FDA Approves Rituxan- The First Targeted B-Cell Therapy for Treatment of Moderate-to-Severe Rheumatoid Arthritis

Only Therapy To Show Improvement in Signs and Symptoms Through 24 Weeks Following One Treatment Course February 28, 2006 -- Genentech, Inc. and Biogen Idec, Inc. announced that the U.S. Food and Drug Administration (FDA) has approved, following Priority Review, the therapeutic antibody Rituxan® (Rituximab) in combination with methotrexate (MTX) to reduce signs and symptoms in adult patients with moderately-to-severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies. Rituxan is the first treatment for RA that selectively targets immune cells known as CD20-positive B-cells. Through this unique mechanism of action, Rituxan may affect multiple pathways by which B-cells are believed to contribute to the initiation and development of RA. "The FDA approval of Rituxan for RA provides an important new treatment approach for patients who do not respond adequately to TNF antagonist therapy," said Stephen Paget, M.D., chairman, professor of medicine and physician-in-chief at the department of medicine, division of rheumatology, at the Hospital for Special Surgery in New York. "In clinical trials, Rituxan demonstrated significant improvement in joint pain, inflammation and physical function from a single course of therapy in this difficult-to-treat patient population." Clinical Study Results for Rituxan in RA The FDA based its approval decision for Rituxan for RA on data from three randomized, double-blind, placebo-controlled studies of patients with active RA. Results of the pivotal Phase III trial known as REFLEX showed that a significantly greater proportion of patients who received a single treatment course of two infusions of Rituxan (1000 mg on days one and 15) with a stable dose of MTX achieved American College of Rheumatology (ACR) 20, 50 and 70 response rates compared to patients who received placebo and MTX. The study included patients with active RA who had an inadequate response or were intolerant to prior treatment with one or more TNF antagonist therapies and current MTX therapy. At 24 weeks, patients receiving Rituxan displayed clinically and statistically significant improvements in RA signs and symptoms, including pain and disability. In patients receiving Rituxan: • 51 percent achieved ACR 20, the primary endpoint of the study, versus 18 percent of placebo patients • 27 percent achieved ACR 50, versus 5 percent of placebo patients • 12 percent achieved ACR 70, versus 1 percent of placebo patients • Rituxan was also shown to reduce biologic markers of inflammation. In REFLEX, the most frequently reported adverse events that occurred with Rituxan were primarily infusion-associated. Serious adverse events occurred in 7 percent of patients receiving Rituxan and MTX compared to 10 percent in patients receiving placebo and MTX. Less than 1 percent of acute infusion reactions were serious. The incidence of serious infections was 2 percent in Rituxan-treated patients and 1 percent in placebo-treated patients. The companies are committed to monitoring long-term safety of Rituxan. "The FDA approval of Rituxan for RA marks an important milestone in our ongoing efforts to advance the understanding of B-cell–mediated autoimmune diseases," said Hal Barron, M.D., Genentech's senior vice president, Development and chief medical officer. "This milestone, coupled with the additional new indication for Rituxan in diffuse large B-cell lymphoma, further establishes the companies at the forefront of novel B-cell research." "Today marks a significant milestone in Biogen Idec and Genentech's commitment to delivering first-in-class, innovative therapies for patients with significant unmet medical needs," said Burt Adelman, M.D., executive vice president, development, Biogen Idec. About ACR Response ACR 20, ACR 50 and ACR 70 responses indicate a 20, 50 and 70 percent improvement in the number of swollen and tender joints, respectively, as well as a 20, 50 and 70 percent improvement compared with baseline in three of five disease-activity measures: patient assessment, physician assessment, pain scale, Health Assessment Questionnaire and the value for one acute phase reactant (erythrocyte sedimentation rate or C-reactive protein). About the Role of B-cells While RA has traditionally been considered a T-cell–mediated disease, new research suggests that other immune cells called B-cells may play multiple roles in the initiation and development of RA, including: • Presentation of antigens (substances capable of triggering an immune response), which may contribute significantly to T-cell responses • Production of antibodies that trigger an immune attack against a person's own cells or tissues (autoantibodies) and perpetuate the disease process • Production of chemical signal molecules (cytokines) known to promote inflammation and joint damage • About RA RA is a debilitating autoimmune disease that affects more than two million Americans1 and hinders the daily activities of sufferers. RA occurs when the immune system inappropriately attacks joint tissue, causing painful chronic inflammation and irreversible destruction of cartilage, tendons and bones, often resulting in disability. Common RA symptoms include inflammation of the joints, swelling, fatigue, stiffness and pain. Additionally, since RA is a systemic disease, it can have effects in other tissues such as the lungs, eyes and bone marrow. Rituxan Safety Profile The safety profile