# Presentation: 790227

## Tysabri (Natalizumab) for Crohn’s Disease

**Anil Rajpal, M.D.**
- FDA Medical Officer
- Division of Gastroenterology Products
**July 31, 2007**

## Outline

- Background
- Efficacy
- Induction studies (2)
- Maintenance study
- Subgroup analyses
- Safety

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

**BACKGROUND**

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Original Approval for MS (Nov 2004)

- Efficacy in MS1
- Treatment effect “unprecedented in the MS field”1
- Reduction in relapse rate:
- Monotherapy study:  49%
- Add-on study (for relapsers on IFN-β):  42%
- Accelerated Approval – based on 1-year data
- other MS agents 2-year data

- 1  From Original BLA Review 125104/0 by Wilson W. Bryan, M.D. (11/23/04)

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Original Approval for MS (Nov. 2004) [cont.]

- Safety1
- Infections: ordinary, uncomplicated course
- Hypersensitivity:  anaphylaxis/anaphylactoid <1%
- Depression:  small increased trends
- Menstrual disorders

- 1  From Original BLA Review 125104/0 by Wilson W. Bryan, M.D. (11/23/04)

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## PML Cases

- Two cases in MS
- Concurrent Avonex (IFN-β)
- ~2.5-3 yrs Natalizumab before PML symptoms
- One fatal, other disabled
- One case in CD
- Technically on monotherapy
- Prior history long immunosuppressant use
- Bone marrow suppression history
- Fatal

- * From Regulatory Briefing Presentation by Susan McDermott, M.D. (2/24/06)

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Review of Possible PML Cases & Risk Estimation

- Detailed retrospective safety analysis of possible cases of PML from clinical trials1
- 3116 patients (~1/3 CD patients)
- No new cases identified
- Suggested risk PML ~1 in 1000 pts (treated mean 17.9 mo’s)
- Risk of longer treatment not known

- 1. Yousry TA et al.,* Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. *N Engl J Med. 2006 Mar 2;354(9):924-33.

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Prior Advisory Committee Conclusions (March 2006)

- PML risk not limited to concomitant therapy
- Washout if switching from immune modulators
- First line therapy: Yes 7 vs. No 5
- No additional studies needed for return to market

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Prior FDA Review Conclusions (June 2006) 

- Magnitude of treatment effect makes risk acceptable for some1
- Generally for those who had inadequate response to / unable to tolerate alternate MS therapies
- Monotherapy
- Studied prospectively
- But limited data to support reduced risk
- Short courses of steroids to treat relapses reasonable2
- Return to market under TOUCH program

- 1. BLA Review of 125104/15 by Dr.’s Susan S. McDermott and Alice Hughes (5/18/06)
- 2.  From Team Leader Memo for BLA 125104/15 by Dr. Wilson W. Bryan (6/5/06)

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## PROPOSED INDICATION 

- “TYSABRI® is indicated for _inducing and maintaining_ sustained response and remission, and _eliminating corticosteroid use_ in patients with moderately to severely active Crohn’s disease with inflammation, as evidenced by _elevated CRP level or another objective marker_.”

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## PROPOSED INDICATION [cont.]

- “Because TYSABRI® increases the risk of PML, an opportunistic viral infection of the brain that usually leads to death or severe disability, TYSABRI® is _generally recommended for patients who have had an inadequate response to, or are unable to tolerate, conventional Crohn’s disease therapies.”_

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

**EFFICACY**

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Key Studies

- Phase 3 studies
- CD301:  Induction *(↑CRP post-hoc analysis)*
- CD303:  Maintenance (CD301 responders)
- CD307:  Induction (↑CRP prospectively)

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Concomitant Meds – Across Studies(CD301, CD303, & CD307)

- Anti-TNF’s prohibited
- Continuation of azathioprine, 6-MP, MTX, steroids, 5-ASA allowed
- New CD treatment allowed for rescue therapy only

