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.”

On September 19, 2016 Diffusion Pharmaceuticals Inc. (OTCQX:DFFN), a clinical stage biotechnology company focused on the development of novel small molecule therapeutics for cancer and other hypoxia-related diseases, reported the successful completion of dosing of two animal toxicology studies required by the U.S. Food and Drug Administration (FDA) to support Diffusion’s planned Phase 3 clinical trial testing its lead molecule trans sodium crocetinate (TSC) in newly diagnosed Glioblastoma (GBM) patients (Press release, Diffusion Pharmaceuticals, SEP 19, 2016, View Source [SID:SID1234515214]).

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As outlined at the end of Phase 2 FDA meeting, the number of TSC dosing exposures per patient will double in the planned Phase 3 trial as compared to the Phase 2 trial. As part of the agreement reached on a trial design for the Phase 3 study, the FDA requested that Diffusion augment its existing TSC toxicology studies with additional three month TSC toxicology data in both rats and dogs. The animal dosing for these three month studies has now been successfully completed.

David G. Kalergis, Diffusion’s Chairman and Chief Executive Officer, said, "The successful completion of dosing for these three month animal toxicology studies is an important milestone in support of Diffusion’s ability to conduct a Phase 3 pivotal trial of TSC in newly diagnosed GBM patients."

On September 19, 2016 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported that it has entered into a new five-year strategic manufacturing agreement with PCT, a Caladrius company, ("PCT") a subsidiary of Caladrius Biosciences (Nasdaq:CLBS) for the supply of Adaptimmune’s SPEAR T-cell therapies (Press release, Adaptimmune, SEP 19, 2016, View Source [SID:SID1234515212]). Under the contract, Adaptimmune will benefit from exclusive access to an EU and FDA compliant manufacturing unit at PCT as well as dedicated, specialist staff.

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Adaptimmune’s relationship with PCT, a contract manufacturer of patient cell therapy products, is intended to provide Adaptimmune with maximum operational flexibility for the manufacture of its SPEAR T-cell products from development, through clinical manufacturing and ultimately, subject to marketing authorizations, into commercialization.

"PCT is an elite contract manufacturing organization in the field of patient-specific cell therapies, and we are very pleased to strengthen and develop our existing relationship," said Dr. Gwendolyn Binder-Scholl, Adaptimmune’s Chief Technology Officer. "We have worked with PCT over the past three years and their commitment to high quality manufacturing, allied to timely delivery, makes them an ideal manufacturing partner for Adaptimmune. This arrangement will also complement well our new manufacturing plant currently under construction in Philadelphia."

"We are pleased to significantly advance our relationship with Adaptimmune, which began with earlier-phase clinical trials. PCT is committed to adapting our service arrangements to support our client’s evolving needs as they proceed through late-stage trials and into commercial manufacturing," said Robert A. Preti, PhD, President of PCT and Senior Vice President, Manufacturing and Technical Operations of Caladrius Biosciences. "We appreciate Adaptimmune’s continued trust in PCT’s ability to support the distribution of their groundbreaking technologies in the U.S. and Europe."

Adaptimmune’s SPEAR T-cell therapies are novel cancer immunotherapies that use enhanced affinity T-cell receptors (TCRs) to target and destroy cancer cells by strengthening a patient’s natural T-cell response. T-cells are a type of white blood cell that play a central role in a person’s immune response to disease.

The manufacturing process for Adaptimmune’s SPEAR T-cell therapies consists of isolating T-cells from the blood of cancer patients; transferring affinity enhanced TCRs, which have been modified to recognize cancer cells, into the cells; activating and expanding the T-cells; and, introducing the affinity enhanced cells back into the patient to enable the patient’s immune system to attack cancer.

On September 19, 2016 Seattle Genetics, Inc. (NASDAQ: SGEN) reported enrollment of the first patient in a multicenter phase 1 clinical trial of SGN-CD123A for patients with relapsed or refractory acute myeloid leukemia (AML) (Press release, Seattle Genetics, SEP 19, 2016, View Source [SID:SID1234515205]). SGN-CD123A is an investigational antibody-drug conjugate (ADC) targeted to CD123 utilizing Seattle Genetics’ proprietary technology, an engineered cysteine antibody (EC-mAb) stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer. CD123 is expressed across AML subtypes, including leukemic stem cells, which are difficult to kill and may be responsible for high relapse rates even following intensive therapy. The trial is designed to assess the safety and anti-leukemic activity of SGN-CD123A. SGN-CD123A represents Seattle Genetics’ second clinical-stage program in development for AML, reflecting the company’s commitment to addressing the significant unmet need for these patients.

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"AML is an aggressive, life-threatening disease with at least 33,000 newly diagnosed cases in the U.S. and Europe each year, and those patients have few effective treatment options," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "ADCs are an established treatment modality designed to specifically target cancer cells and minimize toxic side effects. The significant unmet need for AML and frequent expression of the validated target CD123 on leukemic stem cells support initiating this phase 1 clinical trial. Through our SGN-CD123A program, alongside vadastuximab talirine targeted to CD33 and currently in a phase 3 study, we are making a substantial effort to develop novel treatment options for AML patients."

The study is a phase 1, open-label, multicenter, dose-escalation clinical trial. It will initially evaluate the maximum tolerated dose of SGN-CD123A, followed by an expansion cohort to further define safety and estimate anti-leukemic activity. In addition, the trial will assess pharmacokinetics, remission rate, duration of complete remission and overall survival. The study is designed to evaluate SGN-CD123A administered every three weeks and will enroll up to approximately 100 relapsed or refractory patients at multiple centers in the United States.

Preclinical SGN-CD123A data presented at the 2015 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting demonstrated enhanced anti-leukemic activity across multiple AML disease models, including those typically resistant to chemotherapy. With more than 15 years of experience and innovation, Seattle Genetics is the leader in ADC development. ADCs are designed to selectively deliver cell-killing agents to tumor cells, and thus reduce many of the toxic effects of traditional chemotherapy while enhancing antitumor activity.

For more information about the trial, including enrolling centers, please visit www.clinicaltrials.gov.

About Acute Myeloid Leukemia

Acute myeloid leukemia, also called acute myelocytic leukemia or AML, is an aggressive type of cancer of the bone marrow and blood that progresses rapidly without treatment. AML starts in the bone marrow (the interior part of bones, where new blood cells are made) and quickly moves into the blood. According to the SEER database and Kantar Health Sciences, in 2016 approximately 33,000 new cases of AML (mostly in adults) will be diagnosed in the U.S. and Europe. In the U.S. alone, nearly 10,500 deaths will occur from AML this year.

About SGN-CD123A

SGN-CD123A is a novel ADC targeted to CD123 utilizing Seattle Genetics’ proprietary technology. CD123 is expressed across AML subtypes, including on leukemic stem cells, which are difficult to kill and may be responsible for high relapse rates even following intensive therapy. The CD123 antibody is attached to a highly potent DNA binding agent, a pyrrolobenzodiazepine (PBD) dimer, via a proprietary site-specific conjugation technology to a monoclonal antibody with engineered cysteines (EC-mAb). PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the site-specific conjugation technology (EC-mAb) allows uniform drug-loading of the cell-killing PBD agent to the anti-CD123 antibody. The ADC is designed to be stable in the bloodstream and to release its potent DNA binding agent upon internalization into CD123-expressing cells.