DERMATOLOGIC AND OPHTHALMIC DRUGS
ADVISORY COMMITTEE MEETING

9 SEPTEMBER 2003

 

 

 

RAPTIVAä (Efalizumab)

 

 

 

 

 

 

 

 

 

 

Genentech, Inc.
1 DNA Way
South San Francisco, CA  94080‑4990

 

 

 

 

Available for Public Disclosure without Redaction

 

TABLE OF CONTENTS

 

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1..... EXECUTIVE SUMMARY.......................................................................... ............................................................................................................ 3

1.1.... Proposed Indication....................................................................... .................................................................................................. 4

1.2.... Efficacy........................................................................................ .................................................................................................. 4

1.3.... Safety.......................................................................................... .................................................................................................. 7

1.4.... Conclusions.................................................................................. .................................................................................................. 9

2..... OVERVIEW............................................................................................ .......................................................................................................... 10

2.1.... Background.................................................................................. ................................................................................................ 10

2.2.... Pathophysiology of Psoriasis.......................................................... ................................................................................................ 10

2.3.... Mechanism of Action of Raptiva...................................................... ................................................................................................ 11

3..... PHARMACOLOGY................................................................................. .......................................................................................................... 14

3.1.... Clinical Pharmacology of Raptiva.................................................... ................................................................................................ 14

3.1.1.... Raptiva Pharmacodynamics............................................... .................................................................................... 14

3.1.2.... Raptiva Pharmacokinetics.................................................. .................................................................................... 17

3.1.3.... Raptiva Immunology and Immunocompetence..................... .................................................................................... 19

3.2.... Nonclinical Pharmacology Toxicology Data...................................... ................................................................................................ 20

4..... OVERVIEW OF CLINICAL TRIALS.......................................................... .......................................................................................................... 22

5..... CLINICAL EFFICACY.............................................................................. .......................................................................................................... 26

5.1.... Overview of Study 2390................................................................. ................................................................................................ 26

5.1.1.... Study 2390....................................................................... .................................................................................... 26

5.2.... Supportive Studies Providing Additional Efficacy Data...................... ................................................................................................ 39

5.2.1.... Study 2600....................................................................... .................................................................................... 39

5.2.2.... Study 2058....................................................................... .................................................................................... 40

5.2.3.... Study 2059....................................................................... .................................................................................... 42

5.3.... Comparison of Results in Subpopulations........................................ ................................................................................................ 44

5.4.... Treatment beyond 12 Weeks......................................................... ................................................................................................ 46

5.5.... Clinical Efficacy Conclusions........................................................... ................................................................................................ 50

 

TABLE OF CONTENTS (cont’d)

 

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6..... CLINICAL SAFETY................................................................................. .......................................................................................................... 52

6.1.... Overview...................................................................................... ................................................................................................ 52

6.2.... Clinical Results.............................................................................. ................................................................................................ 53

6.2.1.... Demographics and Baseline Characteristics........................ .................................................................................... 53

6.2.2.... Subject Disposition (Phase III Studies)............................... .................................................................................... 55

6.2.3.... Drug Exposure (Phase III Studies)..................................... .................................................................................... 56

6.2.4.... Common Adverse Events (Phase III Studies)...................... .................................................................................... 57

6.2.5.... Drug‑Related Adverse Events (Phase III Studies)................ .................................................................................... 59

6.2.6.... Acute Adverse Reactions (Phase III Studies)...................... .................................................................................... 60

6.2.7.... Deaths and Other Serious Adverse Events......................... .................................................................................... 62

6.2.8.... Malignancies (All Psoriasis Studies)................................... .................................................................................... 65

6.2.9.... Infection‑Related Adverse Events (Phase III Studies).......... .................................................................................... 69

6.2.10.. Thrombocytopenia (All Psoriasis Studies)........................... .................................................................................... 71

6.2.11.. Adverse Events of Psoriasis (Phase III Studies).................. .................................................................................... 75

6.2.12.. Arthritis (Phase III Studies)................................................ .................................................................................... 78

6.2.13.. Hypersensitivity‑Related Adverse Events
(Phase III Studies)............................................................ .................................................................................... 78

6.2.14.. Injection‑Site Adverse Events (Phase III Studies)................ .................................................................................... 80

6.2.15.. Audiologic Assessments.................................................... .................................................................................... 80

6.3.... Laboratory Safety Tests (Phase III Studies).................................... ................................................................................................ 80

6.4.... Long‑Term Clinical Results............................................................. ................................................................................................ 81

6.5.... Retreatment Results...................................................................... ................................................................................................ 85

6.6.... Withdrawal Results........................................................................ ................................................................................................ 86

6.7.... Drug–Drug and Drug–Demographic Interactions.............................. ................................................................................................ 88

6.7.1.... Drug–Drug Interactions..................................................... .................................................................................... 88

6.7.2.... Drug–Demographic Interactions......................................... .................................................................................... 89

6.8.... Drug Abuse, Overdose, and Withdrawal Effects.............................. ................................................................................................ 89

6.9.... Self‑Administration of Subcutaneous Raptiva................................... ................................................................................................ 89

6.10... Safety Data from Other Indications................................................. ................................................................................................ 90

6.11... Clinical Safety Summary and Conclusions........................................ ................................................................................................ 91

TABLE OF CONTENTS (cont’d)

 

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7..... BENEFITS AND RISKS........................................................................... .......................................................................................................... 92

7.1.... Unmet Medical Need..................................................................... ................................................................................................ 92

7.2.... Benefit–Risk Conclusions............................................................... ................................................................................................ 93

REFERENCE LIST.......................................................................................... .......................................................................................................... 94

 

TABLES AND FIGURES

Table 1:....... Abbreviations and Terms............................................................. ................................................................................................ 1

Table 2:....... Overall Maximal Effects for Down‑Modulation of CD11a Expression and Saturation of Available CD11a Binding Sites on Leukocyte Subpopulations by Raptiva during Weekly Treatment in the Clinical Studies....................................................................................... .............................................................................................. 14

Table 3:....... Clinical Development of Raptiva:  Completed Psoriasis Studies...... .............................................................................................. 23

Table 4:....... Clinical Development of Raptiva:  Ongoing Psoriasis Studies.......... .............................................................................................. 25

Table 5:....... Demographic and Baseline Characteristics of Randomized Subjects in Study 2390............................................................................. .............................................................................................. 29

Table 6:....... Baseline Psoriasis Characteristics of Treated Subjects in Study 2390................................................................................. .............................................................................................. 30

Table 7:....... Subject Disposition and Reasons for Discontinuation of Treatment in Study 2390............................................................................. .............................................................................................. 31

Table 8:....... PASI‑75 Response to Treatment at 12 Weeks for Randomized Subjects in Study 2390................................................................ .............................................................................................. 32

Table 9:....... PASI Response at 12 Weeks as Percent Improvement from Baseline in Study 2390................................................................ .............................................................................................. 33

Table 10:..... PGA Response at 12 Weeks for Subjects in Study 2390................ .............................................................................................. 35

Table 11:..... Improvement from Baseline in Overall DLQI Score at Week 12 in Study 2390................................................................................. .............................................................................................. 36

Table 12:..... Mean (SD) Improvement from Baseline in the Itching Scale at Week 12 in Study 2390............................................................... .............................................................................................. 38

Table 13:..... Efficacy Results at 12 Weeks for Randomized Subjects in Study 2600................................................................................. .............................................................................................. 40

Table 14:..... PASI‑75 and PASI‑50 Responses after 24 Weeks of Continuous Treatment for Subjects:  Study 2391............................................ .............................................................................................. 47

 

TABLE OF CONTENTS (cont’d)

 

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TABLES AND FIGURES (cont’d)

Table 15:..... Treatment beyond 24 Weeks, Overview of Efficacy by PASI Response in Study 2243:  PASI Response from Baseline during First and Extended Treatment (> 12 Weeks) with Raptiva............... .............................................................................................. 48

Table 16:..... Baseline Demographics for Subjects in the Phase III, Placebo‑Controlled Studies 2390, 2600, 2058, and 2059............... .............................................................................................. 54

Table 17:..... Baseline Psoriasis Characteristics for Subjects in the Phase III, Placebo‑Controlled Studies 2390, 2600, 2058, and 2059............... .............................................................................................. 55

Table 18:..... Subject Disposition and Reasons for Premature Discontinuation for Subjects during the First 12 Weeks of Treatment in the Phase III, Placebo‑Controlled Studies 2390, 2600, 2058, and 2059............... .............................................................................................. 56

Table 19:..... Extent of Exposure to Study Drug for Subjects during the First 12 Weeks of Treatment in the Placebo‑Controlled Studies 2390, 2600, 2058, and 2059................................................................. .............................................................................................. 57

Table 20:..... Adverse Events That Occurred in ³ 5% of Subjects in Any Raptiva or Placebo‑Treated Group during the First 12 Weeks of Treatment in the Placebo‑Controlled Studies................................................. .............................................................................................. 58

Table 21:..... Study Drug–Related Adverse Events That Occurred in ³ 5% of Subjects in Any Raptiva or Placebo‑Treated Group during the First 12 Weeks of Treatment in the Placebo‑Controlled Studies............. .............................................................................................. 60

Table 22:..... Acute Adverse Reactions Experienced by Subjects during the First 12 Weeks of Treatment in the Placebo‑Controlled Studies............. .............................................................................................. 61

Table 23:..... Deaths....................................................................................... .............................................................................................. 63

Table 24:..... Serious Adverse Events That Occurred during the First 12 Weeks of Treatment in the Placebo‑Controlled Studies............................. .............................................................................................. 64

Table 25:..... Incidence Rates for Malignancies in the Psoriasis Clinical Trials...... .............................................................................................. 66

Table 26:..... Observed versus Expected Rates of Malignancies:  Raptiva‑Treated Subjects............................................................ .............................................................................................. 68

Table 27:..... Adverse Events Diagnostic of Infection That Occurred during the First 12 Weeks of Treatment in the Placebo‑Controlled Studies...... .............................................................................................. 70

Table 28:..... Observed versus Expected Infections Requiring Hospitalization...... .............................................................................................. 71

Table 29:..... NCI‑CTC Grade 3 or 4 Thrombocytopenia Events or Thrombocytopenia Occurrences Classified by the Investigators as Serious...................................................................................... .............................................................................................. 72

Table 30:..... Thrombocytopenia during the First 12 Weeks of Treatment in the Placebo‑Controlled Studies.......................................................... .............................................................................................. 74

