Data Sheet
RAPTIVA®
Efalizumab (rch) powder for injection
Name of Medicine
RAPTIVA® for Injection, efalizumab (rch) 125mg Powder for Injection.
CAS. No. : 214745-43-4
Presentation
RAPTIVA is supplied as a sterile, white to off-white, lyophilised powder in single-use glass vials for subcutaneous (SC) injection. Each vial is designed to deliver 125 mg of efalizumab. Reconstitution with 1.3 mL of supplied Sterile Water for Injections yields a clear to slightly opalescent and colourless to pale yellow solution containing 100 mg/mL efalizumab. Other excipients include 2.5 mg polysorbate 20, 3.55 mg histidine, 5.70 mg histidine-hydrochloride, 102.7 mg sucrose, and 1.3 mL Sterile Water for Injections.
Uses
Actions
Efalizumab binds specifically to the CD11a alpha-chain of LFA-1 (leukocyte function associated antigen-1) and inhibits the adhesion of T lymphocytes to other cell types presumably by inhibiting the binding of LFA-1 to ICAM-1 (intercellular adhesion molecule-1). This results in reduced inflammation by any or all of the following mechanisms: inhibition of CD11a expression, inhibition of T lymphocyte proliferation, inhibition of T lymphocyte trafficking to psoriatic lesions; inhibition of T lymphocyte interaction with keratinocytes.
Pharmacodynamics
In studies using a conditioning dose of 0.7 mg/kg followed by 11 weekly doses of 1.0 mg/kg/wk, RAPTIVA maximally reduced expression of CD11a on circulating T lymphocytes to approximately 15 to 30% of pre-dose baseline levels, and CD11a binding site availability to drop to < 5%. The full effect on CD11a expression and binding availability was observed 24 to 48 hours following the first dose, and was maintained between weekly SC doses.
Within 5 to 8 weeks following the 12th and final dose of RAPTIVA administered at 1.0 mg/kg/wk, CD11a levels returned to within 25% of baseline values.
Another pharmacodynamic marker was the increase in the absolute counts of circulating leukocytes observed during RAPTIVA treatment. Increased absolute counts were apparent within 24 hours of the first dose, remained elevated with weekly dosing, and returned to baseline after treatment cessation.
The largest increase occurred in the absolute count of circulating lymphocytes. In clinical trials, mean lymphocyte counts approximately doubled relative to baseline in subjects receiving 1.0 mg/kg/wk of RAPTIVA. The increase included CD4 T lymphocytes, CD8 T lymphocytes, B lymphocytes, and natural killer (NK) cells, although NK cells and CD4 cells increased less relative to other cell types. Following discontinuation of SC dosing lymphocyte levels returned to within 10% of baseline by 8 weeks post last dose. The observed increase in lymphocytes is related to the mechanism of action of RAPTIVA, which leads to a redistribution of lymphocytes from the inflamed tissue(s) to the vascular system.
Pharmacokinetics
Absorption
Average RAPTIVA bioavailability following SC administration was estimated at 30 to 50%.
Distribution
RAPTIVA shows non-linear pharmacokinetics with disproportionate increases in AUC with increasing doses. This may be due to saturation of the CD11a receptor on leukocytes. In studies using a conditioning dose of 0.7 mg/kg followed by 11 weekly doses of 1.0 mg/kg/wk, RAPTIVA serum concentrations reached a steady-state by 4 weeks with mean trough and peak concentrations of approximately 9 μg/mL and 12 μg/mL respectively. Average RAPTIVA bioavailability following SC administration was estimated to be at 30% to 50%.
Metabolism
Apparent steady-state clearance was non-linear and averaged 24 mL/kg/day (range = 5 to 76 mL/kg/day, n = 25) at the 1.0 mg/kg/wk SC dose.
Based on data from 1,088 patients, body weight was found to be the most significant covariate affecting RAPTIVA clearance, consistent with weight-based dosing. The clearance of RAPTIVA was not significantly affected by gender, race, baseline Psoriasis Area and Severity Index (PASI), baseline lymphocyte count or age.
