On November 23, 2015 Merrimack (Nasdaq: MACK) and Baxalta Incorporated (NYSE: BXLT) reported that The Lancet has published the article "Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomized, open-label phase 3 trial" online in advance of its print issue (Press release, Merrimack, NOV 23, 2015, View Source [SID:1234508325]). The Lancet is considered one of the most prestigious peer-reviewed general medical journals in the world.

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"The publication of the NAPOLI-1 data in The Lancet is significant, as it will provide physicians with comprehensive data on this recently approved treatment that has demonstrated improved overall survival for patients with metastatic adenocarcinoma of the pancreas who had progressed after gemcitabine-based therapy," said Prof. Li-Tzong Chen, M.D., Ph.D., corresponding author, Investigator on the NAPOLI-1 trial and Director, National Institute of Cancer Research, National Health Research Institutes in Tainan, Taiwan. "We thank the patients and their caregivers, study sites, steering committee members and the chairs for their contributions to this important study."

Andrea Wang-Gillam, M.D., Ph.D., lead author of the NAPOLI-1 article and Associate Professor of Medicine, Clinical Director of GI Oncology Program, Division of Oncology, at Washington University School of Medicine, St. Louis added, "ONIVYDE in combination with fluorouracil and leucovorin extends median overall survival to six months, a 45% increase, with a well-defined safety profile in patients with metastatic adenocarcinoma of the pancreas who previously received gemcitabine-based therapy, representing a new treatment option for this patient population."

The NAPOLI-1 study results were the basis of the recent U.S. Food and Drug Administration (FDA) and Taiwan FDA approval of ONIVYDE (irinotecan liposome injection) in combination with fluorouracil (5-FU) and leucovorin for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. ONIVYDE is not indicated for use as a single agent. ONIVYDE, also known as MM-398 or "nal-IRI," is the first and only FDA approved therapy in this setting. ONIVYDE is irinotecan encapsulated in liposome nanoparticles. The liposome is designed to keep irinotecan in the circulation — sheltered from conversion to its active metabolite (SN-38) — longer than unencapsulated irinotecan, which would increase and prolong intratumoral levels of both irinotecan and SN-38 compared with free irinotecan1. Data from the NAPOLI-1 study were previously presented at the 2014 European Society for Medical Oncology World Congress on Gastrointestinal Cancer and the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2015 Gastrointestinal Cancers Symposium.

The NAPOLI-1 Study and Results1

NAPOLI-1 was a randomized, open label Phase 3 study in patients with metastatic adenocarcinoma of the pancreas who received prior gemcitabine-based therapy, and was the largest Phase 3 study in this setting to date. Patients were enrolled at 76 sites in North America, South America, Europe, Asia and Oceania.

The study evaluated ONIVYDE, in combination with 5-FU and leucovorin administered every two weeks and as a monotherapy administered every three weeks. Each ONIVYDE containing arm was compared to a control arm of 5-FU and leucovorin. A total of 417 patients were randomized across the three arms. The primary endpoint of the study was overall survival. Key findings of the study as published in The Lancet include:

The ONIVYDE combination regimen demonstrated a significant increase in median overall survival versus 5-FU and leucovorin alone: 6.1 months vs 4.2 months (p=0.012, unstratified hazard ratio for death (HR) =0.67, 95% CI: [0.49-0.92]). The monotherapy regimen in this study did not show improvement over the 5-FU and leucovorin arm: 4.9 vs 4.2 months (p=0.94, HR=0.99, 95% CI: [0.77-1.28]).

ONIVYDE in combination with 5-FU and leucovorin achieved a longer progression-free survival compared with the 5-FU and leucovorin arm (3.1 months versus 1.5 months; unstratified HR=0.56 [95% CI, 0.41-0.75]).

Unconfirmed objective response rate was higher in the ONIVYDE in combination with 5-FU and leucovorin arm than in the 5-FU and leucovorin arm: 16% (19/117) versus 1% (1/119) (difference 15.4 percentage points, 95% CI, 8.5-22.3; p < 0.0001).
The most common grade 3 or 4 adverse events that occurred more frequently in the ONIVYDE in combination with 5-FU and leucovorin arm ( > 2% incidence versus 5-FU and leucovorin) were neutropenia, diarrhea, vomiting, and fatigue.

