On October 18, 2016 Shire plc (LSE: SHP, NASDAQ: SHPG) reported that the European Commission (EC) has granted Marketing Authorization of ONIVYDE (pegylated liposomal irinotecan hydrochloride trihydrate), also known as nal-IRI or MM-398, for the treatment of metastatic adenocarcinoma of the pancreas, in combination with 5-fluorouracil (5-FU) and leucovorin (LV), in adult patients who have progressed following gemcitabine-based therapy (Press release, Shire, OCT 18, 2016, View Source [SID1234515897]). ONIVYDE is the first and only approved treatment option for this patient population.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

With this approval, Shire is authorized to market ONIVYDE in the 28 Member States of the European Union (EU), as well as in Iceland, Liechtenstein and Norway. ONIVYDE was previously approved in the U.S. by the Food and Drug Administration (FDA), in October 2015.

"As the only treatment for metastatic pancreatic cancer following gemcitabine-based therapy that may improve patient survival, ONIVYDE is the first innovation that offers the potential to improve outcomes for this challenging patient population," said Philip J. Vickers, Ph.D., Global Head of Research and Development at Shire. "The approval of ONIVYDE marks a significant step forward in Shire’s focus to develop and commercialize treatments that represent the most promising science in oncology."

Pancreatic cancer is the fourth leading cause of cancer death in the regioniii and there are limited treatment options available.iv In September 2015, the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) stated that use of MM-398 (ONIVYDE) when available in all countries, may be the best option for patients following gemcitabine-based therapy.v Gemcitabine-based therapy is commonly used as a first-line treatment for patients with metastatic disease or locally advanced disease that cannot be treated with surgery, or as adjuvant therapy.vi

"The burden of pancreatic cancer for patients, their families and healthcare providers is profound and the treatment options available, especially to those with metastatic disease, have not substantially evolved for decades," said Alfredo Carrato, M.D., Professor of Medical Oncology at Alcala University and Director of the Medical Oncology Department at Ramon y Cajal University Hospital in Madrid, Spain. "With the approval of ONIVYDE, we have the first and only treatment approved for metastatic adenocarcinoma following gemcitabine-based therapy, and an option that may improve patient survival. This is an important advance for the field of oncology and the lives of those impacted by pancreatic cancer."

The Marketing Authorization is based on the data from the pivotal, Phase 3 NAPOLI-1 study that demonstrated ONIVYDE combined with 5-FU/LV significantly improved overall survival (OS) (primary endpoint), as well as progression-free survival (PFS) and objective response rate (ORR) relative to the 5-FU/LV control arm (secondary endpoints). In the trial, the most common Grade 3 or higher adverse events with greater than five percent difference in patients receiving ONIVYDE and 5-FU/LV, versus 5-FU/LV alone, were neutropenia, fatigue, diarrhoea, and vomiting.ii

About Pancreatic Cancer
Pancreatic cancer is a significantly underserved disease in Europe and is almost always fatal.vi At the time of diagnosis, more than 80 percent of people diagnosed with pancreatic cancer have metastatic disease or locally advanced disease that cannot be removed with surgery.vii The disease has a median five-year survival rate of about 5 percent,v and an overall median survival of typically less than a year, as supported by real-world European systematic review.vi The only curative treatment for pancreatic cancer is surgical resection in the primary stage, which can improve five-year survival to 10 percent.viii

The signs and symptoms of pancreatic cancer are non-specific (common presenting symptoms include jaundice, abdominal pain, weight loss, steatorrhoea, and new-onset diabetes)v and may not appear until the disease has spread locally or metastasized.vii Therefore, most patients are not candidates for surgery upon diagnosis.vii

Even though it accounts for less than three percent of all cancer cases,ix pancreatic cancer is the seventh leading cause of cancer death worldwide,x and the fourth in Europe.iv Worldwide, pancreatic cancer prognosis is typically poor, with an estimated 337,900 new cases and 330,400 deaths each year.xi

