CLINICAL TRIALS

"There are multiple chemotherapy medicines for women with advanced breast cancer, so it is important to understand Avastin's efficacy and safety in combination with these different treatments," said Dr. Nicholas Robert, M.D., co-chair of the Breast Cancer Research Committee, U.S. Oncology, Inc., and physician investigator of the RIBBON 1 study. "The growing body of evidence about combining Avastin with commonly used chemotherapies may give physicians more flexibility to tailor the most appropriate course of Avastin-based therapy for patients."

RIBBON 1 comprised two independently powered study groups. Group One evaluated capecitabine plus Avastin versus capecitabine plus placebo. Group Two evaluated a taxane or anthracycline-based chemotherapy plus Avastin versus the chemotherapy plus placebo. The taxanes in the study were protein-bound paclitaxel or docetaxel. The anthracycline-based chemotherapies were doxorubicin- or epirubicin-based regimens.

Patients receiving Avastin plus capecitabine (Group One) had a 45 percent improvement in the time they lived without their disease worsening or death compared to those who received the chemotherapy alone (hazard ratio=0.69; p=0.0002, 31 percent risk reduction). Patients receiving Avastin plus taxane or anthracycline-based chemotherapies (Group Two) had a 55 percent improvement in the time they lived without their disease worsening or death compared to those who received chemotherapy alone (hazard ratio=0.64; p<0.0001, 36 percent risk reduction).

"Avastin has been studied as a first-line treatment in more than 2,600 women with advanced breast cancer in three Phase III trials, and we have confidence in its ability to help delay breast cancer progression," said Hal Barron, M.D., executive vice president, Global Development and chief medical officer, Genentech. "We plan to submit data from the RIBBON 1 and AVADO studies to the FDA in the second half of 2009."

Avastin was approved for advanced breast cancer in February 2008 under the U.S. Food and Drug Administration's (FDA) accelerated approval program, which allows provisional approval of medicines for cancer or other life-threatening diseases. Avastin, in combination with paclitaxel, is indicated for the treatment of patients who have not received chemotherapy for advanced HER2-negative breast cancer. The effectiveness of Avastin in metastatic breast cancer is based on an improvement in PFS. Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Avastin in breast cancer.

FDA review of data from the positive RIBBON 1 and AVADO studies is required for the accelerated approval to be converted into a full approval. Genentech will also provide data from three additional ongoing or planned randomized trials.

RIBBON 1 Study Results
RIBBON 1: Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Chemotherapy With or Without Bevacizumab for First-Line Treatment of HER2-Negative Locally-Recurrent or Metastatic Breast Cancer (Abstract #1005) - Monday, June 1, 2009, 11:15 a.m. - 11:30 a.m. EDT, West Hall D2

RIBBON 1 was an international, multicenter, randomized, double-blind, placebo-controlled clinical study of 1,237 patients with locally recurrent or metastatic HER2-negative breast cancer who had not received chemotherapy for their metastatic disease. Avastin was administered every three weeks until disease progression. Secondary endpoints included objective response rate, one-year survival rate and overall survival at the time of PFS analysis.

The RIBBON 1 study assessed select adverse events based on the type of chemotherapy. Specific severe (Grade 3 or 4) adverse events (AEs) that occurred at a rate of at least 2 percent more often in patients who received Avastin plus chemotherapy versus chemotherapy alone were:

About Avastin
Avastin was the first anti-angiogenesis therapy approved by the FDA and is approved for the treatment of four tumor types. Avastin is indicated for the first- and second-line treatment of metastatic colorectal cancer in combination with intravenous 5-FU-based chemotherapy; for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel; for previously untreated, metastatic HER2-negative breast cancer in combination with paclitaxel; and for glioblastoma that has progressed following prior therapy.

The effectiveness of Avastin in metastatic breast cancer is based on an improvement in PFS. Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Avastin in breast cancer.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate as assessed by magnetic resonance imaging (MRI) and measured using World Health Organization radiographic criteria along with decreased or stable corticosteroid use. MRI does not necessarily distinguish between the tumor, swelling (edema) or tissue death (necrosis) caused by prior radiation therapy. Currently, no data are available from randomized controlled trials demonstrating an improvement in disease-related symptoms or increased survival with Avastin in glioblastoma.

BOXED WARNINGS and Additional Important Safety Information
Patients treated with Avastin may experience side effects. In clinical trials, some patients treated with Avastin experienced serious side effects, including:

Gastrointestinal (GI) perforation:
Treatment with Avastin can result in the development of a serious side effect called GI perforation, which is the development of a hole in the stomach, small intestine, or large intestine. In clinical trials, this side effect occurred in 0.3 to 2.4 percent of patients and in some cases resulted in fatality. Avastin therapy should be permanently stopped in people with GI perforation.

Surgery and wound healing problems:
Treatment with Avastin can lead to slow or incomplete wound healing (for example, when a surgical incision has trouble healing or staying closed). In some cases this event resulted in fatality. In a clinical trial, 15 percent of patients with metastatic colorectal cancer who had surgery while receiving Avastin treatment had serious and fatal complications compared to 4 percent of patients who did not receive Avastin. Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Avastin therapy should be permanently stopped in patients with wound healing problems that require medical treatment. The appropriate waiting time between stopping treatment with Avastin and having surgery has not been determined.

Severe bleeding:
Severe or fatal bleeding, including hemoptysis (coughing up of blood), GI bleeding, hematemesis (bloody vomit), central nervous system (CNS) hemorrhage (bleeding in the brain), epistaxis (nose bleeds), and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, Grade 3 or higher (severe or fatal) bleeding events have occurred in 1.2 to 4.6 percent of patients receiving Avastin. In patients with previously treated glioblastoma, intracranial hemorrhage (bleeding within the brain) occurred in eight of 163 patients and two people had Grade 3 to 4 (severe) bleeding. In patients treated with Avastin and chemotherapy for lung cancer, serious and sometimes fatal pulmonary hemorrhage (bleeding in the lungs) occurred in four of 13 (31 percent) patients with squamous cell histology and two of 53 (4 percent) patients with non-squamous NSCLC, compared to none of 32 (0 percent) patients treated with chemotherapy. People with serious bleeding or recent hemoptysis should not receive Avastin.

In clinical trials, additional serious side effects seen across different cancer types, in some cases resulting in fatality, included the following: formation of an abnormal passage from parts of the body to another part (non-GI fistula formation - less than 0.3 percent); stroke or heart problems (arterial thromboembolic events - 2.6 percent); high blood pressure (5 to 18 percent); nervous system and vision disturbances known as RPLS (reversible posterior leukoencephalopathy syndrome - less than 0.1 percent); severe infusion reactions (0.2 percent of people), too much protein in the urine and kidney damage (nephrotic syndrome - less than 1 percent).

The most common adverse reactions observed in Avastin patients at a rate of more than 10 percent and at least twice the control arm rate were nose bleeds, headache, high blood pressure, irritation of the nose (rhinitis), protein in the urine, taste alteration, dry skin, rectal bleeding, tear production disorder (lacrimation) and inflammation of the skin (exfoliative dermatitis).

Avastin may cause problems getting pregnant. People who are pregnant or thinking of becoming pregnant should talk with their doctor about the potential risks of loss of pregnancy or the potential risk of Avastin to the fetus. Nursing mothers should not breast-feed while receiving Avastin or for a short period of time after treatment is finished.

For full Prescribing Information and Boxed WARNINGS on Avastin visit http://www.avastin.com.

About Genentech
Founded more than 30 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious or life-threatening medical conditions. The company, a wholly-owned member of the Roche Group, has headquarters in South San Francisco, Calif. For additional information about the company, please visit http://www.gene.com.

# # #

NEW YORK-- Pfizer Inc announced that it has become the first pharmaceutical company to be accredited by the Association for the Accreditation of Human Research Protection Programs (AAHRPP) for ensuring the protection of human subjects taking part in early-stage clinical trials.