Baxalta Incorporated is responsible for the development and commercialization of ONIVYDE outside of the United States and Taiwan under the exclusive licensing agreement with Merrimack. In May 2015, the European Medicines Agency accepted for review Baxalta’s marketing authorization application for ONIVYDE based on the same clinical results.

PharmaEngine, Inc. (Taipei, Taiwan) holds the rights to commercialize ONIVYDE in Taiwan. PharmaEngine filed a New Drug Application with the Taiwan FDA on May 29, 2015, and received the approval of ONIVYDE on October 22, 2015.

About Pancreatic Cancer

Pancreatic cancer is a rare and deadly disease. There are approximately 49,000 patients diagnosed with pancreatic cancer each year in the United States2, the overwhelming majority of whom have adenocarcinoma3. Globally there are approximately 338,000 new cases each year4. Most patients receive gemcitabine-based therapy during either adjuvant/neoadjuvant treatment for locally advanced disease or during first- or second-line therapy for metastatic disease5, but are left with no standard of care therapy upon progression. ONIVYDE in combination with 5-FU and leucovorin is now approved in the U.S. and Taiwan for these patients whose disease has progressed following gemcitabine-based therapy.

About ONIVYDE [pronounced \ ‘on – ih – vide \]

ONIVYDE (irinotecan liposome injection), also known as MM-398 or "nal-IRI," is a novel encapsulation of irinotecan in a liposomal formulation. The activated form of irinotecan is SN-38, which functions by inhibiting topoisomerase I (an essential enzyme involved in DNA transcription and replication) and promoting cell death. ONIVYDE was recently approved by the U.S. Food and Drug Administration 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.

IMPORTANT SAFETY INFORMATION

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.

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. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any 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.

On November 23, 2015 CytRx Corporation (NASDAQ: CYTR), a biopharmaceutical research and development company specializing in oncology, reported that it has achieved its target enrollment of 28 patients with unresectable glioblastoma multiforme (GBM), a deadly form of brain cancer, in its Phase 2 trial with aldoxorubicin (Press release, CytRx, NOV 23, 2015, View Source [SID:1234508321]).

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To date, aldoxorubicin has shown evidence of tumor shrinkage, and overall survival has not yet been reached. Additionally, an advisory board of neuro-oncologists recently met to review the updated Phase 2 results and concluded that aldoxorubicin should be evaluated in combination with Avastin in what could potentially be a pivotal trial in patients with late-stage GBM.

"The initial findings strongly indicate that aldoxorubicin has significant anti-tumor activity in patients with GBM," said Morris D. Groves, M.D., Neuro-Oncologist, Texas Oncology-Austin Brain Tumor Center and co-principal investigator of the trial. "Pseudo-progression prevented us from determining the true efficacy of this agent since subjects may have been removed from aldoxorubicin treatment prematurely. Adding Avastin to aldoxorubicin may increase the uptake of this drug into tumors leading to improved efficacy. "

The open-label, multisite single-arm trial is investigating the preliminary efficacy and safety of aldoxorubicin in patients whose tumors have progressed following prior treatment with surgery, radiation and temozolomide. Patients to date received from 1 to 20 cycles of either 350 mg/m2 (260 mg/m2 doxorubicin equivalents) (n=6) or 250 mg/m2 (185 mg/m2 doxorubicin equivalents) (n=22) of aldoxorubicin intravenously on Day 1, and every 21 days thereafter until discontinuation. Median overall survival (range: 1 to 16+ months) has not yet been reached. Fifty-seven percent (16 of 28) of patients continue to be followed for survival with six patients still receiving aldoxorubicin treatment. Clear evidence of pseudo-progression was demonstrated in the tumor lesions of at least 4 subjects either after surgical debulking or by Dynamic Susceptibility Contrast MRI. Other subjects demonstrated extensive tumor necrosis on pathology with small amounts of residual tumor. Pseudo-progression refers to post-treatment imaging changes in the tumor where the tumor appears larger compared to the pre-treatment baseline images. These changes can be misleading in that the tumor appears to get worse (true progression), when in fact the changes may be the result of tumor destruction and related swelling around the tumor bed.

Aldoxorubicin was well tolerated at both dose levels, with all adverse events consistent with known doxorubicin toxicities. No subject has had a decrease in their cardiac function. At the 250 mg/m2 dose, the most common grade 3 or 4 adverse events included neutropenia, fatigue, thrombocytopenia and mucositis. All adverse events resolved prior to the subsequent dose of aldoxorubicin. Only four patients have had aldoxorubicin-related serious adverse events and all have been resolved successfully.

