# Presentation: 751385

## Back Up Slides

- July 29, 2008

## 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

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

**WA17822**

**WA18062**

**% ACR50 ****Responders**

| N= | 110 | 110 | 110 | 109 | 108 | 109 | 111 | 105 | 104 | 87 | 67 | 55 | 19 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| N= | 152 | 153 | 151 | 150 | 152 | 152 | 153 | 138 | 137 | 123 | 93 | 69 | 26 |
| N= | 164 | 168 | 167 | 167 | 166 | 166 | 168 | 156 | 156 | 139 | 104 | 76 | 31 |

**TCZ 8 mg/kg****Open-label**

**TCZ 8 mg/kg****Open-label**

| N= | 56 | 59 | 60 | 58 | 58 | 57 | 60 | 47 | 39 |  | 31 | 15 | 6 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| N= | 102 | 102 | 105 | 103 | 104 | 101 | 106 | 93 | 64 |  | 49 | 29 | 11 |
| N= | 121 | 125 | 122 | 125 | 125 | 125 | 126 | 104 | 84 |  | 55 | 24 | 8 |

## 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

## Neutrophil Time Course in Healthy Volunteers

**Neutrophil Time Course in Healthy Volunteers**

## Sample Size and RR

| Event of Interest | Published Rate | Patients Needed to Detect HR > 2 | Detectable RR for 2500 patients (12500 PYs)  | Detectable RR for 5000 patients (25000 PYs) |
| --- | --- | --- | --- | --- |
| MI* | 5.3 per 1,000 | 2660 | 1.55 | 1.38 |
| Stroke* | 5.1 per 1,000 | 2762 | 1.56 | 1.38 |
| Hospitalized Infections** | 3864.3 per 100,000 | 414 | 1.19 | 1.13 |
| Malignancies*** | 1295.6 per 100,000 | 1120 | 1.34 | 1.23 |
|    Lung | 228.8 per 100,000 | 6088 | 1.89 | 1.60 |
|    Lymphoma | 91.7 per 100,000 | 15110 | 2.56 | 2.02 |
|    NHL | 85.5 per 100,000 | 16202 | 2.63 | 2.06 |
|    Stomach | 8.1 per 100,000 | 170506 | 10.40 | 6.33 |
|    Cervix | 8.2 per 100,000 | 168426 | 10.31 | 6.28 |
| GI perforations**** | 1.32 per 1,000 | 10514 | 2.24 | 1.82 |
| Serious Liver Events***** | 1.0 per 1,000 | 13860 | 2.48 | 1.97 |
| Liver events***** | 5.56 per 1,000 | 2538 | 1.54 | 1.37 |

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

## Percentage of Patients Experiencing a Serious Infection

|  | TCZ 8 mg/kg (N=288) | MTX
(N=284) | TCZ 4 mg/kg + MTX (N=774) | TCZ 8 mg/kg + DMARD (N=1582) | Placebo + DMARD
(N=1170) |
| --- | --- | --- | --- | --- | --- |
| Diabetes at Baseline: No   | 4/273
(1%) | 1/263
(0.4%) | 12/702
(2%) | 30/1445
(2%) | 17/1069
(2%) |
| Diabetes at Baseline: Yes  | 1/15
(7%) | 1/21
(5%) | 1/72
(1%) | 8/137
(6%) | 1/101
(1%) |
| Age < 50 | 1/127
(0.8%) | 0/135
(0%) | 2/335
(0.6%) | 6/545
(1%) | 3/451
(0.7%) |
| Age 50-64  | 2/121
(2%) | 1/113
(0.9%) | 5/316
(2%) | 23/765
(3%) | 10/520
(2%) |
| Age > 65 | 2/40
(5%) | 1/36
(0.3%) | 6/123
(5%) | 9/272
(3.3%) | 5/199
(2.5%) |