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

**Induction Studies (CD301, CD307)**

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Design  (CD301 & CD307)

|  | CD301 | CD307 |
| --- | --- | --- |
| N | 905 | 509 |
| Rand. (Nat:Pl) | 4:1 | 1:1 |
| Dose | 300 mg Q 4 wks X 3 |  |
| 10 Endpoint | Response Wk 10 | Response Wks 8 & 12 |
| 20 Endpoint (main) | Remission Wk 10 | Remission Wks 8 & 12 |
| ↑ CRP | Post-hoc (n=660) | Prospective |
| Response = CDAI decrease 70 or more; Remission = CDAI<150; CRP: > 2.87 mg/L  |  |  |

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Prior Meds* for CD (CD301 & CD307)

|  | CD301 (n=905) | CD307 (n=509) |
| --- | --- | --- |
| Treatment Naïve | 1%# | 1% |
| 5-ASA | 86% | 45% |
| Steroids | 89% | 70% |
| Immunosuppressants | 67% | 43% |
| Anti-TNFs | 40% | 48% |

- * Includes subjects continuing prior meds as baseline concomitant meds
- # <1% Natalizumab, 3% Placebo

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Concomitant Meds at Baseline (CD301 & CD307)

|  | CD301 (n=905) | CD307 (n=509) |
| --- | --- | --- |
| 5-ASA | 47% | 49% |
| Steroids | 39% | 40% |
| Immunosuppressants | 33% | 38% |

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Induction Study ResultsClinical Response

| Induction Study #1 (CD301) – ITT |  |  |  |  |
| --- | --- | --- | --- | --- |
| Response | Plac (n=181) | Nat (n=724) | Nat-Plac | p-value |
| Wk 10  | 48.6% | 56.4% | 7.8% | 0.051 |
|  |  |  |  |  |
| Induction Study #1 (CD301) - CRP Post-hoc Analysis  |  |  |  |  |
| Response | Plac (n=134) | Nat (n=526) | Nat-Plac | p-value |
| Wk 10 | 44.8% | 57.6% | 12.8% | 0.007 |
|  |  |  |  |  |
| Induction Study #2 (CD307) – ITT ( CRP Prospective) |  |  |  |  |
| Response | Plac (n=250) | Nat (n=259) | Nat-Plac | p-value |
| Wks 8 & 12 | 32.4% | 47.9% | 15.5% | <0.001 |

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Induction Study ResultsClinical Remission

| Induction Study #1 (CD301) – ITT |  |  |  |  |
| --- | --- | --- | --- | --- |
| Remission | Plac (n=181) | Nat (n=724) | Nat-Plac | p-value |
| Wk 10  | 30.4% | 36.9% | 6.5% | 0.124 |
|  |  |  |  |  |
| Induction Study #1 (CD301) - CRP Post-hoc Analysis  |  |  |  |  |
| Remission | Plac (n=134) | Nat (n=526) | Nat-Plac | p-value |
| Wk 10 | 27.6% | 39.5% | 11.9% | 0.014 |
|  |  |  |  |  |
| Induction Study #2 (CD307) – ITT ( CRP Prospective) |  |  |  |  |
| Remission | Plac (n=250) | Nat (n=259) | Nat-Plac | p-value |
| Wks 8 & 12 | 16.0% | 26.3% | 10.3% | 0.002 |

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

**Subgroup **
**Analyses of the Induction Studies**

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Subgroup Analyses

- Attempt to identify a population that might have:
- Higher efficacy
- Greater medical need
- Higher severity & more refractory - Possible surrogates:
- CDAI score at baseline (may vary with disease activity)
- Prior medication use
- Failures of prior meds (no rigorous criteria to identify)
- Determine if similar efficacy: monotherapy vs.  concomitant immunosuppressants or steroids
- No prospective monotherapy study
- Limitations of exploratory subgroup analyses

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Subgroup Analyses [cont.]

