# Presentation: 448064

## Tysabri® (natalizumab)Biogen Idec Inc.BLA 125104/15

**Peripheral and Central Nervous System **
**Drugs Advisory Committee **
**Gaithersburg, Maryland**
**March 7-8, 2006**
**Susan S. McDermott, M.D. **
**Division of Neurology Products**

**Center for Drug Evaluation and Research**** **

## Review of Efficacy and PML

## Outline

**Regulatory background**
** ****Pivotal trials**
**Efficacy results**
**Anti-natalizumab antibodies**
**Progressive multifocal leukoencephalopathy (PML)**
**Retrospective safety evaluations**

## Regulatory Background

**Accelerated approval (11/23/04)**
**21 CFR 601.40 - 46**
**Natalizumab effect at one year reasonably likely to predict effect at two years **
**Primary endpoints for MS therapy trials**
** ****Relapse rate**
** ****Disability accumulation**

## Study 1801 EfficacyFDA Analysis

|  | Natalizumab |  | Placebo |  |
| --- | --- | --- | --- | --- |
| Number randomized | 627 |  | 315 |  |
| Number reaching sustained disability progression

Absolute difference 
Hazard ratio 
p – value | 
104 (17 %) |  | 
84 (27 %) |  |
|  |   | 
10 %
0.58
0.0002 |  |  |
| Annualized relapse rate

Absolute difference 
p – value | 0.24 |  |  | 0.73 |
|  | 
0.49
< 0.001 |  |  |  |

## Study 1802 EfficacyFDA Analysis

|  | Natalizumab 
+ Avonex |  | Placebo 
+ Avonex |
| --- | --- | --- | --- |
| Number randomized | 589 |  | 582 |
| Number reaching sustained disability progression

Absolute difference 
Hazard ratio 
p – value | 
129 (22 %) |  | 
156 (27 %) |
|  |   
   | 
5 %
0.76
0.0238 |  |
| Annualized relapse rate

Absolute difference 
p - value | 0.34 |  | 0.75 |
|  | 
0.41
< 0.001 |  |  |

## Anti-natalizumab Antibodies

**6% of subjects developed persistent anti-natalizumab antibodies**
**Persistent antibody development was associated with less efficacy, compared to antibody-negative subjects**

## Efficacy Summary 

**Efficacy**
**Relapse rate**
**Disability progression**
**Add-on therapy**
**Immunogenicity**

## PML Case 1

**46 year old woman with RRMS in Study 1802 who received natalizumab infusions April 2002 through January 2005 (37 doses)**
**November 2004: PML symptoms began, and were initially thought to be worsening MS**
**December 2004: MRI changes atypical for MS; received 2 short courses of steroids**
**February 2005: Positive CSF JC virus; subject died**

## PML Case 2

**46 year old man with RRMS in Study 1802 who received a total of 28 doses from October 2002 through December 2004**
**October 2004: atypical frontal lesion on routine MRI**
**November 2004: behavioral changes seen**
**December 2004: worsening symptoms and new MRI lesions consistent with PML**
**Natalizumab stopped mid-December 2004**
**February 2005: JC virus was found in serum, CSF, and brain tissue; Avonex stopped**
**Subject continued to decline, now disabled**

## PML Case 3

**60 year old man with Crohn’s disease died after taking a total of 8 natalizumab doses**
**Subject was on natalizumab monotherapy when his initial PML symptoms developed, but had a complicated history of intermittent concomitant immunosuppressant use**
**Originally diagnosed as an astrocytoma, but retrospective tumor pathology review revealed PML**
**Retrospective analysis: banked serum samples became positive for JC virus two months prior to symptom development **

## Retrospective Safety AnalysisNatalizumab Exposure

| Doses | < 12 | ≥ 12  | ≥ 24 | ≥ 36 | Total |
| --- | --- | --- | --- | --- | --- |
| MS 
Safety Trial | 718 | 1151 | 1053 | 279 | 1869 |
| CD / RA
Safety Trial | 721 | 499 | 285 | 18 | 1220 |

## PML Summary

**Three cases of PML identified**
**Other than natalizumab, additional risk factors were not identified**
**Relationship between concomitant immunosuppression and PML is unclear; risk of monotherapy v. combination therapy is unclear**

## CDER FDA Review Team

_**Regulatory Project Manager (DNP)**_**	**_**Product (DMA)**_
- Katherine Needleman, M.S., RAC		Elena Gubina, Ph.D.
**	****	****	****	****	****	**Chana Fuchs, Ph.D., Team Leader
_**Clinical**_**	**** (DNP)****	****	**
- Susan S. McDermott, M.D. **	****	**_**Pharm/Tox (DNP)**_
- Alice Hughes, M.D.** ****	****	****	**Barbara Wilcox, Ph.D.
- Wilson Bryan, M.D., Team Leader		Lois Freed, Ph.D.,Team Leader
- Marc Walton, Ph.D., M.D., Deputy Director
- Russell Katz, M.D., Director		_**Labeling (DDMAC)**_
**	****	****	****	****	****	**Catherine Gray, Pharm.D.
_**Clinical Pharmacology (OCBP)**_**	****	****	**
- Iftekhar Mahmood, Ph.D.			_**RiskMAP Review Team (ODS)**_
- Hong Zhao, Ph.D., Team Leader
_**Statistics (OPSS)**_**	****	****            **
- Sharon Yan, Ph.D.
- Kun Jin, Ph.D., Team Leader