On March 17, 2020 Circle Pharma, Inc., a macrocycle drug discovery and development company focused on intractable cancer targets, reported that it has raised $45 million in a Series B financing (Press release, ShangPharma Innovation, MAR 17, 2020, View Source [SID1234555735]).

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The financing was led by The Column Group, with participation by Nextech Invest. All investors from the prior round – ShangPharma, LifeForce Capital, and the Berkeley Catalyst Fund – joined the financing.

In conjunction with the financing, Peter Svennilson, founder and managing partner of The Column Group, and Thilo Schroeder, Ph.D., partner at Nextech Invest were appointed to the board. John Josey, Ph.D., formerly President and CEO of Peloton Therapeutics, was appointed to the board as Chairman.

Proceeds from the investment will be used to advance Circle’s work to develop inhibitors of Cyclin A and Cyclin E, and to expand the company’s pipeline.

"We are delighted to have these premier life science investors supporting our Series B financing," said David J. Earp, J.D., Ph.D., Circle’s President and CEO. "With this strong backing, we will expand our team, drive our cyclin targeted programs towards the clinic, and apply our macrocycle platform to additional intractable targets."

Circle’s new board appointments:

Peter Svennilson is the founder and managing partner of The Column Group. He was the chairman of Aragon Pharmaceuticals (acquired by Johnson & Johnson) and Seragon Pharmaceuticals (acquired by Roche / Genentech) and was a board director of Gritstone Oncology, NGM Biopharmaceuticals, Immune Design and Constellation Pharmaceuticals. He is currently a board director of ORIC Pharmaceuticals, Ribon Therapeutics and Carmot Therapeutics.

Thilo Schroeder, Ph.D., is a partner at Nextech Invest, a Zurich-based oncology-focused investment firm. He previously served on the board of Peloton Therapeutics (acquired by Merck) and Blueprint Medicines. He is currently a board director at IDEAYA Biosciences, Revolution Medicines, PMV Pharma, Silverback Therapeutics and a board observer at Black Diamond Therapeutics.

John Josey, Ph.D., served as the President, Chief Executive Officer, and member of the Board of Directors at Peloton Therapeutics from 2013 until its acquisition by Merck in 2019. From 2011 to 2013, he was President and Chief Scientific Officer at Peloton, and from 1998 to 2011, Vice President of Discovery Chemistry at Array Pharma.

The continuing members of Circle’s board of directors are Walter H. Moos, Ph.D., CEO of ShangPharma Innovation and Managing Director of Pandect Bioventures, Matthew P. Jacobson, Ph.D., Circle Pharma co-founder, chair of the department of pharmaceutical chemistry at U.C. San Francisco and also co-founder of Global Blood Therapeutics, Relay Therapeutics and Cedilla Therapeutics, and David J. Earp, J.D., Ph.D., President and Chief Executive Officer of Circle Pharma.

On march 17, 2020 Oncotarget reported the cover for issue 11 of Oncotarget features Figure 6, "Effects of AZD8186 in combination with anti-PD1 on syngeneic models," by Owusu-Brackett, et al.

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In vitro cell viability assay and immunoblotting demonstrated that PTEN loss was significantly correlated with AZD8186 sensitivity in triple-negative breast cancer cell lines.

AZD8186 in combination with paclitaxel, eribulin had synergistic effects on growth inhibition in PTEN loss cells.

AZD8186 significantly enhanced the antitumor efficacy of anti-PD1 antibodies in the PTEN-deficient BP murine melanoma xenograft model, but not in the PTEN-wild-type CT26 xenograft model.

In vitro, cell proliferation and colony formation assays were performed to determine cell sensitivity to AZD8186.

AZD8186 has single-agent efficacy in PTEN-deficient TNBC cell lines in vitro but has limited single-agent efficacy in vivo.

Dr. Funda Meric-Bernstam from the Department of Surgical Oncology, the Department of Investigational Cancer Therapeutics, the Department of Breast Surgical Oncology, as well as The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy at The University of Texas MD Anderson Cancer Center, in Houston, Texas, USA said, "Phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway is an important regulator of many physiological cellular processes that promote differentiation, proliferation and survival of a normal cell."

"Phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway is an important regulator of many physiological cellular processes that promote differentiation, proliferation and survival of a normal cell."

– DR. FUNDA MERIC-BERNSTAM, DEPARTMENT OF INVESTIGATIONAL CANCER THERAPEUTICS, THE DEPARTMENT OF BREAST SURGICAL ONCOLOGY & THE SHEIKH KHALIFA BIN ZAYED AL NAHYAN INSTITUTE FOR PERSONALIZED CANCER THERAPY

Mutations, loss of copy number, epigenetic silencing and downregulation of PTEN protein by mi RNA can result in PTEN function inactivation, leading to activation of PI3K/AKT/mTOR pathway, which subsequently increases tumor growth, invasion and metastasis across a diverse set of solid tumors including breast, endometrial, prostate, renal cell, hepatocellular, glioblastoma, and colorectal cancers.

