On April 29, 2015 Bristol-Myers Squibb reported that the U.S. Food and Drug Administration (FDA) has accepted for filing and review the supplemental Biologics License Application (sBLA) for Opdivo (nivolumab) for the treatment of previously untreated patients with unresectable or metastatic melanoma (Press release, Bristol-Myers Squibb, APR 29, 2015, View Source [SID:1234503222]). The FDA also granted Priority Review for this application. The projected FDA action date is August 27, 2015.

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Opdivo was first approved by the FDA in December 2014 for patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. This initial indication was approved under accelerated approval based on tumor response rate and durability of response from CheckMate -037 clinical trial results. This new sBLA accepted by the FDA includes data from CheckMate -066, which evaluated Opdivo in treatment naïve patients with BRAF wild-type advanced melanoma as compared to dacarbazine chemotherapy (DTIC). In the trial, safety and tolerability were well-characterized with fewer treatment-related Grade 3/4 adverse events observed with Opdivo than dacarbazine.

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"The CheckMate -066 trial marked the first time that a PD-1 immune checkpoint inhibitor showed a survival benefit in a randomized Phase III trial," said Michael Giordano, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb. "We look forward to continuing to work with the FDA to ensure cancer patients are provided the latest clinical advances that have the potential for improved responses and long-term survival."

About Advanced Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease, and occurs when cancer spreads beyond the surface of the skin to the other organs, such as the lymph nodes, lungs, brain or other areas of the body. The incidence of melanoma has been increasing for at least 30 years. In 2015, an estimated 73,870 melanoma cases will be diagnosed in the U.S. Melanoma is mostly curable when treated in its early stages. However, in its late stages, the average survival rate is just 6 months with a 1-year survival of 25.5%, making it one of the most aggressive forms of cancer.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that has received approval from the U.S. FDA as a monotherapy in two cancer indications. On March 5, 2015, Opdivo received FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

In the U.S., Opdivo is also indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma.

Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 7,000 patients have been enrolled worldwide.

Immuno-Oncology at Bristol-Myers Squibb

Surgery, radiation, cytotoxic or targeted therapies have represented the mainstay of cancer treatment over the last several decades, but long-term survival and a positive quality of life have remained elusive for many patients with advanced disease.

To address this unmet medical need, Bristol-Myers Squibb is leading research in an innovative field of cancer research and treatment known as immuno-oncology, which involves agents whose primary mechanism is to work directly with the body’s immune system to fight cancer. The company is exploring a variety of compounds and immunotherapeutic approaches for patients with different types of cancer, including researching the potential of combining immuno-oncology agents that target different pathways in the treatment of cancer.

Bristol-Myers Squibb is committed to advancing the science of immuno-oncology, with the goal of changing survival expectations and the way patients live with cancer.

About the Bristol-Myers Squibb and Ono Pharmaceutical Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical, Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Bristol-Myers Squibb and Ono Pharmaceutical further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 1. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.

Immune-Mediated Colitis

In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.

Immune-Mediated Hepatitis

In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.

Immune-Mediated Nephritis and Renal Dysfunction

In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.

Immune-Mediated Hypothyroidism and Hyperthyroidism

In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Other Immune-Mediated Adverse Reactions

The following clinically significant, immune-mediated adverse reactions occurred in less than 2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone- replacement therapy.

Embryofetal Toxicity

Based on its mechanism of action, OPDIVO 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 treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

Serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.

Common Adverse Reactions

The most common adverse reaction (≥20%) reported with OPDIVO was rash (21%).
Please see US Full Prescribing Information for OPDIVO.

On April 29, 2015 Bellicum Pharmaceuticals reported it has entered into a license agreement with Leiden University Medical Center (LUMC), Netherlands, for worldwide rights to develop, manufacture and commercialize high-affinity TCR (T cell receptor) product candidates targeting solid tumors expressing the preferentially-expressed antigen in melanoma, or PRAME (Filing, 8-K, Bellicum Pharmaceuticals, APR 29, 2015, View Source [SID:1234503221]).

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TCRs are engineered T cells that are activated when in the presence of target antigens in cancer cells. The lead TCRs under this license agreement have been shown to have a high affinity to PRAME, a cancer antigen that is preferentially expressed in melanomas, sarcomas, neuroblastomas and other solid tumors, but generally not expressed in normal tissue.

