# Presentation: 305327

## Biologic License Application STN BL 125036/0: Alefacept for the Treatment of Chronic Plaque Psoriasis 

**Dermatologic and Ophthalmic Drugs Advisory Committee Meeting **
**May 23, 2002**

**Center for Biologics Evaluation and Research**** **

## Indications and Usage

**AMEVIVE is indicated for the treatment of patients with chronic plaque psoriasis who are candidates for photo- therapy or systemic therapy**

## Psoriasis 

**1-3% US population**
**Polygenic inheritance **
**Infrequent in Native Americans, African Americans, and Japanese **
**Men:women equal ratio**
**Onset bimodal: 16-22 and 57-60 years**

## Psoriasis in Children

**Irregular course, generally more severe disease expression**** **
**Positive family history (50% first degree relatives) HLA-Cw6 positivity**** **
**Need for clinical trials in children **
**Risk-to-benefit considerations**

## Psoriasis: Clinical Significance

**Hyper-proliferative, inflammatory, **
**   ****skin disease**
**Usually not life-threatening**
**In 30% of patients moderate to severe disease with significant morbidity**** **
**Decreased quality of life and increased risk of suicide**

## Analysis of Clinical Trials 

**Phase 1 Studies in Healthy Subjects and in Patients with Psoriasis**

## Phase 1 Single-Dose Studies in Healthy Subjects: Results

**Decreased CD2+, CD4+ and CD8+ cell counts **
**Transient (< 24 hrs) neutrophilia (up to >5X) in 2/3 of subjects**
**Long alefacept elimination t****1/2**** (250 hrs)**
**IM 50% less bioavailable than IV **

## Phase 1 Studies in Patients with Psoriasis

**C96-703: Randomized, double-blind multiple-dose, dose-escalation study**
**Alefacept once weekly x 8 wk  N=33**
**0.005-0.075 mg/kg IV;  0.05 mg/kg IM **
**Dose-dependent drops <LLN in CD2, CD4 and CD8 cells, recovery to normal**
**DTH shifts from baseline (+) to (-)  e.g. tetanus**
**From pos. to neg.**** (N=8/9) **
**From neg. to pos. (N=0/0)**

## Analysis of Clinical Trials

**Phase 2 and 3 Studies**

## Phase 2 and 3 Trials

**All randomized double-blind placebo-controlled **
**C97-708: 0.025, 0.075, 0.15 mg/kg IV weekly x 12 wk N=229**
**C99-711:  7.5 mg IV weekly x12 wk  (2 courses)  N=565**
**C99-712:  10, 15 mg IM weekly x 12 weeks****  ****N=526**
**12 weeks post-treatment follow up**

##  Primary Efficacy Outcomes

**C97-708: Static PGA  “mild” or better**
**C99-711, -712: PASI **_**>**_**75% reduction from baseline **
**Analysis of patients using disallowed therapies**
**Response at 2 weeks post-treatment**

## Study C97-708

**Phase 2**

## Study 708

**Dose-ranging study: placebo, 0.025, 0.075, or 0.150 mg/kg I.V.**
**Certain concomitant antipsoriatic medications allowed**
**Dosing withheld if CD4+ count < 300 **

##  Treatment Response by Dose Group at Post-treatment Week 2

| Dose (mg/kg) | 0 
N=50 | 0.025
N=47 | 0.075
N=45 | 0.150
N=48 |
| --- | --- | --- | --- | --- |
| PGA mild or better | 5/50
(10a) | 14/47
(30) | 15/45
(33) | 14/48
(29) |
| Difference
(95% C.I.) | ----- | 20%
(2,37) | 23%
(5,42) | 19%
(2,37) |

