On July 25, 2016 Janssen Research & Development, LLC reported that the U.S. Food and Drug Administration (FDA) has granted a Breakthrough Therapy Designation to the immunotherapy daratumumab (DARZALEX) in combination with lenalidomide (an immunomodulatory agent) and dexamethasone, or bortezomib (a proteasome inhibitor [PI]) and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy (Press release, Johnson & Johnson, JUL 25, 2016, View Source [SID:1234514044]). This marks the second time daratumumab has received a Breakthrough Therapy Designation, which is intended to expedite the development and review timelines of potential new medicines to treat serious or life-threatening diseases, where preliminary clinical evidence shows that the medicine may provide substantial improvement over existing therapies. 1 Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow.2,3

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"Despite tremendous progress in the past 15 years, multiple myeloma remains a highly complex and difficult disease to treat, with most patients relapsing or becoming resistant to therapy," said MMY3003 (POLLUX) lead study author Meletios A. Dimopoulos, M.D., Department of Clinical Therapeutics, National and Kapodistrian 2 University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece. "Daratumumab has already shown pronounced activity as a monotherapy in heavily pre-treated patients. This designation underscores the potential of daratumumab in combination with either a proteasome inhibitor or an immunomodulatory agent to provide much-needed benefit to patients with at least one prior therapy."

Breakthrough Therapy Designation was granted to daratumumab based on data from two Phase 3 studies:

The MMY3004 (CASTOR) clinical trial evaluating daratumumab in combination with bortezomib and dexamethasone, compared to bortezomib and dexamethasone alone, in patients with multiple myeloma who received at least one prior therapy. Overall, the daratumumab combination therapy demonstrated a reduction in the risk of disease progression or death.
o These results were presented at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in June 2016. More information can be found at www.ClinicalTrials.gov (NCT02136134).

The MMY3003 (POLLUX) clinical trial evaluating daratumumab in combination with lenalidomide and dexamethasone, compared to lenalidomide and dexamethasone alone, in patients with multiple myeloma who received at least one prior therapy. Overall, the addition of daratumumab reduced the risk of disease progression or death in these patients.
o These results were presented at the 21st Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in June 2016. More information can be found at www.ClinicalTrials.gov (NCT02076009).

"We are pleased that the FDA has granted a second Breakthrough Therapy Designation to daratumumab. This is an important recognition of the transformative potential of daratumumab and its possible benefit as a backbone therapy in combination with two of the most widely used regimens for multiple myeloma," said Craig L. Tendler, M.D., Vice President, Late-Stage Development and Global Medical Affairs for Oncology, Hematology and Supportive Care, Janssen Research & Development, LLC. "We look forward to working closely with the FDA throughout the review process and remain committed to exploring the full clinical benefit of this promising compound for multiple myeloma patients who are eagerly awaiting new treatment options."

In November 2015, daratumumab (DARZALEX) was approved by the FDA for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.4

In May 2013, daratumumab received Breakthrough Therapy Designation from the FDA for this indication. 3 In May 2016, the European Commission (EC) granted conditional approval to DARZALEX for monotherapy of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.

About DARZALEX (daratumumab)

DARZALEX (daratumumab) injection for intravenous use is the first CD38-directed monoclonal antibody (mAb) approved anywhere in the world.4 CD38 is a surface protein that is highly expressed across multiple myeloma cells, regardless of disease stage. 5 Daratumumab is believed to induce tumor cell death through multiple immunemediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), as well as through apoptosis, in which a series of molecular steps in a cell lead to its death.4 Daratumumab is also believed to induce tumor cell death through immunomodulatory effects, according to a study recently presented at the 57th Annual Meeting and Exposition of the American Society of Hematology (ASH) (Free ASH Whitepaper).6 DARZALEX is being evaluated in a comprehensive clinical development program that includes five Phase 3 studies across a range of treatment settings in multiple myeloma, such as in frontline and relapsed settings. Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases in which CD38 is expressed, such as smoldering myeloma, non-Hodgkin’s lymphoma and a solid tumor indication. DARZALEX was the first mAb to receive regulatory approval to treat relapsed or refractory multiple myeloma.4

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialize DARZALEX. DARZALEX is commercialized in the U.S. by Janssen Biotech, Inc. For more information, visit www.DARZALEX.com.

