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Ipsen Announces Publication of First Matching-Adjusted Indirect Comparison of Cabometyx® (cabozantinib) Versus regorafenib in Advanced Hepatocellular Carcinoma in Advances in Therapy

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Ipsen (Euronext: IPN; ADR: IPSEY) today announced that data from the matching-adjusted indirect comparison (MAIC) of Cabometyx® (cabozantinib) versus Stivarga® (regorafenib) for the second-line (2L) treatment of patients with advanced hepatocellular carcinoma (aHCC) who received sorafenib as the only prior systemic therapy were published in Advances in Therapy. The MAIC represents the first published analysis of the comparative efficacy and safety of two key 2L treatments for aHCC.1

Preliminary data from the MAIC were presented by Dr. Katie Kelley, Associate Professor of Clinical Medicine, Department of Medicine (Hematology/Oncology) at the University of California, San Francisco, and lead investigator of this analysis, at the 13th Annual Conference of the International Liver Cancer Association (ILCA 2019) in September 2019.2

The MAIC examined data from the Phase III CELESTIAL and RESORCE trials and concluded that in the 2L CELESTIAL sub-population who had received sorafenib as the only prior systemic therapy, median progression-free survival (PFS) with Cabometyx® was significantly longer, with an additional 2.5 months provided vs. regorafenib (5.6 months [95% confidence interval (CI): 4.9-7.3] vs. 3.1 months [95% CI: 2.8-4.2], p=0.0005). Overall survival (OS) was numerically longer with cabozantinib, with a median OS of almost 1 year (11.4 months vs. 10.6 months), though statistical significance was not met.1

In the previously published randomized, double-blind, Phase III CELESTIAL trial evaluating Cabometyx® compared with placebo in previously treated patients with aHCC, in the overall CELESTIAL intent-to-treat population (n=707), Cabometyx® significantly improved median PFS, with an additional 3.3 months provided versus placebo (5.2 months vs. 1.9 months [hazard ratio (HR) 0.44, 95% CI: 0.36-0.52], p<0.0001), and median OS was numerically longer with cabozantinib, with an additional 2.2 months versus placebo (10.2 months vs. 8.0 months [HR 0.76, 95% CI: 0.63-0.92], p=0.0049).3

“Hepatocellular carcinoma is a devastating disease with only a few treatment options available to improve survival for patients with advanced disease, though we have seen significant progress with multiple new treatments demonstrating efficacy in the past few years,” said Dr. Kelley. “This MAIC analysis brings further insight into the comparative effectiveness of the key new second-line treatments for advanced hepatocellular carcinoma, particularly in relation to important endpoints like progression-free survival. The results published today may help clinicians in making informed treatment decisions for their patients.”

Grade 3/4 adverse events (AEs) affecting more than 5% of patients were similar for the two studies, except for diarrhea, which was significantly lower with regorafenib (p<0.001).1

MAICs are a way of providing a timely comparison of the effectiveness of different medical interventions in the absence of head-to-head randomized trials.4 While indirect comparisons of treatments across separate studies can be performed, these analyses may be biased by cross-trial differences in patient populations, sensitivity to modeling assumptions, and differences in the definitions of outcome measures.

MAICs have been used to inform clinical decision-making across a range of cancer types, including HCC, in the absence of direct comparative data.5-10 They use individual patient data (IPD), also referred to as individual-level data (ILD), from trials of one treatment to match baseline (BL) summary statistics reported from trials of another treatment and reduce observed cross-trial differences.4 After matching, treatment outcomes are compared across balanced trial populations. It should be noted that even after matching, bias may still occur in MAIC due to imbalance in unobserved factors, and it cannot completely replace a head-to-head randomized, controlled trial.1

“At Ipsen, our mission is to prolong and improve patients’ lives and health outcomes, and we acknowledge the importance of providing healthcare professionals with the best available evidence to achieve these goals for their patients,” said Amauri Soares, Vice-President, Medical Affairs Oncology at Ipsen. “The recent rapid development of new second-line treatments for patients with advanced hepatocellular carcinoma has led to the generation of information mainly based on placebo-controlled trials. While alternative methodological approaches such as MAIC are not substitutes for evidence-based prospective clinical trials, the publication of the MAIC for cabozantinib versus regorafenib provides healthcare professionals with timely new insights into the comparative effectiveness of current treatment approaches.”

