biologic license application stn bl 125075/0: efalizumab for the treatment of chronic plaque...

Biologic License ApplicationBiologic License Application STN BL STN BL 125075/0: Efalizumab 125075/0: Efalizumab for the Treatment of Chronic for the Treatment of Chronic

Plaque Psoriasis Plaque Psoriasis

Biologic License ApplicationBiologic License Application STN BL STN BL 125075/0: Efalizumab 125075/0: Efalizumab for the Treatment of Chronic for the Treatment of Chronic

Plaque Psoriasis Plaque Psoriasis

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

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

Center for Drugs Evaluation and ResearchCenter for Drugs Evaluation and Research

2Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003

Proposed IndicationProposed Indication

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

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


Proposed Dose, Route and Proposed Dose, Route and Mode of UseMode of Use

Proposed Dose, Route and Proposed Dose, Route and Mode of UseMode of Use

• 1 mg/kg/wk SC

• Long-term continuous treatment

• 1 mg/kg/wk SC

• Long-term continuous treatment


PsoriasisPsoriasis PsoriasisPsoriasis

• 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

• 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 ChildrenPsoriasis in ChildrenPsoriasis in ChildrenPsoriasis 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

• 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 SignificancePsoriasis: Clinical SignificancePsoriasis: Clinical SignificancePsoriasis: 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

• Usually not life-threatening

• In 30% of patients moderate to severe disease with significant morbidity

• Decreased quality of life and increased risk of suicide

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

Analysis of Clinical Trials Analysis of Clinical Trials Analysis of Clinical Trials Analysis of Clinical Trials

Phase 1 and 2 Studies in Patients with Psoriasis

Phase 1 and 2 Studies in Patients with Psoriasis


Phase 1 and 2: Efalizumab in Phase 1 and 2: Efalizumab in Moderate to Severe PsoriasisModerate to Severe PsoriasisPhase 1 and 2: Efalizumab in Phase 1 and 2: Efalizumab in Moderate to Severe PsoriasisModerate to Severe Psoriasis

StudyDose mg/kg, route

Durationtreatment

NumberTreated

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

HUPS2560.3-1 IV, 1-4 SC

12 wk 68


Phase 1 Studies in Patients with Phase 1 Studies in Patients with PsoriasisPsoriasis


• Dose-dependent infusion reactions (meningismus, headache, nausea, vomiting, fever,chills, myalgia and arthralgia)

• Infusion reactions more common after the first dose “first dose” effect

• Dose-dependent infusion reactions (meningismus, headache, nausea, vomiting, fever,chills, myalgia and arthralgia)

• Infusion reactions more common after the first dose “first dose” effect




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

• 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 Analysis of Phase 3 Clinical TrialsTrials

Analysis of Phase 3 Clinical Analysis of Phase 3 Clinical TrialsTrials

Four StudiesFour Studies


Phase 3: Efalizumab in Phase 3: Efalizumab in Moderate to Severe PsoriasisModerate to Severe Psoriasis

Phase 3: Efalizumab in Phase 3: Efalizumab in Moderate to Severe PsoriasisModerate to Severe Psoriasis

StudyDose 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 2390Study 2390Study 2390Study 2390

Phase 3 study of to-be-marketed efalizumab

Phase 3 study of to-be-marketed efalizumab


Study 2390Study 2390Study 2390Study 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

• 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 EndpointsEfficacy EndpointsEfficacy EndpointsEfficacy 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

• 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 Study 2390: Key Eligibility Study 2390: Key Eligibility 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)

• 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 DemographicsStudy 2390: Patient DemographicsStudy 2390: Patient DemographicsStudy 2390: Patient Demographics

• 556 patients enrolled (placebo: 187 efalizumab: 369)

• Age: mean 45 years

• Race: 90% Caucasian

• Gender distribution: 69% men and 31% women.

• 556 patients enrolled (placebo: 187 efalizumab: 369)

• Age: mean 45 years

• Race: 90% Caucasian

• Gender distribution: 69% men and 31% women.


