Summary Basis of Decision for Raptiva

Human pharmacology and efficacy results were evaluated based on pivotal studies conducted with efalizumab manufactured by Genentech. This decision was based on the fact that the Sponsor failed to demonstrate bio-equivalency between the two formulations of efalizumab (Xoma and Genentech). Clinical efficacy and safety data obtained in clinical trials conducted on efalizumab manufactured by Genentech were considered pivotal and data obtained in clinical trials on efalizumab manufactured by Xoma were considered supportive.

3.3.1 Pharmacodynamics

In the PD data collected, efalizumab down-modulated both CD11a expression and its available binding sites on circulating T-lymphocytes. Mean lymphocyte counts approximately doubled relative to baseline in subjects receiving 1.0 mg/kg/wk of efalizumab. This increase included CD4 T-lymphocytes, CD8 T-lymphocytes, B-lymphocytes, and NK cells, although NK cells and CD4 cells increased less relative to other cell types.

In conjunction with immunosuppressive regimens, co-administration of efalizumab resulted in down-modulation of CD11a expression as was seen in earlier studies with psoriasis subjects.

3.3.2 Pharmacokinetics

One study was conducted to determine the PKs and PDs of multiple doses of efalizumab in the presence of adjunctive immunosuppressive agents. During the study, renal transplant subjects administered both 0.5 and 2.0 mg/kg/week efalizumab doses produced higher serum levels of efalizumab than was predicted or found in psoriasis subjects from earlier studies who were given equivalent doses. The average trough concentrations measured at day 84 were similar for the two renal transplant groups receiving 2.0 mg/kg/wk efalizumab, however, these were more than two-fold the values obtained from the dose-matched psoriasis subjects. At 2.0 mg/kg/wk, the steady state trough concentrations in the renal transplant patients and psoriasis subjects were 33.5 ± 16.1 μg/mL and 13.8 ± 11.4 μg/mL respectively. The steady state clearance (Cl_ss ) amongst the two renal transplant dose groups was also similar. There were slower clearance rates in the two renal transplant dose groups than in dose-matched psoriatic subjects. This may be due to fewer circulating T-lymphocytes in the renal transplant subjects due to the immunosuppressive activity of medication which is associated with a lower systemic clearance of efalizumab as well as absence of activated T-lymphocytes.

In renal transplant patients, the data obtained suggested that adjunctive treatment with immunosuppressive regimens affected the PKs but not the PDs of efalizumab when compared with the psoriatic patients. Furthermore, the PKs of the immunosuppressive agents were not altered by the presence of efalizumab. The changes in the PK of efalizumab cannot be attributed to the presence of the immunosuppressive agents, but are probably due to the factors mentioned earlier as well as due to the functional state of the kidneys as this affects renal clearance. Data from these studies also indicate that the study drug is effective when administered by SC injection with a bioavailability of approximately 50%.

In a Phase I, single dose, dose escalation, multi-centre study, 31 subjects with severe plaque psoriasis were enrolled at 7 study centres. Each subject received a single dose ranging from 0.03-10.0 mg/kg efalizumab administered by IV infusion. Efalizumab exhibited non-linear PKs in this study as analysis of the PK data collected through day 72 revealed a concentration-dependent clearance with a decrease in clearance rate from 380 mL/day/kg at 0.03 mg/kg dose to approximately 6.64 mL/day/kg at the 10.0 mg/kg dose level. This was indicative of receptor-mediated clearance which was saturable at plasma efalizumab concentrations above 1.0 μg/mL. There were notable inter-subject variations, and in three of the seven dose groups, PK parameters were calculated from one or two subjects in the dose group. The sample size of the study was small, therefore, it was regarded as a pilot study.

In a second Phase I, open label, multiple dose, dose escalation, multi-centre study, a total of 39 subjects were enrolled at 8 study centres and administered efalizumab by IV infusion at doses ranging from 0.1 to 1.0 mg/kg/week. In the 0.6 mg/kg/wk dose group, steady-state plasma levels were not achieved, as by day 42 there was a statistically significant difference in efalizumab trough values between days 21 and 42. There was a dose-dependent increase in both peak and trough efalizumab plasma levels at day 42. As in the previous study, the PK results demonstrated that clearance of the drug was receptor-mediated and therefore was reduced at higher dosage due to receptor saturation. The Cl_ss evaluated during the week of the last dose tended to decrease consistently with increasing weekly dose from 95.7 ± 27.6 mL/day/kg at 0.1 mg/kg/wk to 11.2 ± 8.5 mL/day/kg at 1.0 mg/kg/wk. The area under the concentration-time curve (AUC) was also dose-dependent. Due to the sample size, this study was also regarded as a pilot study.