of Rituxan has been established in more than 730,000 patient exposures over a period of eight years. In general, the adverse events observed in patients with RA were similar in type to those seen in patients with non-Hodgkin's lymphoma (NHL). The most common adverse events observed in patients treated with Rituxan for RA in clinical trials were infusion reactions and infections. No significant change in average immunoglobulin levels was observed in Rituxan-treated patients in clinical trials. There was no increase in hematologic malignancies, demyelinating events or risk of opportunistic infections (including tuberculosis) in Rituxan-treated patients over 24 weeks of treatment. Although 5 percent of Rituxan-treated patients developed human anti-chimeric antibodies (HACA), this was not associated with loss of clinical response or additional safety observations. The majority of patients experience infusion-related symptoms with their first Rituxan infusion. These symptoms include but are not limited to: flu-like illness, fever, chills/rigors, nausea, urticaria, headache, bronchospasm, angioedema, hypotension and hypoxia. These symptoms vary in severity and generally are reversible with medical intervention. Severe infusion reactions have been reported in patients treated with Rituxan, some with fatal outcomes in patients with NHL. These severe reactions typically occur during the first infusion. The most severe manifestations and sequelae include pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, and anaphylactic and anaphylactoid events. Patients who develop clinically significant infusion reactions should have their Rituxan infusion discontinued and receive medical treatment. Acute renal failure requiring dialysis with instances of fatal outcome has been reported in the setting of tumor lysis syndrome following treatment with Rituxan. Severe mucocutaneous skin reactions, some with fatal outcome, have been reported in association with Rituxan treatment. Patients experiencing a severe mucocutaneous reaction should not receive any further infusions and seek prompt medical evaluation. Abdominal pain, bowel obstruction and perforation, in some cases leading to death, were observed in patients receiving Rituxan in combination with chemotherapy for diffuse large B-cell (DLBCL), CD20-positive, non-Hodgkin's lymphoma. Other serious or potentially life-threatening adverse reactions that have been reported following Rituxan therapy include Hepatitis B reactivation with fulminant hepatitis, other viral infections, hypersensitivity reactions, and cardiac arrhythmias. About Rituxan Rituxan is a therapeutic antibody that targets and selectively depletes CD20-positive B-cells without targeting stem cells or existing plasma cells. In patients with RA, Rituxan is given as two 1000 mg IV infusions separated by two weeks, in combination with MTX. It is recommended to administer the steroid methylprednisolone 100 mg IV 30 minutes prior to each infusion. In addition to RA, Rituxan is being studied in other autoimmune diseases with significant unmet medical needs, including systemic lupus erythematosus, lupus nephritis, multiple sclerosis and ANCA-associated vasculitis. Rituxan, discovered by Biogen Idec, received FDA approval in November 1997 for the treatment of relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma. It was also approved in the European Union under the trade name MabThera® in June 1998. In addition, Rituxan received FDA approval in February 2006 for the treatment of DLBCL in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens in previously untreated patients. Genentech Provides Update On Phase II Study With Avastin In Platinum-Refractory Ovarian Cancer September 23, 2005 -- Genentech, Inc. announced that enrollment into a multi-center, single-arm Phase II study of Avastin® (bevacizumab) in platinum-refractory ovarian cancer patients has been discontinued due to a higher rate of gastrointestinal (GI) perforations reported than in previous studies with Avastin. Enrollment was discontinued following reports of five GI perforations observed in the first 44 patients enrolled in the proposed 53-patient study. The patients currently enrolled in the trial will be informed of the new safety information and, in consultation with their physician, may continue to receive protocol treatment with Avastin or elect to discontinue treatment. The decision to discontinue enrollment was made by Genentech in consultation with the FDA. Study investigators are being notified today so they can have informed conversations with their patients. "The limited overall number of GI perforations seen in this study prevent us from ascertaining definitive risk factors for this adverse event. Patients enrolled in this study had more advanced disease, which typically involves the bowel, and had received more prior chemotherapy than in previous clinical trials of Avastin in ovarian cancer," said Barron. About Avastin Avastin is a therapeutic antibody designed to inhibit Vascular Endothelial Growth Factor (VEGF), a protein that plays an important role in tumor angiogenesis and maintenance of existing tumor vessels. By binding to VEGF, Avastin is designed to interfere with the blood supply to tumors, a process that is critical to tumor growth and metastasis. The FDA approved Avastin on February 26, 2004 as a first-line treatment for metastatic colorectal cancer in combination with intravenous 5-FU-based chemotherapy. For full prescribing information, including