| ONCOLOGY DEVELOPMENT UPDATES |
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| NEWS HIGHLIGHTS - NOVEMBER 2008 | |
| |  At the recommendation of the independent Data Monitoring Committee (DMC), following a planned safety data review of 600 patients, Amgen and Takeda Pharmaceutical Company temporarily suspended enrollment in the phase III clinical trial (protocol ID: 20050201; NCT00460317), dubbed MONET1 (Motesanib NSCLC Efficacy and Tolerability Study), evaluating motesanib (AMG 706) in combination with paclitaxel and carboplatin for the first line treatment of advanced non-small cell lung cancer (nsclc), based on an observation of higher early mortality rates in the motesanib group compared to the placebo group. In addition, the DMC recommended that patients with squamous nsclc immediately discontinue motesanib therapy based on an observation of a higher incidence of hemoptysis (see News and New Drugs modules).
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| | The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) issued a positive opinion, recommending granting a centralized marketing authorization to IDM Pharma’s drug mifamurtide (L-MTP-PE), known as MEPACT in Europe, for the treatment of patients with nonmetastatic, resectable osteosarcoma in combination with chemotherapy based on an overall survival after 6 years of follow-up that was 78% with L-MTP-PE and chemotherapy compared to 70% with chemotherapy alone, representing a 30% decrease in the risk of death (see News and New Drugs modules). |
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| | A global phase III clinical trial (protocol ID: BO18192; NCT00556712), dubbed SATURN, with Tarceva (erlotinib) administered immediately following initial treatment with platinum-based chemotherapy, in patients with advanced non-small cell lung cancer (nsclc) met its primary endpoint by significantly extending progression-free survival (PFS) compared to placebo; OSI Pharmaceuticals, Genentech and Roche are contemplating next steps for a potential new indication for Tarceva with the FDA and European health authorities (see News, Marketed Drugs and Combination Trials modules). |
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| | The FDA approved Cephalon’s Treanda (bendamustine hydrochloride) for Injection for the treatment of patients with indolent B-cell non-Hodgkin's lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab (Rituxan) or a rituximab-containing regimen (see News and Marketed Drugs modules). |
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| | Genzyme and Osiris entered a strategic alliance for the development and commercialization of Prochymal and Chondrogen, two novel, adult stem cell treatments in late stage of development that may treat a wide range of diseases. Genzyme will make a $130 million upfront payment to Osiris and potentially a total of up to $1.25 billion in milestone payments (See News and New Drugs modules). |
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| | According to a draft guidance, NICE in the UK found Revlimid not to be cost effective and disputed the estimate of 3 years of extra life gained by treatment with this drug that costs £36,000 per patient per year and breaches the cost effectiveness threshold set by NICE by more than 2-fold (see Marketed Drugs module). |
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| | Clinical Data entered into a definitive merger agreement to acquire Avalon Pharmaceuticals for approximately $10 million in Clinical Data’s common stock (see News, Company and New Drugs modules). |
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| | Celgene terminated its licensing agreement with MethylGene for oncology histone deacetylase (HDAC) inhibitors, including MGCD0103 and other HDAC and sirtuin inhibitors, and returned the rights to these programs to MethylGene (see News, and New Drugs modules). |
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| | VioQuest Pharmaceuticals disclosed in its recent filing with the SEC that it has an immediate need for additional capital to cover its current obligations and future operating expenses, and fund its clinical development programs (see News, Company and New Drugs Module). |
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| | GlaxoSmithKline (GSK) decided not to exercise its option to license Exelixis’ drug XL184 and also informed the company that it would not license any of the earlier compounds in the collaboration, including XL281, XL228, XL820, and XL844, thus ending the 6-year collaboration between Exelixis and GSK to discover and develop oncology compounds. As a result, Exelixis retains the rights to develop, commercialize, and/or license all of the compounds, subject to payment to GSK of a 3% royalty on net sales of any product incorporating XL184 (see News and New Drugs modules). |
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| | NICE declined to reimburse Tyverb (lapatinib), for its approved indication in the UK, in combination with capecitabine, in patients with HEr2-expressing breast cancer refractory to standard chemotherapy and trastuzumab, because its 2-month TTP advantage did not justify the £1,068 cost for a 4-week supply; a final decision is expected on November 19, 2008 (see Marketed Drugs module). |