Average time taken to eliminate RAPTIVA after the last steady-state dose was 25 days (range 13 to 35 days, n=17).
The terminal half-life (t1/2) of RAPTIVA when administered subcutaneously at its indicated dose of 1.0 mg/kg, is approximately 5 days.
No studies have been conducted in subjects with hepatic or renal impairment, or in children.
Indications
Raptiva is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis, who are candidates for phototherapy or systemic therapy. The duration of the therapy is 12 weeks. Therapy may only be continued in patients who respond to treatment (PASI 50 or better).
Dosage and Administration
RAPTIVA is given as a SC injection.
Adult Dose
RAPTIVA should be administered as a single conditioning dose of 0.7 mg/kg followed by weekly injections of 1.0 mg/kg. The maximum single dose should not exceed a total of 200 mg.
Fever and flu-like symptoms can be treated with paracetamol or non-steroidal anti-inflammatory drug (NSAID). Pre-medication with these drugs may decrease the incidence of these events and further increase the tolerability of RAPTIVA.
Reconstitution
RAPTIVA should be administered using the sterilised, disposable pre-filled syringe and needles provided (see PRESENTATION). Remove the cap from the pre-filled syringe containing Sterile Water for Injection for reconstitution and attach the needle to the syringe. Before needle insertion, remove the plastic cap protecting the rubber stopper of the RAPTIVA vial. Do not touch the top of the vial. To prepare the RAPTIVA solution, slowly inject the 1.3 mL of Sterile Water for Injections in the provided pre-filled syringe into the RAPTIVA vial. Swirl the product vial with a GENTLE rotary motion without removing the syringe. DO NOT SHAKE (Shaking will cause foaming of the RAPTIVA solution). Generally, dissolution of RAPTIVA takes less than 5 minutes.
The reconstituted solution should be clear to slightly opalescent and colourless to pale yellow. The solution is to be used immediately. Although not recommended, the solution may be stored at 2°C to 8°C (Refrigerate. Do not Freeze) for up to 24 hours.
Administration
Visually inspect the solution for particulate matter and discolouration prior to administration. The solution should not be used if discoloured or cloudy or if particulate matter remains. Invert the vial and, taking care to keep the needle below the level of the liquid, withdraw the solution into the syringe, removing from the vial only the dose to be given.
Replace the needle on the syringe with a new needle and remove any air bubbles.
No other medications should be added to solutions containing RAPTIVA, and RAPTIVA should not be reconstituted with other diluents.
Sites for self-injection include thigh, abdomen, or upper arm. Injection sites should be rotated.
Individual reconstituted vials should be for single patient use only. Following administration, discard any unused reconstituted RAPTIVA solution.
Contraindications
RAPTIVA is contraindicated in:
- Patients with hypersensitivity to efalizumab, or to any of the excipients (see PRECAUTIONS);
- Patients with malignancies;
- Patients with active tuberculosis or severe infection.
Warnings and Precautions
Infections
Selective immunosuppressive agents that affect T lymphocyte function, including RAPTIVA, may affect host defenses against infections and potentially increase the risk or severity of infection. Patients receiving such therapies may be at higher risk of developing serious infections eg., reactivate latent chronic infections such as JC virus infection. In placebo-controlled trials, the overall rate of diagnosed infection was comparable in patients receiving a 12 week course of RAPTIVA or placebo. Patients developing infection while undergoing treatment with RAPTIVA should be monitored, and according to severity, RAPTIVA should be discontinued. Physicians should exercise caution when considering the use of RAPTIVA in patients with a history of significant recurring infections.