**a**** percentage (%) of patients responding.**

- placebo

- alefacept

## Mean Total Lymphocyte Count by Dose and Time

**LLN=910 cells/mcL.**

## Number of Patients with Decreased CD4+ T Cell Counts

| Dose group mg/kg | 0
N=59 | 0.025 N=57 | 0.075 N=55 | 0.15 N=58 |
| --- | --- | --- | --- | --- |
|  <400 | 12(20) | 15(26) | 26(47) | 40(69) |
|  <300 | 1 (2) | 2 (4) | 15 (27) | 23 (40) |
|  <200 | 0 | 0 | 3 (5) | 6 (10) |
|  <100 | 0 | 0 | 0 | 0 |
| LLN=320 cells/mcL.   Incidence at any time after first dose. |  |  |  |  |

## Number of Patientsa with Study Drug Substituted by Placebo

| Dose (mg/kg) |    | 0.025 | 0.075 | 0.15 |
| --- | --- | --- | --- | --- |
|  |  | 51 | 48 | 49 |
| Number of | 1-3               | 4 | 6 | 10 |
| Substitutions | 4-6 | 0 | 7 | 8 |
|  | 7-9 | 0 | 0 | 6 |
|  | 10-11 | 0 | 0 | 1 |
|  |    Total | 4(8) | 13 (27) | 25(51) |

**a**** Patients receiving all 12 injections.**

## DTH Shifts by Dose: Positive to Negative as a Percentage of Subjects Positive at Baseline

| Antigen | 0 | 0.025 | 0.075 | 0.15 |
| --- | --- | --- | --- | --- |
| Tetanus | 47
(15/32) | 50
(13/26) | 64
(18/28) | 64
(9/14) |
| Diphtheria | 40
(4/10) | 50
(3/6) | 73
(8/11) | 73
(8/11) |
| Strep | 71
(5/7) | 100
(3/3) | 75
(3/4) | 100
(5/5) |

## DTH Shifts by Dose: Positive to Negative as a Percentage of Subjects Positive at Baseline (cont.)

| Antigen | 0 | 0.025 | 0.075 | 0.15 |
| --- | --- | --- | --- | --- |
| Tuberculin | 78
(7/9) | 100
(7/7) | 86
(12/14) | 82
(9/11) |
| Candida | 60
(3/5) | 75
(6/8) | 88
(7/8) | 75
(3/4) |
| Tricophyton | 100
(3/3) | 71
(5/7) | 67
(4/6) | 100
(2/2) |
| Proteus | 36
(4/11) | 53
(8/15) | 46
(6/13) | 69
(9/13) |

## Study C708: Efficacy Conclusions

**20% more patients in the alefacept-treated groups respond compared to placebo**** **
**Patients receiving concomitant anti-psoriatic therapies not declared failures**
**Insufficient discrimination between relative  activity of doses studied **
**Onset of response to alefacept: begins after 60 days**
**Median time in response post-treatment: 70 days**

## Study C708: Effects on Immune Parameters 

**Alefacept induces dose-dependent  drops in CD2+ lymphocyte counts (primarily CD4 and CD8)**
**CD4 and CD8 counts return to normal but don’t reach pre-treatment baseline**
**Decrease in Delayed-Type Hypersensitivity Reactions**

## Study C99-711

**Phase 3 Intravenous Dosing Study**

## Study C99-711: Design

|  | Course 1 |  | Course 2 |  |
| --- | --- | --- | --- | --- |
| Cohort | Tx 12wks | FU 12wks | Tx 12wks | FU 12wks |
| 1 | Alefacept |  | Alefacept |  |
| 2 | Alefacept |  | Placebo |  |
| 3 | Placebo |  | Alefacept |  |

## Efficacy Outcomes: First Treatment Course

|  | Placebo
N=186 | 7.5 mg
N=367 |  | 95% CI
for  |
| --- | --- | --- | --- | --- |
| Primary
  PASI-75 | 7 (4%)a | 53 (14%)a |  | 5,17% |
| Secondary
1)  PGA: “almost clear”    
     or “clear” | 7 (4%) | 42 (11%) |  | 2,14% |
| 2) PASI-50 | 18 (10%) | 138 (38%) |  | 20,36% |
|  |  |  |  |  |

