On December 18, 2015 Amgen (NASDAQ:AMGN) reported that the European Commission has approved the use of IMLYGIC (talimogene laherparepvec) for the treatment of adults with unresectable melanoma that is regionally or distantly metastatic (Stage IIIB, IIIC and IVM1a), with no bone, brain, lung or other visceral disease (Press release, Amgen, DEC 18, 2015, View Source [SID:1234508597]). IMLYGIC is the first oncolytic immunotherapy to demonstrate therapeutic benefit for patients with metastatic melanoma in a Phase 3 clinical trial.

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IMLYGIC is derived from the herpes simplex type 1 virus (HSV-1) , commonly called the cold sore virus. IMLYGIC has been modified to replicate within tumors and to produce the immune stimulatory protein human granulocyte-macrophage colony-stimulating factor (GM-CSF). Administered via intralesional injection, IMLYGIC is designed to cause the death of tumor cells and initiate an anti-tumor immune response.

"As the first oncolytic immunotherapy authorized in the European Union, the approval of IMLYGIC is an important milestone for this new class of drugs, bringing patients with a rare and deadly form of skin cancer a much needed new treatment option," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "By igniting the body’s own immune system IMLYGIC can initiate an anti-tumor immune response, providing meaningful and durable response rates in the early stage metastatic melanoma patient."

Melanoma remains a significant public health concern in the European Union (EU), with an estimated 22,000 deaths from the disease in 2012.1,2 While melanoma is curable when detected in the early stages, metastatic melanoma continues to be one of the most difficult-to-treat cancers because it is highly aggressive and complex.3 Even with recent new options in immune-oncology, a large number of patients with metastatic melanoma still do not respond to treatment.4

The European approval included a review of exploratory subgroup analyses of Study 005/05, referred to as OPTiM. The durable response rate (DRR) in patients with Stage IIIB, IIIC and IVM1a disease was 25.2 percent compared to 1.2 percent in those treated with GM-CSF. In the study, patients with Stage IIIB, IIIC and IVM1a disease achieved an overall response rate (ORR) of 40.5 percent when treated with IMLYGIC compared to 2.3 percent with GM-CSF. The median overall survival (OS) for IMLYGIC patients with Stage IIIB, IIIC and IVM1a disease was 41.1 months compared to 21.5 months for patients treated with GM-CSF. While the pivotal study was not powered to evaluate efficacy in these individual subgroups, patients with no visceral disease derived greater benefit from IMLYGIC treatment than those with more advanced disease. Due to the exploratory nature of the analysis and based on the current evidence, it has not been established that IMLYGIC is associated with an effect on OS.

The most commonly reported treatment-related adverse events were fatigue, chills, pyrexia, nausea, influenza-like illness and injection-site pain. Overall, 98 percent of these adverse reactions reported were mild or moderate in severity. The most common grade 3 or higher adverse reaction was cellulitis. No fatal treatment-related adverse events occurred.5

This approval grants a centralized marketing authorization in the 28 countries that are members of the EU. Norway, Iceland and Liechtenstein, as members of the European Economic Area (EEA), will take corresponding decisions on the basis of the decision of the EC.

About the OPTiM Study
OPTiM was a global, randomized, open-label Phase 3 trial evaluating the safety and efficacy of IMLYGIC in patients with Stage IIIB, IIIC or IV melanoma when resection was not recommended compared to GM-CSF. In the 436-patient study, IMLYGIC significantly improved DRR, the primary endpoint of the trial, in the intent-to-treat population. DRR is defined as the percent of patients with complete response (CR) or partial response (PR) maintained continuously for a minimum of six months. In the study, 16.3 percent of patients treated with IMLYGIC achieved a DRR compared to 2.1 percent of patients treated with GM-CSF (p<0.0001) in the intent-to-treat population. Of the patients who experienced a durable response, 29.1 percent had a durable CR and 70.8 percent had a durable PR. In the study, the median time to response was 4.1 months (range: 1.2 to 16.7) in the IMLYGIC arm.

A key secondary endpoint was OS. In the intent-to-treat population, the median OS was 23.3 months in the group treated with IMLYGIC compared to 18.9 months for those treated with GM-CSF (p=0.0511). These results were not statistically significant. The ORR for patients in the intent-to-treat population was 26.4 percent for those treated with IMLYGIC compared to 5.7 percent in the GM-CSF arm. In an analysis to evaluate the systemic activity of IMLYGIC, 34 percent of patients in the intent-to-treat population had an overall decrease of at least 50 percent in non-visceral lesions that were not injected.