Study 2390: Baseline DiseaseStudy 2390: Baseline DiseaseStudy 2390: Baseline DiseaseStudy 2390: Baseline DiseasePlacebo 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 ResultsStudy 2390: Efficacy ResultsStudy 2390: Efficacy ResultsStudy 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: 2390Mean Change in PASI: 2390Mean Change in PASI: 2390Mean Change in PASI: 2390

0 14 28 42 56 70 840

2

4

6

8

10

12

Me

an

Imp

rove

me

nt i

n P

AS

I

Study Day

Placebo Efalizumab


Study 2390: Efficacy by SubgroupStudy 2390: Efficacy by SubgroupStudy 2390: Efficacy by SubgroupStudy 2390: Efficacy by Subgroup

• Treatment effect present in subgroups defined by

– gender

– age

– baseline PASI score

– history of systemic therapy

• Treatment effect present in subgroups defined by

– gender

– age

– baseline PASI score

– history of systemic therapy


% PASI Change from Baseline% PASI Change from Baseline% PASI Change from Baseline% PASI Change from Baseline

-100-80

-60-40

-200

2040

6080

100

Percent Change in PASI (positive = improved)

0

10

20

30

40

50

60N

umbe

r of

Pat

ient

s Placebo (n=175) Efalizumab (n=347)


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

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

Study PASI 75 (95% CI)

2058 37% (28%, 46%)

2059 17% (9%, 27%)

2390 22% (16%, 29%)

2600 21% (15%, 27%)


RetreatmentRetreatmentRetreatmentRetreatment

Study 2058Study 2058


Study Schema: 2058Study Schema: 2058Study Schema: 2058Study Schema: 2058

Placebo (12 wks)

Efalizumab(12 wks)

PASI 75

PASI<75

PASI75

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 RT-A: Subject Disposition During RetreatmentDuring Retreatment

RT-A: Subject Disposition RT-A: Subject Disposition During RetreatmentDuring Retreatment

Subject Status

E-P

(n=27)

E-E1 mg/kg(n=32)

E-E2 mg/kg(n=23)

Completed RT

8 26 16

Discontinued RT

19 6 7


Retreatment: PASI ResponseRetreatment: PASI Response(% Change from Initial Baseline)(% Change from Initial Baseline)Retreatment: PASI ResponseRetreatment: PASI Response(% Change from Initial Baseline)(% 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 Long-term Continuous TreatmentTreatment





• 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

• 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: 2059Study Design: 2059Study Design: 2059Study Design: 2059


Extended Treatment in Extended Treatment in Responders (ET-AR): Responders (ET-AR):

Maintenance of PASI 75Maintenance of PASI 75

Extended Treatment in Extended Treatment in Responders (ET-AR): Responders (ET-AR):

Maintenance of PASI 75Maintenance 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 Extended treatment in Responders (ET-AR): RelapseResponders (ET-AR): Relapse

Extended treatment in Extended treatment in Responders (ET-AR): RelapseResponders (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: 2059Study Design: 2059Study Design: 2059Study Design: 2059


Extended Treatment in Non-Extended Treatment in Non-responders: 2059responders: 2059

Extended Treatment in Non-Extended Treatment in Non-responders: 2059responders: 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 Efficacy of Extended Treatment Efficacy of Extended Treatment 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.

• 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 SafetyIntegrated Summary of SafetyIntegrated Summary of SafetyIntegrated Summary of Safety


Safety Database: Efalizumab Safety Database: Efalizumab Exposure in Psoriasis TrialsExposure in Psoriasis TrialsSafety Database: Efalizumab Safety Database: Efalizumab Exposure in Psoriasis TrialsExposure 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

• 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 Deaths in Efalizumab-treated PatientsPatients

Deaths in Efalizumab-treated Deaths in Efalizumab-treated PatientsPatients

• 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

• 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 Serious Infections: First 12 Weeks of Controlled Trials Weeks of Controlled Trials Serious Infections: First 12 Serious Infections: First 12 Weeks of Controlled Trials 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 Incidence of Serious Infections Incidence of Serious Infections Incidence of Serious Infections

Treatment group

EventsSubject 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 Serious Infections: Controlled Clinical ExperienceClinical Experience

