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					Oncology
    at
 Roche
R         oche Pharma R&D Pipeline Today
            Total of 19 NME’s + 22 Additional Indications (AIs)
           Phase 0                 Phase 1                   Phase II                      Phase III
           (6 NMEs)                (8 NMEs)              (5 NMEs + 7 AIs)                  filed (3)
                                                                                             (15 AIs)
 R769    Phase 0
           Oncology            R1550   breast cancer    R1273   solid tumours                    Phase 0
                                                                                       R435 Avastin oncology
 R1507      Oncology           R1454   solid tumours    R1492   solid tumours          R1415 Tarceva oncology
 R547 solid tumours            R1559   solid tumours    R1536   solid tumours
 R1530 solid tumours           R1645   solid tumours
                               CHU solid tumours        CHU bone matastases            R1569   MRA        SoJIA

 GEN basal cell carcinoma      GEN cancer therapy
                                                                                       R105 Mabthera CLL
                Hematologic                                       chemotherapy-                         mainten.
 R1594          malignancies   ANT   solid tumours      R744    induced anemia                            iNHL
                                                                          all                           pancreatic
                               ARQ    solid tumours     R105 Mabthera diseases         R1415 Tarceva      cancer
                                                                                                          mCRC
                                                                                       R340 Xeloda        combo
                                                                          NSCLC                         adj. CRC
                                                        R1415 Tarceva     1st line                        mono
 R                                                                         adjuvant                      adj. BC
     Roche managed projects                                                NSCLC
 XX                                                                     glioblastoma   R435 Avastin     adj. CRC
     Participations                                                      NSCLC                          pancreatic
 XX                                                                      2nd line                         cancer
     Opt-in Opportunities                                                ovarian                           RCC
                                                        R435 Avastin      cancer
 XX                                                                       gastric                        NSCLC
     CHU     Chugai                                     R597 Herceptin    cancer
     GEN     Genentech                                                                                    mBC
     ANT     Antisoma
     ARQ     ArQule                                                                    R597 Herceptin     adj. BC

 R                                                                                                        mBC
                                                                                                         combo
     Major new indications
                                                                                       R484 Bondronat      MBP


Status as of December 31 , 2004                                                        CHU        Femara BC
NME = new molecular entity




R         oche Oncology
              4 Major Mechanistic Approaches to Cancer Treatment

                                                 Research focus on the 5 most common
                                                 and deadly forms of cancer:

                                                          • Lung
                                                          • Breast
                                                          • Colon
                                                          • Prostate
                                                          • Lymphoma

                                                 Active research programs in other
                                                 common tumor types as well.
                                                       For more information, please see
                                                       http://www.roche.com/oncology-AACR.htm
                              R   oche Oncology Focus

                                        By integrating diagnostic              identify and deliver the optimal drug
                                         techniques with these                 combinations that will improve the
                                          novel molecular-based                efficacy of cancer therapies;
                                           therapeutics, we expect to          – by limiting non-specific, undesirable
                                             improve efficacy in a number      side effects, we improve the patient’s
                                               of ways – by partnering         quality of life as well as compliance.
                                                 drugs with diagnostics
                                                to identify the optimal        With our expertise in diagnostics,
                                              patient population for           genetics/genomics and drug
                                             any given therapeutic;            discovery, Roche is uniquely
                                         – by understanding the                positioned to continue to drive this
                                       molecular mechanisms by which           trend in Oncology and assume a
                                    our drugs work, we will be able to         leadership position in the field.




T he goal of Roche
The goal of Roche
Oncology Research is to
Oncology Research is to
provide more effective
provide more effective
                                                               P
                              Traditionally, anticancer drugs have
                                                                  reclinical Research Strategy
                                                                              loss of response to negative growth
cancer therapies through      been relatively non-specific, and               regulation)
cancer therapies through
the discovery and             frequently directed against general           • defective apoptosis regulation
the discovery and develop-
development of novel          processes (i.e., metabolism, microtubule      • invasion
ment of novel therapeutics
therapeutics that treat the   dynamics, microtubule dynamics) rather        • metastasis
that treat the specific       than against tumor-specific molecular         • angiogenesis
specific molecular lesions
molecular lesions             targets. Although efficacious, these          • escape from immune surveillance.
associated with cancer.
associated with cancer.       agents are limited as a result of both        While the major driver for new
Roche understands that        their side effect profile and the fact that   cancer therapeutics remains improved
effective cancer cures are    in most cases, the response rates to          efficacy, our approach at Roche to
often accompanied by          treatment are low.                            achieving this goal is changing as a
undesirable side effects.                                                   result of our improved understanding
undesirable side effects.
                              In addition, the identification of new        of the disease at a molecular, cellular
Thus, Roche also seeks
Thus, Roche also seeks
                              drug combinations is usually experimen-       and physiological level. One such
novel and effective
novel and effective           tal and empirical. We now view tumor          research project is on potential p53
supportive care products
supportive care products      biology as being driven by an iterative       pathway activators. Nutlins, the first
that allow physicians to
that allow physicians to      process of mutation and selection,            potent and selective small molecules to
aggressively treat cancer
aggressively treat cancer     resulting in the acquisition of multiple      activate the p53 pathway by preventing
while also helping patients   novel properties by the malignant cells.      the p53 inhibitor MDM2 from binding
while also helping patients
feel better and engage                                                      to the p53 gene, were discovered by
feel better and engage in
in normal daily activities.   These include:                                Roche scientists. Preclinical data indicate
normal daily activities.
This also fulfills our        • the acquisition of genetic instability      that these small molecules may provide
This also fulfills our
mission of “Targeting         • de-differentiation                          a novel strategy for treating tumours
Cancer of “Targeting
mission With Care.”           • loss of growth control (aberrant            with a normal p53 gene.
Cancer With Care.”              growth promoting responses and                                                            Page 1
         T
         arget Specific Intervention
          Cellular Growth                and   Signaling
                                                        of




             In contrast to normal cells, tumor cells grow in an
             uncontrolled manner, failing to respond appropriately
             to normal growth, regulatory and survival signals.
             Roche scientists are focused on developing tumor
             selective therapies by understanding and targeting
             the aberrant processes that are responsible for this
             loss of control.The goal is to restore or trigger
             normal cell cycle and cell death responses, thereby
             leading to the development of drugs with improved
             efficacy and safety profiles as compared to current
             anticancer agents.




