On September 4, 2017 Ipsen (Euronext: IPN; ADR: IPSEY) reported that irinotecan liposome injection (Onivyde), cabozantinib (Cabometyx), lanreotide (Somatuline Autogel / Depot), telotristat ethyl (Xermelo) and neuroendocrine tumors are the subject of 16 presentations at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) (ESMO 2017) congress. The meeting takes place in Madrid (Spain) September 8-12, 2017(Press release, Ipsen, SEP 4, 2017, View Source [SID1234520365]).

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"Ipsen has its strongest presence in oncology at ESMO (Free ESMO Whitepaper) 2017 with 16 abstracts presenting clinical outcomes in pancreatic cancer, renal cell carcinoma, neuroendocrine tumors and carcinoid syndrome. Key highlights from the Ipsen oncology portfolio include new results from the CABOSUN study that investigated Cabometyx in 1st line advanced renal cell carcinoma. The results have been selected as part of ESMO (Free ESMO Whitepaper)’s official program on Sunday September 10th," said Alexandre Lebeaut, MD, Executive Vice-President, R&D, Chief Scientific Officer, Ipsen.

Ipsen and its partner Exelixis will host a IR / media meeting on September 10th at 6:45pm to present the latest developments related to cabozantinib (Cabometyx) (Room Colon). Details about the conference call and the web conference (audio and video webcast) will be available at www.ipsen.com.

Abstracts on the following topics will be presented beginning Saturday, September 9, 2017 in IFEMA – Feria de Madrid:

Irinotecan liposome injection (Onivyde) is featured in 2 abstracts:

Poster Display Session, September 9th 13:15-14:15 Hall 8

GASTROINTESTINAL TUMOURS, COLORECTAL

741P – Prognostic value of baseline neutrophil-to-lymphocyte ratio for predicting clinical outcome in metastatic pancreatic ductal adenocarcinoma (mPDAC) patients treated with liposomal irinotecan (nal-IRI) + 5-fluorouracil and leucovorin (5-FU/LV) vs 5-FU/LV alone
Presenter: R A Hubner (Manchester, England) [Ipsen-sponsored study]

70TiP – NIFE-Trial: Liposomal irinotecan (nal-IRI) plus 5-fluorouracil (5-FU) and leucovorin (LV) or gemcitabine plus cisplatin in advanced biliary-tract cancer – an open label, randomized, multicenter phase II trial of the AIO
Presenter: TJ Ettrich (Ulm, Germany) [Investigator-lead study]

Cabozantinib (Cabometyx) is featured in 7 abstracts selected for oral presentation or poster sessions:

Proffered Paper Session, September 9th 09:15-10:45 Madrid Auditorium

Genitourinary tumours, non-prostate

846O – Final results of a phase I study of cabozantinib (Cabo) plus nivolumab (Nivo) and CaboNivo plus Ipilimumab (Ipi) in patients (pts) with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies
Presenter: R Nadal (Bethesda, USA) [Investigator-lead study]

Poster session, September 10th 13:15-14:15 Hall 8

872P – Outcomes based on plasma biomarkers in METEOR, a randomized phase 3 trial of cabozantinib (C) vs everolimus (E) in advanced renal cell carcinoma (RCC)
Presenter: T Powles (London, UK) [Exelixis-sponsored study]

876P – Efficacy of cabozantinib (C) after PD-1/PD-L1 checkpoint inhibitors in metastatic Renal Cell Carcinoma (mRCC): the Gustave Roussy experience.
Presenter: L Derosa (Villejuif, France) [Investigator-lead study]

901P – Safety and efficacy of Cabozantinib for metastatic renal cell carcinoma (mRCC): real world data from an Italian Expanded Access Program (EAP)
Presenter: G Procopio (Milan, Italy) [Investigator-lead study]

912P – Cabozantinib for the treatment of patients with metastatic variant histology renal cell carcinoma (vhRCC): a retrospective study
Presenter: M T Campbell (Houston, USA) [Investigator-lead study]

927TiP – Cabozantinib in patients with advanced penile squamous cell carcinoma (PSCC): the open-label, single-arm, single-center, phase 2, CaboPen trial
Presenter: A Necchi (Milan, Italy) [Investigator-lead study]

Poster Discussion Session, September 10th, 14:45-16:15, Cordoba Auditorium

LBA38 – Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): cabozantinib versus sunitinib as initial targeted therapy for patients (pts) with metastatic renal cell carcinoma (mRCC)
Presenter: TK Choueiri (Boston, USA) [Investigator-lead study]

Lanreotide (Somatuline Autogel) is featured in 2 abstracts:

Poster session, September 10th, 13:15 – 14:15, Hall 8

451P – Final analysis of time to subsequent disease progression/death in patients with metastatic enteropancreatic neuroendocrine tumours progressing under placebo and switched to lanreotide Autogel/Depot 120 mg in the CLARINET open-label extension
Presenter: Jarosław B. Ćwikła (Olsztyn, Poland) [Ipsen-sponsored study]