About ONIVYDE (nal-IRI)
ONIVYDE is a first-of-its-kind formulation (encapsulation) of irinotecan in a long-circulating liposomal form designed to improve delivery of length of tumor exposure to irinotecan and its active metabolite SN-38. Studies have suggested that encapsulation helps to improve delivery of irinotecan to tumors, such as metastatic pancreatic cancer.xii

In the pivotal Phase 3 NAPOLI-1 study, ONIVYDE demonstrated significantly improved overall survival in adult patients with metastatic ADENOCARCINOMA of the pancreas who have progressed following gemcitabine-based therapy.ii Gemcitabine, both as monotherapy as well as in combination, is commonly used in the first-line treatment of locally advanced and/or metastatic pancreatic adenocarcinoma, as well as in the adjuvant (treatment after surgery) and neo-adjuvant (treatment before surgery) settings.ii

Shire is responsible for the development and commercialization of ONIVYDE outside of the United States and Taiwan under an exclusive licensing agreement with Merrimack Pharmaceuticals, Inc. (NASDAQ: MACK). Merrimack markets ONIVYDE in the United States after having received US Food and Drug Administration (FDA) approval in October 2015 for the treatment of patients with metastatic adenocarcinoma of the pancreas who have progressed following treatment with gemcitabine-based therapy. ONIVYDE product license was granted in Taiwan in March 2016, where PharmaEngine holds the commercialization rights.

About NAPOLI-1ii
NAPOLI-1 is the first global, randomized open-label Phase 3 trial to show extended overall survival in metastatic pancreatic adenocarcinoma after gemcitabine-based therapy through treatment with ONIVYDE combined with 5-FU and LV. NAPOLI-1 is the largest Phase 3 study in this setting to date showing overall survival benefit. Patients were enrolled at 76 sites in 14 countries across North America, Europe, Asia, South America, and Australia. The study evaluated ONIVYDE (80mg/m2) in combination with 5-FU/LV administered intravenously every two weeks and as a monotherapy (120 mg/m2) administered every three weeks. Each ONIVYDE containing arm was compared to a control arm of 5-FU/LV.

NAPOLI-1 met the following primary and secondary endpoints by demonstrating that ONIVYDE combined with 5-FU/LV significantly improved OS, progression-free survival (PFS) and objective response (OR) compared to 5-FU/LV alone in patients with metastatic pancreatic cancer.i ONIVYDE plus 5-FU/LV demonstrated a significant increase in median overall survival versus 5-FU/LV alone: 6.1 months vs 4.2 months (based on a non-stratified hazard ratio [HR] of 0.67; 95% CI 0.49-0.92, p=0.012).i, ii

Grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned ONIVYDE plus 5-FU/LV were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]).ii

Important Safety Information
The most common adverse reactions (incidence ≥20 percent) seen with ONIVYDE in combination with 5-FU/LV were: diarrhoea, nausea, vomiting, decreased appetite, neutropenia, fatigue, asthenia, anaemia, stomatitis, and pyrexia.i Early-onset (within 1 day of treatment) diarrhoea occurred in 30 percent of patients on ONIVYDE combined with 5-FU/LV and was usually transient.i Early-onset diarrhoea was accompanied by cholinergic symptoms in 3.4 percent of patients taking ONIVYDE in combination with 5-FU/LV.i Median time to late-onset diarrhoea was 8 days following the ONIVYDE dose.i Of patients taking ONIVYDE combined with 5-FU/LV, 11 percent of patients discontinued treatment.i

On October 17, 2016 Eli Lilly and Company (NYSE: LLY) reported it will contribute cancer research data to the National Cancer Institute’s Blood Profiling Atlas, an open access liquid biopsy database being created in response to Vice President Joe Biden’s call to action and in alignment with the goals of the Cancer Moonshot initiative (Press release, Eli Lilly, OCT 17, 2016, View Source [SID1234515873]). The database is an effort to reduce the development time of effective and safe blood profiling diagnostic technologies.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

"We are honored to be a part of this unique partnership," said Andrew Schade, M.D., Ph.D., a distinguished medical fellow in Lilly’s clinical diagnostics laboratory. "Liquid biopsies are going to be critical in the future to both identify specific patients for targeted therapies and to follow their treatment to better determine response to therapy. We hope knowledge gained from our research efforts in this area will help to accelerate the development of safe and effective blood profiling diagnostic technologies that help people with cancer."

