Shire notes the announcement made by Takeda (Press release, Shire, APR 19, 2018, View Source [SID1234525813]). The Board of Shire (the "Board") confirms that it has received three conditional proposals from Takeda regarding a possible offer for the Company, on 29 March 2018 (the "First Proposal"), 11 April 2018 (the "Second Proposal") and 13 April 2018 (the "Third Proposal").

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The First Proposal comprised £28 per share in new Takeda shares, to be listed in Japan and in the US through an ADR listing, and £16 per share in cash, representing a potential value of £44 per share and approximately £41 billion for the total issued and to be issued share capital of the Company. Based on Takeda’s current market capitalisation, Shire shareholders would own approximately 50 per cent. of the enlarged Takeda.

Following a thorough review of the First Proposal with its advisers and a Board meeting on 8 April 2018, the Board unanimously rejected the First Proposal, concluding that it significantly undervalued the Company, its growth prospects and pipeline.

The Board has since received two further proposals:

·the Second Proposal comprised £28.75 per share in new Takeda shares, to be listed in Japan and in the US through an ADR listing, and £16.75 per share in cash, representing a potential value of £45.50 per share, only a marginal increase to the First Proposal, and approximately £43 billion for the total issued and to be issued share capital of the Company. Based on Takeda’s current market capitalisation, Shire shareholders would own approximately 51 per cent. of the enlarged Takeda; and

·the Third Proposal also comprised £28.75 per share in new Takeda shares, to be listed in Japan and in the US through an ADR listing, and £17.75 per share in cash, representing a potential value of £46.50 per share and approximately £44 billion for the total issued and to be issued share capital of the Company. Based on Takeda’s current market capitalisation, Shire shareholders would own approximately 51 per cent. of the enlarged Takeda.

The Board met again and thoroughly considered the Third Proposal with its advisers and unanimously rejected it, concluding that it continues to significantly undervalue the Company and Shire’s growth prospects and pipeline.

Following the Board meeting on 14 April 2018 which rejected the Third Proposal, at the Board’s request Shire’s advisers entered into a dialogue with Takeda’s advisers to discuss whether a further, more attractive, proposal may be forthcoming and to understand the basis on which such a proposal would be made.

The Board and management of Shire remain committed to enhancing shareholder value and are focused on fully evaluating internal and external opportunities to maximise value for shareholders, including any further proposals from Takeda.

Person responsible

Stephen Williams, Deputy Company Secretary, is responsible for arranging the release of this announcement on behalf of the Company.

Publication on a website

In accordance with Rule 26.1 of the Code, a copy of this announcement will be made available, subject to certain restrictions relating to persons resident in restricted jurisdictions, on Shire’s website at www.shire.com by no later than noon (London time) on the business day following this announcement. The content of this website is not incorporated into and does not form part of this announcement.

Further information

This announcement is not intended to, and does not, constitute or form part of any offer, invitation or the solicitation of an offer to purchase, otherwise acquire, subscribe for, sell or otherwise dispose of, any securities whether pursuant to this announcement or otherwise.

The distribution of this announcement in jurisdictions outside the United Kingdom may be restricted by law and therefore persons into whose possession this announcement comes should inform themselves about, and observe, such restrictions. Any failure to comply with the restrictions may constitute a violation of the securities law of any such jurisdiction.

Citigroup Global Markets Limited, which is authorised by the Prudential Regulation Authority and regulated in the UK by the Financial Conduct Authority and the Prudential Regulation Authority in the United Kingdom, is acting for Shire and no one else in connection with the matters described in this announcement and shall not be responsible to anyone other than Shire for providing the protections afforded to clients of Citigroup Global Markets Limited, or for giving advice in connection with the matters described in this announcement or any matter referred to therein.

Goldman Sachs International, which is authorised by the Prudential Regulation Authority and regulated by the Financial Conduct Authority and the Prudential Regulation Authority in the United Kingdom, is acting for Shire and no one else in connection with the matters described in this announcement and will not be responsible to anyone other than Shire for providing the protections afforded to clients of Goldman Sachs International, or for giving advice in connection with the matters described in this announcement or any matter referred to herein.

Morgan Stanley & Co. International plc, which is authorised by the Prudential Regulation Authority and regulated by the Financial Conduct Authority and the Prudential Regulation Authority in the United Kingdom, is acting for Shire and no one else in connection with the matters described in this announcement and will not be responsible to anyone other than Shire for providing the protections afforded to clients of Morgan Stanley & Co. International plc, or for giving advice in connection with the matters described in this announcement or any matter referred to herein.

