On April 20, 2018 Dr. Michael Rosenblum and his team at MD Anderson Cancer Center, Houston, TX, reported that presented updated data on TGI (Targeted Granzyme B immunotherapy) at the 2018 American Association of Cancer Research Annual Meeting (AACR) (Free AACR Whitepaper) (Press release, Mirata BioPharma, APR 20, 2018, View Source [SID1234525564]). The research was supported by Mirata Biopharma LLC and conducted by the Clayton Foundation for Research ("Clayton Foundation").

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Dr. Rosenblum’s team developed a fusion protein, GrB-Fc-IT4 (MRT-101), that contains a humanized scFv binding domain targeting the cell surface receptor Fn14, an antigen highly expressed in a variety of solid tumors, and containing the human serine protease granzyme B (GrB) as the cytotoxic payload. The construct includes the IgG hinge Fc domain linker for efficient dimerization and an overall high molecular weight, thereby designed to provide a prolonged serum half-life (~40 h in mice). This unique format mimics human immune effector cell function and induces target cell death through the activation of a variety of well described pro-apoptotic cascade signals.

The poster, entitled "Molecular mechanistic and in vivo efficacy studies of Fn14-targeted fusion constructs containing human granzyme B," demonstrated that Western blot studies on human TNBC cells (MDA-MD-231) have shown that intact MRT-101 is translocated into the cytosol in less than 1 hour after exposure and is detectable in the cytosol for at least 8 hours. The free GrB component is also detected by the Western blot 4 hours after treatment and persists for up to 8 hours. Both of these agents trigger apoptotic cascades through activation of various caspases and induction of mitochondrial damage. Studies demonstrating cytochrome C release and mitochondrial depolarization are ongoing and will be reported. Incubation with the lysosomotropic agent chloroquine did not alter the IC50 of MRT-101, suggesting that the fusion protein is not appreciably held in the endosomal compartment.

In vivo studies have shown that MRT-101 is well tolerated in BALB/c mice after intravenous administration of 5 doses at 20 mg/kg/dose. This dose level showed no evidence of toxicity in any of the major organs such as liver and kidneys. In vivo efficacy studies conducted on NSGNOD scid mice demonstrated significant tumor growth inhibition of established orthotopic breast tumors (MDA-MB-231), with no tumor growth for up to 30 days after implantation. Treatment of nude mice bearing lung PDX tumors showed a 60% tumor growth inhibition when compared to the vehicle control group. These results, in combination with previous in vitro and in vivo studies, demonstrate that the completely human MRT-101 construct is a selective, highly potent, non-toxic and effective antigen-driven drug with significant potential for the treatment of Fn14 positive tumors that acts through a new and unique mechanism of action.

Full poster from the AACR (Free AACR Whitepaper) can be accessed via Mirata Biopharma website: View Source

Shire notes the announcement made by Takeda and confirms it has received a fourth proposal on 20 April 2018 regarding a possible offer for the Company (the "Fourth Proposal") (Press release, Shire, APR 20, 2018, View Source [SID1234525816]).

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The Fourth Proposal comprises £26 per share in new Takeda shares, to be listed in Japan and in the US through an ADR listing, and £21 per share in cash, representing a potential value of £47 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 49 per cent. of the enlarged Takeda.

The Board of Shire is considering its position with respect to the Fourth Proposal and will issue a further announcement in due course.

This announcement is made without the consent of 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 19, 2018 Tocagen Inc. (Nasdaq: TOCA), a clinical-stage, cancer-selective gene therapy company, and Beijing Apollo Venus Biomedical Technology Limited, an affiliate of ApolloBio Corp. (NEEQ: 430187), a biopharmaceutical company focused on oncology (collectively, "ApolloBio"), reported they have entered into a license agreement providing ApolloBio with an exclusive license to develop and commercialize Toca 511 & Toca FC within the greater China region, including mainland China, Hong Kong, Macao and Taiwan (Press release, Tocagen, APR 19, 2018, View Source;p=RssLanding&cat=news&id=2343446 [SID1234525579]).

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Toca 511 & Toca FC is a cancer-selective immunotherapy currently under evaluation in an international Phase 3 trial, called Toca 5, for patients with recurrent high grade glioma (HGG), a type of brain tumor. The product candidate has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) and PRIority MEdicines (PRIME) designation from the European Medicines Agency (EMA).

