On September 19, 2016 Infinity Pharmaceuticals, Inc. (NASDAQ: INFI) reported the publication of new findings by research collaborators at University of California San Diego School of Medicine and Moores Cancer Center and Infinity scientists in the September 19 online issue of Nature (Press release, Infinity Pharmaceuticals, SEP 19, 2016, View Source [SID:SID1234515231]). The paper, entitled "PI3K-gamma is a molecular switch that controls immune suppression,"1 describes research showing that targeting macrophage signaling pathways by inhibiting phosphoinositide-3-kinase (PI3K)-gamma may open the possibility to further improving and refining emerging immunotherapies that boost the body’s own abilities to fight a range of diseases, including cancer. Infinity is conducting a Phase 1 clinical study of IPI-549, an orally administered immuno-oncology development candidate that selectively inhibits PI3K-gamma. IPI-549 is the only PI3K-gamma inhibitor in clinical development.

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"Immunotherapies, such as T cell checkpoint inhibitors, are showing great promise in early treatments and trials, but they are not universally effective," said Judith A. Varner, PhD, professor in the departments of Pathology and Medicine at UC San Diego School of Medicine. "We have identified a new method to boost the effectiveness of current immune therapy. Our findings also improve our understanding of key mechanisms that control cancer immune suppression and could lead to the development of more effective immunotherapies."

"The findings published today build upon other work by Infinity and our collaborators, reinforcing the therapeutic potential of Infinity’s selective PI3K-gamma inhibitor, IPI-549, to alter the immune-suppressive microenvironment, promoting an anti-tumor immune response that leads to tumor growth inhibition," stated Jeffery Kutok, M.D., Ph.D., vice president of biology and translational science at Infinity Pharmaceuticals and a co-author of the paper. "Infinity is excited to be at the forefront of advancing PI3K-gamma inhibition as a new immunotherapeutic approach that could potentially enhance existing treatment options, including checkpoint inhibitors."

When confronted by pathogens, injury or disease, the initial response of the body’s immune system comes in the form of macrophages, a type of white blood cell that express pro-inflammatory proteins called cytokines that, in turn, activate T cells, another immune cell, to attack the health threat. The macrophages then switch gears to express other cytokines that dampen T cell activation, stimulating tissue repair. In cancer, highly abundant macrophages express anti-inflammatory cytokines that induce immune suppression, leading to enhanced tumor growth.

In the Nature paper, researchers pinpoint a key, suspected player: an enzyme in macrophages called PI3K-gamma. In mouse studies, they found that macrophage PI3K-gamma signaling promotes immune suppression by inhibiting activation of anti-tumor T cells. Blocking PI3K-gamma activated the immune response and significantly suppressed growth of implanted tumors in animal models. It also boosted sensitivity of some tumors to existing anti-cancer drugs and synergized with existing immune therapy to eradicate tumors. Researchers also identified a molecular signature of immune suppression and response in mice and cancer patients that may be used to track the effectiveness of immune therapy.

Earlier this year, Infinity initiated its first clinical study of IPI-549 designed to explore safety, tolerability, pharmacokinetics and pharmacodynamics of IPI-549 as a monotherapy and in combination with an anti-PD-1 antibody, a checkpoint inhibitor, in approximately 150 patients with advanced solid tumors, including non-small cell lung cancer and melanoma.2

"Infinity’s first clinical study of IPI-549 is progressing well, and we expect to initiate the first combination therapy cohort this Fall," said Julian Adams, Ph.D., president, research and development at Infinity. "We also look forward to the presentation of early clinical and new preclinical data at an immuno-therapy conference later this month."

Recently, Infinity announced that new preclinical data as well as early clinical data from the ongoing Phase 1 study will be presented for IPI-549 during the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference (CIMT) (Free CIMT Whitepaper): Translating Science into Survival taking place September 25-28, 2016, in New York City. The IPI-549 presentations will take place during the poster session being held on Monday, September 26, from 5:15 p.m. – 7:45 p.m. ET (Poster Boards B070 and B032).

About IPI-549
IPI-549 is an orally administered immuno-oncology development candidate that selectively inhibits PI3K-gamma. In preclinical studies, IPI-549 inhibits immune-suppressive macrophages within the tumor microenvironment, whereas other immunotherapies such as checkpoint modulators more directly target immune effector cell function. As such, IPI-549 may have the potential to treat a broad range of solid tumors and represents a potentially complementary approach to restoring anti-tumor immunity in combination with other immunotherapies such as checkpoint inhibitors.

