As the year draws to a close, there is just time to reflect on the past 12 months and to highlight those companies and drugs that have triumphed and failed. With only seven major new drug approvals in the US and Europe, compared to 11 in 2007, it would seem that the pharmaceutical industry and regulators are suffering from the knock-on effects of the current financial climate, where prudence is now key.
The year got off to a good start, when in January the EC granted marketing approval to Abraxis BioScience's Abraxane (paclitaxel protein-bound particles for injectable suspension; albumin-bound) for the treatment of metastatic breast cancer in patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline-containing therapy is not indicated. The first US approval came in the form of Cephalon's Treanda (bendamustine) for Injection, for the treatment of patients with chronic lymphocytic leukaemia (CLL) in March. Later in the year, the FDA also approved bendamustine for the treatment of patients with indolent B-cell non-Hodgkin's lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. In October, the EC granted a full marketing authorisation, in the form of a positive Commission Decision, for EpiCept's Ceplene (histamine dihydrochloride) for the remission maintenance and prevention of relapse in adult patients with acute myeloid leukaemia in first remission.
The major winners of 2008 were definitely in the field of supportive care for cancer. In January, the EC and FDA approved Merck & Co's fosaprepitant dimeglumine (MK-0517) for Injection, an intravenous therapy for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV). Available as Emend in the US and Ivemend in the EU, the drug was approved for use in combination with other anti-emetic medicines for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately- and highly-emetogenic cancer CT. A further approval came in September, as the FDA approved ProStrakan's Sancuso (granisetron), a novel, patent-protected transdermal patch for the prevention of CINV; the product was launched in the US in November.
Another approval to support cancer patients came in April when the EC granted marketing authorisation to Cephalon's Effentora, a buccal tablet formulation of fentanyl, for the treatment of breakthrough cancer pain in adult patients who are already receiving maintenance opioid therapy for chronic pain. More good news came as both the FDA and EC approved Progenics Pharmaceuticals/Wyeth Pharmaceuticals' Relistor (methylnaltrexone injection), in April and July, respectively, for subcutaneous use for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. In what could be the final approval of the year, in December, the FDA granted marketing authorisation to Genzyme's Mozobil (plerixafor injection), a drug intended to be used in combination with G-CSF to mobilise haematopoietic stem cells to the bloodstream for collection and subsequent autologous transplantation in patients with NHL and multiple myeloma. Hopefully 2009 will be a more fruitful year.
Matthew Dennis - Editor, Cancer Drug News
Thursday, December 18, 2008
Cancer to lead death toll in 2010?
Despite the fact that cancer incidence and death rates for men and women in the developed world continue to decline, cancer is projected to become the leading cause of death worldwide in the year 2010, and low- and middle-income countries will feel the impact of higher cancer incidence and death rates more sharply than industrialised countries.
To coincide with the International Agency for Research on Cancer releasing the new edition of the World Cancer Report, in the US, the nation's leading cancer organisations joined forces at an event called Conquering Cancer: A Global Effort, to focus attention on the growing global cancer burden and discuss efforts needed to address the problem. The American Cancer Society, the Lance Armstrong Foundation and Susan G. Komen for the Cure discussed how each organisation is addressing the global cancer problem and together issued a call to action for the incoming US presidential administration and Congress.
According to the report, the burden of cancer doubled globally between 1975 and 2000. It is estimated that it will double again by 2020 and nearly triple by 2030. This translates to far greater numbers of people living with and dying from the disease. The report estimates that there were some 12 million new cancer diagnoses worldwide in 2008, and more than 7 million people will die from the disease.
The projected numbers for the year 2030 are 20 to 26 million new diagnoses and 13 to 17 million deaths. The growing cancer burden includes global increases of incidence of approximately 1 per cent each year, with larger increases in China, Russia and India. Reasons for the increased rates include adoption of Western habits in less developed countries, such as tobacco use and higher-fat diets, and demographic changes, including a projected population increase of 38 per cent in less developed countries between 2008 and 2030. In addition to increases in cancer incidence and death rates, the report identifies challenges in cancer care, especially in Africa, where pain management and palliative care are very limited because any use of narcotics is prohibited by law in several countries.
The call to action steps issued by the three organisations include: 1) making vaccines that prevent cancer-causing infections more widely available to low-income nations, including efforts to make the human papillomavirus vaccine accessible and affordable; 2) committing to a comprehensive tobacco control approach in the US, which includes taking measures proven effective in reducing smoking rates and having Congress grant the FDA authority to regulate tobacco; 3) ratifying immediately the Framework Convention on Tobacco Control, the first ever global public health treaty that sets forth comprehensive measures to reduce health and economic impacts of tobacco; 4) supporting efforts of non-governmental organisations to build advocacy and resources, empower survivors and reduce suffering in low- to middle-income countries by working with governments, medical professionals and the corporate sector to enable individuals to adopt healthier behaviours; 5) promoting culturally-sensitive risk reduction and education campaigns by leveraging US efforts to help build capacity of non-governmental organisations in other countries; and 6) investing in cancer research and expanding access to prevention and early detection measures in the US, with a specific focus on increasing federal funding of medical research.
Matthew Dennis - Editor, Cancer Drug News
To coincide with the International Agency for Research on Cancer releasing the new edition of the World Cancer Report, in the US, the nation's leading cancer organisations joined forces at an event called Conquering Cancer: A Global Effort, to focus attention on the growing global cancer burden and discuss efforts needed to address the problem. The American Cancer Society, the Lance Armstrong Foundation and Susan G. Komen for the Cure discussed how each organisation is addressing the global cancer problem and together issued a call to action for the incoming US presidential administration and Congress.
According to the report, the burden of cancer doubled globally between 1975 and 2000. It is estimated that it will double again by 2020 and nearly triple by 2030. This translates to far greater numbers of people living with and dying from the disease. The report estimates that there were some 12 million new cancer diagnoses worldwide in 2008, and more than 7 million people will die from the disease.
The projected numbers for the year 2030 are 20 to 26 million new diagnoses and 13 to 17 million deaths. The growing cancer burden includes global increases of incidence of approximately 1 per cent each year, with larger increases in China, Russia and India. Reasons for the increased rates include adoption of Western habits in less developed countries, such as tobacco use and higher-fat diets, and demographic changes, including a projected population increase of 38 per cent in less developed countries between 2008 and 2030. In addition to increases in cancer incidence and death rates, the report identifies challenges in cancer care, especially in Africa, where pain management and palliative care are very limited because any use of narcotics is prohibited by law in several countries.
The call to action steps issued by the three organisations include: 1) making vaccines that prevent cancer-causing infections more widely available to low-income nations, including efforts to make the human papillomavirus vaccine accessible and affordable; 2) committing to a comprehensive tobacco control approach in the US, which includes taking measures proven effective in reducing smoking rates and having Congress grant the FDA authority to regulate tobacco; 3) ratifying immediately the Framework Convention on Tobacco Control, the first ever global public health treaty that sets forth comprehensive measures to reduce health and economic impacts of tobacco; 4) supporting efforts of non-governmental organisations to build advocacy and resources, empower survivors and reduce suffering in low- to middle-income countries by working with governments, medical professionals and the corporate sector to enable individuals to adopt healthier behaviours; 5) promoting culturally-sensitive risk reduction and education campaigns by leveraging US efforts to help build capacity of non-governmental organisations in other countries; and 6) investing in cancer research and expanding access to prevention and early detection measures in the US, with a specific focus on increasing federal funding of medical research.
Matthew Dennis - Editor, Cancer Drug News
Wednesday, December 3, 2008
More teens needed for trials
A new UK study has highlighted the small number of teenagers who are enrolled in clinical trials for cancer, despite the benefits of being involved. Inclusion in studies has been shown to improve cancer survival, because it provides access to new drugs, better quality of care through frequent monitoring and access to a wider group of specialists. The results of the work have been published in the 1st December online edition of the British Journal of Cancer (10.1038/sj.bjc.6604751).
Scientists from University College London analysed enrolment in Phase III trials from April 2005 to March 2007 involving teenagers and young adults (TYA), as well as children. All of the young patients involved in trials had been diagnosed with leukaemia, lymphoma, brain and central nervous system, bone sarcomas or male germ cell tumours. The researchers found that only 25.2 per cent of 15 to 19-year-olds and 13.1 per cent of 20 to 24-year-olds were enrolled in clinical trials, compared with 43.2 per cent of ten to 14-year-olds. Rates increased among ten to 14-year-olds and 15 to 19-year-olds during April 2006 to March 2007 compared with the previous 12 months, but fell among 20 to 24-year-olds.
The investigators noted that there were four trials available for patients with CNS tumours, yet no over-16s were enrolled in these trials. They also observed that over-15s were much less likely to take part in clinical trials in England than children and younger teenagers. The variations in open trials, trial age eligibility criteria and extent of trial activation in treatment centres in part explain this observation. However, other possible influences, such as difficulties associated with the consent of TYA require further evaluation.