460P – Elevated levels of 5-HIAA and CgA in Patients with Pancreatic Neuroendocrine Tumors (PanNETs) from the CLARINET Study
Presenter: Alexandria T. Phan (Albuquerque, United States of America) [Ipsen-sponsored study]

Neuroendocrine tumors clinical research is featured in 1 abstract:

Poster session, September 10th, 13:15 – 14:15, Hall 8

463P – Plasma Protein Fingerprinting for the Diagnosis of Small Intestinal Neuroendocrine Tumors: The Nordic NET Biomarker Group EXPLAIN Study
Presenter: Magnus M. Kjellman (Stockholm, Sweden) [Ipsen-sponsored study]

Telotristat ethyl (Xermelo) is featured in 4 posters

Poster session, September 10th, 13:15 – 14:15, Hall 8

443P – Identifying Symptom and Quality of Life Improvements in Patients with Carcinoid Syndrome Treated with Telotristat Ethyl: Qualitative Patient Exit Interviews from the TELESTAR Trial
Presenter: Florence Marteau ([Ipsen] Boulogne-Billancourt, France) [Ipsen-sponsored analysis]

445P – Relationship between Symptoms and Health-Related Quality of Life Benefits in Patients with Carcinoid Syndrome: Post-Hoc Analyses from TELESTAR
Presenter: Marianne Pavel (Berlin, Germany) [Ipsen-sponsored analysis]

442P ­– Long-term Survival of Patients With Carcinoid Syndrome in Clinical Trials of Telotristat Ethyl
Presenter: Pablo Lapuerta ([Lexicon] The Woodlands, USA) [Lexicon-sponsored study]

Poster discussion session, September 11th, 11:00 – 12:00, Alicante Auditorium

440PD – Efficacy and Safety of Telotristat Ethyl in Patients With Carcinoid Syndrome Inadequately Controlled by Somatostatin Analogs: Analysis of the Completed TELESTAR Extension Period
Presenter: Dieter Hörsch (Bad Berka, Germany) [Lexicon-sponsored study]

Nota bene: Approved indications for products vary by country and not all indications are available in every country. The product safety and efficacy profiles have not yet been established outside the approved indications.

ABOUT ONIVYDE

ONIVYDE is a novel encapsulation of irinotecan in a long-circulating liposome. This long-circulating liposomal form is designed to increase length of tumor exposure to both irinotecan and its active metabolite, SN- 38. ONIVYDE is approved by the U.S. FDA in combination with fluorouracil and leucovorin for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. For full prescribing information, including Boxed WARNING, please visit www.ONIVYDE.com.

INDICATION

ONIVYDE (irinotecan liposome injection) is indicated, in combination with fluorouracil (5-FU) and leucovorin (LV), for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. Limitation of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas.

IMPORTANT SAFETY INFORMATION – UNITED STATES

WARNING: SEVERE NEUTROPENIA and SEVERE DIARRHEA

Fatal neutropenic sepsis occurred in 0.8% of patients receiving ONIVYDE. Severe or life threatening neutropenic fever or sepsis occurred in 3% and severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil (5-FU) and leucovorin (LV). Withhold ONIVYDE for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment.

Severe diarrhea occurred in 13% of patients receiving ONIVYDE in combination with 5- FU/LV. Do not administer ONIVYDE to patients with bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2-4 severity.

CONTRAINDICATION

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

WARNINGS AND PRECAUTIONS

Severe Neutropenia

ONIVYDE can cause severe or life-threatening neutropenia and fatal neutropenic sepsis. In a clinical study, the incidence of fatal neutropenic sepsis was 0.8% among patients receiving ONIVYDE, occurring in 1/117 patients in the ONIVYDE/5-FU/LV arm and 1/147 patients receiving ONIVYDE as a single agent. Severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE/5-FU/LV vs 2% of patients receiving 5-FU/LV. Grade 3/4 neutropenic fever/neutropenic sepsis occurred in 3% of patients receiving ONIVYDE/5-FU/LV, and did not occur in patients receiving 5-FU/LV.

In patients receiving ONIVYDE/5-FU/LV, the incidence of Grade 3/4 neutropenia was higher among Asian (18/33 [55%]) vs White patients (13/73 [18%]). Neutropenic fever/neutropenic sepsis was reported in 6% of Asian vs 1% of White patients.

Severe Diarrhea

ONIVYDE can cause severe and life-threatening diarrhea. Do not administer ONIVYDE to patients with bowel obstruction. Severe and life-threatening late-onset (onset > 24 hours after chemotherapy) and early-onset diarrhea (onset ≤24 hours after chemotherapy, sometimes with other symptoms of cholinergic reaction) were observed. An individual patient may experience both early- and late-onset diarrhea.

In a clinical study, Grade 3/4 diarrhea occurred in 13% of patients receiving ONIVYDE/5-FU/LV vs 4% receiving 5-FU/LV. Grade 3/4 late-onset diarrhea occurred in 9% of patients receiving ONIVYDE/5-FU/LV vs 4% in patients receiving 5-FU/LV; the incidences of early-onset diarrhea were 3% and no Grade 3/4 incidences, respectively. Of patients receiving ONIVYDE/5-FU/LV, 34% received loperamide for late-onset diarrhea and 26% received atropine for early-onset diarrhea.

