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 20, 2018 Nordic Nanovector ASA (OSE: NANO) reported that it has appointed Tone Kvåle to the position of Interim Chief Executive Officer (CEO) in addition to her current role as Chief Financial Officer (Press release, Nordic Nanovector, APR 20, 2018, View Source [SID1234553506]). The appointment is made to conform to Norwegian Companies Law. A search for a full-time CEO is progressing.

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On April 19, 2018 Quest Diagnostics Incorporated (NYSE: DGX), the world’s leading provider of diagnostic information services, reported that financial results for the first quarter ended March 31, 2018 (Press release, Quest Diagnostics, APR 19, 2018, View Source [SID1234525534]).

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"We delivered strong revenue and earnings growth in the first quarter," said Steve Rusckowski, Chairman, President and CEO. "We grew revenue 3.7 percent despite severe winter weather and the impact of lower Medicare reimbursement under PAMA. Earnings growth was driven by our continued strong execution as well as the benefits of tax reform. Our two-point strategy of accelerating growth and driving operational excellence continues to produce results."

As used in this press release the term "reported" refers to measures under the accounting principles generally accepted in the United States ("GAAP"). The term "adjusted" refers to non-GAAP measures as follows: (i) for the purpose of income measures the term "adjusted" refers to operating performance measures that exclude special items such as restructuring and integration charges, excess tax benefit ("ETB") associated with stock based compensation and other items; and (ii) the term "adjusted diluted EPS excluding amortization" represents the company’s diluted EPS before the impact of special items (described above) and amortization expense.

Non-GAAP adjusted measures are presented because management believes those measures are useful adjuncts to GAAP results. Non-GAAP adjusted measures should not be considered as an alternative to the corresponding measures determined under GAAP. Management may use these non-GAAP measures to evaluate our performance period over period and relative to competitors, to analyze the underlying trends in our business, to establish operational budgets and forecasts and for incentive compensation purposes. We believe that these non-GAAP measures are useful to investors and analysts to evaluate our performance period over period and relative to competitors, as well as to analyze the underlying trends in our business and to assess our performance. The additional tables attached below include reconciliations of adjusted measures to GAAP measures.

Conference Call Information

Quest Diagnostics will hold its quarterly conference call to discuss financial results beginning at 8:30 a.m. Eastern Time today. The conference call can be accessed in listen-only mode by dialing 773-756-0467, passcode 3214469. The company suggests participants dial in approximately 10 minutes before the call.

A replay of the call may be accessed online at www.QuestDiagnostics.com/investor or by phone at 800-846-1910 for domestic callers or 402-280-9953 for international callers. Telephone replays will be available from approximately 10:30 a.m. Eastern Time on April 19, 2018 until midnight Eastern Time on May 3, 2018. Anyone listening to the call is encouraged to read the company’s periodic reports, on file with the Securities and Exchange Commission, including the discussion of risk factors and historical results of operations and financial condition in those reports.

On April 19, 2018 Medigene AG (FSE: MDG1, Prime Standard, TecDAX) reported that researchers from Medigene and Oslo University Hospital presented a poster on the generation of dendritic cell vaccines for Medigene’s ongoing Phase I/II clinical trial with Acute Myeloid Leukemia (AML) patients at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago, USA (Press release, MediGene, APR 19, 2018, View Source [SID1234525552]).

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Dr. Kai Pinkernell, Chief Medical and Chief Development Officer (CMO/CDO) of Medigene, commented: "These results clearly demonstrate the feasibility and robustness of our production protocol for high numbers of clinical grade TLR7/8-polarized fast mature DCs from heavily pretreated AML patients, allowing for long-term vaccination of trial subjects."

A total of 20 patients with an average age of 59 years (range 24 – 73 years) were recruited to this ongoing trial. For vaccine production, autologous apheresis material was collected from each patient. Following isolation of DC precursor cells, fast DC generation was performed using Medigene’s proprietary TLR7/8-agonist containing maturation cocktail. The final DC vaccine product was cryopreserved in multiple aliquots prepared to deliver 5-10 million cells per vaccine dose.

Successful production runs of dendritic cells for vaccination were achieved for all 20 AML patients. An additional apheresis for a second production run in order to generate sufficient vaccine doses for the intended treatment period was performed during the trial for only 4 out of the 20 patients enrolled in the trial.

The production runs were performed at the Department of Cellular Therapy at the Oslo University Hospital, Norway.
To view the abstract of the poster entitled "Generation of clinical grade autologous TLR7/8-polarized fast dendritic cell vaccines for active immunotherapy of patients with AML" please visit: tiny.cc/12mtry

About Medigene’s DC vaccines: The platform for the development of antigen-tailored DC vaccines is the most advanced of Medigene’s highly innovative and complementary immunotherapy platforms. Currently Medigene evaluates its DC vaccines in a company-sponsored Phase I/II clinical trial in acute myeloid leukaemia (AML).

Dendritic cells (DCs) are the most potent antigen-presenting cells of our immune system. Their task is to take up, process and present antigens on their cell surface, which enables them to activate antigen-specific T cells for maturation and proliferation. This way T cells can recognize and eliminate antigen-bearing tumor cells. Dendritic cells can also induce natural killer cells (NK cells) to attack tumor cells. The team of Medigene Immunotherapies scientists has developed new, fast and effective methods for generating dendritic cells ex-vivo, which are able to activate both T cells and NK cells. The DC vaccines are developed from autologous (patient-derived) precursor cells, isolated from the patient’s blood, and can be loaded with tumor-specific antigens to treat different types of cancer. Medigene’s DC vaccines are in development for the treatment of minimal residual disease or for use in combination therapies.

About Medigene’s DC vaccine clinical trial: Medigene’s Phase I/II trial (NCT02405338) includes 20 AML patients who show complete remission after standard chemotherapy, but who are not eligible for stem cell transplantation that would reduce the risk of a relapse. All patients will be vaccinated with Medigene’s DC vaccines for two years. The primary objective is to assess safety and feasibility of the active immunotherapy with Medigene’s dendritic cells. Secondary objectives of the study are induction of immune responses, overall survival (OS), progression free survival (PFS), control of minimal residual disease (MRD) and time to progression (TTP).

About acute myeloid leukaemia (AML): Acute myeloid leukaemia is a malignant disease of the hematopoietic system, affecting mainly adults above 60 years of age. In Germany, about 3,600 incidences are registered annually.

AML is caused by uncontrolled growth of dysfunctional hematopoietic precursor cells in the bone marrow. These cells prevent the generation of normal blood cells, causing a drop in erythrocytes and platelets, for example. Typical symptoms of AML include anemia, fever, increased risk of infection, and blood coagulation disorder. AML progresses rapidly and may be fatal within a few weeks if untreated.

AML is treated initially with intensive chemotherapy. Another treatment option is allogeneic hematopoietic stem cell transplantation. Unfortunately, the majority of patients suffer a relapse. Only about 15 – 20% of the patients show long-term remission after conventional chemotherapy. Allogeneic hematopoietic stem cell transplantation is the only treatment option that offers a more positive prognosis.

Medigene AG (FSE: MDG1, ISIN DE000A1X3W00, Prime Standard, TecDAX) is a publicly listed biotechnology company headquartered in Martinsried near Munich, Germany. The company is developing highly innovative immunotherapies to target various forms and stages of cancer. Medigene concentrates on the development of personalized T cell-based therapies, with associated projects currently in pre-clinical and clinical development.