About Multiple Myeloma

Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow.7,8 Refractory cancer occurs when a patient’s disease is resistant to treatment or in the case of multiple myeloma, patients progress within 60 days of their last therapy.9,10 Relapsed cancer means the disease has returned after a period of initial, partial or complete remission.7,11 Accounting for approximately one percent of all cancers and 15 percent to 20 percent of haematologic malignancies worldwide, multiple myeloma is designated as an orphan disease in both the U.S. and Europe. 11 Globally, it is estimated that 124,225 people were diagnosed, and 87,084 died from the disease in 2015. 12,13 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone fracture or pain, low red blood counts, fatigue, calcium elevation, kidney problems or infections.14 Patients who relapse after treatment with standard therapies (including PIs or immunomodulatory agents) typically have poor prognoses and few remaining options.3

DARZALEX (daratumumab) Important Safety Information – Professional 4

CONTRAINDICATIONS – None

WARNINGS AND PRECAUTIONS
Infusion Reactions – DARZALEX can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, and hypertension. Signs and symptoms may include respiratory symptoms, such as cough, wheezing, larynx and throat tightness and irritation, laryngeal edema, pulmonary edema, nasal congestion, and allergic rhinitis. Less common symptoms were hypotension, headache, rash, urticaria, pruritus, nausea, vomiting, and chills.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients the first and second day after all infusions. Patients with a history of obstructive pulmonary disorders may require additional postinfusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with obstructive pulmonary disorders.

Interference with Serological Testing – Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX.

Interference with Determination of Complete Response – Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Adverse Reactions – The most frequently reported adverse reactions (incidence ≥20%) were: infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). 5 Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%).

DRUG INTERACTIONS – No drug interaction studies have been performed

On July 25, 2016 Medigene AG (MDG1, Frankfurt, Prime Standard), a clinical stage immune-oncology company focusing on the development of T cell immuno-therapies for the treatment of cancer, reported the grant of US patent US9,341,617B2 (Press release, MediGene, JUL 25, 2016, View Source [SID:1234514024]). The patent, with an expected life-span until 2030, claims a method for the identification of antigens recognized by CD4+ T cells, including tumor infiltrating CD4+ T cells.

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This patent expands Medigene’s T-cell receptor (TCR) platform technology with an additional fast and efficient method for the direct identification of antigens and respective epitopes recognized by CD4+ tumor infiltrating lymphocytes and opens the way to identify immune relevant patient-specific neoantigens. Rapid definition of epitopes recognized by CD4+ T helper cells for generation of tumor vaccines also becomes potentially possible.

Prof. Dolores Schendel, CEO and CSO of Medigene, explains: "This newly patented method provides the company with a potential additional source for new TCR candidates and also allows us to identify patient-specific neoantigens seen by CD4+ T cells. While CD4+ tumor infiltrating T cells have been known in the past, finding the antigens for which these T cells are specific was very time-consuming and complex. With the covered method we are now able to overcome these problems and it helps us to provide expanded options for adoptive T-cell therapies with transgenic T-cell receptors."

Medigene holds an exclusive license to the patent that was issued to Helmholtz Zentrum München (German Research Center for Environmental Health). Patents within the same patent family have already been granted in Europe, Australia and Canada.

About Medigene’s TCR patent portfolio: Medigene’s IP-portfolio relating to the TCR platform comprises 4 patent families covering methods for the identification of tumor-antigen specific T cell receptors and T cell receptors targeting specific tumor antigens. The 4 patent families in turn comprise 47 granted patents (including validations in Europe) and 14 pending applications. In addition, Medigene is constantly expanding its IP portfolio by filing applications for new methods and newly identified T-cell receptors specific for various tumor-antigens.