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 Reactions

Irinotecan HCl can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction.

Embryo-Fetal Toxicity

Based on animal data with irinotecan HCl and the mechanism of action of ONIVYDE, 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 1 month after ONIVYDE treatment.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions in which patients receiving ONIVYDE/5- FU/LV experienced a ≥5% higher incidence of any Grade vs the 5-FU/LV arm, were diarrhea (any 59%, 26%; severe 13%, 4%) (early diarrhea [any 30%, 15%; severe 3%, 0%], late diarrhea [any 43%, 17%; severe 9%, 4%]), fatigue/asthenia (any 56%, 43%; severe 21%, 10%), vomiting (any 52%, 26%; severe 11%, 3%), nausea (any 51%, 34%; severe 8%, 4%), decreased appetite (any 44%, 32%; severe 4%, 2%), stomatitis (any 32%, 12%; severe 4%, 1%), pyrexia (any 23%, 11%; severe 2%, 1%).

Of less common (< 20%) adverse reactions, patients receiving ONIVYDE/5-FU/LV who experienced Grade 3/4 adverse reactions at a ≥2% higher incidence of Grade 3/4 toxicity vs the 5-FU/LV arm, respectively, were sepsis (3%, 1%), neutropenic fever/neutropenic sepsis (3%, 0%), gastroenteritis (3%, 0%), intravenous catheter-related infection (3%, 0%), weight loss (2%, 0%), and dehydration (4%, 2%).

The laboratory abnormalities in which patients receiving ONIVYDE/5-FU/LV experienced a ≥5% higher incidence vs the 5-FU/LV arm, were anemia (any 97%, 86%; severe 6%, 5%), lymphopenia (any 81%, 75%; severe 27%, 17%), neutropenia (any 52%, 6%; severe 20%, 2%), thrombocytopenia (any 41%, 33%; severe 2%, 0%), increased alanine aminotransferase (any 51%, 37%; severe 6%, 1%), hypoalbuminemia (any 43%, 30%; severe 2%, 0%), hypomagnesemia (any 35%, 21%; severe 0%, 0%), hypokalemia (any 32%, 19%; severe 2%, 2%), hypocalcemia (any 32%, 20%; severe 1%, 0%), hypophosphatemia (any 29%, 18%; severe 4%, 1%), hyponatremia (any 27%, 12%; severe 5%, 3%), increased creatinine (any 18%, 13%; severe 0%, 0%).

ONIVYDE can cause cholinergic reactions manifesting as rhinitis, increased salivation, flushing, bradycardia, miosis, lacrimation, diaphoresis, and intestinal hyperperistalsis with abdominal cramping and early-onset diarrhea. Grade 1/2 cholinergic symptoms other than early diarrhea occurred in 12 (4.5%) ONIVYDE-treated patients.

Infusion reactions, consisting of rash, urticaria, periorbital edema, or pruritus, occurring on the day of ONIVYDE administration were reported in 3% of patients receiving ONIVYDE or ONIVYDE/5-FU/LV.

The most common serious adverse reactions (≥2%) of ONIVYDE were diarrhea, vomiting, neutropenic fever or neutropenic sepsis, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia.

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

Advise pregnant women of the potential risk to a fetus. Advise males with female partners of reproductive potential to use effective contraception during and for 4 months after ONIVYDE treatment.

Lactation

Advise nursing women not to breastfeed during and for 1 month after ONIVYDE treatment.

Pediatric

Safety and effectiveness of ONIVYDE have not been established in pediatric patients.

DOSAGE AND ADMINISTRATION

The recommended dose of ONIVYDE is 70 mg/m2 intravenous (IV) infusion over 90 minutes every 2 weeks, administered prior to LV and 5-FU. The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m2 administered by IV infusion over 90 minutes. There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal. Premedicate with a corticosteroid and an anti-emetic 30 minutes prior to ONIVYDE. Withhold ONIVYDE for Grade 3/4 adverse reactions. Resume ONIVYDE with reduced dose once adverse reaction recovered to ≤Grade 1. Discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction and in patients with a confirmed diagnosis of ILD.

Do not substitute ONIVYDE for other drugs containing irinotecan HCl.

Please see full U.S. Prescribing Information for ONIVYDE.

ABOUT CABOMETYX

Cabometyx is the tablet formulation of cabozantinib. Its targets include MET, AXL, and VEGFR receptors in tumor cells. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance.

Cabozantinib is the first and only monotherapy to demonstrate statistically significant superiority in overall survival, progression-free survival, and objective response rate compared with everolimus in patients with RCC who have failed previous treatment with anti-angiogenic therapy.[1] [2]

Indications: CABOMETYX is indicated for the treatment of advanced renal cell carcinoma (RCC) in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy.