Study leader Dr Lorna Fern, who co-ordinates research into TYA with cancer at the National Cancer Research Institute has said that the US and Australia had also reported a similar trend. Young people are constantly falling through the gap between paediatric and adult cancer specialists and there are not enough trials for the types of cancers that affect them. This is an important study that can be used as the base on which progress is measured in the UK. Before now, it was not known how many young people with cancer were recruited onto clinical trials. It is hoped that in the future, closer dialogue between those involved in planning and running trials for children and for adults will improve trial availability and recruitment.
Amending the age eligibility criteria is one possible solution, although it may not completely address the problem of recruiting TYA. In the EURAMOS-1 trial (an international osteosarcoma trial), a fall off in recruitment has been seen beyond the age of 15, despite an age eligibility criteria which spans the whole paediatric and TYA population. Average accrual to EURAMOS-1 in England, Scotland and Wales has demonstrated a decline in accrual from 42.7 per cent for patients aged ten to 14 years, 38.3 per cent for those aged 15 to 19, and 15.7 per cent of patients aged 20 to 24 from 2005 to 2008.
It is feared that significant improvements in outcomes from cancer for TYA will remain elusive without a coalition of forces including funders, policy makers, biologists, clinicians and patients.
Matthew Dennis - Editor, Cancer Drug News
Scientists from University College London analysed enrolment in Phase III trials from April 2005 to March 2007 involving teenagers and young adults (TYA), as well as children. All of the young patients involved in trials had been diagnosed with leukaemia, lymphoma, brain and central nervous system, bone sarcomas or male germ cell tumours. The researchers found that only 25.2 per cent of 15 to 19-year-olds and 13.1 per cent of 20 to 24-year-olds were enrolled in clinical trials, compared with 43.2 per cent of ten to 14-year-olds. Rates increased among ten to 14-year-olds and 15 to 19-year-olds during April 2006 to March 2007 compared with the previous 12 months, but fell among 20 to 24-year-olds.
The investigators noted that there were four trials available for patients with CNS tumours, yet no over-16s were enrolled in these trials. They also observed that over-15s were much less likely to take part in clinical trials in England than children and younger teenagers. The variations in open trials, trial age eligibility criteria and extent of trial activation in treatment centres in part explain this observation. However, other possible influences, such as difficulties associated with the consent of TYA require further evaluation.
Study leader Dr Lorna Fern, who co-ordinates research into TYA with cancer at the National Cancer Research Institute has said that the US and Australia had also reported a similar trend. Young people are constantly falling through the gap between paediatric and adult cancer specialists and there are not enough trials for the types of cancers that affect them. This is an important study that can be used as the base on which progress is measured in the UK. Before now, it was not known how many young people with cancer were recruited onto clinical trials. It is hoped that in the future, closer dialogue between those involved in planning and running trials for children and for adults will improve trial availability and recruitment.
Amending the age eligibility criteria is one possible solution, although it may not completely address the problem of recruiting TYA. In the EURAMOS-1 trial (an international osteosarcoma trial), a fall off in recruitment has been seen beyond the age of 15, despite an age eligibility criteria which spans the whole paediatric and TYA population. Average accrual to EURAMOS-1 in England, Scotland and Wales has demonstrated a decline in accrual from 42.7 per cent for patients aged ten to 14 years, 38.3 per cent for those aged 15 to 19, and 15.7 per cent of patients aged 20 to 24 from 2005 to 2008.
It is feared that significant improvements in outcomes from cancer for TYA will remain elusive without a coalition of forces including funders, policy makers, biologists, clinicians and patients.
Matthew Dennis - Editor, Cancer Drug News
Thursday, November 27, 2008
Last chance for Iressa?
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
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 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
Tuesday, October 21, 2008
GVAX: development halted
Cell Genesys has decided to terminate the Phase III VITAL-1 (Vaccine ImmunoTherapy with Allogeneic Prostate Cancer Cell Lines) trial of GVAX immunotherapy in patients with asymptomatic, metastatic hormone-refractory prostate cancer (HRPCA) following an independent Data Monitoring Committee (IDMC) analysis, which indicated that the trial had a <30 per cent chance of meeting its predefined primary endpoint of an improvement in survival. In August, the company halted VITAL-2, the second Phase III trial investigating GVAX in PCA, after a recommendation from the IDMC following the observation of an imbalance in deaths between the two treatment arms.
Following the termination of VITAL-2, Cell Genesys requested the IDMC conduct a futility analysis of the VITAL-1 trial, which was fully enrolled in 2007 with 626 patients and compared GVAX to Taxotere (docetaxel) plus prednisone. The latest news hit the company's stock price hard, with shares falling by 73 per cent from a close of US$0.61 on 15th October to open at US$0.16 on 16th October.
In view of these terminations, Cell Genesys is to place on hold the further development of GVAX for PCA pending a review of the programme with its collaborator, Takeda Pharmaceutical. As a result, Cell Genesys will reduce its staff of 290 by approximately 75 per cent by the end of 2008, with further reductions anticipated in the first half of 2009 as additional activities are phased out. As of 30th September, the company had approximately US$150 million in cash and currently estimates that the year-end cash will be approximately US$128 million. Personnel-related restructuring charges of approximately US$12.8 million are expected to be incurred in the fourth quarter of 2008.
Cell Genesys has also reported results of a preliminary analysis of the VITAL-2 trial. In contrast to VITAL-1, the VITAL-2 study was conducted in patients with symptomatic, metastatic HRPCA and compared the combination of GVAX+docetaxel to docetaxel+prednisone as a control. At the time that this study was terminated, the IDMC reported an imbalance in deaths between the two treatment arms that was observed during a routine safety monitoring meeting of the committee. More specifically, of 114 deaths at the time of the IDMC review, 67 occurred in the GVAX+docetaxel treatment arm and 47 in the docetaxel+prednisone control arm.
A total of 408 patients had been enrolled in the study up to that point in time. The company has now conducted an initial analysis of the incomplete trial data set that was reviewed by the IDMC in August. The analysis has revealed no apparent imbalance in patient baseline characteristics with respect to both demographic and disease prognostic factors. In addition, no significant toxicities in the GVAX+docetaxel therapy arm were observed that could explain the imbalance in deaths and in fact, the vast majority of deaths in both treatment arms were reported as due to progression of PCA. Of note, fewer treatment cycles with docetaxel were administered to patients in the GVAX+docetaxel arm compared to the control arm, a difference which was statistically significant.
In a conference call, the company's Chief Executive Officer, Stephen Sherwin, stated that Cell Genesys has since found no evidence that the GVAX regimen carried toxic effects that could explain the additional deaths. "We don't have all the answers," he commented, although cancer sufferers, shareholders and employees will wish that he at least had some.
Matthew Dennis - Editor, Cancer Drug News
Following the termination of VITAL-2, Cell Genesys requested the IDMC conduct a futility analysis of the VITAL-1 trial, which was fully enrolled in 2007 with 626 patients and compared GVAX to Taxotere (docetaxel) plus prednisone. The latest news hit the company's stock price hard, with shares falling by 73 per cent from a close of US$0.61 on 15th October to open at US$0.16 on 16th October.
In view of these terminations, Cell Genesys is to place on hold the further development of GVAX for PCA pending a review of the programme with its collaborator, Takeda Pharmaceutical. As a result, Cell Genesys will reduce its staff of 290 by approximately 75 per cent by the end of 2008, with further reductions anticipated in the first half of 2009 as additional activities are phased out. As of 30th September, the company had approximately US$150 million in cash and currently estimates that the year-end cash will be approximately US$128 million. Personnel-related restructuring charges of approximately US$12.8 million are expected to be incurred in the fourth quarter of 2008.
Cell Genesys has also reported results of a preliminary analysis of the VITAL-2 trial. In contrast to VITAL-1, the VITAL-2 study was conducted in patients with symptomatic, metastatic HRPCA and compared the combination of GVAX+docetaxel to docetaxel+prednisone as a control. At the time that this study was terminated, the IDMC reported an imbalance in deaths between the two treatment arms that was observed during a routine safety monitoring meeting of the committee. More specifically, of 114 deaths at the time of the IDMC review, 67 occurred in the GVAX+docetaxel treatment arm and 47 in the docetaxel+prednisone control arm.
A total of 408 patients had been enrolled in the study up to that point in time. The company has now conducted an initial analysis of the incomplete trial data set that was reviewed by the IDMC in August. The analysis has revealed no apparent imbalance in patient baseline characteristics with respect to both demographic and disease prognostic factors. In addition, no significant toxicities in the GVAX+docetaxel therapy arm were observed that could explain the imbalance in deaths and in fact, the vast majority of deaths in both treatment arms were reported as due to progression of PCA. Of note, fewer treatment cycles with docetaxel were administered to patients in the GVAX+docetaxel arm compared to the control arm, a difference which was statistically significant.
In a conference call, the company's Chief Executive Officer, Stephen Sherwin, stated that Cell Genesys has since found no evidence that the GVAX regimen carried toxic effects that could explain the additional deaths. "We don't have all the answers," he commented, although cancer sufferers, shareholders and employees will wish that he at least had some.