About IMLYGICTM (talimogene laherparepvec) in the EU
IMLYGIC is an oncolytic immunotherapy that is derived from HSV-1, which is commonly called the cold sore virus. IMLYGIC has been modified to replicate within tumors and to produce the immune stimulatory protein human GM-CSF. IMLYGIC causes the death of tumor cells and the release of tumor-derived antigens. It is thought that, together with GM-CSF, it will promote a systemic anti-tumor immune response and an effector T cell response.

Important EU Product Safety Information

This product is subject to additional monitoring. All suspected adverse reactions should be reported in accordance with the national reporting system.

The safety of IMLYGIC was evaluated in the pivotal study where 292 patients received at least one dose of IMLYGIC (see section 5.1). The median duration of exposure to IMLYGIC was 23 weeks (5.3 months). Twenty six (26) patients were exposed to IMLYGIC for at least one year.

The most commonly reported adverse reactions (≥ 25 percent) in IMLYGIC-treated patients were fatigue (50.3 percent), chills (48.6 percent), pyrexia (42.8 percent), nausea (35.6 percent), influenza-like illness (30.5 percent), and injection site pain (27.7 percent). Overall, ninety eight percent (98 percent) of these adverse reactions reported were mild or moderate in severity. The most common grade 3 or higher adverse reaction was cellulitis (2.1 percent) (see section 4.4).

Please refer to the Summary of Product Characteristics for full European prescribing information.

About IMLYGIC (talimogene laherparepvec) in the U.S.
In the U.S., IMLYGIC is indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. IMLYGIC has not been shown to improve overall survival or have an effect on visceral metastases.

Important U.S. Safety Information

Contraindications

Do not administer IMLYGIC to immunocompromised patients, including those with a history of primary or acquired immunodeficient states, leukemia, lymphoma, AIDS or other clinical manifestations of infection with human immunodeficiency viruses, and those on immunosuppressive therapy, due to the risk of life-threatening disseminated herpetic infection.
Do not administer IMLYGIC to pregnant patients.

Warnings and Precautions

Accidental exposure to IMLYGIC may lead to transmission of IMLYGIC and herpetic infection, including during preparation and administration. Health care providers, close contacts, pregnant women, and newborns should avoid direct contact with injected lesions, dressings, or body fluids of treated patients. The affected area in exposed individuals should be cleaned thoroughly with soap and water and/or a disinfectant.

Caregivers should wear protective gloves when assisting patients in applying or changing occlusive dressings and observe safety precautions for disposal of used dressings, gloves, and cleaning materials. Exposed individuals should clean the affected area thoroughly with soap and water and/or a disinfectant.

To prevent possible inadvertent transfer of IMLYGIC to other areas of the body, patients should be advised to avoid touching or scratching injection sites or occlusive dressings.

Herpetic infections: Herpetic infections (including cold sores and herpetic keratitis) have been reported in IMLYGIC treated patients. Disseminated herpetic infection may also occur in immunocompromised patients. Patients who develop suspicious herpes-like lesions should follow standard hygienic practices to prevent viral transmission.

Patients or close contacts with suspected signs or symptoms of a herpetic infection should contact their health care provider to evaluate the lesions. Suspected herpetic lesions should be reported to Amgen at 1-855-IMLYGIC (1-855-465-9442). Patients or close contacts have the option of follow-up testing for further characterization of the infection.

IMLYGIC is sensitive to acyclovir. Acyclovir or other antiviral agents may interfere with the effectiveness of IMLYGIC. Consider the risks and benefits of IMLYGIC treatment before administering antiviral agents to manage herpetic infection.

Injection Site Complications: Necrosis or ulceration of tumor tissue may occur during IMLYGIC treatment. Cellulitis and systemic bacterial infection have been reported in clinical studies. Careful wound care and infection precautions are recommended, particularly if tissue necrosis results in open wounds.

Impaired healing at the injection site has been reported. IMLYGIC may increase the risk of impaired healing in patients with underlying risk factors (e.g., previous radiation at the injection site or lesions in poorly vascularized areas). If there is persistent infection or delayed healing of the injection site, consider the risks and benefits of continuing treatment.

Immune-Mediated events including glomerulonephritis, vasculitis, pneumonitis, worsening psoriasis, and vitiligo have been reported in patients treated with IMLYGIC. Consider the risks and benefits of IMLYGIC before initiating treatment in patients who have underlying autoimmune disease or before continuing treatment in patients who develop immune-mediated events.

Plasmacytoma at Injection Site: Plasmacytoma in proximity to the injection site has been reported in a patient with smoldering multiple myeloma after IMLYGIC administration in a clinical study. Consider the risks and benefits of IMLYGIC in patients with multiple myeloma or in whom plasmacytoma develops during treatment.

