# Presentation: 685798

## Efficacy of Natalizumab in Crohn’s Disease

*Stephen Jones, MBBS*
*Director, Clinical Development*

## Natalizumab for the Treatment of Crohn’s Disease

- Mechanism of action of natalizumab
- Treatment objectives for Crohn’s disease, and the clinical trial tools used to evaluate them
- Efficacy of natalizumab in the Phase III clinical development program
- Induction of response (CD301, CD307)
- Maintenance of response (CD303)
- Summary of Efficacy

## Integrins Mediate Leukocyte Adhesion During Inflammation

**VCAM**

## Natalizumab Inhibits the Trafficking of Leukocytes into Inflamed Tissues

## Crohn’s Disease Treatment Objectives

- Induce response and remission
- Maintain response and remission
- Reduce steroid use
- Improve quality of life

## Outcomes Measured inCD Clinical Trials

- Crohn’s Disease Activity Index (CDAI)
- Primarily based on
- Subject completed diary, recording bowel activity, abdominal pain and general well-being
- Physician assessment including weight and hematocrit
- Score range: 0-600
- Moderate-to-severely active: 220-450
- Clinical response: ≥70 point reduction in CDAI from baseline value
- Clinical remission: < 150 on CDAI

## Additional Outcomes Measured inCD Clinical Trials

- Inflammatory Bowel Disease Questionnaire (IBDQ)
- Disease-specific quality of life questionnaire
- Total scale: score ranges from 32 (worst) to 224 (best)
- A score of ≥170 equates to clinical remission
- Short Form 36 (SF-36)
- General quality of life questionnaire
- Steroid sparing
- Proportion of patients discontinuing steroids at a particular time-point
- C-Reactive Protein (CRP)
- Objective marker of inflammation
- Change over time

## Clinical Development Program in CD

**Clinical Development Program in CD**

**CD301**
**Induction Study**
**12 weeks****(905 subjects)**

**CD303**
**Maintenance Study**
**12 months**** (428 subjects) **

**CD351**
**Open-label**
**2-year safety study **
**(1100 subjects in total)**

**Phase 2 Program**

**Phase 3 Program**

**CD202**
**Induction Study**

**CD201**
**Pilot Study**

**CD307**
**Induction Study**
**12 weeks**
**(509 subjects)**

*Induction of response/remission in patients with moderately to severely active Crohn’s disease*

**CD301**

## CD301: Study Design 

** ****(12 Wks)**

**Screening Phase **
**(1-2 Wks)**

**WEEK**

**0**

**4**

**8**

**R**

**-2**

**12**

**R – Patient Randomization **

**CD301: Study Design **

**R**

**R**

**R**

**R**

**R**

**905 patients with moderate to severely active Crohn’s disease (CDAI ******** 220 to ******** 450)**

**20**

**Follow-up Phase (8 Wks) or entry in CD303**

**4:1 **
**Natalizumab (N=724) : Placebo (N=181)**

**10**

**6**

**2**

**905 patients with moderate to severely active Crohn’s disease (CDAI ≥ 220 to ≤ 450)**

**4:1 **
**Natalizumab (N=724) : Placebo (N=181)**

##  CD301: Patient Disposition

| Population | Placebo
n (%) | Natalizumab
n (%) |
| --- | --- | --- |
| ITT | 181 | 724 |
|   Complete Week 12 visit
  Did not complete | 141 (78)
  40 (22)  | 602 (83)
122 (17) |
| Lack of efficacy/ Worsening of CD | 16 (9) | 48 (7) |
| Non CD related AE
Other  |   8 (4)
16 (9) | 42 (6)
32 (4) |

## CD301: Baseline Characteristics

|  | Placebo
N=181 | Natalizumab
N=724 |
| --- | --- | --- |
| Gender: female | 60% | 57% |
| Mean age (yr) | 39.4 | 38.0 |
| Mean weight (kg) | 71.1 | 71.6 |
| Disease duration (yr) | 9.1 | 10.1 |
| Current smoker | 24% | 23% |
| Baseline CDAI | 303.4 | 301.8 |
| Concurrent meds |  |  |
| 5-ASA compounds | 44% | 48% |
| Steroids | 39% | 39% |
| Immunosuppressant | 29% | 34% |
| Prior meds |  |  |
| Anti-TNF | 38%  | 40% |

## CD301: Response (≥ 70 Reduction in CDAI)Primary Outcome – Week 10

**33**

**45**

**53**

**50**

**49**

**51**

**40**

**51**

**58**

**57**

**56**

**61**

**30**

**35**

**40**

**45**

**50**

**55**

**60**

**65**

**70**

**Week 2**

**Week 4**

**Week 6**

**Week 8**

**Week 10**

**Week 12**

**Placebo (N=181)**

**300 mg  (N=724)**

**Patients (%)**

***P*****=0.051**

## CD301: Response for Patients with Elevated Baseline CRP Post Hoc Analysis

**CD301: Response for Patients with ****Elevated Baseline CRP**** ****Post Hoc Analysis**

***P*****=0.007**

**Patients (%)**

## CD307

*Induction of response/remission in patients with moderately to severely active CD and elevated CRP*