Matthew Dennis - Editor, Cancer Drug News
Tuesday, October 14, 2008
NICE set to block Tyverb's use on NHS
A draft recommendation by the UK's National Institute for Health and Clinical Excellence (NICE) in a second technology appraisal consultation document (ACD) has indicated that GlaxoSmithKline's Tyverb (lapatinib; known as Tykerb in the US and certain other markets) should not be used in the NHS, except in clinical trials. The oral drug is currently approved in the EU in combination with Xeloda (capecitabine) for the treatment of women with ErbB2 (HER2)-positive advanced breast cancer (BC), whose disease has stopped responding to Herceptin (trastuzumab). The draft guidance comes despite GSK proposing a patient access programme (PAP), where it would bear the cost of the drug for the first 12 weeks of treatment.
Lapatinib, in combination with capecitabine, is the only treatment option that is licensed for use in patients with this aggressive form of advanced BC, who have limited treatment options remaining if their cancer has continued to grow despite treatment with standard chemotherapies and trastuzumab for advanced disease. In a pivotal trial that led to its EU licence, lapatinib+capecitabine significantly increased the time-to-progression (TTP) for patients with ErbB2-positive BC compared with capecitabine alone. In its draft guidance, NICE acknowledged that lapatinib is a clinically-effective option and noted that lapatinib+capecitabine was associated with improved TTP and progression-free survival.
In recognition that the first ACD from NICE did not consider lapatinib to be cost effective in treating this patient population, GSK proposed a PAP, where the company would bear the cost of lapatinib for all eligible patients, for up to the first 12 weeks of treatment. The NHS would commence payment only for those patients who continue to receive clinical benefit beyond 12 weeks. Criteria for continuation of therapy beyond 12 weeks would be determined by the individual person's clinician, based on reduction in lesion size, presence of stable disease or improvement in other response criteria such as symptoms. This programme was designed to provide access to all eligible patients and deliver cost-effectiveness at a threshold that should have been acceptable to NICE.
The cost effectiveness of lapatinib+capecitabine was supported by a comparison to trastuzumab-containing regimens and capecitabine alone, representing the established treatment regimens in NHS clinical practice. Whilst NICE accepted that trastuzumab is widely used following progression of the disease, the Committee suggested that it was unlikely to be cost effective, and therefore did not accept trastuzumab as a valid comparator. According to GSK, the way in which the decision was made makes it very difficult to ever demonstrate the cost effectiveness of lapatinib in this patient population, even in light of the proposed PAP.
Following the ACD, GSK will continue to work with NICE to demonstrate the cost effectiveness of lapatinib in all eligible patients by seeking to validate trastuzumab as a legitimate comparator. The next meeting will be held on 19th November, however, it looks as though NICE will stick with its current draft guidance and recommend against funding lapatinib on the NHS.
Matthew Dennis - Editor, Cancer Drug News
Lapatinib, in combination with capecitabine, is the only treatment option that is licensed for use in patients with this aggressive form of advanced BC, who have limited treatment options remaining if their cancer has continued to grow despite treatment with standard chemotherapies and trastuzumab for advanced disease. In a pivotal trial that led to its EU licence, lapatinib+capecitabine significantly increased the time-to-progression (TTP) for patients with ErbB2-positive BC compared with capecitabine alone. In its draft guidance, NICE acknowledged that lapatinib is a clinically-effective option and noted that lapatinib+capecitabine was associated with improved TTP and progression-free survival.
In recognition that the first ACD from NICE did not consider lapatinib to be cost effective in treating this patient population, GSK proposed a PAP, where the company would bear the cost of lapatinib for all eligible patients, for up to the first 12 weeks of treatment. The NHS would commence payment only for those patients who continue to receive clinical benefit beyond 12 weeks. Criteria for continuation of therapy beyond 12 weeks would be determined by the individual person's clinician, based on reduction in lesion size, presence of stable disease or improvement in other response criteria such as symptoms. This programme was designed to provide access to all eligible patients and deliver cost-effectiveness at a threshold that should have been acceptable to NICE.
The cost effectiveness of lapatinib+capecitabine was supported by a comparison to trastuzumab-containing regimens and capecitabine alone, representing the established treatment regimens in NHS clinical practice. Whilst NICE accepted that trastuzumab is widely used following progression of the disease, the Committee suggested that it was unlikely to be cost effective, and therefore did not accept trastuzumab as a valid comparator. According to GSK, the way in which the decision was made makes it very difficult to ever demonstrate the cost effectiveness of lapatinib in this patient population, even in light of the proposed PAP.
Following the ACD, GSK will continue to work with NICE to demonstrate the cost effectiveness of lapatinib in all eligible patients by seeking to validate trastuzumab as a legitimate comparator. The next meeting will be held on 19th November, however, it looks as though NICE will stick with its current draft guidance and recommend against funding lapatinib on the NHS.
Matthew Dennis - Editor, Cancer Drug News
Market jitters affecting takeovers?
As the world financial crisis deepens, the potential takeover deals involving Genentech and Roche, as well as ImClone Systems and Bristol-Myers Squibb, continue to play out. The current market situation could have an impact on the first takeover, although the second looks more likely to proceed smoothly.
For the first time since Roche made its bid to acquire Genentech in July for US$89.00 per share, the latter's shares have dropped below the offer price, ending on 29th September at US$85.30. The uncertainty now surrounding the bid has fuelled speculation that an improved offer may not be made. When Roche proposed the deal, the cost of borrowing was not as high as it in the current climate. Now there are concerns that Roche would have trouble financing the deal, which currently stands at US$43.7 billion, given the current credit market conditions. However, many analysts believe Roche's strong balance sheet and predictable cash flow will still allow it to secure funding for the deal.
The current situation could ultimately work in Roche's favour as the company may choose to draw out the process in order to extract the lowest possible price for Genentech's remaining shares. It may be that many Genentech shareholders would also prefer to wait, given that interim results are expected in November from a key clinical trial looking at the use of Avastin (bevacizumab) in colon cancer patients who have had tumours surgically removed; final results of the 2,700-patient study are due in 2009.
As for BMS' takeover offer for ImClone, which currently stands at US$62.00 per share in cash, Carl Icahn, ImClone's Chairman of the Board, recently commented that the "hostile tender of US$62, at this time, seems absurd". ImClone reportedly has an offer from another large pharmaceutical company of US$70.00 per share, also in cash, subject to due diligence, which was scheduled to be finished on 28th September. ImClone is expecting that a solid offer from this company will be made or a formal rejection, in which case the suitor will be identified, by the end of business on 1st October. Both of these offers, BMS' valued at US$4.7 billion and the other at US$6.1 billion, do not rely on either company raising funds so should not be affected by recent financial developments.
But to add to the uncertainty, Merck KGaA has entered the fray. Although the company has said that it will not bid for ImClone on its own, it has stated that it may consider taking part in a potential approach for the company. Could it join forces with rumoured suitors, such as Eli Lilly and Pfizer, which has coincidentally said recently that it will focus its early-stage research and development programmes on high growth areas, including cancer?
Matthew Dennis - Editor, Cancer Drug News
For the first time since Roche made its bid to acquire Genentech in July for US$89.00 per share, the latter's shares have dropped below the offer price, ending on 29th September at US$85.30. The uncertainty now surrounding the bid has fuelled speculation that an improved offer may not be made. When Roche proposed the deal, the cost of borrowing was not as high as it in the current climate. Now there are concerns that Roche would have trouble financing the deal, which currently stands at US$43.7 billion, given the current credit market conditions. However, many analysts believe Roche's strong balance sheet and predictable cash flow will still allow it to secure funding for the deal.
The current situation could ultimately work in Roche's favour as the company may choose to draw out the process in order to extract the lowest possible price for Genentech's remaining shares. It may be that many Genentech shareholders would also prefer to wait, given that interim results are expected in November from a key clinical trial looking at the use of Avastin (bevacizumab) in colon cancer patients who have had tumours surgically removed; final results of the 2,700-patient study are due in 2009.
As for BMS' takeover offer for ImClone, which currently stands at US$62.00 per share in cash, Carl Icahn, ImClone's Chairman of the Board, recently commented that the "hostile tender of US$62, at this time, seems absurd". ImClone reportedly has an offer from another large pharmaceutical company of US$70.00 per share, also in cash, subject to due diligence, which was scheduled to be finished on 28th September. ImClone is expecting that a solid offer from this company will be made or a formal rejection, in which case the suitor will be identified, by the end of business on 1st October. Both of these offers, BMS' valued at US$4.7 billion and the other at US$6.1 billion, do not rely on either company raising funds so should not be affected by recent financial developments.
But to add to the uncertainty, Merck KGaA has entered the fray. Although the company has said that it will not bid for ImClone on its own, it has stated that it may consider taking part in a potential approach for the company. Could it join forces with rumoured suitors, such as Eli Lilly and Pfizer, which has coincidentally said recently that it will focus its early-stage research and development programmes on high growth areas, including cancer?