Disclosure requirements of the Code

Under Rule 8.3(a) of the Code, any person who is interested in 1% or more of any class of relevant securities of an offeree company or of any securities exchange offeror (being any offeror other than an offeror in respect of which it has been announced that its offer is, or is likely to be, solely in cash) must make an Opening Position Disclosure following the commencement of the offer period and, if later, following the announcement in which any securities exchange offeror is first identified. An Opening Position Disclosure must contain details of the person’s interests and short positions in, and rights to subscribe for, any relevant securities of each of (i) the offeree company and (ii) any securities exchange offeror(s). An Opening Position Disclosure by a person to whom Rule 8.3(a) applies must be made by no later than 3.30 pm (London time) on the 10th business day following the commencement of the offer period and, if appropriate, by no later than 3.30 pm (London time) on the 10th business day following the announcement in which any securities exchange offeror is first identified. Relevant persons who deal in the relevant securities of the offeree company or of a securities exchange offeror prior to the deadline for making an Opening Position Disclosure must instead make a Dealing Disclosure.

Under Rule 8.3(b) of the Code, any person who is, or becomes, interested in 1% or more of any class of relevant securities of the offeree company or of any securities exchange offeror must make a Dealing Disclosure if the person deals in any relevant securities of the offeree company or of any securities exchange offeror. A Dealing Disclosure must contain details of the dealing concerned and of the person’s interests and short positions in, and rights to subscribe for, any relevant securities of each of (i) the offeree company and (ii) any securities exchange offeror(s), save to the extent that these details have previously been disclosed under Rule 8. A Dealing Disclosure by a person to whom Rule 8.3(b) applies must be made by no later than 3.30 pm (London time) on the business day following the date of the relevant dealing.

If two or more persons act together pursuant to an agreement or understanding, whether formal or informal, to acquire or control an interest in relevant securities of an offeree company or a securities exchange offeror, they will be deemed to be a single person for the purpose of Rule 8.3.

Opening Position Disclosures must also be made by the offeree company and by any offeror and Dealing Disclosures must also be made by the offeree company, by any offeror and by any persons acting in concert with any of them (see Rules 8.1, 8.2 and 8.4).

Details of the offeree and offeror companies in respect of whose relevant securities Opening Position Disclosures and Dealing Disclosures must be made can be found in the Disclosure Table on the Takeover Panel’s website at www.thetakeoverpanel.org.uk, including details of the number of relevant securities in issue, when the offer period commenced and when any offeror was first identified. You should contact the Panel’s Market Surveillance Unit on +44 (0)20 7638 0129 if you are in any doubt as to whether you are required to make an Opening Position Disclosure or a Dealing Disclosure.

On April 18, 2018 Tusk Therapeutics, an immuno-oncology company focused on developing immune-modulating therapeutics by targeting immune cells in cancer, presented pre-clinical proof-of-concept data generated in collaboration with Cancer Research UK and University College London (UCL), relating to its anti-CD25 programme at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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Tusk Therapeutics presented data on its first-in-class anti-CD25 programme that has entered pre-clinical development. The antibody depletes regulatory T cells (Tregs) while preserving IL-2 binding and signalling on effector T cells (Teffs). Tusk, together with the University College London research group led by Dr. Sergio Quezada, has shown that targeting Tregs with non-IL-2 blocking anti-CD25 antibodies creates highly potent anti-tumour responses in monotherapy and combination therapy. Proof-of-concept has been established in multiple pre-clinical models.

Tregs, a subpopulation of T cells, are key players in the suppressive tumour microenvironment (TME). Tregs in the TME hinder the body’s ability to control the growth of cancerous cells and their presence is correlated with a worse prognosis in multiple cancers. Effective Treg targeting has been a topic in the cancer field for several years and Tusk’s approach demonstrates it is possible to deplete Tregs in solid tumour which leads to tumour control. Tusk’s antibody is specifically selected to preserve signalling of the IL-2 cytokine on effector cells which is a key regulator of immune-activation.

Commenting on the data, Luc Dochez, Chief Executive Officer of Tusk Therapeutics, said: "The data presented at AACR (Free AACR Whitepaper) demonstrate the unique mechanism of action of our anti-CD25 antibody. Unlike existing aCD25 antibodies our antibody has the ability to deplete Tregs without inhibiting effector cell responses. Based on the promising pre-clinical data, we believe that our anti-CD25 candidates will be an ideal combination partner for existing standard of care and immuno-oncology treatments."

​The data was presented as an oral presentation by Dr. Sergio Quezada, Group Leader and Cancer Research UK Senior Research Fellow at The UCL Cancer Institute, and Chairman of Tusk Therapeutics’ Scientific Advisory Board and in two posters, presented by the Tusk and UCL teams. Tusk Therapeutics’ first-in-class anti-CD25 antibody programme was built on novel biology discovered by Tusk Therapeutics in collaboration with Dr. Quezada and his team at UCL. Tusk Therapeutics, Cancer Research UK (via its Commercial Partnerships Team) and UCL announced in 2017, an exclusive licensing and collaboration deal to develop and commercialise antibody-based therapeutics against CD25.

