, among other things, the uncertainties inherent in research and development, including in relation to safety of drug candidates, cost of, progression of, and results from, our ongoing and planned clinical trials, review and approvals by regulatory authorities in the United States, Europe and worldwide, of our drug and diagnostic candidates, potential commercial success of elafibranor if approved, exchange rate fluctuations, our continued ability to raise capital to fund our development, as well as those risks and uncertainties discussed or identified in the Company’s public filings with the AMF, including those listed in Chapter 2 “Main Risks and Uncertainties” of the Company’s 2022 Universal Registration Document filed with the AMF on April 18, 2023, which is available on the Company’s website (www.genfit.com) and on the website of the AMF (www.amf-france.org) and public filings and reports filed with the U.S. Securities and Exchange Commission (“SEC”) including the Company’s 2022 Annual Report on Form 20-F filed with the SEC on April 18, 2023 and subsequent filings and reports filed with the AMF or SEC, including the Half-Year Business and Financial Report at June 30, 2023 or otherwise made public, by the Company. In addition, even if the Company’s results, performance, financial condition and liquidity, and the development of the industry in which it operates are consistent with such forward-looking statements, they may not be predictive of results or developments in future periods. These forward-looking statements speak only as of the date of publication of this document. Other than as required by applicable law, the Company does not undertake any obligation to update or revise any forward-looking information or statements, whether as a result of new information, future events or otherwise.

References

Younossi ZM, et al. 2019. Diagnosis and Management of Primary Biliary Cholangitis. Am J Gastroenterol. 114(1):48–63.
European Association for the Study of the Liver. 2017. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 67(1):145-172.
Galoosian A, et al. 2020. Clinical updates in primary biliary cholangitis: trends, epidemiology, diagnostics, and new therapeutic approaches. J Clin Transl Hepatol. 8(1), pp. 49-60.
Kumagi T & Heathcote EJ. 2008. Primary biliary cirrhosis. Orphanet J Rare Di. 3:1.
Ali AH, Byrne TJ, Lindor KD. 2015. Orphan drugs in development for primary biliary cirrhosis: challenges and progress. Orphan Drugs: Research and Reviews. 5(1), pp..83-97 numbers.
Corpechot C, et al. 2011. Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. J Hepatol. 55:1361-7.
Aguilar MT and Chascsa DM. 2020. Update on emerging treatment options for primary biliary cholangitis. Hepat Med. Pp.69-77.
Kowdley. K.V, et al. NEJM. 2023. DOI: 10.1056/NEJMoa2306185

Attachment

PR_Elafibranor FDA NDA and EMA validation_07122023

ELATIVE^® Phase III trial confirms potential for investigational elafibranor as a novel, first-in-class, dual PPAR α,δ agonist for patients with primary biliary cholangitis.

Elafibranor demonstrates significant improvements in biomarkers of disease progression versus placebo, including significant treatment benefit with improvement in biochemical response and alkaline phosphatase (ALP) normalization, along with patient-reported outcomes data suggesting a possible improvement in pruritus.

Elafibranor was generally well-tolerated with a well-documented safety profile consistent with previous trials.

PARIS, FRANCE, 13 November, 2023 – Ipsen (Euronext: IPN; ADR: IPSEY) and GENFIT (Nasdaq and Euronext: GNFT) today announced full results from the pivotal Phase III ELATIVE^® trial, which are being presented in a late-breaking oral session (Abstract #484, Monday, 13 November at 16.45 EST)at the American Association for the Study of Liver Disease (AASLD) and simultaneously published in the New England Journal of Medicine (NEJM). This trial evaluated the efficacy and safety of investigational elafibranor, an oral, dual PPAR α,δ agonist, as a potential novel class of treatment for patients with the rare, autoimmune cholestatic liver disease, primary biliary cholangitis (PBC).

Results show statistically significant improvements in biomarkers of disease progression across key endpoints with a significant treatment benefit achieved in the primary composite endpoint, demonstrating a 47% placebo-adjusted difference (P<0.001) between patients on elafibranor 80mg (51%) compared with patients on placebo (4%) achieving a biochemical response. In the trial, a biochemical response is defined as alkaline phosphatase (ALP) <1.67 x upper limit of normal (ULN), an ALP decrease ≥ 15 percent and total bilirubin (TB) ≤ ULN at 52 weeks. ALP and bilirubin are important predictors of PBC disease progression. Reductions in levels of both can indicate reduced cholestatic injury and improved liver function.