- Subgroup Analyses:
- Baseline CDAI - quartiles
- Prior Meds
- Inadequate Response to Prior Meds
- Concomitant Meds
- Treatment effect in each subgroup generally similar to overall

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Baseline CDAI (CD301 Elevated CRP Subset) 

| Clinical Response Wk 10 |  |  |  |
| --- | --- | --- | --- |
| Quartiles (Baseline CDAI score) | Plac | Nat | Nat-Plac |
| Overall | 45% | 58% | 13% |
| 1:  165-256 | 38% | 51% | 13% |
| 2:  256-293 | 50% | 63% | 13% |
| 3:  293-345 | 42% | 59% | 17% |
| 4:  345-518 | 49% | 57% | 9% |

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Baseline CDAI (CD307)

| Clinical Response Wk 10 |  |  |  |
| --- | --- | --- | --- |
| Quartiles (Baseline CDAI score) | Plac | Nat | Nat-Plac |
| Overall | 32% | 48% | 15% |
| 1:  147-250 | 31% | 44% | 13% |
| 2:  250-286 | 36% | 46% | 10% |
| 3:  286-342 | 33% | 51% | 18% |
| 4:  342-483 | 30% | 52% | 22% |

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Prior* Meds(CD301 Elevated CRP Subset)

| Clinical Response Wk 10 |  |  |  |
| --- | --- | --- | --- |
| Prior* Med | Plac | Nat | Nat-Plac |
| Overall (100%) | 45% | 58% | 13% |
| Steroids (51%) | 43% | 56% | 13% |
| Immunosuppressants (36%) | 44% | 53% | 8% |
| Anti-TNF Agents (40%) | 31% | 54% | 23% |

- * Does not include concomitant meds

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Prior* Meds (CD307)

| Clinical Response Wks 8 & 12 |  |  |  |
| --- | --- | --- | --- |
| Prior* Med (% Popln) | Plac | Nat | Nat-Plac |
| Overall (100%) | 32% | 48% | 15% |
| Steroids (52%) | 31%  | 48% | 17% |
| Immunosuppressants (36%) | 24%  | 44%  | 20% |
| Anti-TNF Agents (48%) | 21% | 37% | 16% |

- * Does not include concomitant meds

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Inadequate Responders to Prior Meds(CD301 Elevated CRP Subset)

| Clinical Response Wk 10 |  |  |  |
| --- | --- | --- | --- |
| Inadequate Responders* (% popln)  | Plac | Nat | Nat-Plac |
| Overall (100%) | 45% | 58% | 13% |
| Steroids (62%) | 46% | 56% | 10% |
| Immunosuppressants (47%) | 44% | 55% | 11% |
| Anti-TNF Agents (27%) | 36% | 48% | 12% |

- * Inadequate Response defined as unresponsive or intolerant to prior meds.
-    For steroids, “inadequate response” also includes steroid-dependent.

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Inadequate Responders to Prior Meds (CD307)

| Clinical Response Wks 8 & 12 |  |  |  |
| --- | --- | --- | --- |
| Inadequate Responders* (% popln) | Plac | Nat | Nat-Plac |
| Overall (100%) | 32% | 48% | 15% |
| Steroids (41%) | 29% | 42% | 13% |
| Immunosuppressants (37%) | 26% | 43% | 18% |
| Anti-TNF Agents (30%) | 13% | 39% | 26% |

- * Inadequate Response defined as unresponsive or intolerant to prior meds.
-    For steroids, “inadequate response” also includes steroid-dependent.

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Concomitant Meds (CD301 Elevated CRP Subset)

- * includes baseline therapy and rescue therapy while on study
- # Monotherapy:  defined as no immunosuppressants and no steroids used concomitantly

| Clinical Response at Wk 10 |  |  |  |
| --- | --- | --- | --- |
| Concomitant Med* (% popln) | Plac | Nat | Nat-Plac |
| Overall (100%) | 45% | 58% | 13% |
| Monotherapy# (35%) | 57% | 64% | 7% |
| Steroids (47%) | 40% | 52% | 13% |
| Immunosuppressants (37%) | 35%  | 57%  | 22% |

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Concomitant Meds (CD307)

| Clinical Response Wks 8 & 12 |  |  |  |
| --- | --- | --- | --- |
| Concomitant Med* (% popln) | Plac | Nat | Nat-Plac |
| Overall (100%) | 32% | 48% | 15% |
| Monotherapy# (24%) | 37% | 66% | 29% |
| Steroids (44%) | 31% | 42% | 10% |
| Immunosuppressants (36%) | 32% | 44% | 12% |