About the MAIC of cabozantinib and regorafenib
The aim of this MAIC was to compare the efficacy and safety of cabozantinib and regorafenib for patients with aHCC who have received sorafenib as the only prior systemic therapy. Through the MAIC, IPD from patients enrolled in the CELESTIAL trial3 who had received cabozantinib as 2L therapy following sorafenib as the sole prior therapy (N=495) were adjusted to match the average BL characteristics of the 573 patients enrolled in the regorafenib study RESORCE,10 for which ILD are not available.

After matching, the selected BL characteristics were balanced across trials. The BL characteristics available for matching for both trials and deemed potential effect modifiers by key opinion leaders were:1

  • age group
  • race
  • geographical region
  • Eastern Cooperative Oncology Group (ECOG) performance status
  • Child-Pugh class
  • duration of prior sorafenib treatment
  • extrahepatic disease
  • macrovascular invasion
  • etiology of HCC (hepatitis B, alcohol use and hepatitis C)
  • alpha-fetoprotein tumor marker (AFP) level

In the first indirect comparison of cabozantinib and regorafenib in 2L HCC (post-sorafenib):1

  • Cabozantinib significantly improved median PFS, with an additional 2.4 months provided vs. regorafenib (5.6 months [95% CI: 4.9-7.3] vs. 3.1 months [95% CI: 2.8-4.2], p<0.0005)
  • OS was numerically longer with cabozantinib, with a median OS of almost 1 year (11.4 months vs. 10.6 months), though statistical significance was not met

Grade 3/4 AEs affecting more than 5% of patients were comparable for the two studies, except for diarrhea which was significantly lower with regorafenib (p<0.001).1

It should be noted that, even after matching, bias may still occur in MAIC due to imbalance in unobserved factors, and it cannot replace a head-to-head randomized controlled trial.1 While our MAIC procedures reduced the impact of potentially effect-modifying baseline characteristics, they could not adjust for between-trial differences in assessment schedules or for potential impact of sorafenib-intolerant patients in the CELESTIAL population.1

About CELESTIAL
CELESTIAL is a randomized, double-blind, placebo-controlled global Phase III study of cabozantinib versus placebo in patients with aHCC who have been previously treated with sorafenib. The study was conducted at more than 100 sites globally in 19 countries. The trial was designed to enroll 760 patients with aHCC who previously received sorafenib and may have received up to two prior systemic cancer therapies for hepatocellular carcinoma (HCC) and had adequate liver function. Enrollment of the trial was completed in September 2017, and 773 patients were ultimately randomized. Patients were randomized 2:1 to receive 60 mg of cabozantinib once daily or placebo and were stratified based on etiology of the disease (hepatitis C, hepatitis B or other), geographic region (Asia versus other regions) and presence of extrahepatic spread and/or macrovascular invasion (yes or no). No cross-over was allowed between the study arms.3

The primary endpoint for the trial is OS, and secondary endpoints include objective response rate and PFS. Exploratory endpoints included patient-reported outcomes, biomarkers and safety.3

Based on available clinical trial data from various published trials conducted in the 2L setting of aHCC, the CELESTIAL trial statistics for the primary endpoint of OS assumed a median OS of 8.2 months for the placebo arm. A total of 621 events provide the study with 90 percent power to detect a 32 percent increase in median OS (HR 0.76) at the final analysis. Two interim analyses were planned and conducted at 50 percent and 75 percent of the planned 621 events.3

The CELESTIAL trial met its primary endpoint of OS, with cabozantinib providing a statistically significant and clinically meaningful improvement in median OS compared with placebo in patients with aHCC. The independent data monitoring committee for the study recommended that the trial should be stopped for efficacy following review of the second planned interim analysis. The safety data in the study were consistent with the established profile of cabozantinib.3

About HCC
HCC is an aggressive and lethal disease with the number of deaths per year close to its incidence worldwide.12 It accounts for about 90% of all liver cancers and there were over 840,000 new cases of liver cancer worldwide in 2018. It is the fifth most common cancer and the second most frequent cause of cancer-related death globally.13,14

About Ipsen products
This press release mentions investigational uses of Ipsen products. Product indications and approvals for use vary by jurisdiction; please see SmPC/PI for full indications and safety information.