On April 18, 2018 Genocea Biosciences, Inc. (NASDAQ:GNCA), a biopharmaceutical company developing neoantigen cancer vaccines, reported highlights from its scientific presentations at the 2018 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (AACR 2018), taking place April 14-18, 2018 in Chicago, IL (Press release, Genocea Biosciences, APR 18, 2018, View Source [SID1234525509]).

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Jessica Flechtner, Ph.D., Genocea’s chief scientific officer commented on the AACR (Free AACR Whitepaper) presentations: "We continue to generate data that demonstrate the versatility of our ATLAS platform. As the studies presented at AACR (Free AACR Whitepaper) indicate, ATLAS is a differentiator for Genocea – allowing us to do what in silico approaches cannot – to both identify and characterize neoantigens for use in personalized cancer vaccines. We believe that our ability to find stimulatory and inhibitory antigens during the neoantigen selection process combined with our capacity to explore mechanisms of inhibitory antigens in a murine model, may enable us to help cure cancer by pioneering next-generation cancer vaccines."

Summary of AACR (Free AACR Whitepaper) Poster #730, "Empirical neoantigen identification using the ATLAS platform across thousands of mutations and multiple tumor types highlights advantages over algorithmic prediction methods":

ATLAS enables identification of biologically relevant CD4+ and CD8+ T cell neoantigens in subjects in an unbiased manner, by using subjects’ own antigen-presenting cells (APCs) and T cells rather than predictive algorithms to identify and characterize T cell responses to all candidate neoantigens.
Neoantigen screening was performed on 23 individuals across eight tumor types with mutational burden ranging from 9 to 319 unique mutations.
Empiric identification of neoantigens derived from somatic mutations from each patient’s tumor independently of HLA type and without predictions resulted in the following observations:
ATLAS identified stimulatory neoantigens of both CD4+ and CD8+ T cells, which Genocea believes confirms the importance of including antigens of relevance for both T cell subsets in neoantigen vaccines;
There is little overlap between CD4+ and CD8+ T cell neoantigens; fewer than 2% of empirically confirmed neoantigens were shared between T cell subsets;
Prediction algorithms missed up to 69% of ATLAS-identified neoantigens, with only 2% of CD8+ neoantigens and 24% of CD4+ neoantigens accurately predicted;
The major histocompatibility complex (MHC) class I algorithm appeared to better predict CD4+, not CD8+, neoantigens;
ATLAS also identified inhibitory neoantigens of both CD4+ and CD8+ T cells
Inhibitory neoantigens outnumbered stimulatory neoantigens more than three-fold in aggregate in the screened patients;
Inhibitory antigens currently cannot be identified using in silico approaches.
Summary of Poster #5718, "ex vivo ATLASTM identification of neoantigens for personalized cancer immunotherapy in mouse melanoma":

The B16F10 mouse melanoma model was utilized to characterize neoantigens. More than 1,600 tumor-specific mutations (possible neoantigens) were interrogated using the ATLAS technology and CD8+ T cells from tumor-bearing C57BL/6 mice.
Similar to human neoantigen screens, mouse ATLAS (mATLAS) identified both stimulatory and inhibitory neoantigens:
99% of mutations identified using whole exome sequencing were screened;
68 stimulatory (4% of total mutations) and 57 inhibitory (3% of total mutations) neoantigens were identified.
NetMHCPan, a MHC-binding prediction algorithm, failed to identify the majority of mATLAS-identified neoantigens:
Only 2% of B16F10 neoantigens predicted by algorithms were empirically confirmed to be stimulatory antigens;
91% of stimulatory neoantigens empirically identified with mATLAS were not predicted;
6% of algorithm-predicted neoantigens were inhibitory.
These data demonstrate that inhibitory antigens can be identified in mouse models, allowing for future research into the mechanism of ATLAS-identified inhibitory responses and their relationship to stimulatory neoantigens in mediating tumor control.

On April 18, 2018 OBI Pharma, Inc., a Taiwan biopharma company (TPEx: 4174), reported that the U.S. Food and Drug Administration (FDA) has cleared an investigational new drug (IND) application for a Phase I/II study of OBI-3424, a first-in-class DNA alkylating agent that targets cancers that overexpress the aldo-keto reductase 1C3 (AKR1C3) enzyme (Press release, OBI Pharma, APR 18, 2018, View Source [SID1234525525]).

