Raptiva

1
Raptiva (efalizumab)Safety

• Richard Chin, MD
• Director of Clinical Research,Specialty
  Biotherapeutics
• Genentech, Inc.

2
Outline

• Overview
• Clinical Adverse Events
• During Treatment
• After Treatment
• Laboratory Findings
• Extended Treatment Safety Data
• Summary

3
Raptiva

• Large safety database
• Low overall rate of serious adverse events
• Well tolerated
• Favorable extended treatment safety profile

4
Raptiva Safety Database is Extensive

• 2762 patients with moderate-to-severe psoriasis
  treated with Raptiva
• More than 900 patients treated with Raptiva for 6
  months or longer
• More than 200 patients treated with Raptiva for
  one year or longer
• 1790 patient-years of experience in Raptiva
  treated patients

Data based on BLA submitted to FDA
5
Raptiva Psoriasis Studies
Phase Study Number Route Study Design Number of Patients Enrolled
III 2390 SC Placebo-controlled Double-blind Randomized 556
III 2600 SC Placebo-controlled Double-blind Randomized 686
III 2058 SC Placebo-controlled Double-blind Randomized 498
III 2059 SC Placebo-controlled Double-blind Randomized 597
III 2062 SC Open-label Retreatment 536
III 2243 SC Open-label Long-term 339
III 2391 SC Open-label Follow-Up to 2390 516
II HUPS252 IV Placebo-controlled Double-blind Randomized 145
I HU9602 IV Open-label Single Dose 31
I HUPS249 IV Open-label Multiple Dose 39
I HUPS254 SC Open-label Single and Multiple Dose 57
I HUPS256 SC/IV Open-label Randomized 77
I 2142 SC Open-label PK 70
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Placebo vs. Raptiva Patient-years
1790 patient-years
Patient-years exposure
186 patient-years
Placebo
Raptiva
(n 762)
(n 2762)
715 from phase III and 47 from phase II
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Outline

• Overview
• Clinical Adverse Events
• During Treatment
• After Treatment
• Laboratory Findings
• Extended Treatment Safety Data
• Summary

8
Common Adverse Events during Placebo-controlled
Period
Raptiva Raptiva
Placebo(n 715) 1 mg/kg(n 1213) 2 mg/kg(n 407)
Patients with at least one adverse event 73.6 82.4 87.0
Headache 22.2 32.2 37.1
Chills 4.5 12.7 13.0
Pain 5.3 10.1 11.1
Fever 3.4 6.6 11.3
Flu syndrome 4.1 6.8 4.7
Nausea 7.1 10.6 13.8
Myalgia 4.9 8.4 7.9
Adverse events occurring in at least 5 of
placebo or 1 mg/kg patients, and at least 2
more often in the 1 mg/kg group. Data from
controlled studies.
9
Acute Adverse Reactions
Headache, fever, chills, nausea/vomiting, or
myalgia occurring within 48 hours of a Raptiva
injection
of subjects
Weeks
Placebo-controlled period from all Phase III
controlled studies
10
Serious Adverse Events during Placebo-controlled
Period
Raptiva Raptiva
Placebo (n 715) 1 mg/kg (n 1213) 2 mg/kg (n 407)
Patients with at least one serious adverse event 1.7 2.0 2.9
Cellulitis 0.0 lt0.1 0.5
Kidney calculus 0.0 0.2 0.2
Accidental injury 0.0 lt0.1 0.2
Atrial fibrillation 0.0 lt0.1 0.2
Coronary artery disease 0.0 lt0.1 0.2
Gastroenteritis 0.1 lt0.1 0.2
Pneumonia 0.0 0.2 0.0
Skin carcinoma 0.1 0.2 0.0
Depression 0.3 lt0.1 0.0
Placebo-controlled period from all Phase III
controlled studies
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Specific Adverse Events