 

TABLE OF CONTENTS (cont’d)

 

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TABLES AND FIGURES (cont’d)

Table 31:..... Psoriasis Adverse Events Experienced by Subjects Previously Treated with Raptiva during Washout........................................... .............................................................................................. 76

Table 32:..... Psoriasis Adverse Events by Medication Received during Washout for Evaluable Subjects from Studies HUPS254, HUPS256, 2058, 2059, 2142, 2243, and 2062........................................................ .............................................................................................. 77

Table 33:..... Rate of Adverse Events of Psoriasis, Excluding Mild and Guttate Psoriasis, by Concomitant Therapy during Washout....................... .............................................................................................. 77

Table 34:..... Hypersensitivity Adverse Events That Occurred during the First 12 Weeks of Treatment in the Placebo‑Controlled Studies............. .............................................................................................. 79

Table 35:..... Adverse Events Experienced by ³ 5% of Subjects by 12‑Week Course of Raptiva Treatment....................................................... .............................................................................................. 83

Table 36:..... Serious Adverse Events Reported for 2 or More Subjects Treated with Raptiva within Any 12‑Week Treatment Period of the Placebo‑Controlled and Open‑Label Studies................................. .............................................................................................. 84

Table 37:..... Adverse Events Experienced by ³ 5% of Subjects Treated with Raptiva following a Period of Non‑Treatment................................. .............................................................................................. 85

Table 38:..... Serious Adverse Events Reported for 2 or More Subjects during the First or Second Raptiva Treatment Course in the Placebo‑Controlled and Open‑Label Studies................................. .............................................................................................. 86

Table 39:..... Home Dosing:  Subjects without PASI‑75 Response during the First 12 Weeks of Treatment Achieving PASI‑75 during the Second 12 Weeks of Treatment............................................................... .............................................................................................. 90

 

Figure 1a:.... PASI Response at 12 Weeks of Treatment in Study 2390.............. ................................................................................................ 6

Figure 1b:.... PASI Response following 12 and 24 Weeks of Treatment in Studies 2390 and 2391................................................................ ................................................................................................ 6

Figure 2:...... Psoriasis.................................................................................... .............................................................................................. 11

Figure 3:...... Raptiva’s Mechanism of Action..................................................... .............................................................................................. 12

Figure 4:...... Mean Serum Raptiva Concentration (PK), CD11a Expression, and Available CD11a Binding Sites and Absolute Lymphocyte Counts (PD) following Administration of 1.0 mg/kg/wk Raptiva for 12 Weeks in Study 2142.............................................................. .............................................................................................. 16

Figure 5:...... Study 2390................................................................................. .............................................................................................. 26

Figure 6:...... Mean ± SEM Percent Improvement in PASI Score over Time in Study 2390................................................................................. .............................................................................................. 34

 

TABLE OF CONTENTS (cont’d)

 

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TABLES AND FIGURES (cont’d)

Figure 7:...... Mean ± SEM Improvement in DLQI over Time in Study 2390.......... .............................................................................................. 37

Figure 8:...... Study 2058................................................................................. .............................................................................................. 41

Figure 9:...... Study 2059................................................................................. .............................................................................................. 43

Figure 10:.... Raptiva Minus Placebo PASI‑75 Rates at Day 84 by Demographic Subgroups (95% CI)................................................................... .............................................................................................. 45

Figure 11:.... Raptiva Minus Placebo PASI‑75 Rates at Day 84 by Disease‑Related Subgroups (95% CI).......................................... .............................................................................................. 46

Figure 12:.... Acute Adverse Reactions Experienced by Subjects during the First 12 Weeks of Treatment in Placebo‑Controlled Studies................... .............................................................................................. 62

Figure 13:.... Percent PASI Improvement during Raptiva Treatment and Washout for Two Cohorts in Study 2059..................................................... .............................................................................................. 87

 

APPENDICES

Appendix A:.... Proposed Package Insert

Appendix B:.... Psoriasis Area and Severity Index

Appendix C:.... Physicians Global Assessment (Formerly known as the Overall Lesion Severity Scale)

Appendix D:.... Physician’s Global Assessment of Change

Appendix E:.... Copies of Publications

 

The abbreviations used in this document are defined in Table 1 below.

 

 

 

1.       EXECUTIVE SUMMARY

Raptiva represents a novel approach to the treatment of moderate to severe psoriasis.  It is a recombinant humanized monoclonal antibody that binds to lymphocyte cell surface marker CD11a, and it inhibits activation and trafficking of T‑cells. 

Raptiva has been extensively studied in 13 psoriasis clinical trials in which 2,762 subjects were treated with Raptiva.  Four of the studies were placebo‑controlled, randomized, Phase III trials.  Subjects treated with Raptiva experienced rapid, clinically meaningful, and statistically significant benefits across every measured endpoint in all Phase II and III clinical studies.  Subjects receiving Raptiva had fewer psoriatic skin lesions, less itching, and improved quality‑of‑life as well as sustained benefits while on therapy.  Few subjects experienced serious adverse effects from Raptiva therapy; most adverse events were mild and transient.  Below is a list of key conclusions drawn from the Raptiva clinical studies:

·       Raptiva improves signs and symptoms of psoriasis:

After 12 weeks of Raptiva treatment, 27% of subjects had PASI‑75 improvement and 59% of subjects had PASI‑50 improvement compared with placebo rates of 4% and 14%, respectively.

All other secondary endpoints, including global psoriasis assessment (PGA), quality‑of‑life scale (DLQI), and itching scale, showed statistically and clinically significant benefit.

·       Raptiva has an early onset of action, with reduction in PASI score demonstrated 4 weeks after the start of treatment.

·       The beneficial effects of Raptiva are consistent across patient subgroups.

·       The efficacy of Raptiva improves with continuous treatment past 12 weeks. 

After 24 weeks of Raptiva treatment, 44% of subjects had PASI‑75 improvement and 66% of subjects had PASI‑50 improvement.

·       Raptiva is well tolerated, and its overall safety profile is favorable:

The rate of serious adverse events was low (2% in the proposed to‑be‑marketed 1 mg/kg/wk dose group) and similar to the rate in placebo‑treated subjects.

The most common adverse events were mild, self‑limited, and associated with the first two doses.  These events included headache, chills, nausea, fever, myalgia, and asthenia.

A small number of subjects (~1 in 500) had NCI Grade 3 or 4 thrombocytopenia that was reversible upon discontinuation of Raptiva.  A causal relationship with Raptiva could not be ruled out.

There is no evidence to suggest that Raptiva affects the overall rate of malignancies and infections compared with placebo.

·       Withdrawal of Raptiva results in a loss of benefit.  In some subjects (~13%), rapid return of disease or a change in morphology was observed.  Transition to other therapies after discontinuation largely reduces the occurrence of these adverse events.

·       Raptiva maintains its favorable safety profile even with extended treatment.

 

1.1     Proposed indication

Raptiva is indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis.

 

1.2     Efficacy

Primary support for the efficacy of Raptiva in moderate to severe plaque psoriasis is provided by the adequate and well‑controlled Phase III study (2390) in subjects with moderate to severe plaque psoriasis.  Supportive data come from the randomized, double‑blind, placebo‑controlled studies (2600, 2058, and 2059), which used the same basic eligibility criteria and design of the first 12‑week treatment course as Study 2390.

Subjects participating in the Phase III, placebo‑controlled studies all had a diagnosis of moderate to severe plaque psoriasis as defined by a score of at least 12 on the Psoriasis Area and Severity Index (PASI) and psoriatic involvement of at least 10% of body surface area (BSA).  Subjects were required to be candidates for systemic psoriasis treatment or had to have received prior therapy with systemic treatments. 

Raptiva treatment commenced with an initial dose of 0.7 mg/kg, followed by 11 weekly doses of 1.0 mg/kg.  In Studies 2058 and 2059, subjects were also randomized to receive 2.0 mg/kg Raptiva weekly during the first 12‑week treatment period. 

The primary efficacy endpoint was the proportion of subjects who achieved 75% or greater improvement from baseline in PASI (referred to as PASI‑75) on Day 84.  Secondary efficacy variables included the PASI‑50, Physician’s Global Assessments, a validated quality‑of‑life assessment—the Dermatology Life Quality Index (DLQI)—and other subject‑reported assessments focusing on symptoms and itching.

In the pivotal study (2390), the PASI‑75 and PASI‑50 responses were statistically significantly higher for the Raptiva‑treated group compared with the placebo‑treated group (p<0.001; see Figure 1a).  In all three supportive studies, the benefit of Raptiva treatment was consistent with that seen in Study 2390 and was statistically significant.

The efficacy of continuous treatment with 1.0 mg/kg/wk Raptiva beyond 12 weeks is demonstrated by data from the open‑label extension study (2391), which allowed subjects who completed Study 2390 to continue Raptiva treatment for a further 12 weeks.  The PASI‑75 response rate increased from 27% at the end of 12 weeks of treatment to 44% at the end of 24 weeks of treatment (p<0.001; see Figure 1b).  The percentage of subjects achieving a PASI‑50 was also increased with a further 12 weeks of treatment.

Figure 1a
PASI Response at 12 Weeks of Treatment in Study 2390

 

 

Figure 1b
PASI Response following 12 and 24 Weeks of Treatment
in Studies 2390 and 2391

The placebo rate for 24 weeks is not available because placebo‑treated patients rolled over to Raptiva at 12 weeks.

The efficacy of Raptiva was consistent across patient subgroups.  In particular, Raptiva appears to be equally effective in patients with moderate, severe, or very severe disease.

Raptiva has a rapid onset of action.  In Study 2390, at Day 28 the mean PASI percent improvement from baseline was significantly greater (p < 0.001) in the Raptiva 1.0 mg/kg group compared with the placebo‑treated group. 

In addition, early response to treatment was observed in the quality‑of‑life measure, the DLQI:  the mean improvement from baseline in DLQI was significantly greater (p < 0.001) by Day 28 (the first post‑baseline assessment) in the Raptiva‑treated group compared with the placebo‑treated group.  Further, for the Raptiva‑treated subjects, the improvement at Day 28 had reached 70% of the total DLQI improvement achieved by Day 84, indicating a substantial early quality‑of‑life benefit. 

 

1.3     Safety

Raptiva was studied in 2,762 subjects with psoriasis.  Of these, 1,620 subjects were treated in the placebo‑controlled, randomized Phase III trials.

