On December 19, 2018 AstraZeneca and Merck & Co., Inc., Kenilworth, N.J., US (Merck: known as MSD outside the US and Canada) reported that the US Food and Drug Administration (FDA) has approved Lynparza for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy, as detected by an FDA-approved companion diagnostic test (Press release, AstraZeneca, DEC 19, 2018, View Source [SID1234532137]).

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This is the first regulatory approval for a PARP inhibitor in the 1st-line maintenance setting for BRCAm advanced ovarian cancer. The approval was based on positive results from the pivotal Phase III SOLO-1 trial in which Lynparza reduced the risk of disease progression or death by 70 percent in patients with BRCAm advanced ovarian cancer who were in complete or partial response to platinum-based chemotherapy (HR 0.30 [95% CI 0.23-0.41], p<0.0001) compared to placebo following platinum-based chemotherapy. The safety profile of Lynparza was consistent with previous trials.

Dave Fredrickson, Executive Vice President, Head of the Oncology Business Unit, AstraZeneca, said: "Women with ovarian cancer are often first diagnosed with advanced disease, which is associated with poor outcomes. In SOLO-1, Lynparza in the first-line maintenance setting reduced the risk of disease progression or death by 70 percent for patients with BRCAm advanced ovarian cancer. Today’s approval is a critical advancement and brings us closer to our goal of helping these patients achieve long-term remission."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "The expanded approval of Lynparza based upon the SOLO-1 trial has the potential to change medical practice and reinforces the importance of knowing a woman’s BRCA status at diagnosis. We continue to work in collaboration with AstraZeneca on our overall goal of improving outcomes for patients."

In the SOLO-1 trial, with median 41 months of follow-up, the median progression-free survival (PFS) for patients treated with Lynparza was not reached compared to 13.8 months for patients treated with placebo. Sixty percent of patients receiving Lynparza remained progression-free at three years compared to 27 percent of patients receiving placebo. The data from the SOLO-1 trial can be found in the 21 October 2018 online issue of the New England Journal of Medicine.

Kathleen Moore, co-principal investigator of the SOLO-1 trial and Associate Director for Clinical Research, Stephenson Cancer Center at The University of Oklahoma, Oklahoma City, Oklahoma, said: "SOLO-1 is truly a landmark trial in gynecologic cancer. This approval will likely change the way we treat women with BRCA-mutated advanced ovarian cancer. The ability to offer this important first-line maintenance treatment option to eligible patients may slow down or even stop the natural course of disease progression."

AstraZeneca and MSD are exploring additional trials in advanced ovarian cancer, including the ongoing GINECO/ENGOTov25 Phase III trial, PAOLA-1. This trial is testing the effect of Lynparza in combination with bevacizumab as a maintenance treatment for patients with newly-diagnosed advanced ovarian cancer, regardless of their BRCA status. Results are expected during the second half of 2019.

Financial considerations

Under the oncology collaboration with MSD and following this new approval for Lynparza, AstraZeneca will receive $70 million as Ongoing Externalisation Revenue.

About SOLO-1

SOLO-1 is a Phase III randomised, double-blinded, placebo-controlled, multicentre trial to evaluate the efficacy and safety of Lynparza tablets (300mg twice daily) as maintenance monotherapy compared with placebo, in patients with BRCAm advanced ovarian cancer following 1st-line platinum-based chemotherapy. The trial randomised 391 patients with a deleterious or suspected deleterious germline or somatic BRCA1 or BRCA2 mutation who were in clinical complete or partial response following platinum-based chemotherapy. Patients were randomized (2:1) to receive Lynparza or placebo for up to two years or until disease progression. Patients who had a partial response at two years were permitted to stay on therapy at the investigator’s discretion. The primary endpoint was PFS and key secondary endpoints included time to second disease progression or death, time to first subsequent treatment and overall survival.

About Lynparza

Lynparza is a first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of tumour types with defects and dependencies in the DDR.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, is approved for advanced ovarian cancer and metastatic breast cancer and has been used in over 20,000 patients worldwide. Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

About ovarian cancer

Ovarian cancer is a leading cause of cancer death in women worldwide, with a five-year survival rate of 19%.[i] In 2018, there were over 295,000 new cases diagnosed and around 185,000 deaths.[ii] For newly-diagnosed advanced ovarian cancer, the primary aim of treatment is to delay progression of the disease for as long as possible and maintain the patient’s quality of life with the intent of achieving complete remission or cure.[iii],[iv],[v],[vi]

About BRCA mutations

BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role in maintaining the genetic stability of cells. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly, and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

About the AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and selumetinib in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and selumetinib in combination with their respective PD-L1 and PD-1 medicines.

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 driver 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.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas – Oncology, Cardiovascular, Renal & Metabolism and Respiratory. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca.com and follow us on Twitter @AstraZeneca.