Page 2
                            T
                            umor Invasion, Metastasis   and Angiogenesis




In order to continue to
grow and invade new
areas of the body, tumors
must usurp many normal
physiological processes.
One example of this is
the ability of a tumor
to attract the growth
of new blood vessels
that supply it with the
nutrients required for
continual growth.
Here, our goal is to
discover drugs that
target those normal
processes that, while
essential for tumor
growth and survival,
are not vital for
normal physiology.
These agents are
expected to be
used for the long-term
treatment of cancer
patients, with few or
easily managed side
effects, and would
be designed to
target metastasis
and angiogenesis.




                                                                           Page 3
         C
         ytostatic/Cytotoxic Therapy


             The most important anti-tumor therapeutics used in
             oncology today are drugs designed to suppress cancer
             growth and kill tumor cells.




                                                                                     At Roche, scientists are
                                                                                     looking for
                                                                                       • novel and improved
                                                                                         compounds in
                                                                                         this area
                                                                                      • ways to optimize
                                                                                        tumor selectivity
                                                                                        using prodrugs
                                                                                      • evaluating new tumor-
                                                                                        targeting approaches




                         As a leading health care company, Roche is committed to discovering novel
                                and effective therapeutic agents for the treatment of cancer
Page 4
                                                     R       oche Biomarker
                                                               Program in Oncology
                                                     In Oncology, integrated approaches aim to combine


G
enomic Technologies
  Target Discovery
      in Oncology
                                       for           specific anticancer drugs with specific diagnostic tests,
                                                     thereby improving the treatment of cancer by selecting
                                                     suitable patients and monitoring therapy success.The
                                                     overall goal is to make cancer therapy more personal-
Cancer development is a complex process              ized - safer and more efficacious, thereby reducing
of selection for multiple genetic lesions that       overall cancer morbidity and mortality.
provide phenotypic advantages to tumor cells
for growth, survival, metastasis and drug            In recent years, cancer research has revealed an
resistance. Any one of numerous combinations         overwhelming number of genes, proteins, signaling
of genetic defects can lead to pathologically        pathways and regulation mechanisms involved in cellular
similar cancer phenotypes. Cancer drugs of the       differentiation processes, cell cycle control, apoptosis,
future will be designed to modulate specific         angiogenesis, and metastases.This research has resulted
molecular targets required by the cancer             in greater understanding of the molecular mechanisms
cell. Therefore, the future of cancer therapy will   underlying carcinogenesis and opened the doors for
rely greatly on choosing the most appropriate        drug-specific biomarker test development.
combination of drugs for each individual based
                                                     To increase the chance of identifying a predictive marker
on the genetic profile of the individual’s tumor.
                                                     or set of multiple markers associated with a particular
The realization of such “individualized cancer
                                                     Roche drug; research begins early in the agent’s life
care” through rational integration of diagnostics
                                                     cycle. At the preclinical stage, potential predictive
and therapeutics is a major focus of Roche
                                                     biomarkers are investigated by exploring the mode of
Oncology. With this paradigm of “targeting the
                                                     action of the compounds. In many cases, parallel
right drugs to the right patient” in mind, one
                                                     assessment of multiple markers is required.
focus of Roche Oncology is to employ the
most innovative genomics tools that will
                                                     To cope with the increasing complexity of biomarker
allow us to identify and validate, as rapidly as
                                                     analysis in Oncology clinical trials, Roche has invested in
possible, the critical targets for cancer drug
                                                     a comprehensive portfolio of cutting-edge technologies
discovery and diagnostic development.
                                                     such as proteomics, RNA gene expression profiling,
                                                     SNP technology, DNA-methylation pattern analysis, and
                                                     real-time PCR. Preclinical findings are further confirmed
                                                     and validated in early clinical trials to assess if the iden-
                                                     tified markers can be unambiguously correlated with
                                                     clinical data. Once a clear relationship between the
                                                     presence or absence of one or more biomarkers and
                                                     the clinical data are shown, a standardized diagnostic
                                                     test will be developed during clinical registration trials
                                                     and prepared for regulatory approval alongside the
                                                     drug. Professional diagnostic expertise must therefore
                                                     be sought early in clinical development. Under the
                                                     umbrella of the Biomarker Program combining drug
                                                     and test development expertise, Roche Oncology is
                                                     uniquely positioned as the leader in truly personalized
                                                     cancer care.                                                    Page 5
         B     usiness Development
                and Alliance Strategy                  at   Roche
                                                                                                         Our Mission:
         Pharma Partnering Strategy                                                                      “Pharma Partnering builds
         Roche – through its Pharma Partnering division – is a major                                     a network of world-class
         player in biotechnology. We recognize that no one company                                       alliances that strengthens
         has a monopoly on innovation. We have the ability and                                           Roche’s portfolio. With
         willingness to be a true partner, to share our expertise and to                                 our partners and col-
                                                                                                         leagues, we transform
         enable biotechnology companies to bring promising products                                      scientific innovation into
         to patients as quickly as possible.The key ingredient to our                                    medicines that make a
         deals is autonomy. We believe the best way to foster innova-                                    difference in patients’ lives.”
         tion is to encourage our partners to develop as independent
                                                                                                         Roche is now a valued
         companies. Our alliances with Genentech in the US, Chugai in
                                                                                                         partner to more than
         Japan and Antisoma in the UK are examples of that.                                              75 companies worldwide,
                                                                                                         covering a wide range of
                                                                                                         therapeutic areas. In 2004
                                                                                                         alone, 40 partner transac-