Thirdly, an open label study was conducted to characterize the PKs and PDs of 12 weeks of treatment with efalizumab administered SC in up to 70 subjects. Each subject had moderate to severe plaque psoriasis and was each given 1.0 mg/kg/wk or 2.0 mg/kg/wk of efaluzimab following a conditioning dose of 0.7 mg/kg. There were dose-dependent increases in the PK parameters when the two dose groups were compared. The steady-state serum efalizumab concentration levels were achieved at the fourth week of dosing in the 1.0 mg/kg/wk group and at the eighth week of dosing in the 2.0 mg/kg/wk dose group. Clearance was lower in the higher dose group as occurred in earlier studies.

In a population pharmacokinetics (PPK) study, data from four different studies were analysed. The analysis encompassed a total of 1868 efalizumab concentrations from 1087 patients who received 1.0 or 2.0 mg/kg efalizumab as a weekly SC dose for 77 days. A total of 483 of the patients (44%) were treated with the Genentech formulation. In developing models for this PPK analysis, a one-compartmental linear model was fitted to efalizumab concentration-time data with the basic parameters as apparent clearance (CL/F), apparent volume of distribution (V/F), and a first order absorption rate constant k_a. CL/F was the only PK structural parameter that would influence efalizumab steady state trough concentrations in the Phase II and Phase IIIb data sets (as used in the analysis). Covariate effects were evaluated only for CL/F.

The analyses showed that the baseline bodyweight is the most important covariate for efalizumab CL/F value which would explain inter-individual variability. Baseline Psoriasis Area Severity Index (PASI), baseline lymphocyte count, age, sex, and race/ethnicity did not result in clinically important changes in efalizumab CL/F_ss.

Data from six of the PK/PD studies conducted demonstrated that efalizumab exhibits non-linear PK. Disproportionate dose-dependent profiles in serum concentrations were achieved at the 4^th or 8^th weekly dosing. Population PK data showed that baseline bodyweight was the only covariate that affected efalizumab's apparent clearance CL/F value.

3.3.3 Clinical Efficacy

Study ACD2390g was used as the pivotal study to assess the efficacy of efalizumab. Efficacy of the 12-week course of 1.0 mg/kg/week efalizumab was also assessed in study ACD2600g as a secondary endpoint.

Seven Phase III study reports were submitted including: 2 pivotal studies, 3 supporting studies, and 2 protocols of preliminary study results. The primary efficacy endpoint was the proportion of patients who achieved ≥ 75% improvement in the PASI score at the end of a 12 week treatment with 1.0 mg/kg/wk. Of the subjects treated, 26.6% of subjects treated with efalizumab manufactured by Genentech achieved ≥ 75% improvement in the PASI score at the end of a 12-week treatment with 1.0 mg/kg/wk as compared to 4.3% of subjects treated with placebo. The demonstrated treatment effect was 22.3%.

Statistically significant differences favouring efalizumab were demonstrated for the following secondary endpoints: the proportion of patients who achieved overall lesion severity index (OLS) of minimal or clear (25.7% of efalizumab-treated patients versus 3.2% of placebo-treated patients) and the proportion of patients who achieved a PASI response of ≥ 50% (58.5% in the efalizumab-treatment group compared to 13.9% in the placebo treatment group). A physician's global assessment (PGA) of excellent or cleared was demonstrated for 33.1% of efalizumab-treated subjects compared to 5.3% of placebo-treated subjects. Severity of itching as measured by the itching scale, exhibited mean improvement at day 84 relative to day 0. The improvement was statistically significant in the efalizumab group as compared to the placebo group. In terms of the Psoriasis Symptom Assessment (PSA), a comparison of the improvement in psoriasis specific symptoms for the efalizumab group versus the placebo group was statistically significant for both the frequency and severity of symptoms. All secondary efficacy endpoints achieved statistical significance after multiplicity adjustments were performed. Efalizumab treatment effect was observed on day 28 after initiation of treatment in the pivotal study. The duration of response was not assessed in the pivotal study conducted with the efalizumab formulation manufactured by Genentech.

In the pivotal study ACD2600g, 23.6% of efalizumab-treated patients achieved a PASI response of ≥ 75%. In a supportive study, similar results were confirmed in a subgroup analysis of patients who were not controlled by, contraindicated to, or intolerant to two or more systemic therapies (CLEAR study IMP24011).

Long-term data up to 108 weeks have been obtained in one open-label study (ACD2243g). In order for patients to enter long-term continuous therapy in the maintenance treatment period, they had to have achieved at least a PASI ≥ 50 response or an OLS rating of Clear, Minimal or Mild at Week 12. Patients, who did not achieve this level of clinical benefit at week 12, were withdrawn from the study. Of the 339 patients recruited to the study, 86% (n=290) achieved the required clinical benefit at week 12. PASI ≥ 75 and PASI ≥ 50 responses were 41% and 82%, respectively. The initial response to efalizumab therapy was maintained with continuous treatment over a 108-week period for those patients who remained on treatment.

