# Presentation: 879593

## Biologic License Application STN BL 125075/0: Efalizumab for the Treatment of Chronic Plaque Psoriasis 

**Dermatologic and Ophthalmic Drugs Advisory Committee Meeting **
**September 9, 2003**

**Center for Drugs Evaluation and Research**** **

## Proposed Indication

**  ****Efalizumab for the treatment of adult patients with moderate to severe plaque psoriasis**

## Proposed Dose, Route and Mode of Use

**1 mg/kg/wk SC**
**Long-term continuous treatment**

## 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

**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 and 2 Studies in Patients with Psoriasis**

## Phase 1 and 2: Efalizumab in Moderate to Severe Psoriasis

| Study | Dose mg/kg, route | Duration
treatment | Number
Treated |
| --- | --- | --- | --- |
| HU9602 | 0.03-10 IV |    1 wk |     31 |
| HUPS249 | 0.1-1 IV |    7 wk |     39 |
| HUPS252 | 0.1-0.3 IV |    8 wk |     97 |
| HUPS254 | 0.5-2 SC |    1- 8 wk |     52 |
| HUPS256 | 0.3-1 IV, 
1-4 SC |    12 wk |     68 |

## Phase 1 Studies in Patients with Psoriasis

**Dose-dependent infusion reactions (meningismus, headache, nausea, vomiting, fever,chills, myalgia and arthralgia)**
**Infusion reactions more common after the first dose******** “first dose” effect**

## Phase 1 Studies in Patients with Psoriasis

**The dose-dependent adverse events led to the development of an initial low tolerization dose (0.7 mg/kg SC)**

## Analysis of Phase 3 Clinical Trials

**Four Studies**

## Phase 3: Efalizumab in Moderate to Severe Psoriasis

| Study | Dose mg/kg, route | Treatment Duration
(wks) | n |
| --- | --- | --- | --- |
| 2058 (XOMA) | 1, 2; SC |    12-24  |    498 |
| 2059 (XOMA>GNE) | 1, 2; SC |    12-24 |    597 |
| 2390 (GNE) | 1, SC |    12  |    555 |
| 2600 (GNE) | 1, SC |    12  |    685 |

## Study 2390

**Phase 3 study **
**of to-be-marketed efalizumab**

## Study 2390

**Double blind, placebo-controlled, parallel group, multi-center **
**Dose: efalizumab 1 mg/kg/wk SC for 12 weeks**
**Randomization 2:1 (active: placebo)**
**Stratification by baseline PASI and history of systemic anti-psoriatic therapy **

## Efficacy Endpoints

**Primary endpoint**
**Proportion of patients achieving **_**>**_**75% improvement in PASI at Day 84**
**Principal secondary endpoint**
**Proportion of patients achieving “minimal” or “clear”  by static Physician’s  global assessment (sPGA) at Day 84**

## Study 2390: Key Eligibility 

**Adults (18-70 years) with**** plaque psoriasis ******** 10% BSA and PASI ******** 12**
**Guttate, erythrodermic, pustular psoriasis excluded**
**Psoriasis diagnosed for at least 6 months **
**Clinically stable psoriasis (3 months)**

## Study 2390: Patient Demographics

**556 patients enrolled (placebo: 187 efalizumab: 369)**
**Age: mean 45 years**
**Race: 90% Caucasian**
**Gender distribution: 69% men and 31% women.**

## Study 2390: Baseline Disease

|  | Placebo | Efalizumab |
| --- | --- | --- |
| Psoriasis duration years (mean) | 19 | 19 |
| History prior systemic anti-psoriatic therapy | 74% | 77% |
| PASI score (mean) | 19 | 19 |
| BSA affected (mean) | 27% | 28% |
| sPGA “moderate” to  “very severe” | 93% | 94% |

## Study 2390: Efficacy Results

|  | Placebo | Efalizumab |
| --- | --- | --- |
| PASI  75 * | 4% | 26% |
| PASI  50 * | 14% | 59% |
| sPGA *
“minimal” or “clear” | 3% | 26% |
| *Fisher’s exact p value efalizumab vs. placebo: <0.001 |  |  |