Matthew Dennis - Editor, Cancer Drug News
Tuesday, September 16, 2008
Bidding war to start for ImClone?
ImClone Systems' Chairman of the Board, Carl Icahn, has stated that the Special Committee of ImClone's Board of Directors has informed Bristol-Myers Squibb that following the Special Committee's review and discussion, and based upon the advice it received from its advisors, the Special Committee has determined that the unsolicited offer that ImClone received from BMS to acquire ImClone for US$60 per share in cash is inadequate.
Icahn also disclosed that he has had several conversations with the Chief Executive Officer of a large pharmaceutical company. As a result of such conversations, the pharmaceutical company has submitted a proposal, subject to due diligence, but not subject to financing, to acquire ImClone for US$70 per share in cash. Names being bandied about for the unknown bidder include Merck KGaA, Pfizer and GlaxoSmithKline, as well as AstraZeneca and sanofi-aventis. The Special Committee has determined, subject to the execution of a confidentiality agreement, to allow this company to conduct due diligence for a two-week period, subject to extension by mutual consent. No determination has been made as to whether US$70 per share would be adequate.
In response to this disclosure, BMS sent a letter to Icahn stating its disappointment that the offer had been rejected without discussing its merits with BMS and its advisors. BMS also noted that, in contrast to the competing offer, it has made a formal written offer that has been approved by its Board of Directors, is not subject to due diligence and has been fully disclosed to ImClone's stockholders.
BMS currently holds the exclusive long-term marketing rights in the US to Erbitux (cetuximab) and related compounds, including IMC-11F8. BMS stated that it has no intention of agreeing to any modifications to these rights. Additionally, ImClone should understand that BMS’ offer is for the entire company, and any potential restructuring of ImClone could severely jeopardise its value and deprive stockholders of the benefits of the BMS offer.
BMS continues to look forward to engaging directly with ImClone and its financial and legal advisors to discuss the merits of its all-cash offer to acquire the approximately 83 per cent of the company that BMS does not already own. In reply, ImClone submitted a letter to BMS in which it stated that with regard to the assertion concerning rights to IMC-11F8 (which, if ultimately approved for sale, may have a significant competitive effect on Erbitux), ImClone disagrees that BMS' rights are clear and does not waive any rights that ImClone may have with regard thereto. If BMS wishes to make another offer that it believes ImClone would not find inadequate, it is free to do so. Upon receipt of that offer, ImClone will respond appropriately. However, BMS' Chief Financial Officer Jean-Marc Huet has stated that the company is willing to "walk away" from the deal if needed.
Exactly what belongs to whom in the BMS-ImClone partnership will be a key question of interest as ImClone's new mystery bidder conducts its due diligence over the next few weeks. It seems likely that Merck KGaA may be the interested party because it partners with ImClone in selling Erbitux in some countries outside North America and has touted the drug's prospects of being approved for other types of cancer. Perhaps the bidding will now start in earnest?
Matthew Dennis - Editor, Cancer Drug News
Icahn also disclosed that he has had several conversations with the Chief Executive Officer of a large pharmaceutical company. As a result of such conversations, the pharmaceutical company has submitted a proposal, subject to due diligence, but not subject to financing, to acquire ImClone for US$70 per share in cash. Names being bandied about for the unknown bidder include Merck KGaA, Pfizer and GlaxoSmithKline, as well as AstraZeneca and sanofi-aventis. The Special Committee has determined, subject to the execution of a confidentiality agreement, to allow this company to conduct due diligence for a two-week period, subject to extension by mutual consent. No determination has been made as to whether US$70 per share would be adequate.
In response to this disclosure, BMS sent a letter to Icahn stating its disappointment that the offer had been rejected without discussing its merits with BMS and its advisors. BMS also noted that, in contrast to the competing offer, it has made a formal written offer that has been approved by its Board of Directors, is not subject to due diligence and has been fully disclosed to ImClone's stockholders.
BMS currently holds the exclusive long-term marketing rights in the US to Erbitux (cetuximab) and related compounds, including IMC-11F8. BMS stated that it has no intention of agreeing to any modifications to these rights. Additionally, ImClone should understand that BMS’ offer is for the entire company, and any potential restructuring of ImClone could severely jeopardise its value and deprive stockholders of the benefits of the BMS offer.
BMS continues to look forward to engaging directly with ImClone and its financial and legal advisors to discuss the merits of its all-cash offer to acquire the approximately 83 per cent of the company that BMS does not already own. In reply, ImClone submitted a letter to BMS in which it stated that with regard to the assertion concerning rights to IMC-11F8 (which, if ultimately approved for sale, may have a significant competitive effect on Erbitux), ImClone disagrees that BMS' rights are clear and does not waive any rights that ImClone may have with regard thereto. If BMS wishes to make another offer that it believes ImClone would not find inadequate, it is free to do so. Upon receipt of that offer, ImClone will respond appropriately. However, BMS' Chief Financial Officer Jean-Marc Huet has stated that the company is willing to "walk away" from the deal if needed.
Exactly what belongs to whom in the BMS-ImClone partnership will be a key question of interest as ImClone's new mystery bidder conducts its due diligence over the next few weeks. It seems likely that Merck KGaA may be the interested party because it partners with ImClone in selling Erbitux in some countries outside North America and has touted the drug's prospects of being approved for other types of cancer. Perhaps the bidding will now start in earnest?
Matthew Dennis - Editor, Cancer Drug News
Telomerase finally gives up its structure
In a landmark study, researchers from the Wistar Institute have deciphered the structure of the active region of telomerase, an enzyme that plays a major role in the development of nearly all cancers. It is hoped that this achievement will open the door to the creation of new, broadly-effective cancer drugs, as well as anti-ageing therapies. The results of the work have been published in the 31st August online edition of Nature (10.1038/nature07283).
Scientists have been searching for over ten years to develop drugs that shut down telomerase, which is considered the best target for the development of new cancer treatments, but they have been hampered in large part by a lack of knowledge of the enzyme's structure. The new findings should help investigators in their efforts to design effective telomerase inhibitors. According to lead study author, Dr Emmanuel Skordalakes, assistant professor in Wistar's Gene Expression and Regulation Program: "Telomerase is an ideal target for chemotherapy because it is active in almost all human tumours, but inactive in most normal cells. That means a drug that deactivates telomerase would likely work against all cancers, with few side effects."
In humans, telomerase adds multiple repeats of a short DNA sequence to the ends of chromosomes, known as telomeres, thus preventing damage and the loss of genetic information during cell division. When telomerase is dormant, telomeres shorten each time a cell divides, eventually leading to genetic instability and cell death. The enzyme is active in cells that multiply frequently, such as embryonic stem cells, but is switched off almost entirely in normal adult cells. Cancer cells, however, often regain the ability to activate telomerase, which has been implicated in 90 per cent of human tumours. The enzyme permits cells to replicate indefinitely and achieve the cellular immortality that is the hallmark of cancer.
Telomerase is a complex structure made up of multiple protein domains and a stretch of RNA, which contains the template the enzyme uses to synthesise telomeres. In 2007, the researchers solved the structure of a key segment of the molecule, the TRBD domain, where RNA binding occurs. However, the complexity of telomerase has proved a roadblock to determining the enzyme's overall architecture, as has the ability to obtain sufficient quantities of the enzyme.
By screening a wide variety of organisms, including protozoa and insects, the scientists discovered that a gene from the red flour beetle could produce telomerase in copious amounts, and a stable form. The researchers used X-ray crystallography, to determine the 3D structure of the enzyme's active region, the catalytic component called telomerase reverse transcriptase protein (TERT). The work revealed surprising features, including the fact that the molecule's three domains are organised into a doughnut shape, an unexpected configuration. Knowledge of the structure allowed the researchers to create a model of the enzyme's function. Looking forward, the scientists plan to further study TERT and search for new telomerase inhibitors that could become cancer therapies, as well as looking at modifying existing drugs. Now telomerase has finally given up its structure, the hard work really starts.
Matthew Dennis - Editor, Cancer Drug News
Scientists have been searching for over ten years to develop drugs that shut down telomerase, which is considered the best target for the development of new cancer treatments, but they have been hampered in large part by a lack of knowledge of the enzyme's structure. The new findings should help investigators in their efforts to design effective telomerase inhibitors. According to lead study author, Dr Emmanuel Skordalakes, assistant professor in Wistar's Gene Expression and Regulation Program: "Telomerase is an ideal target for chemotherapy because it is active in almost all human tumours, but inactive in most normal cells. That means a drug that deactivates telomerase would likely work against all cancers, with few side effects."
In humans, telomerase adds multiple repeats of a short DNA sequence to the ends of chromosomes, known as telomeres, thus preventing damage and the loss of genetic information during cell division. When telomerase is dormant, telomeres shorten each time a cell divides, eventually leading to genetic instability and cell death. The enzyme is active in cells that multiply frequently, such as embryonic stem cells, but is switched off almost entirely in normal adult cells. Cancer cells, however, often regain the ability to activate telomerase, which has been implicated in 90 per cent of human tumours. The enzyme permits cells to replicate indefinitely and achieve the cellular immortality that is the hallmark of cancer.