The use of Raptiva may be associated with an increased risk of Progressive Multifocal Leukoencephalopathy (PML). One case of JC virus infection resulting in PML has been reported in post-marketing surveillance in a patient with psoriasis receiving Raptiva. Patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML (such as impaired cognition, visual disturbances, hemiparesis, altered mental state or behavioural changes). If PML is suspected, further dosing must be suspended until PML has been excluded. The clinician should evaluate the patient to determine if the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms are possibly suggestive of PML. If any doubt exists, further evaluation, including Magnetic Resonance Imaging (MRI) scan preferably with contrast, cerebrospinal fluid (CSF) testing for JC viral DNA and repeat neurological assessment, should be considered.
If a patient develops PML, Raptiva treatment must be permanently discontinued (see discontinuation section below).
In post-marketing experience, serious bacterial, viral, fungal and opportunistic infections have occurred including pneumonia, sepsis, meningitis and encephalitis. Some of these infections have been fatal. Post-marketing reports include cytomegaloviral infections; blastomyces, cryptococcal and tuberculous pneumonia; serious herpes infection; severe pneumonia with neutropenia (ANC 60/mm³); sepsis with seeding of distant sites; necrotising fasciitis; and worsening of infection (eg. cellulitis, pneumonia) despite antimicrobial treatment.
Malignancy and lymphoproliferative disorders
RAPTIVA is an immunosuppressive agent. Many immunosuppressive agents like RAPTIVA exert immunosuppressive activities with the potential to increase the risk of malignancy. The role of RAPTIVA in the development of malignancy or lymphoproliferative disorders is not known. Caution should be exercised when considering the use of RAPTIVA in patients at high risk of malignancy or with a history of malignancy. If a patient develops a malignancy, RAPTIVA should be discontinued.
Use with other agents
The safety and efficacy of RAPTIVA in combination with other immunosuppressive agents or phototherapy have not been evaluated. RAPTIVA should therefore, not be used in combination with such agents because of the possibility of increased risk of infections and malignancies.
Immunization
The safety and efficacy of vaccines administered to patients receiving RAPTIVA have not been studied. Antibody responses to tetanus toxoid were reduced in chimpanzees receiving efalizumab. Acellular, live and live-attenuated vaccines should not be administered during RAPTIVA treatment.
Thrombocytopenia
Platelet counts at or below 52,000 cells/μL were observed in 9 (0.3%) RAPTIVA treated patients during clinical trials compared with none among the placebo-treated patients (see ADVERSE REACTIONS). Six of the 9 patients received a course of systemic steroids. Thrombocytopenia resolved in 8 patients receiving adequate follow-up (1 patient was lost to follow-up). Physicians should follow patients closely for the signs and symptoms of thrombocytopenia. Assessment of platelet counts is recommended on initiation and periodically during treatment with RAPTIVA (see Laboratory Test).
If a patient presents ecchymoses, spontaneous bruising, or bleeding from mucocutaneous tissues, RAPTIVA should be stopped immediately and a platelet count should be performed.
Haemolytic Anemia*
In post-marketing Surveillance, rare cases of severe haemolytic anemia have been reported during treatment with RAPTIVA. In such circumstances, RAPTIVA should be discontinued.
Sensitivity
As for any recombinant product, RAPTIVA is potentially immunogenic. Consequently, if any serious hypersensitivity or allergic reaction occurs, RAPTIVA should be discontinued immediately and appropriate therapy initiated (see ADVERSE REACTIONS).
Psoriasis
Cases of exacerbation of psoriasis including pustular and erythrodermic psoriasis, have been observed during treatment with RAPTIVA.
Arthritis
Cases of arthritis have been observed during treatment or after discontinuation with RAPTIVA. Subjects improved after discontinuation of RAPTIVA with or without anti-arthritis therapy.
Neurological Events
Cases of inflammatory polyradiculoneuropathy have been observed in post-marketing surveillance in patients receiving RAPTIVA. Most patients improved after discontinuation of RAPTIVA, therefore RAPTIVA should be stopped following the diagnosis of inflammatory polyradiculoneuropathy.