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: As most events can occur early in the course of treatment, the physician should evaluate the patient closely during the first eight weeks of treatment to determine if dose modifications are warranted. Events that generally have early onset include hypocalcaemia, hypokalaemia, thrombocytopenia, hypertension, palmarplantar erythrodysaesthesia syndrome (PPES), proteinuria, and gastrointestinal (GI) events (abdominal pain, mucosal inflammation, constipation, diarrhoea, vomiting). Dose reductions and dose interruptions due to an AE occurred in 59.8% and 70%, respectively, of cabozantinib-treated patients in the pivotal clinical trial. Two dose reductions were required in 19.3% of patients. The median time to first dose reduction was 55 days, and to first dose interruption was 38 days.Perforations and fistulas: Serious gastrointestinal perforations and fistulas, sometimes fatal, have been observed with cabozantinib. Patients who have inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis, peritonitis, diverticulitis, or appendicitis), have tumour infiltration in the GI tract, or have complications from prior GI surgery (particularly when associated with delayed or incomplete healing) should be carefully evaluated before initiating cabozantinib therapy and subsequently they should be monitored closely for symptoms of perforations and fistulas including abscesses. Persistent or recurring diarrhoea while on treatment may be a risk factor for the development of anal fistula. Cabozantinib should be discontinued in patients who experience a GI perforation or a fistula that cannot be adequately managed.

Thromboembolic events: Events of venous thromboembolism, including pulmonary embolism, and events of arterial thromboembolism have been observed with cabozantinib. Cabozantinib should be used with caution in patients who are at risk for, or who have a history of, these events. Cabozantinib should be discontinued in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Haemorrhage: Severe haemorrhage has been observed with cabozantinib. Patients who have a history of severe bleeding prior to treatment initiation should be carefully evaluated before initiating cabozantinib therapy. Cabozantinib should not be administered to patients that have or are at risk for severe haemorrhage.

Wound complications: Wound complications have been observed with cabozantinib. Cabozantinib treatment should be stopped at least 28 days prior to scheduled surgery, including dental surgery, if possible. The decision to resume cabozantinib therapy after surgery should be based on clinical judgment of adequate wound healing. Cabozantinib should be discontinued in patients with wound healing complications requiring medical intervention.

Hypertension: Hypertension has been observed with cabozantinib. Blood pressure should be well-controlled prior to initiating cabozantinib. During treatment with cabozantinib, all patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensives, the cabozantinib dose should be reduced. Cabozantinib should be discontinued if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of cabozantinib. In case of hypertensive crisis, cabozantinib should be discontinued.

Palmar-plantar erythrodysaesthesia syndrome: Palmar-plantar erythrodysaesthesia syndrome (PPES) has been observed with cabozantinib. When PPES is severe, interruption of treatment with cabozantinib should be considered. Cabozantinib should be restarted with a lower dose when PPES has been resolved to grade 1.

Proteinuria: Proteinuria has been observed with cabozantinib. Urine protein should be monitored regularly during cabozantinib treatment. Cabozantinib should be discontinued in patients who develop nephrotic syndrome.

Reversible posterior leukoencephalopathy syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), also known as Posterior Reversible Encephalopathy Syndrome (PRES), has been observed with cabozantinib. This syndrome should be considered in any patient presenting with multiple symptoms, including seizures, headache, visual disturbances, confusion or altered mental function. Cabozantinib treatment should be discontinued in patients with RPLS.

Prolongation of QT interval

Cabozantinib should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. When using cabozantinib, periodic monitoring with on-treatment ECGs and electrolytes (serum calcium, potassium, and magnesium) should be considered.

Interactions: CYP3A4 inducers and inhibitors: cabozantinib is a CYP3A4 substrate. Concurrent administration of cabozantinib with the strong CYP3A4 inhibitor ketoconazole resulted in an increase in cabozantinib plasma exposure. Caution is required when administering cabozantinib with agents that are strong CYP3A4 inhibitors. Concurrent administration of cabozantinib with the strong CYP3A4 inducer rifampicin resulted in a decrease in cabozantinib plasma exposure. Therefore, chronic administration of agents that are strong CYP3A4 inducers with cabozantinib should be avoided. P-glycoprotein substrates: Cabozantinib was an inhibitor but not a substrate, of P-glycoprotein (P-gp) transport activities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp. Subjects should be cautioned regarding taking a P-gp substrate while receiving cabozantinib. MRP2 inhibitors: Administration of MRP2 inhibitors may result in increases in cabozantinib plasma concentrations. Therefore, concomitant use of MRP2 inhibitors should be approached with caution. Bile salt-sequestering agents: Bile salt-sequestering agents may interact with cabozantinib and may impact absorption (or reabsorption) resulting in potentially decreased exposure. The clinical significance of these potential interactions is unknown. Excipient related warnings: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Pregnancy and lactation: Avoid pregnancy, use effective methods of contraception and discontinue breast-feeding during treatment with cabozantinib, and for at least 4 months after completing therapy.