During the first 12‑week, placebo‑controlled treatment period, the overall rate of adverse events was slightly higher for the Raptiva‑treated groups compared with the placebo‑treated group (73.6% in the placebo‑treated group, 82.4% in the Raptiva 1.0 mg/kg/wk group, and 87.0% in the Raptiva 2.0 mg/kg/wk group).  Headache, chills, fever, nausea, and myalgia were among the most frequently reported adverse events in the Raptiva‑treated subjects.  These events were part of “acute adverse reactions” that were predefined in the clinical program.  The reactions were generally mild, self‑limited, and short‑lived and occurred most often with the initial two doses.

During the first 12‑week, placebo‑controlled treatment period, the overall rate of serious adverse events was low and similar between the placebo‑treated group (1.7%) and the Raptiva 1.0 mg/kg/wk group (2.0%).  Most types of serious adverse events were reported for a single subject, and no pattern of serious adverse events suggestive of toxicity was noted.

Overall rates of adverse events leading to discontinuation of treatment were low (2.5% for the 1.0 mg/kg/wk group compared with 2.0% for the placebo‑treated group) over the first 12 weeks.

Malignancies were reported infrequently and occurred at comparable rates between the placebo‑treated and Raptiva‑treated groups.  The overall incidence rate of malignancies per 100 subject‑years was 1.62 in the placebo‑treated group and 1.68 in the Raptiva‑treated group. 

The overall frequency of infections during the first 12 weeks was comparable between the placebo‑treated group (26.3%) and the 1.0 mg/kg/wk Raptiva‑treated group (28.9%).  The rates of serious infections requiring hospitalization were low and relatively similar between the Raptiva‑ and placebo‑treated groups (1.61 per 100 subject‑years vs. 1.18 per 100 subject‑years, respectively), and were consistent with the expected background rate based on external epidemiological data.

Clinical trials were designed such that Raptiva was discontinued without taper or transition to other therapies in the clinical program.  In addition, use of other psoriasis medications was usually restricted even when subjects experienced return of psoriasis.  Adverse events of psoriasis were experienced by 13.0% of the subjects during the 12‑week period following discontinuation of Raptiva, most of which were mild to moderate in severity.  Only 6 (0.5%) of 1,166 subjects who underwent Raptiva washout experienced a serious adverse event of psoriasis.  In the subset of subjects who initiated psoriasis medications during treatment withdrawal, the rate of psoriasis adverse events was substantially lower. 

Out of the 2,762 Raptiva‑treated subjects in the clinical program, there were six reports of reversible NCI Grade 3 or 4 thrombocytopenia (TCP) that were consistent with a possible drug‑induced effect.  Four of the 6 subjects had received medications or had concurrent medical conditions that could have contributed or predisposed subjects to the onset of TCP.  Although causality has not been established, these results suggest that reversible thrombocytopenia may occur infrequently (approximately 1 in 500 patients) in patients treated with Raptiva.  However, the overall rate of TCP observed during Raptiva treatment appears less than that reported with other treatments used in patients with moderate to severe psoriasis (e.g., NEORAL^â [package insert]).

During the Raptiva program, there were no clinically significant differences in laboratory abnormalities observed between the Raptiva‑ and placebo‑treated subjects.  A total of 6.3% of the subjects developed anti‑Raptiva antibodies, but almost all had extremely low titers.  There were no clinically relevant safety or efficacy effects associated with the antibodies.  Preliminary vaccination data suggest that secondary response to immunization may be reduced by Raptiva treatment.  Studies are currently ongoing to evaluate immune responses during and following administration of weekly SC doses of Raptiva.  The current recommendation is to hold Raptiva treatment for 4–8 weeks before an immunization. 

Raptiva was well tolerated over the treatment periods beyond the initial 12 weeks.  An examination of adverse events for subjects treated with Raptiva beyond the initial 12 weeks of treatment up to 1 year indicates no increase in the percentage of subjects reporting adverse events with longer Raptiva exposure and no change in the rate of serious adverse events.

1.4     Conclusions

Raptiva has been demonstrated to be safe and effective for the treatment of psoriasis.  Raptiva has a rapid onset of action and is well tolerated over long durations of treatment.  Extended therapy with Raptiva provides increased clinical efficacy with no increase in adverse events.  Overall, there were few serious adverse events associated with Raptiva therapy, no evidence of organ toxicity, and no evidence of increased malignancies or infections.

Raptiva provides a significant new, safe, and efficacious alternative for patients with moderate to severe plaque psoriasis. 

2.       OVERVIEW

2.1           BACKGROUND

The clinical development of Raptiva was performed collaboratively by XOMA (Berkeley, CA) and Genentech, Inc.  (South San Francisco, CA).

In December 2002, a Biologics License Application (BLA) was submitted.  In May 2003, a Safety Update was provided to the Food and Drug Administration (FDA).  Except where otherwise noted, the data in this briefing document are drawn from the BLA and the Safety Update.

2.2           Pathophysiology of Psoriasis

Psoriasis is a T cell–mediated, inflammatory disease characterized by accumulation of activated T lymphocytes in the epidermis and dermis that stimulate hyperproliferation of keratinocytes to produce psoriatic lesions (see Figure 2) (Griffiths et al.  1995; Gottlieb 1998; Austin et al.  1999; Bos and De Rie 1999; Nickoloff 1999).  The antigen that causes psoriasis is unknown, but the pathophysiology has been studied extensively, particularly with regard to T cells.  In order to mediate the cellular changes in the dermis that lead to psoriasis, T lymphocytes first undergo three key interactions with other cell types.

Step 1:  Antigen‑presenting cells (APCs) must first be activated in the epidermis, where antigen is internalized, enzymatically processed, and presented on the APC surface.  Activated APCs then travel to the regional lymph nodes, where they interact with naive T lymphocytes, resulting in T‑lymphocyte activation. 

Step 2:  T‑lymphocyte binding to venous endothelial cells occurs, followed by trafficking into dermal and epidermal tissue.

Step 3:  T‑lymphocyte reactivation by a second exposure to the specific antigen, which occurs in the dermis or epidermis.  This leads to release of pro‑inflammatory cytokines and other inflammatory mediators, which stimulate the increased keratinocyte proliferation.

Whereas Step 1 occurs only once, it is followed by proliferation of the activated T cells, providing an amplification of the process.  Steps 2 and 3 occur in an iterative fashion, causing the persistence of the disease.

A large number of integrins and selectins on T lymphocytes contribute in their interaction with APCs or endothelial cells.

 

 

Figure 2

Psoriasis

Step 1

Step 3

Step 2

Schematic based on Krueger JG. J Am Acad Dermatol 2002;46(1):1–23.

 

 

2.3     MECHANISM OF ACTION OF Raptiva

LFA‑1 (lymphocyte function–associated antigen‑1, a leukocyte cell surface protein) is an adhesion molecule whose expression is limited to leukocytes.  LFA‑1 is composed of two subunits:  CD11a and CD18.  Whereas CD18 is also part of other adhesion molecules, CD11a is unique to LFA‑1.  This restricted expression of CD11a limits the potential effects of Raptiva to cells that express LFA‑1.  Although LFA‑1 is a key adhesion molecule, leukocytes express multiple other members of the integrin and selectin families.  Variation in distribution of these multiple adhesion molecules leads to variation in the relative functional importance of LFA‑1.  Binding of Raptiva to the CD11a subunit of LFA‑1 inhibits LFA‑1 function.  Raptiva does not induce apoptosis or mediate cell killing.  Effects of Raptiva on lymphocytes and other cell types are reversible.

LFA‑1 binds to members of the ICAM (intercelluar adhesion molecule) family.  ICAM is expressed by APCs and is up‑regulated on endothelial cells and keratinocytes in psoriasis plaques.  Inhibition of LFA‑1 function by Raptiva interferes in several key steps of psoriasis pathophysiology. 

Raptiva inhibits adhesion of T lymphocytes to other cell types by inhibiting the binding of LFA‑1 to ICAM‑1 (see Figure 3).  This mechanism of action (MOA) has a number of effects, depending on the cell type, including the following:

·       Inhibition of T‑lymphocyte activation (proliferation, cytokine release)

·       Inhibition of T‑lymphocyte trafficking and extravasation

·       Inhibition of T‑lymphocyte interactions with tissue‑specific cells (keratinocytes)

 

Figure 3

Raptiva’s Mechanism of Action

Inhibition of Step 3 2

Inhibition of Step 2 2

Inhibition of Step 1

 

Treatment with Raptiva can potentially interfere at several critical points in the pathophysiology of psoriasis:

·       Inhibition of initial activation of naive T cells in regional lymph nodes

·       Inhibition of T‑lymphocyte proliferation and interleukin‑2 (IL‑2) receptor expression

·       Inhibition of T‑lymphocyte trafficking to psoriatic lesions

·       Inhibition of secondary T‑lymphocyte activation in the dermis and epidermis

·       Inhibition of T‑lymphocyte interactions with keratinocytes

·       Inhibition of T‑lymphocyte release of cytokines that drive further inflammation within the psoriatic plaque

Projected actions of Raptiva were verified in skin biopsies from moderate to severe psoriasis subjects participating in the clinical trials.  The number of infiltrating T cells in both the dermis and epidermis was decreased by Raptiva treatment.  This was accompanied by decreased expression of inflammatory markers (decreased ICAM‑1 and HLA‑DR) and normalization of keratinocyte differentiation as reflected by keratin 16 expression.  Epidermal and dermal thickness returned to the normal range.  Raptiva treatment produced full morphological and immunohistochemical normalization of lesional psoriatic skin.

 

3.       PHARMACOLOGY

3.1     clinical pharmAcology of Raptiva

3.1.1   Raptiva Pharmacodynamics

Binding of CD11a by Raptiva results in saturation of available CD11a binding sites on lymphocytes, down‑modulation of cell surface CD11a expression on lymphocytes and elevation of peripheral blood lymphocytes.  As documented in the Phase I dose‑ranging studies, the extent and duration of these effects was dose‑dependent. 

At the proposed marketed dose of 1.0 mg/kg/wk SC, Raptiva produced maximal effects on pharmacodynamic markers, throughout the dosing interval i.e., reduced CD11a expression to ~15%–30% of baseline and saturated CD11a on T lymphocytes in the peripheral blood to < 5% of baseline available binding sites.  After cessation of treatment, CD11a expression returned to baseline as Raptiva was eliminated from the body.  Similarly, Raptiva also affects other leukocyte populations, although the extent of maximal effect is different for the different subpopulations and less than that on T lymphocytes (see Table 2).