On December 19, 2018 MiNA Therapeutics, the pioneer in RNA activation therapeutics, reported that enrolment of the first patients treated with MTL-CEBPA in combination with Sorafenib in OUTREACH, the multi-centre Phase 1b clinical trial in patients with advanced liver cancer (Press release, MiNA Therapeutics, DEC 19, 2018, View Source [SID1234532155]). The study is designed to assess the safety, tolerability and clinical activity of MTL-CEBPA in combination with Sorafenib. OUTREACH is currently being conducted at multiple clinical trials sites in the United Kingdom, Singapore and Taiwan.

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Evaluation of MTL-CEBPA in combination with Sorafenib follows the evaluation of MTL-CEBPA as a single agent in 38 patients with advanced liver cancer. Preliminary clinical results of MTL-CEBPA as a single agent presented in June 2018 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting showed encouraging safety, pharmacology and clinical activity. Furthermore in September 2018 at the International Liver Cancer Association (ILCA) Conference, investigators reported complete tumour responses in patients off-study when subsequently administered Sorafenib. Sorafenib is the standard of care for first line treatment of advanced liver cancer.

Robert Habib, CEO of MiNA Therapeutics, commented, "We are encouraged by our initial clinical evaluation of MTL-CEBPA as a single agent and are excited about its potential in combination with approved therapies that on their own have demonstrated only modest benefit to patients. We look forward to continue to collaborate with our clinical investigators and evaluating the combination of MTL-CEBPA and Sorafenib into the expansion of the OUTREACH trial."

MTL-CEBPA consists of a double stranded RNA formulated in a liposomal nanoparticle and is designed to activate the CEBPA gene. The CEBPA gene encodes CCAAT/enhancer binding protein alpha (C/EBP-α), a transcription factor that acts as a master regulator of cell lineage determination and differentiation in several tissues including myeloid cells, liver cells and adipose tissue. In cancer, C/EBP-α plays important roles in regulating both tumour growth and the tumour immune microenvironment.

On December 19, 2018 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that it filed a new drug application to the Ministry of Health, Labour and Welfare (MHLW) for a ROS1/TRK inhibitor entrectinib for the treatment of NTRK fusion-positive solid tumors (Press release, Chugai, DEC 19, 2018, View Source [SID1234532139]). Entrectinib received Sakigake designation and orphan drug designation from MHLW.

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"Entrectinib obtained the first Sakigake designation for Chugai. Entrectinib demonstrated efficacy across tumor types in extremely rare NTRK fusion-positive solid tumors in the global studies," said Dr. Yasushi Ito, Chugai’s Executive Vice President, Co-Head of Project & Lifecycle Management Unit. "Chugai is committed to seek approval of entrectinib so that we may contribute to advancing personalized healthcare which may enable the most optimal treatment decision for patients based on genetic profiles of individual tumors."

This application for approval is based on an integrated analysis of an open-label, multicenter, global phase II study (the STARTRK-2 study) and three overseas phase I studies (the STARTRK-NG study, the STARTRK-1 study and the ALKA-372-001 study). Efficacy was evaluated in 54 patients with untreated NTRK fusion-positive solid tumors while safety assessment was conducted with 355 patients registered in the four trials.

[Reference information]
About the integrated analysis results
Media release issued by Roche on October 21, 2018
Title: Roche’s investigational personalised medicine entrectinib shrank tumours in people with NTRK fusion-positive solid tumours
View Source

Entrectinib has been granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration (FDA) in May 2017, Priority Medicines (PRIME) designation by the European Medicines Agency (EMA) in October 2017 for the treatment of NTRK fusion-positive, locally advanced or metastatic solid tumors in adult and pediatric patients who have either progressed following prior therapies or have no acceptable standard therapies.

As the top pharmaceutical company in the field of oncology in Japan, Chugai will work for the early approval to provide entrectinib as a new treatment option for patients and medical professionals.

About entrectinib
Entrectinib is an investigational, oral medicine in development for the treatment of locally advanced or metastatic solid tumors that harbor NTRK1/2/3 or ROS1 gene fusions. It is a selective, CNS-active tyrosine kinase inhibitor designed to inhibit the kinase activity of the TRK A/B/C and ROS1 proteins, whose activating fusions drive proliferation in certain types of cancer. Entrectinib can block ROS1 and NTRK kinase activity and inhibit proliferation of cancer cells with ROS1 or NTRK gene fusions. Entrectinib is being investigated across a range of solid tumor types, including breast, cholangiocarcinoma, colorectal, gynaecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers.