Drive and use machines: Caution is recommended

Undesirable effects:

The most common serious adverse reactions associated with cabozantinib are abdominal pain (3%), pleural effusion (3%), diarrhoea (2%), and nausea (2%). The most frequent adverse reactions of any grade (experienced by at least 25% of patients) included diarrhoea (74%), fatigue (56%), nausea (50%), decreased appetite (46%), palmar-plantar erythrodysaesthesia syndrome (PPES) (42%), hypertension (37%), vomiting (32%), weight decreased (31%), and constipation (25%). Other very common adverse reactions: anemia, hypophosphataemia, hypoalbuminaemia, hypomagnesaemia, hyponatraemia, hypokalaemia,hyperkalaemia, hypocalcaemia, hyperbilirubinemia, dysgeusia, headache, dizziness, dysphonia, dyspnea, cough, stomatitis, abdominal pain, dyspepsia, rash, dry skin, muscle spasms, arthralgia, proteinuria, mucosal inflammation, serum ALT, AST, and ALP increased, creatinine increased, triglycerides increased, hyperglycaemia, hypoglycaemia, lymphopenia, neutropenia, thrombocytopenia, GGT increased, amylase increased, blood cholesterol increased, lipase increased

For all common and uncommon adverse reactions, please refer to full SmPC. For more information, see the regularly updated registered product information on the European Medicine Agency www.ema.europa.eu

ABOUT SOMATULINE

Somatuline Autogel / Depot is made of the active substance lanreotide, which is a somatostatin analogue that inhibits the secretion of growth hormone and certain hormones secreted by the digestive system.

The main indications of Somatuline and Somatuline Autogel are the following:

Treatment of acromegaly when circulating levels of growth hormone and/or Insulin-like Growth Factor-1 remain abnormal after surgery and/or radiotherapy, or in patients who otherwise require medical treatment.
Treatment of symptoms associated with carcinoid syndrome related to neuroendocrine tumors (ex-US).
Anti-proliferative treatment of gastroenteropancreatic neuroendocrine tumors.

IMPORTANT SAFETY INFORMATION –

Contraindications:

Somatuline is contraindicated in patients with hypersensitivity to lanreotide. Allergic reactions (including angioedema and anaphylaxis) have been reported following administration of lanreotide.

Warnings and Precautions:

Cholelithiasis and Gallbladder Sludge: Somatuline may reduce gallbladder motility and lead to gallstone formation. Periodic monitoring may be needed.

Hypoglycemia or Hyperglycemia: Pharmacological studies show that Somatuline, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Blood glucose levels should be monitored when Somatuline treatment is initiated, or when the dose is altered, and antidiabetic treatment should be adjusted accordingly.

Cardiac Abnormalities: Somatuline may decrease heart rate. In 81 patients with baseline heart rates of ≥ 60 beats per minute (bpm) treated with Somatuline in the GEPNETs clinical trial, the incidence of heart rate < 60 bpm was 23% (19/81) with Somatuline vs 16% (15/94) with placebo; 10 patients (12%) had documented heart rates < 60 bpm on more than one visit. The incidence of documented episodes of heart rate < 50 bpm or bradycardia reported as an adverse event was 1% in each treatment group. Initiate appropriate medical management in patients who develop symptomatic bradycardia.

In patients without underlying cardiac disease, Somatuline may lead to a decrease in heart rate without necessarily reaching the threshold of bradycardia. In patients suffering from cardiac disorders prior to treatment, sinus bradycardia may occur. Care should be taken when initiating treatment in patients with bradycardia.

Drug Interactions: The pharmacological gastrointestinal effects of Somatuline may reduce the intestinal absorption of concomitant drugs. Concomitant administration of Somatuline may decrease the relative bioavailability of cyclosporine and may necessitate the adjustment of cyclosporine dose to maintain therapeutic levels.

Adverse Reactions:

In the overall pooled safety studies in acromegaly, the most commonly reported adverse reactions reported by > 5% of patients who received Somatuline (N=416 patients) were gastrointestinal disorders (diarrhea, abdominal pain, nausea, constipation, flatulence, vomiting, loose stools), cholelithiasis and injection site reactions.

In the GEP-NET pivotal trial, the most common adverse reactions (incidence >10% and more common than placebo) in patients treated with Somatuline vs placebo were abdominal pain (34% vs 24%), musculoskeletal pain (19% vs 13%), vomiting (19% vs 9%), headache (16% vs 11%), injection site reaction (15% vs 7%), hyperglycemia (14% vs 5%), hypertension (14% vs 5%), and cholelithiasis (14% vs 7%).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reaction via the national reporting system.

Please see the full Prescribing Information for Somatuline by accessing the following link.

ABOUT XERMELO (TELOTRISTAT ETHYL)

Xermelo is a novel, orally administered, inhibitor of the enzyme tryptophan hydroxylase (TPH). Through inhibition of TPH, the rate-limiting step in the synthesis of serotonin, Xermelo was designed to reduce the production of serotonin within neuroendocrine tumors.

On 22 October 2014, Ipsen and Lexicon announced that they had entered into an exclusive licensing agreement for Ipsen to commercialize Xermelo (telotristat ethyl) in all territories excluding the United States and Japan, where Lexicon retains the rights. On 28 February 2017, Lexicon received U.S. Food and Drug Administration (FDA) approval for Xermelo as a first and only orally administered therapy for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy.

On 20 July 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Xermelo, intended for the treatment of carcinoid syndrome diarrhoea in combination with a somatostatin analogue.

Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.