- aNumbers represent proportion of responders

## PASI Score

- Course 1

- Course 2

- Start
- 1st Dose

- 2 wks Post Tx

- 12 wks Post Tx

- Start 1st Dose

- 2 wks Post Tx

- 12 wks Post Tx

- Placebo

- Placebo

- LFA

- LFA

- LFA

- LFA

## Observed Mean Changesa in Patient Reported Outcomes

| Mean ± SD | Drug/drug | Drug/plac | Plac/drug |
| --- | --- | --- | --- |
|  DLQI Overall | -4.6 ± 6.2 | -4.2 ± 6.9 | -1.7 ± 6.5 |
|  DQOLS Scale  |  |  |  |
| Psychosoc | -9 ± 20 | -11 ± 21 | -6 ± 16 |
| Activities | -11 ± 20 | -9 ± 18 | -4 ± 16 |
| Symptoms | -18 ± 21 | -19 ± 22 | -9 ± 21 |

**a****Course 1: Two weeks post treatment compared to pretreatment**

## Duration of Treatment Response

**Duration of Treatment Response**

## Number of Treatment Respondersa by Body Weight Quartile

| Weight (kg) | Placebo | Alefacept |  in % |
| --- | --- | --- | --- |
| <75 | 1 (3)b | 19 (21) b | 18 |
| 75 - <87.2 | 1 (2) | 15 (20) | 18 |
| 87.2 - <102 | 3 (6) | 10 (11) | 5 |
| 102+ | 2 (4) | 9 (8) | 4 |
|  85 | 2 (3) | 33 (22) | 19 |
| > 85 | 5 (4) | 20 (9) | 5 |

**a**** ********75% improvement in PASI from baseline at 2 weeks post treatment.**
**b ****N (%) **

## Relation Between Efficacy and CD4

| Max % Reduction in PASI at any Time | Lowest CD4 at Any Time (cells/mcL) |  |  |
| --- | --- | --- | --- |
|  | <300  | 300-<400 | 400+ |
| <50% | 20 (11%) | 40 (21%) | 127 (68%) |
| 50-<75% | 41 (26%) | 29 (18%) | 89 (56%) |
| 75%+ | 68 (33%) | 39 (19%) | 100 (48%) |

- Spearman correlation r=-0.2.

##  CD4 Counts by Cohort by Course

- Start 1st
- Tx Dose

- 2 wks Post Tx

- 12 wks Post Tx

- Start 1st Tx Dose

- 2 wks Post Tx

- 12 wks Post Tx

- Placebo

- LFA

- LFA

- LFA

- LFA

- Placebo

## Subjects with Low CD4+ T Cell Counts at Any Time

| Count | 1: Drug/drug |  | 3: Placebo |
| --- | --- | --- | --- |
| (/mcL) | Course 1 | Course 2 | Course 1 |
| <400 | 80 (44) | 66 (43) | 13 (7) |
| <300 | 33 (18) | 31 (21) | 1 (1) |
| <200 | 2 (1) | 4 (3) | 0 |
| <100 | 0 | 0 | 0 |
| Note: LLN=404 cells/mcL. |  |  |  |

## Course 1:CD56+ NK Cells

**Decrease during treatment**
**Mean % changes at nadir**
** ****42% in alefecept group N=296**
** ****33% in the placebo group N=153**
**Mean NK cell counts returned to baseline by 12 weeks post dosing**

## Number of Patientsa with Study Drug Substituted by Placebo

|  |  | Drug/drug
Course1 Course2 |  | Plac/drug
Course2 |  |
| --- | --- | --- | --- | --- | --- |
|  |  | 134 | 103 |  | 108 |
| Number of | 1-3               | 14  | 6 |  | 4 |
| Substitutions | 4-6 | 2  | 2 |  | 4 |
|  | 7-9 | 1  | 0 |  | 0 |
|  | 10-11 | 0 | 0 |  | 0 |
| Total |  | 17 | 8 |  | 8 |

