Products in Clinical
Development and Discovery
Details on the status of the clinical pipeline products of Astex Pharmaceuticals™ follow.
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DACOGEN® (MDS)
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Dacogen—Hypomethylator (MDS)
Dacogen (decitabine) for Injection is a DNA hypomethylating agent currently approved for the treatment of myelodysplastic syndromes (MDS) in more than 30 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.
A 485-patient phase 3 trial in elderly patients with acute myelogenous leukemia has been completed and our partners have filed for regulatory approvals for this indication in both the United Stated and the European Union.
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.
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DACOGEN® (AML)
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Dacogen—Hypomethylator (AML)
Dacogen (decitabine) for Injection is a DNA hypomethylating agent currently approved for the treatment of myelodysplastic syndromes (MDS) in more than 30 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.
A 485-patient phase 3 trial in elderly patients with acute myelogenous leukemia has been completed and our partners have filed for regulatory approvals for this indication in both the United Stated and the European Union.
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.
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AT13387
+/-AT13387—Hsp90 inhibitor (GIST)
AT13387 is a small molecule inhibitor of Hsp90, a so called “Heat Shock” protein, believed to be responsible for supporting many tumor cells becoming cancerous. 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.
AT13387 is currently completing a phase 1 study designed to assess the safety and tolerability of AT13387 in patients with advanced refractory tumors. This study, which is investigating two different dosing schedules, is being conducted at multiple clinical sites in the USA. The study is also intended to provide early evidence of clinical efficacy.
Based upon the results of this initial phase 1 study, Astex Pharmaceuticals™ has initiated a phase 2 study in patients with refractory gastrointestinal stromal tumors (GIST).
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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SGI-110
+/-SGI-110—DNMT inhibitor (MDS + AML)
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 phase 1-2 clinical study has two parts, a Dose Escalation Segment and a Dose Expansion Segment. The Dose Escalation Segment seeks 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. Patients will be randomized to receive one of two dosing schedules of either a daily subcutaneous injection for 5 days or a single weekly subcutaneous injection for three injections, both in a 28-day cycle. The Dose Expansion Segment will include expansion of the number of patients treated at the selected dosing schedule 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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Amuvatinib/MP-470
+/-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).
Currently amuvatinib is in a clinical proof of concept ESCAPE phase 2 study, to include 21 to 50 patients. Patients are being screened and at least 16 centers will be participating globally.
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AT7519
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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.