IPI-549 is an investigational compound and its safety and efficacy has not been evaluated by the U.S. Food and Drug Administration or any other health authority.

On September 19, 2016 BioInvent International (OMXS: BINV) reported that it has been granted additional patent protection in Japan, Russia and China for BI-505, its lead immune-oncology programme currently in Phase II for the treatment of multiple myeloma (Press release, BioInvent, SEP 19, 2016, View Source [SID:SID1234515224]). These patents cover the use of BI-505 in the treatment of patients previously treated for cancer that have either not responded or subsequently relapsed. The patents now granted, add to patents previously granted in these countries, as well as in the US, Europe and other countries for BI-505 and its use in the treatment of cancer. BI-505 has received Orphan Drug Designation for multiple myeloma by both the U.S. Federal Drug Administration (FDA) and European Medicines Agency (EMA).

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BI-505 is a fully human antibody targeting cell adhesion molecule (ICAM-1), a protein on the surface of myeloma cells which can cause resistance to current treatment options. BI-505 switches off the resistant cell’s survival signaling and stimulates the recruitment of macrophages that kill the myeloma tumor cells.

Earlier this year, BioInvent initiated a Phase ll study in collaboration with Penn Medicine in the US to investigate if BI-505 can deepen the anti-cancer response in multiple myeloma patients who have received high dose chemotherapy and underwent an autologous stem cell transplant.

BI-505, and its target ICAM-1, were identified using F.I.R.S.T – BioInvent’s translational discovery engine that allows simultaneous target and drug discovery.

Michael Oredsson, President and CEO of BioInvent, said: "We are pleased to have added three more patent approvals to our intellectual property portfolio for BI-505 covering the treatment of relapsed cancer in these important territories. BI-505 has the potential to provide a life line to multiple myeloma patients who are no longer responsive to standard of care and who have no other treatments options for this fatal disease".

On September 19, 2016 Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL) and Tarveda Therapeutics, Inc. reported an exclusive worldwide license agreement providing for the discovery, development and commercialization by Tarveda of products based on Madrigal’s HSP90 Drug Conjugate program, including the lead clinical candidate, PEN-866 (Press release, Synta Pharmaceuticals, SEP 19, 2016, View Source [SID:SID1234515216]). Madrigal is a clinical-stage biopharmaceutical company focused on the development and commercialization of innovative therapeutic candidates for the treatment of cardiovascular, metabolic and liver diseases, and Tarveda Therapeutics, Inc., is a biopharmaceutical company discovering and developing Pentarins as a new class of targeted anti-cancer medicines to advance the treatment of patients with solid tumors.

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HSP90 drug conjugates are designed to increase cancer cell killing while reducing collateral damage to normal cells and overcome the challenges of current chemotherapies and other payloads, which are commonly limited by insufficient drug exposure in the tumor and/or systemic toxicities. HSP90 drug conjugates are small-molecule conjugates consisting of an HSP90 targeting molecule joined to an anti-cancer payload via a linker that is optimized for controlled release of the payload inside cancer cells. The conjugate’s sustained anti-tumor effect comes from selectively accumulating and retaining the conjugate and, importantly, its potent payload in tumors. HSP90 drug conjugates contrast with previous HSP90 inhibitors that were designed to only inhibit HSP90. Madrigal acquired the drug conjugate platform via its recent merger with Synta Pharmaceuticals, Inc.

The lead HSP90 drug conjugate, PEN-866, is a small-molecule drug conjugate that comprises an HSP90 ligand conjugated to SN-38, the highly-potent, active metabolite of the chemotherapeutic agent irinotecan. PEN-866 binds with high affinity to the intracellular HSP90 target. Once bound to its target, PEN-866 delivers the tumor-killing SN-38 payload. PEN-866 has shown an impressive degree of efficacy and durability of response in multiple preclinical tumor models, including patient-derived xenograft models. Studies demonstrate that SN-38 released from PEN-866 accumulated at high levels within the tumors and was associated with increased and widespread cancer cell death when compared with irinotecan alone.

Under the terms of the agreement, Madrigal will receive an upfront payment and is eligible to receive up to an aggregate of $163 million of contingent payments based upon the achievement of specified development, regulatory and sales milestones related to the first HSP90 drug conjugate product developed under the agreement. Madrigal is also eligible to receive a tiered, single-digit royalty based on future worldwide sales of HSP90 drug conjugate products. Potential development, regulatory and sales milestone payments related to a second HSP90 drug conjugate product would be lower. Tarveda will be responsible for all of the development costs for the HSP90 drug conjugate program.