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Bellicum’s first TCR product candidate under this agreement, BPX-701, targets PRAME and is expected to enter Phase 1/2 clinical trials before the end of 2015. BPX-701 incorporates Bellicum’s proprietary safety mechanism, CaspaCIDe, for improved control over the cells.

Bellicum also exclusively licensed LUMC’s TCR technology targeting POU-2AF1. These TCRs have a high affinity to the B cell transcription factor expression product of POU-2AF1, which is present in primary chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), mantle cell lymphoma and multiple myeloma.

"TCRs are demonstrating broad potential for the treatment of solid tumors," said Tom Farrell, President and Chief Executive Officer of Bellicum Pharmaceuticals. "The cancer targets under this license, combined with our CaspaCIDe safety mechanism, form the basis of a growing portfolio of differentiated T cell therapies with the potential to address a wide range of cancers."

On April 29, 2015 OncoMed reported new discoveries related to the company’s anti-cancer immuno-oncology pipeline during the company’s first Research and Development (R&D) Day for analysts and investors (Press release, OncoMed, APR 29, 2015, View Source [SID:1234503219]).

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"OncoMed has always been focused on developing transformative anti-cancer therapeutics, and the drug discovery efforts we apply to every program have led us to identify some truly first-in-class candidates targeting fundamental cancer stem cell and immuno-oncology pathways," said Paul J. Hastings, OncoMed’s Chairman and Chief Executive Officer. "During today’s R&D Day event, we showcased the clinical, translational medicine and research science taking place at OncoMed, unveiled emerging programs that haven’t yet been in the spotlight, and provided an in-depth understanding of the way we think about drug discovery and development across our portfolio."

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Among the highlights of OncoMed’s R&D Day were data from a series of experiments that identified a novel immune therapy mechanism for demcizumab (anti-DLL4, OMP-21M18) and demonstrated synergistic activity when anti-DLL4 is combined with an anti-PD1 checkpoint inhibitor. Anti-DLL4 modulates T-cell response by reducing the accumulation of monocytic myeloid-derived suppressor cells, a key population of immunosuppressive cells that inhibit anti-tumor immune responses that are otherwise not addressed by anti-PD1 therapy. When anti-DLL4 is combined with anti-PD1, researchers observed increased inhibition of tumor growth and more robust anti-tumor immune responses in immunocompetent xenograft models as compared to either agent alone. Further, the combination of anti-DLL4 and anti-PD1 reduced tumor growth in re-implantation experiments. These results indicate that dual targeting of DLL4 and PD1 may promote effective and durable cancer therapy by increasing anti-tumor immune response and long-term immunological memory. This research could provide the foundation for a novel clinical development strategy. These data were recently presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting.

A new approach, discovered by OncoMed researchers, to inhibit a known immune-oncology receptor was also disclosed publicly for the first time. GITR, a member of the tumor necrosis factor family, is known to be an important receptor in T-cell activation and regulation. OncoMed scientists have devised a novel strategy for the creation of robust T cell activating agents that utilizes fully human single-gene GITRL trimeric ligand attached to an antibody framework. The unique design of OncoMed’s proprietary strategy also enables the creation of novel bispecific agents. In preclinical studies, OncoMed’s GITRL-Fc candidate results in a potent anti-tumor immune response.

A third example of OncoMed’s immuno-oncology research efforts revealed the discovery of a novel and previously "missing" checkpoint target. Tumor cells are believed to take advantage of the immune system’s so called "checkpoints" to escape detection. While significant advances have been made in the understanding of checkpoint inhibitors, a number of orphan targets exist and these have been the subject of extensive research by OncoMed scientists for several years. One outcome of these efforts is discovery of a receptor (nicknamed "PD2"), which appears to be an activating receptor for the known checkpoint inhibitor PD-L2. Initial research by OncoMed demonstrates that "PD2" mediates important immunological functions associated with PD-L2. Activation of PD-L2 may provide an entirely new pathway by which to engage the body’s own immune system in combatting tumor cells.