Telomerase is a complex structure made up of multiple protein domains and a stretch of RNA, which contains the template the enzyme uses to synthesise telomeres. In 2007, the researchers solved the structure of a key segment of the molecule, the TRBD domain, where RNA binding occurs. However, the complexity of telomerase has proved a roadblock to determining the enzyme's overall architecture, as has the ability to obtain sufficient quantities of the enzyme.
By screening a wide variety of organisms, including protozoa and insects, the scientists discovered that a gene from the red flour beetle could produce telomerase in copious amounts, and a stable form. The researchers used X-ray crystallography, to determine the 3D structure of the enzyme's active region, the catalytic component called telomerase reverse transcriptase protein (TERT). The work revealed surprising features, including the fact that the molecule's three domains are organised into a doughnut shape, an unexpected configuration. Knowledge of the structure allowed the researchers to create a model of the enzyme's function. Looking forward, the scientists plan to further study TERT and search for new telomerase inhibitors that could become cancer therapies, as well as looking at modifying existing drugs. Now telomerase has finally given up its structure, the hard work really starts.
Matthew Dennis - Editor, Cancer Drug News
Price may prohibit HPV vaccination in developing world
As vaccinations against human papillomavirus (HPV) begin for girls in another western country, this time in Scotland, questions remain about how best to utilise this technology in other world regions. As discussed at the World Cancer Congress, which was held from 27th to 31st August, in Geneva, Switzerland, the development of highly-effective vaccines against HPV and promising new screening tests provide an unprecedented opportunity to tackle the disease in poor countries, where pap smear screening has largely failed because it is too expensive and too complicated to implement.
At present, approximately 80 per cent of cervical cancer (CC) deaths occur in developing countries, and estimates predict that if current trends continue, these regions will face a 75 per cent increase in the number of cases in the next two decades. Presented at the Congress was the first broad analysis of the cost-effectiveness of introducing HPV vaccination and new screening methods into the hardest hit regions of the world, which include Asia-Pacific, Latin America and the Caribbean. The benefits varied, depending on the size and make-up of the population and the burden of CC in each country.
It was determined that in the Asia-Pacific region, which accounts for more than half of the world's CC cases, vaccination would be cost-effective, even in the poorest countries, if the cost per vaccinated girl was between US$10 and US$25. For Latin America and the Caribbean, the cost per vaccinated girl, including delivery and logistics costs, would have to be less than US$25 to be cost-effective for all countries. In the most developed populations in the region, vaccination would be cost-saving if the cost per vaccinated girl is between US$25 and US$60, and cost-effective at higher prices.
According to Professor Francesc Xavier Bosch of the Catalan Institute of Oncology: "Efforts are needed now to adapt the current price of the vaccines so they meet what individual countries can afford; the solution may be tiered pricing according to gross national income per capita and according to the scale of country effort. Currently the vaccine's price in the private sector is approximately US$120 per dose, or US$360 per vaccinated girl. Many countries will need subsidies for some time."
The price of the vaccine and the support for massive vaccination campaigns is one of the biggest barriers for the moment, but several other challenges lay ahead. Those include generating the political support for an intervention whose pay-off is two or more decades away, cultural acceptability of the vaccine and monitoring the circulating virus. Uncertainties that may affect the success of vaccination programmes include the duration of protection and whether booster shots might be needed, and whether the vaccines will be as effective in girls whose immune systems are suppressed by either malnutrition or other chronic infections, such as HIV or malaria.
For the near future, in developing countries, both vaccination and screening will be needed. However, in the beginning, many countries may have to continue to focus on screening alone until the vaccine becomes more affordable.
Matthew Dennis - Editor, Cancer Drug News
At present, approximately 80 per cent of cervical cancer (CC) deaths occur in developing countries, and estimates predict that if current trends continue, these regions will face a 75 per cent increase in the number of cases in the next two decades. Presented at the Congress was the first broad analysis of the cost-effectiveness of introducing HPV vaccination and new screening methods into the hardest hit regions of the world, which include Asia-Pacific, Latin America and the Caribbean. The benefits varied, depending on the size and make-up of the population and the burden of CC in each country.
It was determined that in the Asia-Pacific region, which accounts for more than half of the world's CC cases, vaccination would be cost-effective, even in the poorest countries, if the cost per vaccinated girl was between US$10 and US$25. For Latin America and the Caribbean, the cost per vaccinated girl, including delivery and logistics costs, would have to be less than US$25 to be cost-effective for all countries. In the most developed populations in the region, vaccination would be cost-saving if the cost per vaccinated girl is between US$25 and US$60, and cost-effective at higher prices.
According to Professor Francesc Xavier Bosch of the Catalan Institute of Oncology: "Efforts are needed now to adapt the current price of the vaccines so they meet what individual countries can afford; the solution may be tiered pricing according to gross national income per capita and according to the scale of country effort. Currently the vaccine's price in the private sector is approximately US$120 per dose, or US$360 per vaccinated girl. Many countries will need subsidies for some time."
The price of the vaccine and the support for massive vaccination campaigns is one of the biggest barriers for the moment, but several other challenges lay ahead. Those include generating the political support for an intervention whose pay-off is two or more decades away, cultural acceptability of the vaccine and monitoring the circulating virus. Uncertainties that may affect the success of vaccination programmes include the duration of protection and whether booster shots might be needed, and whether the vaccines will be as effective in girls whose immune systems are suppressed by either malnutrition or other chronic infections, such as HIV or malaria.
For the near future, in developing countries, both vaccination and screening will be needed. However, in the beginning, many countries may have to continue to focus on screening alone until the vaccine becomes more affordable.
Matthew Dennis - Editor, Cancer Drug News
Wednesday, August 13, 2008
Draft NICE guidance denies RCC drugs
The UK's National Institute for Health and Clinical Excellence (NICE) has issued preliminary recommendations for the treatment of renal cell carcinoma (RCC), concluding that Roche/Genentech's Avastin (bevacizumab), Bayer/Onyx Pharmaceuticals' Nexavar (sorafenib), Pfizer's Sutent (sunitinib) and Wyeth Pharmaceuticals' Torisel (temsirolimus) are not recommended as treatment options for advanced and/or metastatic disease. Although the drugs were shown to be clinically effective and extend life for RCC patients, they were deemed to not be a cost-effective use of NHS resources. NICE is expected to issue final guidance in January 2009.
Following the decision, Cancer Research UK (CRUK) has called for NICE to alter the way that it appraises the value of drugs for rare diseases, such as metastatic RCC, where clinical benefit is proven but evidence is limited due to the small number of available patients. Professor Peter Johnson, CRUK's chief clinician, stated: "We are disappointed at NICE's view that although these drugs are clinically effective, their high price means that they are not considered to be value for money for the NHS. These drugs have shown a small but definite improvement in an illness where there are few alternative treatments. If this decision stands it will be very frustrating for cancer patients and their clinicians."
The charity put forward that possible solutions include looking at the way that pharmaceutical companies are charging the NHS for drugs, and whether appropriate allowances are being made by NICE to compensate for the lack of large-scale trials in these areas. However, it turns out that proposals were submitted by two of the manufacturers relating to drug acquisition costs. But these were not considered by the Department of Health as they had not been agreed before the appraisal.
The preliminary guidance raises questions as to how NICE evaluates cancer drugs, particularly for cancers that only affect a relatively small number of people. The gold-standard method of testing whether a treatment works and is safe is through the use of clinical trials. The larger the number of patients enrolled in a study, and the longer it lasts, the more sure researchers can be about its results. This works for diseases that affect large numbers of people, such as breast and lung cancer, but only around 2,000 people every year are diagnosed with metastatic RCC. Further, only one in ten people diagnosed with this stage of the disease is alive five years later. This means that for relatively rare diseases like this, it can take a long time to conduct large enough studies to gather the evidence needed to gain approval from regulatory agencies.
Even if these studies do demonstrate benefit, as those for the four drugs did, there is still the cost-effectiveness hurdle to overcome. When NICE analysed the data from the trials with its models, it found that the drugs were expensive (around £20,000 to £35,000 per patient per year) compared to the benefit they brought patients. However, concerns have also been raised about these models, which are designed to examine giving drugs to large numbers of people. Are they equally valid for looking at relatively uncommon diseases, such as metastatic RCC? Hopefully NICE will be able to answer these questions when its final guidance is published.
Matthew Dennis - Editor, Cancer Drug News
Following the decision, Cancer Research UK (CRUK) has called for NICE to alter the way that it appraises the value of drugs for rare diseases, such as metastatic RCC, where clinical benefit is proven but evidence is limited due to the small number of available patients. Professor Peter Johnson, CRUK's chief clinician, stated: "We are disappointed at NICE's view that although these drugs are clinically effective, their high price means that they are not considered to be value for money for the NHS. These drugs have shown a small but definite improvement in an illness where there are few alternative treatments. If this decision stands it will be very frustrating for cancer patients and their clinicians."