An Advisory Board of neuro-oncology experts recently reviewed the data from this trial. They concluded that aldoxorubicin clearly demonstrated anti-tumor activity with a favorable safety profile and that a randomized, comparative pivotal trial combining aldoxorubicin with Avastin compared to Avastin in patients who have relapsed after initial therapy was warranted.

"By adding Avastin to a treatment regimen with aldoxorubicin, we may be able to improve upon the activity of the agents in these very needy patients," said Daniel Levitt, M.D., Ph.D., CytRx Executive Vice President and Chief Medical Officer. "We plan to develop a protocol for a comparative potential pivotal trial based on the positive feedback from our advisors. We look forward to discussing the protocol with regulatory agencies, like the FDA, once we have the final data from the Phase 2 trial."

This Phase 2 study follows positive confirmatory results reported in 2013 from a preclinical study in which aldoxorubicin demonstrated statistically significant efficacy (p<.0001) in the treatment of rapidly growing human brain (glioblastoma) cancer in the brains of animals. In that study, animals treated with aldoxorubicin had median survival of more than 63 days, compared with approximately 25 days for animals treated with doxorubicin or saline. In addition, because aldoxorubicin uptake was confined to the tumor in the brain rather than normal brain tissue, the principal investigator concluded that aldoxorubicin has the potential to safely shrink glioblastoma tumors, which could dramatically prolong patient survival.

About Glioblastoma Multiforme

Glioblastoma is the most common and most malignant primary brain tumor in adults and afflicts more than 12,000 new patients in the U.S. annually. The median survival after diagnosis is approximately 14 months, despite patients subsequently receiving surgical resection, radiotherapy and chemotherapy. Limited efficacy of chemotherapeutic agents has been attributed to several contributing factors including insufficient drug delivery to the tumor site through the blood-brain barrier.

About Aldoxorubicin

The widely used chemotherapeutic agent doxorubicin is delivered systemically and is highly toxic, which limits its dose to a level below its maximum therapeutic benefit. Doxorubicin also is associated with many side effects, especially the potential for damage to heart muscle at cumulative doses greater than 450 mg/m2. Aldoxorubicin combines doxorubicin with a novel single-molecule linker that binds directly and specifically to circulating albumin, the most plentiful protein in the bloodstream. Protein-hungry tumors concentrate albumin, thus increasing the delivery of the linker molecule with the attached doxorubicin to tumor sites. In the acidic environment of the tumor, but not the neutral environment of healthy tissues, doxorubicin is released. This allows for greater doses (3 ½ to 4 times) of doxorubicin to be administered while reducing its toxic side effects. In studies thus far there has been no evidence of clinically significant effects of aldoxorubicin on heart muscle, even at cumulative doses of drug well in excess of 2,000 mg/m2.

On November 23, 2015 Baxalta Incorporated (NYSE:BXLT), a global biopharmaceutical leader dedicated to delivering transformative therapies to patients with orphan diseases and underserved conditions, reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending marketing authorization for use of ONCASPAR as a component of antineoplastic combination therapy in acute lymphoblastic leukaemia (ALL) in paediatric patients from birth to 18 years, and adult patients (Press release, Baxalta, NOV 23, 2015, View Source [SID:1234508319]).

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The CHMP’s positive opinion will now be referred to the European Commission (EC), which grants marketing authorization for medicines in the European Union. Pending EC approval, Baxalta will be authorized to market ONCASPAR in the 28 member countries of the European Union (EU), as well as Iceland, Liechtenstein and Norway.

Pending EC approval, ONCASPAR will provide an important treatment option for more European patients with this rapidly progressing cancer of the white blood cells responsible for more than 80 percent of childhood leukaemia cases2 – the most common type of childhood cancer.

"We are pleased to receive a positive CHMP opinion for ONCASPAR as part of a multi-agent chemotherapy regimen in paediatric and adult populations; this is a significant milestone in increasing patient access to this important biologic treatment for patients impacted by ALL," said John Orloff, M.D., head of Research & Development and chief scientific officer, Baxalta. "At Baxalta, we are committed to expanding the availability of ONCASPAR globally, and this decision makes a curative treatment available to more patients across the world."