The AAHRPP accreditation was awarded to Pfizer’s clinical research units (CRUs) in New Haven, CT, Brussels, Belgium and Singapore, where the company conducts most of its Phase I clinical research. To earn the accreditation, Pfizer participated in a rigorous, 15-month examination of the clinical research practices at these units.

AAHRPP is an independent, non-profit accrediting body that promotes ethically sound research of the highest quality. Organizations seeking accreditation must provide tangible evidence — through policies, procedures, and practices — of their commitment to ensure human rights protection in clinical research.

“Pfizer is committed to upholding the highest ethical standards in all of our clinical research activities,” said Martin Mackay, PhD, president of Pfizer Global Research & Development. “AAHRPP accreditation is tangible evidence of our continuing commitment to maintain the highest global standards for research by protecting the human rights of the individuals who take part in our early-stage clinical trials.”

CRUs and Phase I Research

Pfizer allowed AAHRPP to audit its three CRUs and demonstrated that these facilities met the high quality and ethical standards set by AAHRPP including requirements for research set by the International Conference on Harmonization (ICH), as well as research regulations in the United States, European Union and Singapore. The process included site visits, interviews and an application for accreditation that exceeded 1,000 pages.

Pfizer’s CRUs are staffed by doctors and other health professionals who maintain close ties with nearby hospitals to advance scientific knowledge and share best practices.

Phase I trials are the first studies of an investigational drug in humans. In these trials, small doses of an investigational medicine are administered under close medical supervision to healthy volunteer subjects. This allows researchers to measure responses to the investigational medicine, determine how it is absorbed by the body and how long it remains in the bloodstream, and assess the safety and tolerability of different doses.

“Safety and scientific excellence are the constant themes of our work,” said Rachel Harrigan, MD, Pfizer’s senior vice president of Development Operations. “This accreditation acknowledges the commitment of Pfizer’s physicians and other staff to the well-being of our volunteers and to our efforts to conduct the highest quality clinical trials at all stages.”

Pfizer voluntarily sought accreditation to demonstrate its commitment to integrity in research and because it wanted to be among more than 150 of the world’s best universities, hospitals, institutional review boards (IRBs) contract research organizations (CROs), and other organizations that are AAHRPP-accredited.

Pfizer worked closely with IRBs and ethics committees in New Haven, Brussels and Singapore, all of which invested considerable effort to evolve their standard procedures and methods of review for Pfizer studies in order to meet AAHRP standards.

“We are very pleased that Pfizer took a leadership position by demonstrating its commitment to human research protections by seeking and successfully achieving AAHRPP Accreditation,” said Felix Khin-Maung-Gyi, PharmD, chief executive officer of Chesapeake Research Review, an AAHRPP-accredited independent IRB based in Maryland. “I hope all others in the research enterprise, including fellow independent IRBs, sponsors, research institutions and sites, and CROs will follow Pfizer’s lead.

“While many companies strive for excellence in this area, there is no substitute for AAHRPP accreditation to cement the American public’s trust in our partnership for conducting clinical trials,” Dr. Khin-Maung-Gyi added. “It is our shared responsibility to those who both participate in and rely upon results from these trials to devote the necessary and appropriate resources for high quality, ethical research.”

Integrity in Research

The AAHRPP accreditation is another step in Pfizer’s ongoing efforts to earn public trust for integrity in research. Others include:

Requiring that all Pfizer sponsored trials – regardless of where they are conducted -- are carried out under the same international standards, including the International Conference on Harmonization (ICH) 1996 Guidelines for Good Clinical Practice and the global principles set forth in the Declaration of Helsinki.

Beginning in November 2008, requiring that all Pfizer U.S. multi-center clinical trials are reviewed only by central IRBs that are AAHRPP-accredited.

Registering clinical trials on the public database www.clinicaltrials.gov. As of 2008, the company registers all clinical trials conducted on a Pfizer product (Phase I and beyond), as well as non-interventional studies with prospective data collection. To date, the company has registered more than 1,000 trials.

Posting the results of its clinical trials at www.clinicalstudyresults.org. As of 2005, summary results of all patient studies conducted on a Pfizer product (Phase I and beyond) are posted, and starting in 2008, the results of all clinical studies, whether in patients or normal volunteers, are posted, as well as the results of prospective observational studies.

Providing a regularly updated public website, describing compounds in its drug development pipeline and detailing their progress.

Building infrastructure of the developing world countries, where an increasing number of clinical trials are taking place. This work is conducted in partnership with local authorities and research institutions.

Conducting training programs in good clinical practice (GCP) standards around the world in countries such as India, a top location for clinical research.

Pfizer is committed to conducting clinical trials globally according to the highest ethical and scientific standards.

Drug development is a worldwide effort and clinical trials are conducted in many countries, providing experience with different patient populations and reflecting the prevalence and incidence of the diseases for which Pfizer is developing medicines. Pfizer posts key company policies related to human subject protection at http://pfizer.com/sciencepolicy . 

About AAHRPP

AAHRPP accredits high-quality human research protection programs in order to promote excellent, ethically sound research. Through partnerships with research organizations, researchers, sponsors, and the public, AAHRPP encourages effective, efficient, and innovative systems of protection for human research participants. AAHRPP, through accredited research programs worldwide, will ensure that all human research participants are respected and are protected from unnecessary harm.

Pfizer Inc: Working together for a healthier world™

Founded in 1849, Pfizer is the world's largest research-based pharmaceutical company taking new approaches to better health. We discover, develop, manufacture and deliver quality, safe and effective prescription medicines to treat and help prevent disease for both people and animals. We also partner with healthcare providers, governments and local communities around the world to expand access to our medicines and to provide better quality health care and health system support. At Pfizer, more than 80,000 colleagues in more than 90 countries work every day to help people stay happier and healthier longer and to reduce the human and economic burden of disease worldwide.

Source: Pfizer Press Release

• Elinogrel offers oral and intravenous formulations, has shown a fast onset of action and could offer physicians a rapid way to reverse its anti-clotting action if needed

• Novartis has responsibility for Phase III trials, manufacturing and commercialization, while collaborating with Portola on ongoing Phase II trials

• Novartis to make USD 75 million upfront payment, Portola eligible for milestones and royalties on future sales

Basel, February 12, 2009 - Novartis has gained the exclusive worldwide rights to elinogrel, a promising anti-clotting agent in Phase II clinical trials that has shown potential to offer clinical improvements over current anti-clotting medications in helping patients avoid heart attacks and strokes.

As part of the agreement with the US biotechnology company Portola Pharmaceuticals, Inc., Novartis will have responsibility for the Phase III development, manufacturing and commercialization of elinogrel.

Elinogrel belongs to a class of cardiovascular medicines that seek to prevent blood platelets circulating in the arterial system from sticking together and forming potentially dangerous clots. These clots can limit or stop the flow of blood to the heart or brain, leading to heart attacks or strokes.

"More than 13 million people die every year from complications related to blood clots, which underscores the ongoing and significant unmet need," said Trevor Mundel, MD, Global Head of Development at Novartis Pharma AG. "Elinogrel is a novel compound with attributes that have the potential to offer clinical benefits over currently approved antiplatelet therapies. Elinogrel will further diversify our cardiovascular pipeline and we hope it will prove to be a strong addition to our portfolio."

Elinogrel is being developed as oral and intravenous formulations. It has an instant onset of action that could quickly provide protection from clotting. Elinogrel's effect is also reversible, which may offer physicians a way to rapidly reverse its anti-clotting actions when necessary. Data from Portola's Phase I and Phase IIa trials showed elinogrel was well tolerated and had predictable, dose-dependent platelet inhibition[1].

INNOVATE-PCI, an 800-patient Phase IIb clinical trial, was initiated in December 2008 involving the intravenous and oral forms of elinogrel to explore the compound's clinical efficacy, biological activity, tolerability and safety. This trial includes a broad group of patients undergoing non-urgent surgery to repair a damaged blood vessel or to unblock a coronary artery (percutaneous coronary intervention). The trial involves a head-to-head assessment of elinogrel's intravenous and oral formulations against clopidogrel (Plavix®), considered the leading antiplatelet agent.