## Mean Change in PASI: 2390

## Study 2390: Efficacy by Subgroup

**Treatment effect present in subgroups defined by **
**gender**
**age **
**baseline PASI score **
**history of systemic therapy **

## % PASI Change from Baseline

## Summary of Treatment Effect: Initial 12-week treatment

| Study | PASI 75 (95% CI) |
| --- | --- |
| 2058 | 37% (28%, 46%) |
| 2059 | 17% (9%, 27%) |
| 2390 | 22% (16%, 29%) |
| 2600 | 21% (15%, 27%) |

## Retreatment

**Study 2058**

## Study Schema: 2058

- Placebo
-  (12 wks)

- Efalizumab
- (12 wks)

- PASI 75

- PASI<75

- PASI75

- E-E
- (12 wks)

- PASI<75

- E-P
- (12 wks)

- E-E
- (12 wks)

- P-E
- (12 wks)

- E-P
- (12 wks)

- P-E
- (12 wks)

- SCRN

- OBSV

- OBSV

- RT-A

## RT-A: Subject Disposition During Retreatment

| Subject Status | E-P

(n=27) | E-E
1 mg/kg
(n=32) | E-E
2 mg/kg
(n=23) |
| --- | --- | --- | --- |
| Completed 
RT | 8 | 26 | 16 |
| Discontinued RT | 19 | 6 | 7 |

## Retreatment: PASI Response(% Change from Initial Baseline)

|  | Placebo | Efalizumab 
1 and 2 mg/kg/wk |
| --- | --- | --- |
|  | n=27 | n=55 |
| >75% | 0 | 17 (31%) |
| >50% | 5 (19%) | 37 (67%) |
| 0-50% | 2 (7%) | 4 (7%) |
| <0% | 1 (4%) | 1 (2%) |
| Missing | 19 (70%) | 13 (24%) |

## Long-term Continuous Treatment

## Long-term Continuous Treatment

**Long term (6 months or greater) continuous treatment: evaluated in a randomized placebo-controlled fashion in Studies 2058 (n=498) and 2059 (n=597)**
**Study 2059: extended treatment for responders as well patients who did not achieve a PASI 75 during the first 12 weeks**
** **

## Study Design: 2059

## Extended Treatment in Responders (ET-AR): Maintenance of PASI 75

|  | Efalizumab/
Placebo | Efalizumab/
Efalizumab * |
| --- | --- | --- |
|  | n=40 | n=79 |
| PASI 75 | 8 (20%) | 61 (77%) |
| PASI <75 | 32 (80%) | 19 (23%) |

- *2 mg/kg weekly or every other week

## Extended treatment in Responders (ET-AR): Relapse

|  | Efalizumab/
Placebo | Efalizumab/
Efalizumab* |
| --- | --- | --- |
|  | n=40 | n=79 |
| Relapsed | 27 (67%) |  6 (8%) |
| Did not relapse | 13 (33%) |  73 (92%) |

- *2 mg/kg weekly or every other week

## Study Design: 2059

## Extended Treatment in Non-responders: 2059

|  | Efalizumab/
Placebo | Efalizumab/
Efalizumab
(4 mg/kg/wk) |
| --- | --- | --- |
|  | n=59 | n=118 |
| PASI 75 | 1 (1.7%) | 15 (12.7%) |
| PASI <75 | 58 (98.3%) | 103 (87.3%) |

## Efficacy of Extended Treatment 

**Among treatment responders, extended treatment with efalizumab beyond the initial 12 weeks maintained PASI 75 in 77% of patients vs. 20% of patients re-randomized to placebo.**
**In non-responders (Day 84 PASI<50), treatment with an additional 12 weeks of efalizumab 4 mg/kg/wk, captured an additional 11% of PASI 75 responders.**

