# Presentation: 729346

## Exjade® (NDA 21-882)Postmarketing Commitments

**Renaud Capdeville, MD**
**Novartis Oncology**

## Consultants for Questions and Answers

**Alan Cohen, MD****	****Physician-in-Chief and ****Medical Director,****Thalassemia Program**
**	****Children’s Hospital of Philadelphia**
**Raimund Hirschberg, MD****	****Professor of Medicine****Division of Nephrology**
**	****Harbor-UCLA Medical Center **

**DRA Introduction 8-3-05.ppt**

## Exjade and Pediatric Patients—Overview

**In the Orphan indication of transfusional iron overload, the benefit/risk assessment has been based on a large, comprehensive set of trials (n = 1005 patients followed for ≥ 1 year)**
**45% of patients were children < 16 years old ****(n = 468; 292 were treated with Exjade****®****)**
**Despite prior deferoxamine therapy in most patients, this pediatric population has high levels of iron burden (LIC, ferritin) and, therefore, a high unmet medical need**
**The further long-term evaluation of Exjade therapy in pediatric patients is a major focus of the ****postmarketing program**

## Therapies for Iron Overload

**Until the approval of Exjade****®****, deferoxamine (Desferal****®****,**** ****DFO) was the only drug available in the US to treat iron overload **
**DFO**** ****must be given by continuous s.c. infusion (5 to 7 nights/wk), leading to compliance issues, altered quality of life, and ultimately to suboptimal therapy for many patients**
**Exjade addresses this high unmet medical need and provides the first oral therapy in the US**

## Exjade® (deferasirox) Package Insert

**INDICATIONS AND USAGE**
**EXJADE****®**** (deferasirox) is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age ****and older. **
**	****(Approval November 2005)**

## Overview of Postapproval Commitments (PACs)Conditions for Accelerated Approval (Subpart H)

**Establish a registry for children 2 to < 6 years of age to enroll approximately 200 patients and follow them for 5 years**
**Complete extension portion of studies 0105E2, 0106E1, 0107E1, 0108E1, and 0109E1 for a total of 4 years after ****core trial**
**Conduct a single-arm study in patients with congenital or acquired anemias and chronic iron overload to obtain additional data in patients with LIC < 7 treated with Exjade****®**** doses of 20 or 30 mg/kg/day**
**Provide full study report for study 0109 in patients with ****sickle cell disease**
**Provide adequate proposal for assessing iron concentration and cardiac function in patients treated with Exjade**

## PAC#1: Proposal for the Pediatric Registry 

**Objective: obtain long-term safety experience in the context of routine medical practice**
**General safety**
**Serum creatinine and liver transaminases**
**Auditory and ophthalmologic assessments**
**Growth and sexual development**
**Serum ferritin**

## PAC#1: Proposal for the Pediatric Registry Patient Selection Criteria and Treatment

**Selection criteria**
**Children 2 to < 6 years of age at entry**
**Transfusion-dependent anemias**
**Chronic iron overload with ****≥ 100 mL/kg cumulative prior PRBC and serum ferritin ≥ 1000 μg/L**
**Patients with or without prior DFO therapy**
**Patients treated with Exjade****®**** in prior short-term trials or with prescription drug**
**Treatment according to local prescribing information in participating countries**

## PAC#1: Proposal for the Pediatric Registry Design

**5-year, prospective, observational multinational study**
**Enroll 200 patients**
**Sample size estimated considering enrollment efficiency in pivotal studies (83 children enrolled in 32 centers in 9 months)**
**In line with the observed frequency of renal, hepatic, ocular, and auditory AEs in pivotal studies, this sample size allows detection of AEs with an incidence of ****≥ ****0.6% (95% CI = 0.02, 1.98)**
**Statistical analysis will be descriptive**

## Proposal for the Pediatric Registry Implementation

**US and selected countries**
**Exjade****®**** approved and commercially available**
**High prevalence of children < 6 years of age with transfusion-dependent anemias**
**Selection of participating centers**
**Highly qualified centers**
**Ability to perform all safety monitoring assessments**
**Timelines**
**Study start: by end of 2006**
**Enrollment over 15 months**
**Final report submission: 2013**

## PAC#2: Ongoing Exjade® Extension Trials Number of Pediatric Patients Enrolled

| Study | Treatment incore trial | Age, years |  |  | Allpatients |
| --- | --- | --- | --- | --- | --- |
|  |  | < 6 | 6 - < 12 | 12 - < 16 |  |
| 0106E1 | ICL670 |   7 |   12 |   16 |   35 |
| 0107E1 | ICL670
DFO | 23
25 |   55
  62 |   50
  44 | 128
131 |
|  | All patients | 48 | 117 |   94 | 259 |
| 0108E1 | ICL670 | 10 |   10 |   12 |   32 |
| 0109E1 | ICL670
DFO |   4
  3 |   25
  15 |   30
  11 |   59
  29 |
|  | All patients |   7 |   40 |   41 |   88 |
| TOTAL |  | 72 | 179 | 163 | 414 |

**72**

**414**

## PAC#3: Conduct a Study to Obtain Additional Data in Patients With LIC < 7 mg/g Treated With 20 or 30 mg/kg/day

**Study 2204**
**Objective**
**Evaluate efficacy and safety of ICL670 dosed according to monitoring of ferritin and creatinine**
**Patients with transfusion-dependent chronic anemia **
**Age ≥ 2 years**
**≥ ****100 mL/kg (or 20 adults units) of prior PRBC**
**Ferritin > 1000 ****μg/L **
**Sample size 300 patients **
**Exjade 20 to 30 mg/kg/day for 1 year **
**Commitment to be addressed by the subset of patients with ****LIC < 7 mg Fe/g dw (~ 50 patients with LIC < 7)**

## PAC#4: Study 0109 Full Study Report

**Commitment**
**Provide the full study report, including safety and efficacy datasets, for study 0109 (Exjade****®**** vs DFO randomized 1-year study in sickle cell disease)**
**Results**
**Safety profile in SCD similar to other trials**
**Efficacy of Exjade similar to other trials**
**Out of 195 patients, a total of 98 patients aged ****2 to < 16 years of age (50.3%) enrolled; 67 randomized to ICL670 and 31 to DFO **
**Timelines**
**Final report submitted: January 31, 2006**

## PAC#5: Provide Adequate Proposal for Assessing Iron Concentration and Cardiac Function in Patients Treated With Exjade®

**Design**
**Cardiac substudy of ongoing open-label, ****single-arm multinational trial 2409 **
**85 β-thalassemia patients ≥ 10 years of age with**
**Cardiac iron overload determined by MRI**
**Normal cardiac function (LVEF ≥ 56% by MRI)**
**Primary endpoint: improvement in T2* after 1 year**
**Treatment with Exjade at 30 mg/kg/day**

## Conclusions

**A large number of pediatric patients have been enrolled in Exjade****®**** clinical trials**
**Novartis recognizes the need to further evaluate long-term therapy with Exjade, particularly in pediatric patients**
**It is therefore a major objective of our ongoing clinical program, including a series of clinical studies and a large pediatric registry to diligently proceed**