About CD4+ T cells in tumor biology: Recent advances in cellular immunotherapy show that cancer cells can be efficiently eliminated by adoptive transfer of modified patient T cells. The main effector functions can be provided by genetically engineered lymphocytes expressing T-cell receptors isolated from tumor antigen-specific cytotoxic CD8+ lymphocytes, which recognize tumor-associated antigens presented on HLA class I molecules. Nevertheless, CD4+ T lymphocytes play a critical role for efficient and sustained cytotoxic CD8+ T cell responses and memory function. Multifunctional CD4+ T cells are essential to activate, control and maintain immune responses. CD4+ T cells recognize antigens presented on HLA class II molecules; thereby HLA class II tumor antigen-positive cells may be efficiently eliminated also by direct CD4+ cytotoxic mechanisms. It was demonstrated that adoptive transfer of tumor antigen-specific CD4+ T cells alone can lead to substantial regression of epithelial tumors (Science. 2014 May 9;344(6184):641-5).

About Medigene’s TCR technology:
The TCR technology aims at arming the patient’s own T cells with tumor-specific T-cell receptors. The receptor-modified T cells are then able to detect and efficiently kill tumor cells. This immunotherapy approach attempts to overcome the patient’s tolerance towards cancer cells and tumor-induced immunosuppression by activating and modifying the patient’s T cells outside the body (ex-vivo). A large number of specific T cells to fight the tumor is thereby made available to patients within a short period of time.

Medigene’s technology for T-cell receptor-modified T cells is one of the company’s highly innovative and complementary immunotherapy platforms for adoptive T-cell therapy. The TCR therapy is designed to treat patients with high tumor loads. Medigene is preparing the clinical development of its first TCR candidates and is developing a library of recombinant T-cell receptors. Moreover, a Good Manufacturing Practice (GMP)-compliant process for their combination with patient-derived T cells is currently being established. Medigene plans to commence its first own clinical TCR trials in 2017 and a second in 2018.

On July 25, 2016 Shire plc (LSE: SHP, NASDAQ: SHPG) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending the marketing authorization for the use of ONIVYDE (irinotecan pegylated liposomal formulation) 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, 25 7/, 2016, View Source [SID:1234514015]).

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"There has been little improvement in the prognosis for patients with metastatic pancreatic cancer in over 20 years. We therefore welcome the CHMP positive opinion for ONIVYDE, a regulatory milestone which brings us a step closer to helping patients with this devastating disease." said Philip J. Vickers, Ph.D., Head of R&D, Shire. "At Shire, we are committed to research and development through innovation in order to identify unique methodologies for treating patients with high unmet needs."

Pancreatic cancer is the third leading cause of cancer death in the region and there are limited treatment options available. 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 second-line treatment of these patients following gemcitabine-based therapy. Gemcitabine-based therapy is commonly used as a first-line treatment for patients with metastatic disease or locally advanced disease who cannot be treated with surgery, or as adjuvant therapy.

"Guidance from ESMO (Free ESMO Whitepaper) indicates the use of ONIVYDE for the treatment of metastatic pancreatic cancer in patients who have progressed following gemcitabine-based treatment," said Volker Heinemann, M.D., Ph.D., a professor of medical oncology at the University of Munich, Germany. "The CHMP positive opinion for ONIVYDE is an important step for patients with this devastating disease."

The CHMP positive opinion is based on pivotal, Phase 3 NAPOLI-1 data that demonstrated nal-IRI combined with 5-FU and LV improved overall survival (OS) (primary endpoint), as well as progression-free survival (PFS) and objective response rate (ORR) relative to the 5-FU and LV control arm (secondary endpoints). The most common Grade 3 or higher adverse events with greater than five percent difference in patients receiving nal-IRI and 5-FU and LV were neutropenia, fatigue and diarrhoea, and vomiting.