Patients being treated with RAPTIVA should be instructed to report any new neurological symptoms to their physician. Prescribers should exercise caution in considering the use of RAPTIVA in patients with significant existing or new onset nervous system adverse effects. RAPTIVA should be discontinued in patients who develop PML.
Discontinuation
Abrupt discontinuation of RAPTIVA without substitution treatment may be followed by recurrence of psoriasis or emergence of new psoriasis morphologies, including erythrodermic and pustular psoriasis. Such recurrences have been observed in 5% to 10% of cases. If RAPTIVA was resumed upon psoriasis relapse, the frequency of full psoriasis flare-ups * was below 1%. In case of abrupt discontinuation, patients should be monitored and given appropriate treatment, if necessary.
Carcinogenesis, Mutagenesis and Impairment of Fertility
No animal studies have been performed to evaluate carcinogenic or mutagenic potential, or whether RAPTIVA affects fertility. Studies in mice, sensitive to lymphoma induction, using analogous antibody (muM17) that selectively inhibits mouse CD11a functional activity revealed no evidence of lymphoma development or any other neoplasia when administered up to 30 mg/kg/week SC for 6 months. No evidence of impaired fertility or general reproductive performance of males or females was observed when mice were administered muM17 at weekly doses of up to 30 mg/kg/week SC.
Use in Pregnancy
Pregnancy Category C
No studies of RAPTIVA have been conducted in pregnant women. It is not known whether RAPTIVA can cause fetal harm when administered to a pregnant woman.Immunoglobulins are known to cross the placental barrier. RAPTIVA should not be given to pregnant women.
Because RAPTIVA does not cross react with CD11a in species other than humans and chimpanzees, animal reproduction studies with RAPTIVA have not been conducted. However, reproduction studies were performed in mice with the surrogate antibody, muM17. No adverse effects on behavioural, reproductive or growth parameters were observed in offsprings (F1 generation) of female mice exposed to muM17 weekly during gestation and lactation at doses up to 30 mg/kg SC. At 11 weeks of age, the F1 generation mice had intact cell mediated immunity and a transient reduction in the primary antibody response, which was normal by 25 weeks of age. In an embryofetal development study at weekly doses up to 30 mg/kg SC during gestation, no evidence of maternal toxicity, embryotoxicity or teratogenicity was observed.
Use in lactation
It is not known whether RAPTIVA is excreted in human milk. The surrogate antibody muM17, when administered to lactating mice, was detected in milk. The offspring of the exposed females exhibited reduction in antibody responses, which returned to normal by 25 weeks of age.
Because immunoglobulins are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from RAPTIVA, women should not breastfeed during treatment with RAPTIVA.
Paediatric Use
The safety and effectiveness of RAPTIVA in paediatric patients (<18 years of age) have not been established.
Geriatric Use
Treatment with RAPTIVA has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. As there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly.
Adverse Reactions
The most frequent symptomatic adverse drug reactions (ADRs) observed during RAPTIVA therapy were mild to moderate dose-related acute flu-like symptoms including headache, fever, chills, nausea and myalgia. In large placebo-controlled clinical studies, one or more of these reactions were observed in approximately 42% of RAPTIVA treated patients and 24% in placebo-treated patients over 12 weeks of treatment. After initiation of therapy, these reactions were generally less frequent and occurred at rates similar to that seen in the placebo group after the third injection.
Human anti-human antibodies (HAHA) to RAPTIVA were detected in approximately 6.3% of patients evaluated. Although exposure to RAPTIVA was apparently reduced in these subjects, the HAHA response had no impact on pharmacodynamic parameters or pharmacokinetics. There was no apparent impact on overall safety, or clinical efficacy of the medicinal product.