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| | Genentech and OSI Pharmaceuticals report that a randomized phase III clinical trial (BeTa Lung) evaluating Avastin (bevacizumab) in combination with Tarceva (erlotinib) in patients with advanced non-small cell lung cancer (nsclc) that progressed following platinum-based chemotherapy, did not meet its primary endpoint of improving overall survival (OS) compared to Tarceva in combination with placebo (see News and Combination Trials module). |
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| | Cell Genesys terminated the VITAL-1 phase III clinical trial (protocol ID: G-0029; NCT00089856) of GVAX immunotherapy in patients with asymptomatic metastatic hormone-refractory prostate cancer (HRPC) based on the results of a previously unplanned futility analysis conducted by the trial’s Independent Data Monitoring Committee (IDMC), which indicated that the trial had <30% chance of meeting its predefined primary endpoint of an improvement in survival. As a result, Cell Genesys will reduce its staff of 290 by approximately 75% by year-end 2008 with further reductions anticipated in the first half of 2009 as additional activities are phased out (see News, New Drugs and Company modules). |
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| | Additional news items are summarized in the News Module. |
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| SPECIAL REPORT - SEPTEMBER 2008 | |
Clinical Trials of Combinations of Approved ErbB-pathway Inhibitors with Novel Agents
Despite the incredible effort invested in the development of targeted therapeutics addressing the ErbB pathway, first generation drugs only provide incremental benefits to patients. Therefore, the quest for improved approaches to target this pathway is proceeding in numerous fronts, such as:
- Better understanding of the role of the ErbB pathway in malignancy
- Identification of other contributors to the role of ErbB in cancer, in terms of upstream and/or downstream effectors
- Improving targeting approaches by the use of novel delivery systems
- Resolving any differences between monoclonal antibody (MAb)-based agents and small molecule receptor tyrosine kinase (RTK) inhibitors in terms of therapeutic effectiveness
- Overcoming intrinsic and acquired resistance of cancer stem/progenitor cells to ErbB pathway inhibitors
- Evaluating combinations of targeted drugs to significantly enhance their effectiveness
- Evaluating biomarkers associated with toxicity and response
- Identifying patient populations most likely to benefit from ErbB inhibitors using in vitro approaches to profile molecular markers expressed in tumors
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As preclinical and clinical research in applying molecularly targeted agents in oncology expands and intensifies, it is becoming clearer and clearer that this approach to cancer treatment is far more complex than ever imagined. Targeted approaches face similar obstacles, as did standard cytotoxic therapies, namely marginal effectiveness in advanced disease, resistance issues, and toxicities. Unlike standard cytotoxics, however, targeted therapeutics also present another serious dilemma for their developers. Although in certain cases they appear to be highly effective, selecting out the patients who may benefit in such occasions leaves significantly fewer candidates for the treatment, negatively impacting the financial incentive of the company developing the drug. The effect of this emerging challenge in the development of targeted therapeutics may be mitigated by the employment of combination strategies using several targeted drugs, either concurrently or sequentially, to address different members of a pathway, including mutant forms, thus removing ‘escape’ routes and combating resistance.
To date, approved ErbB-pathway inhibitors have been evaluated with other approved drugs, mostly cytotoxics in the hope that the anticipated small gains in effectiveness would expand the clinical utility of the targeted agent leading to approvals in new indications or stimulating off-label use. Over 1,200 trials have been initiated worldwide with these agents and about 50% of these trials are still ongoing. The majority of these are combination trials with other approved drugs, including targeted drugs and standard cytotoxics. The amount of data to be generated by these trials is staggering and the interpretation, comparison and assessment of the results a major undertaking, particularly when small improvements either in effectiveness or tolerability separate the results. Results from these trials will have major implications in clinical practice and influence the development of novel agents.
Various molecular moieties and pathways are being considered as potential combination strategies to enhance the sensitivity of cancer cells to ErbB inhibitors. Targets/pathways implicated in the positive or negative effects of ErbB inhibition in cancer are many, varied and their contribution has not been fully elucidated.
A review published in Volume 9 Issue 7/8 of Future Oncology, describes in detail clinical trials involving non-commercialized novel targeted agents in combination with approved ErbB-pathway inhibitors, namely cetuximab (Erbitux; ImClone Systems), panitumumab (Vectibix; Amgen), nimotuzumab, erlotinib (Tarceva; OSI Pharmaceuticals), gefitinib (Iressa; AstraZeneca), trastuzumab (Herceptin; Genentech), and lapatinib (Tykerb; GlaxoSmithKline).