General safety information about Xermelo

In clinical trials, over 230 patients with carcinoid syndrome were treated with Xermelo. The placebo-controlled safety analyses were focused on the integrated data from the 12-week placebo-controlled double-blind periods from the two phase 3 randomized clinical trials. For this safety analysis, 71 patients received placebo and 70 patients received Xermelo 250 mg three times daily. The most commonly reported adverse reactions in patients treated with telotristat ethyl were abdominal pain (26%), gamma-glutamyl transferase increased (11%) and fatigue (10%). They were generally of mild or moderate intensity. The most frequently reported adverse reaction leading to discontinuation of telotristat ethyl was abdominal pain in 7.1% of patients (5/70).

On September 1, 2017 Pfizer Inc. (NYSE:PFE) reported that the U.S. Food and Drug Administration approved MYLOTARG (gemtuzumab ozogamicin) for adults with newly diagnosed CD33-positive acute myeloid leukemia (AML), and adults and children 2 years and older with relapsed or refractory CD33-positive AML (Press release, Pfizer, SEP 1, 2017, View Source [SID1234520362]).1 MYLOTARG is the first therapy with an indication that includes pediatric AML. It is also the only AML therapy that targets CD33, an antigen expressed on AML cells in up to 90% of patients.

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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"The FDA approval of MYLOTARG fills a critical unmet need for many adults and children with AML, which can be fatal in a matter of months or even weeks if not treated and has a high relapse rate," said Liz Barrett, global president, Pfizer Oncology. "Based on clinical data, real-world experience and support from the AML community, we are grateful MYLOTARG now has the potential to help a broad range of AML patients."

MYLOTARG was originally approved in 2000 at a higher dose under the FDA’s accelerated approval program for use as a single agent in patients with CD33-positive AML who had experienced their first relapse and were 60 years or older and who were not considered candidates for other cytotoxic chemotherapy. In 2010, Pfizer voluntarily withdrew MYLOTARG in the U.S. after a confirmatory trial failed to show clinical benefit and there was a higher rate of fatal toxicity compared to chemotherapy. MYLOTARG has remained on the market in Japan and has been available to individual patients through Pfizer’s compassionate use programs. Due to the critical unmet need for patients with AML, there remained great interest among AML clinicians to evaluate MYLOTARG using different doses and different schedules. These independent investigators, with Pfizer’s support, conducted clinical trials that yielded more information on the efficacy and safety of MYLOTARG.

"Today is an important day for patients, their families and the entire AML community, as the approval of MYLOTARG brings forth a long-awaited treatment option that may lead to deeper, more durable remissions for patients with AML," said Jorge Cortes, MD, University of Texas, MD Anderson Cancer Center. "After many years, we are finally seeing progress in the treatment of AML, which has renewed my hope in improving outcomes for my patients. I am pleased that I can now offer many adult and pediatric patients targeted treatment with MYLOTARG."

Today’s approval of MYLOTARG is based on several investigator-led clinical trials, including ALFA-0701, AML-19 and MyloFrance-1.1

The ALFA-0701 trial was a Phase 3, multicenter, randomized, open-label study of 271 patients with newly-diagnosed de novo AML, using a new, lower fractionated dose of MYLOTARG. Patients received MYLOTARG 3 mg/m2 on days 1, 4 and 7 in combination with conventional chemotherapy or chemotherapy alone. The primary endpoint was event-free survival (EFS). Administering MYLOTARG (n=135) in addition to standard induction chemotherapy resulted in a significant improvement in EFS compared with chemotherapy alone (n=136) in patients with newly diagnosed AML. Event-free survival was 17.3 months for patients receiving MYLOTARG compared with 9.5 months for those receiving chemotherapy alone (HR = 0.56 [95% CI: (0.42, 0.76)]).1

Study AML-19 was a multicenter, randomized, open-label Phase 3 study comparing single agent MYLOTARG (n=118) to best supportive care (n=119) for elderly patients who could not tolerate other AML therapies. As initial treatment, patients received MYLOTARG 6 mg/m2 on day 1 and MYLOTARG 3 mg/m2 on day 8. As continued treatment, patients without evidence of disease progression received MYLOTARG 2 mg/m2 on day 1 every 4 weeks. The efficacy of MYLOTARG was established on the basis of a significant improvement in overall survival (OS). Median OS was 4.9 months for patients receiving MYLOTARG compared with 3.6 months for patients receiving best supportive care (HR=0.69 [95% CI: 0.53-0.90] [2-sided p=0.005]).1

MyloFrance-1 was a Phase 2, single-arm, open-label study of 57 adult patients in first relapse. Patients received single agent MYLOTARG 3mg/m2 on days 1, 4 and 7. The efficacy of MYLOTARG was established on the basis of complete remission (CR) rate and duration of remission. In the trial, 15 (26%; 95% CI: 16%-40%) patients achieved a complete remission (CR) and median relapse-free survival (RFS) was 11.6 months.1

The U.S. labeling for MYLOTARG includes a boxed warning for hepatotoxicity, including severe or fatal hepatic veno-occlusive disease (VOD). Veno-occlusive disease has been reported in association with the use of MYLOTARG as a single agent and as part of a combination chemotherapy regimen (5%). In patients who received MYLOTARG, the most common (≥15%) adverse reactions were hemorrhage, infection, fever, nausea, vomiting, constipation, headache, increased ALT, increased AST, rash and mucositis.