Serious Infections: Controlled Serious Infections: Controlled Clinical ExperienceClinical Experience

• Pneumonia in a 74-year-old efalizumab-treated man preceded by a decrease in absolute neutrophil count to 600/mm3 from normal baseline value

• Pneumonia in a 74-year-old efalizumab-treated man preceded by a decrease in absolute neutrophil count to 600/mm3 from normal baseline value


Serious Infection: Serious Infection: Opportunistic InfectionOpportunistic Infection

Serious Infection: Serious Infection: Opportunistic InfectionOpportunistic 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

• 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 Malignancies: First 12 Weeks of Controlled Trialsof Controlled Trials

Malignancies: First 12 Weeks Malignancies: First 12 Weeks of Controlled Trialsof 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 Malignancies Efalizumab-treated Patients: Observed vs. ExpectedPatients: Observed vs. ExpectedMalignancies Efalizumab-treated Malignancies Efalizumab-treated Patients: Observed vs. ExpectedPatients: 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 Lymphoproliferative MalignanciesMalignancies

Lymphoproliferative Lymphoproliferative MalignanciesMalignancies

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

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 PTLD in Renal Transplant Trial of Efalizumabof Efalizumab

PTLD in Renal Transplant Trial PTLD in Renal Transplant Trial of Efalizumabof 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.

• 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 Observed vs. Expected Rates of Lymphomasof Lymphomas

Observed vs. Expected Rates Observed vs. Expected Rates of Lymphomasof Lymphomas

Efalizumab-Number Observed

External Cohort- Number Expected

2 (0.24,7.22) SEER*: 0.9SH†: 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 Observed vs. Expected Rates of Non-melanoma Skin Cancerof Non-melanoma Skin CancerObserved vs. Expected Rates Observed vs. Expected Rates of Non-melanoma Skin Cancerof Non-melanoma Skin Cancer

Efalizumab-observed

External Cohort-expected

20 (12,31) SH: 7 (4, 11)UHC: 7 (4, 11)


Psoriasis Flares Requiring Psoriasis Flares Requiring HospitalizationHospitalization

Psoriasis Flares Requiring Psoriasis Flares Requiring HospitalizationHospitalization

• 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

• 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 Psoriasis Adverse Events Psoriasis Adverse Events 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 Arthritis Serious Adverse Events Events

Arthritis Serious Adverse Arthritis Serious Adverse Events 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

• 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 Arthritis-related Adverse EventsEvents

Arthritis-related Adverse Arthritis-related Adverse EventsEvents

• 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

• 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 Other Inflammation Related Serious Adverse EventsSerious Adverse Events

Other Inflammation Related Other Inflammation Related Serious Adverse EventsSerious 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)

• In 2500 efalizumab-treated patients:

– Interstitial pneumonitis (2 patients)

– Serum sickness-like reaction (1 patient)

– Transverse myelitis (1 patient)

– Idiopathic hepatitis (1 patient)


ThrombocytopeniaThrombocytopeniaThrombocytopeniaThrombocytopenia

• 8 patients with platelets < 52,000 /mm3

– 2 of 8 with platelets 10,000 /mm3

• 5 of 8 patients hospitalized (SAE’s)

• One case identified retrospectively; diagnosed with prostate cancer

• 8 patients with platelets < 52,000 /mm3

– 2 of 8 with platelets 10,000 /mm3

• 5 of 8 patients hospitalized (SAE’s)

• One case identified retrospectively; diagnosed with prostate cancer


Thrombocytopenia: Patient Thrombocytopenia: Patient CharacteristicsCharacteristics

Thrombocytopenia: Patient Thrombocytopenia: Patient CharacteristicsCharacteristics

• Ages: 29-71• 4 men, 4 women• Concomitant medical conditions:

– Pre-existing ITP (1 patient) – Grave’s disease (2 patients)

• Ages: 29-71• 4 men, 4 women• Concomitant medical conditions:

– Pre-existing ITP (1 patient) – Grave’s disease (2 patients)


Thrombocytopenia: SAEs Thrombocytopenia: SAEs Thrombocytopenia: SAEs Thrombocytopenia: SAEs • All 5 treated with systemic steroids• Bone marrow biopsies (n=2): normocellular • Events included