Loss of PTEN and increased PI3K signaling are associated with resistance to trastuzumab and endocrine therapy in hormone receptor-positive breast cancer and with poor prognosis in triple-negative breast cancers.

In vitro, they revealed significant growth inhibition of PTEN-deficient tumors by depleting PIK3CB which encodes PI3K, while no such growth inhibition effect was shown in corresponding PTEN-deficient tumors with downregulation of PIK3CA or PIK3CD encoding PI3K and PI3K, respectively.

Thus, PI3K isoform is the driver of abnormal proliferation in PTEN-null cancers, and as such, PI3K is a promising target for therapy in PTEN-deficient TNBC. AZD8186 is a selective and potent small-molecule inhibitor of PI3K, with additional activity against PI3K isoform.

The Meric-Bernstam Research Team concluded in their Oncotarget Research Paper, "these results provide preclinical evidence of antitumor efficacy of AZD8186 in PTEN-deficient solid tumors. AZD8186 has single-agent efficacy in PTEN-deficient TNBC cell lines in vitro, with modest single-agent efficacy in vivo. Furthermore, AZD8186 enhanced the antitumor efficacy of paclitaxel but stable and progressive disease were noted with this combination in immunosuppressed models. In immunocompetent models, AZD8186 in combination with anti-PD1 resulted in tumor regression in PTEN-deficient BP tumor. We realize that while there appears to be an association of AZD8186 sensitivity to PTEN loss, a cause-effect relationship can only be speculated on. In summary, although further insights are needed into the mechanisms of activity of these combinations, the combination of AZD8186 with taxanes and with anti-PD1 agents hold promise for the treatment of PTEN-deficient solid tumors."

On March 17, 2020 Morphic Therapeutic (NASDAQ: MORF), a biopharmaceutical company developing a new generation of oral integrin therapies for the treatment of serious chronic diseases, reported the appointment of Peter G. Linde, M.D., as chief medical officer (Press release, Morphic Therapeutic, MAR 17, 2020, View Source [SID1234555665]). Dr. Linde was previously vice president of medical research at Acceleron Pharma, Inc., where he was responsible for the design and execution of clinical trials with positive outcomes in both pulmonary and hematologic diseases. Dr. Linde will oversee the development of Morphic’s small molecule integrin inhibitors as the company advances its oral integrin inhibitors toward clinical trials.

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"Dr. Linde has an extensive track record of driving clinical advancement across multiple therapeutic areas including inflammatory, pulmonary and hematologic disease. Notably, his experience includes clinical studies in inflammatory bowel disease, the therapeutic target of MORF-057, our lead oral integrin inhibitor anticipated to enter the clinic this year," commented Praveen Tipirneni, M.D., president and chief executive officer of Morphic Therapeutic. "On behalf of everyone at Morphic, I welcome Dr. Linde to the team. We look forward to his leadership in developing the processes, partners and resources to guide MORF-057 and our portfolio of additional product candidates through development."

Dr. Linde brings more than 15 years of experience in pharmaceutical clinical development and research. Most recently he served as vice president of medical research at Acceleron Pharma, Inc., where he led study design and development for clinical trials in pulmonary and hematologic diseases. These studies included the recently successful Phase 2 study of sotatercept in pulmonary arterial hypertension as well as late-stage development work on luspatercept, which in 2019 obtained FDA approval for treatment of transfusion-dependent patients with beta-thalassemia. Prior to this role, Dr. Linde was a project leader in clinical asset development at AbbVie, Inc., where he guided the global development of renal and immunology products. Dr. Linde also served as a senior director of clinical development at FibroGen, Inc., developing trial protocols and leading clinical studies to treat anemia in hemodialysis patients. Dr. Linde began his pharmaceutical career developing new indications for the decompensated heart failure treatment NATRECOR (nesiritide) as a director of clinical research at Johnson & Johnson, Inc.

"Morphic is built on world-class insight into integrin biology, outstanding medicinal chemistry and a growing body of impressive preclinical data. It has also established itself as the leader in the discovery of small molecule drug candidates that specifically target this important receptor class. Oral integrin therapy has the potential to transform treatments for patients suffering from diseases spanning autoimmunity, fibrosis and cancer," said Dr. Linde. "I am very much looking forward to guiding the clinical development of Morphic’s pipeline."