Adverse Events are listed in Table 1 below
| Body System | Preferred Term | Placebo (N=715) | RAPTIVA 1.0 mg/kg/wk (N=1213) |
|---|---|---|---|
| Body as a Whole | Headache | 159 (22.2%) | 391 (32.2%) |
| Chills | 32 (4.5%) | 154 (12.7%) | |
| Pain | 38 (5.3%) | 122 (10.1%) | |
| Flu like Syndrome | 29 (4.1%) | 83 (6.8%) | |
| Asthenia | 37 (5.2%) | 81 (6.7%) | |
| Fever | 24 (3.4%) | 80 (6.6%) | |
| Back Pain | 14 (2.0%) | 50 (4.1%) | |
| Viral Infection | 8 (1.1%) | 27 (2.2%) | |
| Abdominal Pain | 6 (0.8%) | 25 (2.1%) | |
| Chest Pain | 4 (0.6%) | 20 (1.6%) | |
| Nervous | Migraine | 2 (0.3%) | 16 (1.3%) |
| Digestive | Nausea | 51 (7.1%) | 128 (10.6%) |
| Metabolic/Nutritional | Peripheral Oedema | 18 (2.5%) | 47 (3.9%) |
| Musculoskeletal | Myalgia | 35 (4.9%) | 102 (8.4%) |
| Arthralgia | 19 (2.7%) | 53 (4.4%) | |
| Skin/Appendages | Acne | 4 (0.6%) | 45 (3.7%) |
| Psoriasis | 10 (1.4%) | 39 (3.2%) |
Additional Information
Flu-like syndrome and related symptoms
In large placebo-controlled clinical studies, approximately 20% of subjects in excess of placebo reported one or more acute flu-like symptoms including headaches, chills, fever, nausea and myalgia. The percentage of subjects reporting flu-like symptoms was greatest with the first injection, decreased by more than 50% with the second injection, and diminished thereafter to a percentage comparable to that of subjects treated with placebo. Headache was the most prevalent component of the flu-like symptoms. None of the events were serious and less than 5% were considered severe. Overall fewer than 1% of subjects discontinued therapy because of flu-like symptoms.
Leucocytosis and lymphocytosis
In large placebo-controlled clinical studies, up to 50% of subjects developed sustained asymptomatic lymphocytosis during RAPTIVA therapy. All values were between 2.5x and 3.5x the ULN (Upper Limit of Normal). Lymphocyte count returned to baseline following therapy discontinuation. A slight elevation in absolute neutrophil count and eosinophil count was observed but in a smaller proportion of patients.
Thrombocytopenia
In the combined safety database of 3,291 RAPTIVA treated patients, there were 9 occurrences (0.3%) of thrombocytopenia with less than 52,000 cells per μL reported. Four of these patients had clinical signs of thrombocytopenia. Based on available platelet count measurements, the onset of platelet decline was between 8 and 12 weeks after the first dose of RAPTIVA in 5 patients, but occurred later in the other patients. In one patient, thrombocytopenia occurred 3 weeks after treatment discontinuation. The platelet count nadirs occurred between 12 and 72 weeks after the first dose of RAPTIVA.
Elevation of alkaline phosphatase and liver transaminase (ALT)
In large placebo-controlled clinical studies approximately 3.5% of subjects developed elevation of alkaline phosphatase throughout RAPTIVA therapy. All values were between 1.5x and 3x the ULN, and returned to baseline levels following therapy discontinuation. About 1.7% of subjects (in excess of placebo) developed elevation in ALT during RAPTIVA therapy. All occurrences were asymptomatic and were between 3x and 9x the ULN. All values returned to baseline levels upon therapy discontinuation.
Hypersensitivity and allergic disorders
As with other protein products, RAPTIVA is potentially immunogenic. In large placebo-controlled clinical studies, the percentage of subjects experiencing an adverse event suggestive of hypersensitivity, including urticaria, a rash and allergic reactions was 2.8% higher in the RAPTIVA group (8.3%) than in the placebo group (5.5%). There were no serious or severe adverse events of hypersensitivity. (see PRECAUTIONS).
Class Adverse Reactions
Infections
Therapies that alter T-lymphocyte function may increase the risk of developing infection. In clinical trials, overall infection rates were similar between RAPTIVA treated patients and placebo-treated patients (27% vs 24%).