Clinical trials are planned for elinogrel in patients with acute coronary syndromes and more broadly in patients with a prior heart attack or stroke, and those with peripheral vascular disease.

Novartis is focused on improving the lives of the hundreds of millions of people with cardiovascular and metabolic diseases. As a global leader in cardiovascular and metabolic health for nearly 50 years, Novartis provides innovative therapies and support programs to treat high blood pressure and diabetes - both major public health issues. The portfolio includes the world's most-prescribed angiotensin receptor blocker, the first and only approved direct renin inhibitor, a single pill combining two leading high blood pressure medicines, and a novel DPP-4 inhibitor. Novartis is dedicated to helping physicians and patients through effective medicines, programs and an ongoing commitment to research.

Terms of the agreement

Novartis will make an upfront payment of USD 75 million to Portola for the exclusive worldwide rights to elinogrel. Novartis will share with Portola the costs of the ongoing Phase II trial, but will have responsibility for Phase III clinical development, manufacturing and commercialization. Portola will also be eligible for additional payments based on achieving defined development and commercialization milestones and is also eligible to receive royalties on future sales. In addition, Portola has an option to co-promote elinogrel in the US limited to hospitals and specialty markets and an option to co-fund Phase III clinical trials and other development activities in return for additional royalties. This transaction is subject to customary regulatory approvals.

About Novartis

Novartis AG provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, preventive vaccines, diagnostic tools, cost-saving generic pharmaceuticals, and consumer health products. Novartis is the only company with leading positions in these areas. In 2008, the Group's continuing operations achieved net sales of USD 41.5 billion and net income of USD 8.2 billion. Approximately USD 7.2 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 96,700 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.novartis.com.

References

[1] Gretler DD, Conley PB, Andre P, Jurek M, Pandey A, Ronanko K, Leese PT, Hutchaleelaha A, Phillips DR "First in human" experience with PRT060128, a new direct-acting, reversible, P2Y12 inhibitor for IV and oral use. J Am Coll Cardiol. 2007;9(Suppl 2):326A.

CLL is the most common form of adult leukaemia in the Western world. Patients with refractory CLL need new therapies since less than 25 percent respond to most current treatments while still having to cope with adverse effects.

“The submission of the BLA for ofatumumab brings us closer to the possibility of providing a new treatment to patients with refractory CLL,” said Lisa N. Drakeman, Ph.D., Chief Executive Officer of Genmab. “This is the first BLA ever filed for an antibody produced by Genmab and is a significant achievement in our partnership with GSK.”

The submission is based on an analysis that included 138 patients with CLL who showed limited or no response to both fludarabine and alemtuzumab treatment (fludarabine alemtuzumab refractory) and patients who were refractory to fludarabine and considered inappropriate candidates for alemtuzumab due to bulky tumour masses (>5 cm) in their lymph nodes (bulky fludarabine refractory). The primary endpoint of the study was assessment of response. The overall response rate seen in these patient groups treated with single-agent ofatumumab was 58 percent for the fludarabine alemtuzumab refractory group (n=59) and 47 percent for the bulky fludarabine refractory group (n=79).4,5

The most common adverse events (AEs) seen with ofatumumab were related to infusion reactions and infections. AEs seen in at least 10 percent of patients included fever, cough, diarrhoea, rash, low white blood cell counts, fatigue, pneumonia, anaemia, shortness of breath and nausea. In clinical trials to date, infusion reactions that were serious yet manageable were seen in three percent of patients. One case of progressive multifocal leukoencephalopathy (PML), a rare brain infection resulting in death or causing severe disability, and one case of tumour lysis syndrome were reported.4,5 These data were presented at the 50th Annual Meeting of the American Society of Haematology (ASH) in December 2008.

Potential to Combat CLL in Earlier Stages

The companies also announced today the initiation of an additional Phase III study of ofatumumab in combination with fludarabine and cyclophosphamide (FC) for patients with CLL when initial treatment no longer works (second-line treatment). The open-label study will randomise 352 patients to evaluate progression-free survival (PFS) of ofatumumab in combination with FC therapy versus FC therapy alone for the treatment of relapsed CLL.6 Enrolment for this study will begin shortly.

“Bolstered by the positive results of ofatumumab for advanced stage CLL, we’re now investigating ofatumumab in earlier stages in the treatment continuum,” said Paolo Paoletti, M.D., Senior Vice President of Oncology R&D, GSK. “The clues we’re seeing from ofatumumab also suggest possible activity in other oncology settings, which we’re currently evaluating through several clinical trials.”

GSK and Genmab will conduct additional studies of ofatumumab in CLL and non-Hodgkin’s lymphoma (NHL) settings. In CLL, a Phase III front-line study is evaluating ofatumumab combined with chlorambucil in patients with previously untreated CLL. In NHL, an ongoing Phase II study will assess ofatumumab in patients with Waldenstrom’s Macroglobulinemia – a rare type of slow-growing NHL.7 Finally, a Phase II study is evaluating ofatumumab plus ICE or DHAP chemotherapy regimen in relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

About Ofatumumab

Ofatumumab is an investigational monoclonal antibody that targets a membrane-proximal (close to the cell surface), small loop epitope (a portion of a molecule to which an antibody binds) on the CD20 molecule on B-cells.8 This epitope is different from the binding sites targeted by other CD20 antibodies currently available.9 The CD20 molecule is a key target in CLL therapy because it is highly expressed in most B-cell malignancies.10

Ofatumumab is being developed to treat chronic lymphocytic leukaemia, non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma, rheumatoid arthritis, and relapsing-remitting multiple sclerosis under a co-development and commercialisation agreement between Genmab and GlaxoSmithKline. It is not yet approved in any country.

The companies intend to submit an application for marketing approval in Europe shortly.

About CLL

CLL is the most common adult leukaemia1,2 and one of the most common malignant lymphoid diseases.11 Based on 2007 worldwide estimates, leukaemia accounted for more than 330,000 new cases and more than 245,000 deaths.12

CLL cells are malignant B-cells13 that have low surface expression levels of CD20 molecules.8 B-cells normally protect the body from invading pathogens by developing into plasma cells, which make antibodies. These antibodies directly inactivate pathogens or attach to pathogens to prepare them for destruction by other white blood cells.13,14

GlaxoSmithKline – one of the world’s leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer.  For further information please visit www.gsk.com

GSKOncology is dedicated to producing innovations in cancer that will make profound differences in the lives of patients. Through GSK’s revolutionary ‘bench to bedside’ approach, we are transforming the way treatments are discovered and developed, resulting in one of the most robust pipelines in the oncology sector. Our worldwide research in oncology includes collaborations with more than 160 cancer centres. GSK is closing in on cancer from all sides with a new generation of patient-focused cancer treatments in prevention, supportive care, chemotherapy and targeted therapies.

Genmab A/S is a leading international biotechnology company focused on developing fully human antibody therapeutics for the potential treatment of cancer. Genmab’s world class discovery, development and manufacturing teams are using cutting-edge technology to create and develop products to address unmet medical needs. Our primary goal is to improve the lives of patients who are in urgent need of new treatment options. For more information on Genmab’s products and technology, visit www.genmab.com.

Arzerra™ is the proposed registered trademark to be used in the United States and Europe.

Roche announced that MabThera (rituximab) can significantly inhibit structural damage to joints in patients with early rheumatoid arthritis (RA) who have not been treated with methotrexate (MTX), the current standard of care for RA treatment.

Results from the IMAGE (1) study showed that at one year initiating treatment with MabThera in combination with MTX exhibited a significant reduction in the rate of progressive joint damage (2), compared to initiating treatment with MTX alone. The trial was conducted in patients not previously treated with MTX and studied MabThera infusions of either the currently approved 1000mg dose or low dose 500mg in combination with MTX. Patients in each MabThera dosing group were compared to patients receiving MTX alone. Only the standard, currently approved 1000mg MabThera dose showed ability to significantly inhibit structural joint damage.