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OBI plans to enroll patients with local solid tumors, including hepatocellular carcinoma (HCC) and castrate-resistant prostate cancer (CRPC). OBI Pharma’s Chief Medical Advisor, Tillman Pearce, M.D., noted, "This clinical trial intends to verify the safety and preliminary activity profile of OBI-3424, a novel first-in-class prodrug of a DNA alkylating cancer therapeutic that is selectively activated by AKR1C3, an enzyme that is overexpressed in a variety of solid and liquid tumors. We are delighted to conduct this first-in-man clinical trial at the University of Texas M.D. Anderson Cancer Center and The James Cancer Hospital and Solove Research Institute of Ohio State University, two of America’s leading academic oncology research institutions".

Amy Huang, General Manager of OBI Pharma, added, "OBI Pharma is proud to further develop our unique targeted cancer pipeline, including targets like the Globo series and AKR1C3. OBI-3424 enhances OBI’s pipeline in solid and liquid tumors for cancer patients who over-express AKR1C3. OBI is taking a first-step towards testing the safety and initial efficacy of a new class of AKR1C3 targeted therapy. We are excited to develop novel targeted therapeutics in the fight against cancers of unmet need."

About OBI-3424

OBI-3424 is a first-in-class novel small-molecule prodrug that selectively targets cancers overexpressing the enzyme aldo-keto reductase 1C3 (AKR1C3), and selectively releases a potent DNA alkylating agent in the presence of the AKR1C3 enzyme. This selective mode of activation distinguishes OBI-3424 from traditional alkylating agents, such as cyclophosphamide and ifosfamide, which are non-selective.

AKR1C3 overexpression has been documented in a number of treatment-resistant and difficult-to-treat cancers including: hepatocellular carcinomas (HCC), castrate-resistant prostate cancer (CRPC), and T-cell acute lymphoblastic leukemia (T-ALL). AKR1C3 is highly expressed in up to 15 solid and liquid tumors.

Furthermore, individualized patient selection by staining for AKR1C3 overexpression by immunohistochemistry can be performed based on tumor biopsies or circulating tumor cells to identify patients with other tumor types most likely to respond to treatment with OBI-3424, and thus offering the possibility for a streamlined clinical development strategy.

OBI Pharma holds worldwide rights for OBI-3424 with the exception of the following countries, whose rights are held by Ascenta Pharma: China, Hong Kong, Macao, Taiwan, Japan, South Korea, Singapore, Malaysia, Thailand, Turkey, and India.

On April 18, 2018 Computational drug design company Numerate reported that it has signed a letter of intent to join an open consortium of scientists staffed from two U.S. national laboratories, industry, and academia working to transform drug discovery and development into an approach that is rapid, integrated and with better patient outcomes (Press release, Numerate, APR 18, 2018, View Source [SID1234525510]).

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Accelerating Therapeutics for Opportunities in Medicine (ATOM) formed in October 2017 with the goal of reducing preclinical drug discovery from six years to just one, using cancer as the exemplar disease.

ATOM is integrating high-performance computing and biological, chemical, preclinical, and clinical data from public and industry sources to create an active learning platform that considers all aspects of drug discovery and pharmacology. ATOM will integrate emerging high-fidelity, data-rich experimental technologies, and cutting-edge software into the approach.

"This will create an ecosystem which will foster the rapid and dynamic collaboration needed to advance precision medicine and tremendously benefit patients," wrote Guido Lanza, president and CEO of Numerate, and Brandon Allgood, CTO, in the letter signed April 3, 2018.

"Our organization’s business priorities and directions are strongly aligned with the fundamental elements of ATOM … and we look forward to outlining the specific contributions we can make to the ATOM consortium as collaborators," they wrote.

John Baldoni, ATOM founder and governing board co-chair, and senior vice president for R&D at GSK, said Numerate is well-known for its innovative software approach to drug discovery.

"This collaboration provides Numerate with extensive and unique data sources and computer power with which they can optimize their drug discovery algorithms," Baldoni said. "This letter of intent signals how cutting-edge private-sector organizations can benefit in this public/private consortium."

Numerate joins the founding members of ATOM: GSK, the National Cancer Institute’s Frederick National Laboratory for Cancer Research (FNLCR), the University of California, San Francisco (UCSF), and the Department of Energy/National Nuclear Security Administration (NNSA)’s Lawrence Livermore National Laboratory (LLNL), which is contributing supercomputer resources and cognitive simulation expertise to the ATOM consortium. ATOM headquarters is located in the Mission Bay neighborhood of San Francisco.

ATOM seeks other organizations to join the consortium to bring their expertise into this new environment.

"We are excited to see the addition of industry leaders to the consortium and to the effort to bring effective new drugs to cancer patients more rapidly," said Eric Stahlberg, director of high performance computing at the Frederick National Laboratory.

The partners agree to work together to develop, test, and validate a multidisciplinary approach to drug discovery where science, technology and engineering, supercomputing simulations, data science, and artificial intelligence are integrated into a drug-discovery platform, ultimately to be shared with the drug development community at large.