 

 

Reduction in CD11a expression was rapid after intravenous (IV) and SC administration.  The full effect on pharmacodynamic markers following SC administration was seen after 24–48 hours.

Multiple weekly IV doses of ³ 0.3 mg/kg were required to maintain CD11a down‑modulation between doses, whereas weekly IV doses of ³ 0.6 mg/kg were required to maintain full CD11a saturation between weekly doses.

Multiple weekly SC doses of 1.0 mg/kg were required to maintain both CD11a down‑modulation and saturation between doses.  Limited data are available at SC doses of < 1.0 mg/kg/wk.

Following the 12th and last dose of 1.0 mg/kg/wk SC, CD11a expression returned to baseline as Raptiva was cleared from circulation.  Between 5 and 8 weeks following the last dose, mean CD11a expression was within 25% of baseline values (see Figure 4).

 

Figure 4

Mean Serum Raptiva Concentration (PK), CD11a Expression, and Available CD11a Binding Sites and Absolute Lymphocyte Counts (PD) following Administration of 1.0 mg/kg/wk Raptiva for 12 Weeks in Study 2142

PD = pharmacodynamics; PK = pharmacokinetics.

 

Increases in the absolute counts of circulating leukocytes were observed following administration of Raptiva.  Absolute white blood cell (WBC) counts increased by 2.5–3.5 ´ 10³ cells/mL following 1.0 and 2.0 mg/kg/wk Raptiva to ~10 ´ 10³ cells/mL.  The largest change occurred in the absolute count of circulating lymphocytes.  T‑lymphocyte and B‑lymphocyte counts approximately doubled, whereas natural killer (NK) cell counts increased by ~50%.  Increased counts were apparent within 24 hours of the first dose.

Leukocyte counts remained elevated with weekly dosing and returned to baseline after treatment cessation.  The time course of the changes was closely related to the effects of Raptiva on CD11a expression and available CD11a binding sites.  After administration of 1.0 mg/kg/wk for 12 weeks, lymphocyte levels returned to within 10% of baseline by 8 weeks following the last dose.  Similar to the maximum effects on CD11a expression, maximum circulating leukocyte counts were comparable at doses of 1.0 and 2.0 mg/kg/wk.

 

3.1.2   Raptiva Pharmacokinetics

Raptiva showed dose‑dependent nonlinear pharmacokinetics, which can be explained by its saturable specific binding to its cell surface receptor, CD11a.

Mean maximum concentration of drug was 12.4 and 30.9 mg/mL for the 1.0 and 2.0 mg/kg/wk doses, respectively; at steady state, peak concentrations were achieved by ~2 days after SC doses.  The mean time from last dose to the time when Raptiva plasma concentrations fell below the limit of detection (0.019 mg/mL) was 25 and 44 days for the 1.0 and 2.0 mg/kg/wk doses, respectively.

With SC doses of 1.0 mg/kg/wk, relative bioavailability of Raptiva was ~50%. 

Steady‑state trough levels were achieved 4 weeks following administration of 1.0 mg/kg/wk and 8 weeks following administration of 2.0 mg/kg/wk, as assessed from Raptiva serum trough levels after weekly dosing.

In the Phase III Study 2390, mean ± standard deviation (SD) steady‑state Raptiva trough levels at Day 84 were 11.1 ± 7.9 mg/mL (n = 275) following 12 weekly SC doses of Raptiva at 1.0 mg/kg.  In subjects from this study, Raptiva reduced CD11a expression to 19% of baseline and saturated CD11a to < 5% of baseline available binding sites on T lymphocytes in the peripheral blood.  Maximal effects observed in this study indicate that subjects achieved adequate exposure to Raptiva.

Consistent trough levels measured during five consecutive 12‑week treatment periods in the 3‑year extension study (2243) indicate that there was no unexpected accumulation during long‑term treatment.

There was a 6.3% (67/1063 subjects) incidence of anti‑Raptiva antibodies in subjects for whom serum samples were available during the follow‑up period after elimination of Raptiva from serum.  Anti‑Raptiva antibody titers were low.  There was an apparent decrease in efalizumab serum levels in subjects who had anti‑Raptiva antibodies.  Anti‑Raptiva antibodies interfere with the efalizumab serum assay; therefore this decrease could be an artifact.  Anti‑Raptiva antibodies did not affect the pharmacodynamics since the peripheral blood lymphocytes stayed elevated and lymphocyte CD11a saturation was maintained.  There was no impact on efficacy or safety (see Section 6.3).

Through population pharmacokinetic analyses, weight was found to be the most significant covariate affecting Raptiva SC clearance, confirming the validity of weight‑based dosing.  The population pharmacokinetic model indicated that the clearance of Raptiva was 24% lower at a dose level of 2.0 mg/kg/wk compared with 1.0 mg/kg/wk, consistent with dose‑dependent nonlinear pharmacokinetics.  The other pathophysiologic covariates of baseline PASI, baseline lymphocyte count, and age had only modest effects on clearance; sex and race had no effect on Raptiva clearance.

CD11a expression and saturation in peripheral blood are good biologic markers for adequate dosing based on three factors:  1) integration of CD11a expression in peripheral blood; 2) CD11a expression in skin (immunohistology); and 3) psoriasis disease assessment by PASI improvement.  Mechanistically, the pharmacodynamic effect is related to maximal saturation of CD11a on peripheral blood T lymphocytes.

At Phase III doses (1.0 and 2.0 mg/kg/wk for 12 weeks SC), maximal effects were seen on these pharmacodynamic markers (i.e., CD11a was fully down‑modulated and saturated).

No clinically meaningful relationship was found between steady‑state Raptiva level (summarized by quartiles) and any measure of overall efficacy or safety events in the Phase III studies, which used doses of 1.0 and 2.0 mg/kg/wk.

 

3.1.3   Raptiva Immunology and Immunocompetence

T‑lymphocyte proliferation was not impaired in vitro in the mixed lymphocyte reaction when using peripheral blood mononuclear cells (PBMCs) obtained from subjects receiving Raptiva treatment.  The preparation of such PBMCs included washing procedures that removed Raptiva from T cells, suggesting that T lymphocytes rapidly regain their normal activation potential after drug removal or clearance.

A transient increase of CD69 expression (an early activation marker) on a small percentage of circulating T lymphocytes was observed after the first IV or SC dose of Raptiva and after subsequent IV doses when the previous dose was too low to maintain saturation of CD11a.  No concomitant up‑regulation of CD25 (a second early activation marker) or increases in cytokines typically produced by activated T lymphocytes were noted, suggesting that the CD69⁺ T lymphocytes were not fully activated.

Adverse events (e.g., fever, chills, etc.) observed after the initial administration of Raptiva (first‑dose effects) were accompanied by small transient increases in plasma levels of acute phase reactants such as IL‑6, C‑reactive protein, and fibrinogen.  These changes were not associated with T‑lymphocyte activation.

In a Phase I study (HU9602), subjects were vaccinated with bacteriophage fX174 1 day after receiving a single dose of Raptiva.  The data from this study suggest that that secondary response to immunization may not be effective during Raptiva treatment, particularly at dose levels of > 0.6 mg/kg IV (Gottlieb 1998).

Subjects did not experience a decrease or increase in preexisting serum concentrations of anti‑cytomegalovirus or anti‑tetanus toxoid antibodies after treatment.  Secondary booster vaccinations in humans during Raptiva treatment are currently under investigation.  The safety and efficacy of vaccines, specifically live or live‑attenuated vaccines, administered to patients being treated with Raptiva have not been studied.

To study immune responses in greater detail, a Phase I, randomized, placebo‑controlled, single‑blind, parallel‑group, single‑center study (2244) is in progress.  Study 2244 is designed to evaluate immune responses during and following administration of 12 weekly SC doses of 1.0 mg/kg Raptiva in 60 adult subjects with moderate plaque psoriasis.

 

3.2     NonClinical Pharmacology Toxicology Data

Because of the species specificity of Raptiva in humans and chimpanzees and the limited availability of chimpanzees, a chimeric rat/mouse anti–mouse CD11a antibody (muM17), was developed and evaluated as a surrogate for Raptiva.  Safety studies were performed with Raptiva in chimpanzees and with muM17, an anti–mouse CD11a antibody, in mice to provide a comprehensive safety evaluation.

The nonclinical pharmacology, pharmacokinetics, and toxicology of Raptiva are consistent with the binding of the antibody to its ligand, CD11a.  All safety signals observed in the nonclinical safety evaluation of Raptiva or muM17 can be explained by the known immunomodulatory effects of these antibodies.  These effects occurred at doses approximately equivalent to the clinical dose of 1.0 mg/kg/wk Raptiva.

Consistent with the pharmacologic activity of these antibodies, CD11a expression was greatly reduced on T cells in chimpanzees and mice treated with Raptiva and muM17, respectively.  Similar effects have been seen in humans.  The clinical relevance of the occasional overexpression of CD11a following clearance of Raptiva from the serum is unknown because no safety signals were observed in animals during this period of overexpression.

Both Raptiva and muM17 appear to alter the trafficking of lymphocytes such that there is a reduction in the cellularity of the lymph nodes, increased spleen weights (evaluable with muM17 in mice only), and increases in the circulating WBC count (noted with both Raptiva in chimpanzees and humans and with muM17 in mice).  These changes do not appear to have any adverse toxicologic consequences.

In a developmental toxicity study conducted in mice using muM17, no evidence of maternal toxicity, embryotoxicity, or teratogenicity was observed.  No adverse effects on behavioral, reproductive, or growth parameters were observed in offspring of female mice exposed to an anti‑mouse CD11a antibody during gestation and lactation.  At 11 weeks of age, the offspring had intact cell‑mediated immunity and a reduction in the primary antibody response.  At 25 weeks of age, the offspring had a normal primary antibody response.

In a fertility and general reproduction study with muM17, no adverse effects were noted on mating, fertility, or reproduction parameters in male and female mice.

A 6‑month study was conducted in TSG‑p53^â wild‑type mice, a strain shown to be susceptible to lymphoma development.  Additionally, cyclosporine has been shown to produce lymphomas in this strain when mice were treated for a period of 6 months (Storer et al.  2001).  The study was conducted to address the chronic safety of muM17 and to determine the potential for treatment‑related effects on lymphoma development.  Results of this study indicated that treatment of mice for 6 months with muM17 was well tolerated; there was no treatment‑related increase in lymphomas whereas one lymphoma was observed in placebo‑treated mice.  Expected findings, including increased spleen weight and lymphoid organ changes, were consistent with trafficking/demargination changes related to the pharmacologic activity of the antibody.  Additional long‑term animal studies have not been conducted to evaluate the carcinogenic potential of Raptiva. 