• Malignancies
• Infections
• Thrombocytopenia
• Psoriasis and arthritis

12
Malignancies Incidence per 100 patient-years
Placebo Raptiva
All Malignancies 1.62 (3/185 pt-yr) 1.68 (30/1782 pt-yr)
NMSC 1.08 (2/186 pt-yr) 1.12 (20/1784 pt-yr)
Melanoma 0.00 (0/186 pt-yr) 0.06 (1/1791 pt-yr)
Solid Tumor 0.54 (1/186 pt-yr) 0.45 (8/1790 pt-yr)
Lymphoma 0.00 (0/186 pt-yr) 0.06 (1/1791 pt-yr)
All studies, all periods. Some patients had more
than one malignancy.
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Infections during Placebo-controlled Period
Raptiva Raptiva
Placebo (n 715) 1 mg/kg (n 1213) 2 mg/kg (n 407)
Any diagnosis of infection 26.3 28.9 28.0
Miscellaneous infection 15.4 13.7 14.5
Herpes simplex 3.4 4.0 6.1
Urinary tract infection 1.3 1.6 2.0
Bronchitis 1.3 2.2 1.0
Viral infection 1.1 2.2 0.7
Gastroenteritis 3.4 2.4 1.2
Bacterial infection 0.6 1.2 1.0
Otitis media 1.3 1.5 1.2
Fungal dermatitis 0.1 0.4 2.2
Cellulitis 0.4 0.7 1.0
Fungal infection 0.0 0.5 0.2
Furunculosis 0.4 0.3 0.7
Placebo-controlled period from all Phase III
controlled studies
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Serious Infections Requiring HospitalizationIncid
ence per 100 patient-years
Placebo Raptiva External psoriasis cohort
Incidence Rate 1.18(2/169 pt-yrs) 1.61(27/1681 pt-yrs) 1.8(73/4056 pt-yrs)
95 CI 0.13 3.89 1.06 2.34 1.41 2.27
Saskatchewan Health claim database
All patients, all studies
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Infections

• There were no deaths attributed to an infection
• Less than 1 discontinued treatment for a serious
  or non-serious infection
• In most cases, Raptiva was continued or was held
  for 1-2 doses during an infection

16
Other Infections

• One case of legionella recovered without
  sequelae
• Not observed tuberculosis, pneumocystis carinii
  pneumonia, histoplasmosis, toxoplasmosis,
  Mycobacterium avium complex, etc.
• Rare reports of serious infections, such as
  vertebral osteomyelitis and severe sinusitis

All studies, all periods
17
Six Cases of Possible Drug-inducedImmune
Thrombocytopenia

• All platelet counts rapidly returned to baseline
  with Raptiva discontinuation corticosteroid
• Nadir platelet counts between 3,000 and 52,000
• Causality unclear
• In four of the six cases, potential other causes
  of thrombocytopenia included Graves disease
  (n2), viral syndrome (n3), and other drugs
  (n1)
• Physicians and patients should be advised to
  observe for gum bleeding, petechiae, bruising

18
Psoriasis Adverse Events on Treatment

• 1.4 of placebo and 3.2 of Raptiva treated
  patients experienced psoriasis adverse event
  during the placebo-controlled period
• The psoriasis adverse event rate declined over
  time
• Most frequent event was mild to moderate guttate
  psoriasis
• Less than 0.5 of the patients discontinued
  Raptiva due to a psoriasis adverse event
• 5 patients (lt 0.2) experienced serious adverse
  event of psoriasis during treatment with Raptiva
• 4 events were erythrodermic psoriasis
• All patients recovered without sequelae

19
Arthritis Adverse Events during
Placebo-controlled Period
Placebo (n 715) 1 mg/kg (n 1213) 2 mg/kg (n 407)
16 (2.2) 29 (2.4) 16 (3.9)
Most events were mild to moderate in
severity Most of these patients had prior history
of arthritis
Placebo-controlled period from all Phase III
controlled studies
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Outline

• Overview
• Clinical Adverse Events
• During Treatment
• After Treatment
• Laboratory Findings
• Long-term Safety Data
• Summary

21
Psoriasis during Withdrawal of Raptiva

• Effects of Raptiva on immune function are
  reversible
• In general, most patients return gradually to
  baseline/near baseline after Raptiva treatment

Raptiva then Placebo
Placebo
80
Washout
Treatment
60
Mean SE PASI improvement
40
20
0
12
10
8
6
4
4
2
2
12
10
8
6
0
Off Treatment
During Treatment
Study Week
Data from study 2059
22
Restricted Use of Other Medications after
Treatment with Raptiva