**a**** Number of patients receiving all 12 injections.**

## Study C711: Efficacy Conclusions

**Alefacept superior  to placebo by PASI-75**
**First course: 11% absolute**
**Second course: 15% (course 1 baseline); **
**6% (course 2 baseline)**
**Body weight **
**Lower treatment response in subjects > 85 kg**
**insufficient data in subjects <50kg**
**DLQI: improvement  in score favors alefacept **

## Study C711: Immunologic Parameters

**Alefacept lowers lymphocytes counts**
**CD4, CD8, affected most**
**CD16/CD56 (NK cells) to a lesser degree**
**Lymphocyte reduction may be cumulative **
**Decrease in CD4 counts weakly associated with treatment response**

## Study C711: Immunologic Parameters

**Lymphocyte counts may not return to baseline for up to 9 months post-treatment**
**Pharmacologic effects potentially greater without appropriate monitoring**
**CD4 counts >250 before dosing**

## Study C99-712

**Phase 3 Intramuscular Dosing Study**

## Study C712: Design

**Randomization (1:1:1) to IM placebo, 10 mg,  or 15 mg alefacept (weekly x12 wks), stratified by PASI and prior systemic therapy (N=506)**

## Efficacy Outcomes

|  | Placebo
N=168 | 10 mg
N=173 | 15 mg
N=166 | 95% CI
for  |
| --- | --- | --- | --- | --- |
| Primary |  |  |  |  |
|   -PASI-75 | 9 (5) |  21(12) | 35 (21) | 7, 25% |
| Secondary |  |  |  |  |
| 1) PGA:  almost clear or clear | 8 (5) | 18 (10) | 23 (14) | 1, 18% |
| 2) PASI-50 | 30 (18) | 62 (36) | 68 (41) | 13, 34% |

## Number of Treatment Respondersa by Body Weight Quartile

| Weight (kg) | Placebo | 10 mg | 15 mg |
| --- | --- | --- | --- |
| <75 | 1 (2)b | 10 (21)  | 12 (22) |
| 75  - <87.2 | 4 (9) | 5 (11) | 10 (21) |
| 87.2- <102 | 3 (7) | 4 (10) | 7 (19) |
| 102+ | 1 (3) | 2 (5) | 6 (22) |

**Number of Treatment Responders****a**** by Body Weight Quartile**

**a**** ********75% improvement in PASI from baseline at 2 weeks post treatment**
**b ****N (%) **

## Relation Between Efficacy and CD4

| Max % Reduction in PASI at any Time | Lowest CD4 at Any Time (cells/mcL) |  |  |
| --- | --- | --- | --- |
|  | <300  | 300-<400 | 400+ |
| <50% | 6 (3%) | 30 (13%) | 190 (84%) |
| 50-<75% | 13 (9%) | 21 (15%) | 103 (75%) |
| 75%+ | 12 (8%) | 25 (17%) | 107 (74%) |

- Spearman correlation r=-0.1.

## Time to Treatment Response

## Duration of Treatment Response

## Observed Mean Changesa in Patient Reported Outcomes

| Mean (SD) | Placebo | 10 mg |  15 mg |
| --- | --- | --- | --- |
| DLQI  | -2.3 (5.7) | -3.4 (5.6) | -5.0 (6.6) |
|  DQOLS Scales |  |  |  |
| Psychosocial | -5 (17) | -7 (16) | -11 (18) |
| Activities | -3 (15) | -5 (14) | -9 (18) |
| Symptoms | -6 (20) | -11 (17) | -16 (21) |

**a****Two weeks post treatment compared to pretreatment**

## Subjects with Low CD4+ T Cell Counts at Any Time

|  | Placebo | 10mg | 15mg |
| --- | --- | --- | --- |
| <400 | 18 (11) | 42 (24) | 47 (28) |
| <300 | 3 (2) | 13 (8) | 15 (9) |
| <200 | 0 | 3 (2) | 4 (2) |
| <100 | 0 | 0 | 0 |
| Note: LLN=404 cells/mcL. |  |  |  |

