Key Research: Interim phase II data presented at the recent meeting of the American Society of Clinical Oncology demonstrated that panitumumab engendered an overall response rate of 10% in patients with advanced colorectal cancer and resulted in disease stabilization in 38% of all cases; the drug was generally well-tolerated, and no instances of anaphylaxis were observed. Response was independent of prior treatment, suggesting that the drug may be of value in refractory disease.

The Company Line: www.amgen.com/rnd/pipeline.html#Panitumumab

Current Clinical Trials:
Two Dose Schedules of Panitumumab in Subjects With Advanced Solid Tumors

ABX-EGF (Panitumumab) Monotherapy in Subjects With Metastatic Colorectal Cancer Following Treatment With Fluoropyrimidine, Irinotecan, and Oxaliplatin Chemotherapy

Notes: Avastin, which inhibits tumor angiogenesis via action against vascular endothelial growth factor, has been established as safe and effective in the management of metastatic colorectal cancer (in conjunction with chemotherapy); it was approved in February 2004 by the FDA to treat this condition. Genentech, the maker of Avastin, is now evaluating the drug in the treatment of other forms of cancer.

Key Research: Phase III trials are underway testing Avastin against renal cell carcinoma, advanced NSCLC, metastatic breast cancer, and metastatic and locally advanced pancreatic cancer, including investigations of the drug in combination with a variety of other treatment options.

The Company Line: www.gene.com/gene/pipeline/status/oncology/avastin

Current Clinical Trials:
Visit www.clinicaltrials.gov

Notes: In the third quarter of 2004, Genentech—in collaboration with OSI Pharmaceuticals and Roche—filed a New Drug Application (NDA) with the FDA for Tarceva, which targets the epidermal growth factor receptor. The drug appears to be an extremely promising treatment for non-small cell lung cancer; a September 22 article on Forbes.com states that the drug has “blockbuster potential” and quotes a Banc of America Securities estimate suggesting that the FDA may approve Tarceva in the latter half of 2005.

Key Research: A review published in the June 15, 2004, issue of Clinical Cancer Research noted that treatment with Tarceva was associated with a response rate of 12% and 40% one-year survival when used to treat NSCLC in phase II trials; the phase II response rate of bronchoalveolar carcinoma was more than 25%. Researchers suffered a setback in October of 2003, when results from a pair of phase III studies—TRIBUTE, the US arm of the study, and TALENT, the European arm—indicated that the use of Tarceva did not translate into clinical benefit. However, a subsequent, pivotal phase III trial—the results of which were presented at ASCO ’04—found that Tarceva effected a 42% improvement in median survival and a 45% improvement in one-year survival when compared to placebo in a population of 731 previously-treated patients with relapsed NSCLC.

The Company Line: www.gene.com/gene/pipeline/status/oncology/tarceva

Current Clinical Trials:
There are more than 40 trials involving Tarceva listed on Clinical Trials.gov, including five trials that were not yet enrolling patients at the time of this writing. For more information, visit www.clinicaltrials.gov/ct/search?term=tarceva&submit=Search.

Notes: With its lead product, Advexin, Introgen is likely to become the first pharmaceutical company to receive approval for a medication that falls under the heading of “tumor suppressor therapy.” Advexin is a low-toxicity genetic therapy; its active ingredient is the p53 tumor suppressor gene, which kills cancer cells or stops tumor growth via an adenoviral delivery system without harming normal cells.

Key Research: At the time of this writing, more than 600 patients have received more than 4,000 doses of Advexin in the 20 studies (involving eight different cancer types) conducted to date. Data from two earlier, phase II studies assessing Advexin as monotherapy demonstrated that patients treated with Advexin experienced an 88% improvement in median survival time and experienced tumor stabilization or shrinkage in nearly three quarters of all cases. Advexin appears to be well tolerated to an almost unprecedented degree for a cancer therapy. Physicians and patients with questions about clinical trial enrollment are encouraged to e-mail clinicaltrials@introgen.com for more information.

The Company Line: “We believe that our administration of proteins in the form of biopharmaceuticals with a short half-life, using genes that do not integrate into the patient’s genome and are rapidly cleared from the body after administration, is an emerging field that presents a new approach for treating many cancers without the toxic side effects common to traditional therapies,” says Channing Burke, Director of Communications, Introgen Therapeutics. We will be initiating the marketing application [for Advexin] in 2004, and we expect it to take about a year to complete this. We project that Advexin might be on the market in 2005-2006.”