         Avastin  ™
                                                        C     linical Development
                                                                                                         tions were finalized. Our
                                                                                                         leadership position in
                                                                                                         oncology was enhanced
                                                                                                         due to the number and the
                                                                                                         quality of these alliances.
         Avastin™ (bevacizumab) is the first treatment that inhibits angiogenesis – the growth of a
                                                                                                         We believe no other pharma
         network of blood vessels that supply nutrients and oxygen to cancerous tissues. Avastin
                                                                                                         company has elevated the
         targets a naturally occurring protein called VEGF (Vascular Endothelial Growth Factor), a
                                                                                                         role of “alliance manage-
         key mediator of angiogenesis, thus choking off the blood supply that is essential for the
                                                                                                         ment” to the level that
         growth of the tumour and its spread throughout the body (metastasis).
                                                                                                         we have and integrated it
                                                                                                         into every level of decision
                               The development of Avastin represents the culmination of many
                                                                                                         making. Our partners
                               years of research that is the realisation of the long-hoped for
                                                                                                         know that.That’s why
                               evidence that anti-angiogenic therapy has a significant role to play
                                                                                                         18 have signed further deals
                               in cancer treatment.
                                                                                                         to extend our collabora-
                                                                                                         tions into strategic
                               Avastin was approved in February 2004 in the US for use in combi-
                                                                                                         alliances.
                               nation with intravenous 5-Fluorouracil-based chemotherapy as a
                               treatment for patients with first-line — or previously untreated —
                                                                                                         We are committed to part-
         metastatic cancer of the colon or rectum, and by the European Commission in January
                                                                                                         nering in the development
         2005 for the treatment of patients with previously untreated metastatic colorectal cancer.
                                                                                                         of antibodies, small mole-
                                                                                                         cules, and proteins for
         Safety: Gastrointestinal Perforations/Wound Healing Complications: AVASTIN administration
                                                                                                         cancer, hematopoietic, or
         can result in the development of gastrointestinal perforation and wound dehiscence, in
                                                                                                         supportive care therapies.
         some instances resulting in fatality. Gastrointestinal perforation, sometimes associated with
                                                                                                         Through successful part-
         intra-abdominal abscess, occurred throughout treatment with AVASTIN (i.e., was not
                                                                                                         nerships and strategic
         correlated to duration of exposure).The incidence of gastrointestinal perforation in
                                                                                                         alliances, Roche will
         patients receiving bolus-IFL with AVASTIN was 2%.The typical presentation was reported
                                                                                                         develop and commercialize
         as abdominal pain associated with symptoms such as constipation and vomiting.
                                                                                                         innovative medicines which
         Gastrointestinal perforation should be included in the differential diagnosis of patients
                                                                                                         will make a significant
         presenting with abdominal pain on AVASTIN. AVASTIN therapy should be permanently
                                                                                                         impact on the lives of
         discontinued in patients with gastrointestinal perforation or wound dehiscence requiring
                                                                                                         cancer patients.
         medical intervention.The appropriate interval between termination of AVASTIN and
         sequent elective surgery required to avoid the risks of impaired wound healing/ wound
                                                                                                         General inquiries:
         dehiscence has not been determined.priate interval between termination of AVASTIN and
                                                                                                         pharma.partnering@roche.com
         subsequent elective surgery required to avoid the risks of impaired wound healing/wound
Page 6
C   linical Development
          (from page 6)