In support of this overarching mission, Lilly is studying approaches for the profiling of exosomes for mRNA and non-coding RNA expression and will share sample preparation methods, next-generation quantitative PCR-based methods, and next generation sequencing-based methods along with data related to disease characterization through gene expression analysis.

"Our scientists are dedicated to discovering and developing new cancer treatments to help people living with this disease," said Jan Lundberg, Ph.D., executive vice president of science and technology and president of Lilly Research Laboratories. "In addition to our own research, external partnerships are paramount, and we look forward to collaborating with other experts as part of the Cancer Moonshot initiative."

The Blood Profiling Atlas is part of the Cancer Moonshot initiative, which was established to improve the way research is conducted and expedite the delivery of medicines to patients. Allowing approved researchers access to raw unprocessed datasets in a scalable and reproducible manner, the open database will feature the following data: raw data sets from circulating tumor cells, circulating tumor DNA, and exosome assays, as well as relevant clinical data, sample preparation, and handling protocols from 12 different studies. The Blood Profiling Atlas pilot will be curated by a partnership between the University of Chicago and Seven Bridges, a biomedical data analysis company. For more information about the Blood Profiling Atlas, please click here.

On October 17, 2016 Teva Pharmaceutical Industries Ltd., (NYSE and TASE:TEVA) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending an indication extension of Trisenox (arsenic trioxide) (Press release, Teva, OCT 17, 2016, View Source [SID1234515855]). The indication extension is for use in newly diagnosed low to intermediate risk Acute Promyelocytic Leukemia (APL) in combination with retinoic acid. Trisenox, in combination with retinoic acid, has shown a very high overall survival rate with almost no relapses after more than four years (50 months) of median follow-up. If the European Commission approves this label extension, it would mark the first time that a form of acute leukemia can be effectively treated with a regimen that is entirely chemotherapy-free.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

APL is a life-threatening type of leukemia as it can cause uncontrollable bleeding and can kill within hours or days if left untreated. In Europe, approximately 1,500 to 2,000 people are diagnosed with APL each year. In light of its rarity, and because most cases present with low blood cell count and low leukemic cells in the blood, diagnosis can be difficult. However, the rapid progression of APL leading to early mortality is a substantial problem, affecting up to 30% of patients. Rapid diagnosis and commencement of treatment is essential to avoid early mortality. Trisenox is currently indicated for second line treatment of patients, who have not responded to treatment with retinoids and chemotherapy, or when their disease has returned after this type of treatment.
Commenting on the announcement, Francesco Lo-Coco, Professor of Haematology and Head of the Laboratory of Integrated Diagnosis of Oncohematologic Diseases, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Italy said, "This CHMP opinion is very encouraging. Considering it was based on existing published academic data only, this opinion points to a recognition by the EMA that treating low to intermediate risk APL with a chemo-free regimen of Trisenox plus retinoic acid can increase survival rates and dramatically reduce the risk of relapse and chemotherapy-related side effects in patients suffering from this rare and aggressive form of leukemia. In particular, avoiding the risk of life-threatening infection and that of developing secondary leukemias due to chemotherapy is a great gain for patients. The success of this regimen represents a major breakthrough and a paradigm of targeted therapy in oncology and medicine. This is therefore good news, not only for APL patients, but also for the whole medical community."

The CHMP positive opinion is a formal recommendation to grant marketing authorization for an extended indication for first line treatment for Trisenox. The recommendation will now be reviewed by the European Commission, which has authority to approve medicines for use in the 28 countries of the European Union along with Norway, Liechtenstein and Iceland. A final decision by the European Commission is expected by the end of the year.