Only patients receiving elafibranor achieved normalization of ALP (upper limit of normal 104 U/L in females and 129 U/L in males) at Week 52 (15% vs 0% placebo, P=0.002), a key secondary endpoint of the trial. The significant biochemical effect of elafibranor measured by ALP reduction was further supported by data demonstrating reductions from baseline in ALP levels were rapid, seen as early as Week 4 in the elafibranor group, and were sustained through Week 52, with a decrease in ALP of 41% on elafibranor compared with placebo.

“When managing PBC our first goal is to effectively control the disease progression which can lead to liver failure. The results from ELATIVE provide compelling evidence that elafibranor has the potential to achieve this goal, with evidence of a highly significant treatment benefit that is associated with improved clinical outcomes,” said Dr Christopher Bowlus, Professor of Gastroenterology and Hepatology, University of California Davis, U.S. “In addition, our patients need relief from the significant symptom burden of PBC, particularly those with moderate to severe itch. Data from ELATIVE demonstrated the possibility of improved pruritus for patients taking elafibranor compared with those on placebo. Taken together, these data suggest elafibranor could offer an effective new treatment opportunity for PBC management.”

ELATIVE investigated the effect of treatment with elafibranor on pruritus (severe itch) across three separate patient-reported outcome measures. On the key secondary endpoint using the PBC Worst Itch NRS score, the reduction of pruritus observed for elafibranor versus placebo was not statistically significant (LS mean, –1.93 versus –1.15; difference, –0.78; 95% CI, –1.99 to 0.42; P=0.20). Two other secondary patient-reported outcome measures were used to assess itch, and greater reductions in pruritus were observed with elafibranor compared with placebo at Week 52, according to the itch domain of PBC-40 quality of life questionnaire (LS mean difference -2.3; 95% CI, -4.0 to -0.7) and 5-D Itch total score (LS mean difference, -3.0; 95% CI, -5.5 to -0.5).

“We believe these data suggest that elafibranor could be a paradigm-changing treatment meeting the unmet need for an effective second-line option,” said Christelle Huguet, EVP and Head of Research and Development, Ipsen. “These data from ELATIVE have provided a better understanding of how we can effectively manage both disease progression and the symptom burden still experienced by many people living with PBC. It would not have been possible for us to investigate the potential for new innovative treatments without the involvement of the patients and their wider families and caregivers, to whom we are immensely grateful. We are also enormously grateful to the study investigators, who have supported us and provided us with the benefit of their expertise in designing and running this study.”

PBC is a rare, autoimmune, cholestatic liver disease, affecting approximately nine women for every one man. A build-up of bile and toxins (cholestasis) and chronic inflammation causes irreversible fibrosis (scarring) of the liver and destruction of the bile ducts. It is a life-long condition that can worsen over time if not effectively treated, leading to liver transplant and in some cases, premature death. PBC impacts patient’s daily lives through debilitating symptoms including most commonly pruritus and fatigue. Currently, there are no approved treatments available that can effectively manage both disease progression and life-impacting symptoms.

“Living with PBC can be very challenging for many people. The fear of the disease progressing hangs over you, and you have to manage as best you can with the daily symptom burden, symptoms that can sometimes be so debilitating it takes every ounce of strength to get through another day,” explained Mo Christie, Head of Patient Services, PBC Foundation, UK. “As someone who is living with PBC, I appreciate the need for clinicians, other patients, and families to understand the condition and the impact that coming to terms with living with an incurable condition can have on a person’s life. The impact can be enormous, so it is vitally important to all aspects of our lives that we can access knowledge, care and effective medicines, when we see our clinicians.”

Elafibranor was well tolerated in the trial. Similar percentages of patients in the treatment group and the placebo group experienced adverse events, treatment-related adverse events, severe or serious adverse events or adverse events leading to discontinuation. Adverse events occurring in >10% of patients and more frequently on elafibranor versus placebo included abdominal pain, diarrhea, nausea, and vomiting. Elafibranor has a well-documented safety profile across a broad patient population and is consistent with cumulative safety data from past elafibranor trials in other indications, including NASH.

Data from ELATIVE are being used to support submissions for elafibranor as a treatment for PBC with regulatory authorities worldwide.

