# Presentation: 293076

## Abatacept (ORENCIA) for Rheumatoid Arthritis

- Biological License Application
**Arthritis Advisory Committee**
**September 6, 2005**

## Abatacept

- Proposed indications for abatacept:
- For use in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more biologic or non-biologic DMARDs
- Reducing signs and symptoms
- Inducing major clinical response
- Inhibiting the progression of structural damage
- Improving physical function
- Abatacept may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARD therapy

## Overview of FDA Presentation

- Clinical Development Program and Study Design
- Efficacy Data
- Improvement of Signs and Symptoms
- Improvement of Physical Function
- Inhibition of Radiographic Progression
- Safety Data
- Summary

## Abatacept BLA

**CLINICAL DEVELOPMENT PROGRAM**
**&**
**STUDY DESIGN**

## Abatacept Clinical TrialsRandomized, Double-Blind, Placebo-Controlled

## Study Design-Common Features

- Randomized, double-blind, placebo-controlled studies
- Major Inclusion Criteria:
- Diagnosis of RA (1987 ARA criteria)
- Active disease despite DMARD therapy at randomization
- ≥ 10 swollen joints (66 joint count)
- ≥ 12 tender joints (68 joint count)
- CRP ≥ 1 mg/dL
- Stable doses of prednisone and NSAIDs allowed
- Abatacept Dosing: Week 0, 2, and 4, then Q4 weeks
- Weight-based dosing
- Weight-Tiered-based dosing
- <60kg: Abatacept 500 mg IV
- 60 kg to 100 kg: Abatacept 750 mg IV
- > 100 kg: Abatacept 1000 mg IV

## Study Design-Common Features

- Statistical Analyses
- Modified ITT efficacy analyses performed for all trials
- Sequential testing for co-primary endpoints
- Co-primary endpoint tested for significance only if preceding co-primary endpoint was statistically significant
- Type I error rate of 5% maintained
- Adjustment for multiple doses performed using global testing then pairwise comparisons for individual doses

## Study Design-Common Features

- Statistical Analyses
- ACR and Health Assessment Questionnaire (HAQ) response rates
- Categorical Endpoints
- Chi-square Test
- Non-responder imputation for missing data
- Radiographic Progression
- Genant-modified Sharp Score
- Rank-based nonparametric ANCOVA model
- Linear extrapolation for missing data

## Study IM101-102: Concomitant MTX Study

- 12 month study
- Active RA despite MTX therapy
- 656 patients randomized 2:1
- Weight-Tiered-dose Abatacept + MTX (n=433)
- Placebo + MTX (n=219)
- Sequential Co-Primary Endpoints
- ACR 20 response at 6 months
- Improvement in Physical Function (HAQ) at 12 months
- Inhibition of Radiographic Progression at 12 months

## Study IM101-100:  Dose-Ranging Study

- 12 month Study
- Active RA despite MTX therapy
- 339 patients randomized 1:1:1
- Abatacept 10 mg/kg + MTX (n=115)
- Abatacept 2 mg/kg + MTX (n=105)
- Placebo + MTX (n=119)
- Primary Endpoint
- ACR 20 response at 6 months

## Study IM101-029:  TNF-Blocker Failure Study

- 6 month Study
- Active RA despite TNF-blocker therapy ± DMARD
- Etanercept or Infliximab
- Following drug-washout 393 patients with active RA randomized 2:1
- Weight-Tiered-dose Abatacept + DMARD (n=258)
- Placebo + DMARD (n=133)
- Co-Primary Endpoints
- ACR 20 response at 6 months
- Improvement in Physical Function (HAQ) at 6 months

## Study IM101-031:  Clinical Practice Study

- 12 month Study
- Active RA despite DMARD therapy
- non-biologic and/or biologic DMARDs
- Patients with co-morbid conditions permitted
- 1441 patients randomized 2:1
- Baseline therapy + Weight-tiered dose Abatacept (n=959)
- Baseline therapy + Placebo (n=482)
- Primary Objective
- Safety
- Exploratory Endpoint
- Improvement in Physical Function (HAQ) at Day 365

## Clinical Studies-Study Conduct

- Baseline Patient Demographics (mean):
- 52 years of age
- 79% Female
- 85% White and 4% Black
- Baseline Disease Activity (mean):
- 10 years RA duration
- 21 swollen joints
- 31 tender joints
- 79% RF(+)
- MTX 16 mg Qweek