The charity put forward that possible solutions include looking at the way that pharmaceutical companies are charging the NHS for drugs, and whether appropriate allowances are being made by NICE to compensate for the lack of large-scale trials in these areas. However, it turns out that proposals were submitted by two of the manufacturers relating to drug acquisition costs. But these were not considered by the Department of Health as they had not been agreed before the appraisal.
The preliminary guidance raises questions as to how NICE evaluates cancer drugs, particularly for cancers that only affect a relatively small number of people. The gold-standard method of testing whether a treatment works and is safe is through the use of clinical trials. The larger the number of patients enrolled in a study, and the longer it lasts, the more sure researchers can be about its results. This works for diseases that affect large numbers of people, such as breast and lung cancer, but only around 2,000 people every year are diagnosed with metastatic RCC. Further, only one in ten people diagnosed with this stage of the disease is alive five years later. This means that for relatively rare diseases like this, it can take a long time to conduct large enough studies to gather the evidence needed to gain approval from regulatory agencies.
Even if these studies do demonstrate benefit, as those for the four drugs did, there is still the cost-effectiveness hurdle to overcome. When NICE analysed the data from the trials with its models, it found that the drugs were expensive (around £20,000 to £35,000 per patient per year) compared to the benefit they brought patients. However, concerns have also been raised about these models, which are designed to examine giving drugs to large numbers of people. Are they equally valid for looking at relatively uncommon diseases, such as metastatic RCC? Hopefully NICE will be able to answer these questions when its final guidance is published.
Matthew Dennis - Editor, Cancer Drug News
BMS moves to buy ImClone
Bristol-Myers Squibb has proposed to enter into an agreement to acquire ImClone Systems for US$60.00 per share in cash, or a total payment of approximately US$4.5 billion. BMS currently owns approximately 17 per cent of all outstanding shares of ImClone. BMS' all-cash offer, which is not conditioned on the receipt of financing or on the conduct of due diligence, represents a premium of approximately 30 per cent over ImClone's closing stock price on 30th July, a premium of approximately40 per cent over the average closing price of ImClone's stock during the most recent one-month period and a premium in excess of 40 per cent for the average closing stock prices of ImClone stock during each of the most recent three- and 12-month periods.
James M Cornelius, BMS' Chairman and Chief Executive Officer, stated that the transaction represents an evolutionary development in the companies' seven-year-long relationship. BMS is the natural partner for ImClone as it possesses the knowledge base and resources to advance the company's growth over the long-term, not only with respect toErbitux (cetuximab), which the companies jointly commercialise, but also in terms of developing ImClone's pipeline assets.
ImClone's Board of Directors has formed a committee to study the acquisition offer and to retain advisors to assist it in determining the appropriate course of action. However, the Board's preliminary view is that the offer substantially undervalues the company. ImClone pointed out that its Board has been discussing the possibility of separating the company into its Erbitux and its pipeline businesses in order to maximise the value of the company.
Chairman of ImClone's Board, Carl C Icahn, has stated that he was disturbed that one of the directors on the ImClone Board who is the BMS designee was privy to the information discussed at previous meetings concerning the potential separation of ImClone into two separate components and how this restructuring might enhance stockholder value. Accordingly, the Board is reviewing whether BMS had access to confidential information concerning ImClone and its pipeline. Additionally, Icahn pointed out that ImClone has a pipeline antibody, IMC-11F8, under development which, if ultimately approved for sale, might have a significant competitive effect on Erbitux and that BMS may have no rights to market that product under its agreements with the company.
If BMS gained control of all the Erbitux revenues it would fill a long-term hole caused by the loss of patent protection, starting in 2012 and 2013,surrounding the company's heart disease drug, Plavix (clopidogrel),and antihypertensive, Avapro (irbesartan). Erbitux is indicated for use in the treatment of patients with metastatic colorectal cancer and in the treatment of squamous cell carcinoma of the head and neck. Under the agreement between BMS and ImClone, which expires in September2018, ImClone receives a distribution fee based on a flat rate of 39 per cent of Erbitux net sales in North America. This agreement was amended in July 2007 to provide for additional development funding for certain indications.
Merck KGaA is also a partner in the co-development and co-commercialisation of Erbitux in Japan and other markets outside of the US. As such, it could perhaps emerge as the most likely competitor for ImClone. It would make sense for Merck to protect its investment in the drug, since it was the company's own clinical trial that finally persuaded the FDA to approve Erbitux, and a new Merck trial has shown it to be efective in fighting lung cancer as well.
Matthew Dennis - Editor, Cancer Drug News
James M Cornelius, BMS' Chairman and Chief Executive Officer, stated that the transaction represents an evolutionary development in the companies' seven-year-long relationship. BMS is the natural partner for ImClone as it possesses the knowledge base and resources to advance the company's growth over the long-term, not only with respect toErbitux (cetuximab), which the companies jointly commercialise, but also in terms of developing ImClone's pipeline assets.
ImClone's Board of Directors has formed a committee to study the acquisition offer and to retain advisors to assist it in determining the appropriate course of action. However, the Board's preliminary view is that the offer substantially undervalues the company. ImClone pointed out that its Board has been discussing the possibility of separating the company into its Erbitux and its pipeline businesses in order to maximise the value of the company.
Chairman of ImClone's Board, Carl C Icahn, has stated that he was disturbed that one of the directors on the ImClone Board who is the BMS designee was privy to the information discussed at previous meetings concerning the potential separation of ImClone into two separate components and how this restructuring might enhance stockholder value. Accordingly, the Board is reviewing whether BMS had access to confidential information concerning ImClone and its pipeline. Additionally, Icahn pointed out that ImClone has a pipeline antibody, IMC-11F8, under development which, if ultimately approved for sale, might have a significant competitive effect on Erbitux and that BMS may have no rights to market that product under its agreements with the company.
If BMS gained control of all the Erbitux revenues it would fill a long-term hole caused by the loss of patent protection, starting in 2012 and 2013,surrounding the company's heart disease drug, Plavix (clopidogrel),and antihypertensive, Avapro (irbesartan). Erbitux is indicated for use in the treatment of patients with metastatic colorectal cancer and in the treatment of squamous cell carcinoma of the head and neck. Under the agreement between BMS and ImClone, which expires in September2018, ImClone receives a distribution fee based on a flat rate of 39 per cent of Erbitux net sales in North America. This agreement was amended in July 2007 to provide for additional development funding for certain indications.
Merck KGaA is also a partner in the co-development and co-commercialisation of Erbitux in Japan and other markets outside of the US. As such, it could perhaps emerge as the most likely competitor for ImClone. It would make sense for Merck to protect its investment in the drug, since it was the company's own clinical trial that finally persuaded the FDA to approve Erbitux, and a new Merck trial has shown it to be efective in fighting lung cancer as well.
Matthew Dennis - Editor, Cancer Drug News
Review confirms Gardasil's safety; predicted sales hit
Based on the review of available information, the FDA and the Centers for Disease Control and Prevention (CDC) have reaffirmed that Gardasil (quadrivalent human papillomavirus [HPV] types 6, 11, 16, 18 recombinant vaccine) continues to be safe and effective, and its benefits continue to outweigh its risks.
To date, the manufacturer, Merck & Co has distributed over 16 million doses of Gardasil in the US and as of 30th June, there have been 9,749 reports of adverse events following vaccination. Of these, 94 per cent were classified as reports of non-serious events, and 6 per cent as serious events. The non-serious events include syncope, pain at the injection site, headache, nausea and fever.
However, concerns have been raised about reports of deaths occurring in individuals after receiving Gardasil. As of 30th June, 20 deaths had been reported, although there was not a common pattern that would suggest they were caused by the vaccine. According to the review, in cases where autopsy, death certificate and medical records were available, the cause of death was explained by factors other than the vaccine.
Guillain-Barré syndrome (GBS) has also been reported in individuals following vaccination with Gardasil. The FDA and CDC have reviewed the reports and, to date, there is no evidence that Gardasil has increased the rate of GBS above that expected in the population. Thromboembolic disorders have also been reported in people who have received Gardasil. Most of these individuals had risk factors for blood clots, such as use of oral contraceptives, which are known to increase the risk of clotting. Thromboembolic disorders as well as other medical events are being studied through the Vaccine Safety Datalink Project in previously-planned, controlled studies. Merck has also committed to conduct a large post-marketing study to further assess the vaccine's safety.
The vaccine is one of Merck's flagship products but its sales have been under pressure. The company has recently predicted 2008 Gardasil sales of between US$1.4 billion and US$1.6 billion, down from prior estimates of US$1.9 billion to US$2.1 billion. The lower forecast is due, in part, to Merck's failure earlier in the year to receive US approval to market the vaccine to older women aged 27 to 45 years, as well as to extend its indication to include HPV types not included in the vaccine.