- * includes baseline therapy and rescue therapy while on study
- # Monotherapy:  defined as no immunosuppressants and no steroids used concomitantly

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

**Maintenance Study (CD303)**

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Design – Study CD303 (Maintenance)

| Population | CD301 Responders at Wks 10 & 12 |
| --- | --- |
| Eligibility Criteria | Mildly Active (150≤CDAI<220) at Wk 12 or 
Remission (CDAI<150) at Wk 12 |
| N  | 428  |
| Dose | 300 mg Q 4 wks X 12 |
| Rand. | 1:1 (Nat:Pl) |
| Analysis | CD301 Natalizumab Responders Population (n=339) |
| 10 Endpt | Maintenance of Response Through Month 9   |
| 10 Endpt (#2) | Maintenance of Remission Through Month 9  |
| 20 Endpt | Steroid Taper from start of CD303  |
| CRP | Not part of entry criteria (Post-hoc analyses done) |

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Concomitant Meds* – CD303

|  | CD303 (n=339) |
| --- | --- |
| 5-ASA | 51% |
| Steroids | 40% |
| Immunosuppressants | 39% |
| Anti-TNFs | 1%# |
| * During the treatment phase of CD303; 7% on no concomitant CD meds.
#  Not permitted by protocol; were all in placebo group
N=339:  Natalizumab responders from Study CD301 |  |

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Maintenance Study Results (CD303)Maintenance of Response

| ITT  | Plac
[n=170] | Nat
[n=168] | Nat-Plac  | P value |
| --- | --- | --- | --- | --- |
| Month 9  | 28% | 61% | 33% | <0.001 |
| Month 15  | 20% | 54% | 34% | <0.001 |
|  |  |  |  |  |
| ↑CRP* | Plac 
(n=128) | Nat (n=129) | Nat-Plac  | p value |
| Month 9 | 26% | 61% | 35% | <0.001 |
| Month 15 | 19% | 54% | 35% | <0.001 |

** **CRP at baseline of Study CD301 (Induction)*

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Maintenance Study Results (CD303)Maintenance of Remission

| ITT | Plac [n=120] | Nat
[n=130] | Nat-Plac  | P value |
| --- | --- | --- | --- | --- |
| Month 9  | 26% | 44% | 18% | 0.003 |
| Month 15  | 15% | 39% | 24% | <0.001 |
|  |  |  |  |  |
| ↑CRP* | Plac (n=94) | Nat (n=98) | Nat-Plac  | p value |
| Month 9 | 25% | 47% | 22% | 0.002 |
| Month 15 | 14% | 42% | 28% | <0.001 |

** **CRP at baseline of Study CD301 (Induction)*

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

**Subgroup Analyses of the Maintenance Study**

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Subgroup Analyses

- Subgroup Analyses:
- Baseline CDAI - Quartiles
- Prior Meds
- Inadequate Response to Prior Meds
- Concomitant Meds
- Treatment effect in each subgroup generally similar to overall

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Baseline CDAI (CD303)

| Response Through Mo. 9 |  |  |  |
| --- | --- | --- | --- |
| Quartiles (Baseline CDAI score) | Plac | Nat | Nat-Plac |
| Overall | 28% | 61% | 33% |
| 1:  <=67 | 38% | 65% | 28% |
| 2:  67-110 | 32% | 73% | 41% |
| 3:  110-150 | 33% | 61% | 28% |
| 4:  150-254 | 13% | 43% | 30% |

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Prior Meds* (CD303)

| Response through Mo. 9 |  |  |  |
| --- | --- | --- | --- |
| Prior Med* (% popln) | Plac  | Nat  | Nat-Plac |
| Overall (100%) | 28% | 61% | 33% |
| Steroids (46%) | 35% | 60% | 25% |
| Immunosuppressants (32%) | 17% | 51% | 34% |
| Anti-TNF (36%) | 10% | 58% | 48% |