Boxed Warnings for Avastin and information about Avastin and angiogenesis, visit http://www.gene.com or http://www.avastin.com Based on data showing that VEGF may play a broad role in a range of cancers, Genentech is pursuing a late-stage clinical development program with Avastin evaluating its potential use in adjuvant and metastatic colorectal, renal cell (kidney), breast, non-small cell lung and ovarian cancers. Avastin is also being evaluated in earlier stage trials as a potential therapy in a variety of solid tumor cancers and hematologic malignancies. Avastin Safety Profile Avastin has a well-established safety profile. In Genentech-sponsored studies, the most serious adverse events associated with Avastin were gastrointestinal perforation, wound healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome and congestive heart failure. The most common Grade 3-4 adverse events (occurring in greater than two percent of patients in the Avastin arm, compared to the control group) were asthenia, pain, hypertension, diarrhea and leukopenia. The most common adverse events (occurring in greater than two percent of patients in the Avastin arm, compared to the control group) of any severity were asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis and proteinuria. Source: Genentech Press Release

Genentech Announces Plans to File for FDA Approval of Lucentis for the Treatment of Wet Age-Related Macular Degeneration in December

September 7, 2005 -- Genentech, Inc. announced today plans to file a complete Biologics License Application (BLA) for the investigational drug Lucentis? (ranibizumab) in December 2005. In addition, the company announced that it is in discussion with the U.S. Food and Drug Administration (FDA) regarding plans to initiate a Phase IIIb clinical study of Lucentis for patients with wet age-related macular degeneration (AMD). The study is anticipated to begin before the end of 2005. One-year Phase III data from the MARINA study presented at the annual meeting of the American Society of Retina Specialists in July showed Lucentis improved vision in patients with wet AMD. "We recognize the significant unmet medical needs of those with wet AMD and hope to make Lucentis available to patients by seeking FDA approval as quickly as possible," said Hal Barron, M.D., Genentech senior vice president, development and chief medical officer. "We are encouraged by the magnitude of the benefit observed in the one-year Lucentis MARINA data and are excited about this new Phase IIIb trial, which will help provide more information about the safety profile of Lucentis and the treatment regimen for this chronic disease." The Phase IIIb SAILOR (Safety Assessment of Intravitreal Lucentis for AMD) study is being designed to evaluate the safety of two different doses (0.3 mg and 0.5 mg) of Lucentis in a broad wet AMD population. Patients will receive Lucentis once a month for three months with criteria-based re-treatment options. Genentech anticipates that patients with wet AMD who have not received prior treatment for their disease or who continue to have active disease despite treatment with FDA-approved therapies may be eligible to enroll in SAILOR. The study will be conducted at more than 100 sites in the United States and enroll approximately 5,000 patients. Genentech has also recently been notified that the FDA did not grant the company's request for fast-track designation, which allows for a rolling BLA submission. The FDA's decision will not affect the timing for BLA submission in December or the potential to obtain priority review for Lucentis. Phase III MARINA Results In July, Genentech announced positive preliminary Phase III data on Lucentis from a study of 716 patients with wet AMD. In addition to meeting the study?s primary efficacy endpoint of maintaining vision in patients with wet AMD, 25 percent (59/238) of patients treated with 0.3 mg of Lucentis and 34 percent (81/240) treated with 0.5 mg of Lucentis improved vision by a gain of 15 letters or more compared to approximately 5 percent (11/238) of patients in the control group as measured by the Early Treatment of Diabetic Retinopathy (ETDRS) eye chart. Nearly 40 percent (188/478) of Lucentis-treated patients achieved a visual acuity score of 20/40 or better at 12 months compared to 11 percent (26/238) in the control group. At 12 months, patients treated with Lucentis gained an average of seven letters in visual acuity compared to study entry, while those in the control group lost an average of 10.5 letters. An analysis of the one-year data showed that adverse events were similar to those seen in earlier trials of Lucentis. Common side effects occurring more frequently in the Lucentis arms than in the control group were mild to moderate and included conjunctival hemorrhage, eye pain and vitreous floaters. Serious ocular adverse events occurring more frequently in Lucentis-treated patients were uncommon (<1 percent) and included uveitis and endophthalmitis. There appeared to be no imbalance in serious non-ocular adverse events. Ongoing Phase III Studies Genentech and Novartis Pharma AG are conducting an additional Phase III study of Lucentis, ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic CHORoidal Neovascularization in AMD). This is a randomized, multi-center, double-masked, active treatment controlled study comparing two different doses of Lucentis to PDT in 423 patients. The trial is ongoing in the United States, Europe and Australia in patients with