About CABOMETYX® (cabozantinib)
CABOMETYX® is not marketed by Ipsen in the U.S.

CABOMETYX® 20mg, 40mg and 60mg film-coated unscored tablets

Active ingredient: Cabozantinib (S)-malate 20mg, 40mg and 60mg

Other components: Lactose

Indications: CABOMETYX® is currently approved in 51 countries, including in the European Union, the U.K., Norway, Iceland, Australia, Switzerland, South Korea, Canada, Brazil, Taiwan, Hong-Kong, Singapore, Macau, Jordan, Lebanon, Russian Federation, Ukraine, Turkey, United Arab Emirates, Saudi Arabia, Serbia, Israel, Mexico, Chile and Panama for the treatment of advanced RCC in adults who have received prior VEGF-targeted therapy; in the European Union, the U.K., Norway, Iceland, Canada, Australia, Brazil, Taiwan, Hong Kong, Singapore, Jordan, Russian Federation, Turkey, United Arab Emirates, Saudi Arabia, Servia, Israel, Mexico, Chile and Panama for previously untreated intermediate- or poor-risk advanced RCC; and in the European Union, the U.K., Norway, Iceland, Canada, Australia, Switzerland, Saudi Arabia, Serbia, Israel , Taiwan, Hong Kong, South Korea, Singapore, Jordan, Russian Federation, Turkey, United Arab Emirates, and Panama for HCC in adults who have previously been treated with sorafenib.

Dosage and administration: The recommended dose of CABOMETYX® is 60 mg once daily. Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs. Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of CABOMETYX therapy. For dose modification, please refer to full SmPC. CABOMETYX® is for oral use. The tablets should be swallowed whole and not crushed. Patients should be instructed to not eat anything for at least 2 hours before through 1 hour after taking CABOMETYX®.

Contraindications: Hypersensitivity to the active substance or to any of the excipients listed in the SmPC.

Special warnings and precautions for use:
Monitor closely for toxicity during first 8 weeks of therapy. Events that generally have early onset include hypocalcemia, hypokalemia, thrombocytopenia, hypertension, palmar-plantar erythrodysaesthesia syndrome (PPES), proteinuria, and gastrointestinal (GI) events.

Perforations and fistulas: serious gastrointestinal perforations and fistulas, sometimes fatal, have been observed with cabozantinib. Patients with inflammatory bowel disease, GI tumor infiltration or complications from prior GI surgery should be evaluated prior to therapy and monitored; if perforation and unmanageable fistula occur, discontinue cabozantinib.

Thromboembolic events: use with caution in patients with a history of or risk factors for thromboembolism; discontinue if acute myocardial infarction (MI) or other significant arterial thromboembolic complication occurs.

Hemorrhage: not recommended for patients that have or are at risk of severe hemorrhage.

Wound complications: treatment should be stopped at least 28 days prior to scheduled surgery (including dental).

Hypertension: monitor blood pressure (BP); reduce with persistent hypertension and discontinue should uncontrolled hypertension or hypertensive crisis occur.

Palmar-plantar erythrodysesthesia (PPES): interrupt treatment if severe PPES occurs.

Proteinuria: discontinue in patients with nephrotic syndrome.

Reversible posterior leukoencephalopathy syndrome (RPLS): discontinue in patients with RPLS.

QT interval prolongation: use with caution in patients with a history of QT prolongation, those on antiarrhythmics or with pre-existing cardiac disease.

Excipients: do not use in patients with hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Hepatic encephalopathy: In the HCC study (CELESTIAL), hepatic encephalopathy was reported more frequently in the cabozantinib than the placebo arm.

Hepatic effects: Abnormalities of liver function tests have been frequently observed in patients treated with cabozantinib. Liver function tests should be performed before initiation and monitored closely during treatment. If there is worsening of liver function tests with no alternative cause evident, the dose should be modified as per SmPC.

