Details on the status of the Astex Pharmaceuticals™ pipeline follow.

  • DACOGEN® – Hypomethylator (MDS)

    Eisai Janssen

    Dacogen—Hypomethylator (MDS)

    Dacogen (decitabine) for Injection is a DNA hypomethylating agent currently approved for the treatment of myelodysplastic syndromes (MDS) in more than 35 countries worldwide including key markets such as the United States, Brazil, China, India, Russia and Turkey.

    Eisai Inc. manages the product rights in the United States, Canada and Mexico and Janssen-Cilag International NV and other affiliates of Cilag GmbH International manage the marketing and development rights for Dacogen in all other markets. Janssen-Cilag International NV is one of the Janssen Pharmaceutical Companies of Johnson & Johnson.

    Dacogen is approved in selected markets for treatment of patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS of all French-American-British (FAB) subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, chronic myelomonocytic leukemia), and Intermediate-1, Intermediate-2 and High-Risk International Prognostic Scoring System (IPSS) groups.

    Important Safety Information

    Treatment with Dacogen is associated with neutropenia and thrombocytopenia. Complete blood and platelet counts should be performed as needed to monitor response and toxicity but at a minimum prior to each dosing cycle. After administration of the recommended dosage for the first cycle, treatment for subsequent cycles should be adjusted if indicated by dose adjustment guidelines. Clinicians should consider the need for early institution of growth factors and/or antimicrobial agents for the prevention or treatment of infections in patients with MDS.

    Dacogen may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Dacogen and for 1 month following completion of treatment. Women of childbearing potential should be counseled to use effective contraception during this time. Men should be advised not to father a child while receiving treatment with Dacogen and for 2 months following completion of treatment. Dacogen may cause fetal harm. Men with female partners of childbearing potential should use effective contraception during this time.

    Other commonly occurring reactions include fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia.

    If hematologic recovery from a previous Dacogen treatment cycle requires more than 6 weeks when administering the 3-day dosing, then the next Dacogen cycle should be delayed and dosing temporarily reduced. When administering the 5-day dosing, the Dacogen cycle should be delayed until there is hematologic recovery. If the following nonhematologic toxicities are present, Dacogen treatment should not be restarted until the toxicity is resolved: (1) serum creatinine greater-than or equal to 2 mg/dL; (2) SGPt, total bilirubin greater-than or equal to 2 × ULN; and (3) active or uncontrolled infection.

    Because there are no data on use of Dacogen in patients with renal or hepatic dysfunction, Dacogen should be used with caution in these patients.

    For Dacogen full prescribing information, please click here.

  • DACOGEN® – Hypomethylator (Elderly AML)

    Eisai Janssen

    Dacogen (decitabine) for Injection is a DNA hypomethylating agent currently approved in the European Union (EU) for the treatment of adult patients (age 65 years and above) with newly diagnosed de novo or secondary acute myeloid leukemia (AML), according to the World Health Organization (WHO) classification, who are not candidates for standard induction chemotherapy. DACOGEN® also has Orphan Drug designation for the treatment of AML.

    Eisai Inc. manages the product rights in the United States, Canada and Mexico and Janssen-Cilag International NV and other affiliates of Cilag GmbH International manage the marketing and development rights for Dacogen in all other markets. Janssen-Cilag International NV is one of the Janssen Pharmaceutical Companies of Johnson & Johnson.

