# Presentation: 879231

## Natalizumab Safety

*Gordon Francis, MD*
*Senior Vice President,**Clinical Development*

## Natalizumab Safety

- Exposure
- General safety overview
- Infections
- Other safety events of interest based on MOA
- Post-marketing safety during 2nd MS launch in June 2006

## Safety Population Clinical Development Program 

## CD Studies Used in Safety Analysis

- Short-term placebo-controlled studies of active CD
- Generally 3 months of dosing
- >80% of patients were in CD301 and CD307
- 431 placebo patients and 983 natalizumab patients
- The remainder were from the Phase 2 Studies
- Short and long-term dosing
- 1563 patients exposed to natalizumab for up to 3 years
- Includes placebo-controlled and open-label data

## Long-Term Natalizumab Exposure 

|  | During 
CD351 | During CD351 and Feeder Studies |
| --- | --- | --- |
| Number of patients | 1100 | 1100 |
| Mean number monthly infusions
(SD) | 11.0
(8.6) | 14.8
(10.9) |
| Median | 8 | 12 |
| Range | 1-24 | 1-39 |

## General Safety

## Overview of Adverse Events in CDShort-Term, Placebo-Controlled Studies of Active CD

|  | Placebo
N=506
% | Natalizumab
N=1182
% |
| --- | --- | --- |
| AEs | 85.6 | 87.4 |
| Infections | 36.2 | 40.4 |
| SAEs | 14.0 | 14.9 |
|    Non-Crohn’s SAEs |   7.8 | 10.1 |
|    Serious infections |   2.4 |   2.4 |
|    Serious systemic hypersensitivity | 0 |   0.1 |
| Malignancy |   0.2 |   0.6 |

## SAEs by Organ SystemExcluding Crohn’s DiseasePlacebo-Controlled Studies of Active CD

| SAE | Placebo
N=506
% | Natalizumab
N=1182
% |
| --- | --- | --- |
| Overall | 7.8 | 10.1 |
| Gastrointestinal | 2.4 | 3.9 |
| Infection | 2.4 | 2.4 |
| Musculoskeletal | 0.6 | 0.6 |
| Nervous system | 0.2 | 0.5 |
| General | 0.8 | 0.6 |
| Cardiac | 0 | 0.4 |
| Immune system | 0.2 | 0.4 |
| Hepatobiliary | 0 | 0.4 |

## Discontinuations Due to AEs Short-Term Placebo-Controlled Studies of Active CD

|  | Placebo
N=506
% | Natalizumab
N=1182
% |
| --- | --- | --- |
| Total patients discontinued | 11.3 | 9.1 |
|   Crohn’s disease | 7.9 | 3.7 |
|   Urticaria | 0.2 | 0.8 |
|   Abdominal pain | 0.0 | 0.4 |
|   Dyspnea | 0.0 | 0.3 |
|   Flushing | 0.0 | 0.3 |
|   Nausea | 0.2 | 0.3 |
|   Pruritus | 0.2 | 0.3 |

**Discontinuations Due to AEs ****Short-Term Placebo-Controlled Studies of Active CD**

## Deaths in CD Program

| Placebo-Controlled Experience |  |  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Age/Gender |  | Cause of Death |  | Infusion # |  | Mo. Since Infusion |  | Medications/Relevant History |
| 42/M |  | Asphyxiation |  | 1 |  | — |  | None |
| Open-Label Experience |  |  |  |  |  |  |  |  |
| Age/Gender |  | Cause of Death |  | Infusion# |  | Mo. Since Infusion |  | Medications/Relevant History |
| 49/F | Peritonitis, renal failure |  | 3 |  | 1 |  | Post-op complications |  |
| 60/M | PML |  | 8 |  | 6 |  | AZA, lymphopenia |  |
| 75/M | Pulmonary aspergillosis |  | 10 |  | 3 |  | Prednisolone, GI bleed, hospitalization |  |
| 67/M | MI, shock |  | 28 |  | 2 |  | Hypertension |  |
| 69/M | PCP |  | 34 |  | 3 |  | Cirrhosis, ARF, sepsis |  |