During the first 12 weeks of controlled trials, serious infections occurred in 0.4% of RAPTIVA treated patients compared with 0.1% of placebo-treated patients. The most frequent serious infections were pneumonia, cellulitis, infections not otherwise specified and sepsis. In both controlled and uncontrolled studies, the overall incidence of hospitalisations for infections was 1.6 per 100 patient-years for RAPTIVA and 1.2 per 100 patient-years for placebo treated patients.*
Malignancies
A higher incidence of malignancy has been associated with therapies affecting activity of the immune system. In placebo-controlled clinical trials, the overall incidence of malignancy were similar in RAPTIVA-treated patients and in placebo treated patients. Among psoriasis patients who received RAPTIVA at any dose, the overall incidence of malignancies of any kind was 1.8 per 100 patient-years for RAPTIVA-treated patients compared with 1.6 per 100 patient-years for placebo treated patients. Malignancies observed in the RAPTIVA-treated patients included non-melanoma skin cancer, non-cutaneous solid tumours, Hodgkin's lymphoma and non-Hodgkin's lymphoma and malignant melanoma. The incidences of non-cutaneous tumours on RAPTIVA-treated patients were in-line with those observed in control psoriasis populations. The majority of the malignancies observed during clinical development were non-melanoma skin cancers (NMSC). In clinical studies, the incidence of NMSC was comparable for RAPTIVA treated patients and placebo treated patients. However, the size of the placebo groups and the duration of follow-up were limited and a difference in rates of NMSC cannot be excluded.*
Other events observed during the pre-marketing evaluation and post marketing:
Skin/Appendages: Common: Psoriasis including erythrodermic and pustular forms
Application site reaction: Uncommon: Injection site reaction
Musculoskeletal: Uncommon: Psoriasis arthritis
Body as a whole: Not known (frequency likely to be rare): Severe infections including JC virus infection resulting in PML (frequency not known)
Nervous system disorders: Not known (frequency likely to be rare): Aseptic Meningitis; Inflammatory polyradiculoneuropathy, facial palsy
Interactions
Interactions with other drugs
There have been no formal drug interaction studies conducted with RAPTIVA. For a monoclonal antibody, no interactions with cytochrome P450 enzyme metabolism are anticipated.
The interaction of RAPTIVA with other systemic anti-psoriatic therapies have not been studied. Because of concerns regarding excessive immunosuppression, RAPTIVA should not be used with other immunosuppressive drugs (see PRECAUTIONS).
RAPTIVA has been used in combination with topical corticosteroids in psoriasis patients. Concomitant use of these treatments did not appear to affect safety. Use of such combinations did not result in improved efficacy compared to use of RAPTIVA alone.
Effects on Laboratory Tests:
Monitoring and Laboratory Tests
Assessment of platelet counts is recommended upon initiating and periodically while receiving RAPTIVA treatment. It is recommended that assessments be more frequent when initiating therapy (e.g monthly) and may decrease frequency with continued treatment (e.g every 3 months). Severe thrombocytopenia has been observed (see PRECAUTIONS).
Overdosage
In a clinical study, where subjects were exposed to a higher dose of RAPTIVA (up to 10 mg/kg IV), one subject receiving a 3 mg/kg IV dose experienced a symptom complex of hypertension, chills, and fever on the day of study drug dosing, which required hospitalisation. Another subject who received 10mg/kg IV experienced severe vomiting following administration of RAPTIVA, which also required hospitalisation. Both occurrences fully resolved without any clinical sequelae. Doses up to 4 mg/kg/wk for 10 weeks have been administered by subcutaneous route without any toxic effect.
Advise your patients to immediately contact their doctor or the Poisons Information Centre (in Australia telephone 131 126, in New Zealand telephone 0800 764 766) if they are concerned that they have given themselves too much RAPTIVA.
There is no known antidote to RAPTIVA or any specific treatment for RAPTIVA overdose other than withholding treatment and patient observation. In case of overdose, it is recommended that the patient be monitored under close medical care and appropriate symptomatic treatment instituted immediately.