## CD307: Study Design

**CD307: Study Design**

**WEEK**

**0**

**4**

**8**

**R**

**-2**

**12**

**R – Patient Randomization **

**0**

**4**

**8**

**R**

**-2**

**R – Patient Randomization **

**0**

**4**

**8**

**R**

**-2**

**R – Patient Randomization **

**0**

**4**

**8**

**R**

**-2**

**0**

**4**

**8**

**R**

**-2**

**R**

**-2**

**509 patients with moderate to severely active CD (CDAI ≥ 220 to ≤ 450) and elevated serum CRP (> 2.87 mg/L)**

**20**

**Follow-up Phase (8 Wks)**

**1:1 **
**Natalizumab (N=259) : Placebo (N=250)**

**12**

**Treatment Phase**
** ****(12 Wks)**

**Screening Phase **
**(1-2 Wks)**

**0**

**4**

**8**

**R – Patient Randomization **

## CD307 Objectives and Endpoints

- Primary endpoint – response (≤ 70 point reduction in CDAI from baseline) at weeks 8+12
- Secondary endpoints
- Remission (<150) at weeks 8+12
- Response at week 12
- Remission at week 12

##  CD307: Patient Disposition

| Population | Placebo
n (%) | Natalizumab
n (%) |
| --- | --- | --- |
| ITT | 250 | 259 |
|   Complete Week 12 visit | 208 (83) | 220 (85) |
|   Did not complete |   42 (17) |   39 (15) |
|      Lack of efficacy/Worsening of CD |   29 (12) | 12 (5) |
|      Non CD related AE
     Other  |   6 (2)
  7 (3) | 17 (7)
10 (4) |

## CD307: Baseline Characteristics

**CD307: Baseline Characteristics**

|  | Placebo
N=250 | Natalizumab
N=259 |
| --- | --- | --- |
| Gender: female | 59% | 59% |
| Mean age (years) | 37.7 | 38.1 |
| Mean weight (kg) | 74 | 72 |
| Disease duration (years) | 10 | 10.1 |
| Current smoker | 19% | 22% |
| Mean CDAI score | 299.5 | 303.9 |
| Concurrent meds |  |  |
| 5-ASA compounds | 48% | 49% |
| Immunosuppressants | 38% | 37% |
| Steroids | 38% | 42% |
| Prior meds |  |  |
| Anti-TNF | 45% | 50% |

## CD307: Response (≥ 70 Point Reduction in CDAI)Primary Outcome (Weeks 8 & 12)

**Natalizumab (n=259)**

***P*****<0.001**

**51**

**60**

**48**

**37**

**44**

**32**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**Week 4**

**Week 12**

**Weeks 8 & 12**

**40**

**56**

**Week 8**

**Patients (%)**

**CD307: Response (≥ 70 Point Reduction in CDAI)****Primary Outcome (Weeks 8 & 12)**

## CD307: Remission (CDAI <150)Secondary Outcome (Weeks 8 & 12)

**Patients (%)**

***P*****=0.002**

**24**

**32**

**38**

**26**

**16**

**21**

**25**

**16**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**45**

**Week 4**

**Week 8**

**Week 12 **

**Weeks 8 & 12**

**Placebo (n=250)**

**Natalizumab (n=259)**

## CD307: Median CRP Over Time

**Median CRP**

**14.2**

**13.5**

**12.7**

**6.5**

**Week 0**

**Week 4**

**Week 8**

**Week 12**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**16**

**Placebo**

**Natalizumab**

## CD307 ITT vs CD301 Elevated CRP PopulationConsistent Induction of Response At Weeks 8 & 12

**Patients (%)**

** *****P*****<0.001**

***P*****=0.002**

**CD307 ITT vs CD301 Elevated CRP Population****Consistent Induction of Response At Weeks 8 & 12**

**N=250**

**N=259**

**N=134**

**N=526**

## CD307: Response (Weeks 8+12) Patients Failed Other CD Therapies vs ITT

***P*****<0.001**

***P*****=0.003**

***P*****<0.001**

**CD307: Response (Weeks 8+12) Patients Failed Other CD Therapies vs ITT**

**Placebo **

**Natalizumab **

**N=168  N=187**

**N=172  N=182**

**N=83   N=89**

**N=250**

**N=259**

***P*****=0.007**

- IMM = Immunosuppressants

## Summary of Induction of Response/Remission

- Induced response/remission in patients with objective evidence of inflammation
- Induced response/remission consistently across subgroups of patients who failed other therapies
- Steroids
- Immunosuppressants
- TNF- inhibitors
- Natalizumab is an effective treatment for patients with moderately to severely active Crohn’s disease