dehiscence has not been determined.
Hemorrhage: Serious, and in some cases
fatal, hemoptysis has occurred in patients
with non—small cell lung cancer treated with
chemotherapy and AVASTIN. In a small study, the
incidence of serious or fatal hemoptysis was 31% in
                                                                                                          fractures and
patients with squamous histology and 4% in
                                                                                                       other clinical
patients with adenocarcinoma receiving
                                                                                                     consequences.
AVASTIN as compared to no cases in patients
                                                                                          Approval for the use of
treated with chemotherapy alone. Patients with
                                                                                Bondronat for the prevention of
recent hemoptysis should not receive AVASTIN.
                                                              skeletal related evens in patients with breast cancer and
                                                              bone metastases was received from the European
In Genentech-sponsored clinical studies, other serious
                                                              Commission in October 2003. Bondronat is available in
adverse events associated with Avastin were aterial
                                                              oral and intravenous (i.v.) formulations. Bondronat has
thromboembolic events, hypertensive crises, nephrotic
                                                              also been used for a number of years for the treatment
syndrome, and congestive heart failure.The most
                                                              of hypercalcaemia of malignancy (high concentrations
common grade 3-4 adverse events were asthenia, pain,
                                                              of calcium in the blood stream). In hypercalcaemia of
hypertension, diarrhea, and leukopenia. The most
                                                              malignancy, Bondronat has been registered in over
common adverse events of any severity were asthenia,
                                                              50 countries world-wide with over 500,000 patients
pain, abdominal pain, headache, hypertension, diarrhea,
                                                              treated to date (but not in the USA).
nausea, vomiting, anorexia, stomatitis, constipation, upper
respiratory infection, epistaxis, dyspnea, exfoliative
                                                              Three phase III studies have assessed the efficacy of
dermatitis, and proteinuria.
                                                              both i.v. and oral formulations of Bondronat compared
                                                              with placebo in metastatic bone disease. In all three
Please see attached full Prescribing Information, includ-
                                                              studies, the primary endpoint was the number of
ing Boxed WARNINGS for additional safety information.
                                                              12-week periods with new bone complications (e.g.
                                                              fractures, need for radiotherapy or surgery), expressed
On commercialization, Genentech has the marketing
                                                              as the skeletal morbidity period rate (SMPR). Bone pain,
rights in the US. Outside the US, Roche has the marketing
                                                              analgesic consumption, quality of life and safety were
rights and is responsible for commercialization in these
                                                              also assessed.The results of the three trials showed that
territories; in Japan Roche works through its
                                                              both formulations of Bondronat were equally effective.1,2
partner Chugai.
                                                              Both i.v. and oral Bondronat significantly reduced the
                                                              SMPR to a similar extent (20% reduction vs placebo
Roche and Genentech are pursuing a comprehensive
                                                              treatment).
clinical programme investigating the use of Avastin in
advanced colorectal cancer with other chemotherapies
                                                              Due to the favourable renal safety profile of Bondronat,
and also expanding into the adjuvant setting (post
                                                              routine renal monitoring prior to each infusion is not
operation). As Avastin’s mechanism may be relevant in
                                                              necessary. Bondronat can be used in patients with renal
a number of malignant tumours, Roche and Genentech
                                                              impairment (<30mL/min)3.
are also investigating the potential clinical benefit of
Avastin in other cancers, including non-small cell lung
                                                              Bondronat has shown a sustained relief of metastatic
cancer, pancreatic cancer, renal cell carcinoma and
                                                              bone pain (MBP) below baseline. MBP is the most
others. Approximately 15,000 patients are expected
                                                              common symptom of MBD which occurs in over
to be enrolled into clinical trials over the next years
                                                              three-quarters of MBD patients. MBP is caused by bone
worldwide.
                                                              weakening or destruction and is usually felt as a deep
                                                              aching or boring sensation. It has a considerable impact
                                                              on sleep quality, mobility and daily living activities and
Bondronat ®                                                   can therefore seriously impact on patient quality of life.
Bondronat® (ibandronate) is a third generation, nitro-
                                                              In Phase III trials, both oral and i.v. Bondronat demon-
gen-containing bisphosphonate for the treatment of
                                                              strated sustained relief of MBP that was suppressed
metastatic bone disease (MBD). MBD occurs when the
                                                              below baseline levels throughout the two year duration
cancerous cells from the original tumour spread to the
                                                              of clinical trials. In addition, small size phase II loading
bone via the blood stream resulting in bone pain,                                                                            Page 7
         C       linical Development
                        (from page 7)


         dose studies with Bondronat demonstrated                                  the treatment of
         significant reduction in MBP within 3 days which                          patients with metastatic
         was sustained for at least 6 months. Additional                           breast cancer whose
         studies are ongoing. The study results will then be                       tumors overexpress the
         submitted for regulatory approval in late 2006 and                        HER2 protein and who
         will be available for publication in early 2007.                          have received one or
         References:                                                               more chemotherapy
         1. Body JJ, Diel IJ, Lichinitser MR, et al. Intravenous ibandronate       regimens for their
         reduces the incidence of skeletal complications in patients with          metastatic disease.
         breast cancer and bone metastases. Ann Oncol 2003;14: 1399–405.
         2.Tripathy D, Body JJ, Diel I, Bergstrom B. Oral daily ibandronate:
         efficacy in reducing skeletal complications in patients with metastatic   Safety: CARDIOMYOPATHY
         bone disease from breast cancer. Proc ASCO 2003;22:46 (abstract 185).     HERCEPTIN® (Trastuzumab) administration can
         3. Bondronat Summary of Product Characteristics. 23/07/03                 result in the development of ventricular dysfunction
                                                                                   and congestive heart failure. Left ventricular
                                                                                   function should be evaluated in all patients prior
         Herceptin®                                                                to and during treatment with HERCEPTIN.
         Herceptin is a biologically engineered, monoclonal                        Discontinuation of HERCEPTIN treatment should
         antibody designed to target and block the function                        be strongly considered in patients who develop a
         of HER2 (human epidermal growth factor recep-                             clinically significant decrease in left ventricular
         tor-2), a cancer gene associated with aggressive dis-                     function.The incidence and severity of cardiac
         ease. Herceptin therapy is different from conven-                         dysfunction was particularly high in patients who
         tional chemotherapy as it does not destroy nor-                           received HERCEPTIN in combination with
         mal, healthy cells, which is the primary cause of                         anthracyclines and cyclophosphamide.
         unwanted side effects associated with chemotherapy.
                                                                                   HYPERSENSITIVITY REACTIONS INCLUDING
         Herceptin is used to treat women with advanced                            ANAPHYLAXIS INFUSION REACTIONS
         breast cancer, whose tumours overproduce                                  PULMONARY EVENTS
         HER2, known as HER2-positive breast cancer.                               HERCEPTIN administration can result in severe
         Approximately 20–30 percent of breast cancer                              hypersensitivity reactions (including anaphylaxis),
         patients have HER2-positive disease, which has a                          infusion reactions, and pulmonary events. Rarely,
         poor prognosis.
                         1
                                                                                   these have been fatal. In most cases, symptoms
                                                                                   occurred during or within 24 hours of administra-
         Herceptin has demonstrated efficacy in treating                           tion of HERCEPTIN. HERCEPTIN infusion should
         advanced breast cancer when given on its own as                           be interrupted for patients experiencing dyspnea
         monotherapy, as well as in combination with stan-                         or clinically significant hypotension. Patients should
         dard chemotherapy. It improves response rates                             be monitored until signs and symptoms completely
         and overall survival while maintaining quality of life                    resolve. Discontinuation of HERCEPTIN treatment
         in women with HER2-positive advanced breast                               should be strongly considered for patients who
         cancer 2-6. Herceptin is available for the treatment                      develop anaphylaxis, angioedema, or acute
         of advanced breast cancer in approximately 90                             respiratory distress syndrome.
         countries worldwide. In Europe, it is indicated for
                                                                                   Please see attached full Prescribing Information, including
         use in combination with Taxotere® as a first-line                         Boxed WARNINGS for additional safety information.
         therapy for HER2-positive disease in patients who
         have not received chemotherapy for their metasta-                         Herceptin’s efficacy is currently being evaluated in
         tic disease, as a first-line therapy in combination                       clinical trials in combination with hormonal therapy
         with Taxol® where anthracyclines are unsuitable,                          in advanced breast cancer, as well as in early breast
         and as a single agent in second- and third-line                           cancer and gastric cancer. On commercialization,
         therapy. In the US, Herceptin in combination with                         Genentech has the marketing rights in the US.
         paclitaxel is indicated for treatment of patients                         Outside the US, Roche has the marketing rights
         with metastatic breast cancer whose tumors over-                          and is responsible for commercialization in these
         express the HER2 protein and who have not                                 territories; in Japan Roche works through its
         received chemotherapy for their metastatic                                partner Chugai.
Page 8   disease. Herceptin as a single agent is indicated for
          C    linical Development
                    (from page 9)