Pharmaceutical Precautions
Shelf-life:
48 months
Reconstituted RAPTIVA should be used immediately. Although not recommended the solution may be stored at 2°C to 8°C (Refrigerate. Do not Freeze) for up to 24 hours. Contains no antimicrobial agent. Use once and discard any residue.
Special Precaution for Storage:
RAPTIVA should be stored at 2°C to 8°C (Refrigerate. Do not Freeze) in its original container. Protect from light.
Medicine Classification
Prescription Medicine
Package Quantities
RAPTIVA is supplied as a kit containing a single tray. Each single tray contains 4 vials of efalizumab 125 mg lypholised powder, 4 pre-filled syringe(s) containing 1.3 mL Water for injections and 8 needles.
The vial and pre-filled syringe do not contain latex. RAPTIVA is for single patient use only.
Further Information
Clinical Trials
The safety and efficacy of RAPTIVA were assessed in four well-controlled randomised, double-blind, placebo-controlled phase III studies that included a total of 2336 patients with moderate to severe plaque psoriasis, who had been identified as candidates for phototherapy or systemic therapy. Patients with clinically significant flares and patients with guttate, erythrodermic or pustular psoriasis as the sole predominant form of psoriasis were excluded from the studies. Also excluded were patients with a history of opportunistic infection, history of hepatitis B or C, active tuberculosis, seropositivity for HIV, or evidence of other active infection. Patients with a history of malignancy within the last five years (apart from fully resolved basal cell or squamous cell carcinoma of the skin) were also excluded.
Patients were evaluated using the Psoriasis Area and Severity Index (PASI) during the studies. PASI is a physician-performed assessment of the extent of psoriasis and the degree of erythema, scaling and thickness. Possible score ranges from 0 (no disease) to 72 (maximal disease).
The primary efficacy endpoint in three of the pivotal studies (ACD2390g, ACD2058g and ACD2059g) was the proportion of patients with a ≥ 75% improvement in the PASI score (a PASI 75 response) relative to baseline when assessed one week after a 12 week treatment course.
The principal secondary efficacy endpoint was the proportion of subjects who achieved a rating of Minimal or Clear on a static Physician's Global Assessment (PGA), the Overall Lesion Severity (OLS) Index. Additional secondary efficacy endpoints included the proportion of patients with a ≥ 50% improvement in PASI score (a PASI 50 response) relative to baseline after 12 weeks of treatment, the time-course of mean PASI percentage improvement from baseline, improvement in the Dermatology Life Quality Index (DLQI), pruritus, Psoriasis Symptom Assessment (PSA), the Physician's Global Assessment of change, change in the PASI thickness component, and change in the body surface area affected.
In the three studies, patients randomised to the RAPTIVA dose group achieved statistically significantly better responses than placebo on the primary endpoint (PASI 75 response) (see Table 2) and on all the secondary efficacy endpoints.
Pivotal Study ACD2600g, was primarily a safety study with efficacy measured by PASI 75 (principal secondary endpoint), the OLS Index and PASI 50 (additional secondary endpoints). Statistically significant improvement with RAPTIVA compared with placebo was observed with PASI 75 (see Table 2) as well as with all other measures of efficacy.
| Table 2 Primary Efficacy Endpoint: Proportion of Patients with a PASI 75 Response after 12 Weeks of Treatment |
|||
|---|---|---|---|
| Efalizumaba | |||
| Study No. | Placebo | 1.0 mg/kg/wk | Treatment effect [95%CI] |
| ACD2390g | 4% (n = 187) |
27% (n = 369) |
22% [16%, 29%]b |
| ACD2058g | 2% (n = 170) |
39% (n = 162) |
37% [28%, 46%]b |
| ACD2059g | 5% (n = 122) |
22% (n = 232) |
18% [9%, 27%]b |
| ACD2600g | 3% (n = 236) |
24% (n = 450) |
21% [15%, 27%]b |
| a p-values compared each RAPTIVA group with placebo using Fisher's Exact Test within
each study. b p < 0.001. |
|||
Statistically significant improvement in patient's condition as measured by the PASI score was seen as early as 2
weeks (studies ACD2058g and ACD2059g) or 4 weeks (study ACD2390g) in the RAPTIVA arm compared to placebo.