– 40 yr-old woman (plt nadir 10,000/mm3) heavy GU bleeding, antiplatelet antibody

positive, remains on prednisone– 73 yr-old woman (plt nadir 3,000/mm3)

failed prednisone taper; event ongoing

• All 5 treated with systemic steroids• Bone marrow biopsies (n=2): normocellular • Events included

– 40 yr-old woman (plt nadir 10,000/mm3) heavy GU bleeding, antiplatelet antibody

positive, remains on prednisone– 73 yr-old woman (plt nadir 3,000/mm3)

failed prednisone taper; event ongoing


Common Adverse Events With Common Adverse Events With Efalizumab Treatment Efalizumab Treatment

Common Adverse Events With Common Adverse Events With Efalizumab Treatment 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 Clinical Laboratory Changes with to-be-marketed with to-be-marketed

Efalizumab Efalizumab

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

Efalizumab Efalizumab


Effects of Efalizumab on WBCEffects of Efalizumab on WBCEffects of Efalizumab on WBCEffects 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

• Mean WBC increased 30%- 40% from baseline

• Mean lymphocyte counts doubled

• Mean eosinophil counts increased 50%

• Mean neutrophil counts increased slightly


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

BaselineBaseline

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

BaselineBaseline

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 LevelsAlkaline Phosphatase LevelsAlkaline Phosphatase LevelsAlkaline 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

• 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 Shift to >ULN in Liver Function Tests*Tests*

Shift to >ULN in Liver Function Shift to >ULN in Liver Function Tests*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 Effect of Efalizumab on Markers of InflammationMarkers of InflammationEffect of Efalizumab on Effect of Efalizumab on Markers of InflammationMarkers of Inflammation

• Acute phase reactants higher in efalizumab than placebo

– C reactive protein

– Fibrinogen

• Thrombocythemia

• Acute phase reactants higher in efalizumab than placebo

– C reactive protein

– Fibrinogen

• Thrombocythemia


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

C-Reactive Protein Mean Changes C-Reactive Protein Mean Changes from Baseline: Study 2600from 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 AntibodiesAnti-efalizumab AntibodiesAnti-efalizumab AntibodiesAnti-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

• 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


ConclusionsConclusionsConclusionsConclusions

Efficacy and Safety of Efalizumab

Efficacy and Safety of Efalizumab


Efalizumab EfficacyEfalizumab EfficacyEfalizumab EfficacyEfalizumab 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

• 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 EfficacyEfalizumab EfficacyEfalizumab EfficacyEfalizumab 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.

• 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 SafetyEfalizumab SafetyEfalizumab SafetyEfalizumab Safety

• No deaths in the controlled portion of clinical trials

• No deaths linked causally to the use of efalizumab in psoriasis trials

• No deaths in the controlled portion of clinical trials

• No deaths linked causally to the use of efalizumab in psoriasis trials


MalignanciesMalignanciesMalignanciesMalignancies• 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

• 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 SafetyEfalizumab SafetyEfalizumab SafetyEfalizumab 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)

• 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 EfalizumabSafety EfalizumabSafety EfalizumabSafety Efalizumab

• Rare, inflammatory/autoimmune adverse events: transverse myelitis, interstitial pneumonitis, idiopathic hepatitis, serum sickness-like reaction

• Thrombocytopenia consisting of platelets < 52,000 cells/mm3 in 8 efalizumab-treated patients resulting in hospitalization in 5 patients

• Rare, inflammatory/autoimmune adverse events: transverse myelitis, interstitial pneumonitis, idiopathic hepatitis, serum sickness-like reaction

• Thrombocytopenia consisting of platelets < 52,000 cells/mm3 in 8 efalizumab-treated patients resulting in hospitalization in 5 patients


Laboratory AbnormalitiesLaboratory AbnormalitiesLaboratory AbnormalitiesLaboratory Abnormalities

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

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


Potential Areas for Further StudyPotential Areas for Further StudyPotential Areas for Further StudyPotential 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

• 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

biologic license application stn bl 125075/0: efalizumab for the treatment of chronic plaque...

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