          infiltrates, acute respiratory distress syndrome,
          myocardial infarction, ventricular fibrillation or cardio-
          genic shock. Approximately 80% of fatal infusion
          reactions occurred in association with the first infusion.
                                                                       The FDA based its approval decision for Tarceva on
          Patients who develop severe infusion reactions               results from a randomized, double-blind, placebo-
          should have Rituxan infusion discontinued and                controlled pivotal Canadian Phase III trial of patients
          receive medical treatment.                                   with second- and third-line advanced NSCLC.The
                                                                       trial included 731 patients with advanced NSCLC for
          Tumor Lysis Syndrome (TLS): Acute renal failure              whom one or more chemotherapy regimens had
          requiring dialysis with instances of fatal outcome has       failed.The study met its primary endpoint of overall
          been reported in the setting of TLS following treat-         survival. In addition, the study demonstrated an
          ment with Rituxan.                                           improvement in median survival (6.7 versus 4.7
                                                                       months).Tarceva also met the secondary endpoints
          Severe Mucocutaneous Reactions: Severe mucocuta-             of improving progression-free survival and increasing
          neous reactions, some with fatal outcome, have been          tumor response rate.Tarceva has been filed in the
          reported in association with Rituxan treatment.              E.U. in 2004 as well as other countries.

          Please see attached full Prescribing Information, includ-    Safety: There have been infrequent reports of serious
          ing Boxed WARNINGS for additional safety information.        interstitial lung disease (ILD), including fatalities, in
                                                                       patients receiving Tarceva.Treatment should be inter-
          MabThera is being evaluated in Phase III clinical            rupted for acute onset of new or progressive, unex-
          trials for the potential treatment of relapsed chronic       plained pulmonary symptoms; and if ILD is diagnosed,
          lymphocytic leukemia (CLL). We are preparing a               Tarceva should be discontinued.Women of childbearing
          filing in frontline aggressive non-Hodgkin’s lymphoma        potential should be advised to avoid breastfeeding
          (NHL). In the indolent NHL setting, Genentech is             and pregnancy while on Tarceva (Pregnancy Category
          currently in discussions with the U. S. Food and             D). Asymptomatic increases in liver transaminases
          Drug Administration (FDA) to file a combined                 have been observed in Tarceva treated patients,
          supplemental Biologics License Application for the           periodic liver function tests should be considered.
          Rituxan R-CVP and 1496 maintenance studies.This              Dose reduction or interruption of Tarceva should be
          product is being developed in collaboration with             considered if changes in liver function are severe.
          Genentech and Biogen Idec Inc.                               Co-treatment with the potent CYP3A4 inhibitor
                                                                       ketoconazole increases erlotinib AUC by 2/3. Caution
                                                                       should be used when administering or taking Tarceva
          Tarceva™                                                     with ketoconazole and other strong CYP3A4
          Tarceva™ (erlotinib), is a small molecule human              inhibitors. Pre-treatment with the CYP3A4 inducer
          epidermal growth factor type 1/epidermal growth              rifampicin decreased erlotinib AUC by about 2/3.
          factor receptor (HER1/EGFR) inhibitor which                  Alternate treatments lacking CYP3A4 inducing
          demonstrated, in a Phase III clinical trial, an increased    activity should be considered. If an alternative treat-
          survival in advanced non-small cell lung cancer              ment is unavailable, a Tarceva dose greater than
          (NSCLC) patients.                                            150mg should be considered. If the Tarceva dose is
                                                                       adjusted upward, the dose will need to be reduced
          The FDA approved Tarceva in November 2004.                   upon discontinuation of rifampicin or other inducers.
          Tarceva is approved for the treatment of patients            In clinical trials, the most common adverse reactions
          with locally advanced or metastatic NSCLC after              in patients receiving Tarceva were rash and diarrhea.
          failure of at least one prior chemotherapy regimen.          Grade 3/4 rash and diarrhea occurred in nine and six
          Results from two multicenter, placebo-controlled, ran-       percent, respectively, in Tarceva-treated patients. Rash
          domized Phase III trials conducted in first-line patients    and diarrhea each resulted in study discontinuation in
          with locally advanced or metastatic NSCLC showed             one percent of Tarceva-treated patients. One and six
          no clinical benefit with the concurrent administration       percent of patients needed dose reduction for rash
          of Tarceva with platinum-based chemotherapy                  and diarrhea, respectively.
          (carboplatin and paclitaxel or gemcitabine and cis-          Please see attached full Prescribing Information for
Page 10   platin), and its use is not recommended in that setting.     additional safety information.
C   linical Development
                    (from page 8)