Drug interactions: Cabozantinib is a CYP3A4 substrate. Potent CYP3A4 inhibitors may result in an increase in cabozantinib plasma exposure (e.g. ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice). Coadministration with CYP3A4 inducers may result in decreased cabozantinib plasma exposure (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St John's Wort). Cabozantinib may increase the plasma concentration of P-glycoprotein substrates (e.g. fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan). MRP2 inhibitors may increase cabozantinib plasma concentrations (e.g. cyclosporine, efavirenz, emtricitabine). Bile salt sequestering agents may impact absorption or reabsorption resulting in potentially decreased cabozantinib exposure. No dose adjustment when co-administered with gastric pH modifying agents. A plasma protein displacement interaction may be possible with warfarin. INR values should be monitored in such a combination.

Women of childbearing potential/contraception in males and females: Ensure effective measures of contraception (oral contraceptive plus a barrier method) in male and female patients and their partners during therapy and for at least 4 months after treatment.

Pregnancy and lactation: CABOMETYX® should not be used during pregnancy unless the clinical condition of the woman requires treatment. Lactation – discontinue breast-feeding during and for at least 4 months after completing treatment. Drive and use machines: Caution is recommended

Adverse reactions:
The most common serious adverse reactions are hypertension, diarrhea, PPES, pulmonary embolism, fatigue and hypomagnesaemia. Very common (>1/10): anaemia, hypothyroidism, decreased appetite, hypomagnesaemia, hypokalaemia, dysgeusia, headache, dizziness, hypertension, haemorrhage, dysphonia, dyspnoea, cough, diarrhoea, nausea, vomiting, stomatitis, constipation, abdominal pain, dyspepsia, PPES, rash, pain in extremity, fatigue, mucosal inflammation, asthenia, peripheral oedema, weight decreased, serum ALT increased, AST increased. Common (>1/100 to <1/10): abscess, thrombocytopenia, neutropenia, dehydration, hypoalbuminaemia, hypophosphataemia, hyponatraemia, hypocalcaemia, hyperkalaemia, hyperbilirubinaemia, hyperglycaemia, hypoglycaemia, peripheral sensory neuropathy, tinnitus, venous thrombosis, arterial thrombosis, pulmonary embolism, gastrointestinal perforation, fistula, gastroesophageal reflux disease, haemorrhoids, oral pain, dry mouth, hepatic encephalopathy, pruritus, alopecia, dry skin, dermatitis acneiform, hair colour change, muscle spasms, arthralgia, proteinuria, blood ALP increased, GGT increased, blood creatinine increased, amylase increased, lipase increased, blood cholesterol increased, white blood cell count decreased. Uncommon (>1/1000 to <1/100): lymphopenia, convulsion, pancreatitis, glossodynia, hepatitis cholestatic, osteonecrosis of the jaw, blood triglycerides increased, wound complications. Frequency not known: cerebrovascular accident, myocardial infarction. Aneurysms and artery dissections. Selected adverse reactions: GI perforation, hepatic encephalopathy, diarrhoea, fistulas, haemorrhage, RPLS. Prescribers should consult the SmPC in relation to other adverse reactions.

Selected adverse event (AEs): GI perforation, hepatic encephalopathy, diarrhoea, fistulas, hemorrhage, RPLS.

Prescribers should consult the SPC in relation to other adverse reactions.

For more information, see the regularly updated registered product information on the European Medicine Agency www.ema.europa.eu.

CABOMETYX® is marketed by Exelixis, Inc. in the United States. Ipsen has exclusive rights for the commercialization and further clinical development of CABOMETYX® outside of the United States and Japan.

U.S. Indications and Important Safety Information

Indications:
CABOMETYX® (cabozantinib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

CABOMETYX® (cabozantinib) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

IMPORTANT SAFETY INFORMATION

Warnings and precautions:
Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: GastrointestinaI (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of perforations and fistulas, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic event requiring medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension occurred in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Proteinuria: Proteinuria occurred in 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 28 days prior to scheduled dental surgery or invasive dental procedures. Withhold CABOMETYX for development of ONJ until complete resolution.

Wound Complications: Wound complications were reported with CABOMETYX. Stop CABOMETYX at least 28 days prior to scheduled surgery. Resume CABOMETYX after surgery based on clinical judgment of adequate wound healing. Withhold CABOMETYX in patients with dehiscence or wound healing complications requiring medical intervention.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse reactions
The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, and vomiting.

Drug interactions:
Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

Use in specific populations:
Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

Please see full Prescribing Information for more information.