Damage to the structure of joints ultimately contributes to joint deformity and loss of mobility. As a result, prevention of structural joint damage, particularly in early disease, is a major goal of treatment in RA.

The study also showed that both doses of MabThera in combination with MTX were superior to MTX alone in relieving the signs and symptoms of RA (ACR scores (3). Relieving the debilitating symptoms of the disease is another very important objective of RA therapy.

“The results of IMAGE show that MabThera has the potential to alter the course of rheumatoid arthritis by preventing the early damage to joints which ultimately causes deformity and disability. These pivotal findings add support for the early use of MabThera in the treatment of rheumatoid arthritis to allow patients to maintain a life as normal as possible,” said William M. Burns, CEO Pharmaceuticals Division of Roche.

MabThera is the first and only selective B cell therapy available for the treatment of RA. It has already demonstrated significant clinical and radiographic benefits when used later in the RA treatment pathway. It is currently licensed for patients with severe disease who have had an inadequate response or intolerance to one or more tumour necrosis factor (TNF) inhibitors.

Data from the IMAGE study will be submitted for presentation at upcoming international scientific meetings. Roche plans to file the IMAGE data together with data from two other studies with the European health authorities in 2009 to extend the current label for MabThera.

RA is one of the most common autoimmune diseases, affecting more than 21 million people worldwide, with as many as three million sufferers in Europe alone. It is twice as common in women as in men and also impacts on the average life expectancy, shortening it by three to seven years. Seventy per cent of people with rheumatoid arthritis have signs of permanent joint damage within two years of the start of their disease.(4)

About the IMAGE study

 IMAGE is a phase III international study involving 755 MTX-naïve patients with active RA. The study was conducted at 168 study sites across 27 countries. In this Phase III, randomised, controlled, double-blind, parallel-group multicenter study, patients received either MabThera (500mg or the currently approved 1000mg dose) or placebo by intravenous infusion on days 1 and 15, in combination with newly initiated MTX. The eligible patients who were not in DAS28 (5) remission at week 24 received a second course of MabThera at the same dose as the first course. The study aimed to determine the efficacy of MabThera in reducing the progression of structural joint damage, as demonstrated by changes in validated radiographic parameters. The study also assessed the efficacy of MabThera in improving the signs and symptoms of RA and patients’ physical function. A preliminary analysis of the data did not reveal any unexpected safety signals and the overall safety profile was consistent with that reported in previous studies.

About Rheumatoid Arthritis and MabThera

 Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation that leads to stiff, swollen and painful joints. This ultimately results in irreversible joint damage and disability. MabThera selectively targets B cells and represents a new highly effective therapeutic approach for RA in addition to existing treatments such as DMARDs and TNF inhibitors.

B cells are known to play a key role in the inflammation associated with RA. As the first and only selective B cell therapy available for the treatment of RA, MabThera represents a proven and truly different alternative for RA patients. MabThera is the only RA treatment that has demonstrated the ability to preserve joint structure in patients who have inadequate response or are not able to tolerate TNF inhibitor therapy and offers an unprecedented duration of response of at least six months with each course. Each course of MabThera also provides the opportunity of sustained or improved relief for patients from the signs and symptoms of their disease.

MabThera is marketed in the US by Genentech and Biogen Idec under the brand name Rituxan®.

For a selection of broadcast footage clips relating to MabThera and rheumatoid arthritis please visit www.thenewsmarket.com/roche.

To view and download high resolution stills and media materials please visit the MabThera Virtual Press Office at www.mabthera-ra.com

About Roche in Rheumatoid Arthritis

One of the most important drivers for growth at Roche over the next few years is expected to be the company’s emerging franchise in autoimmune diseases with rheumatoid arthritis as the first indication. Following the launch of MabThera (rituximab) there are a number of projects in development, potentially allowing Roche to build on further opportunities. MabThera is the first and only selective B-cell therapy for RA, providing a fundamentally different treatment approach by targeting B cells, one of the key players in the pathogenesis of RA. Actemra is Roche’s second novel medicine and is a humanised monoclonal antibody to the interleukin-6 (IL-6) receptor, inhibiting the activity of IL-6, a protein that plays a major role in the RA inflammation process. Additional projects creating a rich pipeline include compounds in Phase I, II and III clinical trials. Notably, ocrelizumab, a humanised anti-CD20 antibody, has entered phase III development for RA.

About Roche

Headquartered in Basel, Switzerland, Roche is one of the world’s leading research-focused healthcare groups in the fields of pharmaceuticals and diagnostics. As the world’s biggest biotech company and an innovator of products and services for the early detection, prevention, diagnosis and treatment of diseases, the Group contributes on a broad range of fronts to improving people’s health and quality of life. Roche is the world leader in in-vitro diagnostics and drugs for cancer and transplantation, and is a market leader in virology. It is also active in other major therapeutic areas such as autoimmune diseases, inflammatory and metabolic disorders and diseases of the central nervous system. In 2007 sales by the Pharmaceuticals Division totalled 36.8 billion Swiss francs, and the Diagnostics Division posted sales of 9.3 billion francs. Roche has R&D agreements and strategic alliances with numerous partners, including majority ownership interests in Genentech and Chugai, and invested over 8 billion Swiss francs in R&D in 2007. Worldwide, the Group employs about 80,000 people. Additional information is available on the Internet at www.roche.com.

All trademarks used or mentioned in this release are legally protected.

References

1) IMAGE refers to International study in Methotrexate-nAïve subjects investiGating Rituximabs Efficacy

2) As measured by the change from baseline in total Genant modified Sharp score at week 52

3) The ACR response is a standard assessment used to measure patients’ responses to anti-rheumatic therapies, devised by the American College of Rheumatology (ACR). It requires a patient to have a defined percentage reduction in a number of symptoms and measures of their disease. For example, a 20%, 50% or 70% level of reduction (the percentage of reduction of RA symptoms) is represented as ACR20, ACR50 or ACR70. An ACR70 response is exceptional for existing treatments and represents a significant improvement in a patient’s condition.

4) O’Dell JR. N Engl J Med 2004; 350: 2591-2602

5) The Disease Activity Score (DAS28) is a combined index that measures disease activity in patients with RA. It combines information from 28 tender and swollen joints (range 0-28), erythrocyte sedimentation rate, and a general health assessment on a visual analog scale. The level of disease activity is interpreted as low (DAS28 < 3.2), moderate (3.2 < DAS28 < 5.1) or high (DAS28 >5.1). DAS28 <2.6 corresponds to being in remission according to the criteria of the American Rheumatism Association (ARA).

This confirmation of Avastin's survival benefit is important because overall survival is of key importance for patients with advanced colorectal cancer.

The data presented came from a cetuximab study called the CRYSTAL trial which showed that cetuximab in combination with chemotherapy failed to deliver a significant overall survival benefit in either the general population or in patients tested for K-Ras status. In contrast, an earlier analysis of Avastin first-line in combination with chemotherapy achieved significant overall survival for over two years (27.7 months) for patients with mCRC with K-Ras wild-type. Avastin therefore remains the best treatment option for patients with mCRC, regardless of oncogene mutations (e.g. K-Ras).

"Extending the lives of my patients remains a key goal for me as a treating physician" said Dr Mark Kozloff, Associate Professor, Department of Oncology, University of Chicago, School of Medicine, US. "Avastin is the only biologic in combination with chemotherapy which allows us to achieve this essential outcome and should therefore be used first-line in the majority of patients with metastatic colorectal cancer regardless of their K-Ras status".