About NTRK fusion gene positive cancer
NTRK fusion gene is an abnormal gene that can be formed by fusing the NTRK genes (NTRK1, NTRK2, NTRK3 encode TRKA, TRKB, TRKC protein, respectively) and other genes (ETV6, LMNA, TPM3, etc.) as a result of chromosomal translocation. The TRK fusion kinase made from NTRK fusion gene is thought to promote cancer cell proliferation. There is very rare expression of NTRK fusion but in various adult and pediatric solid tumors, including appendiceal cancer, breast cancer, cholangiocarcinoma, colorectal cancer, gastrointestinal stromal tumor (GIST), infantile fibrosarcoma, lung cancer, mammary analogue secretory carcinoma of the salivary gland, melanoma, pancreatic cancer, thyroid cancer, and various sarcomas.

On December 19, 2018 Kyn Therapeutics, a biotechnology company advancing new immunometabolism therapies for treating cancer, reported the initiation of two clinical trials of ARY-007 (also known as Grapiprant), an EP4 receptor antagonist, in collaboration with Merck (known as MSD outside the United States and Canada) (Press release, KYN Therapeutics, DEC 19, 2018, View Source [SID1234532156]). ARY-007 will be assessed in combination with Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab) in checkpoint-refractory and -resistant solid tumors, an area of high unmet medical need.

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Prostaglandin E2 (PGE2) has been shown to contribute to an immunosuppressive environment in cancer by enhancing the activity of regulatory immune cells and suppressing the activity of effector immune cells. EP4 is a high-affinity receptor of PGE2 and is known to facilitate these immunosuppressive activities. ARY-007 is an oral, potent and highly selective antagonist of EP4. In preclinical models, EP4 inhibition leads to antitumor activity and also significantly enhances the antitumor activity of checkpoint inhibitors. While in development for a non-oncology indication, ARY-007 was found to be well-tolerated in multiple studies which enrolled approximately 1000 human subjects.

The Phase 1b/2 multicenter, open-label, single arm clinical trials are designed to assess the safety and efficacy of ARY-007 in combination with pembrolizumab in patients with advanced or progressive Microsatellite Stable (MSS) Colorectal Cancer (CRC), and with advanced or metastatic PD-1/L1 refractory Non-Small Cell Lung Cancer (NSCLC) adenocarcinoma. MSS CRC is inherently resistant to anti-PD-1 therapies – these agents have only shown activity in the microsatellite instability-high (MSI-H) subset of CRC. The NSCLC study is enrolling patients who have progressed while on PD-1 or PD-L1 therapy. Both studies incorporate a robust translational biomarker strategy.

"The Kyn team believes immunometabolism pathways hold great promise as therapeutics that could deliver breakthrough improvements for patients non-responsive to immunotherapy regimens. We believe EP4 is the right target and ARY-007 is the right molecule for overcoming the immunosuppressive effects of PGE2 in these cancers where increased pathway expression is associated with poor outcome," said Mark Manfredi, Ph.D., president and chief executive officer of Kyn Therapeutics. "We welcome the opportunity to collaborate with Merck as we initiate clinical studies."

About ARY-007
ARY-007 is an orally available, potent and highly selective antagonist of the EP4 receptor, a component of the prostaglandin E2 (PGE2) pathway which significantly influences the composition of the tumor microenvironment. In preclinical studies, inhibition of EP4 has been shown to boost the immune response through modulation of multiple immune cell types, and in combination with checkpoint inhibitors has yielded significant reduction in tumor growth relative to either agent alone.

On December 19, 2018 Anixa Biosciences, Inc. (NASDAQ: ANIX), a biotechnology company focused on using the body’s immune system to fight cancer, reported that it completed a Pre-Submission (Pre-Sub) meeting with the US FDA on December 17, 2018 (Press release, Anixa Biosciences, DEC 19, 2018, View Source [SID1234532175]).

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The meeting was focused on discussing Anixa’s Cchek test, an artificial intelligence (AI) based liquid biopsy for the early detection of cancer. Specifically, the discussion focused on using Cchek for prostate cancer testing, as prostate cancer will be the first commercial application.

Dr. Amit Kumar, President and CEO of Anixa Biosciences said, "The meeting was very positive and productive, with discussions that included the intended use of the test, the path for regulatory approval, and the use of AI. We are eager to move Cchek-Prostate towards commercialization." Dr. Kumar continued, "Standard of care for screening for prostate cancer includes a prostate specific antigen (PSA) measurement, followed by a digital rectal exam (DRE). It is well known that these current tests are imperfect, and cause hundreds of thousands of men to undergo painful, expensive and risk-laden biopsies that are negative and may be unnecessary. Our preliminary data, which we presented to the FDA, demonstrates that Cchek-Prostate could potentially eliminate a large number of these unnecessary procedures. The FDA was very supportive and appreciated us initiating the dialogue with them. As we continue through the regulatory process, we anticipate additional productive meetings and submissions with the FDA."

Anixa Biosciences expects the official minutes of the Pre-Sub meeting to be available in January. On January 24, 2019 Anixa plans to hold a conference call where it will discuss the commercialization path and timeline for Cchek-Prostate, as well as an update on its CAR-T therapeutics program. The details of the conference call will be provided at a later date.