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
3Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
4Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
5Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
6Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
8Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
9Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
Phase 1 Studies in Patients with Phase 1 Studies in Patients with PsoriasisPsoriasis
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
10Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
Phase 1 Studies in Patients with Phase 1 Studies in Patients with PsoriasisPsoriasis
Phase 1 Studies in Patients with Phase 1 Studies in Patients with PsoriasisPsoriasis
• 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)
Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
12Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
Study 2390Study 2390Study 2390Study 2390
Phase 3 study of to-be-marketed efalizumab
Phase 3 study of to-be-marketed efalizumab
14Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
15Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
16Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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)
17Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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.
18Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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%
19Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
20Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
21Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
22Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
% 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)
23Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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%)
Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
RetreatmentRetreatmentRetreatmentRetreatment
Study 2058Study 2058
25Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
26Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
27Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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%)
28Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
Long-term Continuous Long-term Continuous TreatmentTreatment
Long-term Continuous Long-term Continuous TreatmentTreatment
29Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
Long-term Continuous Long-term Continuous TreatmentTreatment
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
30Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
Study Design: 2059Study Design: 2059Study Design: 2059Study Design: 2059
31Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
32Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
33Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
Study Design: 2059Study Design: 2059Study Design: 2059Study Design: 2059
34Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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%)
35Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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.
Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
Integrated Summary of SafetyIntegrated Summary of SafetyIntegrated Summary of SafetyIntegrated Summary of Safety
37Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
38Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
39Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
40Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
41Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
42Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
43Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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%)
44Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
45Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
46Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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.
47Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
48Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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)
49Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
50Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
51Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
52Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
53Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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)
54Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
55Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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)
56Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
57Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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%
58Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
59Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
60Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
61Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
62Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
63Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
64Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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)
65Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
ConclusionsConclusionsConclusionsConclusions
Efficacy and Safety of Efalizumab
Efficacy and Safety of Efalizumab
67Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
68Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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.
69Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
70Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
71Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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)
72Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
73Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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
74Dermatologic and Ophthalmic Drugs Dermatologic and Ophthalmic Drugs Advisory Committee Advisory Committee September 9, 2003
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