Main findings from CRYSTAL were:

There was no statistical difference in overall survival (OS) in the K-Ras wild-type population – the study was negative for this secondary endpoint (24.9 vs. 21.0 months in the cetuximab and control arm respectively) (HR 0.84, p 0.22) There was no statistical difference in OS in the general study population – the study therefore failed to meet this key secondary endpoint (19.9 vs. 18.6 months in the cetuximab and control arm respectively) (HR 0.93, p 0.30) Main outcomes from pivotal Avastin 2107 study which demonstrated Avastin’s superior K-Ras data:

Avastin provides a statistically significant OS advantage in the K-Ras wild-type population (27.7 vs. 17.6 months in the Avastin and Control arm respectively) (HR 0.58, p 0.04) Avastin also provides statistically significant improvements in the time patients live without their disease worsening for both K-Ras wild-type (PFS improved by 82%, from 7.4 to 13.5 months, hazard ratio: 0.44, p<0.0001) and K-Ras mutant patients (PFS improved by 69%, from 5.5 to 9.4 months, hazard ratio: 0.41, p=0.0008). Avastin provides a statistically significant gain in OS in the general population (20.3 vs. 15.6 months in the Avastin and control arm respectively) (HR 0.66, p<0.001) The overall survival benefit of Avastin has been confirmed in two large community-based studies (First BEAT / BRiTE), including some 4,000 patientsIn January 2008, Avastin received a broad label in the EU allowing it to be used in combination with fluoropyrimidine-based chemotherapy for first and later treatment lines in patients with mCRC. This means that virtually all patients with metastatic colorectal cancer have access to Avastin’s benefits.

About Roche

Headquartered in Basel, Switzerland, Roche is one of the world’s leading research-focused healthcare groups in the fields of pharmaceuticals and diagnostics. As the world’s biggest biotech company and an innovator of products and services for the early detection, prevention, diagnosis and treatment of diseases, the Group contributes on a broad range of fronts to improving people’s health and quality of life. Roche is the world leader in in-vitro diagnostics and drugs for cancer and transplantation, and is a market leader in virology. It is also active in other major therapeutic areas such as autoimmune diseases, inflammatory and metabolic disorders and diseases of the central nervous system. In 2007 sales by the Pharmaceuticals Division totalled 36.8 billion Swiss francs, and the Diagnostics Division posted sales of 9.3 billion francs. Roche has R&D agreements and strategic alliances with numerous partners, including majority ownership interests in Genentech and Chugai, and invested over 8 billion Swiss francs in R&D in 2007. Worldwide, the Group employs about 80,000 people. Additional information is available on the Internet at www.roche.com.

Source: Roche Press Release

This multicenter, randomized open-label Phase 2 single-arm study is enrolling patients with metastatic androgen-independent prostate cancer who have developed disease progression during or within 60 days of receiving docetaxel-based chemotherapy or demonstrated intolerance to docetaxel-based therapy. A total of 132 patients are expected to be enrolled at various centers, including those that participate in the Department of Defense's Prostate Cancer Consortium. This Phase 2 study is designed to evaluate the efficacy and safety of both IMC-A12 and IMC-1121B combined with mitoxantrone and prednisone. IMC-A12 and IMC-1121B are administered weekly, whereas mitoxantrone is administered every three weeks with oral daily prednisone.

"We are very pleased about beginning another disease-directed, proof-of-concept trial which efficiently evaluates two of our pipeline antibodies with distinct mechanisms of action, yet each with potential applicability in the treatment of prostate cancer based on preclinical investigations performed by ImClone and academic collaborators," said Eric K. Rowinsky, M.D., Chief Medical Officer and Executive Vice President of ImClone. "The results of any one of the study arms, or even both, in conjunction with those of other ongoing clinical and preclinical studies, may serve as platforms for subsequent registration directed activity in several early- and advanced-stage prostate cancer settings."

IMC-A12 is a fully human IgG1 monoclonal antibody designed to specifically target the human IGF-1R, thereby inhibiting certain ligands known as IGFs 1 and 2 from binding to and activating the receptor. This action blocks a signaling pathway that enhances tumor cell proliferation and survival. In 2007, ImClone completed enrollment into two Phase 1 studies of IMC-A12 which demonstrated favorable safety and pharmacokinetic profiles, as well as preliminary evidence of antitumor activity as a single agent when administered either weekly or every two weeks. In addition to this Phase 2 study announced today, Phase 2 studies of IMC-A12 in adult and adolescent patients with soft tissue sarcoma, untreated advanced prostate, pancreatic, colorectal, liver, and head and neck cancers, as well as a series of Phase 1/2 studies in pediatric malignancies and another evaluating the combination of IMC-A12 and temsirolimus, have begun to enroll patients.

IMC-1121B is a fully human IgG1 monoclonal antibody designed to bind to the extracellular domain of VEGFR-2 found on tumor vasculature, thereby inhibiting certain ligands known as vascular endothelial growth factors from binding to and activating the receptor. This action blocks a signaling pathway key to new blood vessel formation in growing tumors, which has been shown to starve tumors of their nutrient supply and result in significant tumor growth inhibition in pre-clinical models. In addition to this Phase 2 study announced today, disease-directed studies of IMC-1121B in patients with advanced melanoma, liver and renal cancers have begun to enroll patients, and additional Phase 2 and 3 evaluations are in various stages of development. In April 2008, ImClone announced an agreement with the Food and Drug Administration on a Special Protocol Assessment for a Phase 3 study of IMC-1121B in women with metastatic breast cancer, which recently commenced.

About ImClone Systems

ImClone Systems Incorporated is a fully integrated global biopharmaceutical company committed to advancing oncology care by developing and commercializing a portfolio of targeted biologic treatments designed to address the medical needs of patients with a variety of cancers. The Company's research and development programs include growth factor blockers and angiogenesis inhibitors. ImClone Systems' headquarters and research operations are located in New York City, with additional administration and manufacturing facilities in Branchburg, New Jersey. For more information about ImClone Systems, please visit the Company's web site at http://www.imclone.com.

Source: ImClone Systems Incorporated Press Release

BARCELONA, Spain-- June 26, 2008--Amgen announced updated results from the STEPP (Skin Toxicity Evaluation Protocol with Panitumumab) trial, the first prospective study to examine differences between preemptive and reactive skin treatment for skin toxicities in metastatic colorectal cancer (mCRC) patients receiving epidermal growth factor receptor (EGFr) therapy. The analysis found that preemptive treatment reduced the incidence rate of grade 2 and greater skin toxicities by over 50 percent without additional side effects when compared to reactive skin treatment. The incidence of grade 3 or greater skin toxicities were 62 percent and 29 percent in the reactive and preemptive treatment groups respectively (odds ratio (95 percent CI): 0.3 (0.1. 0.6)). These data were presented at the 10th World Congress on Gastrointestinal Cancer in Barcelona, Spain.

In this patient population, the time to severe skin toxicity was significantly delayed by preemptive skin treatment; at 6 weeks the event- (grade 2 or greater skin toxicity) free probabilities were 70 percent and 38 percent for the preemptive and reactive arms respectively (difference: 32.2 percent (95 percent CI: 12.8, 51.7) in favor of the preemptive arm). Time-to-first-occurrence of any specific grade 2 or higher skin toxicity was also significantly delayed in the preemptive arm. The estimated median time to the first occurrence was 2.7 weeks (95 percent CI: 2.1, 6.3) in the reactive arm and it was not reached in the preemptive arm.

Skin toxicity, or rash, is one of the most common side effects of EGFr inhibitors like Vectibix(R) (panitumumab). The secondary endpoints were safety and efficacy and the analysis included data from 95 patients who had the opportunity to complete 14 weeks on study. Consistent with previous results, analyses by KRAS favored the wild-type group for all efficacy endpoints.

Since skin rash is the most common side effect of EGFr therapy, the results of the STEPP trial showing that skin rash may be controlled by a relatively simple preemptive treatment, represent a significant advancement, said David Chang, M.D., vice president for oncology clinical development at Amgen. In addition, these data add to the growing body of evidence supporting the utility of Vectibix in combination with chemotherapy for patients with wild-type KRAS tumors.