Raptiva was considered to be generally well tolerated in chimpanzees at doses of up to 40 mg/kg/wk IV for 6 months, providing an exposure ratio of 339‑fold based on cumulative dose and 174‑fold based on the cumulative area under the curve compared with a clinical dose of 1.0 mg/kg/wk for 12 weeks.  The surrogate antibody, muM17, was also well tolerated in mice at doses up to 30 mg/kg/wk SC for 6 months, providing an exposure ratio of 10‑ to 25‑fold based on plasma concentration compared with the clinical dose of Raptiva.

 

4.       OVERVIEW OF CLINICAL TRIALS

Early evaluation of Raptiva was conducted in seven Phase I and II clinical studies.  Data on the safety and efficacy of Raptiva were subsequently obtained from the pivotal study, 2390, which used the to‑be‑marketed product.  This trial was conducted in adults (³18 years old) with moderate to severe plaque psoriasis who were candidates for systemic therapy and who had a baseline PASI score of ³12.0, with plaque psoriasis covering ³ 10% of total BSA (Krueger et al.  2000).  Extensive supportive data are provided in three additional Phase III placebo‑controlled studies (2600, 2058, and 2059).  Support for the long‑term use of Raptiva is provided by the open‑label study, 2391, which provides extended treatment for subjects treated in Study 2390, and also by Studies 2058 and 2059 and the ongoing open‑label study, 2243.  Support for retreatment and additional long‑term continuous treatment data were obtained from Study 2062, which provided Raptiva treatment for subjects who had participated in earlier clinical trials.

There were five Phase I studies (HU9602, HUPS249, HUPSS254, HUPS256, and 2142) and one Phase II study (HUPS252) performed using Raptiva in the treatment of psoriasis.  Two of the Phase I studies (HU9602 and HUPS249) and the Phase II study (HUPS252) used an IV formulation of Raptiva; the safety data for these three studies are not reviewed in this document except in the discussion of malignancy events.  The safety data from three of the remaining four Phase I studies (HUPS254, HUPS256, and 2142), which used an SC formulation of Raptiva, are part of the pool of data from subjects in the first 12‑week treatment period of the open‑label and placebo‑controlled studies.  Table 3 summarizes the completed Phase I, II, and III psoriasis studies.  Table 4 summarizes the ongoing studies.

 

 

5.       CLINICAL EFFICACY

5.1     Overview OF STUDY 2390

5.1.1   Study 2390

Study 2390 was a Phase III, randomized, double‑blind, parallel‑group, placebo‑controlled, multicenter trial designed to evaluate the efficacy and safety of Raptiva (as the to‑be‑marketed product) in subjects with moderate to severe plaque psoriasis who were candidates for systemic therapy.

a.  Study Design and Treatment

Following a 2‑ to 4‑week screening period, eligible subjects were randomized in a 2:1 ratio to receive SC treatment with either 1.0 mg/kg/wk Raptiva or placebo equivalent for 12 weeks (see Figure 5).  (During the first 12 weeks of treatment, subjects received an initial dose of 0.7 mg/kg followed by 11 weekly SC doses of 1.0 mg/kg.)  Subjects were to return 1 week after the last SC treatment for Day 84 assessments.  Randomization was stratified within study center using the Day 0 PASI score (£ 16.0, ³ 16.1) and prior treatment for psoriasis (naive to systemic treatment vs. prior systemic treatment).

 

Figure 5

Study 2390

 

 

The only concomitant psoriasis treatments allowed during the study were emollients, tar or salicylic acid preparations for scalp psoriasis, and low‑potency (Grade VI or VII) topical corticosteroids if needed for lesions on the face, hands, feet, axillae, or groin.  Oral antihistamines were allowed if needed for pruritus.  Thus, the results are representative of Raptiva monotherapy.

b.  Study Population

Adults with plaque psoriasis covering ³ 10% of total BSA and a PASI score of ³ 12.0 who were either candidates for systemic psoriasis therapy or had a history of receiving systemic therapy were randomized into the study.  A total of 556 subjects were enrolled at 29 sites in the United States and Canada.

c.  Efficacy Outcome Measures

The primary efficacy endpoint was the proportion of subjects with a ³ 75% improvement in PASI relative to baseline (PASI‑75) at the end of 12 weeks of treatment referred to as PASI responders.  PASI is a physician‑performed assessment of both the extent of psoriasis on the four body areas (head, trunk, upper limbs, and lower limbs) and the degree of plaque erythema, scaling, and thickness (Fredriksson et al.  1983).  The PASI score accounts for both the extent of BSA affected by the erythema, scaling, and thickness and the severity of the erythema, scaling, and thickness.  The possible scores range from 0 (no disease) to 72 (maximal disease) (see Appendix B).

Observations on the PASI were corroborated by two Physician’s Global Assessment scales:

·       A static Physicians Global Assessment (PGA) reflecting the appearance of the subject on the day of observation, with rankings ranging from very severe to clear (see Appendix C)

During the clinical studies this assessment was known as Overall Lesion Severity (OLS) scale.  The principal secondary endpoint was the proportion of subjects rated as minimal or clear at the end of 12 weeks of treatment on this scale.

·       A dynamic Physician’s Global Assessment (PGA) of Change, ranging from worse to cleared (see Appendix D)

This scale reflects a global assessment of the degree of improvement from baseline.  Photographs obtained at baseline, clinic notes, and other materials were used by the investigator as desired in making this assessment.  The endpoint was the proportion of subjects rated as excellent or cleared at the end of 12 weeks of treatment.

Other secondary endpoints were mean improvement in the thickness component of the PASI score, mean improvement in the percentage of BSA affected by psoriasis, proportion of subjects with ³ 50% improvement in PASI score relative to baseline after 12 weeks of treatment (PASI‑50), and mean percent PASI improvement over time.  The following patient‑reported scales were used:  the Itching Scale, Dermatology Life Quality Index (DLQI), and frequency and severity subscales of the Psoriasis Symptom Assessment (PSA).  Developed for the Raptiva trials, the PSA rates frequency and severity for eight symptoms of psoriasis and is similar to the Skindex (Chren et al.  1996).  All subject‑reported outcomes were assessed as change from baseline after 12 weeks of treatment. 

d.  Demographic and Baseline Characteristics

Demographic and baseline characteristics for all randomized subjects are summarized in Table 5.  Overall, the two treatment groups were comparable with regard to demographic and baseline characteristics, with no statistically significant differences noted.

 

The two treatment groups were comparable at baseline with regard to the state of their psoriasis, with no statistically significant differences noted (see Table 6).

 

 

 

e.  Subject Disposition

A total of 556 subjects were enrolled and randomized into the study:  187 subjects in the placebo‑treated group and 369 subjects in the 1.0 mg/kg/wk Raptiva‑treated group.

A total of 36 subjects (6.5%) discontinued treatment (see Table 7).

 

 

The primary reason cited for discontinuation was subject’s decision, followed by adverse events.  The proportion of subjects who chose to discontinue was similar in the placebo‑treated and Raptiva‑treated groups.

f.   Efficacy Results

PASI‑75.  The proportion of PASI‑75 responders was statistically significantly greater in the Raptiva‑treated group than in the placebo‑treated group (p < 0.001; see Table 8).  A 22.3% treatment effect (i.e., the difference in the proportion of responders between the Raptiva‑treated group and the placebo‑treated group) was observed, with a 95% confidence interval (CI) of 15.8%–29.5%.

 

 

A more detailed examination of the distribution of percent improvement in PASI achieved at Day 84 demonstrates a general shift toward improvement in the Raptiva‑treated group compared with a minimal change in the placebo‑treated group.  There was a greater proportion of subjects who experienced a PASI worsening at Day 84 compared with baseline (i.e., < 0% improvement from baseline) in the placebo‑treated group (21.4%) than in the Raptiva‑treated group (6.5%) (see Table 9).

 

 

The majority of subjects receiving Raptiva (58.5%) experienced ³ 50% improvement from baseline in PASI score compared with 13.9% of subjects receiving placebo.

Improvement occurred in each of the three key morphologic characteristics of psoriasis lesions (thickness, erythema, and scaling) as measured by improvement in the corresponding components of the PASI score.  The mean improvement in the PASI thickness component at Day 84 relative to Day 0 was statistically significantly greater for subjects in the Raptiva‑treated group compared with subjects in the placebo‑treated group (p < 0.001).  The mean improvement (decrease) from baseline for the Raptiva‑treated group was at least three times that observed for the placebo‑treated group.  Although they were not formal endpoints of the study, the mean percent improvement in erythema and scaling corresponded closely to the mean percent improvement in thickness.

In addition, mean psoriatic BSA declined from 28% to 17% in subjects receiving Raptiva compared with a decline from 27% to 25% in those receiving placebo (p < 0.001).  Thus, Raptiva improves all of the cardinal features of psoriasis that contribute to the overall PASI score. 

Subjects in the Raptiva‑treated group showed a significant mean percent improvement in PASI score versus the placebo‑treated group as early as 28 days following initial treatment (p < 0.001).  The mean percent improvement in PASI score is presented over time for each treatment group in Figure 6.

 

Figure 6

Mean ± SEM Percent Improvement in PASI Score over Time in Study 2390

SEM = standard error of mean.

 

PGA.  The proportion of subjects with a PGA rating of minimal or clear in the Raptiva‑treated group (95 of the 369 subjects; 25.7%) was statistically significantly higher than that in the placebo‑treated group (6 of the 187 subjects; 3.2%) (p < 0.001; see Table 10).

 

 

DLQI.  A comparison of improvement from baseline in the DLQI overall scores at Day 84 for the Raptiva‑treated group with the placebo‑treated group was performed using the Wilcoxon rank‑sum test.  A decrease in DLQI overall scores represents improvement in dermatologic‑related functionality and subject well‑being.  The improvement in mean DLQI overall scores was statistically significant in favor of the Raptiva‑treated group compared with the placebo‑treated group (p < 0.001; see Table 11).  The improvement in the DLQI overall scores for the Raptiva‑treated group was at least three times that observed for the placebo‑treated group.