Pfizer is committed to helping patients gain access to Pfizer medicines, including MYLOTARG, and related educational tools, resources and services, regardless of their financial or health insurance status through the company’s patient assistance programs. Patients can visit www.MYLOTARG.com or call 1-877-744-5675 to learn more.

The full prescribing information, including BOXED WARNING, for MYLOTARG can be found here: View Source

IMPORTANT MYLOTARG (gemtuzumab ozogamicin) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

WARNING: Hepatotoxicity, including severe or fatal hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), has been reported in association with the use of MYLOTARG as a single agent, and as part of a combination chemotherapy regimen. Monitor frequently for signs and symptoms of VOD after treatment with MYLOTARG.

Hepatotoxicity, Including Veno-occlusive Liver Disease (VOD): An increased risk of VOD was observed in patients with moderate/severe hepatic impairment and patients who received MYLOTARG either before or after HSCT. Assess ALT, AST, total bilirubin, and alkaline phosphatase prior to each dose of MYLOTARG. After treatment with MYLOTARG, monitor frequently for signs and symptoms of VOD; these may include elevations in ALT, AST, and total bilirubin, hepatomegaly, rapid weight gain, and ascites. Monitoring only total bilirubin may not identify all patients at risk of VOD. For patients who develop abnormal liver tests, more frequent monitoring of liver tests and clinical signs and symptoms of hepatotoxicity is recommended. For patients who proceed to HSCT, monitor liver tests frequently during the post-HSCT period, as appropriate. Manage signs or symptoms of hepatic toxicity by dose interruption or discontinuation of MYLOTARG. In patients who experience VOD, discontinue MYLOTARG and treat according to standard medical practice.

Infusion-Related Reactions (Including Anaphylaxis): Life-threatening or fatal infusion-related reactions can occur during or within 24 hours following infusion of MYLOTARG. Signs and symptoms of infusion-related reactions may include fever, chills, hypotension, tachycardia, hypoxia, and respiratory failure. Premedicate prior to MYLOTARG infusion. Monitor vital signs frequently during infusion. Interrupt infusion immediately for patients who develop evidence of infusion reaction, especially dyspnea, bronchospasm, or hypotension. Monitor patients during and for at least 1 hour after the end of the infusion or until signs and symptoms completely resolve. Discontinue use of MYLOTARG in patients who develop signs or symptoms of anaphylaxis, including severe respiratory symptoms or clinically significant hypotension.

Hemorrhage: MYLOTARG is myelosuppressive and can cause fatal or life-threatening hemorrhage due to prolonged thrombocytopenia. Assess blood counts prior to each dose of MYLOTARG and monitor blood counts frequently after treatment with MYLOTARG until resolution of cytopenias. Monitor patients for signs and symptoms of bleeding during treatment with MYLOTARG. Manage severe bleeding, hemorrhage, or persistent thrombocytopenia using dose delay or permanent discontinuation of MYLOTARG, and provide supportive care per standard practice.

QT Interval Prolongation: QT interval prolongation has been observed in patients treated with other drugs containing calicheamicin. When administering MYLOTARG to patients who have a history of or predisposition for QTc prolongation, who are taking medicinal products that are known to prolong QT interval, and in patients with electrolyte disturbances, obtain electrocardiograms and electrolytes prior to the start of treatment and as needed during administration.

Adverse Cytogenetics: In a subgroup analysis in ALFA-0701, the addition of MYLOTARG to standard combination chemotherapy did not improve event-free survival in the subgroup of patients having adverse-risk cytogenetics. For patients being treated with MYLOTARG in combination with daunorubicin and cytarabine for newly diagnosed de novo AML, when cytogenetics testing results become available consider whether the potential benefit of continuing treatment with MYLOTARG outweighs the risks for the individual patient.

Embryo-Fetal Toxicity: MYLOTARG can cause embryo-fetal harm when administered to a pregnant woman. Advise patients of reproductive potential to use effective contraception during and for 3 and 6 months following treatment for males and females, respectively. Apprise pregnant women of the potential risk to the fetus. Advise women to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with MYLOTARG.

Adverse Reactions: The most common adverse reactions (greater than 15%) were hemorrhage, infection, fever, nausea, vomiting, constipation, headache, increased AST, increased ALT, rash, and mucositis.

Contraindications: Hypersensitivity to MYLOTARG or any of its components. Reactions have included anaphylaxis.

The full prescribing information, including BOXED WARNING, for MYLOTARG can be found here: View Source.