References
1. Harries M, Smith I.The development and clinical use of trastuzumab
                                                                             Kytril Injection
(Herceptin). Endocr Relat Cancer 9: 75-85, 2002.
                                                                             PONV (postoperative nausea and vomiting)
2. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus
                                                                             The most frequently reported clinical adverse
a monoclonal antibody against HER2 for metastatic breast cancer that         event associated with Kytril Injection (>5%) in
overexpresses HER2. N Engl J Med 2001;344:783–92                             postoperative patients were pain, constipation,
3. Cobleigh MA,Vogel CL,Tripathy D, et al. Multinational study of the        anemia, headache, fever, abdominal pain and elevated
efficacy and safety of humanized anti-HER2 monoclonal antibody in
women who have HER2-overexpressing metastatic breast cancer that
                                                                             hepatic enzymes.The use of Kytril in patients
has progressed after chemotherapy for metastatic disease.                    following abdominal surgery or in patients with
J Clin Oncol 1999;17:2639–2648                                               chemotherapy-induced nausea and vomiting may
4.Vogel C, Melody A, Cobleigh M, et al. Efficacy and safety of trastuzumab   mask a progressive ileus and/or gastric distention.
as a single agent in first-line treatment of HER2-overexpressing
metastatic breast cancer. J Clin Oncol 2002;20:719–726
                                                                             * Prevention and Treatment of Postoperative Nausea and Vomiting
5. Osoba D, Slamon DJ, Burchmore M, et al. Effects on quality of life of
combined trastuzumab and chemotherapy in women with metastatic               (PONV) is not an approved indication in Canada.
breast cancer. J Clin Oncol 2002;20:3106–3113                                References: 3. Goodin S Cunningham R. 5-HT(3)-receptor antagonists for the
                                                                             treatment of nausea and vomiting:a reappraisal of their side effect profile.
6. Extra JM, Cognetti F, Maraninchi D, et al.Trastuzumab (Herceptin)
                                                                             Oncologist 2002;7(5):424-36 4. Bernard SA, Bruera E. Drug interactions in pal-
plus docetaxel versus docetaxel alone as first-line treatment of HER2-
                                                                             liative care. J Clin Oncol 2000 Apr;18(8):1780-99 5. Blower PR. 5-HT3-receptor
positive metastatic breast cancer (MBC): results of a randomised
                                                                             antagonists and the cytochrome P450 system: clinical implications. Cancer J
multicentre trial. Eur J Cancer. 2004;2:125. Abstract 239.
                                                                             2002 Sep-Oct;8(5):405-14 6. Kaiser R et al. Patient-tailored antiemetic treat-
                                                                             ment with 5-hydroxytryptamine type 3 receptor antagonists according to
                                                                             cytochrome P-4502D6 genotypes. J Clin Oncol. 2002;20:2805-2811.


Kytril ®
One of the most common side effects with cancer                              MabThera®/Rituxan®
therapy is nausea and vomiting. Roche markets Kytril®                        MabThera® is a therapeutic anti-
(granisetron) which provides proven safety and                               body which binds to the CD20
efficacy for the prevention of nausea and vomiting                           antigen on the surface of normal
induced by chemotherapy and/or radiation therapy.                            and malignant B-cells. From there,
Kytril is also indicated for the prevention and treat-                       it recruits the body's natural
ment of postoperative nausea and vomiting. A single                          defenses to attack and kill the
dose of Kytril provides patients once a day protection                       marked B-cells. Stem cells (B-cell
with no CV warnings and low potential risk for drug                          progenitors) in bone marrow lack
interactions which may be important for elderly                              the CD20 antigen, allowing
cancer patients 3. Kytril is the only 5HT3 receptor                          healthy B-cells to regenerate after
antagonist not metabolized by CYP2D6. Drug metab-                            treatment and return to normal
olization may be important in choosing supportive                            levels within several months.
care agents 4,5,6. CYP2D6 is an enzyme pathway linked
to genetic polymorphism 5. Kytril has not been shown                         Approved Uses: Rituxan® received FDA approval in
to induce or inhibit hepatic metabolism.                                     November 1997 for the treatment of patients with
                                                                             relapsed or refractory, low-grade or follicular, CD20-
Important Safety Information                                                 positive, B-cell non-Hodgkin’s lymphoma (NHL). In
Kytril IV,Tablets and Oral (CINV and RINV)–                                  April 2001, an sBLA was approved for Rituxan for
The most frequently reported adverse events for                              these additional uses: retreatment of patients with
both Kytril Injection and Tablets (>5%) were                                 Rituxan who have relapsed following initial Rituxan
headache,constipation, asthenia, diarrhea, abdominal                         therapy, use of eight weekly doses (compared to
pain and dyspepsia.* The clinical adverse events                             original four) per course of treatment, treatment of
reported by patients receiving Kytril Tablets and                            patients with bulky disease (lesions > 10 cm).
concurrent radiation were similar to those reported                          MabThera is approved for the treatment of indolent
by patients receiving Kytril Tablets prior to chemo-                         and agressive NHL in the E.U.
therapy. Headache, however, was less prevalent in
this patient population.                                                     Safety: Fatal Infusion Reactions: Deaths within 24
                                                                             hours of RITUXAN infusion have been reported.
* Associated with Kytril Tablets only. Safety information derived
                                                                             These fatal reactions followed an infusion reaction
from US product insert.
                                                                             complex which included hypoxia, pulmonary
                                                                                                                                                              Page 9
                                                          C     linical Development
                                                                       (from page10)



                                                          A phase III study in the first line setting of locally advanced or metastatic
                                                          pancreatic cancer patients also showed a significant improvement in overall
                                                          survival when Tarceva was used in combination with chemotherapy.

                                                          Trials are being conducted with Tarceva in solid tumours, such as ovarian,
                                                          colorectal, pancreatic, head and neck, renal cell carcinoma, and glioma.