## Infections

- General overview of infections
- Serious
- Risk of infection over time
- Infection with concomitant medication use
- Viral reactivation
- Herpes family
- Opportunistic infections, including PML

## Serious Infections Short-Term Placebo-Controlled Studies of Active CD

|  | Placebo
N=506
% | Natalizumab
N=1182
% |
| --- | --- | --- |
| Overall | 2.4 | 2.4 |
|   Perianal abscess | 0.6 | 0.6 |
|   Abdominal abscess | 0.2 | 0.3 |
|   Gastroenteritis | 0.2 | 0.2 |
|   Meningitis viral | 0 | 0.2 |
|   Urinary tract infection | 0 | 0.2 |
| Individual events only listed for serious infections occurring in ≥ 2 natalizumab-treated patients |  |  |

## Incidence and Rate of Infection Over TimeShort- and Long-Term Dosing

|  | Time interval (months) |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | 0-6
n=1563 | 7-12
n=681 | 13-18
n=529 | 19-24
n=427 | 25-30
n=294 |
| Incidence  (%) | 48.9 | 48.0 | 42.0 | 38.2 | 28.9 |
| Exposure (person-years) | 739 | 307 | 241 | 198 | 122 |
| Rate of infection per person-year | 1.8 | 1.8 | 1.4 | 1.2 | 0.9 |

- Most common infections – nasopharyngitis, influenza, URTI, sinusitis, viral infection

## Rate of Serious Infection Over Time Short- and Long-Term Dosing

**Serious Infection Rate (95% CI)**

**0-6**

**6-12**

**12-18**

**18-24**

**24-31**

**0.00**

**n=1563****	**

**Months**

**0.02**

**0.04**

**0.06**

**0.08**

**0.10**

**n=681**

**n=427**

**n=294**

**n=509**

## Incidence of Infection with Concomitant Medication  Placebo-Controlled Studies in Active CD

**Incidence of Infection with Concomitant Medication **** ****Placebo-Controlled Studies in Active CD**

**Patients With an Infection (%)**

**0**

**10**

**20**

**30**

**40**

**50**

**n=340**

**39**

**n=264**

**41**

**n=373**

**41**

**n=205**

**40**

**Natalizumab**
**alone**

**Natalizumab +****immunosuppressants**
**and steroids**

**Natalizumab +**
**steroids**

**Natalizumab +****immunosuppressants**

## Serious Infections withConcomitant Medication Use Short-Term, Placebo-Controlled Studies of Active CD 

|  | n
Placebo/Natalizumab | Placebo
% | Natalizumab
% |
| --- | --- | --- | --- |
| Monotherapy | 154/373 | 1.3 | 1.9 |
| + Immunosuppressants | 89/205 | 1.1 | 3.9 |
| + Steroids | 154/340 | 1.3 | 2.6 |
| + IS + Steroids | 109/264 | 6.4 | 1.9 |

- IS=Immunosuppressants

## Incidence of Herpetic Infections Short-term Placebo-Controlled Studies of Active CD

|  | Placebon=506 | Natalizumabn=1182 |
| --- | --- | --- |
| Total patients with herpes infections | 	6	(1.2) | 	20	(1.7) |
|   Herpes simplex | 	4	(0.8) | 	15	(1.3) |
|   Herpes zoster | 	1	(0.2) | 	4	(0.3) |
|   Herpes viral infection NOS | 	0 | 	1	(<0.1) |
|   CMV infection (colitis) | 	0 | 	1	(<0.1) |

- Number (%) of Patients

## Summary of Serious Herpes InfectionsShort- and Long-term CD Population

| Patients Age/Gender | Infection
Type | Infusion# |    Meds/             Relevant Hx |      Outcome |
| --- | --- | --- | --- | --- |
| 36/F | HSV Vaginitis | 0 | Developed          pre-treatment | Acyclovir, recovered |
| 12/M | Herpes zoster | 1 | Developed          pre-treatment | Acyclovir, recovered |
| 33/F | CMV colitis | 2 |   AZA | Recovered |
| 33/M | CMV infection | 1 |   6MP | Recovered |
| 30/F | Varicella pneumonia | 8 | Son with      chicken pox | Acyclovir, recovered |
| 25/M | Herpes zoster | 14 | Prednisolone, AZA | Acyclovir, recovered |