In commenting on the CHMP positive opinion, Rob Koremans, President & CEO, Teva Global Specialty Medicines said, "As a company committed to providing medicines and solutions that really make a difference in patients’ lives, we’re pleased to reach this important milestone, and hope soon to be able to offer a chemotherapy-free treatment regimen for APL patients at the point of diagnosis. Recognizing the high unmet patient need in this orphan disease, we’ve put everything in place to obtain the label extension for this life-saving treatment. We look forward to receiving an approval from the European Commission for Trisenox as a first line treatment."

About Acute Promyelocytic Leukemia
Acute Promyelocytic Leukemia is a form of acute myeloid leukemia (AML), a cancer of the blood-forming tissue (bone marrow). Approximately 10% to 15% of patients initially diagnosed with AML present with the aggressive sub-type of the condition, APL.
In normal bone marrow, hematopoietic stem cells produce red blood cells (erythrocytes) that carry oxygen, white blood cells (leukocytes) that protect the body from infection, and platelets (thrombocytes) that are involved in blood clotting. In APL, immature white blood cells called promyelocytes accumulate in the bone marrow. The overgrowth of promyelocytes leads to a shortage of normal white and red blood cells and platelets in the body, which causes many of the signs and symptoms of the condition.

People with APL are especially susceptible to developing bruises, small red dots under the skin (petechiae), nosebleeds, bleeding from the gums, blood in the urine (hematuria), or excessive menstrual bleeding. The abnormal bleeding and bruising occur because substances are released that cause excessive blood clotting, and as a consequence lead to a low number of platelets in the blood (thrombocytopenia). The low number of red blood cells (anemia) can cause people with acute promyelocytic leukemia to have pale skin (pallor) or excessive tiredness (fatigue). In addition, affected individuals may heal slowly from injuries or have frequent infections due to the decrease of normal white blood cells that fight infection. Furthermore, the leukemic cells can expand into the bones and joints, which may cause pain in those areas. Other general signs and symptoms may occur as well, such as fever, loss of appetite, and weight loss.

APL is generally diagnosed in much younger patients than in AML (the median age is approximately 40 for APL patients and 70 for AML patients), and can be diagnosed in patients of any age.

About Trisenox
On 5 March 2002, the European Commission granted approval for the Marketing Authorization Application (MAA) for Trisenox. The authorization, which was valid throughout the European Union (EU), was granted to treat patients with relapsed or refractory acute promyelocytic leukemia (APL) and characterized by the presence of the t(15;17) translocation and/or the presence of the Pro-Myelocytic Leukaemia/Retinoic-Acid-Receptoralpha (PML/(RARα) gene. Trisenox, a targeted drug, degrades the PML- RARα fusion protein. Trisenox received marketing authorization in 2000 by the U.S. Food and Drug Administration.
The marketing approval for Trisenox was granted based on results from a multicenter study in which 40 relapsed APL patients were treated with Trisenox 0.15 mg/kg until bone marrow remission or a maximum of 60 days. Thirty-four patients (85 percent) achieved complete remission after two cycles. When the results for these 40 patients were combined with those for the 12 patients in a pilot trial, an overall response rate of 87 percent was observed.

1mL of Trisenox contains 1mg of arsenic trioxide. Trisenox is a concentrate for solution for infusion. It is a sterile, clear, colorless, aqueous solution. Trisenox must be administered under the supervision of a physician who is experienced in the management of acute leukaemias, and special monitoring procedures must be followed.

Study Results
The APL0406 Intergroup GIMEMA-AMLSG-SAL study was a prospective, randomized, multicenter, open-label, phase III non-inferiority study. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, genetically proven low- or intermediate-risk APL (WBC at diagnosis ≤ 103 x 109/L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively (P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3%v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively (P , .001, P = .0013, and P = .0073, respectively).

Post-induction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm.