On April 18, 2018 AstraZeneca reported that the US Food and Drug AdministrationNSCLC (FDA) has approved Tagrisso (osimertinib) for the 1st-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) mutations, (exon 19 deletions or exon 21 L858R mutations), as detected by an FDA-approved test (Press release, AstraZeneca, APR 18, 2018, View Source [SID1234525521]).The approval is based on results from the Phase III FLAURA trial, which were presented at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2017 Congress and published in the New England Journal of Medicine.

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Dave Fredrickson, Executive Vice President, Head of the Oncology Business Unit at AstraZeneca, said: "Today’s FDA approval of Tagrisso in the 1st-line setting is an exciting milestone for patients and our company. Tagrisso delivered unprecedented median progression-free survival data across all pre-specified patient subgroups, including patients with or without CNS metastases, and could prolong the lives of more patients without their tumours growing or spreading."

Dr. Suresh S. Ramalingam, Principal Investigator of the FLAURA trial, from Winship Cancer Institute of Emory University, Atlanta, said: "The approval of osimertinib in the 1st-line setting represents a major advance in the treatment of patients with EGFR mutations and a significant change in the treatment paradigm. Osimertinib provides robust improvements in progression-free survival with no unexpected safety signals compared to the previous generation of EGFR inhibitors."

The FLAURA trial compared Tagrisso to current 1st-line EGFR tyrosine kinase inhibitors (TKIs), erlotinib or gefitinib, in previously-untreated patients with locally-advanced or metastatic EGFR-mutated (EGFRm) NSCLC. Tagrisso met the primary endpoint of progression-free survival (PFS) (see table below). PFS results with Tagrisso were consistent across all pre-specified patient subgroups, including in patients with or without central nervous system (CNS) metastases. Overall survival data were not mature at the time of the final PFS analysis.

Safety data for Tagrisso in the FLAURA trial were in line with those observed in prior clinical trials. Tagrisso was generally well tolerated, with Grade 3 or higher adverse events (AEs) occurring in 34% of patients taking TAGRISSO and 45% in the comparator arm. The most common adverse reactions (≥20%) in patients treated with Tagrisso were diarrhoea (58%), rash (58%), dry skin (36%), nail toxicity (35%), stomatitis (29%), fatigue (21%) and decreased appetite (20%).

In the US, Tagrisso is already approved for the 2nd-line treatment of patients with metastatic EGFRm NSCLC, whose disease has progressed on or after a 1st-line EGFR-TKI therapy and who have developed the secondary T790M mutation, as detected by an FDA-approved test. In 2017, Tagrisso was granted Breakthrough Therapy and Priority Review designations by the US FDA in the 1st-line treatment setting. Tagrisso is under regulatory review in the European Union and Japan for use in the 1st-line treatment setting with regulatory decisions anticipated in the second half of 2018.

Tagrisso received its first approval for 1st-line use based on the FLAURA data in Brazil in patients with metastatic EGFRm NSCLC on April 16, 2018

NOTES TO EDITORS
About NSCLC

Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths, more than breast, prostate and colorectal cancers combined. Approximately 10-15% of patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC. These patients are particularly sensitive to treatment with EGFR-TKIs, which block the cell-signalling pathways that drive the growth of tumour cells. Tumours almost always develop resistance to EGFR-TKI treatment, however, leading to disease progression. Approximately half of patients develop resistance to approved EGFR-TKIs such as gefitinib, erlotinib and afatinib due to the EGFR T790M resistance mutation. There is also a need for medicines with improved CNS efficacy, since approximately 25% of patients with EGFRm NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis.

About Tagrisso

Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI designed to inhibit both EGFR-sensitising and EGFR T790M-resistance mutations, with clinical activity against CNS metastases. Tagrisso 40mg and 80mg once-daily oral tablets have been approved in the US and Brazil for 1st-line EGFRm advanced NSCLC, and in more than 75 countries including the US, EU, Japan and China for patients with EGFR T790M mutation-positive advanced NSCLC. Tagrisso is also being investigated in the adjuvant setting and in combination with other treatments.

About the FLAURA trial

The FLAURA trial assessed the efficacy and safety of Tagrisso 80mg once daily vs. standard-of-care EGFR-TKIs (either erlotinib [150mg orally, once daily] or gefitinib [250mg orally, once daily]) in previously-untreated patients with locally-advanced or metastatic EGFRm NSCLC. The trial was double-blinded and randomised, with 556 patients across 29 countries.

About AstraZeneca in Lung Cancer

AstraZeneca is committed to developing medicines to help every patient with lung cancer. We have three approved medicines and a growing pipeline that targets genetic changes in tumour cells and boosts the power of the immune response against cancer. Our unrelenting pursuit of science aims to deliver more breakthrough therapies with the goal of extending and improving the lives of patients across all stages of disease and lines of therapy.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as a key growth platform for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by our investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

On April 18, 2018 Tarveda Therapeutics, Inc., a clinical stage biopharmaceutical company discovering and developing Pentarins as a new class of potent and selective cancer medicines, reported that presented data on the efficacy of PEN-866, a novel miniature drug conjugate comprised of a Heat Shock Protein 90 (HSP90) targeting ligand attached through a cleavable linker to SN-38 when combined with Poly ADP ribose polymerase (PARP) inhibitors in preclinical models of human cancer (Press release, Tarveda Therapeutics, 18 18, 2018, View Source [SID1234525520]). SN-38 is a potent topoisomerase 1 inhibitor, and is the active metabolite of irinotecan. The poster titled, "Combination of the miniature drug conjugate PEN-866 with PARP inhibitors as a rational approach to overcoming limitations of PARP inhibitor monotherapy" was presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting taking place April 14-18, 2018 in Chicago.

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The data presented evaluates the use of PEN-866 in combination with PARP inhibitors as an approach to overcoming limitations of PARP inhibitor monotherapy, such as dose limiting toxicities, in preclinical models of human cancer. In efficacy studies carried out in both BRCA mutant and BRCA wildtype tumor xenografts, combinations of PEN-866 and PARP inhibitors resulted in greater efficacy than that of the monotherapy in both tumor types.

"Results presented today show that when combined with PARP inhibitors, PEN-866 could avert the dose limiting toxicities often seen when PARP inhibitors are combined with other anti-cancer therapies," said Richard Wooster, Ph.D., President of Research and Development and Chief Scientific Officer of Tarveda Therapeutics. "The high levels of accumulation and retention of the combination of PEN-866 and a PARP inhibitor in xenograft tumors demonstrate the potential for greater efficacy compared to single agent therapy."

PEN-866’s linker cleavage provides sustained release of SN-38 at a high local tumor concentration leading to DNA damage and apoptosis of tumor cells, which results in broad antitumor activity in a range of preclinical xenograft models. When PEN-866 is administered in combination with PARP inhibitors, the inhibitors reduce DNA repair activity in tumor cells, enabling PEN-866 to maximize its efficacy in damaging cancer cell DNA. A pharmacodynamic assessment of DNA damage performed in tumors responsive to the combination treatment further demonstrated the efficacy of the therapy.

"The mechanistic synergy of PEN-866, carrying the payload SN-38 which is a potent topoisomerase I inhibitor, and PARP inhibitors suggests that this combination therapy could be an attractive approach in the clinical evaluation of PEN-866," said Drew Fromkin, President and Chief Executive Officer of Tarveda Therapeutics. "We look forward to continued studies of PEN-866, including our first-in-human Phase 1 clinical trial of PEN-866 to evaluate safety and efficacy."

About PEN-866
PEN-866 exploits the activation of Heat Shock Protein 90 (HSP90) in tumors to accumulate and release its potent anti-cancer payload, SN-38. PEN-866 is a miniature conjugate that comprises a small molecule, HSP90-targeting ligand linked to SN-38, the active metabolite of irinotecan. The conjugate accumulates and is retained in tumors and, by way of a sustained release of SN-38, causes prolonged DNA damage and tumor regressions in multiple patient-derived and other xenograft tumor models. PEN-866 is currently being studied in first-in-human clinical trials to evaluate safety and efficacy in patients with advanced solid tumors.

About Pentarins
Tarveda is developing Pentarins, potent and selective miniature drug conjugates with high affinity for specific cell surface and intracellular targets. Pentarins are engineered to bind to their tumor cell targets and provide sustained release of their potent therapeutic payloads deep into solid tumor tissue. Comprised of a targeting ligand conjugated to a potent cancer cell killing agent through a tuned chemical linker, Pentarins are designed to overcome the deficits of both larger antibody drug conjugates and small molecules that limit their therapeutic effectiveness against solid tumors. Together, the components of Tarveda’s Pentarins have distinct, yet synergistic, anticancer attributes: the small size of Pentarins allows for rapid and deep penetration into the tumor tissue, the ligand’s targeting ability allows for specific binding and retention in tumor cells, and the chemical linker is tuned to optimize the release of the potent, cell killing payload inside the cancer cells for efficacy.

On April 18, 2018 Rgenix, Inc., a clinical stage biopharmaceutical company developing first-in-class small molecule and antibody cancer therapeutics, reported that it is presenting pre-clinical data from ongoing research of RGX-202, a small molecule compound in development designed to inhibit SLC6a8, a creatine transporter, integral to cancer cell energy metabolism (Press release, Rgenix, APR 18, 2018, View Source [SID1234525519]). In a poster presentation today at the 2018 American Association of Cancer Research Annual Meeting, "RGX-202, a first-in-class small-molecule inhibitor of the creatine transporter SLC6a8, is a robust suppressor of cancer growth and metastatic progression", the data showed RGX-202 to be a robust inhibitor of creatine uptake in cancer cells and to be active in several pre-clinical gastrointestinal cancer models both as a single agent and in combination with chemotherapy.

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RGX-202 is a small molecule that inhibits a novel cancer metabolism target, SLC6a8, which is involved in supplying energy to cancer cells. SLC6a8 is over-expressed in several prevalent cancer types, including gastrointestinal malignancies such as colorectal cancer.

More than 140,000 patients are diagnosed with colorectal cancer annually in the U.S. With approximately 50,000 deaths in the U.S. attributed to the condition annually, it is a leading cause of cancer deaths. Creatine metabolism has been shown to spur the growth of colon cancer. This pathway is activated by colon cancer cells to allow uptake of phosphorylated creatine that can be converted to ATP to fuel survival of cancer cells as they proliferate and spread. RGX-202 inhibits this pathway by blocking the ability of SLC6a8 to import phosphocreatine into cancer cells.

In the pre-clinical research presented today, the impact of RGX-202 was studied alone, and in combination with standard of care chemotherapy agents such as 5-FU.

On its own, RGX-202 induced cancer cell death in vivo and demonstrated anti-tumor activity in both KRAS mutant and KRAS wild-type models of gastrointestinal cancer. RGX-202 also suppressed colon cancer and pancreatic cancer liver metastatic colonization, a model of metastatic cancer progression. Importantly, RGX-202 significantly extended survival of tumor-bearing mice as a single agent.

Studies combining RGX-202 with 5-FU resulted in additive anti-tumor activity, with complete tumor regressions among 50% of treated mice and significantly prolonged survival versus 5-FU treatment alone.

Masoud Tavazoie, MD, PhD, and Chief Executive Officer of Rgenix, said, "The data presented today is just a snapshot of our pre-clinical progress on our research of RGX-202. These data show the strong potential for RGX-202 and support further research of the compound. With these data, we are building a strong foundation for future clinical development of RGX-202, which, with regulatory approval, would diversify our clinical pipeline."

On April 18, 2018 Sosei Group Corporation ("Sosei" or the "Company"; TSE Mothers Index: 4565), the world leader in GPCR medicine design and development, reported that new preclinical data for AZD4635 was presented by AstraZeneca in a poster (abstract 3751) yesterday at the American Association of Cancer Research Annual Meeting, 17 April 2018; Chicago, IL, USA (Press release, Sosei, APR 18, 2018, View Source;sid=1573490 [SID1234525518]).

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AZD4635 is a potent and selective, orally available, small molecule adenosine A2A receptor (A2AR) antagonist. It was discovered by Sosei’s wholly-owned subsidiary Heptares Therapeutics and AstraZeneca licensed exclusive global rights to the molecule in 2015.

The poster is entitled "Inhibition of A2AR by AZD4635 induces anti-tumor immunity alone and in combination with anti-PD-L1 in preclinical models," and highlighted the following results:

Adenosine signalling through the A2AR results in a range of immunosuppressive effects which can promote tumour growth
AZD4635 is an oral, specific A2AR antagonist that is demonstrated to reverse adenosine mediated T cell suppression.
Treatment with AZD4635 alone and in combination with an anti-PD-L1 antibody led to a significant reduction in tumour growth in syngeneic tumour models exhibiting both high and low levels of adenosine
These effects were absent in immune-deficient animals confirming the immune-mediated mechanism of action. Further exploration of target engagement by AZD4635 is ongoing.
These data suggest that AZD4635 has the potential to restore immune responsiveness resulting in anti-tumour benefits alone and in combination with other cancer immunotherapies irrespective of the background tumour adenosine levels
AZD4635 is currently in a Phase 1 clinical trial as a single agent and in combination with AstraZeneca’s anti-PD-L1 antibody IMFINZI (durvalumab) in patients with solid malignancies (NCT02740985).

Notes to Editors

About AZD4635

AZD4635 is a potent and selective, orally available, small molecule adenosine A2A receptor (A2AR) antagonist discovered by Sosei subsidiary Heptares Therapeutics and licensed to AstraZeneca in 2015. High levels of adenosine are found in tumour microenvironments and benefit the progression of cancer. By activating the adenosine A2A receptor increased adenosine levels impair T-cell function and result in suppression of the host immune response. AZD4635 specifically blocks adenosine signalling via the A2A receptor signalling resulting in increased immune responsiveness and potential to destroy cancer cells and decrease tumour burden, A2A receptor antagonism can therefore promote the anti-cancer response of T-cells within the tumour microenvironment, offering a novel mechanism of action as a mono- or combination therapy.

On April 18, 2018 Provectus Biopharmaceuticals, Inc. (OTCQB: PVCT, www.provectusbio.com), ("Provectus" or the "Company"), a clinical-stage biotechnology company developing PV-10 as the first small molecule oncolytic immunotherapy for solid tumor cancers, reported that the Japan Patent Office (JPO) had granted and the European Patent Office (EPO) had allowed the Company’s patent application for the combination of PV-10 with systemic immunomodulatory therapy (i.e., immune checkpoint inhibition) (Press release, Provectus Biopharmaceuticals, APR 18, 2018, View Source [SID1234525516]).Pfizer, Inc. is a co-assignee on the award and allowance.

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The JPO patent and EPO patent allowance are related to U.S. patent (USP) 9,839,688, "Combination of rose bengal and systemic immunomodulative therapies for enhanced treatment of cancer," which was awarded by the United States Patent and Trademark Office (USPTO) in December 2017. USP 9,839,688 is one of the continuations of the Company’s foundational cancer combination therapy patent, USP 9,107,887, which was awarded by the USPTO in August 2015.

Provectus’ patent portfolio provides global intellectual property protection into the 2030s for the synthesis and use of PV-10 and other halogenated xanthene-based therapeutics as monotherapies and part of combination therapies for cancer.

About PV-10

Provectus’ lead investigational cancer drug product, PV-10, the first small molecule oncolytic immunotherapy, can induce immunogenic cell death. It elicits tumor immunity via activation of dendritic cells mediated by the release of damage-associated molecular pattern molecules. PV-10 is undergoing clinical study for adult solid tumor cancers, like melanoma and cancers of the liver, and preclinical study for pediatric cancers.