## CD303

*Maintenance of clinical response/remission*

## CD301/CD303: Study Flow Chart

**1:1 **
**Natalizumab 300 mg: Placebo**

**CD303**

**Treatment Phase**
**(12 months)**

**MONTH:**

**Wk10**

**12**

**0****R**

**1**

**11**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**10**

**CD301**
**Moderately to severely**
**active disease**
**(CDAI ****≥****220, ****≤****450) **
**Treatment Phase**
**(3 months)**

**CD303**
**Responders with mildly active disease **
**(****≥****70 pt ******** & CDAI <220, ****≥****150) OR remission (<150)**

**R ****    ****  ****Randomization**

##  CD303: Patient Disposition

| Population | Placebo
n (%) | Natalizumab
n (%) |
| --- | --- | --- |
| Efficacy Population  | 171 | 168 |
|   Complete Month 12 visit |   51 (30) | 112 (67) |
|   Did not complete | 120 (70) |   56 (33) |
|       Lack of efficacy/Worsening of CD |   84 (49) |   34 (20) |
|       Non CD related AE
      Other | 12 (7)
  24 (14) |   7 (4)
15 (9) |

## CD303: Primary Outcome

- Primary outcome: proportion (%) of patients who did not lose response (CDAI ≥ 220 and increase in CDAI ≥ 70) and no rescue at any assessment through month 6
- Contingent Primary: proportion (%) of patients maintaining remission (CDAI < 150) at any assessment through month 6

## CD303: Sustained ClinicalResponse at Every Assessment

**54%**

**20%**

**61%**

**28%**

**Primary endpoint**

**0**

**20**

**40**

**60**

**80**

**100**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**10**

**11**

**12**

**Time (months)**

**Natalizumab (n=168)**

**Placebo (n=170)**

**Patients (%)**

***P *****< 0.001**

**Start CD303**

****

## CD303: Sustained Clinical Remission at Every Assessment

**Start CD303**

**39%**

**15%**

**26%**

**44%**

**Contingent primary endpoint**

**0**

**20**

**40**

**60**

**80**

**100**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**10**

**11**

**12**

**Patients (%)**

**Time (months)**

***P***** < 0.001**

****

**Natalizumab (n=130)**

**Placebo (n=120)**

## CD303: Mean Total IBDQ Score Over Time

**Remission* **

**P<0.001**

**120**

**130**

**140**

**150**

**160**

**170**

**180**

**190**

**200**

**-3**

**0**

**3**

**6**

**9**

**12**

**Mean Total IBDQ Score**

**Time (months)**

**Baseline**
**CD301**

**Start**
**CD303**

**124**

**182**

**Natalizumab**

**Placebo**

**Natalizumab Responders**

- *Irvine EJ, *Gastroenterology*. 1994.

## CD303: Steroid Withdrawal

- Study CD303 was also designed to investigate:
- Ability of natalizumab maintenance treatment to eliminate oral steroid use
- Number of subjects with a steroid-free remission
- Subjects followed a protocol-defined steroid withdrawal algorithm at Week 10 of CD301 and continued during CD303

## CD303: Proportion of Subjects Withdrawn from Steroids: Month 6 and Month 12

**Patients (%)**

** *****P*****<0.001**

***P*****=0.014**

**CD303: Proportion of Subjects Withdrawn from Steroids: Month 6 and Month 12**

**Steroid Elimination**

**Steroid Free Remission**

## CD303: Secondary Endpoints

| Endpoint | Outcome (Natalizumab vs placebo) | P value |
| --- | --- | --- |
| Sustained response through to Month 12  | 54% vs 20%  | <0.001 |
| Sustained remission through to Month 12 | 39% vs 15%  | <0.001 |
| Time to loss of response | >12 months vs 86 days1  | <0.001 |
| Time to loss of remission | 137 days vs 59 days  | <0.001  |
| Change from CD301 baseline in IBDQ score at Month 6 | +53 vs +39 | <0.001 |
| Patients not taking oral steroids at Month 6 | 58% vs 28% | <0.001 |
| Patients in steroid-free remission at Month 6  | 45% vs 22% |   0.014 |
| 1 The median time to loss of response in the natalizumab group could not be determined as most patients remained in response through to Month 12  |  |  |

## CD303: Response and RemissionWithout Concomitant Immunosuppressants

**Month 12**

**Month 12**

**Response**

**Remission**

**Month 6**

**Month 6**

**Placebo n=111**

**Natalizumab n=106**

**CD303: Response and Remission****Without Concomitant Immunosuppressants**

## CD303: Anti-TNF- Failure Population

**Patients (%)**

**Response**

**Remission**

## Summary – Efficacy of Natalizumab for Crohn’s disease

- Induction
- Demonstrated efficacy for response and remission in patients with an objective marker of inflammation
- Demonstrated efficacy in patients who failed therapy with corticosteroids, with immunosuppressants and patients who failed therapy with an anti-TNF-α inhibitor
- Maintenance
- Demonstrated sustained response and remission with maintenance treatment
- Significant QoL improvements are maintained with natalizumab
- Significant steroid-sparing effect
- Concomitant immunosuppressants were not required to maintain long-term efficacy