About Ipsen
Ipsen is a global specialty-driven biopharmaceutical group focused on innovation and Specialty Care. The Group develops and commercializes innovative medicines in three key therapeutic areas – Oncology, Neuroscience and Rare Diseases. Its commitment to oncology is exemplified through its growing portfolio of key therapies for prostate cancer, neuroendocrine tumors, renal cell carcinoma and pancreatic cancer. Ipsen also has a well-established Consumer Healthcare business. With total sales over €2.5 billion in 2019, Ipsen sells more than 20 drugs in over 115 countries, with a direct commercial presence in more than 30 countries. Ipsen’s R&D is focused on its innovative and differentiated technological platforms located in the heart of the leading biotechnological and life sciences hubs (Paris-Saclay, France; Oxford, UK; Cambridge, US). The Group has about 5,800 employees worldwide. Ipsen is listed in Paris (Euronext: IPN) and in the United States through a Sponsored Level I American Depositary Receipt program (ADR: IPSEY). For more information on Ipsen, visit www.ipsen.com

Forward Looking Statement
The forward-looking statements, objectives and targets contained herein are based on the Group’s management strategy, current views and assumptions. Such statements involve known and unknown risks and uncertainties that may cause actual results, performance or events to differ materially from those anticipated herein. All of the above risks could affect the Group’s future ability to achieve its financial targets, which were set assuming reasonable macroeconomic conditions based on the information available today. Use of the words "believes", "anticipates" and "expects" and similar expressions are intended to identify forward-looking statements, including the Group’s expectations regarding future events, including regulatory filings and determinations. Moreover, the targets described in this document were prepared without taking into account external growth assumptions and potential future acquisitions, which may alter these parameters. These objectives are based on data and assumptions regarded as reasonable by the Group. These targets depend on conditions or facts likely to happen in the future, and not exclusively on historical data. Actual results may depart significantly from these targets given the occurrence of certain risks and uncertainties, notably the fact that a promising product in early development phase or clinical trial may end up never being launched on the market or reaching its commercial targets, notably for regulatory or competition reasons. The Group must face or might face competition from generic products that might translate into a loss of market share. Furthermore, the Research and Development process involves several stages each of which involves the substantial risk that the Group may fail to achieve its objectives and be forced to abandon its efforts with regards to a product in which it has invested significant sums. Therefore, the Group cannot be certain that favorable results obtained during pre-clinical trials will be confirmed subsequently during clinical trials, or that the results of clinical trials will be sufficient to demonstrate the safe and effective nature of the product concerned. There can be no guarantees a product will receive the necessary regulatory approvals or that the product will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Other risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the Group's ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the Group’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The Group also depends on third parties to develop and market some of its products which could potentially generate substantial royalties; these partners could behave in such ways which could cause damage to the Group’s activities and financial results. The Group cannot be certain that its partners will fulfil their obligations. It might be unable to obtain any benefit from those agreements. A default by any of the Group’s partners could generate lower revenues than expected. Such situations could have a negative impact on the Group’s business, financial position or performance. The Group expressly disclaims any obligation or undertaking to update or revise any forward-looking statements, targets or estimates contained in this press release to reflect any change in events, conditions, assumptions or circumstances on which any such statements are based, unless so required by applicable law. The Group’s business is subject to the risk factors outlined in its registration documents filed with the French Autorité des Marchés Financiers. The risks and uncertainties set out are not exhaustive and the reader is advised to refer to the Group’s 2018 Registration Document available on its website (www.ipsen.com).