## Integrated Summary of Safety

## Safety Database: Efalizumab Exposure in Psoriasis Trials

**Total exposed: 2762**
**Approximately 2400 treated weekly for 12 weeks, 939 treated weekly for 24 weeks and 218 for 1 year**
**1620 received efalizumab in placebo-controlled portion of the four phase 3 studies**

## Deaths in Efalizumab-treated Patients

**No deaths in first 12 weeks of placebo controlled studies**
**7 deaths in safety database (2762 patients)**
**Two during efalizumab treatment, 5 after treatment**
**Causes: metastatic rectal cancer (1), cardiac (3), accidental (1), cirrhosis (1), unknown (1)**
**None attributed to efalizumab **
**None attributed to infection**

## Serious Infections: First 12 Weeks of Controlled Trials 

|  | Placebo 
(n=715) | Efalizumab (n=1620) |
| --- | --- | --- |
| No. with serious infection  | 1 (0.1%)  | 7 (0.4%)  |
|   Cellulitis | 0 | 3 |
|   Sepsis | 0 | 1 |
|   Gastroenteritis | 1 | 2 |
|   Pneumonia | 0 | 2 |

## Incidence of Serious Infections 

| Treatment group | Events | Subject years | Incidence per 100 subject years | 95% CI |
| --- | --- | --- | --- | --- |
| efalizumab | 27 | 1680 | 1.6 | 1.1, 2.3 |
| placebo | 2 | 169 | 1.2 | 0.1, 4.3 |

## Serious Infections: Controlled Clinical Experience

**Pneumonia in a 74-year-old efalizumab-treated man preceded by a decrease in absolute neutrophil count to 600/mm****3**** from normal baseline value**

## Serious Infection: Opportunistic Infection

***Legionella***** pneumonia (one case)**
**41 year-old woman**
**History of tobacco use, no concomitant medications**
**Efalizumab (2 mg/kg/wk for 12 wks) **
**Multiple complications, survived**

## Malignancies: First 12 Weeks of Controlled Trials

|  | Placebo
(n=715) | Efalizumab
(n=1620) |
| --- | --- | --- |
| Total | 2 (0.3%) | 2 (0.1%) |
| Gastrointestinal | 1 (0.1%) | 0 |
| Skin Carcinoma | 1 (0.1%) | 2 (0.1%) |

## Malignancies Efalizumab-treated Patients: Observed vs. Expected

| Malignancy category | Observed (95% CI) | Observed subject years | External Cohort | Expected
(95% CI) |
| --- | --- | --- | --- | --- |
| Solid Tumor |   8 (3, 16) | 1790 | SH *
UHC †
SEER ‡  | 7 (4, 12)
5 (2, 8)
8 (NA) |
| Melanoma |   1 (0, 6) | 1790 | SH *
SEER ‡  | 0.4 (0, 2.3)
0.4 (NA) |

*******Saskatchewan Health,****†**** United Health Care**
**‡**** ****Surveillance, Epidemiology End Results**

## Lymphoproliferative Malignancies

**Two EBV negative malignancies, both in efalizumab-treated patients**
**Hodgkin’s disease (nodular sclerosing type) in a 37 year-old man; efalizumab 29 mg/kg over 5 mo.**
**B cell lymphoma in a 57 year-old man; efalizumab 1 mg/kg/wk for 2 yrs**

## PTLD in Renal Transplant Trial of Efalizumab

**PTLD: 3 cases in 38 renal transplant patients; all in the 2 mg/kg/wk x 12 dose (n=19)**
**One resulted in death, judged by the investigator as related to efalizumab**
**All cases were in patients on concomitant immunosuppressive therapy: cyclosporine, MMF and prednisone.**

## Observed vs. Expected Rates of Lymphomas

| Efalizumab-
Number Observed |    External Cohort-
   Number Expected |
| --- | --- |
|   2 (0.24,7.22) | SEER*: 0.9
SH†: 3.7 (1.5, 7.7)
UHC‡: 2.9 (1.1, 6.2) |