In conclusion, the efficacy results observed in the studies were consistent. A 12-week treatment course with 1.0 mg/kg/wk efalizumab was demonstrated to be effective in the treatment of patients with moderate to severe plaque psoriasis compared to treatment with placebo.

3.3.4 Clinical Safety

There were 4 placebo-controlled, Phase III, randomized studies evaluating the safety of the administration of efalizumab. Two of these studies were conducted using efalizumab manufactured by Xoma or both Xoma and Genentech manufactured efalizumab formulations. As a result, a lower proportion of subjects that received efalizumab manufactured by Genentech was included for safety evaluation. Safety results were assessed using a consolidated safety dataset which included subjects treated with efalizumab manufactured by both XOMA and Genetech.

Safety data were examined in subgroups defined by age (18-40, 41-64, ≥ 65 years old), sex, race/ethnicity, baseline PASI score ( ≤ 6.0, 16.1-30.0, >30.0), prior systemic treatment, etc. During clinical trials the most commonly reported adverse events (AE) were reactions related to the first administration of efalizumab. Cases of serious infections were reported in clinical trials as well as in post-marketing reports. Serious cases of immune-mediated thrombocytopenia and haemolytic anaemia were reported.

Common and Acute Adverse Events:

In first exposure (FE), controlled studies, 82% of all subjects had at least one AE and approximately 92% of the subjects receiving 1.0 mg/kg/wk efalizumab experienced at least one AE compared to the subjects receiving placebo.

During the FE/Controlled Studies, 44.4% of all subjects receiving efalizumab and 27.3% of subjects receiving placebo had at least one AE judged by the investigator to be related to study drug administration. The reported acute AEs included headache, chills, fever, flu syndrome, nausea, and myalgia, were reported for 2% -9% more efalizumab-treated subjects than placebo treated subjects. Acute AEs occurred within 48 hours after first administration of efalizumab. These reactions were greatest with the first dose administration, decreasing with the second and subsequent doses. Of subjects treated with Genentech efalizumab, 40% as compared to 20% of placebo-treated subjects experienced at least one acute AE. The most common acute AE reported was headache which was reported in 32.2% of efalizumab treated subjects versus 22.2% of placebo treated subjects in the combined safety database.

In addition, the long-term open-label study, ACD2243g did not show any noteworthy differences in frequency of adverse events up to 108 weeks of continuous treatment as compared to 12 weeks of exposure to efalizumab. The incidence rate of adverse events decreased over time.

Serious Adverse Events

Serious adverse effects (SAEs) were reported in 2.4% of efalizumab-treated subjects and 2.2% of placebo treated subjects.

To increase the power to detect clinically meaningful patterns among rare AEs, all SAEs in the clinical database were combined across all periods for subjects treated with both the Genentech and Xoma formulation of efalizumab in the completed and ongoing studies. Among the 2589 psoriasis subjects treated subcutaneously, the most frequent serious AE was psoriasis (referring to worsening of symptoms or development of a new form) (reported for 19 subjects; 0.7%) followed by arthritis (15 subjects; 0.6%). Approximately half of the events of psoriasis or arthritis occurred after discontinuation of efalizumab. Other relatively frequent SAEs in descending order were: skin carcinoma (12 subjects; 0.5%), accidental injury (9 subjects; 0.3%), cellulitis (8 subjects; 0.3%), pneumonia (7 subjects; 0.3%), bone disorder (6 subjects; 0.2%), deep thrombophlebitis and kidney calculus (5 subjects; 0.2% each), and gastrointestinal carcinoma, sepsis, coronary artery disorder, and myocardial infarct (4 subjects; 0.3% each). All other types of SAEs occurred in 3 (0.1%) or fewer subjects (≤ 0.1% of all treated subjects).

In the FE/Controlled Studies 9.9% of subjects who received efalizumab experienced an SAE compared with 5.1% of subjects who received placebo. Of the Genentech efalizumab-treated subjects, 19 (4.0%) of the subjects who received efalizumab and 1 placebo-treated subject (0.5%) had at least one acute AE that was rated by the investigators as severe in intensity. Headache was the most common severe acute AE, occurring in 16 of 19 subjects.

Adverse Events of Infection

In placebo-controlled clinical trials, infection rates were 27.3% in efalizumab -treated patients versus 24.0% in placebo-treated patients. In both controlled and uncontrolled studies, the overall incidence of hospitalization for infections was 1.6 per 100 patient-years for efalizumab -treated patients compared with 1.2 per 100 patient-years for placebo-treated patients.

There were two potential cases of opportunistic infections: pneumonia (Legionella pneumonia) and osteomyelitis.