About STEPP

Patients enrolled in STEPP received, at the discretion of the investigator, either second-line FOLFIRI-based chemotherapy plus 6.0 mg/kg of Vectibix every two weeks (Q2W) or irinotecan-based chemotherapy plus 9.0 mg/kg Vectibix every three weeks (Q3W) and were randomized to preemptive or reactive skin treatment. Preemptive skin treatment included the administration of skin moisturizer, sunscreen, topical steroid and oral doxycycline. The primary endpoint was the incidence of grade two or greater skin toxicities during the six-week skin treatment period. Secondary endpoints included safety and efficacy.

The analysis of 95 patients showed the following adverse events (AE): 93 percent of all patients had a Vectibix treatment-related AE; 71 percent of all patients had a grade 3/4 AE. Vectibix dose reductions due to skin toxicities occurred in eight percent of patients. Serious adverse events (SAE) were observed in 38 percent of patients and AEs caused 14 percent of patients to end treatment.

About Vectibix

 Vectibix is U.S. Food and Drug Administration (FDA) approved as a monotherapy for the treatment of patients with EGFr- expressing mCRC after disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. The effectiveness of Vectibix as a single agent for the treatment of EGFr-expressing, mCRC is based on progression-free survival. Currently no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Vectibix.

In December 2007, the European Medicines Agency (EMEA) granted a conditional marketing authorization for Vectibix as monotherapy for the treatment of patients with EGFr-expressing mCRC with non-mutated (wild-type) KRAS genes after failure of standard chemotherapy regimens. Vectibix is now available in 11 European countries. In the first half of 2008 Vectibix was approved by health authorities in Canada and Australia.

Important Product Safety Information - EU

 Dermatologic related reactions, a pharmacologic effect observed with epidermal growth factor receptor (EGFR) inhibitors, are experienced with nearly all patients (approximately 90 percent) treated with Vectibix. The majority of dermatological reactions are mild to moderate in nature. In clinical studies, subsequent to the development of severe dermatological reactions (including sore mouth), infectious complications including sepsis, in rare cases leading to death, and local abscesses requiring incisions and drainage were reported. Patients who have severe dermatologic reactions or who develop worsening reactions whilst receiving Vectibix should be monitored for the development of inflammatory or infectious sequelae, and appropriate treatment promptly initiated. Severe infusion reactions occurred with Vectibix in approximately one percent of patients. Severe infusion reactions were identified as anaphylactic reactions, bronchospasm, fever, chills and hypotension. Although fatal infusion reactions have not been reported with Vectibix, they have occurred with other monoclonal antibody products. Severe infusion reactions require stopping the infusion and possibly permanently discontinuing Vectibix, depending on the severity and / or persistence of the reaction.

Important Product Safety Information - US

 Dermatologic toxicities, related to Vectibix blockade of EGF binding and subsequent inhibition of EGF receptor-mediated signaling pathways, included but were not limited to dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Dermatologic toxicities were reported in 89 percent of patients treated with Vectibix and were severe in 12 percent of patients. Severe dermatologic toxicities were complicated by infection, including sepsis, septic death, and abscesses requiring incisions and drainage. Vectibix may need to be withheld or discontinued for severe dermatologic toxicities.

Severe infusion reactions occurred with Vectibix in approximately 1 percent of patients. Severe infusion reactions were identified as anaphylactic reactions, bronchospasm, fever, chills, and hypotension. Although fatal infusion reactions have not been reported with Vectibix, they have occurred with other monoclonal antibody products. Severe infusion reactions require stopping the infusion and possibly permanently discontinuing Vectibix, depending on the severity and/or persistence of the reaction.

About Amgen

 Amgen discovers, develops, manufactures and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science's promise by bringing safe and effective medicines from lab, to manufacturing plant, to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis, and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people's lives. To learn more about our pioneering science and our vital medicines, visit www.amgen.com.

Source: Amgen Press Release

Chicago --May 31, 2008--  Genentech, Inc. announced that Avastin® (bevacizumab), in combination with docetaxel chemotherapy, significantly increased the time women with metastatic breast cancer receiving first-line therapy lived without their disease advancing, as defined by the primary endpoint of progression-free survival (PFS). In this Roche-sponsored, placebo-controlled Phase III trial (AVADO), two dose levels of Avastin in combination with docetaxel chemotherapy showed a statistically significant improvement in PFS compared to docetaxel chemotherapy alone, according to an investigator-assessed analysis. No new safety signals for Avastin were observed in the study.

The results were featured today during a press briefing at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO) and will be presented tomorrow by David Miles, M.D., medical oncologist, Mount Vernon Hospital, United Kingdom (Abstract # LBA1011 – June 1, 2008 at 8:30 a.m. CDT in E Hall D1).

"These results build upon previous data and expand our understanding of Avastin’s efficacy and safety when combined with another commonly used taxane chemotherapy," said Dr. David Miles, principal investigator of the study. "Importantly, this study supports that Avastin can be used with taxane-based chemotherapy to provide a meaningful benefit for patients with advanced HER2-negative breast cancer."

Genentech is required to submit to the U.S. Food and Drug Administration (FDA) by mid-2009 the results of AVADO and RIBBON I, a third Phase III study in first-line metastatic breast cancer. Results for the RIBBON I study are expected later this year.

The pre-specified analysis of AVADO for U.S. regulatory purposes showed that Avastin combined with chemotherapy improved PFS by up to 64 percent (hazard ratio of 0.61; p<0.0001) in the 15 mg/kg treatment arm and by up to 45 percent (hazard ratio of 0.69; p=0.0035) in the 7.5 mg/kg treatment arm, compared to chemotherapy alone. Overall response rate, a secondary endpoint, was also positive and supported the PFS benefit observed in this study. After one year, 83 percent and 78 percent of patients were alive in the 15 mg/kg and 7.5 mg/kg Avastin treatment arms, compared to 73 percent of patients receiving chemotherapy alone.

"The totality of the AVADO results, including positive primary and secondary endpoints and reassurances of safety, support the benefit of Avastin in extending the time women lived without their disease progressing when combined with chemotherapy as a first-line treatment," said Susan Desmond-Hellmann, M.D., M.P.H., president, Product Development. "We are committed to fully evaluating Avastin’s efficacy and safety in metastatic breast cancer and anticipate the results of a third Phase III trial later this year."

About AVADO

AVADO was an international, multicenter, randomized, double-blind, placebo-controlled clinical trial that enrolled 736 patients with locally recurrent or metastatic HER2-negative breast cancer who had not received chemotherapy for their metastatic disease. Patients were randomized to one of two doses of Avastin (15 mg/kg or 7.5 mg/kg) or placebo given every three weeks in combination with docetaxel chemotherapy for a maximum of nine cycles. Patients discontinuing docetaxel for toxicity or after nine cycles were to continue on Avastin only or placebo until disease progression. The AVADO study was not designed to compare the two dose levels of Avastin.

In the 15 mg/kg and 7.5 mg/kg Avastin treatment arms, the 64 percent and 45 percent improvements in PFS observed can also be referred to as 39 percent and 31 percent reductions in the risk of cancer progression or death. Median PFS was 8.8 months, 8.7 months and 8.0 months in the 15 mg/kg and 7.5 mg/kg Avastin plus chemotherapy arms and the chemotherapy alone arm, respectively. Overall response rates were 63 percent (p=0.0001) and 55 percent (p=0.0295) in the 15 mg/kg and 7.5 mg/kg Avastin plus chemotherapy arms, compared to 44 percent in the chemotherapy alone arm.

The study protocol specified analyses for overall survival at the time of primary endpoint analysis and 24 months after the last patient was enrolled. The final analysis for overall survival is expected in 2009. Hazard ratios for the preliminary analysis of overall survival are 0.68 and 0.92 for the 15 mg/kg and 7.5 mg/kg Avastin arms, respectively. These initial results for overall survival are not statistically significant and are based on early information.

1 Each Avastin + docetaxel arm was studied against placebo + docetaxel. The study was not designed to compare the two Avastin arms.

