Cancer Research UK, CRT and Amgen to trial leukaemia immunotherapy drug in other cancers

On December 22, 2014 Cancer Research UK, Cancer Research Technology (CRT) and Amgen Inc. reported an agreement to take forward Amgen’s experimental immunotherapy treatment, AMG319, into its first trial involving patients with solid tumours, following a successful phase one trial of this drug in leukaemia and lymphoma patients (Press release, Cancer Research Technology, DEC 22, 2014, View Source [SID1234523214]).

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The collaboration forms part of Cancer Research UK’s Clinical Development Partnership (CDP) scheme, a joint initiative between Cancer Research UK’s Centre For Drug Development (CDD) and CRT, to develop promising anti-cancer agents for which pharmaceutical companies do not have the resource to progress through early phase clinical trials.

AMG319 targets an important protein called P13 kinase delta to disable the ‘cloaking device’ that tumours use to evade detection by the immune system.

Studies in mice with solid tumours, part-funded by Cancer Research UK, have shown the ability of this class of drug to mount a response against cancer cells by independently stimulating the immune system but this is the first time it has been trialled in patients with solid tumours.*

Cancer Research UK’s Centre for Drug Development will manage and sponsor the study through the Experimental Cancer Medicine Centre (ECMC) network, with the aim of evaluating the safety and biological effect of AMG319 in patients with head and neck cancer.

Dr Jeremy Haigh, Chief Operating Officer for Amgen’s European R&D Organisation, said: "We fully recognise the value of working with Cancer Research UK in this project. Its distinctive expertise and resources will make a big contribution to our deeper understanding of this area of cancer treatment and wider understanding of AMG319. Cancer Research UK brings more than a century of experience in the prevention, diagnosis and treatment of cancer. "

Dr Nigel Blackburn, Cancer Research UK’s Director of Drug Development, said: "We’re pleased that this collaboration will allow patients with a wider variety of cancers to access this promising new immunotherapy treatment, which was originally developed for blood cancer patients. Treatments that train the immune system to recognise and kill cancer cells are showing huge promise, so we look forward to seeing whether this drug could echo those results."

Bristol-Myers Squibb Receives Accelerated Approval of Opdivo (nivolumab) from the U.S. Food and Drug Administration

On December 22, 2014 Bristol-Myers Squibb reported that the U.S. Food and Drug Administration (FDA) approved Opdivo (nivolumab) injection, for intravenous use (Press release Bristol-Myers Squibb, DEC 22, 2014, View Source [SID:1234501237]). Opdivo is a human programmed death receptor-1 (PD-1) blocking antibody 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. Metastatic melanoma is the deadliest form of skin cancer, and despite recent advances, there are limited treatment options available for patients who have been previously treated with approved agents.

“Bristol-Myers Squibb is pleased to be able to offer an important new option for patients who have progressed following treatment for unresectable or metastatic melanoma, which is one of the most aggressive forms of cancer,” said Lamberto Andreotti, chief executive officer, Bristol-Myers Squibb. “The approval of Opdivo, the latest breakthrough medicine from our immuno-oncology pipeline, demonstrates our company’s commitment to meeting the needs of these patients, and to leading advances in the science of immuno-oncology.”

Opdivo is associated with immune-mediated: pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism and hyperthyroidism, other adverse reactions; and embryofetal toxicity. Please see the Important Safety Information section below.

The company expects to begin shipping Opdivo within one to two weeks of today’s approval.

Opdivo Delivered A Response Rate of 32%

Opdivo is the only PD-1 that has demonstrated efficacy in a Phase 3, pivotal clinical trial with advanced melanoma in patients who had been previously treated and progressed with Yervoy and, if BRAF mutation positive, a BRAF inhibitor. The efficacy of Opdivo was evaluated based on a single-arm, non-comparative planned interim analysis of the first 120 patients who received Opdivo with a minimum of 6 months follow-up in the Phase 3 CheckMate -037 trial.

Opdivo achieved a 32% (95% CI: 23, 41) response rate (38/120) with a dosing strength and frequency of 3 mg/kg intravenously over 60 minutes every 2 weeks. 3% of patients (4/120) achieved a complete response, and 28% (34/120) achieved a partial response. Of 38 patients with responses, 33 patients (87%) had ongoing responses with durability of response ranging from 2.6+ to 10+ months, which included 13 patients with ongoing responses of 6 months or longer. Responses to Opdivo were demonstrated in both patients with and without BRAF mutation.