Adverse Reactions

The most commonly reported adverse drug reactions (≥ 25 percent) in IMLYGIC-treated patients were fatigue, chills, pyrexia, nausea, influenza-like illness, and injection site pain. Pyrexia, chills, and influenza-like illness can occur at any time during IMLYGIC treatment, but were more frequent during the first 3 months of treatment.
The most common Grade 3 or higher adverse reaction was cellulitis.
Please see full U.S. Prescribing Information, including Medication Guide, for IMLYGIC at www.Amgen.com and www.IMLYGIC.com.

About Amgen’s Immuno-Oncology Focused Partnerships
Amgen has in place a comprehensive clinical development program investigating oncolytic immunotherapies for their potential in melanoma and in a variety of other cancers.

Amgen’s recent immuno-oncology focused partnerships include:

A collaboration with Merck on developing IMLYGIC (talimogene laherparepvec) and KEYTRUDA (pembrolizumab) Merck’s anti-PD-1 therapy, in melanoma and squamous cell cancer of the head and neck.

A collaboration with Roche on a Phase 1b study to evaluate the safety and efficacy of IMLYGIC in combination with Roche’s investigational anti-PDL1 therapy, atezolizumab (also known as MPDL3280A), in patients with triple-negative breast cancer and colorectal cancer with liver metastases.

A strategic research collaboration and license agreement to develop and commercialise the next generation of novel Chimeric Antigen Receptor (CAR) T-cell immunotherapies with Kite Pharma.

A research collaborative agreement focusing on Amgen’s bispecific T-cell engager (BiTE) antibody constructs with MD Anderson’s Moon Shots Program.

A research and license agreement with Xencor to develop and commercialise novel therapeutics in the areas of cancer immunotherapy and inflammation. The research collaboration brings together Amgen’s capabilities in target discovery and protein therapeutics with Xencor’s XmAb bispecific technology platform.

On December 2, 2015 Boehringer Ingelheim and The University of Texas MD Anderson Cancer Center reported a collaboration focused on developing innovative medicines for pancreatic ductal adenocarcinoma (PDAC) (Press release, Boehringer Ingelheim, DEC 1, 2015, View Source [SID:1234508383]). The new collaboration combines MD Anderson’s unique understanding of potential drivers of PDAC with Boehringer Ingelheim’s experience in drug discovery and development.

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Pancreatic cancer accounts for four percent of cancer deaths worldwide (330,000 people) and is the seventh most common cause of death from cancer. Pancreatic cancer is anticipated to become the second leading cause of cancer-related death in the United States before 2030. Newly diagnosed patients have a median survival of less than one year, and a 5-year survival rate of only 3 to 5 percent. PDAC is one of the most lethal of cancers due to its late detection and resistance to available standard-of-care therapy. Effective medicines directed against PDAC are therefore urgently needed.

"We are excited to be able to work with the leading cancer research and care institution in the world to develop therapies for patients with this devastating cancer," said Clive Wood, senior corporate vice president of Discovery Research at Boehringer Ingelheim. "This partnership is a perfect match because it combines MD Anderson’s outstanding capabilities in preclinical concept validation and clinical testing with Boehringer Ingelheim’s strength in developing innovative medicines in novel target spaces."

The collaboration will focus on identifying and developing therapeutic concepts in novel target areas as well as identification of biomarkers that can accurately identify patients who would respond to potential new therapies.

"At MD Anderson, we have created integrated platforms that will enable the discovery of more effective therapeutics for cancer patients," said Timothy Heffernan, executive director and co-leader for MD Anderson’s Center for Co-Clinical Trials. "This alliance combines expertise in cancer genetics and translational medicine with outstanding drug discovery and development and it has great potential to conquer devastating diseases like pancreatic cancer."

On December 1, 2015 Following an independent Data Monitoring Committee (DMC) meeting, OncoGenex Pharmaceuticals, Inc. (NASDAQ: OGXI) reported that its Phase 3 AFFINITY trial is continuing based on the pre-planned interim futility analysis of the intent-to-treat (ITT) population (Press release, OncoGenex Pharmaceuticals, DEC 1, 2015, View Source [SID:1234508379]). In the final safety review, no new safety issues were identified by the DMC. Both the DMC and OncoGenex remain blinded to all analyses and final results are expected in the second half of 2016, depending on timing of the event-driven final analysis.

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AFFINITY is designed to evaluate whether the investigational treatment custirsen, when combined with cabazitaxel, improves survival in men with metastatic castrate-resistant prostate cancer (CRPC) whose disease has progressed following treatment with docetaxel. The final AFFINITY efficacy analysis is designed to show a survival benefit with 85 percent power based on a hypothesized hazard ratio of 0.75.

Separately, an analysis of a prospectively defined subpopulation of men in the AFFINITY trial who had multiple poor prognostic risk factors revealed that the combination of custirsen and cabazitaxel did not meet the rigorous criteria required to demonstrate an improvement in overall survival (hypothesized hazard ratio ≤0.69, one-sided p value ≤0.015). This subpopulation was identified and evaluated based on a retrospective analysis of a previous Phase 3 trial of men with similar clinical features who experienced a reduced risk of death when custirsen was added to chemotherapy. In addition, OncoGenex pursued the evaluation of this subpopulation, independent of the ITT, in order to obtain an expedited approval for these patients with more aggressive disease.

"The overall survival endpoint of the entire AFFINITY trial remains clinically meaningful and its target hazard ratio of 0.75 is attainable with sufficient power to demonstrate a benefit from custirsen for men who are battling advanced prostate cancer," said Scott Cormack, President and CEO of OncoGenex. "We designed the AFFINITY trial so that the final analysis of the ITT population could stand alone as a Phase 3 submission to regulatory agencies regardless of the outcome of the smaller subgroup."

As part of the Phase 3 development program for custirsen, OncoGenex continues with its ENSPIRIT clinical trial in patients with non-small cell lung cancer (NSCLC). The trial is evaluating the ability of custirsen, in combination with docetaxel treatment as second-line chemotherapy, to extend survival in patients with NSCLC. Based on current enrollment projections, ENSPIRIT results could be available in the second half of 2016.

The company also expects several additional clinical trial milestones in 2016 with its other lead product candidate apatorsen, which include:

Announcing results for the primary progression-free survival endpoint of the Phase 2 Spruce trial in advanced NSCLC
Announcing results of the Phase 2 Borealis-2 trial in patients with metastatic bladder cancer
Completing enrollment in the Phase 2 Pacific trial in metastatic CRPC

Conference Call Details
OncoGenex will host a conference call at 4:30 p.m. Eastern Time today, Tuesday, December 1, 2015, to discuss today’s news. A live event will be available on the Investor Relations section of the OncoGenex website at www.OncoGenex.com. Alternatively, visitors may access the live conference call by dialing (877) 606-1416 (U.S. & Canada) or (707) 287-9313 (International). A webcast replay will be available approximately two hours after the call and will be archived on www.OncoGenex.com for 90 days.

About the AFFINITY Trial
The Phase 3 AFFINITY trial is an international, randomized, open-label study designed to evaluate whether custirsen, when combined with cabazitaxel, has the potential to improve survival outcomes for metastatic CRPC patients whose disease has progressed following treatment with docetaxel. The two primary objectives of the study are overall survival in the ITT population and overall survival in men who had two or more pre-defined clinical prognostic features of metastatic CRPC.

Both groups received cabazitaxel in combination with weekly custirsen or cabazitaxel alone, and treatment continued until disease progression, unacceptable toxicity or completion of 10 cycles. The AFFINITY trial enrolled 630 men with metastatic CRPC at 95 sites throughout North America, Europe, Russia and Australia.

For more information on the AFFINITY trial, please visit ClinicalTrials.gov (NCT01578655).

About prostate cancer
More than 220,000 new cases of prostate cancer are diagnosed each year and prostate cancer is the second leading cause of cancer-related deaths in the United States among men. Approximately 50% of patients with clinically localized prostate cancer are estimated to progress despite initial treatment. Metastatic CRPC often spreads to the bone, making it difficult for some men to perform even the simplest daily activities, like standing up and walking around. Prostate cancer deaths are usually the result of metastatic CRPC, which has a median survival of less than two years.

On Dec. 1, 2015 MabVax Therapeutics Holdings, Inc. (OTCQB: MBVX), a clinical-stage oncology drug development company, reported it has filed an Investigational New Drug Application (IND) with the U.S. Food and Drug Administration (FDA) for the Company’s lead fully human antibody product HuMab 5B1 as a therapeutic agent (Press release, MabVax, DEC 1, 2015, View Source [SID:1234508375]). Subject to FDA acceptance, MabVax plans to initiate the Phase I clinical trial early in 2016.

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The planned Phase I trial will evaluate the safety, tolerability and pharmacokinetics of HuMab 5B1 as a single agent or in combination with the current standard of care chemotherapy regimen in subjects with metastatic pancreatic cancer. The first cohort of patients to be enrolled in the planned clinical trial will be enrolled in a traditional dose escalation regimen to assess safety and determine the optimal dose of the antibody. A second patient cohort will establish the safety and optimized dose of the antibody when administered with standard of care chemotherapy and a third patient cohort will be administered the optimized dose of antibody as a single agent for the treatment of patients with advanced cancer.