About AML

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and accounts for approximately 80% of all cases of acute leukemia.2 About 21,380 people are expected to be diagnosed with AML in the United States in 2017.3 The majority of AML cases occur in adults, but about 500 children are diagnosed with AML each year.4 Acute myeloid leukemia is the second most common leukemia in children.6 The majority of children (85%) will achieve a response after initial treatment, with approximately 5% being refractory to treatment.5 Additionally, approximately 30% of children will have their disease return5. Only one in four patients with AML survive longer than five years.4

About MYLOTARG (gemtuzumab ozogamicin)

MYLOTARG is an antibody-drug conjugate (ADC) composed of the cytotoxic agent calicheamicin, attached to a monoclonal antibody (mAB) targeting CD33, an antigen expressed on the surface of myeloblasts in up to 90 percent of AML patients.6,7,8 When MYLOTARG binds to the CD33 antigen on the cell surface it is absorbed into the cell and calicheamicin is released causing cell death.1,7,8

MYLOTARG is commercially available in Japan where it is approved for the treatment of patients with relapsed or refractory CD33-positive AML who are not considered candidates for other cytotoxic chemotherapy.

MYLOTARG originates from a collaboration between Pfizer and Celltech, now UCB. Pfizer has sole responsibility for all manufacturing, clinical development and commercialization activities for this molecule.

On September 1, 2017 ONCURIOUS NV, a Belgium-based biotech company focusing on the development of innovative oncology treatments, reported that it has reached principle agreement with VIB to acquire exclusive licences to a portfolio of five unique next generation immuno-oncology assets, based on seminal work originating from the VIB-KULeuven labs of Massimiliano Mazzone and Gabriele Bergers, and from the VIB-VUB lab of Jo Van Ginderachter (Press release, Oncurious, SEP 1, 2017, View Source [SID1234520363]).

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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Oncurious broadens its ongoing clinical development activities in orphan pediatric oncology indications with preclinical research and drug development programs, resulting in an exciting pipeline of next-generation immuno-oncology drugs targeting a broad spectrum of cancers.

VIB Discovery Sciences will take the lead in the pre-clinical development of these new projects. As part of this agreement, VIB will increase its stake in Oncurious, with ThromboGenics remaining the majority shareholder. VIB will also receive a royalty on future sales of any of these assets. ThromboGenics invests an additional €2.1 million in Oncurious.

Dr Johan Cardoen, Managing Director of VIB comments, "VIB has been developing a portfolio of next-generation immuno-oncology assets. As there are a lot of synergies within that portfolio, we also see the opportunity to develop all assets within one company. As a venture partner of Oncurious, we are looking forward to take the company to the next level."

Patrik De Haes, MD, Executive Chairman of ONCURIOUS NV comments, "This new collaboration with VIB and the resulting portfolio propels Oncurious into the very exciting area of immuno-oncology, with a focus on next generation therapies. We are very privileged to have the world-class VIB-team as our venture partner."

Oncurious is currently conducting a Phase I/IIa clinical trial for the evaluation of TB-403 in the treatment of medulloblastoma, in collaboration with BioInvent. TB-403 is a humanized monoclonal antibody against placental growth factor (PLGF). PLGF is expressed in several types of cancer, including medulloblastoma.

On September 1, 2017 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, reported that updated data from the ongoing Phase 1b trial of FP-1039/GSK3052230 (hereafter FP-1039) in mesothelioma patients were reported today in an abstract submitted to the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress to be held Sept. 8 – 12, 2017, in Madrid, Spain (Press release, Five Prime Therapeutics, SEP 1, 2017, View Source [SID1234520361]). The abstract titled "Multicenter, Nonrandomized, Open-Label Phase 1b Study of FP-1039/GSK3052230 with Chemotherapy: Results in Malignant Pleural Mesothelioma (MPM)" by Dr. Jose Trigo et al. is available at View Source

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The MPM arm of the study evaluated the safety and efficacy of FP-1039 (IV weekly) in combination with standard pemetrexed + cisplatin. The study design involved dose escalation until maximum tolerated dose (MTD) followed by a cohort expansion phase. Endpoints included safety, overall response rate by modified RECIST 1.1, disease control rate (DCR), progression free survival (PFS) and exploratory translational objectives.

As of the cutoff date of March 17, 2017, 36 patients were dosed at 10, 15 and 20 mg/kg doses of FP-1039. Three DLTs were observed at 20 mg/kg but none occurred at 15 mg/kg; therefore, MTD was declared at this dose.

Safety Data

The most common adverse events (AEs; all grades) observed were: nausea (56%) decreased appetite (36%), fatigue (33%) and infusion reaction (33%).
Efficacy Data

The confirmed objective response rate (ORR) of all evaluable patients at or below the MTD was 48%, with 13 partial responses in 27 patients.

The disease control rate (DCR) was 100%.

The median PFS was 7.4 months.
As of May 8, 2017, six patients stayed on the study for over 1 year, of which three were still ongoing.

About FP-1039

FP-1039 is a protein drug designed to intervene in FGF signaling. As a ligand trap, FP-1039 binds to FGF ligands circulating in the extracellular space (such as FGF2), preventing these signaling proteins from reaching FGFR1 on the surface of tumor cells. Treatment with FP-1039 has not been shown to cause hyperphosphatemia, a side effect seen with small molecule inhibitors of FGF receptors, which block the activity of both cancer-associated FGFs and FGF-23. GlaxoSmithKline (GSK) was the sponsor of the trial.