2 Pre-specified primary endpoint analysis for U.S. regulatory purposes.

3 Among patients with measurable disease at baseline.

The AVADO study provided a comprehensive safety assessment of the Avastin and docetaxel combination by using a placebo control arm and collecting Grade 1 to 5 adverse events in all arms of the study. The most common severe adverse events were generally consistent with those observed in a previous Phase III study of Avastin in metastatic breast cancer.

About Breast Cancer

Breast cancer is the second most common form of cancer and second leading cause of cancer deaths among American women. According to the American Cancer Society, an estimated 182,000 women will be diagnosed with breast cancer and approximately 40,000 will die from the disease in the U.S. in 2008. Genentech estimates that 75 percent of women with newly diagnosed metastatic breast cancer are HER2-negative.

About Avastin

Avastin is a therapeutic antibody designed to specifically inhibit vascular endothelial growth factor (VEGF), a protein that plays an important role in angiogenesis and the maintenance of existing blood vessels throughout the lifecycle of a tumor. By inhibiting VEGF, Avastin is designed to interfere with the blood supply to a tumor, which is thought to be critical to a tumor's ability to grow and spread in the body (metastasize).

Avastin is indicated for the first- and second-line treatment of metastatic colorectal cancer in combination with intravenous 5-FU-based chemotherapy, and for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel. For more information on angiogenesis, visit http://www.gene.com. For full Prescribing Information and Boxed Warnings on Avastin, visit http://www.avastin.com.

Avastin Safety

Avastin has a well-characterized safety profile in its approved indications. The most serious adverse events associated with Avastin across all trials were gastrointestinal perforation, wound healing complications, hemorrhage, non-GI fistula formation, arterial thromboembolic events, hypertensive crisis, reversible posterior leukoencephalopathy syndrome (RPLS), neutropenia and infection, nephrotic syndrome and congestive heart failure.

The most common severe adverse reactions (NCI-CTC Grade 3-5) across clinical trials in metastatic colorectal cancer, NSCLC, and metastatic breast cancer that occurred at a higher incidence (greater than or equal to 2 percent higher rate vs. controls) were hypertension, proteinuria and headache.

About Genentech

Founded more than 30 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines for patients with significant unmet medical needs. The company has headquarters in South San Francisco, California and is listed on the New York Stock Exchange under the symbol DNA. For additional information about the company, please visit http://www.gene.com.

Source: Genentech Press Release

This indication is based on analyses of plasma HIV-1 RNA levels up through 24 weeks in two controlled studies of ISENTRESS [pronounced i-sen-tris].  These studies were conducted in clinically advanced, three-class antiretroviral [nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)] treatment-experienced adults.  The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response.  The safety and efficacy of ISENTRESS have not been established in treatment-naïve adult patients or pediatric patients.  There are no study results demonstrating the effect of ISENTRESS on clinical progression of HIV-1 infection.  Longer term data will be required before the FDA can consider traditional approval for ISENTRESS.

ISENTRESS is the first medicine to be approved in a new class of antiretroviral drugs called integrase inhibitors.  ISENTRESS works by inhibiting the insertion of HIV DNA into human DNA by the integrase enzyme.  Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells.  There are drugs in use that inhibit two other enzymes critical to the HIV replication process - protease and reverse transcriptase - but ISENTRESS is the only drug approved that inhibits the integrase enzyme.

The FDA's decision was based on a 24-week analysis of clinical trials in which ISENTRESS in combination with optimized background therapy (OBT) in treatment-experienced patients, provided significant reductions in HIV RNA viral load and increases in CD4 cell counts.

"The development of ISENTRESS is a significant milestone in the history of HIV/AIDS therapy because we now have a drug that's potent against another key enzyme essential for viral replication," said Joseph J. Eron Jr., M.D., professor of medicine, Division of Infectious Diseases, UNC Chapel Hill School of Medicine.  "It's important for physicians to know that ISENTRESS should always be used in combination with other active agents."

Data from two ongoing Phase III multi-center, double-blind, randomized, placebo-controlled studies (BENCHMRK-1 and BENCHMRK-2) in 699 treatment-experienced adult patients with documented resistance to at least one drug in each of three classes (NRTIs, NNRTIs and PIs) of antiretroviral therapies showed that ISENTRESS 400 mg dosed twice daily in combination with OBT was significantly more effective at both reducing levels of HIV viral RNA and increasing CD4 cell counts in these patients living with HIV, when compared to a regimen of placebo plus OBT.

Pooled analyses from the two Phase III studies showed that after 24 weeks of therapy, 75.5 percent of patients (216 out of 286) receiving ISENTRESS in combination with OBT achieved HIV viral RNA load reduction to below 400 copies/mL compared to 39.3 percent of patients (59 out of 150) receiving placebo plus OBT.  In addition, after 24 weeks of therapy, 62.6 percent of patients (179 out of 286) receiving ISENTRESS plus OBT achieved viral load reduction to below 50 copies/mL compared to 33.3 percent of patients (50 out of 150) receiving placebo plus OBT.  After 24 weeks of therapy, increases in CD4 cell counts from baseline were 89 and 35 cells/mm3 for patients receiving ISENTRESS plus OBT and for those receiving placebo plus OBT, respectively.

Important safety information about ISENTRESS

ISENTRESS does not cure HIV or AIDS and does not prevent passing HIV to others. Healthcare providers should know that immune reconstitution syndrome has been reported in patients treated with antiretroviral therapy, which may necessitate further evaluation and treatment.

The most commonly reported adverse experiences of any severity (mild, moderate or severe) regardless of drug relationship were diarrhea (16.6 percent vs. 19.5 percent), nausea (9.9 percent vs. 14.2 percent), headache (9.7 percent vs. 11.7 percent) and fever (4.9 percent vs. 10.3 percent) for ISENTRESS plus OBT and placebo plus OBT, respectively.

Creatine kinase elevations were observed in subjects who received ISENTRESS. Myopathy and rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events is not known.  ISENTRESS should be used with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medication known to cause these conditions.

Safety and tolerability profile of ISENTRESS

Results from pooled safety analyses from three separate studies in treatment-experienced patients taking 400 mg of ISENTRESS dosed twice daily plus OBT or placebo plus OBT showed that after 24 weeks of therapy the rates of discontinuation of therapy due to adverse experiences were 2.0 percent in patients receiving ISENTRESS plus OBT and 1.4 percent in patients receiving placebo plus OBT.  In addition, drug-related clinical adverse events of moderate to severe intensity occurring in greater than or equal to 2.0 percent of patients were diarrhea (3.7 percent vs. 4.6 percent), nausea (2.2 percent vs. 3.2 percent) and headache (2.4 percent vs. 1.4 percent) for ISENTRESS plus OBT and placebo plus OBT, respectively.

Drug interactions

Based on the results of drug interaction studies and the clinical trials data, no dose adjustment of ISENTRESS is required when coadministered with other antiretroviral agents. Also, preclinical studies show that ISENTRESS is not metabolized by cytochrome P450 enzymes.  Caution should be used when coadministering ISENTRESS with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampin) due to reduced plasma concentrations of ISENTRESS.

About ISENTRESS

ISENTRESS is a single 400 mg tablet taken twice daily without regard to food. ISENTRESS does not require boosting with ritonavir.

Merck has worked closely with the HIV community regarding the price of ISENTRESS.  The wholesale acquisition cost (WAC) of ISENTRESS will be $27 per day, comparable to the price of several available ritonavir-boosted protease inhibitors.

To help patients in the United States who cannot afford treatment with ISENTRESS, the SUPPORT™ program is available.  The SUPPORT program is a patient assistance program to help patients who have been prescribed ISENTRESS by providing personalized support and patient advocacy regarding individual reimbursement issues.  In addition, Merck also participates in the Partnership for Prescription Assistance program, a single point of access to more than 475 public and private patient assistance programs.  ISENTRESS will be available in pharmacies in approximately two weeks.  For more information on ISENTRESS, visit www.isentress.com.