ENDS

ELATIVE

Elafibranor

Elafibranor is a novel, oral, once-daily, dual peroxisome activated receptor (PPAR) alpha/delta (α,δ) agonist, currently under investigation as a treatment for patients with PBC, a rare liver disease. Concurrent α,δ activation targets inflammation, cholestasis and fibrosis in PBC. In 2019, elafibranor was granted a Breakthrough Therapy Designation by the FDA in adults with PBC who have an inadequate response to UDCA. Elafibranor has not received approval by regulatory authorities anywhere in the world.

Ipsen

Ipsen is a global, mid-sized biopharmaceutical company focused on transformative medicines in Oncology, Rare Disease and Neuroscience. With total sales of €3.0bn in FY 2022, Ipsen sells medicines in over 100 countries. Alongside its external-innovation strategy, the Company’s research and development efforts are focused on its innovative and differentiated technological platforms located in the heart of leading biotechnological and life-science hubs: Paris-Saclay, France; Oxford, U.K.; Cambridge, U.S.; Shanghai, China. Ipsen has around 5,300 colleagues worldwide and is listed in Paris (Euronext: IPN) and in the U.S. through a Sponsored Level I American Depositary Receipt program (ADR: IPSEY). For more information, visit ipsen.com

GENFIT

GENFIT is a late-stage biopharmaceutical company dedicated to improving the lives of patients with rare and life-threatening liver diseases characterized by high unmet medical needs. GENFIT is a pioneer in liver disease research and development with a rich history and strong scientific heritage spanning more than two decades. Today, GENFIT has a growing and diversified pipeline with programs at various development stages. The Company’s area of focus is Acute on Chronic Liver Failure (ACLF). Its ACLF franchise consists of five assets in development: VS-01, NTZ, SRT-015, CLM-022 and VS-02-HE. These are all based on differentiated mechanisms of action leveraging complementary pathways. Other assets target other life-threatening disease indications such as cholangiocarcinoma (CCA) and Urea Cycle Disorders (UCD)/Organic Acidemias (OA). GENFIT’s track record in bringing early-stage assets with high potential to late development and pre-commercialization stages is highlighted in the successful 52-week Phase 3 ELATIVE® trial evaluating elafibranor in PBC. Beyond therapeutics, GENFIT’s pipeline also includes a diagnostic franchise focused on MASH (previously known as NASH) and ammonia. GENFIT has facilities in Lille and Paris (France), Zurich (Switzerland) and Cambridge, MA (USA). GENFIT is a publicly traded company listed on the Nasdaq Global Select Market and on compartment B of Euronext’s regulated market in Paris (Nasdaq and Euronext: GNFT). In 2021, IPSEN became one of GENFIT’s largest shareholders and holds 8% of the company’s share capital. For more information, visit www.genfit.com

For further information:

Ipsen Contacts Investors
Craig Marks Vice President, Investor Relations +44 (0)7584 349 193	Nicolas Bogler Investor Relations Manager +33 6 52 19 98 92
Media
Anna Gibbins Global Head of Franchise Communications, Rare Disease +44 (0)7717801900 Amy Wolf VP, Head of Corporate Brand Strategy & Communications +41 79 576 07 23	Ioana Piscociu Senior Manager Global Media Relations +33 6 69 09 12 96

GENFIT contacts

GENFIT | Investors Tel: +33 3 2016 4000 | investors@genfit.com

PRESS RELATIONS | Media Stephanie Boyer – Press relations | Tel: +33 3 2016 4000 | stephanie.boyer@genfit.com

Ipsen’s forward-looking statements

GENFIT’s forward-looking statements

Breakthrough treatment reduces new, abnormal bone formation in soft and connective tissues, in people living with ultra-rare bone disease, fibrodysplasia ossificans progressiva (FOP)
FOP impacts about 400 people in the U.S., it leads to progressive mobility loss, severely limits quality of life and shortens median life expectancy to 56 years
Sohonos^TM may be prescribed immediately in the U.S. for eligible patients, aged 8 years and older for females and 10 years and older for males

PARIS, FRANCE, 16 August 2023 – Ipsen (Euronext: IPN; ADR: IPSEY) announced today approval by the U.S. Food and Drug Administration (FDA) of Sohonos™ (palovarotene) capsules as a retinoid indicated for the reduction in volume of new heterotopic ossification in adults and pediatric patients aged 8 years and older for females and 10 years and older for males with fibrodysplasia ossificans progressiva (FOP).