The novel drugs, targeting a variety of effectors (Exhibit 1), are being combined with approved ErbB-pathway inhibitors based on their mechanism of action and preclinical findings of possible synergism in vivo. These agents (Exhibit 2) represent a cross section of targeted drugs in clinical trials.
The worldwide market for ErbB-pathway inhibitors was $6,678.7 million in 2007 (Exhibit 3), and stood at $4,072.6 million in the first half of 2008 (Exhibit 4).
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| ONCOLOGY DRUG DEVELOPMENT UPDATE - JUNE 2008 | |
| New Medicine's Oncology KnowledgeBASE (nm|OK) Updates Molecularly Targeted Drugs in Oncology |
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There are over 1,000 molecular targets linked to some aspect of neoplasia currently in preclinical or clinical development or on the market. Among the approximately 500 novel molecularly targeted agents that have been evaluated in clinical trials (multitargeted agents may appear in several groups), there are multiple distinct agents addressing some of the most extensively validated oncology targets, among them:
- 41 agents targeting the vascular endothelial growth factor (VEGF) pathway
- 20 agents targeting the ErBb family (EGFr, HEr2, etc.)
- 13 agents targeting the Aurora kinase family
- 11 histone deacetylase inhibitors (HDAC)
- 13 agents targeting PDGF/PDGFr
- 11 agents targeting various heat shock proteins (Hsp)
- 10 drugs targeting various cyclin-dependent kinases (Cdk)
- 10 agents targeting c-Met
- 10 agents targeting IGF/IGFr
- 10 agents targeting FLT-3
- 9 agents targeting c-Kit
Subscribers, to access comprehensive profiles of these agents, please log in and click on the links on the subscriber home page of nm|OK.
Also, a partial list of specific tumor-related molecular targets is presented in a recent press release at PRNewswire.com. Profiles of all of these agents are in nm|OK and may be viewed by entering the target designation in the Target field in the New Drug module Query Screen.
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| ONCOLOGY DRUG DEVELOPMENT UPDATE - MAY 2008 | |
| A New Role for the Epidermal Growth Factor Receptor (EGFr) in Promoting Cancer Cell Proliferation Independently of its Kinase Activity |
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A team at M. D. Anderson Cancer Center (Houston, TX), led by Isaiah J. Fidler, DVM, PhD, and Mien-Chie Hung, PhD, professor and chair of the Department of Molecular and Cellular Oncology, discovered an unexpected role of EGFr that protects cancer cells from starving. This additional role may explain the limited efficacy of EGFr inhibitors in the clinic. Drugs that only block EGFr's activation by growth factors, i.e. its tyrosine kinase activity, result in response rates in only 10% to 20% of patients with various malignancies.
The M. D. Anderson team reports (Weihua Z, etal, Cancer Cell, May 2008;13(5):385-93) that in human cancer cells, the function of kinase-independent EGFr is to prevent autophagic cell death by maintaining intracellular glucose level through interaction and stabilization of the sodium/glucose co-transporter 1 (SGLT1). EGFr protects SGLT1 from destruction by the cell's proteasome complex. Autophagy is thought to be a second type of programmed cell death, with the first being apoptosis.
Because of cancer cells' high metabolic rate, they require more glucose to fuel their activities than do normal cells. Inhibition of the kinase activity of EGFr does not interfere with its SGLT1 stabilizing activity, allowing cancer cells to maintain their intracellular glucose levels. In order to address EGFr's role in preventing cancer cells from accessing glucose, it is necessary to interfere with the receptor per se rather than its activation. Therefore, it may be necessary to knock down both EGFr's glucose-related role and its growth-inducing kinase activity in order to attack epithelial malignancies that make up 80% of all neoplasms. Blocking EGFr itself is expected to induce cancer cell death by self-cannibalization.
In their research, when the M. D. Anderson team addressed the expression of EGFr and not its kinase activity, they found that blocking the receptor's expression with small interfering RNA (siRNA) killed prostate cancer cells. Similar results were obtained in breast cancer and colon cancer cells. The cells did not die from apoptosis but rather of autophagy during which a cell under stress or lacking nutrients consumes part of its cytoplasm and other organelles to survive. Over the long term, this autophagy leads to cell death.
