# Presentation: 442450

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

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

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

## Review of Non-PML Safety Issues

## Outline

**Infections other than PML**
**Immunogenicity and hypersensitivity reactions**
**Carcinogenicity**
**Post-marketing reports of serious adverse events**
**Summary of major safety concerns**

## Natalizumab- and placebo-treated patients had similar incidences of:
infections overall: 73.7% vs. 73.9% (natalizumab vs. placebo)
serious infections: 2.4% vs. 2.3%

Natalizumab- and placebo-treated patients had similar incidences of:
upper respiratory tract infections: 59.6% vs. 59.8%
UTIs: 21.5% vs. 21.4%
serious UTIs: 0.6% vs. 0.5%
gastroenteritis: 9.1% vs. 9.0%

**infections overall: 73.7% vs. 73.9% (natalizumab vs. placebo)**
**serious infections: 2.4% vs. 2.3%**
**Natalizumab- and placebo-treated patients had similar incidences of:**
**upper respiratory tract infections: 59.6% vs. 59.8%**
**UTIs: 21.5% vs. 21.4%**
**serious UTIs: 0.6% vs. 0.5%**
**gastroenteritis: 9.1% vs. 9.0%**

**Infections other than PML:****Placebo-controlled MS studies**

## Infections other than PML:MS studies

**Incidences of specific infections in placebo-controlled studies:**
**all lower respiratory tract infections: 13.3% vs. 12.2% (natalizumab vs. placebo)**
**serious pneumonias: 0.4% vs. 0.2%**
**vaginal infections: 7.5% vs. 6.2%**
**all herpes infections: 7.0% vs. 6.1%**
**gingival infections: 1.1% vs. 0.5%**
**Atypical infections**
**cryptosporidial gastroenteritis with prolonged course (in monotherapy Study 1801)**
**acute CMV infection with transaminitis (in open-label Study 1808)**

## Infections other than PML:Placebo-controlled CD studies

**Incidence of infections overall: **
**40.4% vs. 35.8% (natalizumab vs. placebo)**
**Incidence of serious infections:**
**2.5% vs. 2.6%**
**Incidences of selected infections:**
**URIs: 27% vs. 21% **
**UTIs: 2.9% vs. 2.0% **
**vaginal infections: 2.1% vs. 1.6%**
**all herpes infections: 1.6% vs. 1.0%**
**perianal abcesses: 1.1% vs. 0.6%**
**serious viral meningitides: 0.2% (2) vs. 0**
**serious UTIs: 0.2% (2) vs. 0**
**One serious CMV infection (CMV colitis)**
**Patient also receiving azathioprine**

## Infections other than PML:Long-term CD studies

**Atypical Infections**
**Six serious atypical lower respiratory tract infections**
**Pneumonia with lung abscess**
**Pulmonary aspergillosis**
**Pneumocystis carinii pneumonia**
**Varicella pneumonia**
**Mycobacterium avium intracellulare complex pneumonia**
**Burkholderia cepacia infection**
**Possible tuberculosis infection**
**Unclear role of concomitant immunosuppressive/ immunomodulatory agents and intercurrent illnesses**

## Immunogenicity

**Anti-natalizumab antibody formation assessed every 12 weeks in Phase 3 MS Studies and selected CD studies**
**10% of patients had a positive antibody titer at least once**
**4% of patients were transiently positive and 6% were persistently positive in MS Studies**
**Incidence of anti-natalizumab antibody formation was higher in Study 1802 (12%) than in 1801 (9%)**
**Intermittent (irregular) infusions may lead to higher incidence of antibody formation**

## Immunogenicity

**Anti-natalizumab antibody formation strongly associated with infusion reactions and hypersensitivity reactions**
**Infusion reactions occurred in 77% of persistently antibody-positive patients vs. 20% of antibody-negative patients in MS Studies 1801 and 1802**
**Most frequent infusion reactions in antibody-positive patients: rigors, nausea, headache, urticaria, flushing, pruritus, dyspnea**
**Anaphylactic/ anaphylactoid reactions occurred in 5.3% of antibody-positive patients vs. 0 antibody-negative patients in MS Studies 1801 and 1802**
**Anaphylactic/ anaphylactoid reactions occurred in 1.3% of antibody-positive patients vs. 0 antibody-negative patients in selected CD studies **