Current Clinical Trials:
Cancer.gov lists four trials for Advexin at www.cancer.gov.

Notes: This product is designed to control kidney cancer by impeding both tumor angiogenesis and the proliferation of cancerous cells (by inhibition of RAF kinase and VEGFR/PDGFR, respectively). On April 5, 2004, Bayer announced that the FDA had granted “Fast Track” status to BAY 43-9006, which will allow the pharmaceutical company to submit data to the FDA on a rolling basis as it is acquired, speeding the overall review and approval process.

Key Research: Phase II investigations have yielded compelling results. One study, led by Mark Ratain, MD, Professor of Medicine and Associate Director for Clinical Sciences at the Cancer Research Center of the University of Chicago, assessed 89 patients with renal cell carcinoma. Interim data reported at this year’s ASCO annual meeting suggest that nearly one half of patients treated with BAY 43-9006 experienced tumor shrinkage of greater than 25%, and 13 of at least 50%. Almost 90% of those showing some response were progression-free after six months. Bayer is in the process of enrolling up to 884 patients for a large-scale, phase III trial (TARGETS) that will assess the efficacy and safety of BAY 43-9006 as an addition to best supportive care for kidney cancer.
The Company Line: “The use of BAY 43-9006 in patients with renal cell carcinoma has resulted in a high level of durable disease stabilization or tumor shrinkage. I am excited about the potential it may offer in the fight against this form of kidney cancer,” says Dr. Ratain (www.onyx-pharm.com/products/bay_43_9006.html).

Current Clinical Trials:
Phase II Multicenter Uncontrolled Trial of Bay 43-9006 in Patients With Advanced Hepatocellular Carcinoma

Phase II Randomized Study of BAY 43-9006 in Patients With Refractory Non-Small Cell Lung Cancer

BAY 43-9006 in Patients With Imatinib Mesylate-Resistant Chronic Phase Chronic Myelogenous Leukemia

Phase II Trial of BAY 43-9006 in Metastatic, Androgen-Independent Prostate Cancer

Phase III Randomized Study of BAY 43-9006 in Patients With Unresectable and/or Metastatic Renal Cell Cancer

Notes: GlaxoSmithKline plans to complete its submission of a New Drug Application for nelarabine to the FDA under the Fast Track designation sometime in the fourth quarter of 2004. The drug is a part of the antimetabolite family; more specifically, it is a nucleoside analogue that inhibits DNA synthesis. This effect is especially pronounced when nelarabine interacts with T-cells; accordingly, Glaxo is targeting relapsed or refractory childhood T-cell malignancies with the medication.

Key Research: The phase II study principally responsible for nelarabine’s Fast Track designation enrolled 153 patients with refractory or relapsed T-cell leukemia, all under the age of 21. Response rates to nelarabine were 53% among patients refractory to initial therapy or experiencing first relapse and 26% among patients experiencing second or subsequent relapse or who were refractory to multiple therapies; 23 patients experienced complete remission.

The Company Line: http://science.gsk.com/pipeline/index.htm

Current Clinical Trials:
Combination Chemotherapy in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

506U78 in Patients With Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia or T-Cell Lymphoblastic Lymphoma

Notes: The autocrine endothelin protein is an important mediator of cell proliferation; if a cell’s receptor to this protein is blocked, it will not divide. Xinlay—renamed in June of this year by manufacturer Abbott, which also announced plans to submit a marketing application to the FDA before year’s end—is composed of very small molecules that insert themselves into this receptor in cancer cells. The end result is the slowing or prevention of tumor growth (and attendant pain).

Key Research: At present, most available research on Xinlay relates to its impact on hormone refractory prostate cancer. Two multinational phase II studies were conducted in 2001, establishing that patients receiving Xinlay (then called atrasentan) experienced longer time-to-disease progression than patients treated with placebo (196 days and 129 days, respectively). Subjective assessments of quality of life were also improved in the Xinlay groups. Phase III clinical trials are underway, both focusing on hormone refractory prostate cancer (two different studies will evaluate the metastatic and nonmetastatic forms of the disease).

