# Presentation: 686613

## RaptivaTM (efalizumab)Safety

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

## Outline

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

## Raptiva

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

## 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

## 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 |

## Placebo vs. Raptiva Patient-years

- Placebo

- Raptiva

- 186 patient-years

- 1790 patient-years

- (n = 762*)

- (n = 2762)

- Patient-years exposure

**Placebo vs. Raptiva Patient-years**

- * 715 from phase III and 47 from phase II

## Outline

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

## Common Adverse Events during Placebo-controlled Period

|  |  | 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.

## Acute Adverse Reactions

- % of subjects

- Headache, fever, chills, nausea/vomiting, or myalgia occurring within 48 hours of a Raptiva injection

- Weeks

- Placebo-controlled period from all Phase III controlled studies

## Serious Adverse Events during Placebo-controlled Period

|  |  | 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% | <0.1% | 0.5% |
| Kidney calculus | 0.0% | 0.2% | 0.2% |
| Accidental injury | 0.0% | <0.1% | 0.2% |
| Atrial fibrillation | 0.0% | <0.1% | 0.2% |
| Coronary artery disease | 0.0% | <0.1% | 0.2% |
| Gastroenteritis | 0.1% | <0.1% | 0.2% |
| Pneumonia | 0.0% | 0.2% | 0.0% |
| Skin carcinoma | 0.1% | 0.2% | 0.0% |
| Depression | 0.3% | <0.1% | 0.0% |

- Placebo-controlled period from all Phase III controlled studies

**Serious Adverse Events during Placebo-controlled Period**

## Specific Adverse Events 

- Malignancies
- Infections
- Thrombocytopenia
- Psoriasis and arthritis

## 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.

**Malignancies **Incidence per 100 patient-years

## Infections during Placebo-controlled Period

|  |  | 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

**Infections during Placebo-controlled Period**

## Serious Infections Requiring HospitalizationIncidence 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

## 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

## 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

## Six Cases of Possible Drug-inducedImmune 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 Grave’s disease (n=2), viral syndrome (n=3), and other drugs (n=1)
- Physicians and patients should be advised to observe for gum bleeding, petechiae, bruising

## Psoriasis Adverse Events on Treatment

- 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 (< 0.2%) experienced serious adverse event of psoriasis during treatment with Raptiva
- 4 events were erythrodermic psoriasis
- All patients recovered without sequelae

**Psoriasis Adverse Events on Treatment**

## 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

## Outline

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

## 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

- Data from study 2059

- Mean ± SE% PASI improvement

- Study Week

- 12

- 10

- 8

- 6

- 4

- 4

- 2

- 80

- 2

- 12

- 10

- 8

- 6

- Off Treatment

- During Treatment

- 0

- 40

- 20

- 0

- 60

- Raptiva then Placebo

- Placebo

- Washout

- Treatment

## Restricted Use of Other Medications after Treatment with Raptiva

- 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

**Restricted Use of Other Medications after Treatment with Raptiva**

## Psoriasis Adverse Events after Treatment with Raptiva

- Most events were mild to moderate
- Half the events (6.3%) were plaque recurrence
- 14 patients (<1%) 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

**Psoriasis Adverse Events after Treatment with Raptiva**

## Incidence of Psoriasis Adverse Events

|  | 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) |

**Incidence of Psoriasis Adverse Events**

- Patients who entered follow-up period after Raptiva treatment who had at least 2 PASI evaluations from studies 2058, 2059, 2062, and 2142

- Excluding Mild Psoriasis Events (Post-hoc analysis)

## 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

## 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 (<1%) experienced a serious adverse event of arthritis after Raptiva treatment

## Outline

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

## 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 (>2.5X normal)
- Not associated with elevations in LFT’s
- 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

## Outline

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

## Raptiva Extended Treatment Safety Profile

- Week 0-12: patients from controlled studies
- Other weeks: patients from extended treatment studies

| (n = 1620) | (n = 1115) | (n = 318) | (n = 247) | (n = 228) |
| --- | --- | --- | --- | --- |

- Weeks

- % of patients with adverse event

## 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 Raptiva’s long-term safety profile

## Outline

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

## 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