Under the terms of the agreement, ApolloBio will make an upfront payment of $16 million to Tocagen, plus potential payments of $4 million in near-term development milestones, including completion of enrollment in the Toca 5 study. Tocagen will be eligible for additional future payments totaling up to $111 million upon meeting certain development and commercial milestones. In addition, low double-digit tiered royalty payments will be made based on net sales. ApolloBio will be responsible for all development and commercialization costs in the licensed territory.

"As an innovative biopharmaceutical company in China, ApolloBio is well positioned to leverage China’s recent regulatory changes supporting the development of new medicines," said Marty Duvall, chief executive officer of Tocagen. "ApolloBio brings valuable regional expertise in product development, regulation and healthcare access, positioning our lead product to advance towards patients in the greater China region as quickly and efficiently as possible."

The total number of new diagnoses of HGG expected in 2018 is about 180,000 worldwide and about 47,000 in the greater China region. Standard treatment for newly diagnosed HGG includes safe surgical removal of as much of the tumor as possible, followed by radiation therapy and chemotherapy. However, HGG recurs in most patients even after maximal treatment and there are currently very few treatment options available.

"We are committed to accelerating the availability of novel immuno-oncology treatments to patients with high unmet medical needs in the greater China region," said Dr. Weiping Yang, chief executive officer of ApolloBio. "Toca 511 & Toca FC is a highly promising, best-in-class cancer-selective immunotherapy and we look forward to working with Tocagen to advance this innovative late-stage product towards commercialization."

The license grant to ApolloBio is subject to the satisfaction of customary conditions and is expected to become effective in the second quarter of 2018. For more details, please refer to the corresponding Form 8-K filed today with the U.S. Securities and Exchange Commission (SEC).

About Toca 511 & Toca FC

Tocagen’s lead product candidate is a two-part cancer-selective immunotherapy comprised of an investigational biologic, Toca 511 and an investigational small molecule, Toca FC. Toca 511 (vocimagene amiretrorepvec) is a retroviral replicating vector (RRV) that selectively infects cancer cells and delivers a gene for the enzyme, cytosine deaminase (CD). Through this targeted delivery, infected cancer cells carry the CD gene and produce CD. Toca FC is an orally administered, extended-release formulation of the prodrug, 5-fluorocytosine (5-FC), which is converted into an anti-cancer drug, 5-fluorouracil (5-FU), when it encounters CD. 5-FU kills cancer cells and immune-suppressive myeloid cells in the tumor microenvironment resulting in anti-cancer immune activation and subsequent tumor killing.

On April 19, 2018 Alkermes plc (NASDAQ: ALKS) reported that it will host a conference call and webcast presentation at 8:30 a.m. ET (1:30 p.m. BST) on Thursday, Apr. 26, 2018, to discuss the company’s first quarter 2018 financial results (Press release, Alkermes, APR 19, 2018, View Source;p=RssLanding&cat=news&id=2343568 [SID1234525541]). Management will also provide an update on the company.

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The webcast player and accompanying slides may be accessed on the Investors section of Alkermes’ website at www.alkermes.com. The conference call may be accessed by dialing +1 888 424 8151 for U.S. callers and +1 847 585 4422 for international callers. The conference call ID number is 6037988.

A replay of the conference call will be available from 11:00 a.m. ET (4:00 p.m. BST) on Thursday, Apr. 26, 2018, through 5:00 p.m. ET (10:00 p.m. BST) on Thursday, May 3, 2018, and may be accessed by visiting Alkermes’ website or by dialing +1 888 843 7419 for U.S. callers and +1 630 652 3042 for international callers. The replay access code is 6037988.

On April 19, 2018 Amgen (NASDAQ:AMGN) reported that it will report its first quarter 2018 financial results on Tuesday, April 24, 2018, after the close of the U.S. financial markets (Press release, Amgen, APR 19, 2018, View Source;p=RssLanding&cat=news&id=2343565 [SID1234525542]). The announcement will be followed by a conference call with the investment community at 2 p.m. PT. Participating in the call from Amgen will be Robert A. Bradway, chairman and chief executive officer, and other members of Amgen’s senior management team.

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Live audio of the conference call will be simultaneously broadcast over the internet and will be available to members of the news media, investors and the general public.

The webcast, as with other selected presentations regarding developments in Amgen’s business given by management at certain investor and medical conferences, can be found on Amgen’s website, www.amgen.com, under Investors. Information regarding presentation times, webcast availability and webcast links are noted on Amgen’s Investor Relations Events Calendar. The webcast will be archived and available for replay for at least 90 days after the event. (Press release, Amgen, APR 19, 2018, View Source;p=RssLanding&cat=news&id=2343565 [SID1234525542])