- * Not concomitant

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Inadequate Responders* to Prior Meds (CD303)

| Response through Mo. 9 |  |  |  |
| --- | --- | --- | --- |
| Inadequate Responders* (% popln) | Plac  | Nat  | Nat-Plac |
| Overall (100%) | 28% | 61% | 33% |
| Steroids (61%) | 32% | 60% | 28% |
| Immunosuppressants (44%) | 21% | 58% | 38% |
| Anti-TNF (21%) | 12% | 53% | 41% |

- * Inadequate Response defined as unresponsive or intolerant to prior meds.
-    For steroids, “inadequate response” also includes steroid-dependent.

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Concomitant Meds (CD303)

| Response through Mo. 9 |  |  |  |
| --- | --- | --- | --- |
| Concomitant Med* | Plac | Nat | Nat-Plac |
| Overall (100%) | 28% | 61% | 33% |
| Monotherapy# (36%) | 37% | 66% | 29% |
| Steroids (47%) | 22% | 54% | 31% |
| Immunosuppressants (38%) | 26% | 65% | 39% |

- * includes baseline therapy and rescue therapy while on study
- # Monotherapy defined as no immunosuppressants and no steroids used concomitantly

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

**Efficacy Summary**

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Efficacy Summary

- Induction:
- Study 301:
- A retrospective analysis of CRP showed a treatment effect of 12.8%
- Treatment effect for the entire study was 7.8%
- Study 307:
- Consistent with the finding in the subgroup analysis of Study 301
- Treatment effect of 15.5% (p<0.001)
- No confirmation that CRP predicts response

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Efficacy Summary (cont.)

- Maintenance:
- Efficacy demonstrated in overall population of induction responders.
- 33% treatment effect  (p<0.001)
- Subset with CRP at baseline had a similar response.
- No adjustments made for secondary endpoints including steroid withdrawal.

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Efficacy Summary (cont.)

- Subgroup analyses:
- Treatment effect generally similar across subgroups
- Analyses were exploratory
- No definitive impact on treatment effect from:
- CDAI
- Prior meds
- Inadequate response to prior meds
- Monotherapy - no clear impact on treatment effect

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Previous FDA Safety Review (June 2006)

- Non-PML safety issues identified in review by Neuro*:
- Infections other than PML - concern of:
- Herpes infections
- lower resp tract infections (espec atypical)
- viral meningitides
- Carcinogenicity - no clear increase in risk:
- MS controlled studies:  higher in placebo group
- CD controlled studies:  higher in natalizumab group
- Immunogenicity - ~ 10%
- Hypersensitivity – assoc with immunogenicity

- * Advisory Committee Presentation by Alice Hughes, M.D. (3/7-8/06)

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Current Application Safety Review

- As no new cases of PML, emphasis on:
- Infections (overall, serious, atypical)
- Malignancies
- Deaths

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## MS & CD Studies:  Exposure to 300 mg Fixed Dose*	

|  | MS | CD* | Total |
| --- | --- | --- | --- |
| Total Exposed | 1937 | 1343 | 3315 |
| ≥ 1 yr | 1240  | 518  | 1839  |
| *Short- & Long-term Dosing in CD:  All CD studies but CD354 (n=40) and CD306(n=79) included.
 |  |  |  |

- * Design of the table above from Alice Hughes, M.D.’s  Regulatory Briefing Presentation 2/24/06 and modified/updated based on data in the submission.

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## CD – Overall* Exposure Duration & Concomitant Meds During Time Intervals

| Exposure* to Natalizumab |  |  |  |  |
| --- | --- | --- | --- | --- |
| Duration | Total | ≥1 yr | ≥2 yr | ≥2.5 yr |
| No. Doses | ≥1 | ≥13 | ≥25 | ≥31 |
| No. Subjects | 1563 | 509 | 294 | 81 |
| 
Concomitant Meds During Time Interval |  |  |  |  |
| Time Interval | 0-1 yr | 1-2yr | 2-2.5yr | 2.5 yr+ |
| Monotherapy | 20% | 20% | 20% | 23% |
| Steroid  | 65% | 64% | 64% | 58% |
| Immunosuppressant | 48% | 51% | 50% | 53% |
| *Short- & Long-term Dosing in CD:  All CD studies but CD354 (n=40) and CD306(n=79) included. |  |  |  |  |