    The primary clinical study of DACOGEN® in AML was DACO-016. DACO-016, with 485 study subjects, is the largest AML trial to date in older patients. It was a Phase III, randomized, open-label trial, in newly diagnosed patients ≥65 years of age with de novo or secondary AML and poor- or intermediate-risk cytogenetics. Patients were enrolled globally at 65 clinical sites. Of the 485 patients, 242 were randomized to decitabine and 243 to patient's treatment choice of supportive care or low-dose cytarabine (majority of patients, 88%). Patients treated with decitabine received a 1-hour infusion, once daily for 5 consecutive days every 4 weeks. Patients treated with cytarabine received 20 mg/m2 subcutaneously once daily 10 consecutive days every 4 weeks. The median duration of treatment for patients on decitabine arm was 4.4 months, compared with 2.4 months in the cytarabine group.ii

    Adverse events (AEs) were consistent with the known decitabine safety profile and without major differences between the treatment arms. The most frequently reported Grade 3 or 4 hematologic AEs were thrombocytopenia, anemia, neutropenia, and febrile neutropenia.1

    For more information please see the European Summary of Public Information.

    Dacogen is not approved for AML in the US. For full US prescribing information, please click here.


    1Kantarjian HM et al, Multicenter, Randomized, Open-Label, Phase III Trial of Decitabine Versus Patient Choice, With Physician Advice, of Either Supportive Care or Low-Dose Cytarabine for the Treatment of Older Patients With Newly Diagnosed Acute Myeloid Leukemia, Journal of Clinical Oncology, 2012.

  • AT13387 – HSP90 inhibitor (Prostate & Lung)

    AT13387—Hsp90 inhibitor (GIST, Prostate & Lung)

    AT13387 is a small molecule inhibitor of Hsp90, a so called “Heat Shock” protein, believed to support the growth and proliferation of many cancer cells. Hsp90 acts as a “molecular chaperone” stabilizing and preventing the breakdown of key cancer-forming (oncogenic) proteins. These client proteins and their association with different tumor types include HER2 (the target for Herceptin® in breast cancer), the androgen receptor (the target for hormone therapy in prostate cancer), mutant B-raf (melanoma), c-kit (the target for Gleevec® in gastrointestinal tumors) and mutant EGFr (the target for Tarceva® and Iressa® in the treatment of non small cell lung cancers).

    Although AT13387 is a targeted inhibitor of Hsp90, the functional role of Hsp90 means the product has the potential to control the proliferation of multiple solid tumors and hematological malignancies where uncontrolled cell growth is dependent on the interaction between Hsp90 and its client proteins. These include tumor types that have become resistant to initial therapy.

    Based upon the results of this initial phase 1 study, Astex Pharmaceuticals has initiated phase 2 studies in patients with refractory gastrointestinal stromal tumors (GIST), Castration Resistant Prostate Cancer (CRPC) and ALK positive Lung Cancer.

    In November 2009, Astex Pharmaceuticals entered into a CRADA with the US National Cancer Institute (NCI) to support the further clinical development of AT13387 over the next 5 years with a number of single agent and combination phase 1/2a and phase 2 studies planned.

    AT13387 is wholly owned by Astex Pharmaceuticals.

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  • SGI110 – DNMT inhibitor (MDS, AML, Ovarian & Liver)

    SGI-110—DNMT inhibitor (MDS, AML, Ovarian & Liver)

    SGI-110 is a small molecule, DNA-hypomethyating agent with demonstrated activity in restoring silenced tumor suppressor gene expression in cancer cells by reversal of DNA methylation. A follow-up to the decitabine franchise of Astex Pharmaceuticals™, SGI-110 is currently in a first-in-human phase 1-2 clinical trial in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients. Astex Pharmaceuticals is working with several cancer centers and clinical investigators of the Stand Up to Cancer Epigenetics Dream Team on SGI-110.

    The clinical study has two parts, Dose Escalation and Dose Expansion. The Dose Escalation Part is complete and was designed to evaluate the biological activity, preliminary safety, and efficacy of SGI-110 with two dosing schedules in relapsed or refractory MDS or relapsed or refractory AML subjects. The Dose Expansion Part is ongoing and includes patients randomized to receive either the biologically effective dose or maximum tolerated dose to better evaluate both efficacy and safety in MDS and AML patients.

    SGI-110 is a second generation agent intended to follow up on the Company's currently marketed product, DACOGEN® (decitabine) for Injection that is licensed and marketed by Eisai and Cilag GmbH International, a member of the Johnson & Johnson family of companies.