predominantly classic wet AMD. Results from this study are expected in the fourth quarter of 2005. Genentech is conducting an additional Phase IIIb study, PIER (A Phase IIIb, Multicenter, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal Choroidal Neovascularization with or without Classic CNV Secondary to Age-Related Macular Degeneration), a randomized, double-masked, sham injection-controlled study comparing one of two doses of Lucentis to sham injections in 184 patients in the United States with wet AMD. In this trial, Lucentis is administered once per month for the first three doses followed thereafter by doses once every three months for two years. One-year results from this study are expected in the first half of 2006. Genentech is enrolling the HORIZON Phase III open-label extension study, which allows eligible patients who have completed participation in certain other Lucentis clinical studies to continue to receive the investigational drug. About Lucentis Lucentis (ranibizumab) is a humanized therapeutic antibody fragment developed at Genentech and designed to bind and inhibit VEGF-A, a protein that is believed to play a critical role in angiogenesis (the formation of new blood vessels). Lucentis is designed to block new blood vessel growth and leakiness, which lead to wet AMD disease progression and vision loss. Lucentis is being developed by Genentech and the Novartis Ophthalmics Business Unit. Genentech retains commercial rights for Lucentis in North America (United States, Canada and Mexico). Novartis has exclusive commercialization rights for the rest of the world. About AMD AMD is a major cause of painless central vision loss and is the leading cause of blindness for people over the age of 60 in the United States and Canada. The National Eye Institute estimates that there are 1.6 million people with AMD in the United States alone and that this prevalence will grow to 2.95 million by 2020. In Canada, the Foundation Fighting Blindness estimates that more than 800,000 people are affected by the disease. AMD occurs in two forms: dry and wet. The dry form is associated with atrophic cell death of the central retina or macula, which is required for fine vision used for activities such as reading, driving or recognizing faces. The wet form is caused by growth of abnormal blood vessels also known as choroidal neovascularization (CNV) or ocular angiogenesis under the macula. These vessels leak fluid and blood and cause scar tissue that destroys the central retina. This results in a deterioration of sight over a period of months to years. About Angiogenesis Genentech is a leader in research and product development in the area of angiogenesis, the process by which new blood vessels are formed. In 1989, Napoleone Ferrara, M.D., and a team of scientists at Genentech conducted seminal work in the field, which resulted in the identification and cloning of a gene termed Vascular Endothelial Growth Factor (VEGF), now known as VEGF-A. The VEGF-A protein is believed to play a critical role in angiogenesis and serves as one of the key contributors to physiological or pathological conditions that can stimulate the formation of new blood vessels. The process of angiogenesis is normally regulated throughout development and adult life, and the uncontrolled growth of new blood vessels is an important contributor to a number of pathologic conditions, including wet AMD. Source: Genentech Press Release

EXCLUSIVE FEATURE OUTSOURCING CLINICAL TRIALS: THE NEW DNA OF THE PHARMA INDUSTRY

by Kishore Jethanandani, MA (Economics), MBA Business Editor- MedicineandBiotech.com, bus_editor@medicineandbiotech.com A new biotech century, with the promise of a rich crop of new drugs, has arrived. Right? Wrong. Bad news abounds in the R&D world of bio-tech these days. The yield of successful new products continues to decline, costs of development of each drug are increasing and rates of returns from the successful drugs are plummeting. At the root of the problem is the archetypal pharmaceutical firm which does all its research, development, manufacturing and marketing in-house. In the new biotech century, the industry will be fragmented with increasing number of firms specializing in one or two levels of the value chain. Despite the surging progress in the biomedical sciences, the new drugs submitted for approval have steadily declined. According to statistics quoted by the FDA, the number of new molecule entities declined from 70 in 1993 to a low of 25 in 2003 (1). The old model of commercializing new products in the pharmaceutical industry is broken. The costs of developing new products have zoomed from an average of $300 million to over $800 million (2). Bain and Company, a management consulting company, factored in the cost of failed drugs and estimated that the costs of drug development rose from $1.1 billion per drug in the second half of the 1990s to $1.8 million in the new millennium corresponding to a decline in the success rate from 14% to 8% (3). Almost the entire increase in costs was accounted for by higher costs of clinical trials. One such horror story is of Pfizer which lost $2 billion as a result of failures in liver toxicity (4). In the past, pharmaceutical companies conducted their own research and development as well as clinical trials. The testing methods were uncomplicated with clinical trials were carried out on animals before human trials were conducted. Increasingly, this method of clinical trials is unable to predict with