Adverse Events of Psoriasis

Adverse events of psoriasis, referring to worsening of symptoms or the development of a new form of psoriasis were reported in 3.2% of efalizumab treated patients compared to 1.4% of placebo-treated patients. Examples of new forms of psoriasis included guttate psoriasis, recurrence of plaque psoriasis and psoriatic erythroderma.There was a 0.7% incident rate of an SAE of psoriasis. Cases of inverse psoriasis, palmo-plantar psoriasis, and pustular psoriasis were observed only in efalizumab-treated subjects. Although the majority of psoriasis-related AEs were reported following discontinuation of efalizumab, some were observed during therapy. The mechanism of these events is not clear and should be further explored in future clinical studies.

Adverse Events of Arthritis:

Of the subjects treated with efalizumab 2.4% as compared to 2.2% of subjects treated with the placebo reported AEs of arthritis. In total, 0.4% of these reported instances were serious.

Immuno-modulated Adverse Events (Auto-immune Adverse Events):

Adverse events of thrombocytopenia were reported in placebo-controlled clinical studies as well as in post-marketing safety adverse reports. In the combined safety database (subjects treated with both formulations of efalizumab) there were no cases of thrombocytopenia reported in the placebo group and <0.1% of cases reported in the efalizumab group. Four cases of severe thrombocytopenia were reported in post-marketing reports and one case was lost to follow-up. Treatment with systemic corticosteroids was often initiated, however, platelet transfusions were performed in some cases. The majority of thrombocytopenia AEs occurred within the first 3 months of treatment, however, some cases were reported after several months of treatment.

Two cases of hemolytic anemia were reported in clinical trials. An additional 2 cases of hemolytic anemia were reported in post-marketing experience.

Malignancies:

Of the subjects who received efalizumab, 1.2% were diagnosed with malignancies.

In the placebo-controlled clinical trials, the overall incidences of malignancy (the majority of which were non-melanoma skin cancers) were similar in efalizumab-treated patients and in placebo-treated patients. In addition, the incidences of specific tumours in efalizumab patients (such as lymphoma), were in line with those observed in control psoriasis populations. Among psoriasis patients who received efalizumab at any dose, the overall incidence of malignancies of any kind was 1.7 per 100 patient-years for efalizumab-treated patients compared with 1.6 per 100 patient-years for placebo-treated patients. Twelve-week treatment with efalizumab during placebo-controlled clinical trials has demonstrated that the rate of malignancies was within the expected range in the psoriatic population.

There was no clear evidence of the role of efalizumab in relation to the development of malignancies, however, a relation could not be ruled out. Further study with a significant observation period is required to evaluate the relationship between efalizumab administration and the development of malignancies.

Laboratory Abnormalities:

White Blood Cell Count
In clinical studies, treatment with efalizumab was associated with increases in white blood cell count (35% increase relative to baseline compared to no increase in placebo group).

Absolute Lymphocyte Count
The absolute lymphocyte count approximately doubled relative to baseline in subjects receiving the Genentech efalizumab formulation during the FE/Controlled studies. Such increases were not reported in the placebo-treated patients. This increase is expected, as it is consistent with the mechanism of action of efalizumab.

Absolute Eosinophil Count
The absolute eosinophil count increased by approximately one-third relative to baseline. No increases in placebo-treated subjects were reported.

Absolute Neutrophil Count
The absolute neutrophil count increased by approximately 10% relative to baseline in subjects receiving the Genentech efalizumab formulation. No increases were reported in placebo-treated subjects.

Platelet Count
The mean platelet count declined 2.5% in subjects receiving efalizumab and 1.6% in subjects receiving placebo.

Alkaline Phosphatase
Elevations in alkaline phosphatase levels were reported in subjects treated with efalizumab, however, there was no association with elevations of other hepatic tests.

C-Reactive Protein (CRP)
Increases in CRP and fibrinogen were reported more often in efalizumab-treated subjects than in placebo-treated subjects.

Haemolytic Anaemia
There was 1 case reported in a Periodic Safety Update Report (PSUR), 2 cases were reported in clinical trials. The United States Food and Drug Administration published a warning, reporting 2 cases of haemolytic anaemia during the post-marketing experience and requested the update of current labelling to incorporate the incidence of AEs of haemolytic anaemia.

Hypersensitivity Adverse Events:

In the combined database, 6.9% of subjects treated with placebo and 7.8% of subjects treated with 1.0 mg/kg/wk efalizumab experienced a hypersensitivity AE.

Raptiva is contraindicated in:

• Patients who are hypersensitive to efalizumab, or to any ingredient in the formulation, or Chinese Hamster Ovary cell proteins. For a complete listing, please refer to the Product Monograph.
• Patients with a history of malignancies.
• Patients with immunodeficiencies.
• Patients with active tuberculosis and other severe infections.