                                                          The world-class corporate alliance of OSI Pharmaceuticals, Genentech, Inc.
                                                          and Roche provides all the essential elements for the rapid, comprehensive,
                                                          and competitive development of Tarceva — innovation, experience,
                                                          respected positions in research and oncology, as well as success in manu-
                                                          facturing and commercializing cancer drugs.


                                                          Xeloda®
                                                          In the area of cytotoxic drugs, Roche has been developing its oral anti-cancer
                                                          agent Xeloda® (capecitabine) as monotherapy and in combination with
                                                          other agents for the treatment of colorectal and breast cancers. Xeloda
                                                          was rationally designed to mimic continuous infusion 5-fluorouracil (5-FU)
                                                          and to generate 5-FU at the tumor site by exploiting the higher levels of
                                                          the enzyme thymidine phosphorylase in tumor cells compared with healthy
                                                          tissue. 1,2 Xeloda monotherapy is approved in more than 60 countries
                                                          world-wide for patients with metastatic breast cancer in whom prior
                                                          anthracycline and taxane (U.S. paclitaxel) therapy failed. In addition Xeloda
                                                          is now also approved in most countries, including the USA, EU and
                                                          Canada, in combination with docetaxel for patients with metastatic breast
                                                          cancer in whom prior anthracycline therapy failed. As first line monotherapy
                                                          of metastatic colorectal cancer, Xeloda is also approved in more than 60
                                                          countries including the European Union, Canada and the USA. A clinically
                                                          important drug interaction between Xeloda and Warfarin has been
                                                          demonstrated; altered coagulation parameters and/or bleeding, and death
                                                          have been reported.The most common side effects (›20%) of Xeloda
                                                          monotherapy are anemia, diarrhea, hand-and foot syndrome, nausea,
                                                          fatigue, vomiting, hyperbilirubinemia, dermatitis, stomatitis, anorexia, pares-
                                                          thesia, abdominal pain, lymphopenia, neutropenia, and thrombocytopenia.*
                                                          When Xeloda is combined with docetaxel, additional common side effects
                                                          (›20%) include leukopenia, alopecia, edema, pyrexia, asthenia, and constipa-
                                                                                                                   _
                                                          tion. Adverse events were more common in patients > 80 years of age
References:
                                                                                                             _
                                                          receiving Xeloda monotherapy, and in patients > 60 years of age receiving
1. Miwa M, Ura M, Nishida M, et al. Design of a novel     Xeloda in combination with docetaxel. Patients with severe diarrhea should
oral fluoropyrimidine carbamate, capecitabine, which      be carefully monitored. Xeloda is contraindicated in patients who have a
generates 5-fluorouracil selectively in tumours by        known hypersensitivity to 5-fluorouracil, and in patients with severe renal
enzymes concentrated in human liver and cancer
tissue. Eur J Cancer1998;34(8): 1274-81.                  impairment. For patients with moderate renal impairment, dose reduction
                                                          is required. See enclosed in back pocket of this brochure the complete
2. Schüller J, Cassidy J, Dumont E, et al. Preferential   XELODA Prescribing Information including information on indications, con-
activation of capecitabine in tumor following oral
administration to colorectal cancer patients. Cancer
                                                          traindications, warnings including boxed WARNING, precautions, and adverse
Chemother Pharmacol 2000;45(4):291-7                      events.To further evaluate the role of Xeloda in breast and colorectal cancer
                                                          in addition to numerous other solid tumors, there are multiple clinical trials
                                                          currently on-going and planned. For further information on Xeloda please
                                                          visit http://www.xeloda.com (US physicians), http://www.xeloda. roche.com
                                                          (ex-US physicians) or call Roche at 800-526-6367 for full prescribing
                                                          information.                                                                               Page 11
                                                          * Safety information and prescribing information has been derived from US package insert
          P       ipeline/Chugai

          Pipeline Products
                                                      (from page11)