any degree of accuracy the outcomes on human beings. A recent report by the FDA sums the problem as " the current drug discovery process, based as it is on in vitro screening techniques and animal models of (often) poorly understood clinical relevance, is fundamentally unable to identify candidates with a high probability of effectiveness. The current scientific understanding of both physiology and pathophysiologic processes is of necessity reductionistic (e.g., is knowledge at the gene, gene expression or pathway level) and does not constitute knowledge at the level of the systems biology of the cell, organ, or whole organism, and certainly does not reach a systems understanding of the pathophysiology of particular diseases. Reaching a more systemic and dynamic understanding of human disease will require major additional scientific efforts as well as significant advances in bioinformatics (5). The new vision for product development will have recourse to data mining techniques to develop predictive models for improving the success rate of new drugs. "Examples of tools that are urgently needed include better predictors of human immune responses to foreign antigens, methods to further enhance the safety of transplanted human tissues, new techniques for assessing drug liver toxicity, methods to identify gene therapy risks based on assessment of gene insertional and promotional events, and efficient protocols for qualifying biomaterials" (6), according to a recent paper published by FDA. This implies an array of skills in toxicology, bioinformatics and data management and biological knowledge that no drug company can ever dream of acquiring without raising costs to astronomical level. Increasingly, the industry will be fragmented. Clinical trials are increasingly conducted by CROs alone. According to the research conducted by Life Science Insight, the number of companies who are leveraging or considering the option of leveraging the expertise of CROs is 60% (7). Progressively, the vendors are learning to specialize in techniques and diseases to differentiate themselves from numerous others in the industry. The process of outsourcing of clinical trials to CROs is expected to accelerate in the near term future. "The major regulatory change facilitating outsourcing of clinical trials was 21 CFR 11. 21 CFR 11 put guidelines in place for collecting trial data electronically, enabling companies to have more control over data and get data in house more quickly, even when studies are conducted overseas", according to Judy Hanover, Research Analyst, Life Science Insights. Outsourcing to companies overseas has also become attractive as "Offshore trials give sponsors access to treatment-naive subject populations large enough so that companies can do the kind of enrichment and use the study designs they need to get results, while minimizing enrollment-based delays. Operating costs are also lower, making offshore trials, especially in countries like India that increasingly have standards approximating US GCP guidelines", Judy Hanover added. While the risk of loss of intellectual property does exist, it can be controlled by CROs within their precincts. "With increased use of the internet, rising numbers of "chat" and "blog" settings where trial subjects compare their experiences with the drugs they are taking, present a growing risk to confidentiality". Judy Hanover observed. In offshore locations, there is the added perceived risk that companies may not follow the strict standards that American companies adopt. Respected companies such as Biocon in India have taken their own initiatives to assuage such fears. "In an effort to emphasize the company's core policy of transparency, Biocon took the unprecedented initiative to become the first Pharma Company in India to share clinical trial data on its website (July 30, 2004)", a company representative responded to a questionnaire. This was done following a public interest law-suit filed by a non-profit group in India. The increasing specialization in the industry is expected to lower costs, speed up product development and lower the rates of failures. "CROs have considerably improved the processes involved in clinical trials", Ellen Julian, Director, Research, Life Science Insights, an IDC company, summed up. According to a recently completed study of the Life Science Insights, "the percentage of respondents (in its survey), conducting no clinical trial process redesign is expected to fall from 39% to 29% in 2004. The percentage of respondents planning a significant amount of process redesign is expected to rise from 12% to 22% in 2004". The most important reasons attributed to investment in process redesign, according to the Life Science Insight Insights, was reducing the time and cost of trials while improving the quality of the research (8). The birth pangs of the brave new world of biotech innovations need the entrepreneurs to act as the mid-wives of the new era in product development. A demise of the monolithic pharmaceutical companies will signal that a new age in biotech has arrived. Challenge and Opportunity on the Critical Path to New Medical Products. FDA, March 2004 Tufts Centre for the Study of Drug Development "Rebuilding Big Pharma’s Business Model’ by Jim Gilbert, Preston Henske and Ashish Singh, Business and Medicine Report, November 2003 Rotman, D, "Can Pfizer Deliver?" Technology Review, February 2004 Challenge and Opportunity on the Critical Path to New Medical Products. FDA, March 2004 FDA, Op cit "Today’s CRO: Understanding Changing Requirements for Clinical Trials Outsourcing, July 2004, IDC. IDC, op cit *Please reference or credit any material, article or figure cited from http://www.medicineandbiotech.com as: Copyright 2004. MedicineandBiotech.com, http://www.medicineandbiotech.com/ Disclaimer: MedicineandBiotech.com is managed by AstraGen LLC. Please re-distribute this e-magazine. AstraGen LLC and MedicineandBiotech.com do not assume, and hereby disclaim, any liability for any loss or damage caused by errors or omissions in any material published at the web-site http://www.medicineandbiotech.com, whether such errors or omissions resulted from negligence, misstatements or other oversights.

