On December 19, 2018 Genomic Health, Inc. (NASDAQ: GHDX) reported that the National Institute for Health and Care Excellence (NICE) in the United Kingdom has issued its updated guidance again recommending the Oncotype DX Breast Recurrence Score test for use in clinical practice to guide adjuvant chemotherapy treatment decisions for certain patients with early-stage breast cancer (Press release, Genomic Health, DEC 19, 2018, View Source [SID1234532154]). Further, NICE expanded its recommendation to include patients with micrometastases, indicating that some cancer cells have spread to the lymph nodes.

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"Oncotype DX is the only test that provides specific information about an individual patient’s response to chemotherapy, correctly identifying the important minority of patients who will receive substantial treatment benefit and the majority of patients who will not benefit from chemotherapy," said Simon D H Holt, Honorary Consultant Surgical Oncologist, Peony Breast Care Unit at Prince Philip Hospital in Llanelli, UK. "This test allows us to target treatment much more effectively and should be routinely used for all eligible patients."

The recommendation of the Oncotype DX Breast Recurrence Score test in NICE’s updated guidance is based on the test’s unique ability to predict who will benefit from chemotherapy and who will not. Importantly, NICE acknowledges Oncotype DX as the only test that reduces the overall number of patients who receive chemotherapy, as well as the only test supported by long-term patient outcomes evidence, including the recently published landmark TAILORx study. Further, NICE also found the Oncotype DX test to be the most cost-effective tool in guiding chemotherapy treatment.

"We believe this positive endorsement from NICE reflects the growing global recognition of the unique value Oncotype DX provides," said Torsten Hoof, senior vice president, international, Genomic Health. "As we continue to experience an increasing impact of the TAILORx study results on clinical practice, we believe we are one step closer to broadening Oncotype DX access through increased reimbursement in Western Europe and around the world."

The predictive value of the Oncotype DX Breast Recurrence Score test was also recently acknowledged by Germany’s health technology assessment body, the Institute for Quality and Efficiency in Health Care (IQWiG), which concluded that only the Oncotype DX test has sufficient evidence to guide breast cancer adjuvant chemotherapy decisions based on the TAILORx study results.

Additionally, the U.S. National Comprehensive Cancer Network (NCCN) categorized Oncotype DX as the only "preferred" test for chemotherapy treatment decision-making for node-negative, early-stage breast cancer patients in its 2018 updated treatment guidelines.

About Oncotype DX

The Oncotype DX portfolio of breast, colon and prostate cancer tests applies advanced genomic science to reveal the unique biology of a tumor in order to optimize cancer treatment decisions. The company’s flagship product, the Oncotype DX Breast Recurrence Score test, is the only test that has been shown to predict the likelihood of chemotherapy benefit as well as recurrence in invasive breast cancer. Additionally, the Oncotype DX Breast DCIS Score test predicts the likelihood of recurrence in a pre-invasive form of breast cancer called DCIS. In prostate cancer, the Oncotype DX Genomic Prostate Score test predicts disease aggressiveness and further clarifies the current and future risk of the cancer prior to treatment intervention. With more than 950,000 patients tested in more than 90 countries, the Oncotype DX tests have redefined personalized medicine by making genomics a critical part of cancer diagnosis and treatment. To learn more about Oncotype DX tests, visit www.OncotypeIQ.com, www.MyBreastCancerTreatment.org or www.MyProstateCancerTreatment.org.

On December 19, 2018 GlaxoSmithKline plc (LSE/NYSE: GSK) reported that it has reached agreement with Pfizer Inc to combine their consumer health businesses into a new world-leading Joint Venture, with combined sales of approximately £9.8 billion ($12.7 billion)[1] (Press release, GlaxoSmithKline, DEC 19, 2018, View Source [SID1234532172]). GSK will have a majority controlling equity interest of 68% and Pfizer will have an equity interest of 32% in the Joint Venture.

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The proposed all-equity transaction represents a compelling opportunity to build on the recent buyout of Novartis’ stake in GSK Consumer Healthcare, to create a new world-leading consumer healthcare business and to deliver further significant shareholder value. The proposed transaction also supports GSK’s key priority of strengthening its pharmaceuticals business over the next few years by increasing cashflows and providing an effective pathway through the separation of GSK Consumer Healthcare to build further support for investment in its R&D pipeline.