## Immunogenicity

**MS relapses reported more frequently as adverse events in antibody-positive patients (vs. transiently positive and antibody-negative patients)**
**57% vs. 35% (antibody-positive vs. antibody-negative patients)**
**Incidence of infections lower in antibody-positive patients (vs. transiently positive and antibody-negative patients)**
**Overall infections in MS patients: 69% vs. 82% (antibody-positive vs. antibody-negative patients) **
**Herpes infections in MS patients: 2.7% vs. 8.4%**

## Hypersensitivity reactions

**Anaphylactic/ anaphylactoid reactions**
**MS placebo-controlled studies: 0.4% (6) vs. 0.2% (2) [natalizumab vs. placebo]**
**CD placebo-controlled studies: <0.1% (1) vs. 0**
**Long-term CD studies: 1 additional case of anaphylaxis (during first infusion in CD251; 300 days after receiving 4 infusions in prior CD study) **
**Skin and subcutaneous tissue disorder infusion reactions in MS placebo-controlled studies: 4.6% vs. 1.9%**
**Urticaria: 1.6% vs. 0.3%**
**Delayed hypersensitivity events**
**Most  hypersensitivity events occurred during or immediately after second infusion; some occurred later**
**One case of anaphylaxis associated with 13th infusion**

## Carcinogenicity:MS studies

**Malignancies balanced in natalizumab- and placebo-treated patients in placebo-controlled studies (0.7% natalizumab vs. 1.3% placebo)**
**Types of malignancies observed in natalizumab-treated patients in all MS studies: **
**Breast CA**
**Basal cell CA**
**Cervical CA**
**Colon CA**
**Melanoma**
**Squamous cell CA**
**Pituitary adenoma**
**Papillary thyroid CA**

## Carcinogenicity:CD studies

**Malignancies more frequently reported for natalizumab-treated patients in placebo-controlled studies (0.6% vs. 0.2%)**
**Types of neoplasms observed in natalizumab-treated patients in all CD studies: **
**Breast CA**
**Lung CA**
**Bladder CA**
**Colorectal CA**
**Malignant melanoma**
**Uterine CA**
**Basal cell CA**
**Squamous cell CA**
**Uterine CA**
**Renal cell CA (clear cell)**
**Meningioma**
**Craniopharyngioma (suspected)**
**Lymphoma (B-cell)**

## Carcinogenicity:Long-term CD studies

**B-cell lymphoma (1)**
**49 yo man who received 6 infusions of natalizumab in Studies 307 and 351 (9/04 – 2/05)**
**History of infliximab therapy (8 doses ) **
**Concomitant 6-mercaptopurine therapy**
**Had submandibular lymphadenopathy during 9/04 screening examination; not apparent on subsequent exam**
**Presented with painful lymphadenopathy August, 2005 and was diagnosed (CT; biopsy) with B-cell lymphoma**

## Serious adverse events reported in post-marketing setting

**Deaths**
**Infections**
**Herpes CNS infections **
**Meningitis and encephalitis**
**Malignancies**
**Hypersensitivity reactions and other serious events**

## Summary of key safety issues:Non-PML infections

**Types of infections suggest possible compromise in cell-mediated immunity**
**Herpes infections, lower respiratory tract infections (especially those caused by atypical pathogens), and viral meningitides are of particular concern**
**Role of concomitant medications and intercurrent illnesses in pathogenesis of infections is unclear**
**Relative risks for infections similar in MS Studies 1801 (monotherapy) and 1802 (combination therapy)**
**No clear association between increasing number of natalizumab infusions and risk for infections**

## Summary of key safety issues:Immunogenicity and hypersensitivity

**Anti-natalizumab antibodies formed in approximately 10% of patients**
**Persistently positive anti-natalizumab antibodies associated with infusion reactions, hypersensitivity reactions, increased MS relapse/ CD exacerbations, decreased incidence of infections**
**Anaphylactoid reactions occurred in 0.4% of natalizumab-treated MS patients overall and in 5% of antibody-positive patients**
**Hypersensitivity reactions most common with second infusion but may occur much later**

## Summary of key safety issues:Carcinogenicity

**No evident increase in risk for malignancies in MS studies**
**One lymphoma (B-cell) in patient in long-term CD trial**
**concomitant 6-mercaptopurine therapy and history of infliximab therapy**
**No leukemias**
**Longer exposures will be needed before risk for malignancies can be adequately assessed**

## Acknowledgements

**Tysabri 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 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, M.D., Ph.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
** **