## Opportunistic andAtypical Infections

## Opportunistic InfectionsCumulative CD Experience

| Patient Age/Gender |  Infection
Type | Infusion# |   Meds/ 
Medical Hx |      Outcome |
| --- | --- | --- | --- | --- |
| 62/F | Burkholderia cepacia pneumonia | 3 | Tobacco use, CHF, steroids | Recovered |
| 65/F | MAC infection | 8 | Steroids / S.aureus pneumonia | Recovered |
| 60/M | PML |  8 |    AZA / lymphopenia | Death |
| 75/M | Pulmonary aspergillosis | 10 |   Steroids /  GI bleed, prolonged hospitalization | Death |
| 69/M | PCP | 34 |    Cirrhosis, ARF, sepsis | Death |

## Serious Atypical InfectionsCumulative CD Experience

| Age/
Gender |  Infection
Type | Infusion
# | Months since last Infusion |   Meds/ 
Medical Hx |      Outcome |
| --- | --- | --- | --- | --- | --- |
| 33/F | CMV Colitis | 2 | 1 | Azathioprine | Recovered |
| 33/M | CMV Infection | 1 | 6 | 6MP | Recovered |
| 48/F | Candida Sepsis | 1 | 4 | Steroids, azathioprine/multi-organ failure  | Recovered |
| 30/F | Varicella pneumonia | 8 | — | Son with chicken-pox | Recovered |
| 32/M | Cavitating pneumonia | 13 | — | Azathioprine, corticosteroids | Recovered |
| 20/M | Tb Peritonitis | 22 | 5 | Caseating granuloma;  AFB, PCR, culture neg | Recovered |

## Rate of Non-PMLOpportunistic Infections in CD 

|  | Rate/1000 pt-yrs |
| --- | --- |
| Unique opportunistic infections | 0.6* |
| Opportunistic infections seen in CD patients on conventional therapies or TNF- Inhibitors | 0.3-0.5** |
| Opportunistic infections seen in CD patients not on therapy | 0.06-0.2** |

- **Health Benchmarks International database

- * Based on 1771 patient-years

## PML in Natalizumab-Treated Patients

- A total of 3 confirmed cases of PML
- 2 MS patients after 29 and 37 infusions
- Both received IFNβ concurrently
- 1 CD patient after 8 infusions over 18 months
- Long-standing Grade 3 lymphopenia
- 2 cases fatal, 1 survived following development of immune reconstitution inflammatory syndrome (IRIS)

## Overview of PML

- Rare, progressive infection of the CNS
- Often fatal within 6 months of diagnosis
- JC virus, a latent human polyomavirus, produces lytic infection of oligodendroglia as the final step in multi-step process
- Primarily affects immunocompromised individuals
- Hematologic malignancies
- AIDS patients
- Organ transplantation
- Therapy
- No effective therapy
- Improvement seen with IRIS (immune reconstitution inflammatory syndrome) seen in HIV-related PML with HAART or in transplant-related PML with reduction of immune suppressants

## PML in Crohn’s Patient

- 60-year-old male with Crohn’s disease for 28 years
- History of treatment with azathioprine, corticosteroids, infliximab
- Longstanding lymphopenia (<500)
- Natalizumab dosing over 18 months
- 3 doses of natalizumab + azathioprine (CD301)
- 9 doses of placebo + azathioprine (CD303)
- 5 doses of natalizumab ending in June 2003 (CD351)
- Pathological diagnosis of astrocytoma in July 2003
- Progressive worsening leading to death in December 2003
- Pathology reassessment in March 2005: diagnosis of PML