The safety profile of Opdivo has been demonstrated in the pivotal, Phase 3 CheckMate-037 trial. 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. The most common adverse reaction (≥20%) reported with Opdivo was rash (21%). Please see the Important Safety Information section below. "The approval of Opdivo gives patients and physicians an important new treatment option for a population where they were once very limited," said Jeffrey S. Weber, MD, Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center. "For the first time, a PD-1 blocking antibody has shown a response rate of 32% in a Phase 3 randomized clinical trial of patients with unresectable or metastatic melanoma, who have progressed following first line therapy." Efficacy was evaluated in a single-arm, non-comparative, planned interim analysis of the first 120 patients who received Opdivo in the CheckMate -037 trial in whom the minimum duration of follow up was 6 months. "The emergence of effective immuno-oncology therapies that are capable of successfully treating metastatic melanoma has reinvigorated the field of cancer immunology with an optimism that immune based treatments will play a central role in therapeutic strategies for cancer patients," said Jill O’Donnell-Tormey, Ph.D., CEO and director of Scientific Affairs at the Cancer Research Institute, a nonprofit organization dedicated to advancing the science of cancer immunology.

MacroGenics Enters Collaboration and License Agreement with Janssen to Develop MGD011 for Multiple B-Cell Malignancies

On December 22, 2014 MacroGenics reported a global collaboration and license agreement for MGD011 with Janssen Biotech, Inc (Press release MacroGenics, DEC 22, 2014, View Source [SID:1234501226]). This product candidate incorporates MacroGenics’ proprietary platform for Dual-Affinity Re-Targeting (DART) to simultaneously target CD19 and CD3 for the potential treatment of B-cell malignancies.

Under the terms of the agreement and subject to the termination or expiration of any applicable waiting periods under Hart-Scott-Rodino Act, MacroGenics will receive a $50 million upfront license fee and Johnson & Johnson Innovation – JJDC, Inc. will invest $75 million to purchase 1,923,077 new shares of MacroGenics common stock at a price of $39.00 per share. Janssen will be fully responsible for developing MGD011 following submission of the IND, which is planned for 2015. Assuming successful development and commercialization, MacroGenics could receive up to an additional $575 million in clinical, regulatory and commercialization milestone payments. MacroGenics may elect to fund a portion of late-stage clinical development in exchange for a profit share in the U.S. and Canada. If commercialized, MacroGenics would be eligible to receive double-digit royalties on any global net sales and has the option to co-promote the molecule with Janssen in the U.S.

“MGD011 is a promising product candidate and one that we believe is meaningfully differentiated from competing CD19-directed therapies,” said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. “Janssen represents the ideal partner for this product candidate, given their track record of successfully developing and commercializing transformative oncology therapies and their experience in the B-cell malignancy area. We look forward to working with Janssen to significantly expand the development of MGD011 and maximize its value.”

Taiho Pharmaceutical Receives FDA Fast Track Designation for TAS-102 as a Potential Treatment for Refractory Metastatic Colorectal Cancer

On December 21, 2014 Taiho Pharmaceutical reported that the U.S. Food and Drug Administration (FDA) granted Fast Track designation for TAS-102 (nonproprietary names: trifluridine and tipiracil hydrochloride, brand name in Japan ”Lonsurf combination tablet T15, T20”), an oral combination anticancer drug under investigation for the treatment of refractory metastatic colorectal cancer (mCRC), and that the Company has initiated a rolling NDA submission to the FDA (Press release Taiho, DEC 21, 2014, View Source [SID:1234501242]).

The FDA established the Fast Track designation process to facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening conditions, and that demonstrate the potential to address unmet medical needs. Fast Track designated drugs are afforded a rolling review of their New Drug Application (NDA) filing by the FDA.

The results from the Phase III RECOURSE trial of TAS-102 in 800 patients affected with mCRC, whose disease had progressed after or who were intolerant to standard therapies, are the foundation for Taiho’s NDA submission to the FDA. Taiho expects to complete its submission by the end of this year.