New Consumer Healthcare Joint Venture

The new Joint Venture will be well-positioned to deliver stronger sales, cash flow and earnings growth driven by category leading Power Brands, science-based innovation and substantial cost synergies. The combination will bring together two highly complementary portfolios of trusted consumer health brands, including GSK’s Sensodyne, Voltaren and Panadol and Pfizer’s Advil, Centrum and Caltrate. The Joint Venture will be a category leader in Pain Relief, Respiratory, Vitamin and Mineral Supplements, Digestive Health, Skin Health and Therapeutic Oral Health. The Joint Venture will be the global leader in OTC products with a market share of 7.3% ahead of its nearest competitor at 4.1% and have number 1 or 2 market share positions in all key geographies, including the US and China.

The proposed transaction is expected to realise substantial cost synergies, with the Joint Venture expected to generate total annual cost savings of £0.5 billion by 2022 for expected total cash costs of £0.9 billion and non-cash charges of £0.3 billion. Planned divestments targeting around £1 billion of net proceeds are expected to cover the cash costs of the integration. Up to 25% of the cost savings are intended to be reinvested in the business to support innovation and other growth opportunities. Overall the Joint Venture will target an Adjusted operating margin percentage in the ‘mid-to-high 20’s’ by 2022.

GSK expects the proposed transaction to be accretive to Total earnings in the second full year following closing, reflecting the impact and timing for the costs of integration; and to be accretive to Adjusted earnings and free cashflow in the first full year after closing

Future separation

The proposed transaction is transformational to the scale of GSK’s Consumer Healthcare business. Within 3 years of the closing of the transaction, GSK intends to separate the Joint Venture via a demerger of its equity interest and a listing of GSK Consumer Healthcare on the UK equity market. Over this period, GSK will substantially complete the integration and expects to make continued progress in strengthening its Pharmaceuticals business and R&D pipeline.

The intended separation of the Group will allow the two resulting companies to be established with appropriate capital structures for their future investment needs and capital allocation priorities. The new consumer healthcare company with its more durable cash flows will be able to support higher leverage levels than the GSK Group today, creating the opportunity on separation to reduce the leverage in the new Pharmaceuticals/Vaccines company.

Dividend expectations

GSK remains committed to its current dividend policy and confirms it continues to expect to pay 80 pence per share in dividends for 2018. Recognising the significance of this proposed transaction and the importance of dividends to shareholders, the company is today confirming that it expects to pay dividends of 80 pence per share for 2019.

Going forward, the proposed transaction enhances prospects for the Consumer Healthcare business and supports the development of GSK’s Pharmaceuticals business. With expected improvements in both businesses, GSK expects to be well positioned to deliver returns to shareholders alongside continued investment in its strategic priorities.

Emma Walmsley, Chief Executive Officer, GSK, said:

"Eighteen months ago, I set out clear priorities and a capital allocation framework for GSK to improve our long-term competitive performance and to strengthen our ability to bring new breakthrough medicines and better healthcare products to people around the world. We have improved our operating performance and have set out a new approach to R&D. We have also started to reshape the Group’s portfolio through prioritisation of R&D programmes, acquisitions such as that proposed with the oncology biopharmaceutical company, TESARO, the minority buy-out of the consumer healthcare business and a series of non-core product divestments.

"The transaction we have announced today is a unique opportunity to accelerate this work. Through the combination of GSK and Pfizer’s consumer healthcare businesses we will create substantial further value for shareholders. At the same time, incremental cashflows and visibility of the intended separation will help support GSK’s future capital planning and further investment in our pharmaceuticals pipeline.

"With our future intention to separate, the transaction also presents a clear pathway forward for GSK to create a new global Pharmaceuticals/Vaccines company, with an R&D approach focused on science related to the immune system, use of genetics and advanced technologies, and a new world-leading Consumer Healthcare company.

"Ultimately, our goal is to create two exceptional, UK-based global companies, with appropriate capital structures, that are each well positioned to deliver improving returns to shareholders and significant benefits to patients and consumers."

Approvals and closing

The proposed transaction is subject to approval by GSK shareholders and conditional upon the receipt of certain anti-trust authority approvals. Subject to these approvals, the transaction is expected to close in the second half of 2019. The Board intends to recommend that shareholders vote in favour of the proposed transaction.