Today, children in the U.S. diagnosed with ALL have a survival rate of more than 90 percent – a direct result of multi-agent chemotherapy treatments. ONCASPAR is a key component of these curative therapies. Currently, there have been national licenses granted to market ONCASPAR in Argentina, Belarus, Germany, Kazakhstan, Poland, Russia, Ukraine and the United States.

About ONCASPAR (pegaspargase)

In the U.S., ONCASPAR (pegaspargase) is indicated as a component of a multi-agent chemotherapeutic regimen for the first–line treatment of patients with acute lymphoblastic leukaemia (ALL) and for the treatment of patients with ALL and hypersensitivity to native forms of L-asparaginase.

Important Safety Information for ONCASPAR

ONCASPAR is contraindicated in patients with a history of serious allergic reactions to pegaspargase, and in patients with a history of pancreatitis, serious thrombosis, or serious hemorrhagic events with prior L-asparaginase therapy.

The most common adverse reactions with ONCASPAR (=2%) are allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system (CNS) events, thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases. Hyperlipidemia (hypercholesterolemia and hypertriglyceridemia) has been reported in patients exposed to ONCASPAR.

Patients should be observed for one hour after administration as anaphylaxis or serious allergic reactions can occur. Discontinue ONCASPAR in patients that develop pancreatitis, serious allergic reactions, or serious thrombotic events. Patients with abdominal pain should be evaluated for evidence of pancreatitis.

Serum glucose should be monitored as irreversible glucose intolerance can occur in some cases. Coagulopathy and hepatotoxicity can occur; appropriate monitoring should be performed.

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About Acute Lymphoblastic Leukaemia

Acute lymphoblastic leukaemia (ALL) is a rare, fast-growing cancer of the white blood cells, and each year there are approximately 4,000-5,000 new cases in Europe and the United States, respectively. The disease is the most common childhood cancer and is responsible for more than 80 percent of childhood leukaemia cases. The five-year paediatric survival rate has climbed to 90 percent with modern therapies.

On November 23, 2015 Aduro Biotech, Inc. (Nasdaq:ADRO) reported that the European Medicines Agency (EMA) granted Orphan Drug Designation to CRS-207 for the treatment of malignant pleural mesothelioma (MPM) (Press release, Aduro BioTech, NOV 23, 2015, View Source [SID:1234508317]).

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"The receipt of Orphan Drug Designation in the European Union (EU) for CRS-207 for the treatment of MPM marks a significant regulatory milestone for Aduro, as we expand our operations in Europe and advance our therapies closer to the commercial marketplace," said Stephen T. Isaacs, chairman, president and chief executive officer of Aduro. "We look forward to working with the EMA to expeditiously advance CRS-207 through development with the goal of bringing this potential therapy to patients throughout Europe suffering from mesothelioma."

To receive Orphan Drug Designation from the EMA, a therapy must be intended for the treatment of a life-threatening or chronically debilitating rare condition with a prevalence of less than five in 10,000 in the European Union. Orphan Drug Designation provides incentives designed to facilitate development, including protocol assistance and scientific advice and importantly, may provide up to ten years of market exclusivity in the EU following product approval.

Aduro is conducting a Phase 1b study of CRS-207 in combination with standard of care chemotherapy in patients with unresectable malignant pleural mesothelioma. The company plans to advance directly to a Phase 3 clinical trial with CRS-207 in combination with standard-of-care chemotherapy in patients with unresectable MPM in the first half of 2016. In addition to the newly granted Orphan Drug Designation from the EMA, CRS-207 received Orphan Status for the treatment of mesothelioma from the U.S. Food and Drug Administration in March 2015.

About CRS-207

CRS-207 is one of a family of product candidates based on Aduro’s live-attenuated, double-deleted (LADD) Listeria monocytogenes immunotherapy platform that induces a potent innate and T cell-mediated adaptive immune response. CRS-207 has been engineered to express the tumor-associated antigen mesothelin, which is over-expressed in many cancers including mesothelioma and pancreatic, non-small cell lung, ovarian, endometrial and gastric cancers.