Developing Next Generation Cancer Immunotherapy with "Off-the-Shelf" Chimeric Antigen Receptor-Tumor Attacking Natural Killer (CAR-TNK™) Cell Lines

On December 19, 2014 Sorrento Therapeutics and Conkwest, Inc., a privately-held immuno-oncology company developing proprietary Neukoplast (NK-92), a Natural Killer (NK) cell-line based therapy, reported that the companies have entered into a definitive agreement to jointly develop next generation CAR-TNK (pronounced as "Car-Tank") immunotherapies for the treatment of cancer (Press release, Sorrento Therapeutics, DEC 19, 2014, View Source [SID:1234504358]). The CAR-TNK technology platform combines Conkwest’s proprietary Neukoplast cell line with Sorrento’s proprietary G-MAB fully human antibody technology and CAR designs to further enhance the potency and targeting of Neukoplast. Under the terms of the agreement, Sorrento and Conkwest will establish an exclusive global strategic collaboration focused on accelerating the development of CAR-TNKs for the treatment of hematological malignancies as well as solid tumors. Both companies will jointly own and share development costs and revenues from any developed CAR-TNK products. As part of the transaction, Sorrento will make a $9 million strategic equity investment in Conkwest and provide $2 million in research credit payments towards the development of novel CAR-TNK cell lines.

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Adoptive immunotherapy is widely regarded as one of the most impactful and innovative anti-cancer therapy breakthroughs. To date, T-cell based therapies, like CAR-T, have shown the most promise in select hematologic cancers, especially B-cell malignancies such as acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). They have also demonstrated outstanding therapeutic impact, including a high percentage of complete responses (CRs) in leukemia patients using CD19-CAR-T cells. While the clinical results seen have been promising, CAR-T therapies have been associated with some concerning side effects, especially potentially fatal cytokine-release syndrome that is mediated by interleukin-6 (IL-6) released from the T-cells and characterized by high fevers and sudden drops in blood pressure. Afflicted patients often require aggressive support in an intensive care unit setting. Additionally, most current CAR-T approaches rely upon patient derived T-cells, which require individualized processing, and are thus challenging with regard to commercial scalability, quality control, and consistency. Furthermore, this process relies on the ability to obtain sufficient numbers of the patients’ own immune T-cells to make adequate doses of CAR-T cells.

The "off-the-shelf" CAR-TNK approach will utilize Conkwest’s bioreactor-grown NK-92 cell line, Neukoplast, as the immune effector cells. Among the many features that distinguish Neukoplast from patient derived T-cells are the lack of IL-6 expression (the most common mediator of cytokine release syndrome), an innate capability of destroying a broad range of cancer cells as well as cancer stem cells, and scalability with batch-to-batch consistency. These Neukoplast cells can be re-engineered in a virus-free process to express surface receptors using Sorrento’s G-MAB library to yield a stable line of effector cells that recognize and target specific antigens on tumor cells. The CAR-TNK cells can also be generated and produced in large quantities, thereby obviating the need for expensive, decentralized ‘biologistics’- a critical drawback of current CAR-T and dendritic cell therapies.

"We are extremely pleased with this strategic collaboration with Conkwest", said Dr. Henry Ji, President and CEO of Sorrento. "With Sorrento’s expertise in antibody technology and diverse portfolio of fully human antibodies obtained from the G-MAB library, we believe we will be able to generate an army of stable CAR-TNK cell-lines, including but not limited to CD19-CAR-TNK, PDL1-CAR-TNK, PSMA-CAR-TNK, and CD123-CAR-TNK. It is our goal to rapidly move several of our CAR-TNK cell lines into the clinic to offer patients suffering from hematological malignancies and solid tumors an innovative immunotherapy to fight their cancers."

"Conkwest has made important strides in establishing the safety and anti-cancer activity of Neukoplast in both pre-clinical and clinical phase I trials" said Dr. Barry Simon, President and CEO of Conkwest. "We have also unlocked the potential of CAR-modified Neukoplast cells in preclinical models. By drawing from Sorrento’s treasure trove of CARs derived from their G-MAB library, we believe this partnership will enable us to realize an important part of our vision of designing and commercializing next generation Neukoplast products re-engineered to express one or more proprietary CARs that would matter most to disease outcomes. We are very excited about this opportunity in joining our resources and talent and look forward to working with the Sorrento team on this next generation of cancer immunotherapies."