“The FDA approval of Sohonos is a breakthrough for the U.S. FOP community. For the first time doctors have an approved medicine available to them, shown to reduce the formation of new, abnormal bone growth, known as heterotopic ossification (HO), which causes debilitating mobility challenges and has a devastating impact on the lives of people with FOP,” said Howard Mayer, Head of Research and Development, Ipsen. “Development of medicines for rare diseases takes commitment and belief from everyone involved. We at Ipsen are sincerely grateful to the FOP community of patients and medical experts, as the first-ever treatment in the U.S. for managing FOP would not be possible without their participation in the clinical trials and ongoing support.”

FOP impacts the lives of an estimated 400 people in the U.S. and 900 people globally.¹^,2 As the disease continuously progresses with flare-up episodes causing rapid bone growth, HO severely restricts mobility and function.³^,⁴ Most people living with FOP inevitably lose the ability to eat and drink on their own, cannot provide selfcare or use the restroom themselves, and are unable to maintain employment.⁵ By the age of 30 years old, the majority of people with FOP require a wheelchair and full-time caregiver assistance.^3,6 The management of FOP has previously been limited to palliative care and ultimately, FOP shortens the median life expectancy to 56 years, untimely death is often caused by bone formation around the ribcage leading to breathing problems and cardiorespiratory failure, or falls resulting in fractures or head injuries because joint ankylosis prevents bracing from a fall.⁷

“FOP is life-altering to the individuals diagnosed and their families. There’s not a day that goes by where those impacted don’t worry about the debilitating physical pain of muscle that is replaced by bone, another joint locking or the relentless emotional toll of losing the ability to do an activity they love, or hold a loved one close,” explained Michelle Davis, Executive Director of International FOP Association. “The first treatment for FOP has been proven to reduce the volume of new abnormal bone growth, which may result in better health outcomes for people living with FOP.”

The FDA approval is based on the pivotal efficacy and safety data from the Phase III MOVE trial, the first and largest multicenter, open-label trial in adult and pediatric patients. The 18-month data published in the Journal of Bone and Mineral Research,⁸ included 107 patients (12 percent of the estimated number of individuals worldwide living with FOP) who received oral palovarotene compared with untreated individuals from Ipsen’s global FOP Natural History Study.⁹ The study results demonstrated palovarotene effectively reduced annualized heterotopic ossification volume compared with no treatment beyond standard of care, (54% reduction with weighted linear mixed effect model).⁸ The study also demonstrated that palovarotene has a well-characterized safety profile, with adverse events consistent with the systemic retinoid class. The most common treatment emergent adverse reactions reported in the study were mucocutaneous events such as dry skin, lip dryness, alopecia, drug eruption, rash, and pruritus and musculoskeletal events such as arthralgia and premature growth plate closure in growing children.⁸

“As a clinician caring for patients with FOP, I personally see the daily challenges and stresses that our patients and their families must contend with,” said Dr Edward Hsiao, Professor of Medicine, Division of Endocrinology and Metabolism, University of California, San Francisco. “The published Phase III MOVE study showed that Sohonos can decrease new heterotopic ossification, and that palovarotene can be tolerated by many patients with FOP. Sohonos is not for everyone. As with all medicines there are risks in this case especially for young children who may develop early growth plate closure. In addition, Sohonos has the same side effects as other retinoids, including dryness of the skin and mucus membranes. However, since the accumulation of HO in FOP is progressive, irreversible, and life altering, this medication is an important treatment option for our FOP community.”

Sohonos, the first and only treatment for FOP

Sohonos is an oral medicine with particular selectivity for the gamma subtype of retinoic-acid receptors, which are an important regulator of skeletal development and ectopic bone in the retinoid signaling pathway. The medicine is designed to mediate the interactions between the receptors, growth factors and proteins within the retinoid signaling pathway to reduce new abnormal bone formation in FOP. The recommended dosing for Sohonos includes a chronic daily dosage of 5 mg (or weight-based equivalent for pediatric patients under 14 years of age), which can be modified/increased for flare-up symptoms. Sohonos may be prescribed immediately in the U.S. for eligible patients.

To ensure access to Sohonos for eligible individuals in the U.S., Ipsen Cares patient support program is available as a resource to people living with FOP and their caregivers to provide educational support and address coverage, access and reimbursement questions (1-866-435-5677).

Sohonos received Orphan Drug and Breakthrough Therapy Designations from the U.S. Food and Drug Administration (FDA) for the treatment of FOP and was granted Priority Review of the New Drug Application (NDA). Sohonos, under the generic name palovarotene, is also under review with a number of other regulatory authorities. In July 2023, the European Commission did not grant marketing authorization for palovarotene. Sohonos^TM (palovarotene capsules) is currently authorized for use in eligible patients in U.S., Canada,¹⁰ and with a conditional approval in the United Arab Emirates.

With this approval the FDA also issued a Rare Pediatric Disease Priority Review Voucher (PRV). The voucher can be used for subsequent drug applications that would not qualify for a priority review.

Important Sohonos Safety Information

WARNING: EMBRYO-FETAL TOXICITY and PREMATURE PHYSEAL CLOSURE IN GROWING PEDIATRIC PATIENTS

Embryo-Fetal Toxicity
SOHONOS is contraindicated in pregnancy. SOHONOS can cause fetal harm. Because of the risk of teratogenicity and to minimize fetal exposure, SOHONOS is to be administered only if conditions for pregnancy prevention are met.

Premature Epiphyseal Closure
Premature epiphyseal closure occurs in growing pediatric patients treated with SOHONOS, close monitoring is recommended.

Contraindications
SOHONOS is contraindicated in patients during pregnancy, or with a history of allergy or hypersensitivity to retinoids, or to any component of SOHONOS.

Warnings and Precautions

Embryo-Fetal Toxicity: SOHONOS can cause fetal harm and is contraindicated during pregnancy. Advise females of reproductive potential to use an effective method of contraception during treatment with SOHONOS and for 1 month after the last dose. If a pregnancy occurs during Sohonos treatment, discontinue treatment immediately and refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity.
Premature Epiphyseal Closure in Growing Pediatric Patients: SOHONOS can cause irreversible premature epiphyseal closure and potential adverse effects on growth. Prior to starting treatment with SOHONOS, all growing pediatric patients should undergo baseline assessment of skeletal maturity and continued monitoring until patients reach skeletal maturity or final adult height. If appropriate, temporary or permanent discontinuation may be warranted.
Mucocutaneous Adverse Reactions: Dry skin, lip dry, pruritis, rash, alopecia, erythema, skin exfoliation [skin peeling] and, dry eye occurred with SOHONOS. Prophylactic measures to minimize risk and/or treat the mucocutaneous adverse reactions are recommended (e.g., skin emollients, sunscreen, lip moisturizers, or artificial tears). Some may require dose reduction or discontinuation. Photosensitivity reactions have been associated with the use of retinoids and may occur with SOHONOS. Precautionary measures for phototoxicity are recommended (e.g., use of sunscreens, protective clothing, and use of sunglasses).
Metabolic Bone Disorders: Increased risk of radiologically observed vertebral fractures and decreased vertebral bone mineral content and bone density. Periodic radiological assessment of the spine is recommended. Retinoids have been associated with hyperostotic changes (bone spurs) and calcification of tendons or ligaments may occur with SOHONOS.
Psychiatric Disorders: New or worsening psychiatric events were reported with SOHONOS including depression, anxiety, mood alterations, and suicidal thoughts and behaviors. Monitor for development of new or worsening psychiatric symptoms during treatment with SOHONOS. Patients and/or caregivers should contact their healthcare provider if new or worsening psychiatric symptoms develop during treatment with SOHONOS.
Night Blindness: This may be dose-dependent, making driving a vehicle at night potentially hazardous during treatment. Advise patients to be cautious when driving or operating any vehicle at night and seek medical attention in the event of vision impairment.

Adverse Reactions

The most common adverse reactions (≥ 10%) in clinical trials include dry skin, lip dry, arthralgia, pruritus, pain in extremity, rash, alopecia, erythema, headache, back pain, skin exfoliation [skin peeling] , nausea, musculoskeletal pain, myalgia, dry eye, hypersensitivity, peripheral edema, and fatigue.

Drug Interactions

CYP3A4 inhibitors may increase SOHONOS exposure. Avoid concomitant use of strong or moderate CYP3A4 inhibitors, as well as grapefruit, pomelo or juices containing these fruits.
CYP3A4 inducers may decrease SOHONOS exposure. Avoid concomitant use of strong or moderate CYP3A3 inducers.
The use of both vitamin A and SOHONOS at the same time may lead to additive effects. Concomitant administration of vitamin A in doses higher than the recommended daily allowance and/or other oral retinoids must be avoided due to risk of hypervitaminosis A.
Systemic retinoid use has been associated with cases of benign intracranial hypertension (pseudotumor cerebri), some of which involved the concomitant use of tetracyclines. Avoid coadministration of SOHONOS with tetracycline derivatives.