## Abatacept BLA

**EFFICACY ANALYSES**
**Signs and Symptoms**

## IM101-102: Concomitant MTX Study Signs & Symptoms: ACR Responses

***p<0.001**

## IM101-102: Concomitant MTX Study Signs & Symptoms: ACR 20 Response Time Course

## IM101-102: Concomitant MTX Study Signs & Symptoms: Major Clinical Response

## IM101-102: Concomitant MTX Study Median % Improvement in ACR Components at Day 169

## IM101-102: Concomitant MTX StudyDAS28 Response at Day 365

***p<0.001**

## IM101-100: Dose-Ranging Study Signs & Symptoms: ACR Responses

***p≤0.03**

## IM101-029: TNF-Blocker Failure Study  Signs & Symptoms: ACR Responses at Day 169

***p≤0.003**

## IM101-029: TNF-Blocker Failure Study  Signs & Symptoms: DAS28 Response at Day 169

***p<0.001**

## Exploratory AnalysisCriteria to Assess Very Low Disease Activity

- EULAR-definition of remission is defined as a DAS28<2.6
- However, patients with a EULAR definition of remission can still have several swollen or tender joints
- Alternative criterion for very low disease activity DAS28<2.6 AND ≤ 1 swollen and ≤1 tender joint

## Criteria to Assess Very Low Disease Activity IM101-102: Concomitant MTX Study

## Criteria to Assess Very Low Disease Activity IM101-029: TNF-Blocker Failure Study

## Exploratory AnalysisWeight-Tiered-Dosing : ACR20 Responders

## Abatacept BLA

**EFFICACY ANALYSES**
**Improvement in Physical Function**

## IM101-102: Concomitant MTX Study Improvement in HAQ score ≥ 0.3u at Day 365

## IM101-100: Dose-Ranging Study Improvement in HAQ score ≥ 0.3u at Day 360

## IM101-100: Dose-Ranging Study Improvement in HAQ score ≥ 0.3u Open-Label Study

## Abatacept BLA

**EFFICACY ANALYSES**
**Inhibition of Radiographic Progression**

## IM101-102: Concomitant MTX Study Mean Change In Genant-Modified Sharp Scores at Day 365

## IM101-102: Concomitant MTX Study Mean Change in Genant-Modified Sharp Score Components

## Study IM103-002: Monotherapy Study

- 3 month study
- Active RA despite DMARD therapy
- 112 patients randomized
- Abatacept (n=90)
- 0.5 mg/kg (n=26), 2 mg/kg (n=32), or 10 mg/kg (n=32)
- Placebo (n=32)
- Primary Endpoint
- ACR 20 response at Day 85

## Study IM103-002: Monotherapy Study ACR Responses at Day 85

## AbataceptEfficacy Analysis

- Subset Analyses by:
- Baseline Demographics
- Age
- Sex
- Race
- Weight
- Baseline Disease Activity
- Disease Duration
- Swollen & Tender Joints
- CRP
- Genant-modified Sharp Score
- HAQ

## Abatacept BLA

**SAFETY ANALYSES**

## Safety Analyses: Overview

- Safety Assessment Based on 5 Studies:
- IM101100, IM101101, IM101102, IM101029, IM101031
- Double-Blind Periods:
- 1955 Abatacept-treated patients (1688 person-years)
- 989 Placebo-treated patients (795 person-years)
- Open-Label Periods + Double-Blind Periods:
- 2688 Abatacept-treated patients** **

## Cumulative Extent of Exposure

## Deaths

- 26 total deaths
- 16 patients died during the double-blind periods
- 10 (0.5%) abatacept-treated patients
- 4 died from cardiovascular disorders
- 3 found dead at home
- 2 died from malignancies
- 1 died from infection
- 6 (0.6%) placebo-treated patients
- 2 died from cardiovascular disorders
- 1 found dead at home
- 1 died from malignancy
- 2 died from infection

## Deaths

- Analysis of the individual deaths did not suggest a safety signal for any single type of AE
- 8 of the deaths in the Abatacept group occurred during a study that permitted enrollment of patients with co-morbidities

## Serious Adverse Events

- 14% of Abatacept-treated patients had an SAE compared to 12% placebo-treated patients
- 3% of Abatacept-treated patients had an infectious SAE compared to 2% placebo-treated patients