On November 23, 2015 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported results from a phase Ib study of the investigational cancer immunotherapy atezolizumab (MPDL3280A), used in combination with the BRAF inhibitor Zelboraf (vemurafenib) for previously untreated BRAFV600 mutation-positive unresectable or metastatic melanoma (Press release, Hoffmann-La Roche , NOV 23, 2015, View Source [SID:1234508314]).

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Adverse events (AEs) were manageable and generally reversible. The study also showed that the combination resulted in an objective response rate [ORR] of 76% (95% confidence interval [CI:] 50.1%–93.2%) of people (n=17), including three complete responders (CR). The data were presented at the Society of Melanoma Research (SMR) 2015 International Congress.1

"These early efficacy results encourage us to further evaluate combination strategies of atezolizumab and targeted therapies like Zelboraf in people living with advanced melanoma, a disease which is still associated with a poor prognosis", Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development.

Roche is also investigating a triplet regimen with atezolizumab plus the established targeted therapy combination of Zelboraf and Cotellic (cobimetinib), a selective MEK inhibitor, in a phase Ib study.

About the phase Ib study of atezolizumab in combination with Zelboraf

This phase Ib, open-label study aimed to evaluate the safety and pharmacology of atezolizumab in combination with Zelboraf in patients with previously untreated BRAFV600 mutation-positive metastatic melanoma
17 patients were evaluable for safety and efficacy at the time of this data cut
Patients received atezolizumab combined with Zelboraf concurrently (Cohort 1 [C1], n=3) or after a run-in period with Zelboraf alone of 56 days (Cohort 2 [C2]; n=8) or 28 days (Cohort 3 [C3]; n=6)
Patients were given atezolizumab intravenously every 3 weeks at 20 mg/kg (C1) or 15 mg/kg (or 1,200 mg fixed; C2/C3). Oral Zelboraf was given twice daily at 960 mg during the run-in period and at 720 mg during atezolizumab and Zelboraf combined treatment

PD-L1 expression was centrally assayed using immunohistochemistry (IHC; SP142 assay)

About BRAFV600 mutation-positive metastatic melanoma
Melanoma is less common, but more aggressive and deadlier, than other forms of skin cancer.2,3 A mutation of the BRAF protein occurs in approximately half of melanomas, and a test can be used to determine who can be treated with a BRAF-inhibitor.4 When melanoma is diagnosed early, it is generally a curable disease,5,6 but most people with advanced melanoma have a poor prognosis.3 More than 232,000 people worldwide are currently diagnosed with melanoma each year.7 In recent years, there have been significant advances in treatment for metastatic melanoma, and people with the disease have more options. However, it continues to be a serious health issue with a high unmet need and a steadily increasing incidence over the past 30 years.8

About atezolizumab
Atezolizumab (also known as MPDL3280A) is an investigational monoclonal antibody designed to interfere with a protein called PD-L1. Atezolizumab is designed to target PD-L1 expressed on tumour cells and tumour-infiltrating immune cells, preventing it from binding to PD-1 and B7.1 on the surface of T cells. By inhibiting PD-L1, atezolizumab may enable the activation of T cells, restoring their ability to effectively detect and attack tumour cells.

About Zelboraf
Zelboraf was the first approved treatment for patients with unresectable or metastatic melanoma with BRAFV600 mutation as detected by a validated test, such as Roche’s cobas 4800 BRAF Mutation Test. Zelboraf is not indicated for use in patients with wild-type BRAF melanoma.

About Cotellic plus Zelboraf
Cotellic and Zelboraf are used in combination to treat unresectable or metastatic melanoma with BRAFV600 mutation. Found in approximately half of melanomas, mutated BRAF causes abnormal signalling inside certain cancer cells leading to tumour growth. Zelboraf binds to mutant BRAF, to interrupt abnormal signalling that can cause tumours to grow.9,10 Cotellic is designed to inhibit some forms of MEK. Both BRAF and MEK are proteins in a cell signalling pathway that help control cell growth and survival. When used in combination, Cotellic and Zelboraf are thought to reduce cancer cell growth longer than Zelboraf alone. A patient’s healthcare provider will perform a test to make sure Cotellic and Zelboraf are right for the patient. It is not known if Cotellic and Zelboraf are safe and effective in children under 18 years of age.

Cotellic was approved in Switzerland in August 2015 and in the US in November 2015. In September, the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMA) issued a positive opinion for Roche’s marketing authorisation application for Cotellic in the European Union. A decision from the European Commission is expected before the end of 2015.