 

 

There was a consistent trend toward a treatment effect across all DLQI subscales (symptoms and feelings, daily activities, leisure, work and school, personal relationships, treatment).

Subjects in the Raptiva‑treated group showed a clear improvement in DLQI scores versus the placebo‑treated group at the first post‑baseline assessment 28 days following initial treatment (p < 0.001; see Figure 7).  In addition, for the Raptiva‑treated subjects, the mean improvement in DLQI scores at Day 28 was 70% of the mean improvement at Day 84, indicating an early quality‑of‑life benefit.

Comparison of the pattern of improvement over time in DLQI in Figure 7 versus that for PASI in Figure 6 suggests that subjects perceive a quality‑of‑life benefit earlier than the physical improvement assessed by the physician through the PASI.

 

Figure 7

Mean ± SEM Improvement in DLQI over Time in Study 2390

SEM = standard error of mean.

 

Itching Scale.  The mean improvement in the Itching Scale at Day 84 relative to Day 0 was statistically significant in favor of the Raptiva‑treated group relative to the placebo‑treated group (p < 0.001; see Table 12).

 

 

As observed for the PASI and DLQI, subjects in the Raptiva‑treated group showed a clear improvement in mean Itching Scale scores versus the placebo‑treated group at the first post‑baseline assessment 28 days following initial treatment (p < 0.001).

PSA.  A comparison of improvement from baseline in the frequency and severity of the psoriasis‑specific symptom scores at Day 84 for the Raptiva‑treated group versus the placebo‑treated group was performed using the Wilcoxon rank‑sum test.  A decrease in PSA score represents improvement.  Comparisons of the improvement from baseline in the Raptiva‑treated group versus the placebo‑treated group were statistically significant for both frequency of symptoms (p < 0.001) and severity of symptoms (p < 0.001), implying an improvement in psoriasis‑specific symptoms for the Raptiva‑treated group relative to placebo.  The mean improvements in symptom frequency and severity in the Raptiva‑treated group were more than two times those observed in the placebo‑treated group.

Subjects in the Raptiva‑treated group showed a clear improvement in both mean PSA frequency and mean PSA severity scores versus the placebo‑treated group at the first post‑baseline assessment 28 days following initial treatment (p < 0.001).

 

5.2     Supportive Studies Providing Additional Efficacy Data

5.2.1   Study 2600

a.  Study Design and Treatment

Study 2600 was a Phase III, randomized, double‑blind, parallel‑group, placebo‑controlled, multicenter study designed to evaluate the safety of Raptiva (as the to‑be‑marketed product) administered at weekly SC doses of 1.0 mg/kg in subjects with moderate to severe plaque psoriasis who were candidates for systemic therapy.  Subjects were required to have a psoriatic BSA of ³ 10% and PASI ³ 12.0 to be eligible for study enrollment.

Following a screening period, eligible subjects were randomized in a 2:1 ratio to receive SC treatment with 0.7 mg/kg for 1 week followed by 11 weeks of either 1.0 mg/kg/wk Raptiva or placebo equivalent.  Subjects were to return 1 week after the last SC treatment for Day 84 assessments. 

A total of 686 subjects were randomized in an approximate 2:1 ratio to receive either 12 weeks of 1.0 mg/kg/wk SC Raptiva or placebo equivalent at 58 sites in the United States and Canada.  Of these subjects, 236 subjects were in the placebo‑treated group and 450 subjects were in the Raptiva‑treated group.

b.  Efficacy Results

Efficacy endpoints were considered of secondary importance in this safety study.  Efficacy was assessed by determining the proportion of subjects achieving PASI‑75, PASI‑50, and PGA ratings of clear or minimal (see Table 13).  The treatment effect for the PASI‑75 endpoint (i.e., the difference in the proportion of PASI‑75 responders between the two groups) was 20.6%, with a 95% CI of 15.3%–26.6%.

 

 

Raptiva treatment also resulted in a statistically significant improvement in subject‑reported symptoms of psoriasis as measured by the PSA.  The mean improvements in symptom frequency and severity in the Raptiva‑treated group were at least three times those observed in the placebo‑treated group (p < 0.001 for separate comparisons of PSA frequency, PSA severity, and both itching components of the PSA).

 

5.2.2   Study 2058

a.  Study Design and Treatment

The first 12 weeks of Study 2058 were almost identical in design to the first 12 weeks of Study 2390.  The study consisted of first treatment, observation, retreatment, and extended treatment periods, as well as a follow‑up period (see Figure 8).  The study was performed with a version of the product that will not be marketed.

 

Figure 8

Study 2058

 

During the first 12 weeks of treatment, subjects received a conditioning dose of 0.7 mg/kg followed by 11 weekly SC doses of 1.0 mg/kg (low‑dose) Raptiva (n = 162), 2.0 mg/kg (high‑dose) Raptiva (n = 166), or placebo equivalent to low‑dose or high‑dose Raptiva (n = 170 combined).

b.  Efficacy Results for the First 12 Weeks of Treatment

The primary efficacy endpoint was the proportion of subjects with a PASI‑75 response at the end of the first 12 weeks of treatment.  The principal secondary endpoint was the proportion of subjects with a PGA rating of minimal or clear at the end of 12 weeks of treatment.  Other secondary efficacy endpoints were percentage of subjects with a PGA of Change of cleared or excellent, time to relapse after the Day 84 visit for the FT period for subjects who achieved PASI‑75 at the Day 84 visit, mean improvement in the thickness component of the PASI, mean improvement in the Itching Scale, and mean improvement in the BSA affected by psoriasis.

At Day 84, statistically significantly more subjects in the 1.0 mg/kg/wk group (38.9%) and the 2.0 mg/kg/wk group (26.5%) exhibited a PASI‑75 response compared with the placebo‑treated group (2.4%; p < 0.001).  The proportion of subjects with a PGA rating of minimal or clear in the 1.0 mg/kg/wk group (32.1%) and the 2.0 mg/kg/wk group (22.3%) was statistically significantly higher than that in the placebo‑treated group (2.9%; p < 0.001).  Similar statistically significant differences in favor of each Raptiva‑treated group over placebo (p £ 0.001) were observed for all secondary efficacy endpoints tested.  For subjects with a PASI‑75 response, the median time to relapse (loss of ³ 50% of the improvement in the PASI score achieved between Day 0 and Day 84) was 67 days after the last Raptiva dose.

Results for treatment periods beyond the initial 12 weeks of treatment are presented in Section 5.4.

 

5.2.3   Study 2059

a.  Study Design and Treatment

The first 12 weeks of Study 2059 were also almost identical in design to the first 12 weeks of Study 2390.  Following a screening period, eligible subjects were randomized in a 2:1 ratio to a conditioning dose of 0.7 mg/kg followed by 11 weekly SC doses of 1.0 mg/kg Raptiva (n = 232), 2.0 mg/kg Raptiva (n = 243), or to placebo (n = 122).  The study consisted of first treatment (12 weeks) and extended treatment (12 weeks) periods, as well as a follow‑up period (see Figure 9).  The study was performed primarily with a version of the product that will not be marketed.

 

Figure 9

Study 2059

 

b.  Efficacy Results for the First 12 Weeks of Treatment

The primary efficacy endpoint was the proportion of subjects with a PASI‑75 response at the end of 12 weeks of treatment.  The principal secondary endpoint was the proportion of subjects with a PGA rating of minimal or clear at the end of 12 weeks of treatment.  Other secondary efficacy endpoints were percentage of subjects with a PGA of Change of cleared or excellent, mean improvement in the thickness component of the PASI, mean improvement in the Itching Scale, and mean improvement in the BSA affected by psoriasis.

At Day 84, statistically significantly more subjects in the 1.0 mg/kg/wk group (22.4%) and the 2.0 mg/kg/wk group (28.4%) had a PASI‑75 response compared with the placebo‑treated group (4.9%; p < 0.001).  The proportion of subjects with a PGA rating of minimal or clear in the 1.0 mg/kg/wk group (19.4%) and the 2.0 mg/kg/wk group (22.6%) was statistically significantly higher than that in the placebo‑treated group (3.3%; p < 0.001).  Similar statistically significant differences in favor of each Raptiva‑treated group over placebo (p < 0.001) were observed for all secondary efficacy endpoints.

Results for treatment periods beyond the initial 12 weeks of treatment are presented in Section 5.4.

 

5.3     Comparison of Results in Subpopulations

The difference between the Raptiva and placebo PASI rates at Day 84 was summarized by subpopulations using pooled data from the first 12 weeks of treatment in the four placebo‑controlled, Phase III trials (2058, 2059, 2390, and 2600).

Treatment effect for subgroups defined using demographic factors of age, sex, and race is displayed in Figure 10.  As an example of what is plotted in the figure, the pooled placebo PASI‑75 rate was 4% and the pooled Raptiva rate was 27%.  The difference, 23%, is plotted as the circle in the top row.  The 95% confidence interval in this case is approximately 20%–26%, which is plotted as the squares in the first row.  Across the subgroups, the estimated treatment effect is similar, and the 95% confidence intervals are all to the right of the vertical line at zero, demonstrating the efficacy of Raptiva in each subgroup.

Figure 10

Raptiva Minus Placebo PASI‑75 Rates at Day 84 by Demographic Subgroups
(95% CI)

For each subgroup, the solid circle is plotted at the difference between the Raptiva and placebo PASI‑75 rates, and the squares span the 95% confidence interval.

 

Treatment effect for subgroups defined using disease‑related factors of baseline PASI, history of systemic therapy, and duration of disease is displayed in Figure 11.  Again, estimated treatment effect is similar across each of the subgroups, and the 95% confidence intervals are all to the right of zero, demonstrating the efficacy of Raptiva in each subgroup.  Importantly, Raptiva is equally effective in patients with moderate, severe, and very severe disease.

Figure 11

Raptiva Minus Placebo PASI‑75 Rates at Day 84 by Disease‑Related Subgroups
(95% CI)

For each subgroup, the solid circle is plotted at the difference between the Raptiva and placebo PASI‑75 rates, and the squares span the 95% confidence interval.

 

In addition, the difference between the Raptiva and placebo PASI‑75 response rate was also consistent across patient subgroups based on season of treatment, subject weight, and subject body mass index.

