When designing drugs to target and treat cancer, the last thing that you want to happen is for the agents to actually promote tumour growth. But this is what a study by scientists from the UK has found is the case when low doses of an experimental angiogenesis inhibitor were given to mouse models. However, there is hope that turning the findings on their head will help in the development of new ways to make these drugs as effective as possible. In the future, it may be feasible to combine these inhibitors with other drugs to maximise their effectiveness for patients.
Angiogenesis inhibitors are designed to block the supply of blood to the tumour to prevent it from growing. Some of these have proven successful in the clinic and gone on to be widely used, such as Avastin (bevacizumab) and Sutent (sunitinib), while others, such as those that inhibit the v3 and v5 integrins, have entered clinical trials but have generally been unsuccessful.
One such agent under development that targets integrins is cilengitide, which is thought to work by targeting the tumour and its vasculature. The agent is currently being investigated in a Phase III trial for the treatment of glioblastoma multiforme (GBM), as well as a number of Phase II studies in several indications, including advanced non-small cell lung cancer and squamous cell carcinoma of the head and neck. Now, scientists from the Institute of Cancer, Queen Mary's University London, the Institute of Cancer Research and the Beatson Institute for Cancer Research have found evidence to suggest that low doses of cilengitide in laboratory studies can have the opposite effect to what was expected and promote cancer growth.
The work, which was published in the 22nd March online edition of Nature Medicine (10.1038/nm.1941), showed that low concentrations of the drug promoted VEGF-mediated angiogenesis by altering v3 integrin and VEGFr-2 trafficking, thereby promoting endothelial cell migration to VEGF. The study found that while higher concentrations of cilengitide can block angiogenesis, lower concentrations can actually stimulate the supply of blood to the tumour and can promote its growth. These results may explain why initial results from early-stage clinical trials have not been as promising as hoped.
Cilengitide is being developed by Merck Serono (Merck KGaA), which in response to the Nature Medicine article issued a statement citing previous findings in numerous preclinical models of the drug in vitro and in vivo that diverge from the latest results. The company also countered with the fact that cilengitide has been studied in more than 750 patients in various long-term settings supporting its current development. Notably, the clinical data for cilengitide in the treatment of GBM, both as a single agent and in combination, have been encouraging. However, all current Merck Serono studies are investigating cilengitide in combination treatment (either radiotherapy and chemotherapy or chemotherapy and another targeted therapy), so there may be some truth in the fact that this class of drugs will not have utility as single agents. Only time will tell.
Matthew Dennis - Editor, Cancer Drug News
Wednesday, March 25, 2009
Wednesday, March 18, 2009
Dendreon surges on Provenge hope
Shares in Dendreon have increased dramatically over the past few days, possibly as the result of investors trying to cash in before the company releases final results from its make-or-break IMPACT (IMmunotherapy for Prostate AdenoCarcinoma Treatment; also known as D9902B) study. The trial is designed to assess the safety and efficacy of the investigational active cellular immunotherapy, Provenge (sipuleucel-T), in men with metastatic androgen-independent prostate cancer (PCA). Dendreon’s shares closed at US$4.05 on 13th March, up 46 per cent on the closing price on 11th March of US$2.77.
The latest price increase was likely triggered by the release of Dendreon’s fourth quarter and 2008 year-end financial results on 12th March, confirming that it anticipates the IMPACT study to continue to its final analysis, which is expected to be completed by the end of April. Favourable blinded, interim results from the trial were previously reported in October 2008, when the independent Data Monitoring Committee (IDMC), which is overseeing the trial, recorded a 20 per cent reduction in the risk of death in the Provenge arm relative to placebo (hazard ratio=0.80; 95% CI, 0.610 to 1.051). The IDMC observed no safety concerns and recommended that the study continues as planned. However, at that time the company only announced that the final analysis was anticipated in the middle of 2009.
At the final analysis, if the study demonstrates approximately a 22 per cent reduction in the risk of death, based on 304 events, the company would expect the trial to meet its primary endpoint of overall survival (OS). Should the prespecified criterion for statistical significance be achieved, Dendreon would anticipate amending its BLA based on these interim results. The initial BLA filing was based primarily on an improvement in OS observed in the Phase III D9901 trial. Following an FDA Advisory Committee vote that there was substantial evidence of efficacy of Provenge and that it was reasonably safe, the Agency requested additional clinical data to support the proposed efficacy claim. The FDA has since indicated that either a positive interim or final analysis for OS from the IMPACT trial would be sufficient to address the request for additional information to support the proposed efficacy claim.