## Independent PML Safety Evaluation

- All dosing suspended 28 February 2005
- Objectives of safety evaluation
- Determine if additional patients had undiagnosed PML or other atypical infections
- 3819 MS, CD and RA patients eligible for the evaluation
- Vital status confirmed in >99%
- 90% of natalizumab-treated patients participated
- Neurological examination, brain MRI, JCV in plasma and CSF
- No new cases of PML

## Options for PML Monitoring

- JC viral DNA in plasma
- 0/10 patients with JCV detected in blood had MRI or clinical findings suggestive of PML
- Only 1/3 PML cases had JCV in blood pre-symptomatically
- Sensitivity and predictive value of JCV testing is low
- MRI brain scans
- Sensitive but not specific
- Large numbers of scans needed to pre-symptomatically detect rare event
- Helpful diagnostically but not as a practical PML screening test
- Clinical vigilance
- Patient and healthcare provider education
- Monthly pre-infusion questions

## Other Safety Events of Interest

*Infusion Reactions*
*Malignancy*
*Post-Marketing Safety*

## Hypersensitivity and InfusionReactions – CD

- 3.5% of patients in CD301 and 307 experienced hypersensitivity reactions* frequently associated with antibody formation, usually with 2nd or 3rd infusion
- Serious systemic hypersensitivity reactions
- In short-term studies
- 0.1% natalizumab
- In short- and long-term dosing population
- 0.1% natalizumab

- * Hypersensitivity, urticaria, anaphylaxis, pruritus.

## Malignancy

## Malignancy Short-Term Placebo-Controlled Studies of Active CD 

| Event | Placebo
N=506 | Natalizumab
N=1182 |
| --- | --- | --- |
| Overall n (%) | 1 (0.2) | 7 (0.6) |
|  | n |  |
|   Adenocarcinoma of lung | 0 | 2 |
|   Bladder cancer | 0 | 1 |
|   Breast cancer | 0 | 1 |
|   Breast cancer invasive | 0 | 1 |
|   Colon cancer | 0 | 1 |
|   Malignant melanoma | 0 | 1 |
|   Uterine cancer | 1 |  0 |
| Rate per 100 person-years: 0.60 for placebo; 1.6 for natalizumab |  |  |

**Malignancy**** ****Short-Term Placebo-Controlled Studies of Active CD**** **

## Summary of Safety in Clinical Development

- Common adverse events were comparable between treatment groups and generally mild
- Proportions of patients experiencing SAEs comparable
- Infections slightly more common with natalizumab
- Low rate of HS reactions
- Risk of opportunistic infection exists
- Possible signal for malignancy that requires  post-marketing surveillance measures

## Post-Marketing Safety

## Post-Marketing Safety Data

- ~11,500 MS patients world-wide have received natalizumab commercially between June 2006 and May 2007
- Serious infections
- Reporting rate = 1.2% (comparable to clinical trials 2.6-3.2%)
- Urinary and pulmonary infections most common (0.3%)
- 4 cases of atypical herpes infections
- Encephalitis, meningitis during 1st launch
- Multidermatomal zoster and HSV1 esophagitis, considered as OIs during 2nd launch
- Serious herpes infections in label
- Serious hepatic dysfunction
- 4 cases with marked elevation of LFTs, including bilirubin in 3 of 4 cases
- Potential confounding factors – evaluation continuing
- No signal seen in clinical development (adverse events or LFT abnormalities)

## Post-Marketing Safety Data

- Malignancy
- Reporting rate = 6.1/1000 patient years (comparable to clinical trials (3.8-7.3) and SEER database (5.0))
- Hypersensitivity reactions more common in those previously dosed than those naïve to therapy
- Label change being implemented to highlight this for practitioners
- 2 cases of atypical herpes infection reported
- Multi-dermatomal herpes zoster, HSV esophagitis
- No new confirmed case of PML
- No change in safety profile of natalizumab in post-marketing setting compared with clinical trials

## Favorable Benefit-Risk Profile

- Efficacy for inducing and maintaining response and remission
- Benefit consistent in broad range of subgroups
- Safety profile comparable to that seen in MS indication apart from potential increased risk of non-PML opportunistic infections
- RiskMAP in place for MS will be adapted for CD to further evaluate long-term risk