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Selected Infections(Short-term Controlled CD Studies)

|  | Plac (n=506) | Nat (n=1182) |
| --- | --- | --- |
| Infection | 36% | 40% |
| Upper Resp Tract | 22% | 27% |
| Lower Resp Tract | 3.4% | 3.1% |
| UTI | 1.4% | 2.6% |
| Herpes Simplex | 0.8% | 1.3% |

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Serious Infections(Short-term Controlled CD Studies)

|  | Plac (n=506) | Nat (n=1182) |
| --- | --- | --- |
| Serious Infection | 12 (2.4%) | 29 (2.5%) |
| Abscess | 7 (1.4%) | 13 (1.1%) |
| Viral Meningitis | 0 | 2 (0.2%) |
| Cytomegalovirus Infection | 0 | 1 (<0.1%) |

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Serious Infections [cont.](Short-term Controlled CD Studies)

- CMV colitis
- after 2 doses
- concom. azathioprine
- Viral meningitis case #1
- after 1 dose
- concom. budesonide
- Viral meningitis case #2:
- after 2 doses
- concom. prednisone & 6-MP

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Serious Infections (Short and Long-term CD Studies)

- Six serious herpes infections

|  | # Nat Doses | Concomitant Steroids/Immunosuppressants |
| --- | --- | --- |
| Vaginitis  | 1 | -- |
| Zoster - 12 y/o | 1 | -- |
| Zoster - 28 y/o | 2 | prednisone 15 mg/d |
| Conjunctivitis  | 3 | azathioprine |
| Varicella pneumonia  | 7 |  -- |
| Zoster – 25 y/o  | 11 | prednisolone and azathioprine |

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Serious Infections [cont.](Short & Long-Term CD Studies)*

- Six atypical lower respiratory tract infections

|  | # Nat Doses | Concomitant Steroids/Immunosupp |
| --- | --- | --- |
| Burkholder cepacia infection  | 3 | Prednisone 20 mg |
| Mycobacterium avium intracellulare complex pneumonia  | 5 | Prednisone 60 mg & tapering |
| Varicella pneumonia  | 7 | -- |
| Pulmonary aspergillosis# | 10 | Prednisolone 50 mg |
| Pneumonia with lung abscess  | 11 | Aza 3 yrs |
| Pneumocystis carinii pneumonia# | 34 | -- |

- * Clinical Review of 125104/15 by Alice Hughes, M.D. and Sue McDermott, M.D. (5/18/06)

- # Complicated by bacterial infectious processes; outcome was death

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Malignancies

| MS Studies: |  |  |
| --- | --- | --- |
|  | Plac [n=1135] | Nat [n=1617] |
| Incidence | 1.3% (15) | 0.7% (11) |
| Rate* | 0.73 | 0.38 |
| * Per 100 person-yrs |  |  |

| CD Short-term Studies: |  |  |
| --- | --- | --- |
|  | Plac [n=506] | Nat [n=1182] |
| Incidence | 0.2% (1) | 0.6% (7) |
| Rate* | 0.60 | 1.60 |
| * Per 100 person-yrs |  |  |

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Deaths

- 18 deaths in the natalizumab development program
- 14 in natalizumab-treated subjects
- 6 in MS studies
- 6 in CD studies
- 2 in RA studies
- 4 in placebo-treated subjects

| Deaths in Placebo-Controlled Studies* |  |  |  |
| --- | --- | --- | --- |
| MS |  | CD |  |
| Placebo  | Natalizumab | Placebo | Natalizumab |
| 0.26%
(3/1135) | 0.12%
(2/1617) | 0
(0/506) |  0.17%
(2/1182) |
| * Values in table from BLA Review 125104/15 Alice Hughes, M.D. and Susan S. McDermott, M.D. (5/18/06); values same as no new deaths in placebo-controlled studies as per submission. |  |  |  |