## 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

|  | Placebo + DMARD
(N=11) | TCZ 4 mg/kg + MTX
(N=37) | TCZ 8 mg/kg + DMARD
(N=183) |
| --- | --- | --- | --- |
| ≥ 70% improvement in T/SJC | 10 (90%) | 23 (62%) | 84 (46%) |
| Worst 3 improvements in (A) (B) and (C) | 1 (10%) | 1 (4%) | 10 (12%) |
| Worst 3 improvements in (A) (B) and (D) | 0  | 1 (4%) | 6 (7%) |
| Worst 3 improvements in (A) (B) and (E) | 1 (10%) | 0 | 0 |
| Worst 3 improvements in (A) (C) and (D) | 0 | 0 | 9 (11% |
| Worst 3 improvements in (A) (C) and (E) | 0 | 3 (13%) | 1 (1%) |
| Worst 3 improvements in (A) (D) and (E) | 1 (10%) | 1 (4%) | 1 (1%) |
| Worst 3 improvements in (B) (C) and (D) | 2 (20%) | 7 (30%) | 45 (54%) |
| Worst 3 improvements in (B) (C) and (E) | 0 | 2 (9%) | 5 (6%) |
| Worst 3 improvements in (B) (D) and (E) | 0 | 5 (22%) | 3 (4%) |
| Worst 3 improvements in (C) (D) and (E) | 4 (40%) | 2 (9%) | 3 (4%) |
| <70% improvement in T/SJC | 0 | 4 (11%) | 16 (9%) |
| <70% improvement in TJC but ≥ 70% improvement in SJC | 0 | 1 (3%) | 30 (16%) |
| ≥70% improvement in TJC but < 70% improvement in SJC | 1 (9%) | 9 (24%) | 53 (29%) |

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

**ITT**

**Notes:**
Etdasacr70reas_ah140_3062i: 09 May 08

## Planned Education Materials / Tools

| Stakeholder | Tool | Description |
| --- | --- | --- |
| Nurse | Patient EducationFlip Chart | Prior to starting therapy, nurses have the opportunity to use a tool with patients to educate them about what patients could potentially expect while on treatment with ACTEMRA, (including safety information). This tool also describes the requirement of tests prior to and during treatment. |
| Patients | ACTEMRA Patient Education Brochure | Educates patients about what to expect while on treatment with ACTEMRA (including safety information). Also describes the risks of treatment with ACTEMRA and the requirement of tests prior to and during ACTEMRA treatment. Included as part of Patient Starter Kit. |
| Patient & HCPs | Roche Pharmaceuticals Service Center (RPSC)1-800-526-6367  | Medical professionals available live, on the phone to prescribers and patients for assistance regarding prescribing information and information from the Patient Package Insert. |

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

- Mean age:  61 years (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

-  * Disease duration unknown for 2 patients

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

- Mean age: 59 years (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

## Post-marketing surveillance of ACTEMRA® 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)

| Total TCZ Exposure
(8mg/kg)
Study Day | ALT 
(6-34 U/L) | AST
(9-34 U/L) | Total Bilirubin
(3-21 umol/L) | Indirect Bilirubin
(0-21 umol/L) | Direct Bilirubin
(0-7 umol/L) |
| --- | --- | --- | --- | --- | --- |
| 99 | 21 | 21 | 17 | 14 | 3 |
| 113 | 26 | 25 | 26 H | 22 H | 3 |
| 141 | 25 | 21 | 34 H | 29 H | 5 |
| 169; began treatment with MTX (20 mg QS) | 24 | 26 | 38 H | 31 H | 7 |

| Total TCZ Exposure
(8mg/kg)
Study Day | ALT 
(6-34 U/L) | AST
(9-34 U/L) | Total Bilirubin
(0.2-1.2 mg/dL) | Indirect Bilirubin
(0-1.2 mg/dL) | Direct Bilirubin
(0-0.4 mg/dL) |
| --- | --- | --- | --- | --- | --- |
| 191 | 27 | 21 | 1.0 | 0.8 | 0.2 |
| 219 | 137 H | 81 H | 1.7 H | 1.4 H | 0.3 |
| 233 (No TCZ infusion; MTX 10 mg QS) | 569 H | 359 H | 2.7 H | 2.2 H | 0.5 H |
| MTX (20 mg/week) was discontinued from study day 238 to 253;                                                                         MTX re-started on study day 254 at reduced dose (10 mg/week). |  |  |  |  |  |

## Salient summary points

- 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**

**Infliximab**

**0**

**10**

**30**

**20**

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

**11.7**

**3.0**

**12.9**

**19.1**

**19.5**

**               ****59                     50                  19                  56                 20**

**Active RA**

**n=**

**3.1**

**Adalimumab**

**DMARD failures**

- 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.

**1**

**2**

**3,4**

**7**

**8**

**5,6**

**33**

**Notes:**
I presume this is LDL cholesterol on y axis

Could we also add mmol/l in y axis for some guidance please since some countries use mmol/l. 

## Review of anti-TNF – lipid studies

- 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