Sipuleucel-T contains mature, autologous antigen presenting cells (APCs) that are obtained from the patient via a standard procedure approximately two days before each scheduled infusion. The patient's APCs are then transported to a Dendreon manufacturing facility where they are co-cultured with a recombinant fusion protein containing prostatic acid phosphatase. The activated, antigen-loaded APCs (now sipuleucel-T) are then delivered to the physician's office for infusion into the patient. Sipuleucel-T is then infused into the patient, where it can potentially stimulate a T-cell response against PCA cells. Well, that is the theory anyway, and investors buying up Dendreon’s shares will hope that is also the case in the IMPACT study. They will also have their fingers crossed that the company can hit the heady heights of April 2007, when its shares reached US$23.58.
Matthew Dennis - Editor, Cancer Drug News
The latest price increase was likely triggered by the release of Dendreon’s fourth quarter and 2008 year-end financial results on 12th March, confirming that it anticipates the IMPACT study to continue to its final analysis, which is expected to be completed by the end of April. Favourable blinded, interim results from the trial were previously reported in October 2008, when the independent Data Monitoring Committee (IDMC), which is overseeing the trial, recorded a 20 per cent reduction in the risk of death in the Provenge arm relative to placebo (hazard ratio=0.80; 95% CI, 0.610 to 1.051). The IDMC observed no safety concerns and recommended that the study continues as planned. However, at that time the company only announced that the final analysis was anticipated in the middle of 2009.
At the final analysis, if the study demonstrates approximately a 22 per cent reduction in the risk of death, based on 304 events, the company would expect the trial to meet its primary endpoint of overall survival (OS). Should the prespecified criterion for statistical significance be achieved, Dendreon would anticipate amending its BLA based on these interim results. The initial BLA filing was based primarily on an improvement in OS observed in the Phase III D9901 trial. Following an FDA Advisory Committee vote that there was substantial evidence of efficacy of Provenge and that it was reasonably safe, the Agency requested additional clinical data to support the proposed efficacy claim. The FDA has since indicated that either a positive interim or final analysis for OS from the IMPACT trial would be sufficient to address the request for additional information to support the proposed efficacy claim.
Sipuleucel-T contains mature, autologous antigen presenting cells (APCs) that are obtained from the patient via a standard procedure approximately two days before each scheduled infusion. The patient's APCs are then transported to a Dendreon manufacturing facility where they are co-cultured with a recombinant fusion protein containing prostatic acid phosphatase. The activated, antigen-loaded APCs (now sipuleucel-T) are then delivered to the physician's office for infusion into the patient. Sipuleucel-T is then infused into the patient, where it can potentially stimulate a T-cell response against PCA cells. Well, that is the theory anyway, and investors buying up Dendreon’s shares will hope that is also the case in the IMPACT study. They will also have their fingers crossed that the company can hit the heady heights of April 2007, when its shares reached US$23.58.
Matthew Dennis - Editor, Cancer Drug News
Friday, March 13, 2009
Merck to pay US$41.1 billion for Schering-Plough
A definitive merger agreement has been unanimously approved by the Boards of Directors under which Merck & Co and Schering-Plough will combine, under the name Merck, in a stock and cash transaction. Under the terms of the agreement, Schering-Plough shareholders will receive 0.5767 shares and US$10.50 in cash for each share of Schering-Plough. Each Merck share will automatically become a share of the combined company.
Based on the closing price of Merck stock on 6th March, the consideration to be received by Schering-Plough shareholders is valued at US$23.61 per share, or US$41.1 billion in the aggregate. This price represents a premium to Schering-Plough shareholders of approximately 34 per cent based on the closing price of Schering-Plough stock on 6th March. The consideration also represents a premium of approximately 44 per cent based on the average closing price of the two stocks over the last 30 trading days.
Upon closing of the transaction, Merck shareholders are expected to own approximately 68 per cent of the combined company and Schering-Plough shareholders are expected to own approximately 32 per cent. Merck anticipates that the transaction will be modestly accretive to non-GAAP EPS in the first full year following completion and significantly accretive thereafter.
