Results from the Phase III INTEREST (IRESSA Non-small-cell lung cancer Trial Evaluating REsponse and Survival against Taxotere) study, published in the 22nd November edition of The Lancet (2008;372:1809-1818), have shown that patients with pretreated advanced non-small cell lung cancer (NSCLC) who received the oral anticancer drug, Iressa (gefitinib), had comparable survival to those treated with intravenous docetaxel. In addition, gefitinib had a more favourable tolerability profile than docetaxel and significantly more gefitinib-treated patients had an improvement in quality of life.
These results follow previous disappointing data for the drug in the ISEL (IRESSA Survival Evaluation in Lung cancer) study, where gefitinib failed to demonstrate a survival advantage versus placebo in NSCLC patients. This led to a severe restriction on the use of the drug in the US and also to AstraZeneca withdrawing its MAA in Europe. As such, gefitinib is not currently licensed in the EU, however on 2nd May, AstraZeneca submitted an MAA to the EMEA seeking approval as a treatment for locally-advanced or metastatic NSCLC patients pretreated with platinum chemotherapy (CT). The application is based on data from the INTEREST study and is the first time a targeted therapy, an EGFr tyrosine kinase inhibitor, has proven non-inferiority for overall survival (OS) relative to CT in patients with pretreated advanced NSCLC.
The INTEREST study was a randomised, open-label, parallel-group trial evaluating survival with gefitinib versus docetaxel in 1,466 patients with locally-advanced or metastatic recurrent NSCLC who had previously received platinum-based CT. Patients were randomly assigned to receive gefitinib (250mg/day; n=733) or docetaxel (75mg/m2; n=733). The primary objective was to compare OS between the groups with co-primary analyses to assess non-inferiority in the overall per-protocol population and superiority in patients with high EGFr-gene-copy number in the intention-to-treat population.
In the study, 1,433 patients were analysed per protocol (723 in the gefitinib group and 710 in the docetaxel group). Non-inferiority of gefitinib compared with docetaxel was confirmed for OS (593 vs 576 events; hazard ratio [HR]=1.02; 96% CI, 0.905 to 1.150, meeting the predefined non-inferiority criterion; median survival 7.6 vs 8.0 months). Superiority of gefitinib in patients with high EGFr-gene-copy number (85 vs 89 patients) was not proven (72 vs 71 events; HR=1.09; 95% CI, 0.78 to 1.51; p=0.62; median survival 8.4 vs 7.5 months).
Will these new data signal a resurrection for the drug? With such mixed results for gefitinib, it is hard to imagine doctors altering their prescribing habits on the basis of the INTEREST data alone, especially when there are many of other options available for treating LC patients. Tarceva (erlotinib), another EGFr inhibitor, is available, as is Avastin (bevacizumab), with more on the horizon, including Erbitux (cetuximab). One thing that could save gefitinb is the use of pharmacogenomics and a test to predict which patients would be suitable for treatment with the drug. However, this is an expensive and time-consuming undertaking, one that AstraZeneca may not see as financially rewarding or competitive as there are already EGFr inhibitors available, such as cetuximab and Vectibix (panitumumab), that are marketed alongside companion diagnostics. As such, INTEREST could be gefitinib’s final chance of success.
Matthew Dennis - Editor, Cancer Drug News
Thursday, November 27, 2008
Thursday, November 20, 2008
Targeted drugs reduce attrition rates
The results of a new study published in the 14th November online edition of Nature Reviews Drug Discovery (10.1038/nrd2758) suggest that advances in drug development have led to an increase in the number of drugs reaching cancer patients. Scientists from Cancer Research Technology (CRT; Cancer Research UK [CRUK]) obtained data on 974 cancer drugs in clinical development, and calculated that there was a probability that 18 per cent of those entering the clinic would make it to market. Previously it was estimated that in some studies only 5 per cent of cancer drugs in the pipeline become standard treatments for the disease.
The data search was limited to agents which entered Phase I trials after January 1995 and before September 2007, of which 137 are the molecularly-targeted drug class, kinase inhibitors. The research showed that kinase inhibitors were almost three-times more likely to reach patients than other types of anticancer drug. The investigators believe that a better understanding of the basic biology of cancer has enabled the development of this type of new drug, which includes Herceptin (trastuzumab) for breast cancer and Glivec/Gleevec (imatinib) for leukaemia.