                                                                      play a role in cancer cell survival and growth.
                                                                      Omnitarg, which binds to a different epitope of
          CERA                                                        HER2 than Herceptin, may work, unlike Herceptin,
          Continuous Erthropoiesis Receptor Activator
                                                                      in the absence of overexpressed HER2 protein
          This novel erythropoietic agent is now in phase
                                                                      levels. Omnitarg thus has the potential for
          II/III trials. In animal models it has been shown to
                                                                      applications in a wide variety of tumors.
          have long systemic clearance and a long serum half
          life compared with epoetin1. Animal studies with            Single agent activity has been observed in phase I
          CERA have shown it to be a more potent stimulator           and phase II studies in solid tumors. The drug is
          of erythropoiesis than epoetin.The erythropoietic           currently being further pursued in a variety of
          effect is dose dependant and specific, with a similar       tumor types including ovarian cancer, prostate
          response after S.C. or I.V. administration                  cancer, lung cancer and metastatic breast cancer.
          1Haselbeck A. et   al. Blood 2002:100:228a (Abstract 858)   Combination therapy or patient selection strategies
                                                                      may be investigated in the future. Omnitarg is
          Epothilone D                                                being developed in collaboration with Genentech.
          Inhibition of cell cycle is an attractive strategy for
          the development of anticancer drugs. Roche, in
          collaboration with Kosan Biosciences, is                    Development with Chugai
          pursuing the clinical development of epothilones.           Epogin™ –recombinant human erythropoietin
          These novel polyketides arrest cancer cells in the          (Epoetin beta) has been a significant product for
          G2/M-phase by stabilizing the polymerized                   Chugai since 1990 when it was launched. A phase
          microtubules. In preclinical studies, activity against      III trial to evaluate it in chemotherapy associated
          paclitaxel-resistant tumors has been shown. A               anemia in cancer patients was initiated in early
          comprehensive phase II evaluation of the clinical           2004.
          utility of KOS 862 is ongoing. A second epothilone
          (KOS 1584) is being evaluated in phase I.                   MRA (tocilizumab) is a humanized monoclonal
                                                                      antibody against the human interleukin-6 receptor
          Tubulin 2nd Generation                                      (IL-6R). MRA has been shown to compete for
          A representative of a new class of tubulin-poly-            both the membrane-bound and soluble forms of
          merization inhibitors is now in phase I clinical            the human IL-6R and to inhibit IL-6 function. IL-6 is
          testing. It has shown activity in pre-clinical models,      well recognized as being an important factor for
          including multi drug resistant tumors. Compared to          survival and growth of myeloma cells. Phase I/II
          taxanes, less peripheral neurotoxicity may be               studies with MRA in MM are currently ongoing.
          expected based upon preclinical tests.
                                                                      CAL, a humanized anti-PTHrP monoclonal anti-
          mHMFG1                                                      body, is specific for parathyroid hormone-related
          Monoclonal antibodies have become an important              protein (PTHrP). CAL has a hypocalcemic effect
          tool in the armamentarium of oncologists to target          and is being studied in patients with humoral
          cancer. Targeting of MUC-1 glycoprotein is a major          hypercalcemia of malignancy. CAL is in phase II
          area of therapeutic investigation in a joint collabo-       studies.
          ration between Roche and Antisoma. Human Milk               CHC12103, - cytotoxic drugs are known to be
          Fat Globule 1 (muHMFG1) is a murine antibody                effective, but their effectiveness has been limited by
          directed against MUC-1. We are evaluating a                 the side effects. Chugai in collaboration with
          humanized version of the muHMFG1 antibody in                Cell Therapeutics is
          phase I trials for systemic therapy of cancer.              investigating the utility
          Omnitarg™ (2C4) - Pertuzumab                                of a poly-(L-glutamic
          Omnitarg™ is a therapeutic antibody and the first in        acid)-paclitaxel conjugate
          a new class of agents known as HER dimerization             that could improve on
          inhibitors (HDIs). It was developed to bind to the          paclitaxel’s therapeutic
          HER2 extracellular domain and thereby blocks the            window. It has just
          interaction (dimerization) between HER2 and                 completed phase I
          other HER family members (HER1/EGFR, HER2,                  studies in Ovarian cancer
          HER3, and HER4). Pre-clinical research has shown            and Non small cell lung
          that inhibiting receptor dimerization prevents the          cancer in Japan.
Page 12   activation of HER signaling pathways, which may
Our alliance strategy at Roche is to enable our partners to grow through a flexible
and collaborative approach. We recognize that no one company has a monopoly on
innovation. We have the ability and willingness to be a true partner, to share our
expertise as well as to learn from our partners. We work as a team to bring
promising products to patients as quickly as possible. We believe the best way to
foster innovation is to encourage our partners to develop as independent companies.
This allows them to build on their strengths while giving them access to the expertise
at Roche in research, development and global marketing presence.

Our Mission
“Pharma Partnering builds a network of world-class alliances that
strengthens the Roche portfolio. With our partners and colleagues,
we transform scientific innovation into medicines that make a
difference in patients’ lives.”


                  Roche is committed to partnering in the               Interest in immunomodulators, antisense,
                  development of antibodies, small molecules,           re-formulation/delivery system of existing
                  and proteins for cancer, hematopoietic, or            marketed agents, cancer vaccines, and gene
                  supportive care therapies. We are seeking             therapies would require demonstration of
                  worldwide, North American, European, or               superior clinical efficacy in a prospective,
                  Japanese collaborations for products,                 well-controlled, randomized phase II/III trial.
                  product candidates, as well as research/
                  technologies. More specifically, we are               We assure you that your proposal will
                  looking for:                                          receive our fullest attention, and that we
                                                                        will act on it quickly to provide you with
                     - Targeted therapies with novel mecha-             our feedback. Once the deal is signed,
                       nisms and demonstrated in-vivo efficacy          we will make sure that the necessary
                     - Antibodies with demonstrated in-vivo             resources are provided to move the
                       efficacy and evidence of tumor selectivity       project forward, maximizing its value
                                                                        and commercial potential.
                     - Cytotoxics with a clinically
                       demonstrated superior efficacy                   Together with our partners, our aim is
                       comparing to existing agents or efficacy         to develop and commercialize innovative
                       in a refractory patient population               medicines which will make a significant
                     - Hematopoietic agents addressing                  impact on the lives of cancer patients.
                       medical need in anemia or neutropenia            We look forward to working with you
                                                                        as a potential partner.
                     - Supportive care drug candidates
                       addressing medical need for emesis               Please send your proposal to:
                       or neuropathies                                  pharma.partnering@Roche.com
About Roche
Hoffmann-La Roche Inc. (Roche), based in Nutley, N.J., is the U.S. prescription
drug unit of the Roche Group, a leading research-based health care enterprise
that ranks among the world’s leaders in pharmaceuticals and diagnostics.

Roche is a leading healthcare company with a uniquely broad spectrum of
innovative solutions. For more than 100 years, we have been active in the
discovery, development, manufacture and marketing of novel healthcare
solutions. Our products and services address prevention, diagnosis and
treatment of diseases, thus enhancing well-being and quality of life.

Roche discovers, develops, manufactures and markets numerous important
prescription drugs that enhance people’s health, well-being and quality of life.
Among the company’s areas of therapeutic interest are: dermatology;
genitourinary disease; infectious diseases, including influenza; inflammation,
including arthritis and osteoporosis; metabolic diseases, including obesity and
diabetes; neurology; oncology; transplantation; vascular diseases; and virology,
including HIV/AIDS and hepatitis C.

For more information on the Roche pharmaceuticals business in the United
States, visit the company’s website at: http://www.rocheusa.com.



                            Public Affairs
                            Hoffmann-La Roche Inc.
                            340 Kingsland Street
                            Nutley, NJ 07110-1199




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