On October 26, 2016 Evotec AG (Frankfurt Stock Exchange, Prime Standard, ISIN: DE 000 566480 9, WKN 566480) reported that it has made an offer to acquire Cyprotex PLC (AIM Listing: CRX-GB), a specialist pre-clinical contract research organisation in ADME-Tox and DMPK headquartered in UK (Press release, Evotec, OCT 26, 2016, View Source [SID1234516093]). The proposed acquisition, which has been unanimously recommended by the board of Cyprotex, is expected to close before year-end 2016.

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Evotec will pay approximately £ 55.36 m (EUR 62.00 m; £/EUR exchange rate of 1.12) in cash for the acquisition of all 26.1 million issued and to be issued Cyprotex shares and the funding of all existing company debt. The offer of 1.60 £ per Cyprotex share reflects a 9.4% premium to the VWAP of the past 30 trading days at AIM. The offer is intended to be implemented by a scheme of arrangement regulated by the UK takeover code, with already >50% shares secured irrevocable.

On October 26, 2016 Nordic Nanovector ASA (OSE: NANO), reported has entered into a collaboration with Heidelberg Pharma GmbH, a subsidiary of biopharmaceutical company WILEX AG (FSE: WL6) specializing in the development of antibody-drug conjugates (ADCs), to develop novel ADCs for treating leukaemias (Press release, Nordic Nanovector, OCT 26, 2016, View Source [SID1234516028]). Leukaemias are orphan diseases with a significant unmet medical need, applicable indications representing a growing market worth over USD 5 billion by 2020.

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This collaboration is part of Nordic Nanovector’s strategy to develop its pipeline of targeted therapies to include antibody products conjugated to anti-cancer compounds that are not radionuclides. Such conjugates are commonly referred to as ADCs.

Jostein Dahle, Nordic Nanovector’s Chief Scientific Officer, commented: "We are pleased to further expand our R&D activities into the ADC area with Heidelberg Pharma in this second strategic collaboration, following closely the collaboration announced recently with LegoChem. During the past year, we have made important steps to execute our strategy designed to build a pipeline of innovative antibody-radionuclide conjugates (ARCs) and ADCs that combine our expertise and platform with complementary technologies from expert partners. This strategy is aimed at creating multiple new targeted treatment options for patients who suffer a range of leukaemias and lymphomas."

Professor Dr Andreas Pahl, Head of Research & Development and member of the Management Board of WILEX and Heidelberg Pharma, commented: "This project extends our portfolio of ADCs to further haematological cancers. Nordic Nanovector has an established chemistry, manufacturing, and controls (CMC) process for their antibody which will speed up processes and reduce the development costs of an ADC."

On October 26, 2016 Moleculin Biotech, Inc., (NASDAQ: MBRX) ("Moleculin" or the "Company"), a preclinical and clinical-stage pharmaceutical company focused on the development of anti-cancer drug candidates, some of which are based on license agreements with The University of Texas System on behalf of the M.D. Anderson Cancer Center, reported promising initial results of the preclinical toxicology work that has begun for WP1122, a unique inhibitor of glucose metabolism, which is an important driver of glycolytic brain tumor progression and survival (Press release, Moleculin, OCT 26, 2016, View Source [SID1234516024]).

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The Company indicated that preliminary escalating single dose toxicity testing in mice (oral administration) was successfully completed and even at the highest possible dose, no toxic death was observed. In multiple therapeutic doses, WP1122 was well tolerated during intense twice-daily oral dosing. The Company plans to move forward with completing the preclinical toxicology package in order to generate proof of concept in humans.

Moleculin’s Chairman and CEO, Walter Klemp, commented, "As the newest of our technologies, we are pleased to see development work move to the next level. WP1122 has received significant attention from the scientific community as a promising new approach to treating brain tumors. Part of the excitement relates to the unusual nature of WP1122 and its design allowing for high brain uptake and retention. The design uses an alteration similar to that which turns morphine into heroine and enables rapid brain uptake. A similar alteration to our drug allows it to successfully enter the brain in high quantities and increases its circulation time."

Prior to this announcement, the Company had previously announced the presentation of promising preclinical data in July of this year (Moleculin Announces Data on WP1122 Presented at the 28th Annual International Carbohydrate Symposium), supporting the potential for using WP1122 as a treatment for glioblastoma.

