New optimism for patients with cancer n As cancer therapy evolves, new regimens and novel agents that target specific cellular processes allow a more optimistic prognosis for many patients n Bortezomib and tipifarnib are two new targeted treatments for hematologic malignancies

Bortezomib n A proteasome inhibitor n Has shown good efficacy as a single agent and in combination in patients – with relapsed multiple myeloma –as initial treatment, including prior to autologous stem cell transplantation n Has been studied as monotherapy and in combination with standard treatments, such as dexamethasone, chemotherapy, and with newer agents such as the IMiDs, thalidomide and lenalidomide n Is well-tolerated, including in combination

Diagnosis to death Relapsed disease Transient response to therapy Relapsed and refractory Resistant to all therapy Universally fatal Survival (years) 1–2 years 3–4 years –9 months Clinical course of multiple myeloma

Janssen-Cilag 2003 Dipeptidyl boronic acid derivative (reversible inhibitor of chymotryptic active site of proteasome  subunit) 22 Chymo- tryptic site Post- glutamyl site Tryptic site 11 3333 4444 55 6666 7777 Bortezomib Cross-section of  -ring H NB N H O O OH N N Bortezomib: a potent first-in-class proteasome inhibitor

Bortezomib X X X

Summary of bortezomib data in relapsed/refractory MM Blood 2005;105:3058–65 1. Abstracts in Blood 2005;106 (ASH 2005) 2. Blood 2005;105:3058–65 RegimenPhasen CR + PR CR + nCR Reference Single-agent bortezomib (APEX) III33143%16% Richardson ( ) + low-dose IV melphalan I/II2253%5% Popat ( ) + oral cyclophosphamide II5082%12% Kropff ( ) + steroids II3060%6% Suvannasankha ( ) + pegylated liposomal doxorubicin I4273%36% Orlowski 2

Response to bortezomib by prognostic factor and line of treatment Richardson et al. ASCO 2005; Sonneveld et al. IMW 10, Sydney, 2005 n is shown by the number on each bar CR+PR 45% CR+PR 34% >1 prior treatment and MM refractory to prior treatment resulted in lower responses to bortezomib

Bortezomib: higher response rates in second-line therapy than later therapy 1 prior line of therapy >1 prior line of therapy Proportion of patients (%) BortezomibDexBortezomibDex P= P< nCR CRnCRPR Sonneveld et al. IMW 10, Sydney, 2005

Single-agent bortezomib active in newly diagnosed MM nWell tolerated: safety profile similar to previous studies –Neuropathy frequently prevalent at baseline *Stem cells successfully harvested from 13 patients: 12 received transplants Richardson et al. RR (CR+PR), n=28 RR (CR+PR), n=28 45% (67% including MR) Jagannath et al.* RR (CR+nCR+PR) (23 pts evaluable) RR (CR+nCR+PR) (23 pts evaluable) 41% (after 2 cycles), 11% CR+nCR 85% (after addition of Dex), 20% CR+nCR Richardson et al. Blood 2004;104:100a (abstract 336) Jagannath et al. Haematologica 2005;90(Suppl 1):148 (abstract P0.725)

Bortezomib + dexamethasone in newly diagnosed MM Data available for 46/52 patients Data available for 46/52 patients nStem cell collection adequate for all patients (median CD34+ cells 6.7 x 10 6 /kg; range 2–33); median 2 collections required (range 1–4) nWell tolerated: AEs mainly grade 1/2 –PN: 6% grade 3, 8% grade 2 –1 grade 4 GI nResults form basis for IFM Phase III trial of bortezomib + Dex vs VAD After SCT RR after 4 cycles 75% (n=48) 92% (n=42) CR + VGPR 31%52% PR35%33% MR8%7% Harousseau et al. Haematologica 2005;90(Suppl 1):148(abstract P0.724)