 

5.4     Treatment beyond 12 Weeks

a.  Extended Treatment:  Weeks 12–24

Study 2391.  The efficacy of continuous treatment with 1.0 mg/kg/wk Raptiva beyond 12 weeks is demonstrated by combined data from Study 2390 and an uncontrolled, open‑label study, 2391, which allowed subjects who completed the Phase III, randomized, placebo‑controlled Study 2390 to continue Raptiva treatment beyond the initial 12 weeks (see Table 14).  Efficacy was examined in an intent‑to‑treat (ITT) analysis of the cohort of subjects randomized to Raptiva in Study 2390.  The PASI‑75 response rate at the end of this second 12 weeks of treatment reached 44% from 27% at the end of the first 12 weeks of treatment in Study 2390.

 

 

Studies 2058 and 2059.  In Studies 2058 and 2059, many subjects who had received Raptiva for the first 12‑week treatment period entered the Extended Treatment period and received a second course of 12 weekly SC doses of Raptiva or placebo (see Figures 8 and 9).  The results from this second 12 weeks of treatment in Studies 2058 and 2059 were consistent with those seen in the data from Study 2391.  In both studies, continued treatment with Raptiva was demonstrated to be superior to discontinuation.

b.  Treatment beyond 24 Weeks

Long‑term response to treatment with Raptiva is being evaluated in the ongoing, open‑label study, 2243.  Subjects were treated with 2.0 mg/kg/wk Raptiva for the first 12 weeks.  The design of this study stipulated that only subjects achieving a PASI‑50 response or a PGA rating of mild or better were allowed to continue treatment beyond the initial 12 weeks of treatment.  Dosing in these subjects is decreased to 1.0 mg/kg/wk at the beginning of the subsequent Maintenance Treatment period; if a subject experiences relapse, the Raptiva dose is escalated to 2.0 mg/kg/wk for the remaining treatment period.  Of the 339 subjects who started the study, 289 achieved a level of response that allowed them to receive continuous treatment past 12 weeks.

Response rates for cohorts of subjects entering sequential 12‑week treatment courses are presented in Table 15.

 

 

In assessing the long‑term results presented in Table 15, it is recognized that all subjects with continuous dosing beyond 12 weeks did so as subsets of the original psoriatic population at baseline.  In Study 2243, only subjects who achieved a PASI‑50 response or a PGA rating of mild or better at the end of first 12‑week treatment period were provided an opportunity for further continuous dosing to Week 48.  In addition to the response rates by 12‑week treatment segment presented in Table 15, a conservative ITT analysis was performed by assuming that all subjects who did not continue beyond the 12‑week treatment period and all post–first treatment dropouts remained < PASI‑75.  The Week 24 to Week 48 response rates by this conservative method were higher than the Week 12 value of 41.3% (ranging from 44.0% to 46.6%).

c.  Retreatment during Active Relapse

In Study 2058, subjects who achieved a PASI‑75 response at the end of the initial 12‑week treatment period then entered an untreated observation period.  These subjects were followed until they experienced a protocol‑defined relapse of disease, defined as a loss of ³ 50% of the Week 12 improvement in PASI score.  The median time to relapse was 67 days from the last Raptiva dose. 

At the time of relapse, subjects were randomized to double‑blind placebo or Raptiva during a 12‑week retreatment period.  At the end of the retreatment period, 30.9% of Raptiva‑treated subjects re‑achieved a PASI‑75 versus none of the placebo‑treated subjects (p < 0.001), demonstrating the efficacy of Raptiva in the treatment of patients with active relapse of their disease.

Because all the subjects given Raptiva retreatment had been PASI‑75 responders to the first 12 weeks of treatment with Raptiva, the re‑treatment PASI‑75 rate of 30.9% suggests a possible attenuation of the original response.  However, the psoriatic state of subjects at the beginning of retreatment was very different from that of subjects at the beginning the first treatment period. 

Subjects beginning retreatment were in active relapse, in contrast to the stability of subjects beginning first treatment after observation during screening.  The worsening PASI scores of patients entering retreatment did not stabilize, on average, until after 14 days of retreatment, with improvements seen subsequently.  After first treatment in subjects with stable disease, PASI scores improved, on average, after the first 14 days of treatment (see Figure 6). 

This suggests that an intervening recurrence of disease did not appreciably attenuate the subsequent response to treatment, but that retreatment during a phase of rapid worsening is expected to require additional time to demonstrate a stable efficacy response of the magnitude observed after first treatment.

Further support that the efficacy of Raptiva on retreatment is similar to that of first treatment is provided by data from Study 2062, as described in the next section.

d.  Other Retreatment Experience

In Study 2062, subjects who had participated in prior studies of Raptiva were allowed to receive retreatment with Raptiva.  Prior exposure to Raptiva ranged from a single IV dose to 12 weeks of SC Raptiva.  Entry into the Study 2062 was not restricted based on PASI or percent BSA of psoriasis at baseline. 

In the 364 subjects retreated with Raptiva in Study 2062, 25.3% achieved a PASI‑75 response and 56.9% achieved a PASI‑50 response, indicating that response to retreatment is similar to response to initial Raptiva treatment, as seen in the Phase III placebo‑controlled studies.

A further analysis of Study 2062 data was performed in order to mimic the analysis of the Study 2058 retreatment period, but remove the effect of relapse on the results.  For this analysis, subjects who met the following two criteria were selected:

·       Subjects were PASI‑75 responders to Raptiva treatment for 12 weeks in their previous study

·       Subjects were enrolled in Study 2062 with > 67 days between their first dose of Raptiva in Study 2062 and their last dose in the previous study.  The cutoff of 67 days was chosen because this was the median time to relapse prior to the retreatment period in Study 2058

PASI‑75 and PASI‑50 responses were then determined at the end of Study 2062 relative to the PASI baseline of the first 12‑week treatment period in the previous study.

There were 86 subjects who met the two criteria above.  The PASI‑75 rate was 61.6%, and the PASI‑50 rate was 84.9%.  These rates are substantially larger than those observed in the retreatment period of Study 2058 and demonstrate the maintenance of efficacy of Raptiva upon retreatment.

 

5.5     clinical efficacy conclusions

During the first 12 weeks of treatment, statistically significant results favoring Raptiva over placebo were achieved for the primary efficacy endpoint and all secondary endpoints (p < 0.001 for each comparison).  Significant improvement was also seen in all physician‑assessed (PGA of Change, PASI thickness, and psoriatic BSA) and patient‑reported (DLQI, Itching Scale, PSA frequency and severity) outcome measures.

Improvement in PASI was rapid.  Significant improvement in PASI was noted in Raptiva‑treated subjects compared with placebo‑treated subjects 4 weeks after initiation of treatment in Study 2390 (p < 0.001).  In addition, subjects in the Raptiva‑treated group showed a clear improvement in mean DLQI scores, mean Itching Scale scores, mean PSA frequency, and mean PSA severity scores compared with the placebo‑treated group at the first post‑baseline assessment 4 weeks following initial treatment (p < 0.001).

Efficacy was consistent across subgroups.  Similar efficacy was seen in subject groups defined by age, sex, body habitus, history of systemic therapy, duration of disease, season, region, and baseline PASI score.

Continued treatment with Raptiva maintained the improvements achieved during the initial 12 weeks of Raptiva treatment and was associated with further improvement as indicated by a PASI‑75 response rate of approximately 44% after 24 weeks of continued treatment in Study 2390 and its extension, Study 2391. 

 

 

6.       CLINICAL SAFETY

6.1     Overview

A total of 2,762 subjects have been treated with Raptiva in the psoriasis clinical program.  Of these, 1,620 subjects received Raptiva during the 12‑week, placebo‑controlled portion of the four Phase III studies (2390, 2600, 2058, and 2059).  The nearly identical entry criteria and design of the first 12‑week, placebo‑controlled period support an analysis of the pooled data from the first 12 weeks of these studies.  Comparisons between placebo and Raptiva patients are based primarily on this 12‑week period.

Long‑term safety is supported by data from 1,115 subjects who received more than 12 weeks of Raptiva treatment.  Two hundred and twenty‑eight of these subjects received weekly injections for 1 year.

The adverse events that occurred at low frequency are examined using data combined from all of the subcutaneous Raptiva studies.  Incidence rates for these events are presented by subject‑years of observation.  In the current safety database, there are 186 subject‑years of observation for subjects who received placebo and 1,791 subject‑years of observation for subjects who received Raptiva.  Because these observation periods were not concurrent and the average observation time per subject differed between treatment groups, results of the incidence rate analyses should be interpreted with caution.

The majority of the subjects in the Raptiva database received either 1.0 mg/kg/wk or 2.0 mg/kg/wk.  In a few subjects, the dose was as high as 4.0 mg/kg/wk.

Given the 1620 subjects exposed to Raptiva in the placebo‑controlled period of the Phase III trials, the likelihood of observing an adverse event during a 12‑week treatment period with a true incidence of 1% is almost 100% and the likelihood of observing an event with a true incidence of 0.1% is ~80%.  Over all studies of Raptiva with subcutaneous exposure of 8–12 weeks, the likelihood of observing an adverse event with a true incidence of 1% or 0.1% during the treatment period for the 2,556 Raptiva‑treated subjects is approximately 100% and 92%, respectively.

 

6.2     CLINICAL Results

6.2.1   Demographics and Baseline Characteristics

The baseline demographics for subjects treated with Raptiva or placebo during the first 12 weeks in the Phase III studies were comparable (see Table 16).  The high body mass index (BMI) of subjects was consistent with observations that obesity is a frequent co‑morbidity with psoriasis (Stern 1995; Camisa 1998).  Other common co‑morbid conditions were also represented in the study cohort.  Overall, 33.1% of subjects had pre‑existing arthritis, 24.5% had hypertension, 10.2% had hypercholesterolemia, and 9.8% had diabetes. 

 

 

For baseline psoriasis characteristics, the Raptiva and placebo‑treated groups were comparable (see Table 17).

 

 

 

6.2.2   Subject Disposition (Phase III Studies)

Rates of treatment discontinuation during the first 12 weeks of exposure in the placebo‑controlled Phase III studies were low.  Approximately 8% of subjects discontinued treatment during the placebo‑controlled phase of the four Phase III studies, with similar discontinuation rates in the placebo‑treated and Raptiva‑treated groups (see Table 18).

The most common adverse events leading to discontinuation for subjects receiving Raptiva during this period were headache (9 subjects; 0.6%), psoriasis (9 subjects; 0.6%), pain (6 subjects; 0.4%), arthritis (6 subjects; 0.4%), and arthralgia (0.3%).

 

 

 

6.2.3   Drug Exposure (Phase III Studies)

During the first 12 weeks of treatment in the Phase III studies, more than 70% of the subjects received all doses of study drug, with no discernible differences between the placebo and active treatment groups (see Table 19).