The combination significantly broadens Merck's portfolio of medicines driven, in part, by the addition of valuable products with long periods of exclusivity. By leveraging the combined company's expanded product offerings, Merck expects to benefit from additional revenue growth opportunities. For example, the combined company will have expanded opportunities for life-cycle management through the introduction of potential new combinations and formulations of existing products. In addition, Merck and Schering-Plough together have high-potential early-, mid- and late-stage pipeline candidates. The transaction will double the number of potential medicines Merck has in Phase III development, bringing the total to 18. The combined company will have a more diverse portfolio across important therapeutic areas, including oncology.
Schering-Plough's current oncology products, which include Caelyx (pegylated liposomal doxorubicin), Intron A (interferon alpha-2b recombinant for injection)/PegIntron (peginterferon alpha-2b) and Temodar/Temodal (temozolomide) Capsules, will enable Merck to expand its presence in this area and provide the necessary foundation to take advantage of the combined company's promising pipeline. Merck also expects to benefit from a solid portfolio of women's health products, which includes the cervical cancer vaccine, Gardasil (human papillomavirus quadrivalent types 6, 11, 16 and 18 vaccine, recombinant).
The transaction is subject to approval by Merck and Schering-Plough shareholders, and the satisfaction of customary closing conditions and regulatory approvals, including expiration or termination of the applicable waiting period under the Hart-Scott-Rodino Act, as well as clearance by the EC under the EC Merger Regulation and certain other foreign jurisdictions. Merck and Schering-Plough expect to complete the transaction in the fourth quarter of 2009, by which time there may well have been more such acquisitions, with Bristol-Myers Squibb being the current favourite target.
Matthew Dennis - Editor, Cancer Drug News
Based on the closing price of Merck stock on 6th March, the consideration to be received by Schering-Plough shareholders is valued at US$23.61 per share, or US$41.1 billion in the aggregate. This price represents a premium to Schering-Plough shareholders of approximately 34 per cent based on the closing price of Schering-Plough stock on 6th March. The consideration also represents a premium of approximately 44 per cent based on the average closing price of the two stocks over the last 30 trading days.
Upon closing of the transaction, Merck shareholders are expected to own approximately 68 per cent of the combined company and Schering-Plough shareholders are expected to own approximately 32 per cent. Merck anticipates that the transaction will be modestly accretive to non-GAAP EPS in the first full year following completion and significantly accretive thereafter.
The combination significantly broadens Merck's portfolio of medicines driven, in part, by the addition of valuable products with long periods of exclusivity. By leveraging the combined company's expanded product offerings, Merck expects to benefit from additional revenue growth opportunities. For example, the combined company will have expanded opportunities for life-cycle management through the introduction of potential new combinations and formulations of existing products. In addition, Merck and Schering-Plough together have high-potential early-, mid- and late-stage pipeline candidates. The transaction will double the number of potential medicines Merck has in Phase III development, bringing the total to 18. The combined company will have a more diverse portfolio across important therapeutic areas, including oncology.
Schering-Plough's current oncology products, which include Caelyx (pegylated liposomal doxorubicin), Intron A (interferon alpha-2b recombinant for injection)/PegIntron (peginterferon alpha-2b) and Temodar/Temodal (temozolomide) Capsules, will enable Merck to expand its presence in this area and provide the necessary foundation to take advantage of the combined company's promising pipeline. Merck also expects to benefit from a solid portfolio of women's health products, which includes the cervical cancer vaccine, Gardasil (human papillomavirus quadrivalent types 6, 11, 16 and 18 vaccine, recombinant).
The transaction is subject to approval by Merck and Schering-Plough shareholders, and the satisfaction of customary closing conditions and regulatory approvals, including expiration or termination of the applicable waiting period under the Hart-Scott-Rodino Act, as well as clearance by the EC under the EC Merger Regulation and certain other foreign jurisdictions. Merck and Schering-Plough expect to complete the transaction in the fourth quarter of 2009, by which time there may well have been more such acquisitions, with Bristol-Myers Squibb being the current favourite target.
Matthew Dennis - Editor, Cancer Drug News
Synta suspends SYMMETRY study
Based on an analysis by an independent Data Monitoring Committee (DMC), Synta Pharmaceuticals has suspended the Phase III SYMMETRY (Synta Metastatic Melanoma Elesclomol Trial) trial, which was comparing elesclomol (STA-4783) in combination with paclitaxel to paclitaxel alone in chemotherapy-naïve patients with Stage IV metastatic melanoma. Following the suspension, shares in Synta fell from US$6.39 at the end of 26th February to close on 27th February at US$1.36, a decrease in value of nearly 79 per cent.