No curative therapy exists for patients with high-grade brain tumors and new approaches to the treatment of this disease are urgently needed. One new approach to tackling this problem has been to focus on shutting down the metabolism of tumor cells, which can be highly dependent on glucose for continued survival and proliferation. WP1122 has been shown both in vitro and in vivo to induce a destruction of glioma cells, the most aggressive form of brain tumor, by essentially "starving" them. Its translational potential as a drug for brain tumors in general and glioma in particular is promising due to its improved circulation time as well as its increased brain uptake.

On October 26, 2016 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH), reported encouraging preliminary safety and clinical activity results from the dose-escalation part of the Phase I study testing IPH4102 in patients with relapsed/refractory cutaneous T-cell lymphomas ("CTCL"), an orphan disease (Press release, Innate Pharma, OCT 26, 2016, View Source [SID1234516012]). IPH4102 is Innate Pharma’s wholly-owned, first-in-class anti-KIR3DL2 humanized therapeutic antibody, designed to trigger immune cell-mediated killing of CTCL cancer cells.

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These data are presented in a poster at the Third World Congress of Cutaneous Lymphomas (October 26-28, 2016, New-York, USA) and will be discussed by the Principal Investigator, Professor Martine Bagot, Head of the Department of Dermatology at Saint-Louis Hospital (Paris) in the Scientific Session "Endpoints & Clinical Trials" on October 28, 2016, 1:30 – 2:45 p.m. EST.

The Phase I study is currently ongoing. Data are reported for the first seven dose levels (0.0001 to 1.5 mg/kg, 16 patients) of the dose-escalation part. In this population, IPH4102 was well-tolerated with no dose-limiting toxicity reported. The majority of adverse events is typical for CTCL or reflects low grade infusion-related reactions. As of September 10, 2016, the best global response rate was 38% across all dosage levels. Complete responses appeared with increasing doses and/or duration of exposure in skin and blood (respectively 2 and 3, seen in 4 patients)[1]. All responses are ongoing at the time of the analysis, which occurred after a median duration of treatment of 126+ days (range of 41+ to 298+).

Three additional dose levels (3, 6 and 10 mg/kg) remain to be evaluated and the dose escalation part of the trial is now expected to be completed by Q2 2017 (previously expected at the end of 2017).

"These preliminary results are very encouraging and fully support the continuation of the development of the antibody candidate. By targeting KIR3DL2 on CTCL cells and triggering their killing by immune effector cells, IPH4102 has the potential to deliver a new treatment option for patients in high medical need at advanced stages of the disease," said Pierre Dodion, Chief Medical Officer of Innate Pharma. "The development of IPH4102 benefits from long lasting collaborations with Saint Louis Hospital in Paris and reference centers, such as Stanford (US). Together we look forward to the complete safety data of the dose-escalation part of the trial and commencing cohort expansion of this new drug candidate, which is wholly-owned by Innate Pharma."

Martine Bagot, Principal Investigator and Head of the Dermatology Department at the Saint-Louis Hospital, Paris, added: "This study offers preliminary safety and efficacy results that are promising for IPH4102, in patients with CTCL subtypes that historically have been shown to be particularly difficult to treat. We are delighted with the progress that has been made with this candidate through translational research and an exceptional academic-industrial partnership."



The study started enrolling patients in November 2015. So far, 16 patients with KIR3DL2-positive CTCL have been enrolled in seven dose-cohorts, including 13 patients with Sézary syndrome, 2 patients with mycosis fungoides and 1 patient with CD4+ CTCL. Median age was 71 years and patients had received 2 to 8 lines of prior systemic therapy for their disease.

All of the 16 patients treated with IPH4102 were evaluable for safety and clinical activity assessments.

As of September 10, 2016, patients had received up to 18 administrations of IPH4102. Treatment is ongoing in 12 patients. Preliminary results of exploratory endpoints such as pharmacodynamics in skin and blood are in line with clinical activity results (see poster #O-11), and show depletion of KIR3DL2-expressing tumor cells in skin and blood of patients after IPH4102 administrations.



Presentation/ Poster Details

The oral presentation, entitled "First-in-Human, open label, multicenter phase I study of IPH4102, first-in-class humanized anti-KIR3DL2 mAb, in relapsed/refractory CTCL: preliminary safety and clinical activity results" will take place on October 28, 2016, 1:30 – 2:45 p.m. EST. It will be available on the Company’s website, in the Product Pipeline – IPH4102 section following the session. The associated poster is displayed during the entire congress and is available on Innate Pharma’s website.

Simultaneously, poster #O-11 entitled "First-in-Human, open label, multicenter phase I study of IPH4102, first-in-class humanized anti-KIR3DL2 mAb, in relapsed/refractory CTCL: preliminary results of exploratory biomarkers" has been presented by Hélène Sicard, Anne Marie-Cardine and Maxime Battistella and is available on Innate Pharma’s website under Product Pipeline – IPH4102.