Analyst conference call details
09:00 UK Wednesday 19 December

Listen only line: UK: +44 (0) 20 7136 5118 US: +1 857 244 8211 Passcode: 625 844 62
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Slides will be available on the GSK website one hour prior to the call.

Principal terms and conditions of the Transaction

New Joint Venture

GSK and Pfizer have today entered into an agreement under which, upon closing of the proposed transaction, Pfizer will contribute its consumer healthcare business to GSK’s existing consumer healthcare business in return for equity shares in this business. As a result, a new Joint Venture will be created in which GSK will have a controlling 68% equity interest and Pfizer a 32% equity interest.

GSK and Pfizer have provided customary and broadly reciprocal representations, warranties and indemnities to each other in respect of their respective businesses that will be included in the Joint Venture, which are subject to customary limitations of liability.

Combined 2017 global sales for the Joint Venture were approximately £9.8 billion ($12.7 billion)[2]. The Joint Venture will be a category leader in Pain Relief, Respiratory, Vitamin and Mineral Supplements, Digestive Health, OTC Skin Health and Therapeutic Oral Health and will have the largest global market share in OTC at 7.3% ahead of its nearest competitor at 4.1%. The Joint Venture is expected to have number 1 or 2 market share positions in all key geographies, including the US, Western, Central and Eastern Europe, China, India and Australasia.

The Joint Venture will operate under the GSK Consumer Healthcare name in all territories where GSK and Pfizer have a presence, with the exception of GSK’s interest in its listed subsidiary in Nigeria which will be excluded from the Joint Venture. The assets within the scope of, and the proceeds of, GSK’s proposed divestment of Horlicks and other Consumer Healthcare nutrition products to Unilever will not be included in the Joint Venture.

Until separation, the Joint Venture will be consolidated in GSK’s financial statements and is not expected to carry any external debt.

Governance and leadership

The Joint Venture will be subject to a shareholders’ agreement between GSK and Pfizer, under which GSK will have 6 directors and Pfizer 3 directors on the board of the joint venture company. GSK will have control of the joint venture company through the board, while Pfizer will enjoy customary minority shareholder protections.

Emma Walmsley will be Chair of the new Joint Venture until separation. Brian McNamara, currently CEO GSK Consumer Healthcare, will be CEO of the new Joint Venture and Tobias Hestler, currently CFO GSK Consumer Healthcare will be CFO.

Separation rights

As stated above the proposed transaction is transformational to the scale of GSK’s consumer healthcare business and following substantial completion of the integration and further progress in strengthening the pharmaceuticals pipeline, GSK intends to separate the Joint Venture from GSK via a demerger of its equity interest to GSK shareholders and a listing of the GSK Consumer Healthcare business on the UK equity market. This is expected to be within 3 years of the closing of the transaction.

GSK will have the sole right to decide whether and when to initiate a separation and listing for a period of five years from closing of the proposed transaction. GSK has also retained the right to sell all or part of its stake in the Joint Venture in a contemporaneous IPO. In the event of the separation and listing occurring in this period, Pfizer has the option to participate through the demerger of its equity interest in the Joint Venture to its shareholders or the sale of its equity interest in a contemporaneous IPO. After the fifth anniversary of closing of the proposed transaction, both GSK and Pfizer will have the right to decide whether and when to initiate a separation and listing of the Joint Venture.

In circumstances where Pfizer initiates a separation and listing of the Joint Venture after the fifth anniversary of closing of the proposed transaction, GSK will have the right to acquire all (but not part) of Pfizer’s equity interest in the Joint Venture at fair market value. In addition, from the fifteenth anniversary of closing of the proposed transaction, GSK will have the right to acquire all (but not part) of Pfizer’s equity interest in the Joint Venture at fair market value.

As a part of any separation and listing, the Joint Venture will incur borrowings so as to result in an initial ratio of net debt to the aggregate of the Joint Venture’s last four quarters’ Adjusted EBITDA of between 3.5x and 4.0x. The cash proceeds of this recapitalisation will be distributed by the Joint Venture to GSK and Pfizer in proportion to their respective interests in the Joint Venture prior to any separation and listing.

In the event of any separation and listing, GSK also has the right to determine the Joint Venture’s prospective dividend policy provided the pay-out ratio is between 30% and 50% of the aggregate of the Joint Venture’s last four quarters’ Adjusted profit attributable to shareholders.