References

  1. Kelley, R.K. et al. Comparative Efficacy of Cabozantinib and Regorafenib for Advanced Hepatocellular Carcinoma. Advances in Therapy. 2020. DOI: https://doi.org/10.1007/s12325-020-01378-y. Accessed May 2020.
  2. Kelley, R.K., et al. Matching-adjusted indirect comparison of cabozantinib versus regorafenib in advanced hepatocellular carcinoma. Poster/abstract presented at the 13th Annual Conference of the International Liver Cancer Association (ILCA 2019, poster/abstract #P-021). Available at: https://www.ilca-online.org/wp-content/uploads/2019/09/ABSTRACTS-2019-min.pdf. Accessed May 2020.
  3. Abou-Alfa, G.K., et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54–63. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa1717002. Accessed May 2020.
  4. Signorovitch, J.E., et al. Matching-adjusted indirect comparisons: a new tool for timely comparative effectiveness research. Value Health. 2012;15(6):940–947. Available at https://www.ncbi.nlm.nih.gov/pubmed/22999145. Accessed May 2020.
  5. Chowdhury, S., et al. Matching-adjusted indirect comparison of health-related quality of life and adverse events of apalutamide versus enzalutamide in non-metastatic castration-resistant prostate cancer. Adv Ther. 2020;37(1):512–26. Available at https://link.springer.com/article/10.1007/s12325-019-01157-4. Accessed May 2020.
  6. Tremblay, G., et al. Matching-adjusted indirect treatment comparison of ribociclib and palbociclib in HR+, HER2- advanced breast cancer. Cancer Manag Res. 2018;10:1319–27. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968783/pdf/cmar-10-1319.pdf. Accessed May 2020.
  7. Odom, D., et al. A matching-adjusted indirect comparison of sonidegib and vismodegib in advanced basal cell carcinoma. J Skin Cancer. 2017:6121760. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457749/pdf/JSC2017-6121760.pdf. Accessed May 2020.
  8. Venkatachalam, M., et al. Cost of treatment-related adverse events (TRAES) in second-line (2l) advanced hepatocellular carcinoma (AHCC): match adjusted indirect comparison (MAIC) of nivolumab and regorafenib. Value Health. 2017;20(9):A502–A3. Available at https://www.valueinhealthjournal.com/article/S1098-3015(17)30924-5/abstract. Accessed May 2020.
  9. Roskell, N., et al. Indirect treatment comparision of nivolumab versu regorafenib, cabozantinib and best supportive care after treatent with sorafenib for hepatocellular carcinoma (PCN17). Value Health. 2018;21:S17–S8. Available at https://www.valueinhealthjournal.com/article/S1098-3015(18)33399-0/abstract. Accessed May 2020.
  10. Parikh, N., et al. Comparative efficacy of second-line treatments for advanced hepatocellular carcinoma: A network meta-analysis. J Clin Oncol. 2020;38(4_suppl):545. Available at https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.4_suppl.545. Accessed May 2020.
  11. Bruix, J, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389(10064):56–66. Available at: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32453-9/fulltext. Accessed May 2020
  12. Aggarwal, M, et al. Systemic treatment for hepatocellular carcinoma. Chronic Dis Transl Med. 2018;4(3):148–155. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160617/. Accessed May 2020.
  13. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182–236. Available at: https://www.journal-of-hepatology.eu/article/S0168-8278(18)30215-0/pdf. Accessed May 2020
  14. American Institute of Cancer Research. Liver cancer statistics. Available at: https://www.wcrf.org/dietandcancer/cancer-trends/liver-cancer-statistics. Accessed May 2020.

Contact information

Kelly Blaney
Global Communications
+44 (0) 7903 402275
kelly.blaney@ipsen.com

Financial Community
Eugenia Litz
Vice President, Investor Relations
+44 (0) 1753 627721
eugenia.litz@ipsen.com

Myriam Koutchinsky
Investor Relations Manager
+33 (0)1 58 33 51 04
myriam.koutchinsky@ipsen.com

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From home offices to virtual workplaces, the working environment has changed. For the Printed Circuit Board (PCB) design industry, Altium has helped make the transition seamless, empowering collaboration across every aspect of the design process. With Altium 365, the world’s only cloud-based platform for PCB design and realization, many of Altium’s customers were able to stay in motion even during the most challenging times. As the world gets back to business, Altium is making it easy for PCB designers to continue to work from anywhere and connect with anyone. “The workplace is more distributed than ever before, and at the same time our customers are dealing with unprecedented financial challenges,” says Ted Pawela, Altium’s COO. “We want to help the industry get back on track by making it easier than ever before to get the tools they need for PCB design, and work collaboratively in distributed work environments.” Coming Together Without Impacting Workflow Altium’s newest cloud-based p

WORTH Partnership Project: Organic Chairs, Fish Leather and Interactive Clothing4.6.2020 10:00:00 EESTPress release