******* ****Surveillance, Epidemiology     End Results**** **
**†**** ****Saskatchewan Health**** **
**‡**** ****United Health Care**

## Observed vs. Expected Rates of Non-melanoma Skin Cancer

| Efalizumab-observed | External Cohort-
expected |
| --- | --- |
| 20 (12,31) 
 | SH: 7 (4, 11)
UHC: 7 (4, 11) |

## Psoriasis Flares Requiring Hospitalization

**19 patients (0.7%) in  safety database experienced serious psoriasis flares **
**17 of these patients hospitalized for psoriasis**
**Serious psoriasis flares occurred during treatment or after treatment discontinuation**

## Psoriasis Adverse Events 

| Adverse Event | Placebo 
(715) | Efalizumab 
(1620) |
| --- | --- | --- |
| All psoriasis AE’s | 10 (1.4%) | 52 (3.2%) |
|   Erythroderma | 0 | 9  |
|   Pustular | 0 | 4  |
|   Guttate | 2  | 19  |
|   Plaque | 6  | 9  |
|   Unusual
  morphology | 2  | 6  |
|   Inverse | 0 | 5 |
|   Palmo-plantar | 0 | 4 |

## Arthritis Serious Adverse Events 

**15 cases: 0.6% of efalizumab-treated patients **
**Other inflammation-associated findings (e.g. peripheral edema, fever, positive ANA) **
**No cases during first 12 weeks of  placebo-controlled trials**

## Arthritis-related Adverse Events

_**All arthritis AEs**_**: 2.8% (45/1607) in efalizumab and 2.2% (16/715) in placebo**
_**Severe arthritis AEs**_**: 0.6% (n=9) in efalizumab and 0.3% (n=2) in placebo **

## Other Inflammation Related Serious Adverse Events

**In 2500 efalizumab-treated patients:**
**Interstitial pneumonitis (2 patients)**
**Serum sickness-like reaction (1 patient)**
**Transverse myelitis (1 patient)**
**Idiopathic hepatitis (1 patient)**

## Thrombocytopenia

**8 patients with platelets < 52,000 /mm****3**
**2 of 8 with platelets ******** 10,000 /mm****3**
**5 of 8 patients hospitalized (SAE’s)**
**One case identified retrospectively; diagnosed with prostate cancer**

## Thrombocytopenia: Patient Characteristics

**Ages: 29-71**
**4 men, 4 women**
**Concomitant medical conditions: **
**Pre-existing ITP (1 patient) **
**Grave’s disease  (2 patients)**

## Thrombocytopenia: SAEs 

**All 5 treated with systemic steroids**
**Bone marrow biopsies (n=2): normocellular **
**Events included **
**40 yr-old woman (plt nadir 10,000/mm****3****) **
**   ****heavy GU bleeding, antiplatelet antibody positive, remains on prednisone**
**73 yr-old woman (plt nadir 3,000/mm****3****)  failed prednisone taper; event ongoing**

## Common Adverse Events With Efalizumab Treatment 

|  | Placebo
(N=455) | Efalizumab 
(N=869) |
| --- | --- | --- |
| Headache | 19% | 32% |
| Chills | 4% | 12% |
| Flu syndrome | 4% | 9% |
| Pain | 4% | 8% |
| Fever | 2% | 6% |
| Nausea | 6% | 10% |
| Myalgia | 5% | 9% |

## Clinical Laboratory Changes with to-be-marketed Efalizumab 

## Effects of Efalizumab on WBC

**Mean WBC increased  30%- 40% from baseline**
**Mean lymphocyte counts doubled**
**Mean eosinophil counts increased 50%**
**Mean neutrophil counts  increased slightly**

## Change in Alkaline Phosphatase (U/L) from Baseline

|  | PBO | Efalizumab 1 mg/kg | Efalizumab 2 mg/kg |
| --- | --- | --- | --- |
| First 12-weeks/
Controlled Trials | n=432 | n=842 | n=60 |
|  | - 1.03 | 5.29 | 9.57 |

