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Back Up Slides. July 29, 2008. Screening Evaluations and Exclusions. Exclusions for General Safety

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Back up slides

Back Up Slides

July 29, 2008


Screening evaluations and exclusions
Screening Evaluations and Exclusions

Exclusions for General Safety

  • Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (included but not limited to tuberculosis and atypical mycobacterial disease, granulomatous disease on chest X-ray, Hepatitis B and C, and herpes zoster), or any major episode of infection requiring hospitalization or treatment with IV antibiotics within four weeks of screening or oral antibiotics within two weeks prior to screening.

  • Primary or secondary immunodeficiency (history of or currently active)

  • Laboratory Exclusion Criteria

  • White Blood Cells < 3000/mm3

  • Absolute Neutrophil Count < 2000/mm3

  • Absolute Lymphocyte Count < 500/mm3

  • Positive Hepatitis BsAg or Hepatitis C Antibody


Dmard ir anti tnf ir long term response over time

8 mg/kg TCZ + MTX

4 mg/kg TCZ + MTX

Placebo + MTX

100

90

80

70

60

50

40

30

20

10

0

DMARD IR & Anti-TNF IR:Long-Term Response Over Time

% ACR50 Responders

WA17822

WA18062

TCZ 8 mg/kgOpen-label

TCZ 8 mg/kgOpen-label


Immunogenicity summary of combined 6 month controlled and lte studies
Immunogenicity Summary of Combined 6-Month Controlled and LTE Studies

  • Total of 59/3353 (1.8%) developed anti-TCZ HAHAs

    • 12 patients experienced an infusion-related reaction and were positive for anti-TCZ antibodies

      • 5 of these experienced a serious event or event leading to WD

  • 38/3353 (1%) developed neutralizing anti-TCZ HAHAs (blocks binding of TCZ to s-IL-6r)

    • Neutralizing antibody positive patients had a similar safety profile to patients who did not develop anti-TCZ HAHAs

    • No association between neutralizing antibody development and loss of clinical response

      • 1/38 patients discontinued due to lack of efficacy



Sample size and rr
Sample Size and RR

*Solomon et al. 2006 **Smitten et al. 2008 ***Wolfe and Michaud 2007 ****UHC analysis ****Beyeler et al. 1997



Assay to screen for ab positive human serum specimens

or

SA-MTP

TCZ-bio

TCZ-Dig

Pab-<DIG>POD

Pab<TCZ

Assay to screen for AB positive human serum specimens

  • Assay principle: bridging ELISA

  • Sensitivity: fulfills regulatory expectations

    • TCZ immobilization with two distinct biotinylisation labeling processes (labeled at lysines and at the carbohydrates) to avoid epitope masking

  • Measures free anti TCZ AB, isotype independent

  • Adapted as confirmation assay: TCZ spiked in screening positive samples to quench the signal


DMARD Inadequate Responders: Summary of Reasons for Not Achieving an ACR70 Response in Patients Who Achieved DAS28 < 2.6 at Week 24

ITT

A = Phy VAS B = Pt VAS C = Pain VAS D= HAQ E = CRP


Planned education materials tools
Planned Education Materials / Tools Achieving an ACR70 Response in Patients Who Achieved DAS28 < 2.6 at Week 24


Lgi perforations ra n 14 roche and chugai

Mean age: 61 years Achieving an ACR70 Response in Patients Who Achieved DAS28 < 2.6 at Week 24(45-82)

Mean duration RA*: 12.6 years (0.5-33)

Mean number doses TCZ: 20 (2-63)

Sex: 10 F, 4 M

Medications

Corticosteroids: 10

NSAIDs: 9

Unknown: 2

LGI Perforations (RA): n=14Roche and Chugai

* Disease duration unknown for 2 patients


Ugi perforations ra n 6 roche and chugai

Mean age: 59 years Achieving an ACR70 Response in Patients Who Achieved DAS28 < 2.6 at Week 24(49-76)

Mean dur RA: 22 years (11-42, Roche only)

Mean doses TCZ: 21 (2-35)

Sex: 6 F

Medications

Corticosteroids: 5

NSAIDs: 6

UGI Perforations (RA): n=6Roche and Chugai


Post marketing surveillance of actemra in ra in japan
Post-marketing surveillance of Achieving an ACR70 Response in Patients Who Achieved DAS28 < 2.6 at Week 24ACTEMRA®in RA in Japan

  • ACTEMRA® was approved for RA on April 16, 2008

  • All patients survey – Routinely required by the Japanese regulatory agency.

    • Target number of patients: 3,000 in total

    • Observation period: 6 months

    • Focus on Adverse Drug Reactions and Serious ADRs

  • 3-year long-term follow up

    • SAEs of special interests, including Death, Serious Infection

      (1 year), CV events, Malignancy, and GI perforation

  • Current Status (as of July 11, 2008)

    • Number of registered patients: 1,620

    • Estimated number of patients treated with TCZ: 1,424

    • No new safety signal has been detected.


Patient 64069 4798 wa17824 and wa18696
Patient 64069/4798 Achieving an ACR70 Response in Patients Who Achieved DAS28 < 2.6 at Week 24(WA17824 and WA18696)


Salient summary points
Salient summary points Achieving an ACR70 Response in Patients Who Achieved DAS28 < 2.6 at Week 24

  • Inflammation in man  lipids (LDL-c, HDL-c, TG)

    • post MI, post surgery

    • Sepsis, trauma, ITU

    • Cancer, RA

    •  inflammation   lipids

  • Inflammation resolution/ suppression

    •  lipids (HDL-C and LDL-C, plus trigs)

    • In RA TNF-blockers>> DMARDS

    • Responders >> non-responders

  • Yet TNF-blockers (responders)  CVD risk


Review of anti tnf lipid studies
Review of anti-TNF – lipid studies Achieving an ACR70 Response in Patients Who Achieved DAS28 < 2.6 at Week 24

Infliximab

30

Adalimumab

19.1

19.5

20

Change in LDL-cholesterol from baseline (mg/dL)

12.9

11.7

10

3.1

3.0

33

n=

59 50 19 56 20

0

1

2

3,4

5,6

7

8

DMARD failures

Active RA

1. Allanore Y, et al. Clin Chim Acta 2006; 365:143–148. 2. Kiortsis DN, et al. J Rheumatol 2006; 33:921–923. 3. Brulhart L, et al. Ann Rheum Dis 2006; 65:1255–1257. 4. Tam LS, et al.ACR 2005. 5. Allanore Y, et al. ACR 2004. 6. Allanoe Y, et al. EULAR 2004. 7. Voskuyl AE, et al. EULAR 2002. 8. Popa C, et al. Ann Rheum Dis. 2005; 64:303–305.


Review of anti tnf lipid studies1
Review of anti-TNF – lipid studies Achieving an ACR70 Response in Patients Who Achieved DAS28 < 2.6 at Week 24

  • Popa et al ARD (2007) Infliximab 6/12

    •  TC > HDL-C

    • ↓  DAS   lipids

  • Peters (2007) ARD 48 week trial infliximab

    • ↓  DAS   TC and HDL-C


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