Bortezomib combination protocols in previously untreated patients StudyNRegimenCR/nCRCR+PRToxicity Cavenagh ( ) 19PAD VEL (1.0 mg/m 2 ) + Adria + Dex → SCT 17%89% Gr 1-2 PN 16%, no Gr 3-4 PN 6 Gr3 events: abnormal liver function; thrombocytopenia, neutropenia, hyperglycemia, sepsis, anxiety Harousseau ( ) 48 HD Dex VEL + high dose Dex → SCT 21%67% 1 Gr3 PN, others ≤ Gr2 Wang (784 1 ) 36VTD VEL+ Thal + Dex → SCT 31%89% Infection (3), orthostatic hypotension (1), DVT (2) Gr 3 PN (reversible) (3) Barlogie ( ) 162TT3 VEL + DT-PACE → SCT x2 → VDT-PACE + Thal dex 81% at 12 mos NA 6 treatment related deaths, Other toxicity not different from DT-PACE Mateos (786 1 ) 60VMP VEL + M + P (Days 1 – 4) 39%85% Gr 3-4: GI <15%; PN 15%; anemia 12%, neutropenia 39%, thrombocytopenia 46% *VEL: Bortezomib – VELCADE ® 1. Abstracts in Blood 2005;106 (ASH 2005) 2. Abstract in Blood 2004;104 (ASH 2004)

MPV response rates (n=53) Analysis of best response achieved so far 1st cycle MPV 72% 0% 10% 20% 30% 40% 50% 60% 70% CR IF-CRIF+PRMRSD 6% 2% 64% 6% 24% Best response: median 3 cycles 85% 28% 11% 45% 13% 0% 10% 20% 30% 40% 50% 60% 70% CR IF-CR IF+PRSD Mateos et al. Blood 2005;106 (Abs 786) ASH 2005

Adverse events from APEX (all patients) Bortezomib (n=331) % Dexamethasone (n=332) % AEs ≥ grade AEs grade Serious AEs4443 PN* ≥ grade 38**1 Thrombocytopenia ≥ grade 330**6 Discontinuation due to AEs3729 Deaths on study † 14 (4%)25 (8%) Richardson et al. N Engl J Med 2005;352:2487–98 † Deaths within 30 days after last dose *69% of 310 patients on bortezomib reported symptoms of PN at baseline ** SUMMIT/CREST: PN ≥ grade 3, 13% Thrombocytopenia ≥ grade 3, 30%

Tipifarnib n A specific inhibitor of farnesyltransferase n Clinical trials in patients with high-risk acute leukemias and myelodysplastic syndromes have demonstrated good efficacy with tipifarnib, even in patients with poor prognosis and elderly, poor-risk patients

Tipifarnib: targeted farnesyltransferase inhibitor nOral formulation nPotent and selective inhibitor of farnesylation –Key enzyme involved in multiple tumor-promoting pathways –Essential for the functioning of signal transduction cascades associated with cell proliferation nPotent inhibitor of malignant cell line proliferation NH 2 Cl N O N N

Farnesyltransferase Key enzyme in many pathways Farnesylated proteins nRas (H-, K-, N-) nRho (B,E) nLamins (A, B) nCentromere-binding proteins Blocking FTase has therapeutic potential

Response confirmed  28 days after initial response CR7 (5%) 4 (3%)11 (4%) Confirmed CR2 (1%) 1 (1%) 3 (1%) SD (>8 weeks)8 (6%) 5 (4%)13 (5%) Total15 (11%) 9 (8%)24 (10%) (n=135)(n=117) RelapsedRefractoryTotal (n=252) Phase II trial of tipifarnib: efficacy Harousseau et al. Presented at ASH 2003

Targeted therapy n n Is among the most exciting new development in cancer treatment n n Specifically attacks the malignancy for improved efficacy and overall safety n n Underscores an important shift in the treatment paradigm for multiple myeloma and other hematologic malignancies – a shift from empirical chemotherapeutic regimens with significant side effects towards rational, targeted, effective therapies with improved tolerability