Use in Specific Populations

Pregnancy: SOHONOS is contraindicated during pregnancy. Obtain a negative serum pregnancy test within 1 week prior to SOHONOS therapy and periodically, as needed, over the course of treatment with SOHONOS and 1 month after treatment discontinuation unless patient is not at risk of pregnancy. If pregnancy occurs during treatment with SOHONOS, stop treatment immediately and refer the patient to an obstetrician/gynecologist or other specialist experienced in reproductive toxicity for evaluation and advice.
Lactation: Advise females that breastfeeding is not recommended during treatment with SOHONOS, and for at least 1 month after the last dose.
Females and Males of Reproductive Potential: Advise females of reproductive potential to use effective contraception at least 1 month prior to and during treatment, and for 1 month after the last dose unless continuous abstinence is chosen.
Pediatric Use: All growing pediatric patients should undergo baseline assessment of growth and skeletal maturity before starting treatment and continued clinical and radiographic monitoring every 6-12 months until patients reach skeletal maturity or final adult height
Renal or Hepatic Impairment: Use of SOHONOS in patients with severe renal impairment, or with moderate or severe hepatic impairment is not recommended.

Please see full Prescribing Information, including BOXED WARNING on Ipsen.com/us

ENDS

About Ipsen
Ipsen is a global, mid-sized biopharmaceutical company focused on transformative medicines in Oncology, Rare Disease and Neuroscience. With total sales of €3.0bn in FY 2022, Ipsen sells medicines in over 100 countries. Alongside its external-innovation strategy, the Company’s research and development efforts are focused on its innovative and differentiated technological platforms located in the heart of leading biotechnological and life-science hubs: Paris-Saclay, France; Oxford, U.K.; Cambridge, U.S.; Shanghai, China. Ipsen has around 5,300 colleagues worldwide and is listed in Paris (Euronext: IPN) and in the U.S. through a Sponsored Level I American Depositary Receipt program (ADR: IPSEY). For more information, visit ipsen.com

For further information:

Contacts Investors
Craig Marks Vice President, Investor Relations +44 (0)7584 349 193	Nicolas Bogler Senior Manager, Investor Relations +33 6 52 19 98 92
Media
Amy Wolf VP, Head of Corporate Brand Strategy & Communications +41 79 576 07 23 Anna Gibbins Global Head of Franchise Communications, Rare Disease +44 7717801900	Rachel Reiff U.S. Head of Franchise Communications +1 908 616 1680 Ioana Piscociu Senior Manager Global Media Relations +33 6 69 09 12 96

Ipsen’s forward-looking statements
The forward-looking statements, objectives and targets contained herein are based on Ipsen’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 Ipsen’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 Ipsen’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 Ipsen. 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 medicine 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. Ipsen must face or might face competition from generic medicine 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 Ipsen may fail to achieve its objectives and be forced to abandon its efforts with regards to a medicine in which it has invested significant sums. Therefore, Ipsen cannot be certain that favorable results obtained during preclinical 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 medicine concerned. There can be no guarantees a medicine will receive the necessary regulatory approvals or that the medicine 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 healthcare legislation; global trends toward healthcare cost containment; technological advances, new medicine and patents attained by competitors; challenges inherent in new-medicine development, including obtaining regulatory approval; Ipsen’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 Ipsen’s patents and other protections for innovative medicines; and the exposure to litigation, including patent litigation, and/or regulatory actions. Ipsen also depends on third parties to develop and market some of its medicines which could potentially generate substantial royalties; these partners could behave in such ways which could cause damage to Ipsen’s activities and financial results. Ipsen 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 Ipsen’s partners could generate lower revenues than expected. Such situations could have a negative impact on Ipsen’s business, financial position or performance. Ipsen 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. Ipsen’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 Ipsen’s latest Universal Registration Document, available on ipsen.com.