## Subjects with CD4 and CD8  Cell Count <LLNa on Last Visit

|  |    Placebo |        10mg |       15mg   |
| --- | --- | --- | --- |
| CD4  | 1 (<1) | 14 (8) | 13 (8) |
| CD8 | 14 (8) | 35 (20) | 35 (21) |
| LLN=404 cells/mcL for CD4 and 220 cells/mcL for CD8. |  |  |  |

## Study C712: Efficacy Conclusions

**Compared to placebo:**
**15 mg group is superior (15%)**
**10 mg group intermediate activity**
**Response for body weight >85 kg is lower than that for bw ********85 kg in 10 mg dose group**
**Association between efficacy and reduction in CD4 counts weak**

## Study C712: Efficacy Conclusions

_**For Patients Who Responded at any Time**_
**Median time to response near end of the 84-day dosing period **
**90 days approximately for both alefacept and placebo groups**
**Median duration of response **
**64 days for alefacept**
**40 days for placebo**

## Study C712: Safety Conclusions

**Alefacept induced decreases in CD4 and CD8 cell counts that persisted until end of study in some patients**
**4% of subjects developed low titer anti-alefacept antibodies**

## Integrated Summary of Safety

## Toxicology Studies in Cynomolgus Monkeys

**Study of 0, 1, 20 mg/kg (3/sex/group)**
**One year weekly dosing and recovery**
**One B-cell lymphoma at 20 mg/kg**
**Similar toxicities observed at 1 and 20 mg/kg**
**No non-toxic dose identified**

## Serious Infections in Course 1

| No. dosed  | Placebo (413) | Alefacept (876) |
| --- | --- | --- |
| No. with serious infection  | 1 (0.24%)  | 8 (0.91%)  |
|  Cellulitis | 0 | 3 |
| Abscess  | 0 | 1 |
| Wound Infection  | 0 | 1 |
|  Gastroenteritis  | 0 | 2 |
| Asthma (viral URI)  | 0 | 1 |
| Bronchitis | 1 | -- |

## Malignancies in Course 1

| No. dosed  | Placebo
413  | Alefacept
876  |
| --- | --- | --- |
| No. with malignancy  | 2 (0.50%)  | 10 (1.1%)  |
| Skin carcinoma  | 1(BCC) | 6
(2 BCC; 4 SCC) |
| Skin Melanoma  |  | 1 |
| Renal cell ca  |  | 1 |
| Testicular ca  |  | 1 |
| Prostatic ca  | 1 | 1  |

## Incidence During Treatment ofAnti-alefacept Antibodies

**Phase 2 IV study (708) and Pivotal IV study (711): **
**6 patients (<1 %) first developed antibodies during treatment **
**highest titer 1:160**
**Pivotal IM study: **
**14 patients (4%) developed antibodies **
**highest titer 1:40**
**	****	**

## Overall Conclusions

**Efficacy and Safety of Alefacept**

## Alefacept Efficacy

**Responders compared to placebo**
**PASI-75: 10-15% higher**
**PASI-50: ****~**** 25% higher**
**Median Time to response , approximately**
**90 days (IV, IM)**
**Median duration of response, approx**
**105 days (IV); 64 days (IM)**

## Reduced Lymphocyte Numbers

**Phenotypes with higher levels of CD2 expression affected most**
**T cells with memory phenotype**
_**+**_**NK cells **
**Reduction may be cumulative with additional therapy cycles**
**Recovery to normal levels and/or to baseline slow and/or incomplete**
**Incomplete data beyond second cycle**

## Reduced Lymphocyte Numbers (cont.d)

**Reduction in CD4 and CD8 T cells of magnitude likely to impact on immune defense**
**Decreased DTH responses**
**Trends in increased incidence of infections and malignancies**
**Small database to assess risk**

## Reduced Lymphocyte Numbers (cont.d)

**Reduction may be potentially greater without strict monitoring**
**Drug withheld if CD4 count <250/mcL**
**Non-circulating T cell pool not evaluated in humans**

## Additional Clinical Data Needed

**Long-term monitoring of immune function using clinical and laboratory assessments **
**Large scale, long-term studies to assess risk of infection and neoplasms**
**Safety and efficacy in children**