Organic chairs that are “nourished” to reach desired shape, glassware derived from special waste, new alternative materials derived from fish to replace animal leather, illustrated children’s clothing that are enriched with new content through augmented reality and app interactions: Recycling, sustainability and the advanced use of technology attested that the mantra is always at the heart of creativity and innovative experiences by new generation European designers. All designers, under the Worth Partnership Project, an initiative financed by the European Union COSME programme, will be online from the 15th to 21st of June to showcase their projects and their concepts behind. This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20200604005050/en/ Worth Partnership Project_"Lucid", organic chair "nourished” to reach desired shape (Photo: WORTH Partnership Project) 7 video conferences for 7 topics in 7 days: to discover the Worth Part

ADVA launches industry’s first ePRC optical cesium clock solution4.6.2020 10:00:00 EESTPress release

ADVA (FSE: ADV) today launched the industry’s first ePRC optical cesium atomic clock solution, protecting synchronization networks from costly and dangerous interruptions to satellite signals. The Oscilloquartz OSA 3350 ePRC+ provides unprecedented stability and significantly longer lifetime compared to all other ePRC cesium clocks. It’s also the first cesium clock on the market with built-in SNMP support. This innovation in the design of atomic clocks comes at a critical time when GNSS outages caused by jamming and spoofing attacks are on the rise. Long GNSS disruptions can cause severe network outages and so the OSA 3350 ePRC+ offers vital backup for mission-critical infrastructures that depend on satellite-based timing, such as mobile networks and power utilities. The OSA 3350 ePRC+ also meets the stringent performance demands as well as the cost points needed for mobile networks transitioning to 5G. This press release features multimedia. View the full release here: https://www.bus

TMD Security Launches Global Consultancy Program with Deloitte to help ATM Deployers Discover Operational Cost Savings and Benefits From Key-less ATM & Branch Access Management4.6.2020 09:00:00 EESTPress release

TMD Security announced today the launch of a global program with consulting firm Deloitte to help banks and ATM deployers understand the annual operational cost savings and benefits from replacing physical keys and manual processes with a key-less ATM and Branch Access Management solution. Ten Deloitte customer engagements are planned in EMEA, APAC and the Americas and there is availability for a further ten free custom business case engagements before the end of the year. “Reducing ATM operational costs has never been more critical than it is today,’’ said Cees Heuker of Hoek, CEO and Founder, TMD Security. “We are proud to announce this global relationship with Deloitte. A custom business case gives valuable insight into an ATM deployer’s specific cost savings and business benefits potential, depending on their ATM network and current access processes. Our clients discover that replacing keys and manual processes with our Access Management solution results in staggering productivity

Bureau Veritas signs a global framework agreement with Shell to help contribute to the company’s ambition to reduce emissions from operations4.6.2020 08:45:00 EESTPress release

Reducing greenhouse gas emissions represents a major ambition of all energy operators. Bureau Veritas supports clients to meet society’s energy needs while building a more sustainable low carbon future. Methane emissions are a major component of indirect greenhouse gas emissions generated along the oil and gas value chain1. Shell, a leading global energy and petrochemicals group, has set a target to maintain methane emissions intensity below 0.2% by 20252. Bureau Veritas has been awarded a framework agreement to provide support and help enable the company to move towards achieving that target. With worldwide reach, the new enterprise framework agreement with Bureau Veritas allows Shell to benefit from expert solutions in detection of leaks across all assets. Bureau Veritas’ Leak Detection and Repair solutions (LDAR) enable Shell to monitor, quantify and control emissions in order to minimize its carbon footprint. These solutions integrate advanced technologies such as Optical Gas Imagi

Ferring and Igenomix Collaborate to Advance Care in Reproductive Medicine and Maternal Health4.6.2020 08:00:00 EESTPress release

Ferring Pharmaceuticals and Igenomix today announced a two-year research collaboration aimed at the discovery of novel targets and disease mechanisms in infertility and pregnancy-related conditions, including preeclampsia, with the goal of developing innovative diagnostic and therapeutic strategies in these areas of high unmet need. This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20200603005784/en/ A new research hub will be created in Boston, bringing together scientists and expertise from both companies. The hub will focus on investigating molecular signatures, developing novel functional genomic systems and creating translational tools to study for embryo implantation, endometrial microbiome interaction and decidualization biology to drive innovative solutions for patients. “Today, 1 in 6 couples worldwide are affected by fertility issues, with embryo implantation being a critical step to improving success rates in assisted

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