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
Wednesday, November 5, 2008
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
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