• Raptiva clinical studies imposed rigorous
  criteria during the follow-up period after
  Raptiva treatment
• Immediate transition to systemic therapies was
  prohibited
• Raptiva was discontinued without tapering
• Initially, use of other psoriasis therapies was
  restricted, even if the patient started
  experiencing return of psoriasis

23
Psoriasis Adverse Events after Treatment with
Raptiva

• 13 of the patients experienced psoriasis adverse
  events after treatment
• Most events were mild to moderate
• Half the events (6.3) were plaque recurrence
• 14 patients (lt1) experienced a serious adverse
  event of psoriasis after Raptiva treatment (0.5
  during the formal 12 week follow-up period)
• Most events occurred in non-responders
• Most events occurred in patients receiving more
  than 1 mg/kg
• Types of serious adverse events 5 erythrodermic,
  5 pustular, 1 erythrodermic/pustular, 3 flare
• All patients recovered

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Incidence of Psoriasis Adverse Events
Excluding Mild Psoriasis Events (Post-hoc
analysis)
Rate
No psoriasis medication 15.1 (75/497)
Medium potency topical steroids 5.2 (15/290)
High potency topical steroids 1.1 (2/182)
UVB 2.8 (2/71)
Vitamin D derivative 1.0 (1/102)
Systemic retinoids 0.0 (0/24)
Cyclosporine 0.0 (0/54)
Methotrexate 1.3 (1/77)
Patients who entered follow-up period after
Raptiva treatment who had at least 2 PASI
evaluations from studies 2058, 2059, 2062, and
2142
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Raptiva Discontinuation Summary

• There were psoriasis adverse events after Raptiva
  therapy, 14 of which were serious
• Patients should be observed carefully after
  treatment
• Transition to other therapies should be
  considered at discontinuation

26
Arthritis Adverse Events after Treatment

• 4.9 of patients experienced an adverse event of
  arthritis after Raptiva treatment
• In the 1 mg/kg group, 3.7 of the patients
  experienced arthritis adverse events after
  treatment
• 7 patients (lt1) experienced a serious adverse
  event of arthritis after Raptiva treatment

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Outline

• Overview
• Clinical Adverse Events
• During Treatment
• After Treatment
• Laboratory Findings
• Extended Treatment Safety Data
• Summary

28
Laboratory Findings

• Leukocytosis due to demargination, reversible on
  cessation of Raptiva
• Mild elevation of alkaline phosphatase (mean
  elevation of 6.9 U/L in the 1 mg/kg group)
• No patients with Grade 2 evelvations (gt2.5X
  normal)
• Not associated with elevations in LFTs
• Not associated with clinical findings
• Mild elevation of C-reactive protein (mean
  elevation of 0.4 mg/dL in the 1 mg/kg group)
• Not associated with clinical findings
• No sign of hepatic or renal toxicity

29
Outline

• Overview
• Clinical Adverse Events
• During Treatment
• After Treatment
• Laboratory Findings
• Extended Treatment Safety Data
• Summary

30
Raptiva Extended Treatment Safety Profile
of patients with adverse event
(n 1620) (n 1115) (n 318) (n 247) (n 228)
Weeks
Week 0-12 patients from controlled studies Other
weeks patients from extended treatment studies
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Extended Treatment Safety

• No new safety signals observed in the extended
  studies
• No increase in rate of individual adverse events
• Genentech is committed to a phase IV surveillance
  study to further characterize Raptivas long-term
  safety profile

32
Outline

• Overview
• Clinical Adverse Events
• During Treatment
• After Treatment
• Laboratory Findings
• Long-term Safety Data
• Summary

33
Summary of Clinical Safety

• Most common adverse events were mild flu-like
  symptoms
• Low rate of serious adverse events and
  malignancies, similar to placebo
• Low rate of serious infections, similar to
  expected background rate
• Infrequent and reversible thrombocytopenia
• Uncommon and manageable psoriasis adverse events
• No evidence of hepatic or renal toxicity
• Favorable extended treatment safety profile