## Alkaline Phosphatase Levels

**Mean level higher in efalizumab group than placebo **
**Patients with shift to high post baseline values: 4.0% in efalizumab (32/802) vs. 0.5% (2/416) in placebo**
**Liver, intestinal isoenzymes affected**
**Clinical significance not understood**

## Shift to >ULN in Liver Function Tests*

| No. shifting to high | Placebo
(n=604) | Efalizumab
(n=1374) |
| --- | --- | --- |
| None | 93% | 88% |
| One  | 5.1% | 8.7% |
| Two | 1.5% | 3.1% |
| Three  | 0.3% | 0.6% |
| * Alkaline phosphatase, SGPT, SGOT, LDH, and total bilirubin |  |  |

## Effect of Efalizumab on Markers of Inflammation

**Acute phase reactants higher in efalizumab than placebo **
**C reactive protein **
**Fibrinogen **
**Thrombocythemia**

## C-Reactive Protein Mean Changes from Baseline: Study 2600

|  | Baseline (min-max)  | Day 84 (min-max)  | Change (max)  |
| --- | --- | --- | --- |
| Placebo (n=216)  | 0.6 
(0.4-8.9)  | 0.7 
( 0.4-7.0)  | 0.09 
(6.6)  |
| Efalizumab (n=425)  | 0.6 
(0.4-5.4)  | 1.0  
(0.4-22)  | 0.40 
(22)  |

## Anti-efalizumab Antibodies

**Incidence: 67/1063 (6.3%) patients with post-washout samples**
**Median exposure:  167 days**
**Anti-efalizumab antibody positive patients: 20% achieved a PASI 75 and 53% achieved a PASI 50**

## Conclusions

**Efficacy and Safety of Efalizumab**

## Efalizumab Efficacy

**Treatment Response**
**PASI 75: 17% - 37%**
**PASI 50: 36% - 46%**
**sPGA: 16% - 29%**
**Median time to response in PASI 75 responders: 2 months**
**Median duration of response (loss of 50% improvement post-treatment): 67 days**

## Efalizumab Efficacy

**PASI 75 maintained in 77% (61/79) of responders randomized to efalizumab compared to 20% (8/40) of responders randomized to placebo. **
**Efalizumab shows relatively limited ability to recapture PASI 75 response upon relapse**
**31% (17/55) responded with retreatment upon relapse.**

## Efalizumab Safety

**No deaths in the controlled portion of clinical trials**
**No deaths linked causally to the use of efalizumab in psoriasis trials**

## Malignancies

**Solid tumors and melanoma in  efalizumab-treated patients comparable to external cohorts **
**Lymphoproliferative malignancies higher than expected by SEER database and lower compared SH and UHC**
**NMSC: higher than expected based on external cohorts**

## Efalizumab Safety

**Serious infections: higher in efalizumab-treated patients than placebo (0.4% vs. 0.1%)**
**One opportunistic infection, *****Legionella***** pneumonia**
**One infection, pneumonia,  associated with new onset decrease in ANC**
**Serious uncommon (19, 0.7%) adverse events of psoriasis (including psoriatic erythroderma and pustular psoriasis) **

## Safety Efalizumab

**Rare, inflammatory/autoimmune adverse events: transverse myelitis, interstitial pneumonitis, idiopathic hepatitis, serum sickness-like reaction**
**Thrombocytopenia consisting of platelets < 52,000 cells/mm****3**** in 8 efalizumab-treated patients resulting in hospitalization in 5 patients**

## Laboratory Abnormalities

**Elevated: **
**WBC, lymphocytes, eosinophils **
**alkaline phosphatase**
**LFTs**
**acute phase reactants **

## Potential Areas for Further Study

**Intermittent vs. long-term continuous administration**
**Long-term monitoring of immune function using clinical and laboratory assessments **
**Large scale, long-term studies to assess risk of infection, neoplasms and other adverse events**
**Safety and efficacy in children**