Expanded access program

ISENTRESS is currently available worldwide to qualified patients through an expanded access clinical research program, EARMRK.  This global program provides early access to ISENTRESS for patients failing current therapy whose HIV is resistant to drugs in three existing classes (NRTIs, NNRTIs, PIs) of antiretroviral medications.  Information about the program can be found at www.benchmrk.com.

Merck HIV research

Merck is committed to developing innovative therapies that offer advances in the treatment of infectious diseases - including HIV.  Merck's efforts to develop investigational treatments for HIV/AIDS have been under way for more than 20 years and continue today.  Merck began its HIV integrase inhibitor research in 1993 and was the first to demonstrate inhibition of HIV integrase in vitro and in vivo.

Prevalence of HIV/AIDS

In 2006, over one million Americans were living with HIV/AIDS and it is estimated that approximately 40,000 new cases of HIV/AIDS are diagnosed each year in the United States. Worldwide, an estimated 40 million people are infected with HIV/AIDS, and more than four million new infections occurred in 2006.

"As the AIDS crisis continues, new drugs like ISENTRESS are needed, which target the virus in unique ways," said Ben Cheng, deputy director, Forum for Collaborative HIV Research.  "The HIV Advocacy Community is really excited and encouraged by this new treatment."

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first.  Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs.  The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them.  Merck also publishes unbiased health information as a not-for-profit service.  For more information, visit www.merck.com.

Forward-looking statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995.  These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements.  The forward-looking statements may include statements regarding product development, product potential or financial performance.  No forward-looking statement can be guaranteed, and actual results may differ materially from those projected.  Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.  Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the company incorporates by reference.

ISENTRESS™ is a trademark of Merck & Co., Inc.

SUPPORT™ is a trademark of Merck & Co., Inc. 

27 June 2007 — LONDON — Results from an interim analysis of a Phase III study show that CervarixTM, the GlaxoSmithKline (GSK) cervical cancer candidate vaccine, provides up to 100 percent protection against advanced precancerous lesions caused by the most common types of human papillomavirus, types 16 and 18. The study also strengthens earlier preliminary evidence that the vaccine provides significant protection against infection with additional cancer-causing virus types. These results were published today in The Lancet.

 “This landmark trial has provided important new insights into the natural history of cervical lesions, and helps us to more clearly understand the causal link between these lesions and the virus types detected within them,” said Gary Dubin, M.D., Vice President, North American Clinical Development, GSK.

 “These results validate our previous clinical findings, and we believe that the data in this study show the GSK candidate vaccine provided 100 percent protection against precancerous lesions caused by virus types 16 and 18, which are responsible for 70 percent of all cervical cancers,” commented David Stout, President of Pharmaceuticals Operations, GSK.

 In this study, the majority of precancerous lesions included in the primary analysis had multiple cancer-causing virus types detected, making it difficult to clearly determine which virus type was the cause of the lesion. The observation of such a high number of lesions with multiple virus types was not expected based on published data. This necessitated additional analyses to determine which virus type was the cause of the lesion. In these analyses, causality was determined by confirming the presence of the virus in both the lesion and in previous Pap smear samples.

When using the pre-specified analyses which only required detection of virus in the lesion, and not taking previous samples into account, vaccine efficacy in women with virus type 16 and/or 18 in the lesion was 90 percent. When considering the virus type present in both the lesion and previous samples, the vaccine was 100 percent effective in preventing precancerous lesions caused by virus types 16 and/or 18.

“The findings are very encouraging because the women in the study are representative of the patients seen by physicians every day in their practice,” said lead investigator Professor Jorma Paavonen, Department of Obstetrics and Gynecology at Helsinki University Central Hospital, Finland. “This provides a strong indication that this vaccine can protect women from the infections that may develop into cervical cancer.”

 This pivotal, Phase III study involves 18,644 women aged 15-25 from 14 countries across Europe, Asia-Pacific and Latin and North America, making it the single largest cervical cancer vaccine efficacy trial to date.

Cross Protection

In this clinical trial, the vaccine showed significant cross-protection against 6-month persistent infection caused by virus types 45, 31 and 52. Together with virus types 16 and 18, these types are collectively responsible for more than 80 percent of cervical cancer cases globally.

“These results suggest protection from persistent infection with additional cancer-causing virus types beyond those contained in the vaccine,” said Professor Margaret Stanley, Pathology Department, University of Cambridge, UK. “This is important becausepersistent infection is a necessary first step in the development of precancerous lesions and cervical cancers.”

The data also shows that the GSK candidate vaccine, formulated with the innovative adjuvant system AS04, produced a robust immune response for both virus types 16 and 18. This strong immune response has been shown to persist for up to 5.5 years in previous studies.

As in previous studies conducted over the past five years and involving over 40,000 women, the candidate vaccine has been shown to be generally well-tolerated.

About the Study

These data are interim results from an ongoing Phase III randomised, controlled trial of 18,644 women aged between 15-25 years of age from across four continents — Asia-Pacific, Europe, Latin America and North America, in a total of 14 countries.

This interim analysis shows results over an average follow-up time of 15 months after first vaccination, in which a proportion of the women enrolled already had a human papillomavirus infection or abnormal cytology (abnormal Pap smears) at study entry.

The primary objective of the interim analysis was to evaluate the vaccine efficacy against precancerous lesions associated with cancer-causing virus types 16 and 18 among women who were DNA-negative and seronegative for the corresponding vaccine type at study entry. Secondary objectives included efficacy against 6- and 12-month persistent infection with virus types 16, 18 or other cancer-causing virus types, immunogenicity and safety.

About the GSK Cervical Cancer Vaccine

In May, CervarixTM was granted its first licence in a major market by the Therapeutic Goods Administration (TGA) of Australia for the prevention of cervical cancer and precancerous lesions caused by human papillomavirus types 16 and 18 for use in females ages 10 to 45 years. This is the first time that a cervical cancer vaccine has been explicitly indicated anywhere in the world for women over the age of 26.

GSK submitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for its cervical cancer candidate vaccine in March 2007, following earlier regulatory filings with the European Medicines Agency (EMEA) and regulatory filings in Africa, Asia and Latin America.

About Cervical Cancer

Worldwide, more than 500,000 women will be newly diagnosed with cervical cancer and over 280,000 women will die from it each year. In the United States, after breast cancer, cervical cancer is the leading cause of cancer death in women ages 20-39.Cervical cancer and precancerous lesions are a major health, psychological and social burden on women everywhere.

Published data shows that any given time, only 2.3 percent of women ages 14-59 are currently infected with cancer-causing human papillomavirus types 16 and 18. Only 0.1 percent are currently infected with both types. Therefore, the vast majority of these women (up to 99.9 percent) may benefit from vaccination as they are not actively infected with these virus types and are potentially at risk for developing an infection in the future. Naturally occurring infections with cancer-causing virus types may resolve on their own, but this previous exposure may not protect against future infections with the same virus types. Some infections persist and develop into precancerous lesions, which can advance into cancer.

About GlaxoSmithKline

GlaxoSmithKline–one of the world’s leading research-based pharmaceutical and healthcare companies–is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For company information, please visit www.gsk.com/media.

GSK Biologicals (GSK Bio), one of the world’s leading vaccine manufacturers, is headquartered in Rixensart, Belgium, where the majority of GlaxoSmithKline’s activities in the field of vaccine research, development and production are conducted. GSK Bio employs more than 1,500 scientists, who are devoted to discovering new vaccines and developing more cost-effective and convenient combination products to prevent infections that cause serious medical problems worldwide. In 2006, GSK Bio distributed more than 1.1 billion doses of vaccines to 169 countries in both the developed and the developing world — an average of 3 million doses a day. Of those vaccine doses, approximately 136 million were doses of combination paediatric vaccines which protect the world’s children from up to six diseases in one vaccine.

Cervarix is a trademark of the GlaxoSmithKline group of companies.

Source: GSK Press Release

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.