David Hansen, MabVax’s President and Chief Executive Officer, said, "The filing of the first of two planned INDs for our novel HuMab 5B1 antibody is a significant achievement for MabVax. Pending FDA acceptance of the IND, we will begin the dose escalation portion of this Phase I trial as early in 2016 as possible and anticipate reporting on the early safety assessment and determination of a maximum tolerated dose in mid-year 2016. Achievement of this important interim milestone will enable us to move into the combination therapy and monotherapy portions of the trial where we could learn much more about the pharmacological effects of this new therapy. The milestone could also have a positive impact on our future commercial and corporate development activities. We currently anticipate having full enrollment of all three patient cohorts sometime before the end of 2016."

MabVax plans to file a second IND application this month for its HuMab 5B1-based PET imaging agent and, subject to FDA acceptance, will begin this Phase I trial as early as possible in 2016. When the antibody is combined with a radio-label as a novel PET imaging agent, the 89Zr-HuMab 5B1 product has demonstrated high image resolution of tumors in established xenograft animal models, making it attractive as a potential companion diagnostic for the HuMab 5B1 therapeutic product.

"We believe the data generated in the early portions of these two Phase I trials will help demonstrate the initial safety, targeting specificity, and utility of the HuMab 5B1 antibody in this devastating disease," added Mr. Hansen. "We are excited about the potential applicability of our dual-product development approach in other cancers with HuMab 5B1, as well as with follow-on antibodies under development at MabVax."

About HuMab 5B1:

MabVax’s HuMab 5B1 antibody is fully human and was discovered from the immune response of cancer patients vaccinated with an antigen-specific vaccine during a Phase I trial at Memorial Sloan Kettering Cancer Center. In preclinical research, the 5B1 antibody has demonstrated high specificity and affinity, and has shown potent cancer cell killing capacity and efficacy in animal models of pancreatic, colon and small cell lung cancers. The antigen the antibody targets is expressed on more than 90% of pancreatic cancers making the antibody potentially broadly applicable to most patients suffering from this type of cancer.

On December 01, 2015 Advaxis, Inc. (NASDAQ:ADXS), a clinical-stage biotechnology company developing cancer immunotherapies, reported that the European Medicines Agency (EMA) granted Orphan Drug Designation for ADXS-HER2 for the treatment of osteosarcoma (Press release, Advaxis, DEC 1, 2015, View Source [SID:1234508369]).

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"Receiving Orphan Drug Designation from the EMA is another significant step forward for Advaxis as we continue to advance ADXS-HER2," said Daniel J. O’Connor, CEO of Advaxis. "We recently initiated our first-in-human study of our lead Lm Technology immunotherapy product for HER2 expressing solid tumors and we hope to expand that trial into four HER2 expressing tumor types, including breast, gastric, esophageal and osteosarcoma."

Orphan Drug Designation in the EU is granted to drugs or biologics that treat a life-threatening or chronically debilitating rare disease affecting fewer than five in 10,000 individuals in the European Union. Products receiving orphan drug designation are eligible to receive market exclusivity for a period of up to ten years, as well as development incentives such as regulatory and protocol assistance and scientific advice.

About HER2 Expressing Solid Tumor Cancers
Human epidermal growth factor receptor 2 (HER2) is overexpressed in a percentage of solid tumors such as breast, gastric, bladder, brain, pancreatic, ovarian and pediatric bone cancer (osteosarcoma). The American Cancer Society estimates that in 2015 in the United States alone there will be 231,840 new cases of invasive breast cancer; 24,590 new cases of gastric cancer; 74,000 new cases of bladder cancer; 22,850 new cases of brain/spinal cancer; 48,960 new cases of pancreatic cancer; 21,290 new cases of ovarian cancer; and 207 new cases of pediatric osteosarcoma. HER2 expression is associated with more aggressive disease, increased risk of relapse and decreased overall survival, and is an important target for immunotherapy.

About ADXS-HER2
ADXS-HER2 is an Lm Technology immunotherapy product candidate being developed by Advaxis to target HER2 expressing cancers. ADXS-HER2 has received orphan drug designation by the U.S. Food and Drug Administration (FDA) for the treatment of osteosarcoma. Advaxis is developing ADXS-HER2 for both human and animal health, and has seen encouraging data in canine osteosarcoma, which is considered a model for human osteosarcoma. Advaxis has licensed ADXS-HER2 and three other immunotherapy constructs to Aratana Therapeutics, Inc. for the development of pet therapeutics.