Interim Analysis Of Phase III Studies Shows Herceptin Plus Chemotherapy Improves Disease-Free Survival In The Adjuvant Setting For Early-Stage HER2-Positive Breast Cancer Patients

May 2005. Volume 9. Joint Analysis of More Than 3,000 Patients Provides First Positive Data of a Targeted, Biologic Therapy in the Adjuvant Setting. Genentech, Inc. announced that two Phase III trials of Herceptin were stopped early after a preliminary joint interim analysis demonstrated an improvement in the primary endpoint of disease-free survival and in the secondary endpoint of overall survival. The trials compared Herceptin plus chemotherapy to chemotherapy alone as adjuvant therapy following initial treatment with surgery for women with early-stage (or cancer that has not spread beyond the breast and associated lymph nodes) human epidermal growth factor receptor 2 (HER2) positive breast cancer. The two studies were sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, and conducted by a network of researchers led by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the North Central Cancer Treatment Group (NCCTG), who conducted this prospectively-designed joint interim analysis following consultation with the FDA. According to the NCI, the cooperative groups will present results from these studies at the American Society of Clinical Oncology (ASCO) annual meeting, May 13–17, 2005. "The data from these very important Phase III trials suggest for the first time that a therapy that targets women whose tumors have a specific genetic mutation has the potential to reduce the recurrence of disease in early-stage breast cancer patients," said Susan Desmond-Hellmann, M.D., M.P.H., Genentech's president of Product Development. "While further follow-up is necessary, the results of this joint interim analysis suggest that adjuvant therapy with Herceptin plus chemotherapy for women with early-stage HER2-positive breast cancer may increase the chance of long-term survival." "Conducting this type of joint analysis, which enabled the groups to obtain these important results more than two years earlier than expected is unprecedented and we would like to thank the NSABP, NCCTG, the NCI and the FDA for their extraordinary efforts in combining these studies. We would also like to thank the women who participated in this study for their tremendous courage in making these results possible. Based on the strength of the results, we will work with the cooperative groups to prepare these data for discussion with the FDA about a filing for Herceptin in the adjuvant setting based on this interim analysis," continued Dr. Hellmann. The NCCTG study enrolled its first patient in June 2000 and has enrolled 3,406 patients to date; the NSABP study began enrollment in March 2000 and has enrolled 2,085 patients to date. The interim analysis was based on information from 3,300 patients. These studies will stop enrolling new patients and the cooperative groups will continue to monitor patients for longer-term data. Each of the studies was a randomized, controlled trial that evaluated the combination of anthracycline and cyclophosphamide (AC) followed by paclitaxel, with or without Herceptin using different treatment schedules of paclitaxel in women with HER2-positive breast cancer. Adverse events in these studies were consistent with those seen in previous Herceptin clinical trials. Each of these studies has an independent, external Data Monitoring Committee (DMC) that reviewed data from the studies, including cardiac safety data. The DMCs monitored safety data on a regular basis and there were three to four percent more cases of serious or life-threatening (and in rare cases, fatal) cardiac events, most commonly congestive heart failure (weakening of the heart muscle) in patients receiving the combination of Herceptin plus chemotherapy. Patients in these studies will continue to be followed for any additional side effects. Based on the positive results from four recent Phase III trial analyses in the past five weeks, three of which occurred earlier than anticipated, Genentech will continue to evaluate its short- and long-term product demand and to assess its manufacturing plans and capacity to meet expected demand. The company expects to provide further information on manufacturing at the time of Q2 earnings results. About the Herceptin Adjuvant Clinical Trial Program Based on positive data observed when adding Herceptin to chemotherapy in patients with HER2-positive metastatic breast cancer, several cooperative groups are investigating Herceptin in combination with chemotherapy as a potential treatment in early-stage breast cancer. In addition to the NSABP and NCCTG adjuvant studies, two additional international adjuvant trials are underway, evaluating Herceptin