The study highlights the fact that understanding more about the basic biology of cancer is making a real difference to the success rate of new anticancer drug development. Additionally, improved drug-discovery processes and advances in medicinal chemistry have also contributed to better success rates of drugs in development. Furthermore, better understanding of a patient's genetic make-up and how they will respond to certain drugs has led to improvements in clinical trial design.As drug development continues to advance, minimising the number of drugs which fail to make it to market will remain key as the cost of discovery and development of those drugs which do not reach market is borne by those that do. The true cost of a drug reaching the market has recently been estimated to be US$0.8 billion to US$1.0 billion.
According to one of the study authors, Professor Herbie Newell, Director of Translational Research at CRUK: "We strongly believe that both industry and academia must improve the availability of data related to failed as well as successful drug development programmes. The sharing of such information can only be beneficial for clinical, scientific and commercial reasons, and will help measure our progress as well as pinpoint areas for improvement."
Historically, the oncology pipeline has been largely made up of small-molecule cytotoxic drugs, which have a low therapeutic index and can fail in clinical trials due to toxicity or efficacy reasons. The recent explosion of information coming from work into understanding the molecular basis of cancer has led to an increase of drugs targeting specific pathways, drugs that are specifically designed to treat cancer, rather than randomly killing proliferating cells. As more information becomes available and newer drugs that are better targeted move into the pipeline, the attrition rate for cancer drugs may reach levels seen with other therapy areas, such as cardiovascular disease where 20 per cent of agents in development reach the market.
Matthew Dennis - Editor, Cancer Drug News
The data search was limited to agents which entered Phase I trials after January 1995 and before September 2007, of which 137 are the molecularly-targeted drug class, kinase inhibitors. The research showed that kinase inhibitors were almost three-times more likely to reach patients than other types of anticancer drug. The investigators believe that a better understanding of the basic biology of cancer has enabled the development of this type of new drug, which includes Herceptin (trastuzumab) for breast cancer and Glivec/Gleevec (imatinib) for leukaemia.
The study highlights the fact that understanding more about the basic biology of cancer is making a real difference to the success rate of new anticancer drug development. Additionally, improved drug-discovery processes and advances in medicinal chemistry have also contributed to better success rates of drugs in development. Furthermore, better understanding of a patient's genetic make-up and how they will respond to certain drugs has led to improvements in clinical trial design.As drug development continues to advance, minimising the number of drugs which fail to make it to market will remain key as the cost of discovery and development of those drugs which do not reach market is borne by those that do. The true cost of a drug reaching the market has recently been estimated to be US$0.8 billion to US$1.0 billion.
According to one of the study authors, Professor Herbie Newell, Director of Translational Research at CRUK: "We strongly believe that both industry and academia must improve the availability of data related to failed as well as successful drug development programmes. The sharing of such information can only be beneficial for clinical, scientific and commercial reasons, and will help measure our progress as well as pinpoint areas for improvement."
Historically, the oncology pipeline has been largely made up of small-molecule cytotoxic drugs, which have a low therapeutic index and can fail in clinical trials due to toxicity or efficacy reasons. The recent explosion of information coming from work into understanding the molecular basis of cancer has led to an increase of drugs targeting specific pathways, drugs that are specifically designed to treat cancer, rather than randomly killing proliferating cells. As more information becomes available and newer drugs that are better targeted move into the pipeline, the attrition rate for cancer drugs may reach levels seen with other therapy areas, such as cardiovascular disease where 20 per cent of agents in development reach the market.
Matthew Dennis - Editor, Cancer Drug News
Wednesday, November 5, 2008
MethylGene cuts staff
Celgene has terminated its licensing agreement with MethylGene for oncology histone deacetylase (HDAC) inhibitors, including MGCD0103. As a result, MethylGene will reacquire all rights to MGCD0103 and other HDAC and sirtuin inhibitors in territories licensed to Celgene including North America and the EU. As part of the termination provisions, Celgene will continue to support MGCD0103 for a period of 90 days to ensure a smooth transition. As a results of this, MethylGene will implement a strategic initiative to focus its resources on the clinical development of its proprietary pipeline.