On October 26, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) reported the publication of preclinical data on brigatinib, its investigational oral tyrosine kinase inhibitor in development for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) metastatic non-small cell lung cancer (NSCLC) (Press release, Ariad, OCT 26, 2016, View Source [SID1234516007]). The design and preclinical characterization of brigatinib are described in an article titled, "The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models," in the journal Clinical Cancer Research (Zhang, S.; et al. Clin Cancer Res. 2016, DOI: 10.1158/1078-0432.CCR-16-0569 Published 25 October 2016).

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Activating gene rearrangements in ALK account for approximately three to seven percent of NSCLCs. Disease progression in patients treated with the first-generation ALK inhibitor crizotinib can be associated with secondary resistance mutations in ALK, or the development of brain metastases. Resistance mutations in ALK, including G1202R, have also been associated with disease progression in patients treated with the second-generation ALK inhibitors ceritinib and alectinib. In the preclinical studies described in the paper, brigatinib was shown to be a highly potent and selective inhibitor of ALK, inhibiting ALK at lower concentrations than crizotinib, ceritinib, and alectinib. Furthermore, in these studies, brigatinib was the only inhibitor that showed activity against all 17 tested ALK mutants that have been associated with preclinical or clinical resistance to existing ALK inhibitors, including G1202R. In addition, compared to crizotinib, brigatinib was shown to significantly prolong survival of mice with ALK+ tumors in the brain.

"We believe that these preclinical findings support a molecular basis for the promising systemic and intracranial activity in ALK+, crizotinib-resistant NSCLC patients being treated with brigatinib in clinical trials and further validate our ongoing clinical research to understand the potential of brigatinib to address mutations associated with disease progression," said Victor M. Rivera, Ph.D., vice president of preclinical & translational research at ARIAD. "In addition, we believe that these findings support testing brigatinib as initial therapy in ALK+ NSCLC patients, to see if the greater in vitro potency of brigatinib also manifests in human trials as deeper and more durable responses compared to crizotinib, and whether emergence of ALK resistance mutations can be delayed or even circumvented."

ARIAD has commenced the Phase 3 ALTA 1L clinical trial to compare brigatinib and crizotinib in ALK+ NSCLC patients who have not received prior ALK inhibitors.

Brigatinib Medicinal Chemistry Publication

In addition, the medicinal chemistry strategy leading to the discovery of brigatinib was published in an article titled, "Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase," in the Journal of Medicinal Chemistry, (Huang, W.-S.; et al. J. Med. Chem. 2016, 59, DOI: 10.1021/acs.jmedchem.6b00306).

"This publication details, for the first time, specific design elements that ARIAD scientists utilized in synthesizing brigatinib. Brigatinib features an innovative phosphine oxide recognition motif that is designed to enhance potency and selectivity while also conferring favorable pharmacologic properties," said William C. Shakespeare, Ph.D., vice president of drug discovery at ARIAD. "Brigatinib is the only phosphine oxide-containing molecule to have advanced to late stage clinical trials, showcasing how our innovative chemistry platform can deliver novel drug candidates designed to tackle challenging clinical problems."

About Non-Small Cell Lung Cancer and ALK

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85 percent of the estimated 228,190 new cases of lung cancer diagnosed each year in the United States, according to the American Cancer Society. Anaplastic lymphoma kinase (ALK) was first identified as a chromosomal rearrangement in anaplastic large-cell lymphoma (ALCL). Genetic studies indicate that chromosomal rearrangements in ALK are key drivers in a subset of NSCLC patients as well. Since ALK is generally not expressed in normal adult tissues, we believe that it represents a promising molecular target for cancer therapy. Approximately three to eight percent of patients with NSCLC have a rearrangement in the ALK gene.

About Brigatinib

Brigatinib is an investigational, targeted cancer medicine discovered internally at ARIAD Pharmaceuticals, Inc. It is in development for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) whose disease is resistant or intolerant to crizotinib. Brigatinib is currently being evaluated in the global Phase 2 ALTA trial that is the basis for its initial regulatory review. ARIAD has also initiated the Phase 3 ALTA 1L trial to assess the efficacy and safety of brigatinib in comparison to crizotinib in patients with locally advanced or metastatic ALK+ NSCLC who have not received prior treatment with an ALK inhibitor. More information on brigatinib clinical trials, including the expanded access program (EAP) for ALK+ NSCLC can be found here.