¹ Pignolo RJ, et al Prevalence of fibrodysplasia ossificans progressiva (FOP) in the United States: estimate from three treatment centers and a patient organisation. Orphanet J Rare Dis (2021) 16 : 350
² Baujat G, et al. Prevalence of fibrodysplassia ossificans progressiva (FOP) in France: an estimate based on a record linkage of two national databases. Orphanet J Rare Dis (2017) 12: 123
³ Pignolo RJ, et al. Self-reported baseline phenotypes from the International Fibrodysplasia Ossificans Progressiva (FOP) Association Global Registry. Bone 2020;134:115274.
⁴ Pignolo et al. The Natural History of Fibrodysplasia Ossificans Progressiva: A Prospective, Global, 36-Month Study. Genetics in Medicine. 2022. https://doi.org/10.1016/j.gim.2022.08.013
⁵. Al Mukaddam M, et al. Val Health 2022;25:S273 (POSA427)
⁶ Pignolo RJ, et al. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. Pediatr Endocrinol Rev 2013;10 Suppl 2:437– 48.
⁷ Kaplan et al, Early Mortality and Cardiorespiratory Failure in Patients with Fibrodysplasia Ossificans Progressiva. The Journal of Bone & Joint Surgery. 2010. doi: 10.2106/JBJS.I.00705
⁸ Pignolo RJ, et al. Reduction of New HO in the Open-Label, Phase 3 MOVE Trial of Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP). J Bone Miner Res. 2022.
⁹. Pignolo RJ, et al. The natural history of fibrodysplasia ossificans progressiva: A prospective 36-month study. Gen Med. 2022,ISSN 1098-3600,https://doi.org/10.1016/j.gim.2022.08.013.
^10. Government of Canada, Notice: Multiple Additions to the Prescription Drug List (PDL). Viewed 30 November 2022, <https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list/notices-changes/multiple-additions-2022-01-24.html>.

Attachment

Ipsen PR_Sohonos FDA Approval_16082023

Aggregated presentation by day and by market

Name of issuer	Identification code of issuer (Legal Entity Identifier)	Day of transaction	Identification code of financial instrument	Aggregated daily volume (in number of shares)	Daily weighted average price of the purchased shares *	Market (MIC Code)
IPSEN	549300M6SGDPB4Z94P11	03/07/2023	FR0010259150	301	110.31	AQEU
IPSEN	549300M6SGDPB4Z94P11	03/07/2023	FR0010259150	86	110.70	CEUX
IPSEN	549300M6SGDPB4Z94P11	03/07/2023	FR0010259150	1,813	110.28	XPAR
IPSEN	549300M6SGDPB4Z94P11	04/07/2023	FR0010259150	200	111.38	CEUX
IPSEN	549300M6SGDPB4Z94P11	04/07/2023	FR0010259150	12	111.00	TQEX
IPSEN	549300M6SGDPB4Z94P11	04/07/2023	FR0010259150	1,688	110.88	XPAR
IPSEN	549300M6SGDPB4Z94P11	05/07/2023	FR0010259150	35	110.80	AQEU
IPSEN	549300M6SGDPB4Z94P11	05/07/2023	FR0010259150	65	111.60	CEUX
IPSEN	549300M6SGDPB4Z94P11	05/07/2023	FR0010259150	2	110.90	TQEX
IPSEN	549300M6SGDPB4Z94P11	05/07/2023	FR0010259150	1,798	111.19	XPAR
IPSEN	549300M6SGDPB4Z94P11	06/07/2023	FR0010259150	297	108.68	AQEU
IPSEN	549300M6SGDPB4Z94P11	06/07/2023	FR0010259150	576	108.97	CEUX
IPSEN	549300M6SGDPB4Z94P11	06/07/2023	FR0010259150	366	108.68	TQEX
IPSEN	549300M6SGDPB4Z94P11	06/07/2023	FR0010259150	7,761	109.00	XPAR
IPSEN	549300M6SGDPB4Z94P11	07/07/2023	FR0010259150	1,165	109.06	AQEU
IPSEN	549300M6SGDPB4Z94P11	07/07/2023	FR0010259150	1,120	109.00	CEUX
IPSEN	549300M6SGDPB4Z94P11	07/07/2023	FR0010259150	820	109.08	TQEX
IPSEN	549300M6SGDPB4Z94P11	07/07/2023	FR0010259150	5,395	108.94	XPAR

* Two-digit rounding after the decimal			TOTAL	23,500	109.44

Attachment

IPSEN – Buy-back programme – Art 5 of MAR – Week 27 2023