with several different chemotherapy regimens, and in total will enroll more than 13,000 women with early-stage, HER2-positive breast cancer. Each study was designed with interim analyses. About Herceptin Herceptin is a targeted therapeutic antibody treatment for women with HER2-positive metastatic breast cancer, an especially aggressive form of the disease that affects approximately one-fourth of women with breast cancer. Special testing is required to identify women who are HER2-positive and candidates for treatment with Herceptin. Herceptin received U.S. Food and Drug Administration (FDA) approval in September 1998 for use in women with metastatic breast cancer who have tumors that overexpress the HER2 protein. It is indicated for weekly treatment of patients both as first-line therapy in combination with paclitaxel and as a single agent in second- and third-line therapy. Herceptin is marketed in the United States by Genentech, in Japan by Chugai, and internationally by Roche. In clinical trials, Herceptin has shown a survival benefit when used in combination with chemotherapy. In December 2001, Genentech received FDA approval to include data that showed a 24 percent increase in median overall survival for women with HER2-positive metastatic breast cancer treated initially with Herceptin and chemotherapy compared to chemotherapy alone (median 25.1 months compared to 20.3 months). Herceptin Safety Profile Herceptin therapy does involve risks. Serious side effects have occurred in patients treated with Herceptin in metastatic breast cancer. Herceptin administration can result in the development of ventricular dysfunction and cardiac failure. Severe hypersensitivity reactions (including anaphylaxis), infusion reactions, and pulmonary events have been infrequently reported. Rarely, these were fatal. Serious reactions were treated by discontinuing Herceptin and administering supportive therapy. In clinical trials, the incidence and severity of cardiac dysfunction was highest in patients receiving Herceptin with anthracycline and cyclophosphamide (AC). Most patients responded to medical therapy, including discontinuation of Herceptin. However, some patients were successfully managed while continuing Herceptin therapy. Patients receiving Herceptin should be monitored for deteriorating cardiac function. In clinical trials, approximately 40 percent of patients experienced symptoms such as chills and fever during the first infusion. These and other symptoms, including nausea, vomiting, and pain, occurred infrequently with subsequent infusions. In clinical trials, the incidence of moderate to severe neutropenia and of febrile neutropenia were higher in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to those receiving chemotherapy alone. There was an increased incidence of anemia leukopenia, diarrhea, and infection when Herceptin was used in combination with chemotherapy. About Breast Cancer According to the American Cancer Society, an estimated 211,000 women will be diagnosed with breast cancer and approximately 40,000 women will die of the disease in the United States in 2005. Breast cancer is the most common cause of cancer among women in the United States and a woman is diagnosed with breast cancer in the United States every three minutes. Source: Genentech Press Release

An Outline of the Drug Development Process NOTE: Drug Development involves a complex, FDA-regulated process of clinical trials. In every subsequent issue of MedicineandBiotech.com, we will discuss and describe different procedures involved in Clinical Trials-Editor. By Dr. Neerja Sethi, Ph.D. Food and Drug Administration (FDA)-approved drug development process for one drug can extend from 6-12 years and can cost as much as $30 million to $1 billion dollars! The discovery phase or the pre-clinical phase can cost $3-5 million. During this phase, the in vitro and in vivo (animal) testing is performed to determine the efficacy, safety and any toxic side-effects of the drug. If promising results are obtained, the scale-up conditions for the Chemistry, Manufacturing and Controls (CMC) are set-up to manufacture the drug according to Good Manufacturing Practice (GMP) regulations. Following this, the Investigational New Drug (IND) application is filed for FDA approval before progressing to Phase I clinical trials. At this stage, the success of a drug can be rated at 10%. After the approval of IND, the drug’s safety and efficacy are tested in different sub-set of population in different doses, formulations, parameters, etc. during 3 distinct phases of clinical trials; Phase I, Phase II and Phase III. This period of clinical trials can range from 6-9 years and cost $25 million to $80 million dollars. The probability of success of a drug with good results at this stage is 65%. The results obtained, during the Phase I, II and III trials, are compiled for a New Drug Application (NDA) at this stage for FDA approval. This is a very critical step and the total process involves pre-NDA meetings with FDA, preparation, submission of NDA, followed by the review process by the FDA. There is a 75% possibility of success at this stage. FDA approval can extend from 1-3 years. The FDA approval allows the drug to be marketed, after the revisions, restrictions and other suggestions by the FDA are implemented. These steps are outlined in the figure above and show the time-span of the complete drug development process, which can extend from 6-9 years till the final approval by the FDA.