 

 

6.2.4   Common Adverse Events (Phase III Studies)

Overall, 81% of all subjects had at least one adverse event during their first 12 weeks of treatment.  The percentage of subjects experiencing adverse events was approximately 9% greater for the 1.0 mg/kg/wk Raptiva‑treated group and 13% greater for the 2.0 mg/kg/wk Raptiva‑treated group than for the placebo‑treated group.  All adverse events that occurred in ³ 5% of subjects in the 1.0 mg/kg/wk group, 2.0 mg/kg/wk group, or placebo‑treated group are presented in Table 20.

 

 

Headache, chills, fever, nausea, vomiting, and myalgia occurring within 48 hours of any dose of study drug were pre‑specified as acute adverse reactions.  These tended to be mild and self‑limited, and are discussed in greater detail in Section 6.2.6.

Pain was reported for nearly twice as many subjects in the 1.0 mg/kg/wk Raptiva‑treated group as in the placebo‑treated group.  Frequent descriptions of the pain were generalized body aches or pain, pain in the lower extremities (knees, ankles, feet) and dental pain.  Most reports of pain were mild to moderate in intensity, with < 1% reported as severe.  None were serious.  Only 0.4% of patients discontinued treatment because of an adverse event of pain.  In addition to the 1,620 subjects who were first exposed to Raptiva in a placebo‑controlled study, 954 were first exposed in an uncontrolled setting.  The overall percentage of subjects with at least one adverse event and the types and rates of adverse events reported were similar in these two groups of subjects. 

Common adverse events during prolonged treatment, retreatment, and drug withdrawal are presented in Sections 6.4, 6.5, and 6.6, respectively.

 

6.2.5   Drug‑Related Adverse Events (Phase III Studies)

During the first 12 weeks of treatment in the placebo‑controlled studies, investigators reported more adverse events as drug‑related in subjects receiving Raptiva than in those receiving placebo.   The most common types of adverse events judged to be study drug–related were headache, chills, fever, flu syndrome, nausea, and myalgia.  Each of these were reported for 2%–12% more Raptiva‑treated subjects than placebo‑treated subjects (see Table 21).  Of note, headache, chills, fever, nausea, vomiting, and myalgia were pre‑specified in the protocols as potential mild to moderate adverse events associated with initial injections of Raptiva (acute adverse reactions, see Section 6.2.6). 

 

 

 

6.2.6   Acute Adverse Reactions (Phase III Studies)

Acute adverse reactions were pre‑defined as headache, fever, chills, nausea, vomiting, or myalgia starting within 48 hours (day of or two days following) of an injection of study drug.  Acute reactions such as these are not uncommon with biologic agents, especially monoclonal antibodies, and generally tend to occur after the initial doses and to be mild and self‑limited.

During the first 12 weeks of the placebo‑controlled studies, the percentage of subjects experiencing at least one acute adverse reaction was approximately twice as great for Raptiva‑treated subjects than for placebo‑treated subjects.  Headache was the most prevalent type of acute adverse reaction (see Table 22).  The incidence of vomiting was comparable in the placebo‑treated and 1.0 mg/kg/wk Raptiva‑treated groups.

These events were mostly mild to moderate in intensity, and none were serious.  The rate of study discontinuation due to an acute adverse reaction was less than 1%.  The median duration of the events were 1–2 days, and most events were self‑limited or resolved with Tylenol or NSAIDS.

 

 

The percentage of Raptiva‑treated subjects with at least one acute adverse reaction was greatest with the first dose, decreased to less than half the rate with the second dose, and diminished to a percentage comparable to that for subjects treated with placebo following the third and subsequent doses (see Figure 12).

Figure 12

Acute Adverse Reactions Experienced by Subjects during the First 12 Weeks of Treatment in the Placebo‑Controlled Studies

 

 

6.2.7   Deaths and Other Serious Adverse Events

a.  Deaths (All Studies)

In the total psoriasis safety database, death was an infrequent and was reported for 7 of the 2762 Raptiva‑treated subjects (0.3%) and 3 of the 715 placebo‑treated subjects (0.4%).  Two subjects died while receiving Raptiva, and 5 died after completing treatment.  No deaths were attributed to study drug by the investigators.  Table 23 summarizes these events.

 

Table 23 Deaths
Subject/ Study	Age (yr)/ Sex	Most Recent Dose	Duration of Study Drug Exposure	Time since Last Dose	Cause of Death	Clinically Relevant Medical History
11520/ 2058	60/M	1.0 mg/kg	12 Weeks	26.9 Weeks	Metastatic rectal cancer	None
68812/ c 2059	56/M	1.0 mg/kg	12 Weeks	~72 Weeks	Accidental death (plane crash)	None
81235/ 2059	70/M	Placebo	0	9.3 Weeks	Accidental death (drowning)	Hypertension
81601/ 2059	58/M	4.0 mg/kg	9 Weeks	5 Days	Arteriosclerosis	Type 2 diabetes mellitus, hypertension, hypercholesterolemia, double coronary bypass (two procedures), intermittent bilateral leg swelling, anemia
12062/ 2062	68/F	1.0 mg/kg	20 Weeks	~38 Weeks	Unknown	Hypertension, hypercholesterolemia, diabetes, stroke, congestive heart failure, pleural disorder
17907/ 2062	68/F	1.0 mg/kg	12 Weeks	~41 Weeks	Atherosclerotic cardiovascular disease	Dyspnea, palpitations, angina, diabetes, hypertension, claudication right calf, chronic anemia
28913/ 2243	68/M	2.0 mg/kg	11 Weeks	~27 Weeks	Micronodular cirrhosis	Migraines, hypertension, hyperlipidemia, triple coronary bypass (two events), and elevated SGOT and total and direct bilirubin
41011/ 2600	53/F	Placebo	7 Days	25 Days	Sudden cardiac death	COPD
42208/ 2600	47/F	Placebo	7 Days	4 Days	Seizure	Seizures and bipolar disorder
33007/ 2391	52/M	1.0 mg/kg	161 Days	48 Days	Myocardial infarction	Hypertension and smoking
COPD = chronic obstructive pulmonary disease; F = female; M = male.

b.  Serious Adverse Events

First Treatment Period of the Phase III, Placebo‑Controlled Studies

In the first 12‑week treatment period of the placebo‑controlled studies, the percentage of subjects reporting at least one serious adverse event was low in all treatment groups.  Most types of serious adverse events were reported for a single subject, and no pattern suggestive of particular toxicity was apparent.  All serious adverse events reported during this period are presented in Table 24.

 

 

 

Serious adverse events occurring during more prolonged treatment, the second course of treatment, or washout are discussed in Sections 6.4, 6.5, and 6.6, respectively. 

 

6.2.8   Malignancies (All Psoriasis Studies)

Because increased rate of malignancies have been seen with other immunosuppressive agents used to treat psoriasis, malignancy data from the Raptiva clinical program was closely examined.

During the initial 12‑week treatment period of the randomized, placebo‑controlled, Phase III studies, malignancies were reported for 2 subjects receiving placebo (0.3%; one event each of gastrointestinal carcinoma and non‑melanomatous skin cancer [NMSC]) and 4 subjects receiving Raptiva (0.2%; four events of NMSC).  Across all clinical studies of Raptiva in psoriasis, the observed incidence rate of malignancy in Raptiva‑treated subjects was similar to that observed in placebo‑treated subjects (see Table 25).

 

 

The eight solid tumors in Raptiva‑treated patients consisted of four cases of gastrointestinal carcinoma, two of prostatic carcinoma, and one each of breast carcinoma and lung carcinoma. 

NMSC includes both squamous cell and basal cell skin cancers.  For 20 Raptiva‑treated subjects, there were 13 reports of basal cell and 13 reports of squamous cell cancer.  For 2 placebo‑treated subjects, there were two reports each of basal cell and squamous cell cancers.  Thus, for both Raptiva‑treated and placebo‑treated subjects, the ratio of basal cell to squamous cell lesions was 1:1.

At the time of the submission of the Safety Update, there was one reported case of Hodgkin’s lymphoma, which is generally not associated with immunosuppression (see Table 25).  There had been no reported cases of lymphoproliferative disease during the formal study follow‑up period, although one case of cutaneous T‑cell lymphoma, which occurred 28 weeks after the last dose of Raptiva, had been reported.   Since this submission, a B‑cell lymphoma case was reported in a subject participating in an ongoing study.  This additional case of lymphoma, along with an updated estimate for subject‑years of observation (2203.16 subject‑years), yields an incidence rate of 0.09 per 100 subject‑years and a 95% confidence interval of 0.01 and 0.33, which is consistent with the expected background rate.

Because of the disparity in observation time for subjects receiving Raptiva or placebo, and given the low incidence of malignancies, the comparison between placebo and Raptiva must be made with caution.  Therefore, the observed frequency of malignancy in Raptiva‑treated subjects was also compared with expected frequencies derived from up to three external reference cohorts.  These external cohorts were the U.S. general population (age‑ and sex‑adjusted rates from the Surveillance, Epidemiology and End Results [SEER] database, the national tumor registry) and two moderate to severe psoriasis cohorts identified from insurance claims databases:  UnitedHealthcare and Saskatchewan Health. 

At the time of the submission of the Safety Update, the observed numbers of Raptiva‑treated subjects with lymphoma, solid tumors, or malignant melanomas were consistent with the number of expected cases estimated from the reference cohort data (see Table 26).  With the additional B‑cell lymphomas, the observed two cases of lymphoma (one Hodgkin’s lymphoma and one non‑Hodgkin’s lymphoma) in Raptiva‑treated subjects remained within the expected range based on data from two external cohorts (Saskatchewan Health:  3.7 and UnitedHealthcare:  2.9) using updated subject‑years of observation.  The published literature indicates that moderate to severe plaque psoriasis patients are at an increased risk of lymphoproliferative disorder compared with the general population (Margolis et al. 2001).

The observed number of cases of NMSCs in Raptiva‑treated subjects was greater than the expected number based on the Saskatchewan and UnitedHealthcare cohorts.  This difference between the observed and expected cases may represent ascertainment bias, since subjects in the Raptiva clinical trials were subject to more intensive surveillance, particularly of dermatologic lesions, than patients receiving standard clinical care.  Ascertainment bias for skin cancer among in psoriasis study cohorts has been reported in the literature (Marcil and Stern 2001).