Time to relapse ( ≥ 50% loss of improvement) was evaluated in Study ACD2058g for patients who were classified as responders ( ≥ 75% improved on PASI) after 12 weeks of treatment. The median time to relapse among PASI responders is approximately 67 days following the last RAPTIVA dose in the initial treatment period.
Two of the phase III trials (studies ACD2058g and ACD2059g) had second randomised, blinded treatment periods designed to provide guidance for subject management after the initial 12-week treatment course. These trials evaluated extended treatment exposure and retreatment. Specific findings included the following:
- Subjects who achieved a PASI 75 response and discontinued treatment after 12 weeks experienced loss of efficacy (median time to relapse is approximately 67 days);
- Among patients continuing RAPTIVA treatment, approximately 77% of subjects who had achieved a PASI 75 at the end of 12 weeks maintained this response at 24 weeks;
- Partial responders i.e., those who achieved a PASI 50 but not a PASI 75 response, during the initial 12 week treatment demonstrated improvements to responder status with continued treatment. Approximately 40% of the RAPTIVA treated subjects achieved a PASI 75 at 24 weeks, compared to 4% of placebo-treated subjects;
- In patients who responded to an initial course, but in whom psoriasis recurred after RAPTIVA treatment withdrawal, retreatment produced a PASI 75 response in 34% of subjects.
Other studies
An on-going, long-term Phase III open-label study (ACD2243g) assessed the PASI 75 response over multiple 12 week treatment segments. This study recruited 339 patients with moderate to severe plaque psoriasis. At the end of the initial 12 weeks of open-label treatment, 41% of patients achieved a PASI 75 response and 82% achieved a PASI 50 response. Patients were eligible to enter a second open-label maintenance treatment period if they achieved a PASI 50 response or an OLS rating of clear, minimal or mild at week 12. Of the 339 patients originally recruited to the study, 290 entered the maintenance phase. The following PASI responses have been seen;
| PASI 50 | PASI 75 | PASI 90 | |
|---|---|---|---|
| Weeks 12-24 (n 290) | 77% | 52% | 22% |
| Weeks 48-60 (n 290) | 76% | 58% | 29% |
Chemical structure
RAPTIVA (efalizumab) is a full length, IgG1 kappa isotype monoclonal antibody (MoAb), composed of two identical light chains consisting of 214 amino acid residues and two heavy chains consisting of 451 residues with a total molecular weight of approximately 150kD. Each light chain is covalently coupled through a disulfide link at residue 214 to a heavy chain at residue 224. The two heavy chains are covalently coupled to each other through inter-chain disulfide bonds between residues 230 and 233 respectively, consistent with the structure of a human IgG1.
RAPTIVA is a recombinant humanised monoclonal antibody to CD11a produced in a Chinese Hamster Ovary (CHO) cell line, which targets the alpha-chain (CD11a) of the LFA-1 (lymphocytes function-associated antigen-1) adhesion molecule found on all T lymphocytes. RAPTIVA inhibits binding between the T lymphocytes and antigen presenting cells.
RAPTIVA has a binding affinity for CD11a of approximately 3 nM.
Name and address of sponsor
Raptiva® is supplied in New Zealand by:
Pharmacy Retailing t/a Healthcare Logistics
58 Richard Pearse Drive
Airport Oaks
AUCKLAND
Raptiva® is supplied in Australia by:
Merck Serono Australia Pty Ltd
3-4/25 Frenchs Forest Rd
Frenchs Forest NSW 2086
Date of Preparation
20 February 2009
(Raptiva® is a Registered Trademark)