Gardasil is approved in the US for use in girls and women aged nine through 26 years to prevents infection with the types of HPV that cause most cases of cervical cancer and genital warts. The CDC's Advisory Committee on Immunization Practices recommended routine three-dose vaccination of girls aged 11 and 12 years. The vaccine is also recommended for girls and women aged 13 through 26 years who have not yet been vaccinated or who have not received all three doses.
Gardasil is marketed by sanofi pasteur MSD (sanofi-aventis’ joint venture [JV] with Merck) in EU countries covered by the JV and several other European countries. In the remaining European countries, located in Central and Eastern Europe, the vaccine is marketed by Merck Sharp & Dohme under the tradename, Silgard.
Matthew Dennis - Editor, Cancer Drug News
To date, the manufacturer, Merck & Co has distributed over 16 million doses of Gardasil in the US and as of 30th June, there have been 9,749 reports of adverse events following vaccination. Of these, 94 per cent were classified as reports of non-serious events, and 6 per cent as serious events. The non-serious events include syncope, pain at the injection site, headache, nausea and fever.
However, concerns have been raised about reports of deaths occurring in individuals after receiving Gardasil. As of 30th June, 20 deaths had been reported, although there was not a common pattern that would suggest they were caused by the vaccine. According to the review, in cases where autopsy, death certificate and medical records were available, the cause of death was explained by factors other than the vaccine.
Guillain-Barré syndrome (GBS) has also been reported in individuals following vaccination with Gardasil. The FDA and CDC have reviewed the reports and, to date, there is no evidence that Gardasil has increased the rate of GBS above that expected in the population. Thromboembolic disorders have also been reported in people who have received Gardasil. Most of these individuals had risk factors for blood clots, such as use of oral contraceptives, which are known to increase the risk of clotting. Thromboembolic disorders as well as other medical events are being studied through the Vaccine Safety Datalink Project in previously-planned, controlled studies. Merck has also committed to conduct a large post-marketing study to further assess the vaccine's safety.
The vaccine is one of Merck's flagship products but its sales have been under pressure. The company has recently predicted 2008 Gardasil sales of between US$1.4 billion and US$1.6 billion, down from prior estimates of US$1.9 billion to US$2.1 billion. The lower forecast is due, in part, to Merck's failure earlier in the year to receive US approval to market the vaccine to older women aged 27 to 45 years, as well as to extend its indication to include HPV types not included in the vaccine.
Gardasil is approved in the US for use in girls and women aged nine through 26 years to prevents infection with the types of HPV that cause most cases of cervical cancer and genital warts. The CDC's Advisory Committee on Immunization Practices recommended routine three-dose vaccination of girls aged 11 and 12 years. The vaccine is also recommended for girls and women aged 13 through 26 years who have not yet been vaccinated or who have not received all three doses.
Gardasil is marketed by sanofi pasteur MSD (sanofi-aventis’ joint venture [JV] with Merck) in EU countries covered by the JV and several other European countries. In the remaining European countries, located in Central and Eastern Europe, the vaccine is marketed by Merck Sharp & Dohme under the tradename, Silgard.
Matthew Dennis - Editor, Cancer Drug News
Roche looks to buy Genentech
Roche has proposed to acquire the outstanding publicly-held interest in Genentech for US$89.00 per share in cash, or a total payment of approximately US$43.7 billion to equity holders of Genentech other than Roche. Roche acquired a majority stake in Genentech in 1990 and currently owns 55.9 per cent of all outstanding shares.
The offer represents a one-day premium of 8.8 per cent to Genentech's closing price of US$81.82 on 18th July and a one-month premium of 19.0 per cent to Genentech's closing price of US$74.76 on 20th June. However, many analysts predict that the move undervalues the company and Genentech will refuse the initial offer, pricing the company higher at between US$100.00 and US$120.00 per share.
If the deal does go through then it would be the biggest in the sector since Pfizer paid US$57 billion for Pharmacia five years ago. The pharmaceutical sector is witnessing a spate of acquisitions of biotech companies as groups search for new drugs, especially in oncology, to offset the decline in their product pipelines.
Under the proposed acquisition, Genentech will operate as an independent research and early development centre within Roche from its existing campus in South San Francisco, CA, retaining its expertise and approach to discovering and progressing new molecules. The structure of the combined company will allow for a diversity of approaches in research and early development, while also strengthening cross fertilisation between the companies, leading to enhanced overall innovation within the Group. Roche's recently-adopted Disease Biology Area approach, which allows five diverse groups to manage their innovative portfolios, will be maintained and strengthened. This, together with recent moves into RNAi and delivery technologies, as well as licensing activities, continues to provide a stimulating environment for the creation of medically-differentiated medicines.
Roche's Pharma commercial operations in the US will be moved from Nutley to Genentech's site in South San Francisco, CA. The existing US sales organisations of both companies will be maintained, resulting in a very strong presence in several specialty areas. The combined entity will be the seventh largest US pharmaceuticals company in terms of market share. It will generate more than US$15 billion in annual revenues and will employ around 17,500 pharma employees in the US alone, including a combined sales force of approximately 3,000 people. Including diagnostics, the Roche Group will employ around 25,000 people in the US.
With various clinical trial results expected in the next 18 months, analysts expect that Genentech's share price could soar on the back of positive data. Genentech's Avastin (bevacizumab) is in clinical testing as a secondary treatment for colon and breast cancer, and Rituxan (rituximab) is being investigated as a possible lupus treatment. Some experts believe that positive outcomes could bring Genentech an additional US$5 billion in peak sales for Avastin alone. The ultimate goal, however, would be to pair Genentech's therapeutics with Roche’s diagnostics to inform physicians which patients can benefit from specific treatments. The move looks like a smart one for both parties.
Matthew Dennis - Editor, Cancer Drug News
The offer represents a one-day premium of 8.8 per cent to Genentech's closing price of US$81.82 on 18th July and a one-month premium of 19.0 per cent to Genentech's closing price of US$74.76 on 20th June. However, many analysts predict that the move undervalues the company and Genentech will refuse the initial offer, pricing the company higher at between US$100.00 and US$120.00 per share.
If the deal does go through then it would be the biggest in the sector since Pfizer paid US$57 billion for Pharmacia five years ago. The pharmaceutical sector is witnessing a spate of acquisitions of biotech companies as groups search for new drugs, especially in oncology, to offset the decline in their product pipelines.
Under the proposed acquisition, Genentech will operate as an independent research and early development centre within Roche from its existing campus in South San Francisco, CA, retaining its expertise and approach to discovering and progressing new molecules. The structure of the combined company will allow for a diversity of approaches in research and early development, while also strengthening cross fertilisation between the companies, leading to enhanced overall innovation within the Group. Roche's recently-adopted Disease Biology Area approach, which allows five diverse groups to manage their innovative portfolios, will be maintained and strengthened. This, together with recent moves into RNAi and delivery technologies, as well as licensing activities, continues to provide a stimulating environment for the creation of medically-differentiated medicines.
Roche's Pharma commercial operations in the US will be moved from Nutley to Genentech's site in South San Francisco, CA. The existing US sales organisations of both companies will be maintained, resulting in a very strong presence in several specialty areas. The combined entity will be the seventh largest US pharmaceuticals company in terms of market share. It will generate more than US$15 billion in annual revenues and will employ around 17,500 pharma employees in the US alone, including a combined sales force of approximately 3,000 people. Including diagnostics, the Roche Group will employ around 25,000 people in the US.
With various clinical trial results expected in the next 18 months, analysts expect that Genentech's share price could soar on the back of positive data. Genentech's Avastin (bevacizumab) is in clinical testing as a secondary treatment for colon and breast cancer, and Rituxan (rituximab) is being investigated as a possible lupus treatment. Some experts believe that positive outcomes could bring Genentech an additional US$5 billion in peak sales for Avastin alone. The ultimate goal, however, would be to pair Genentech's therapeutics with Roche’s diagnostics to inform physicians which patients can benefit from specific treatments. The move looks like a smart one for both parties.
Matthew Dennis - Editor, Cancer Drug News
Monday, July 21, 2008
TroVax hits problems in TRIST
Following its fourth interim review of the TRIST (TroVax Renal Immunotherapy Survival Trial) study, the independent Data Safety Monitoring Board (DSMB) has advised that TroVax administered according to the protocol will not meet the predefined primary efficacy endpoint. The Phase III study is investigating the vaccine in locally-advanced or metastatic clear cell renal carcinoma (RCC) and has a primary endpoint of overall survival in the TroVax-treated versus the placebo group. TroVax is Oxford BioMedica's (OBM) novel therapeutic cancer vaccine, which is being developed in collaboration with sanofi-aventis.
The DSMB has recommended that the study continues because there is important scientific merit and more to be learned by additional follow-up of all patients, but further vaccinations are discontinued; OBM has implemented the recommendation. In addition, the company intends to amend the statistical plan of the study to determine whether patient outcome is dependent on the number of TroVax doses administered. The news hit the former’s share price hard, as its stock fell from a close of 18.5p on 10th July, to open at 7p on 11th July, before closing the day at 7.5p, a 59 per cent drop.
