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."

On December 19, 2014 ONO PHARMACEUTICAL and Gilead Sciences reported that the companies have entered into an exclusive license agreement for the development and commercialization of ONO-4059, ONO’s oral Bruton’s tyrosine kinase (BTK) inhibitor for the treatment of B-cell malignancies and other diseases (Press release Gilead Sciences, DEC 19, 2014, View Source [SID:1234501243]). Under the terms of the agreement, Gilead will pay ONO an upfront payment plus additional payments based upon achievement of certain development, regulatory and commercial milestones. The companies will collaborate jointly on global development of ONO-4059. Gilead will have exclusive rights to develop and commercialize ONO-4059 in all countries of the world outside of Japan, South Korea, Taiwan, China and the Association of Southeast Asian Nations (ASEAN) countries, where ONO retains development and commercialization rights.

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ONO-4059 is a selective, once-daily, oral inhibitor of BTK, which has been shown to play a role in the survival and proliferation of malignant B-cells. ONO has presented preliminary Phase 1 data showing clinical activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) at several scientific conferences. ONO and Gilead plan to develop ONO-4059 for the treatment of B-cell malignancies and other diseases as a monotherapy and in combination with approved and investigational agents, including combinations with kinase inhibitors in Gilead’s portfolio.

"We are pleased to partner with Gilead to accelerate worldwide development and commercialization of ONO-4059," said Gyo Sagara, ONO’s President, Representative Director and Chief Executive Officer. "Our goal is to bring better therapeutic options as quickly as possible for the patients with B-cell malignancies or other diseases in the world, and we believe we can fulfill the goal by pursuing the development of ONO-4059 with Gilead."

"With this agreement, Gilead now has compounds targeting four unique signaling pathways associated with B-cell malignancies – PI3K delta, Syk, JAK and BTK," said Norbert W. Bischofberger, PhD, Gilead’s Executive Vice President, Research and Development and Chief Scientific Officer. "In addition to evaluating ONO-4059 in combination with standards of care, we believe there is an opportunity to combine this compound with Gilead’s other kinase inhibitors with a goal of achieving more pronounced and more durable response rates. We look forward to working with ONO to move the ONO-4059 development program forward as quickly as possible."

On December 19, 2014 RXi Pharmaceuticals reported that it has entered into an assignment and exclusive global license agreement with Hapten Pharmaceuticals, LLC for the therapeutic use of Samcyprone (Press release RXi Pharmaceuticals, DEC 19, 2014, View Source;FID=26640465 [SID:1234501224]). Samcyprone is a proprietary gel formulation of diphenylcyclopropenone (DPCP), an immunomodulating agent that works by initiating a T-cell response. Although DPCP is not a registered drug, it is used successfully by dermatologists as a topical immunomodulator to treat dermatological diseases. Samcyprone is expected to demonstrate an improved safety and use profile over DPCP as currently applied. A Phase 2a trial to evaluate the efficacy and safety of Samcyprone for the treatment of viral warts has been completed and Phase 2a trials for the treatment of cutaneous metastases of various cancers including melanoma and for the treatment of alopecia areata are underway.

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"Because of its proprietary gel formulation, Samcyprone is expected to demonstrate an improved safety and usage profile over DPCP as currently used," said Dr. William Levis, Lifetime Professor of Dermatology at Rockefeller University. He further added, "Published reports on clinical results with the use of DPCP as an experimental tool for treatment of these three difficult to treat skin conditions support the efficacy of the compound, substantially reducing the clinical risk of the ongoing product development effort."

Under the terms of the Agreement, Hapten will sell and assign to RXi certain patent rights and related assets and rights to Samcyprone. The Agreement will become effective at a closing that is scheduled to occur in early 2015 and which is subject to the satisfaction of certain closing conditions. Once the Agreement is effective, Hapten will receive an upfront payment payable in cash and common stock, will be entitled to receive future milestone payments tied to the achievement of certain clinical and commercial objectives and will receive royalties based on product sales.

"Following the release reporting the Company’s good progress in our Phase 2a program with RXI-109, our sd-rxRNA compound for treatment of hypertrophic scars and keloids, I am very pleased to also announce the acquisition by RXi Pharmaceuticals of Samcyprone, a Phase 2a product. Samcyprone is a proprietary formulation of DPCP, a new chemical entity (NCE), being evaluated in clinical trials in the USA for treatment of alopecia areata, warts, and cutaneous metastases of malignant melanoma," said Dr. Geert Cauwenbergh, President and CEO of RXi Pharmaceuticals. He added that, "Samcyprone, currently in clinical development by Hapten Pharmaceuticals, provides RXi with a second Phase 2 asset for its development pipeline. The published therapeutic benefits of DPCP in the targeted diseases dramatically increase the likelihood of a successful development pathway for Samcyprone which should result in favorable safety and efficacy as well as providing for adequate exclusivity once the product is marketed."

At closing, the assignment and exclusive license of Samcyprone to RXi will immediately add a second clinical development candidate that comes with some unique features:

Many world class academic dermatology centers use DPCP topically as an unregulated experimental tool in alopecia areata, warts and cutaneous metastases of malignant melanoma. This experience supports the efficacy of DPCP as the active ingredient and should significantly increase the likelihood of successful clinical development of Samcyprone as a drug product;
DPCP is a new chemical entity under a U.S. IND. Samcyprone, the proprietary formulation of DPCP, should provide a favorable safety profile while providing a consistent cGMP formulation. It is expected to achieve market exclusivity post approval; and
Multiple synergies exist between RXi’s sd-rxRNA platform and Samcyprone. The mechanism of action of Samcyprone is linked to DPCP’s ability to alter the expression of multiple genes and miRNAs involved in the immune response. These gene targets may be modulated by an RNAi approach, utilizing sd-rxRNAs, to further enhance Samcyprone’s efficacy and response rates. Additionally, this approach may result in the discovery and development of sd-rxRNA or other drugs that are more potent and selective for treatment of alopecia areata, warts or cutaneous metastases of malignant melanoma.

In addition, the Company announced that it has entered into a new purchase agreement with Lincoln Park Capital Fund, LLC, a Chicago-based institutional investor, whereby LPC is committed to purchase an aggregate of up to $10.8 million in shares of RXi common stock over a 28-month term. Prior to entering this new agreement, the Company and LPC mutually agreed to terminate the prior purchase agreement that was in place, with respect to the $18 million unsold balance. The Company plans to use the proceeds from this new agreement with LPC to support the development of Samcyprone, as well as the advancement of the Company’s ophthalmology and dermatology franchises and for other general corporate purposes.