In addition, OncoMed’s 2015 R&D Day included presentations of recently updated clinical data for demcizumab and tarextumab (anti-Notch2/3, OM59R5) that represent the foundation for the company’s four ongoing randomized Phase 2 clinical trials. Additionally, clinical and preclinical proof-of-concept data were presented for two of the company’s biomarker assays in development, and overview of OncoMed’s approach to elucidating cancer biology to identify and validate new leads and inform clinical trial design.

OncoMed’s 2015 R&D Day also featured special guest speakers. Manuel Hidalgo, MD, PhD, Vice Director of Translational Research, Spanish National Cancer Research Centre (CNIO), shared his experience as an investigator in the company’s demcizumab clinical trials in pancreatic cancer. Jorge DiMartino, MD, PhD, Vice President, Translational Development of Celgene Corporation provided a presentation on Celgene’s multi-product collaboration with OncoMed and the research that initially piqued Celgene’s interest.

A webcast of the R&D Day presentations can be accessed under the Investor Relations section of the company’s website (www.oncomed.com). A replay of the webcast will be archived on the OncoMed website for approximately 60 days following the presentation.

On April 29, 2015 Amgen reported that it will discuss the data supporting the Biologics License Application (BLA) for talimogene laherparepvec monotherapy for the treatment of patients with injectable regionally or distantly metastatic melanoma at today’s joint meeting of the U.S. Food and Drug Administration’s (FDA) Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) and Oncologic Drugs Advisory Committee (ODAC)
(Press release, Amgen, APR 29, 2015, View Source [SID:1234503213]).

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At the meeting, Amgen will present the results of the pivotal Phase 3 OPTiM study, which showed that talimogene laherparepvec monotherapy is the first oncolytic immunotherapy to demonstrate therapeutic benefit in a Phase 3 pivotal trial for patients with metastatic melanoma.

"The incidence of melanoma, the most serious form of skin cancer, has continued to rise over the last 30 years, even as many other cancers are in decline," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "Despite recent advances, there is still an unmet need in this disease. For this reason, today’s discussion about talimogene laherparepvec for the treatment of patients with metastatic melanoma is important. If approved, this novel agent could provide physicians and patients with an additional treatment option for this disease."

Talimogene laherparepvec is an investigational oncolytic immunotherapy designed to selectively replicate in tumors (but not normal tissue) and to initiate an immune response to target cancer cells that have metastasized. Talimogene laherparepvec was designed to work in two important and complementary ways. First, it is injected directly into tumors where it replicates inside the tumor’s cells causing the cell to rupture and die in a process called lysis. Then, the rupture of the cancer cells can release tumor-derived antigens, along with granulocyte-macrophage colony-stimulating factor (GM-CSF), which can stimulate a system-wide immune response where white blood cells are able to seek out and target cancer that has spread throughout the body.

Amgen has in place a comprehensive clinical development program for talimogene laherparepvec in metastatic melanoma, which includes combination studies with checkpoint inhibitors in patients with late-stage disease and monotherapy prior to surgery (neoadjuvant) in patients with resectable disease. Additionally, based on its clinical profile, talimogene laherparepvec has the potential to be studied in a variety of solid tumor types.

According to the American Cancer Society, with an estimated 74,000 new melanoma diagnoses and nearly 10,000 deaths this year1, melanoma remains a significant public health concern in the U.S. Additionally, metastatic melanoma continues to be one of the most difficult to treat cancers because it is highly aggressive and complex. Despite recent treatment advances, the five-year survival rate for melanoma is only 20 percent2, so additional safe and effective treatment options are needed.

OPTiM Study Design and Results
Study 005/05, referred to as OPTiM, was a Phase 3, multicenter, open-label, randomized clinical trial comparing talimogene laherparepvec to GM-CSF in patients with advanced melanoma (stage IIIB, IIIC, or IV) that was not surgically resectable. The primary endpoint of the study was durable response rate (DRR).

In the 436-patient study, talimogene laherparepvec significantly improved DRR with 16.3 percent of talimogene laherparepvec patients achieving a complete response (CR) or partial response (PR) within the first 12 months of treatment and maintaining it continuously for at least six months compared to 2.1 percent of patients treated with GM-CSF (p <0.001).