Dr. Linde completed medical school at Stanford University and a residency at the University of Pennsylvania Medical Center in internal medicine. He then went on to complete two fellowships at Massachusetts General Hospital/Harvard Medical School in nephrology and transplantation. Following the completion of his core medical training, Dr. Linde spent approximately 10 years as a practicing clinician, clinical instructor and mentor at several institutions including Allegheny University, Massachusetts General Hospital, Brigham & Women’s Hospital and San Francisco General Hospital. Dr. Linde earned his bachelor’s degrees from the Massachusetts Institute of Technology in both chemical engineering as well as applied biology. He is also an inventor on multiple issued patents relating to stem cell and extracorporeal organ support technologies.

NATRECOR is a registered trademark of Johnson & Johnson.

On March 17, 2020 InnoCare Pharma reported that Beijing priced its Hong Kong IPO at the top end of its proposed range to raise $288 million at a $1 billion valuation, according to insiders (Press release, InnoCare Pharma, MAR 17, 2020, View Source [SID1234555664]). The company develops immunotherapies for cancer and autoimmune diseases. It has three molecules in clinical trials, including its lead product, a BTK inhibitor under NDA review in China for leukemia and lymphoma. The company discovers candidates through its own research and in-licenses products from other biopharmas. Hong Kong has not completed an IPO since January because of the coronavirus outbreak.

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On March 17, 2020 4D pharma plc (AIM: DDDD), a pharmaceutical company leading the development of Live Biotherapeutics, reported an update on the previously reported interim data from an ongoing phase I/II clinical trial, in collaboration with MSD, a tradename of Merck & Co., Inc., Kenilworth, NJ, USA, to evaluate 4D pharma’s lead oncology candidate, MRx0518, in combination with MSD’s anti-PD-1 therapy KEYTRUDA (pembrolizumab), in patients with advanced malignancies who have previously responded and whose disease has then progressed on PD-1/PD-L1 inhibitors (Press release, 4d Pharma, MAR 17, 2020, View Source [SID1234555662]).

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The additional data has been presented to delegates of Chardan’s virtual 2nd Annual Microbiome Medicines Summit, on March 16, 2020. The data was presented by Duncan Peyton, CEO and Alex Stevenson, CSO, 4D pharma. The presentation provides additional detail on headline interim results from the phase I/II clinical trial announced on November 6, 2019. The trial is being conducted, and data compiled at MD Anderson, University of Texas, US.

The data is the first global clinical confirmation of a live biotherapeutic product (LBP) initiating a response in cancer patients. The patients in the live biotherapeutic clinical trial had all previously received multiple lines of treatment with little efficacy, exhausting all currently approved treatment options. 4D pharma believes that the data provide evidence that adding the Company’s product, MRx0518, to the checkpoint inhibitor treatment regimen can induce tumour responses in patients who have previously become refractory to these therapies. 4D believes that, if demonstrated in larger studies, the addition of MRx0518 to checkpoint therapy will enable approved checkpoint inhibitors to work more effectively, for a longer duration, and in a wider patient population.

The phase I/II 4D pharma study is an open label trial to evaluate the safety and preliminary efficacy of MRx0518 and KEYTRUDA in patients with renal cell carcinoma (RCC), melanoma, non-small cell lung cancer (NSCLC) and bladder cancer, who have developed resistance to PD-1/PD-L1 inhibitors. Checkpoint therapies, whilst capable of producing durable anti-tumour responses, are not effective in all patients. In addition, those who do respond can develop resistance over time, leading to disease progression. The study has been designed to investigate this effect in patients with advanced metastatic disease.

Clinical observations from the first six patients in part A were presented, including:

Two partial responses (PR) with evidence of tumor shrinkage who remain on study (one patient for over 10 months)
One patient with stable disease (SD), remains on study for over eight months
Evidence of increased tumor-infiltrating lymphocytes (TILs) following treatment
No drug related serious adverse events
Specifically, one stage IV NSCLC patient had received seven lines of therapy over nearly three years with little response. In this patient the combination of MRx0518 + KEYTRUDA achieved an overall 51% reduction in target tumors at last assessment. The patient has now been on drug for 41 weeks.

"The further interim data from the Phase I/II trial provide significant potential for fresh treatment options for oncology patients that have exhausted all other currently approved therapies," said Duncan Peyton, CEO, 4D pharma.

He added: "4D pharma is now delivering the first global clinical evidence of the therapeutic potential of oral live biotherapeutics in cancer. This confirms the significant impact of microbiome immuno-oncology to the pharmaceutical industry in providing additional treatments for patients with underserved needs and little available therapeutic options. This clinical validation of live biotherapeutics to impact diseases external to the gut significantly supports our wider clinical pipeline in other areas such as neurodegeneration and other cancers."

Recruitment for the trial continues to progress as expected, with recruitment for Part A now completed. 4D expects to announce data for all 12 Part A subjects in Q2 and to commence enrolment for Part B, which will expand the study based on the Part A data. It is expected that the study will be expanded to additional international trial locations and sites, initially in the US. 4D pharma also expects to discuss the findings from Part A and avenues for accelerated development with the regulatory agencies.