When glucose levels were measured in two sets of prostate cancer cells, one treated with a tyrosine kinase inhibitor, and the other with EGFr knocked down by siRNA, glucose levels were unaffected by the tyrosine kinase inhibitor but fell by 50% in the cells with blocked EGFr. Similar results were obtained in breast and colon cancer cells. Increasing the level of glucose in the medium that held the cells halted autophagic cell death. In seeking glucose transporting proteins, the investigators found that when EGFr was knocked down in a cell, levels of SGLT1 also fell, as did glucose levels, resulting in autophagic cell death.
This research was supported by grants from the National Cancer Institute (NCI), including M. D. Anderson's Specialized Program of Research Excellence (SPORE) in prostate and breast cancer.
Numerous agents blocking the tyrosine activity of EGFr have been investigated preclinically and/or clinically. Currently, 6 agents targeting EGFr have been approved and are on the market and 14 separate agents are in active clinical development. Also, many others are in preclinical development.
The nature and activity of EGFr are described in great detail in the Targets in Oncology module of nm|OK.
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| ONCOLOGY DRUG DEVELOPMENT UPDATE - MID-YEAR 2007 | |
| Updated Molecularly Targeted Agents in Development |
In the first 6 months of 2007, 532 agents were entered/updated in nm|OK, including novel cytotoxics, immunotherapeutics/vaccines, and regulatory/cytostatic (molecularly targeted) drugs.
Molecularly targeted agents in development are ushering in the age of personalized medicine. Among the approximately 754 molecularly targeted agents currently in clinical trials (about 403 agents) or preclinical development (multitargeted agents may appear in several groups) are:
- 61 (40 in clinical trials) agents targeting the vascular endothelial growth factor (VEGF) pathway
- 52 (33) agents targeting the ErBb family (EGFr, HEr2, etc.)
- 22 agents (10) targeting the Aurora kinase family
- 21 (9) histone deacetylase inhibitors (HDAC)
- 20 (9) agents targeting c-Kit
- 19 (7) agents targeting various heat shock proteins (Hsp)
- 18 (14) agents targeting PDGF/PDGFr
- 16 (12) drugs targeting various Cdk
- 14 (5) agents targeting c-Met
- 14 (7) agents targeting bcr-abl/abl
- 14 (8) agents targeting IGF/IGFr
- 13 (8) agents targeting Ras
- 12 (5) agents targeting Akt
- 12 (8) agents targeting FLT-3
- 11 (4) agents targeting Raf/B-Raf
- 11 (5) agents targeting the Src pathway
- 10 (5) agents targeting targeting Bcl-2
- other targets include Axl, B-FN, BIRC3, BTK, c-Myc, Rad51, CEA, catenin, CD3, CD19, CD20, CD25, CD30, CD33, CD44, CD80, CD55, CD71, CD95, CD124, CD142, CD289, CR-1, CTLA4, E2F, Epha2, EphrinB2/B4, eIF-4, FAK, JAK2, Hedgehog, HGF/SF, HIF-1alpha, KSP, MAPK/ERK, MEK, melanin, mesothelin, MIF, MMP, mTOR, mucin, NFkappaB, p53, PARP, PI3K, PKB, PKC, PLAU/PLAUr, Plk1, PSA, PSCA, PSMA, STAT3, telomerase, TGFbeta, TRAIL, WNT, XIAP, etc.
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Search Tip for Subscribers
To see the records of drugs targeting a specific marker:
From the New Drugs Query Screen or Marketed Drugs Query Screen,
- select Target Table Report Format from the menu at the top of the query screen
- enter the designation for the marker you would like to search in the Target box
Note: To check proper target designations press the Word Wheel button to the right of the Target box on the query screen or consult the Targets in Oncology module.
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| ABOUT NEW MEDICINE, INC. | |
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New Medicine, Inc., produces two products:
- New Medicine Oncology KnowledgeBASE (nm|OK) is a comprehensive online database of drug development in oncology. nm|OK has been designed for the busy executive as a continuously updated resource that transcends the need to constantly request aides and libraries to perform endless searches, often coming up with inadequate, or redundant information. Inclusion in our database gives pharmaceutical companies exposure to our subscribers and others in the oncology field.
- Future Oncology is a premier analytical newsletter reporting on advancements in the oncology field for executives, researchers, and market analysts in the pharmaceutical, biotechnology, financial, hospital and other health care industries. It provides comprehensive, up-to-date analysis of scientific, technological, clinical and commercial developments in oncology. For a detailed description of the contents of 9 volumes of Future Oncology and a newsletter sample, please visit newmedinc.com.
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