On April 19, 2018 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") (Press release, Shire, APR 19, 2018, View Source [SID1234525577]).

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.

This announcement is made without the consent of Takeda.

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]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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 The biopharmaceutical company MOLOGEN AG reported that it presented data of its EnanDIM molecules, a new generation of potent non chemically-modified TLR9 agonists, at the AACR (Free AACR Whitepaper) Annual Meeting 2018 (American Association for Cancer Research) in Chicago, Illinois, U.S. (14 – 18 April 2018) (Press release, Mologen, APR 19, 2018, View Source [SID1234525553]). In murine tumor models, monotherapy with EnanDIM resulted in beneficial modulation of the tumor microenvironment (TME) translating into remarkable anti-tumor effects with highly increased survival rates. In two cancer models complete tumor regression in the majority of mice was observed. Importantly, in a subsequent re-challenge study all surviving mice rejected tumor cells, which indicates a sustained anti-tumor memory of the immune system. Hence, the data provide an excellent basis for further development of EnanDIM in cancer.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The presented data clearly reveal the enormous potential of the EnanDIM product family. Hence, besides our late-stage candidate lefitolimod, we have strong follow-up molecules and we aim to enter EnanDIM into the clinical phase as soon as possible, of course depending on available resources", said Dr Mariola Soehngen, Chief Executive Officer of MOLOGEN.

"We are excited about the beneficial TME-modulating effects of single-agent EnanDIM which translated into remarkable anti-tumor activity, a clear pre-clinical proof of concept", said Dr Matthias Baumann, Chief Medical Officer at MOLOGEN, "and keep in mind that we have already promising pre-clinical results with EnanDIM and checkpoint inhibitors which have been presented last year. In summary, this is a clear "Go" for further development of EnanDIM in the IO space."

EnanDIM (Enantiomeric, DNA-based, ImmunoModulator), as a new generation of immunomodulators and so called Immune Surveillance Reactivators (ISR), belongs to the class of TLR9 agonists and represents one of MOLOGEN’s follow-up compounds to lefitolimod exhibiting an variable immunomodulatory pattern dependent on the specific EnanDIM molecule, a one-step production process.

The EnanDIM molecules consist entirely of natural DNA, as is also the case with lefitolimod. The main difference between MOLOGEN’s two ISR families is their molecule structure. Whereas lefitolimod is dumbbell-shaped and covalently-closed, EnanDIM molecules have a linear structure. However, as with lefitolimod, due to its specific structure, no chemical modification is needed in order to protect the molecules against degradation by enzymes.

Latest data on the EnanDIM molecules have been presented not only at the AACR (Free AACR Whitepaper) in Chicago, but also at the ITOC-5 Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Conference in Berlin (19 – 21 March 2018).

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]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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.

On April 19, 2018 Argos Therapeutics, Inc. (Nasdaq:ARGS), an immuno-oncology company focused on the development and commercialization of individualized immunotherapies based on the Arcelis precision immunotherapy technology platform, reported interim results from its randomized, active controlled, open-label, multi-center Phase 3 ADAPT trial of Rocapuldencel-T in combination with sunitinib/standard-of-care for the treatment of newly diagnosed metastatic renal cell carcinoma. Based on these results, the Company has decided to discontinue the trial (Press release, Argos Therapeutics, APR 19, 2018, View Source [SID1234525551]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

As previously reported, a total of 462 patients with previously untreated advanced or metastatic renal cell carcinoma were enrolled in the ADAPT trial and randomized 2:1 between combination treatment with Rocapuldencel-T and sunitinib (combination arm) vs. sunitinib monotherapy (control arm) after undergoing cytoreductive nephrectomy. The Company recently submitted a protocol amendment to the U.S. Food and Drug Administration providing for four co-primary endpoints focused on various measures of survival. Based upon review of the interim data, the Company does not believe that it would achieve these endpoints if the trial were to be continued. After consulting with the principal investigators of the trial, the Company has therefore decided to discontinue the trial and has informed the FDA of its decision.

The most recent interim analysis was conducted after 51 new events (deaths) had occurred since the time of the February 2017 interim analysis. Median overall survival for the intent-to-treat patient population, one of the four co-primary endpoints, was estimated using the Kaplan-Meier method. The estimated median overall survival for the combination arm was 28.2 months (95% Confidence Interval (CI): 23.4, 35.2) compared to 31.2 months (95% CI: 23.0, 44.5) for the control arm. The hazard ratio was 1.10 (95% CI: 0.85, 1.42). The two other co-primary endpoints that were evaluated at this time, including overall survival for the patients who remained alive at the time of the February 2017 interim analysis and overall survival for all patients for whom at least 12 months of follow-up was available, also did not demonstrate a favorable result. A fourth endpoint, five-year survival, was not evaluated because there was insufficient data at this time to perform this analysis.

Based on a review of the status of its internal programs, resources and capabilities, Argos plans to explore a wide range of strategic alternatives that may include a potential merger or sale of the Company, among other potential alternatives that could maximize both near and long-term value for our shareholders. The Company has retained Stifel, Nicolaus & Company, Incorporated to serve as its financial advisor in the process.

Argos does not have a defined timeline for the exploration of strategic alternatives and is not confirming that the process will result in any strategic alternative being announced or consummated. Argos does not intend to discuss or disclose further developments during this process unless and until its Board of Directors has approved a specific action or otherwise determined that further disclosure is appropriate.

Argos also today reported that it does not expect to regain compliance with The Nasdaq Capital Market continued listing requirements by the April 24, 2018 deadline. As a result, Argos expects that its common stock will be delisted from The Nasdaq Capital Market and that trading in the Company’s common stock on The Nasdaq Capital Market will be suspended effective at the open of business on April 23, 2018. The Company has filed an application to transfer trading and quotation of its common stock to the OTCQB Venture Market, operated by OTC Markets Group Inc., under its current trading symbol "ARGS," effective as of April 23, 2018. Quotation and trading information for the common stock will be available on www.otcmarkets.com.