The OPTiM study also provided additional secondary and exploratory data that demonstrated the effects of talimogene laherparepvec in patients with Stage III/IV metastatic melanoma, including:

Improved overall (CR + PR) response rate compared with GM-CSF, 26.4 percent vs. 5.7 percent, respectively. In particular, the CR rate was higher in the talimogene laherparepvec arm than in the GM-CSF arm (10.8 percent vs. 0.7 percent, respectively).

A strong trend in overall survival (OS). The median OS was 4.4 months longer in the talimogene laherparepvec arm than in the GM-CSF arm (hazard ratio: 0.79; p=0.051).

Evidence of a systemic effect. Eight of 71 patients (11.3 percent) with visceral lesions that could not be injected (predominately in the lung and liver) had an overall decrease in those lesions of more than 50 percent.

The most commonly reported treatment-related adverse events were fatigue, chills, pyrexia, nausea, influenza-like illness, and injection-site pain. Most adverse reactions reported were mild or moderate in severity and generally resolved within 72 hours. The most common serious adverse reaction was cellulitis.

On April 29, 2015 Agios Pharmaceuticals reported that it plans to advance into clinical development AG-881, a small molecule that has shown in preclinical studies to fully penetrate the blood brain barrier and inhibit isocitrate dehydrogenase-1 (IDH1) and IDH2 mutant cancer models, in collaboration with its cancer metabolism partner Celgene Corporation (Press release, Agios Pharmaceuticals, APR 29, 2015, View Source [SID:1234503204]). The companies have entered into a new joint worldwide development and profit share collaboration for AG-881 and plan to initiate clinical development of AG-881 in the second quarter of 2015. AG-881 will be the third IDH mutant inhibitor discovered by Agios to enter clinical development.

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"The addition of our third IDH mutant inhibitor to our growing pipeline is an exciting milestone for Agios and underscores our goals to lead the scientific understanding of cancer metabolism and help as many patients as possible with an IDH mutant positive cancer," said David Schenkein, M.D., chief executive officer of Agios. "AG-221 and AG-120 remain our lead medicines in clinical development and are advancing rapidly. We believe the addition of AG-881, given its unique profile, provides added flexibility to our portfolio of IDH inhibitors. Based on our preclinical findings, it has the potential to support our ongoing development effort to provide treatment options to patients with glioma, and it represents a possible second-generation molecule for both AG-221 and AG-120 in IDH mutant tumors. We look forward to generating data for AG-881 to inform our future development plans."

Under the terms of the new AG-881 collaboration, Agios will receive an initial payment of $10 million in the second quarter of 2015 and is eligible to receive regulatory milestone payments of up to $70 million. Agios and Celgene will jointly collaborate on the worldwide development program for AG-881, sharing development costs 50/50 worldwide. The two companies have agreed to share any worldwide profits 50/50, with Celgene booking worldwide commercial sales. Agios would lead commercialization in the U.S. with both companies sharing equally in field-based commercial activities, and Celgene would lead commercialization ex-U.S. with Agios providing one third of field-based commercial activities in the major E.U. markets.

Summary of Agios and Celgene Collaboration on IDH Mutant Inhibitors

Agios and Celgene entered a global, strategic collaboration in April 2010 and, to date, three potential new distinct investigational medicines have emerged – the IDH2 mutant inhibitor, AG-221; the IDH1 mutant inhibitor, AG-120; and the pan-IDH mutant inhibitor, AG-881, which as described above is now part of a new collaboration between the companies. These three investigational medicines aim to improve the treatment outcomes for patients whose cancers carry these IDH mutations, including difficult to treat acute myelogenous leukemia and glioma, a type of aggressive brain tumor with poor prognosis. Each of these investigational medicines carries different financial terms and rights under the collaboration, including:

AG-221: Celgene has worldwide development and commercialization rights for AG-221. Agios is eligible for up to $120 million in milestone payments and royalties on any net sales.
AG-120: Agios retains U.S. development and commercialization rights, while Celgene has development and commercialization rights outside the U.S. Agios is eligible to receive royalties on any net sales outside the U.S. and up to $120 million in milestone payments. Celgene is eligible to receive royalties on any net sales in the U.S.
AG-881: Joint worldwide development and 50/50 profit share collaboration. Agios is eligible to receive regulatory milestone payments up to $70 million.