ABC's of Clinical Trials By: Neerja Sethi, Ph.D. Biotech and Pharmaceutical companies conduct clinical trials to prove efficacy and safety of drugs before releasing the therapeutics into the market. A clinical trial (also clinical research) is a research study in human volunteers to answer specific health questions. Carefully conducted clinical trials are the fastest and safest way to find treatments that work in people and ways to improve health. Interventional trials determine whether experimental treatments or new ways of using known therapies are safe and effective under controlled environments. Observational trials address health issues in large groups of people or populations in natural settings. Thousands of chemicals, both synthetic and extracted from "natural" sources, are being examined in the hope of finding new drugs with which to combat human and veterinary diseases. The first step is to use laboratory tests to find if these substances have a significant effect on, for example: cells growing in tissue culture laboratory animals such as rats and mice If the drug achieves the desired effect in laboratory animals, without killing them in the process, the drug developer applies to the U. S. Food and Drug Administration for an IND, an investigational new drug application. Granting of an IND allows testing in humans to begin. This occurs in three phases. Phase I- A small group (20–100) of healthy volunteers is given the drug to see: if it is safe how quickly it is absorbed, metabolized, and excreted from the body Phase II-A group (up to several hundred) of volunteer patients with the disease are given the drug to see: how effective it is against the signs and symptoms of the disease what side effects may occur Phase III-Hundreds to thousands of patients with the disease are given the drug to get more reliable data on its: effectiveness safety best dose rare side effects all compared with the drug(s) that are currently used for the disease. If all goes well, the drug manufacturer applies to the Food and Drug Administration for an NDA, a new drug application. If it is granted, the generic name of the drug is replaced by a brand name chosen by the manufacturer. For example, one of the first drugs used against AIDS was azidodideoxythymidine (AZT). When placed on the market, this name was replaced by the brand name zidovudine. Phase IV trials-post marketing studies delineate additional information including the drug's risks, benefits, and optimal use. Even after a drug is available for prescription, its use is carefully monitored and unexpected side effects are reported. TREATMENT IND: IND stands for Investigational New Drug application, which is part of the process to get approval from the FDA for marketing a new prescription drug in the U.S. It makes promising new drugs available to desperately ill participants as early in the drug development process as possible. Treatment INDs are made available to participants before general marketing begins, typically during Phase III studies. To be considered for a treatment IND a participant cannot be eligible to be in the definitive clinical trial. TREATMENT TRIALS: Refers to trials which test new treatments, new combinations of drugs, or new approaches to surgery or radiation therapy. PREVENTION TRIALS: Refers to trials to find better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vitamins, vaccines, minerals, or lifestyle changes. DIAGNOSTIC TRIALS: Refers to trials that are are conducted to find better tests or procedures for diagnosing a particular disease or condition. Diagnostic trials usually include people who have signs or symptoms of the disease or condition being studied. SCREENING TRIALS: Refers to trials which test the best way to detect certain diseases or health conditions. QUALITY OF LIFE TRIALS (or Supportive Care trials): Refers to trials that explore ways to improve comfort and quality of life for individuals with a chronic illness.