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  • ASTX727 – Oral HMA (MDS)

    ASTX727 - Oral HMA (MDS)

    ASTX727 is intended as a fixed dose oral combination product consisting of decitabine and E7727, a novel cytidine deaminase inhibitor (CDAi) licensed from Eisai Inc.  ASTX727 allows for an efficient oral delivery of decitabine at low doses.  Relevant animal studies revealed that the product can result in therapeutic exposures of decitabine at low doses.  The profile of E7727 is expected to result in low inter-patient variability across doses of decitabine with little or no gastrointestinal safety issues.

    Cytidine deaminase (CDA) is an enzyme that is responsible for the degradation of nucleosides, including decitabine and azacitidine.  High levels of CDA in the gastrointestinal tract and liver rapidly degrade these nucleosides and prohibit or limit their oral bioavailability.  E7727 is a proprietary and patented New Molecular Entity (NME) with a very wide therapeutic margin that inhibits CDA activity.

    Decitabine can be delivered orally and efficiently absorbed in the gut when it is combined with E7727 due to the inhibition of CDA by E7727.  ASTX727 is being developed as a fixed dose oral product that combines E7727 and decitabine.  This oral HMA with the potential to be best-in-class will enter clinical development in 2014.  Astex has a worldwide license to E7727 from Eisai Inc.

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  • Amuvatinib/MP470 (SCLC)

    Amuvatinib/MP-470 (SCLC)

    Amuvatinib (MP-470) targets cancer cells by disrupting DNA repair, an important survival pathway in many human cancers. Amuvatinib is a tyrosine kinase inhibitor active against several cancer targets including mutant c-Kit and PDGFRα. This agent inhibits DNA repair machinery and has synergy when given in combination with platinum chemotherapy drugs. Amuvatinib has a wide therapeutic window and shows little-to-no toxicity in the expected therapeutic dose range, despite suppressing several signaling pathways within cells.

    Amuvatinib has completed two phase 1 studies, totaling 122 patients. It has a good safety profile both as single agent and in combination with different chemotherapy regimens, including platinum, taxol, and etoposide. No overlapping toxicity with chemotherapy has been observed. There is a good efficacy signal in small cell lung cancer and neuroendocrine tumors in combination with platinum/etoposide (VP-16).

    Additionally amuvatinib has completed the first part of a clinical proof of concept ESCAPE phase 2 study in small cell lung cancer (SCLC). The study was not approved to advance to the second part of the study.

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  • AT7519 – CDK inhibitor (MM)


    AT7519—CDK inhibitor (MM)

    AT7519 is a small molecule targeted inhibitor of several cyclin-dependent kinases that regulate two important disease processes: the cell replication cycle and gene expression. The normal regulation of the cell cycle is disrupted in all cancers allowing the uncontrolled tissue growth characteristic of the disease. CDKs 1 and 2 act as key controls of the cell cycle, and the inhibition of these enzymes both prevents cell proliferation and initiates cell death. AT7519 is an inhibitor of both CDK1 and 2 and in preclinical testing induces tumor shrinkage in multiple animal models of cancer.

    In addition to its direct effects on the cell cycle, AT7519 is also a potent inhibitor of RNA polymerase Ⅱ–dependent transcription. This activity results from inhibition by AT7519 of another cyclin-dependent kinase, CDK9. The survival of several tumor types is very dependent on the cellular levels of certain anti-apoptotic proteins (eg, Mcl-1), which require RNA polymerase II activity for their generation. This is true for hematological malignancies in particular (eg, CLL and AML) and AT7519 has been found to induce rapid cell death in leukemia cell lines and tumor shrinkage in relevant animal models.