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Deaths - Selected Cases

- Infections:
- PML case in MS pt – 37 Nat infusions
- PML case in CD pt – 8 Nat infusions
- PCP pneumonia in 69 y/o CD pt – 34 Nat infusions
- Pulmonary aspergillosis in 73 y/o CD pt – 10 Nat infusions
- Malignancy:
- Metastatic malignant melanoma in 38 y/o MS pt – 5 Nat infusions; hx malignant melanoma excised; lesion noticed at time of 1st or 2nd Nat infusion
- Suicide:
- 27 y/o MS pt – 6 mos after 31st Nat infusion

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Immunogenicity

- Ab (+) ~ 10% of those tested
- Ab (+):  Monotherapy > Steroids > Immunosupp.
- CD301:  12% vs. 5% vs. 2%
- CD307:  13% vs. 10% vs. 5%
- Clinical Response (Induction):  Ab (+) < Ab (-)
- CD301 (Response Wk 10):  43% vs. 58%
- CD307 (Response Wks 8 & 12):  41% vs. 50%

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Immunogenicity [cont.]

- Ab (+) associated with infusion reactions:  headache, nausea, urticaria, flushing, pruritus, fatigue
- Rates of anaphylactic/anaphylactoid reactions in Natalizumab-treated patients:
- MS controlled studies:  0.4%
- CD short-term studies: < 0.1%
- No cases in Ab (-), but not all tested

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Clinical Trials Safety Summary

- No new safety issues identified since June 2006 review.
- PML
- Infections other than PML: Herpes infections, lower resp tract infections (espec atypical), viral meningitides
- Carcinogenicity - no clear increase in overall risk
- Hypersensitivity

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

**DISCUSSION**

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Risk-Benefit Considerations

- Therapeutic gains were modest in the induction studies (~8-15%), but higher in the maintenance study (~33-35%)
- Evidence for efficacy in subgroups based on exploratory analyses
- No population clearly has superior efficacy
- Management of CD commonly involves steroids and/or immunosuppressants
- Risk factors for PML unknown
- Long-term safety data in CD are limited (~500 for >1 yr; ~300 for >2 yrs)

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## Risk-Benefit Considerations [cont.]

- Safety issues other than PML
- Risk Management
- Concurrent therapies that are allowed/restricted
- Role of prior history of immunosuppressant drugs
- Role for JCV serum / MRIs / Neuro exams (by neurologist) as screening tools for PML
- Possibility of additional safety and/or efficacy studies

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007

## CDER FDA Review Team

| Regulatory Project Manager (DGP)
Marlene Swider, M.H.S.A.	

Clinical Review Team (DGP, ODE III)
Anil Rajpal, M.D., Reviewer	
John Hyde, Ph.D., M.D., Team Leader
Joyce Korvick, M.D., M.P.H., Deputy Director, DGP
Daniel Shames, M.D., Director (Acting), DGP
Julie Beitz, M.D., Director, ODE III

RiskMAP Review Team (DDRE, OSE)
Claudia Karwoski, Pharm.D., Team Leader, OSE
Mary Willy, Ph.D., Team Leader, OSE
Ann Corken, R.Ph., M.P.H., Safety Evaluator, DDRE
Charlene Flowers, R.Ph., Safety Evaluator, DDRE
Mark Avigan, M.D., C.M., Director, DDRE
Ellis Unger, M.D., Deputy Director, OSE
Gerald Dal Pan, M.D., M.H.S., Director, OSE | Statistics (OBS)		            
Lisa Kammerman, Ph.D., Reviewer
Michael Welch, Ph.D., Team Leader

Clinical Pharmacology (OCP)		
Abimbola Adebowale, Ph.D., Reviewer
Christopher Tornoe, Ph.D., Reviewer
Sue Chih Lee, Ph.D., Team Leader

Product (DMA)
Elena Gubina, Ph.D., Reviewer

 |
| --- | --- |

- Joint GIDAC/DSaRM (Tysabri for CD)

- July 31, 2007