In August, the FDA placed a partial clinical hold on MGCD0103 studies as a result of the voluntary suspension of enrolment of new patients into trials evaluating the drug following observations of pericarditis or pericardial effusion in 19 subjects out of approximately 400 patients treated. Under the partial clinical hold, patients currently enrolled in MGCD0103 trials who are confirmed to have no signs or symptoms of pericarditis or pericardial effusion may continue in their respective studies. MethylGene believes that regaining exclusive rights to MGCD0103 will allow it to accelerate submissions to the FDA aimed at lifting the partial clinical hold.
The termination of the agreement does not affect MethylGene's relationship with Taiho Pharmaceutical for Japan and certain other Asian countries. Celgene acquired the rights to MGCD0103 through its March 2008 acquisition of Pharmion. MethylGene now owns the worldwide rights to three compounds, MGCD0103 (with the exception of certain Asian territories), MGCD265 and MGCD290, all of which are at various stages of clinical development.
MethylGene also announced that after a review of the company's current research, development and business activities, it will focus on advancing its clinical pipeline, which represents the most attractive, near-term value-generating opportunities. Accordingly, the company will begin a process to discontinue its discovery research activities, including a phased workforce reduction. The first phase of the reduction will occur over the next two months with additional reductions planned during 2009 as funded discovery research with Celgene for sirtuin inhibitors for cancer and with Otsuka Pharmaceutical for kinase inhibitors for ocular diseases are concluded. It is expected that approximately half of the company's current staff of 109 full-time employees will be affected by the transition when completed as planned.
With the implementation of this initiative, it is estimated that MethylGene will have sufficient resources to carry out currently-planned development and operational activities into approximately the third quarter of 2010. These plans include the continuing development of MGCD265 into Phase II trials, MGCD290 through Phase I studies and pursuing the removal of the partial clinical hold on MGCD0103. MethylGene will evaluate progressing MGCD290 into Phase II trials after reviewing Phase I data and evaluating potential partnerships and/or additional funding requirements. The company will also evaluate the status of MGCD0103 once the compound is released from partial clinical hold.
Matthew Dennis - Editor, Cancer Drug News
In August, the FDA placed a partial clinical hold on MGCD0103 studies as a result of the voluntary suspension of enrolment of new patients into trials evaluating the drug following observations of pericarditis or pericardial effusion in 19 subjects out of approximately 400 patients treated. Under the partial clinical hold, patients currently enrolled in MGCD0103 trials who are confirmed to have no signs or symptoms of pericarditis or pericardial effusion may continue in their respective studies. MethylGene believes that regaining exclusive rights to MGCD0103 will allow it to accelerate submissions to the FDA aimed at lifting the partial clinical hold.
The termination of the agreement does not affect MethylGene's relationship with Taiho Pharmaceutical for Japan and certain other Asian countries. Celgene acquired the rights to MGCD0103 through its March 2008 acquisition of Pharmion. MethylGene now owns the worldwide rights to three compounds, MGCD0103 (with the exception of certain Asian territories), MGCD265 and MGCD290, all of which are at various stages of clinical development.
MethylGene also announced that after a review of the company's current research, development and business activities, it will focus on advancing its clinical pipeline, which represents the most attractive, near-term value-generating opportunities. Accordingly, the company will begin a process to discontinue its discovery research activities, including a phased workforce reduction. The first phase of the reduction will occur over the next two months with additional reductions planned during 2009 as funded discovery research with Celgene for sirtuin inhibitors for cancer and with Otsuka Pharmaceutical for kinase inhibitors for ocular diseases are concluded. It is expected that approximately half of the company's current staff of 109 full-time employees will be affected by the transition when completed as planned.
With the implementation of this initiative, it is estimated that MethylGene will have sufficient resources to carry out currently-planned development and operational activities into approximately the third quarter of 2010. These plans include the continuing development of MGCD265 into Phase II trials, MGCD290 through Phase I studies and pursuing the removal of the partial clinical hold on MGCD0103. MethylGene will evaluate progressing MGCD290 into Phase II trials after reviewing Phase I data and evaluating potential partnerships and/or additional funding requirements. The company will also evaluate the status of MGCD0103 once the compound is released from partial clinical hold.
Matthew Dennis - Editor, Cancer Drug News
Subscribe to:
Posts (Atom)