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

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New optimism for patients with cancer l.jpg
New optimism for patients with cancer

  • As cancer therapy evolves, new regimens and novel agents that target specific cellular processes allow a more optimistic prognosis for many patients

  • Bortezomib and tipifarnib are two new targeted treatments for hematologic malignancies


Bortezomib l.jpg
Bortezomib

  • A proteasome inhibitor

  • 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

  • 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

  • Is well-tolerated, including in combination


Clinical course of multiple myeloma l.jpg
Clinical course of multiple myeloma

Survival (years)

0

1

2

3

4

5

Diagnosis to death

3–4 years

  • Relapsed disease

  • Transient response to therapy

1–2 years

  • Relapsed and refractory

  • Resistant to all therapy

  • Universally fatal

6–9 months


Slide4 l.jpg

b2

b1

Post-

glutamylsite

Trypticsite

H

b7

b3

N

N

H

Bortezomib

b6

b4

Chymo-

trypticsite

b5

O

OH

N

B

OH

O

N

Bortezomib: a potent first-in-class proteasome inhibitor

Dipeptidyl boronic acidderivative

Cross-section of b-ring

(reversible inhibitor of chymotryptic active site of proteasome  subunit)

Janssen-Cilag 2003


Slide5 l.jpg

X

X

X

Bortezomib


Summary of bortezomib data in relapsed refractory mm l.jpg
Summary of bortezomib data in relapsed/refractory MM

1. Abstracts in Blood 2005;106 (ASH 2005) 2. Blood 2005;105:3058–65


Response to bortezomib by prognostic factor and line of treatment l.jpg

CR+PR 34%

CR+PR 45%

n is shown by the number on each bar

Response to bortezomib by prognostic factor and line of treatment

>1 prior treatment and MM refractory to prior treatment resulted in

lower responses to bortezomib

Richardson et al. ASCO 2005; Sonneveld et al. IMW 10, Sydney, 2005


Bortezomib higher response rates in second line therapy than later therapy l.jpg
Bortezomib: higher response rates in second-line therapy than later therapy

CR

nCR

PR

100

P=0.0035

80

P<0.0001

60

45

Proportion of patients (%)

40

34

26

32

20

13

21

0.5 nCR

23

6

7

13

0

6

2

6

Bortezomib

Dex

Bortezomib

Dex

1 prior line of therapy

>1 prior line of therapy

Sonneveld et al. IMW 10, Sydney, 2005


Single agent bortezomib active in newly diagnosed mm l.jpg
Single-agent bortezomib active in newly diagnosed MM

  • Well 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. Blood 2004;104:100a (abstract 336)Jagannath et al. Haematologica 2005;90(Suppl 1):148 (abstract P0.725)


Bortezomib dexamethasone in newly diagnosed mm l.jpg
Bortezomib + dexamethasone in newly diagnosed MM

Data available for 46/52 patients

  • Stem cell collection adequate for all patients (median CD34+ cells 6.7 x 106/kg; range 2–33); median 2 collections required (range 1–4)

  • Well tolerated: AEs mainly grade 1/2

    • PN: 6% grade 3, 8% grade 2

    • 1 grade 4 GI

  • Results form basis for IFM Phase III trial of bortezomib + Dex vs VAD

Harousseau et al. Haematologica 2005;90(Suppl 1):148(abstract P0.724)


Bortezomib combination protocols in previously untreated patients l.jpg
Bortezomib combination protocols in previously untreated patients

*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 l.jpg

72%

85%

64%

70%

70%

60%

60%

45%

50%

50%

28%

40%

40%

24%

30%

30%

11%

13%

20%

20%

6%

6%

2%

10%

10%

0%

0%

CR IF-

CRIF+

PR

MR

SD

CR IF-

CR IF+

PR

SD

MPV response rates (n=53)Analysis of best response achieved so far

1st cycle MPV

Best response: median 3 cycles

Mateos et al. Blood 2005;106 (Abs 786) ASH 2005


Adverse events from apex all patients l.jpg
Adverse events from APEX (all patients)

†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%

Richardson et al.N Engl J Med 2005;352:2487–98


Tipifarnib l.jpg
Tipifarnib

  • A specific inhibitor of farnesyltransferase

  • 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 l.jpg

Oral formulation

Potent 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

Potent inhibitor of malignant cell line proliferation

Cl

Cl

N

H

2

N

N

O

N

Tipifarnib:targeted farnesyltransferase inhibitor


Farnesyltransferase l.jpg

Key enzyme in many pathways

Farnesylated proteins

Ras (H-, K-, N-)

Rho (B,E)

Lamins (A, B)

Centromere-binding proteins

Farnesyltransferase

Blocking FTase has therapeutic potential


Phase ii trial of tipifarnib efficacy l.jpg
Phase II trial of tipifarnib: efficacy

Response confirmed 28 days after initial response

Relapsed Refractory Total

(n=135)

(n=117)

(n=252)

CR 7 (5%) 4 (3%) 11 (4%)

Confirmed CR 2 (1%) 1 (1%)  3 (1%)

SD (>8 weeks) 8 (6%) 5 (4%) 13 (5%)

Total 15 (11%) 9 (8%) 24 (10%)

Harousseau et al. Presentedat ASH 2003


Targeted therapy l.jpg
Targeted therapy

  • Is among the most exciting new development in cancer treatment

  • Specifically attacks the malignancy for improved efficacy and overall safety

  • 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