Conditions to closing

Pfizer is treated as a related party of GSK for the purposes of the UK Listing Rules by virtue of its interest in ViiV Healthcare and, as such, the proposed transaction is conditional upon the approval of GSK’s shareholders at a general meeting. GSK has agreed that its Board will recommend that shareholders vote in favour of the resolution approving the Proposed Transaction, subject to provisions that allow the recommendation to be withdrawn on account of fiduciary duties. The proposed transaction is also conditional on there being no governmental orders restraining or prohibiting the transaction and certain anti-trust authority approvals.

Expected timetable to closing

A circular setting out further details on the proposed transaction, including the resolution seeking shareholder approval, will be sent to GSK shareholders in the first quarter of 2019. Closing of the proposed transaction is currently expected to occur during the second half of 2019, subject to shareholder approval and relevant anti-trust approvals.

Break fee

GSK has agreed to pay a break fee of US$900 million if (i) the Board changes, withdraws or qualifies its recommendation; (ii) shareholders vote on the proposed transaction and do not approve it; or (iii) shareholders do not approve the proposed transaction by 30 September 2019 (or, at either GSK’s or Pfizer’s option, 31 December 2019 or 31 March 2020 in the case of delayed anti-trust approvals).

By virtue of Pfizer being a related party of GSK under the UK Listing Rules, the break fee constitutes a smaller related party transaction within LR11.1.10R of the UK Listing Rules. GSK has obtained written confirmation from Citi and J. P. Morgan Cazenove that the terms of the break fee are fair and reasonable so far as GSK’s shareholders are concerned.

Advisors

GSK has been advised by Citi, who has been acting as lead advisor, J. P. Morgan Cazenove and Greenhill & Co. Slaughter and May and Kirkland & Ellis LLP have provided legal advice.

Advice to the Board

The Board, which has been so advised by Citi and J. P. Morgan Cazenove, considers the terms of the proposed transaction to be fair and reasonable so far as shareholders are concerned. In providing their advice to the Board, Citi and J. P. Morgan Cazenove have taken into account the Board’s commercial assessment of the proposed transaction.

Information on GSK’s consumer healthcare business

As at 31 December 2017, the value of the gross assets of GSK’s consumer healthcare business to be contributed to the new Joint Venture was £16,071 million. In the financial year ended 31 December 2017, that business had sales of £7,110 million, Adjusted operating profit of £1,254 million, Total operating profit of £891 million and Total profit before tax of £884 million.

Information on Pfizer’s consumer healthcare business

As at 31 December 2017, the value of the gross assets of Pfizer’s consumer healthcare business to be contributed to the new Joint Venture was $10,026 million. In the financial year ended 31 December 2017, that business had sales of $3,469 million, Adjusted operating profit of $600 million, Total operating profit of $471 million and Total profit before tax of $471 million.

Sources of information and bases of calculation

Unless otherwise stated, the financial information in this announcement relating to GSK’s contributed consumer healthcare business is based on the audited consolidated financial statements of GlaxoSmithKline Consumer Healthcare Holdings Limited for the year ended 31 December 2017 (from which Novartis was bought out in June 2018), which were prepared under IFRS, adjusted for the perimeter changes that GSK will make to the business contributed to the new Joint Venture, and that relating to Pfizer’s contributed consumer healthcare business is extracted from carve out accounts prepared by Pfizer under US GAAP, adjusted to exclude certain items that were allocated to the business by Pfizer in preparing those accounts but which are not within the perimeter of the business being contributed to the new Joint Venture. Figures in respect of the combined sales of the new Joint Venture have been calculated by aggregating the 2017 sales of GSK’s consumer healthcare business, prepared under IFRS, and the 2017 sales of Pfizer’s consumer healthcare business, prepared under US GAAP; no reconciliation from US GAAP to IFRS has been performed. Conversions use an exchange rate of £1=US$1.30, being the average exchange rate for 2017.

GSK uses a number of adjusted, non-IFRS, measures to report the performance of its business, as described on page 37 of GSK’s Q3 2018 results, including Adjusted results, free cash flow and CER growth rates. Financial information in this announcement relating to Pfizer is presented on a similar basis. Non-IFRS measures may be considered in addition to, but not as a substitute for or superior to, information presented in accordance with IFRS.

This announcement contains inside information for the purposes of Article 7 of EU Regulation 596/2014. The person responsible for arranging the release of this announcement on behalf of GSK is V.A. Whyte, Company Secretary.

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.