## Malignancies: Double-Blind Periods

## Solid Organ TumorsAbatacept-Treated Patients-Double Blind Periods

## Malignancies: Open-Label Periods

- 47 patients developed 52 neoplasms
- 26 malignancies
- 13 solid-organ tumors
- 4 lung cancers
- 2 ovarian cancers
- 2 endometrial cancers
- 1 case each of breast, prostate, melanoma, cervical, and rectal cancer
- 3 lymphomas

## Most Frequently Observed vs. Expected Malignancies

## Incidence Rates of Malignancies

## Malignancies

- 3 potentially concerning malignancies
- Lung Cancer
- 8 cases of lung cancer in patients receiving abatacept
- Breast Cancer and Lymphoma
- Pre-clinical studies demonstrated increased rate of mammary tumors and lymphomas in mice that was believed to be secondary to abatacept-induced chronic immunosuppression and MMTV and MLV
- Immunosuppression and RA both associated with increased risk of lymphoma

## Lung Cancer Incidence

## Breast Cancer & Lymphoma

_**Breast Cancer**_
**3 (0.1%) cases of breast cancer reported in abatacept-treated patients compared to 2 (0.2%) cases reported in placebo-treated patients**
**Current evidence does not suggest abatacept increases the rate of breast cancer**
_**Lymphoma**_
**4 cases of lymphoma reported in patients receiving abatacept**
**Approximately 4-fold higher than general US population**
**However, increased rate of lymphoma in RA patients, particularly those with high disease activity**

## Serious Infections

## Infections of Special Interest

## AEs in Abatacept w/ Biologic RA Therapy

- A total of 204 patients received abatacept and concomitant biologic RA therapy during the double-blind period representing 173 person-years of exposure
- Majority of patients were from studies IM101-101 (n=85) and IM101-031 (n=103)
- >90% TNF-blocker therapy
- Study IM101-101 compared the combination of abatacept 2 mg/kg + etanercept to placebo + etanercept

## AEs in Abatacept w/ Biologic RA Therapy

## SAEs with Abatacept & Concomitant RA TherapyStudy IM101031

## Infusion Reactions

- Infusion Reactions within 1 hour post-infusion
- 9% of abatacept-treated patients vs. 6% placebo-treated patients
- Infusion Reactions within 24 hours post-infusion
- 23% of abatacept-treated patients vs. 19% placebo-treated patients
- 2 cases of anaphylactic reactions in patients receiving abatacept

## Immunogenicity & Clinical Laboratory Values

- Immunogenicity of Abatacept
- Overall, 1.6% of patients treated with abatacept developed antibodies to abatacept
- 5.8% of abatacept patients who had discontinued therapy for at least 56 days developed antibodies to abatacept
- Changes in Clinical Laboratory Values
- no clinically meaningful differences between patients treated with abatacept compared to placebo regarding blood chemistry and hematologic laboratory values

## Autoimmune Symptoms & Disorders

- 3% of Abatacept-treated patients reported autoimmune-related AEs compared to 2% of placebo-treated patients during the Double-Blind period
- Most common symptoms were associated with RA
- e.g., Keratoconjunctivitis sicca, Sjogren’s syndrome
- Psoriasis was more frequent in patients treated with abatacept compared to placebo (0.5% vs. 0.1%)

## Autoimmune Symptoms & Disorders ANA and ds-DNA Antibody Formation at 12 months

## AEs in patients with Co-MorbiditiesStudy IM101031

- Study IM101-031 permitted patients with co-morbidities including COPD, diabetes, asthma, and CHF
- Diabetes, asthma, or CHF: no apparent increase in AEs or SAEs
- COPD: AEs reported in 97% of abatacept-treated patients vs. 88% of placebo-treated patients
- Respiratory AEs more common with abatacept (43% vs. 24%)
- SAEs more common with (27% vs. 6%)
- No reported deaths

## Summary

- The studies presented here show abatacept-treatment associated differences regarding
- improvement in signs and symptoms
- improvement of physical function
- Inhibition of radiographic progression
- There was a higher rate of serious infections in patients treated with abatacept, especially with patients receiving concomitant TNF-blocking agents
- Overall malignancy rates were not substantially different between abatacept (1.5%) and placebo (1.1%) treated patients
- However, abatacept treated patients had more cases of lung cancer and the rate of lymphomas was higher than expected compared to the general US population

## Summary

- Infusion-related reactions were observed including hypersensitivity reactions and 2 cases of anaphylaxis
- Patients with COPD treated with abatacept had a higher incidence of adverse events and serious adverse events, particularly respiratory disorders