The Company Line:
www.hormonerefractorypca.org/atrasentan.htm

Current Clinical Trials:
Atrasentan in Patients With Hormone-Naive Prostate Cancer Who Are Exhibiting Early Signs of Biochemical Failure

Atrasentan in Patients With Locally Recurrent or Metastatic Renal Cell Carcinoma

Notes: This recombinant human keratinocyte growth factor is designed to “protect the epithelial cells lining the mouth and gut from damage caused by chemotherapy and/or radiotherapy.” Amgen hopes the drug will help the approximately 400,000 individuals in the United States who suffer from oral mucositis as a result of cancer treatment.

Key Research: Amgen submitted a Biologics License Application (BLA) to the FDA on June 24 of this year; approval is pending, but as the drug is being considered under the Administration’s “Fast Track” program, its review should be relatively swift. The phase III investigation serving as the
basis for this submission found that treatment with palifermin reduced the incidence of ulcerative oral mucositis and of severe oral mucositis among patients undergoing chemotherapy (with or without adjuvant radiotherapy), with an adverse event rate similar to that found with placebo.

The Company Line: www.amgen.com/rnd/pipeline.html#Palifermin

Current Clinical Trials:
Pharmacokinetic Study of Palifermin in Subjects Receiving Radiation Therapy and Chemotherapy Followed by Blood Stem Cell Support

Notes: Temsirolimus is a novel agent that “inhibits mTOR-driven cell proliferation.” In simpler terms, temsirolimus blocks the action of the enzyme rapamycin kinase, which helps regulate the life cycle of all cells, thus preventing mitosis. In August 2004, the FDA granted a “Fast Track” designation to temsirolimus for the first-line treatment of advanced renal cell carcinoma; the drug was already being reviewed under the “Fast Track” label for the management of renal cell carcinoma that has failed initial therapy. Temsirolimus is considered an especially important potential weapon in the arsenal of the oncologist, as current methods of treatment for advanced renal cell carcinoma are generally insufficient to prolong survival in most patients.

Key Research: Phase II trials indicated that treatment with temsirolimus engendered an impressive response rate of 7% among patients with advanced renal cell carcinoma who had largely exhausted other therapeutic options; this data prompted the FDA’s decision to grant the drug Fast Track status as a first-line therapy and caused a shift in Wyeth’s approach to the development of the drug (below).

The Company Line: “After the phase II study we decided to change the development strategy to pursue first-line therapy in advanced RCC patients,” says Gary L. Stiles, MD, FACC, Chief Medical Officer, Executive Vice President, Wyeth Pharma-
ceuticals. “Currently a phase III study comparing temsirolimus alone, interferon alpha alone, and temsirolimus with interferon alpha [and survival as the primary endpoint] is underway.” www.wyeth.com/research/pipeline.asp#Immunology/Oncology

Current Clinical Trials:
ClinicalTrials.gov features 14 listings for temsirolimus/CCI-779, for more information, visit www.clinicaltrials.gov/ct/search?term=CCI-779

Notes: At present, standard adjuvant treatment of early breast cancer employs tamoxifen, a regimen that affords no additional benefit to the patient after approximately five years. Since breast cancer recurrence is relatively frequent in the period following the completion of tamoxifen therapy, a way to continue adjuvant therapy, perhaps with a different agent, would be of tremendous value. On June 29 of this year, the FDA began priority review of Femara for a new indication: the extended adjuvant treatment of postmenopausal early breast cancer following the conclusion of tamoxifen treatment.

Key Research: In the November 6, 2003, issue of the New England Journal of Medicine, a team of investigators led by Paul E. Goss, MD, published interim results from a study testing the impact of five years of Femara treatment following five years of tamoxifen treatment on disease-free survival in
5,187 women with postmenopausal breast cancer. At the first interim analysis, the four-year disease-free survival rates were 92% and 87% among women treated with Femara and placebo, respectively. The results of this trial, the landmark MI-17 study, were positive enough that its monitoring committee recommended immediate discontinuation of the placebo arm of the study, and were the basis for the FDA’s decision to grant Priority Review to Femara.

The Company Line: www.pharma.us.novartis.com/newsroom/pressReleases/
releaseDetail.jsp?PRID=1324

Current Clinical Trials:
There are six Femara trials listed on ClinicalTrials.gov. Visit www.clinicaltrials.gov/ct/search?term=femara&submit=Search for more information