    Astex Pharmaceuticals has investigated AT7519 in two phase 1 clinical trials, evaluating different dosing regimens of AT7519 as monotherapy in patients with advanced solid tumors. These studies were conducted at multiple sites in the UK, USA and Canada. Evidence of clinical activity was observed in these trials. A phase 2 study of AT7519 in combination with bortezomib in patients with multiple myeloma has commenced at multiple centers in the US with funding support from the Multiple Myeloma Research Foundation. In addition two phase 2 trials of AT7519 to treat patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are starting, sponsored by the NCIC Clinical Trials Group in Canada.

    Novartis has an option to develop and commercialize AT7519.

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  • AT9283 – JAK/Aurora inhibitor (MM)

    AT9283—Aurora/Jak2 inhibitor (MM)

    AT9283 is a small molecule inhibitor of kinases including aurora A and B, and JAK2. Initial clinical trials have demonstrated early signals of efficacy in patients with hematological malignancies.

    Solid tumors

    AT9283 has been investigated as monotherapy in patients with advanced solid tumors in two phase 1, open-label, dose-escalation trials at centers in the UK, USA and Canada. The two trials confirmed AT9283 is safe and well tolerated in patients with advanced solid malignancies. Oral bioavailability of AT9283 in humans has also been demonstrated. In conjunction with Cancer Research UK, Astex Pharmaceuticals is also investigating the activity of single agent AT9283 in pediatric patients with solid tumors in a trial being conducted at multiple sites in the UK. The study is closed to enrollment, but patients are still receiving therapy.

    Hematological malignancies

    AT9283 has been investigated in a phase 1/2 open-label, dose-escalation trial to assess the safety, tolerability and preliminary efficacy of AT9283 as monotherapy in patients with acute leukemia. The trial was conducted at centers in the USA. AT9283 is also being investigated in a phase 2 setting in a chemotherapy refractory, multiple myeloma patient population in a trial being sponsored by the NCIC Clinical Trials Group in Canada. An additional pediatric leukemia trial being sponsored by Cancer Research UK is due to begin during 2011. To learn more about the development status of this compound, please see the most recent Astex Pharmaceuticals presentations.

    AT9283 is wholly owned by Astex Pharmaceuticals.

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  • AT13148 – AGC kinase inhibitor

    Cancer Research UK

    AT13148 – AGC kinase inhibitor

    AT13148 is an orally active small molecule inhibitor of PKB/Akt and p70S6 kinase, key enzymes in the PI3K/PKB/mTOR tumor cell survival pathway. More than 50 percent of all tumors have an abnormality in this pathway leading to increased Akt activity and enhanced potential for tumor cell survival. In addition, clinical trials have highlighted that activation of this survival pathway is a common resistance mechanism for some cytotoxics (for example, platinum agents) and targeted therapies (for example, BRAF and EGFr inhibitors). By targeting the pathway at two key steps, AT13148 has the potential to be a very effective inhibitor of AKT dependent tumors. PKB inhibitors such as AT13148 have potential for use as both single agents and in combination with cytotoxics and other molecularly targeted agents in the treatment of a range of solid tumors.

    Astex Pharmaceuticals' PKB inhibitor program began in 2003 through a collaboration with The Institute of Cancer Research (ICR) and Cancer Research Technology Limited (CRT) and the program was later partnered with AstraZeneca in 2005. AstraZeneca started clinical trials of a clinical candidate, AZD5363, in April 2011. Astex retained rights to a second chemical series based on research carried out under the original agreement between Astex, ICR and CRT, and AT13148 was selected from this series. Astex retains all commercial rights for AT13148. At the same time, Astex, the ICR and CRT are eligible to receive further milestones and royalties during clinical development and commercialization of AZD5363.

    In September 2008 Astex announced a partnership with Cancer Research UK and CRT to take AT13148 into development under the charity's Clinical Development Partnerships (CDP) program. Under the terms of this agreement, Cancer Research UK's Drug Development Office has carried out further development work on the agent, some of which is done in collaboration with the ICR. CRUK has commenced phase 1 clinical trials of AT13148 at the Royal Marsden Hospital in the UK.

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