"The CHMP positive opinion confirms the strength of the Phase 3 NAPOLI-1 data for the use of ONIVYDE to treat metastatic pancreatic cancer patients in the post-gemcitabine setting." said Professor Thomas Seufferlein, M.D., University of Ulm, Germany. "This data will allow physicians to better evaluate options for extending overall survival of patients diagnosed with a very difficult-to-treat cancer."

The CHMP’s positive opinion will be submitted to the European Commission (EC), which is responsible for granting marketing authorizations for medicines in the European Union (EU). We anticipate a final decision later this year.

J. Marc Pipas, M.D., Senior Medical Director at Merrimack Pharmaceuticals Inc. commented: "We applaud the CHMP’s positive opinion on ONIVYDE as it acknowledges the clinical significance of this therapy for a patient population with few treatment options. We look forward to continuing our work with Shire to expand the global availability of this important therapy to patients facing metastatic pancreatic cancer."

About Pancreatic Cancer

Pancreatic cancer is a significantly underserved disease in Europe and almost always fatal. Half of people diagnosed with pancreatic cancer are diagnosed at Stage 4, which is advanced metastatic disease and no longer curable. The disease has a five-year overall survival (OS) rate of three percent, and a median OS typically less than a year, as supported by real-world European systematic review. The only curative treatment for pancreatic cancer is surgical resection in the primary stage, which can improve five-year survival to 10 percent.

The signs and symptoms of pancreatic cancer are non-specific, (common presenting symptoms include jaundice, abdominal pain, weight loss, steatorrhoea, and new-onset diabetes) and may not appear until the disease has spread locally or metastasized. Therefore, approximately 80 percent of patients are not candidates for surgery upon diagnosis.

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

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 and the length of exposure of irinotecan. Studies have suggested that encapsulation helps to improve delivery of irinotecan to tumors, such as metastatic pancreatic cancer.

In the pivotal Phase 3 NAPOLI-1 study, nal-IRI demonstrated improved survival in patients with metastatic pancreatic cancer after previous gemcitabine-based therapy. 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.

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 currently 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. Approval of ONIVYDE in Taiwan was also received in October 2015, where PharmaEngine holds the commercialization rights.

About NAPOLI-1

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

NAPOLI-1 met the following primary and secondary endpoints by demonstrating that nal-IRI combined with 5-FU and LV significantly improved OS,progression-free survival (PFS) and objective response (OR) compared to 5-FU/LV alone in patients with metastatic pancreatic cancer. In a pivotal analysis, nal-IRI plus 5-FU/LV demonstrated a significant increase in median overall survival versus 5-FU and 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).

The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nal-IRI plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]).

Important Safety Information

The most common adverse reactions (incidence ≥20 percent) seen with nal-IRI in combination with 5-FU and LV compared with 5-FU and LV alone were: diarrhoea, nausea, vomiting, decreased appetite, neutropenia, fatigue, asthenia, anaemia, stomatitis, and pyrexia. Early-onset (within 1 day of treatment) diarrhoea occurred in 30 percent of patients on nal-IRI combined with 5-FU and LV and was usually transient. Early-onset diarrhoea was accompanied by cholinergic symptoms in three percent of patients taking nal-IRI in combination with 5-FU and LV. Median time to late-onset diarrhoea was eight days following the nal-IRI dose. Alopecia occurred in 14 percent of patients in the nal-IRI combined with 5-FU and LV arm versus five percent of patients in the 5-FU and LV arm. Of patients taking nal-IRI combined with 5-FU and LV, 11 percent of patients discontinued treatment versus seven percent of patients receiving 5-FU and LV alone. No significant deterioration in quality of life was observed in patients in either arm of the study compared to baseline.