"We are pleased to have completed this important and potentially valuable agreement with Tarveda," said Paul A. Friedman, M.D., Chairman and CEO of Madrigal. "This transaction is a key element of Madrigal’s strategy to out-license our novel oncology assets to organizations with the oncology focus and resources to fully exploit the opportunity for product development and commercial success."

The Tarveda team is comprised of seasoned oncology leaders, scientists and drug developers who are taking a novel approach to cancer treatment by creating Pentarins, which are miniaturized drug conjugates uniquely designed to target, penetrate and eradicate solid tumors. Creating Pentarin drug conjugates that drive efficacy in solid tumors is the core expertise and focus of the team at Tarveda.

"Tarveda is developing therapeutics to overcome the limitations of current cancer treatments through our Pentarin platform. Pentarins leverage their miniature size and improved pharmacokinetics to penetrate into solid tumors and cause cancer cell death with highly selective cell surface and intracellular targeting, tuned linkers and potent payloads," said Drew Fromkin, President and CEO of Tarveda. "The HSP90 drug conjugate platform with its lead drug candidate PEN-866, which is scheduled to be in the clinic during the first half of 2017, is an ideal fit for our growing Pentarin pipeline of novel oncology therapeutics. The Tarveda pipeline also includes PEN-221, our Pentarin conjugate that binds to the somatostatin cell surface receptor, after which the conjugate’s potent payload is internalized into the cancer cell. PEN-221 is scheduled to enter Phase I trials this year to treat patients with neuroendocrine and small-cell lung cancer tumors. We look forward to advancing both of these novel Pentarin drug candidates into clinical studies in the near term and expanding the Pentarin platform pipeline by developing new conjugates linked to other potent payloads, including challenged but promising payloads being developed by potential pharmaceutical partners."

On September 19, 2016 MabVax Therapeutics Holdings, Inc. (NASDAQ: MBVX), a clinical stage immuno-oncology drug development company reported on the early progress of its lead therapeutic antibody program, MVT-5873, currently in a phase I clinical trial in patients with pancreatic cancer and other CA19.9 positive malignancies (Press release, MabVax, SEP 19, 2016, View Source [SID:SID1234515215]). This trial is designed to establish safety, a recommended phase II dose (RP2D), and evaluate pharmacokinetics of MVT-5873, both as a monotherapy and in combination with the current standard of care chemotherapy. The site investigators for the phase I trial are monitoring patient blood chemistry and hematology for safety as well as disease status using the standard RECIST 1.1 criteria to evaluate tumor response rate and duration of response. The trial was initiated in February of this year. Three clinical investigation sites are currently enrolling patients: Memorial Sloan Kettering Cancer Center and two research sites in the Sara Cannon Research Institute network.

“To date 13 patients, most with stage 3 and 4 metastatic pancreatic cancer, have been enrolled after having exhausted all other standard of care therapies,” stated President and CEO J. David Hansen. “Based on assessments conducted with available unaudited data to date from these patients, we are seeing a pharmacokinetic profile for MVT-5873 that is similar to other monoclonal antibody therapeutics. We are actively dosing patients and plan on generating sufficient safety data in this portion of the phase I trial to allow the initiation, during the fourth quarter of this year, of the second part of the phase I trial where MVT-5873 will be administered in front line therapy in combination with a current standard of care chemotherapy.”

The company has been monitoring patients using the validated tumor biomarker CA19.9 for levels both pre and post dose of MVT-5873, being aware that increasing levels of this biomarker have historically been used as prognostic indicator of disease progression. The company intends on providing a more comprehensive interim data analysis upon obtaining sufficient patient data before year-end.

“We are pleased to note that the dose levels already achieved in the MVT-5873 safety study now exceed the highest dose levels to be administered for the concurrent phase I trial of MVT-2163, the company’s companion PET imaging product that is also under way,” continued Hansen. “In addition, the dose levels achieved in the MVT-5873 trial have also cleared the dose planned for the phase I trial of MVT-1075, the company’s radioimmunotherapy agent also intended to treat pancreatic cancer. We remain on track for submitting the Investigational New Drug Application (IND) for MVT-1075 to the Food And Drug Administration (FDA) later this year, and would initiate the phase I trial in the first half of 2017 after receiving FDA authorization to proceed.”