The decision was based on the results of an analysis by the DMC, which identified safety concerns, including an imbalance in overall survival, with a greater number of deaths occurring in the combination arm (elesclomol+paclitaxel) compared to the control arm of paclitaxel alone. The final analysis of the primary endpoint (progression-free survival) as assessed by independent reviewers has not been carried out yet. Elesclomol is an apoptosis stimulator, which acts by inducing oxidative stress in cancer cells by rapidly producing reactive oxygen species. Response to this oxidative stress leads to apoptosis.
Based on these findings, Synta has also revealed that additional ongoing studies with elesclomol, including a study of elesclomol in combination with docetaxel in hormone-refractory metastatic prostate cancer and a monotherapy dose-escalation study, will be suspended pending further analysis of the results of the SYMMETRY trial. Synta is contacting investigators regarding appropriate patient notification and care. The company is also in discussions with its collaborator, GlaxoSmithKline, about the future development of elesclomol. However, it looks likely that GSK will terminate the collaboration.
Such a huge setback could spell the end for Synta, especially in the current economic climate. However, the company has stated that it has both the resources and a diverse pipeline of novel drug candidates in the oncology and anti-inflammatory areas that will allow it to continue operating. The company has recently received two milestone payments that should help its current cash position. These include an up-front payment of US$16 million from Roche for the development of the Synta CRACM (calcium release-activated calcium modulator) programme for the treatment of inflammatory and autoimmune diseases, as well as committed research funding of US$9 million over the next two years. The second payment of US$10 million was received from GSK after Synta achieved a milestone related to the development of elesclomol.
Synta's pipeline includes: STA-9090, a novel heat shock protein 90 inhibitor that is currently in two Phase I studies in solid tumours; STA-5326 (apilimod mesylate), an oral interleukin (IL)-12/IL-23 inhibitor currently in a Phase IIa study in rheumatoid arthritis; STA-9584, a vascular disrupting agent for cancer in preclinical development; and additional programmes in the research and preclinical development stages. Synta shareholders will hope that these programmes prove more successful than elesclomol.
Matthew Dennis - Editor, Cancer Drug News
The decision was based on the results of an analysis by the DMC, which identified safety concerns, including an imbalance in overall survival, with a greater number of deaths occurring in the combination arm (elesclomol+paclitaxel) compared to the control arm of paclitaxel alone. The final analysis of the primary endpoint (progression-free survival) as assessed by independent reviewers has not been carried out yet. Elesclomol is an apoptosis stimulator, which acts by inducing oxidative stress in cancer cells by rapidly producing reactive oxygen species. Response to this oxidative stress leads to apoptosis.
Based on these findings, Synta has also revealed that additional ongoing studies with elesclomol, including a study of elesclomol in combination with docetaxel in hormone-refractory metastatic prostate cancer and a monotherapy dose-escalation study, will be suspended pending further analysis of the results of the SYMMETRY trial. Synta is contacting investigators regarding appropriate patient notification and care. The company is also in discussions with its collaborator, GlaxoSmithKline, about the future development of elesclomol. However, it looks likely that GSK will terminate the collaboration.
Such a huge setback could spell the end for Synta, especially in the current economic climate. However, the company has stated that it has both the resources and a diverse pipeline of novel drug candidates in the oncology and anti-inflammatory areas that will allow it to continue operating. The company has recently received two milestone payments that should help its current cash position. These include an up-front payment of US$16 million from Roche for the development of the Synta CRACM (calcium release-activated calcium modulator) programme for the treatment of inflammatory and autoimmune diseases, as well as committed research funding of US$9 million over the next two years. The second payment of US$10 million was received from GSK after Synta achieved a milestone related to the development of elesclomol.
Synta's pipeline includes: STA-9090, a novel heat shock protein 90 inhibitor that is currently in two Phase I studies in solid tumours; STA-5326 (apilimod mesylate), an oral interleukin (IL)-12/IL-23 inhibitor currently in a Phase IIa study in rheumatoid arthritis; STA-9584, a vascular disrupting agent for cancer in preclinical development; and additional programmes in the research and preclinical development stages. Synta shareholders will hope that these programmes prove more successful than elesclomol.
Matthew Dennis - Editor, Cancer Drug News
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