The companies will discuss the proposed TRIST protocol amendments with regulatory authorities. With these amendments, a focus of the ongoing TRIST study will be to explore the number of doses that provide optimal benefit. In particular, it may be that the optimal benefit-to-risk ratio is delivered without the requirement for as many vaccinations as specified in the original TRIST study protocol. It is unlikely that the TRIST study alone will support registration of TroVax in RCC, although the trial may ultimately demonstrate a survival advantage for TroVax, and the results may form part of a regulatory submission alongside an additional confirmatory trial.
The randomised, placebo-controlled TRIST study was initiated in November 2006 and completed recruitment of 733 patients in March 2008 at more than 100 sites in the US, EU and Eastern Europe. It is designed to evaluate TroVax in combination with standard-of-care in locally-advanced or metastatic clear cell RCC. The original trial protocol, which was the subject of a Special Protocol Assessment by the FDA, allowed for patients to receive up to 13 immunisations over 73 weeks.
TroVax targets the tumour antigen 5T4, which is broadly distributed throughout a wide range of solid tumours. The product consists of a modified vaccinia Ankara vector, which delivers the gene for 5T4 and stimulates a patient's body to produce an anti-5T4 immune response. This immune response destroys tumour cells carrying the 5T4 antigen.
OBM and sanofi-aventis will evaluate the available data and the implications on the development plan for TroVax, including the planned Phase III trials in colorectal cancer (CRC). The Oncology Clinical Trials Office, part of the Clinical Pharmacology Department of the University of Oxford, has stated that the DSMB's recommendations in relation to the TRIST study "does not impact on our enthusiasm to progress the QUASAR V TroVax study" in adjuvant CRC. But it remains to be seen what the companies' stance on future trials is.
Matthew Dennis - Editor, Cancer Drug News
The DSMB has recommended that the study continues because there is important scientific merit and more to be learned by additional follow-up of all patients, but further vaccinations are discontinued; OBM has implemented the recommendation. In addition, the company intends to amend the statistical plan of the study to determine whether patient outcome is dependent on the number of TroVax doses administered. The news hit the former’s share price hard, as its stock fell from a close of 18.5p on 10th July, to open at 7p on 11th July, before closing the day at 7.5p, a 59 per cent drop.
The companies will discuss the proposed TRIST protocol amendments with regulatory authorities. With these amendments, a focus of the ongoing TRIST study will be to explore the number of doses that provide optimal benefit. In particular, it may be that the optimal benefit-to-risk ratio is delivered without the requirement for as many vaccinations as specified in the original TRIST study protocol. It is unlikely that the TRIST study alone will support registration of TroVax in RCC, although the trial may ultimately demonstrate a survival advantage for TroVax, and the results may form part of a regulatory submission alongside an additional confirmatory trial.
The randomised, placebo-controlled TRIST study was initiated in November 2006 and completed recruitment of 733 patients in March 2008 at more than 100 sites in the US, EU and Eastern Europe. It is designed to evaluate TroVax in combination with standard-of-care in locally-advanced or metastatic clear cell RCC. The original trial protocol, which was the subject of a Special Protocol Assessment by the FDA, allowed for patients to receive up to 13 immunisations over 73 weeks.
TroVax targets the tumour antigen 5T4, which is broadly distributed throughout a wide range of solid tumours. The product consists of a modified vaccinia Ankara vector, which delivers the gene for 5T4 and stimulates a patient's body to produce an anti-5T4 immune response. This immune response destroys tumour cells carrying the 5T4 antigen.
OBM and sanofi-aventis will evaluate the available data and the implications on the development plan for TroVax, including the planned Phase III trials in colorectal cancer (CRC). The Oncology Clinical Trials Office, part of the Clinical Pharmacology Department of the University of Oxford, has stated that the DSMB's recommendations in relation to the TRIST study "does not impact on our enthusiasm to progress the QUASAR V TroVax study" in adjuvant CRC. But it remains to be seen what the companies' stance on future trials is.
Matthew Dennis - Editor, Cancer Drug News
Thursday, July 10, 2008
Europe moves in right direction
The first research to examine recent trends in European cancer incidence, mortality and survival together has shown that cancer prevention and management in Europe is moving in the right direction. However, the work reveals that variations between countries in policies for mass screening, access to healthcare and treatment are reflected in the different cancer rates. The research, consisting of ten papers, has been published in a special July edition of the European Journal of Cancer and coincides with the start of work by the EC to draw up a new EU Cancer Action Plan.
In one study (2008;44:1345-1389), scientists from the Erasmus Medical Centre obtained data on incidence, mortality and five-year survival from the mid-1990s to the mid-2000s from cancer registries in 21 European countries, and used it to analyse trends. The researchers found that generally in the more prosperous countries of Northern and Western Europe the trend was downwards for cancer incidence; the exceptions were for obesity-related cancers, such as colorectal and postmenopausal breast cancer (BC), and for tobacco-related cancers in women, such as lung cancer.
Incidence and mortality from tobacco-related cancer decreased for men in Northern, Western and Southern Europe, they increased for both sexes in Central Europe and for women nearly everywhere in Europe. With the exception of smoking-related cancers, mortality trends generally in most cancers were moving downwards for the majority of Europe.
Survival rates for most cancers generally improved. The investigators state that this is due to better access to specialised diagnostics, staging and treatment. For instance, although the incidence of BC continues to rise in most countries, deaths are declining and survival is improving. The rising incidence and survival rates are partly influenced by the presence of organised BC screening programmes and even opportunistic screening that increases the detection of smaller and less aggressive tumours. Survival and mortality is also influenced by improved staging and treatment, such as the use of tamoxifen in postmenopausal patients and chemotherapy in premenopausal patients.
The impact of mass screening is investigated in greater depth in another paper (2008;44:1404-1413), and in a further paper (2008;44:1425-1437), on the potential ways of closing the gap between Central and Eastern Europe through changes in lifestyles, which could reduce the incidence of some cancers. Another report (2008;44:1451-1456), by scientists from the Institute of Public Health of the Republic of Slovenia, outlines some of the issues for Europe, including the identification of five groups of key stakeholders: patients, health policy, reimbursement and financing agencies, research and finally, pharmaceutical and medical technology industries. Four key resources are identified as the most relevant to successful cancer management: human resources, physical resources, knowledge resources and social resources.
The paper concludes that Europe must focus on four types of interventions: primary prevention and health promotion; secondary prevention with proven screening programmes; more equitable access to optimal treatment and integration of all cancer care services; and sustained and consistent support for advanced independent research. All of those involved in the oncology field will hope that the EC listens to its experts and outlines a plan that will tackle these important issues.
Matthew Dennis - Editor, Cancer Drug News
In one study (2008;44:1345-1389), scientists from the Erasmus Medical Centre obtained data on incidence, mortality and five-year survival from the mid-1990s to the mid-2000s from cancer registries in 21 European countries, and used it to analyse trends. The researchers found that generally in the more prosperous countries of Northern and Western Europe the trend was downwards for cancer incidence; the exceptions were for obesity-related cancers, such as colorectal and postmenopausal breast cancer (BC), and for tobacco-related cancers in women, such as lung cancer.
Incidence and mortality from tobacco-related cancer decreased for men in Northern, Western and Southern Europe, they increased for both sexes in Central Europe and for women nearly everywhere in Europe. With the exception of smoking-related cancers, mortality trends generally in most cancers were moving downwards for the majority of Europe.
Survival rates for most cancers generally improved. The investigators state that this is due to better access to specialised diagnostics, staging and treatment. For instance, although the incidence of BC continues to rise in most countries, deaths are declining and survival is improving. The rising incidence and survival rates are partly influenced by the presence of organised BC screening programmes and even opportunistic screening that increases the detection of smaller and less aggressive tumours. Survival and mortality is also influenced by improved staging and treatment, such as the use of tamoxifen in postmenopausal patients and chemotherapy in premenopausal patients.
The impact of mass screening is investigated in greater depth in another paper (2008;44:1404-1413), and in a further paper (2008;44:1425-1437), on the potential ways of closing the gap between Central and Eastern Europe through changes in lifestyles, which could reduce the incidence of some cancers. Another report (2008;44:1451-1456), by scientists from the Institute of Public Health of the Republic of Slovenia, outlines some of the issues for Europe, including the identification of five groups of key stakeholders: patients, health policy, reimbursement and financing agencies, research and finally, pharmaceutical and medical technology industries. Four key resources are identified as the most relevant to successful cancer management: human resources, physical resources, knowledge resources and social resources.
The paper concludes that Europe must focus on four types of interventions: primary prevention and health promotion; secondary prevention with proven screening programmes; more equitable access to optimal treatment and integration of all cancer care services; and sustained and consistent support for advanced independent research. All of those involved in the oncology field will hope that the EC listens to its experts and outlines a plan that will tackle these important issues.
Matthew Dennis - Editor, Cancer Drug News
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