TRANSPARENCY COMMITTEE OPINION. 1 April 2009

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 1 April 2009 XAMIOL 50 µg/0.5 mg/g, gel Bottle of 60 g (CIP: ) Applicant: LEO PHARMA calcipotriol + betamethasone dipropionate ATC code: D05AX52 List I Date of Marketing Authorisation: 30 October 2008 (Mutual recognition procedure, rapporteur country: Denmark) Reason for the request: Inclusion on the list of medicines reimbursed by National Health Insurance and approved for hospital use. Medical, Economic and Public Health Assessment Division 1

2 1 CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient calcipotriol + betamethasone dipropionate 1.2. Novel aspects Fixed combination of 2 active ingredients in the form of a gel 1.3. Indication Topical treatment of scalp psoriasis Dosage XAMIOL should be applied to the scalp lesions once daily. The recommended duration of treatment is 4 weeks. After this period, treatment with XAMIOL may be repeated under medical supervision. All the affected areas of the scalp may be treated with XAMIOL. Usually an amount between 1 and 4 g is sufficient for treatment of the scalp (4 g corresponds to one teaspoon). 2 SIMILAR MEDICINAL PRODUCTS 2.1. ATC Classification (2008) D : Dermatologicals D05 : Antipsoriatics D05A : Antipsoriatics for topical use D05AX : Other antipsoriatics for topical use D05AX52 : Calcipotriol and combinations 2.2. Medicines in the same therapeutic category Comparator medicines In the treatment of scalp psoriasis, - there is no other topical proprietary product that combines a dermocorticosteroid and a vitamin D3 analogue, - each of the active ingredients of XAMIOL is present in other proprietary products in a non-combined form: - betamethasone (1 to 2 applications per day): BETNEVAL 0.1%, cutaneous emulsion DIPROSONE 0.05 %, lotion - calcipotriol (2 applications per day) : DAIVONEX 50 µg/g, solution for the scalp 2.3. Medicines with a similar therapeutic aim For the treatment of plaque psoriasis: - DAIVOBET, ointment is another fixed combination of the same two active ingredients for psoriasis of the body: topical treatment of plaque-type psoriasis (psoriasis vulgaris), where topical treatment is relevant. 2

3 For the treatment of scalp psoriasis, the products concerned are other topical proprietary products indicated in psoriasis in a pharmaceutical form that is suitable for the scalp (lotions, gels, and shampoo): High-activity dermocorticosteroids (level II): - difluprednane: EPITOPIC 0.05, topical gel - fluocinolone: SYNALAR 0.01%, cutaneous solution - fluocinonide: TOPSYNE, cutaneous solution - hydrocortisone: LOCOÏD, lotion and LOCOÏD cutaneous emulsion Very high-activity dermocorticosteroids: - clobetasol: DERMOVAL, gel CLOBEX, shampoo Vitamin D3 analogues: - tacalcitol: APSOR 4 µg/g, cutaneous emulsion Combination of high-activity dermocorticosteroid (level II) and salicylic acid: - betamethasone and salicylic acid: DIPROSALIC, lotion 3 ANALYSIS OF AVAILABLE DATA 3.1. Efficacy Five studies were submitted by the company: - 2 pivotal efficacy studies versus each of the 2 active ingredients used on their own (MBL 0405 INT and MBL 0406 INT) - 1 efficacy study versus DAIVONEX (MBL 0503 INT), - 1 efficacy study versus placebo (MBL 0502 US) week tolerance study versus calcipotriol (MBL 0407 INT) Study MBL 0405 INT This was a 4-arm randomised double-blind multicentre study of efficacy. The patients were adult patients treated with XAMIOL or betamethasone or calcipotriol or placebo (excipient of the gel) at a dosage of one application per day, including in the group treated with calcipotriol, the usual dosage of which is 2 applications per day. The betamethasone, calcipotriol, and placebo were prepared ad hoc for the study in a non-commercial pharmaceutical form comprising a paraffin-based gel, identical to that of XAMIOL. The score used to measure the patients psoriasis at the time of inclusion was the global scalp psoriasis severity score on a 6-point scale 1. The treatment duration was of 8 weeks. The primary endpoint was the percentage of patients with controlled disease in week 8 of the study (no clinical symptoms or very mild symptoms on the global severity score 1 ). 1 Global scalp-psoriasis severity score determined by the doctor 6 levels: no disease/clearance (0), very mild symptoms (1), mild symptoms (2), moderate symptoms (3), severe symptoms (4), or very severe symptoms (6). 3

4 The secondary endpoints were: - the percentage of patients with controlled disease, in the view of the investigator, in week 2 and week 4, - the percentage of patients who regard the treatment as successful (level 0 or 1 on a 7-level scale), - the week 8 scores for erythema, skin thickening, and desquamation, - the total severity score in week 8 (addition of the scores for each of the abovementioned symptoms). The Cochran-Mantel-Haenszel test, which allows adjustment for centre, was used for the statistical analysis in regard to the primary endpoint. Results: Mean age of the patients: 49 years, 55% were women. The length of time for which the psoriasis had been present and the extent of the scalp lesions were comparable between the groups. On inclusion, 56% of the patients had moderate scalp psoriasis and 37% had severe or very severe psoriasis. Table 1: Distribution of the patients according to global severity score on inclusion Disease XAMIOL Betamethasone Calcipotriol Placebo Mild 8.7 % 4.5 % 5.9 % 7.4 % Moderate 56.2 % 57.0 % 57.4 % 50.7 % Severe 28.8 % 32.9 % 32.0 % 36.0 % Very severe 6.3% 4.6 % 4.8 % 5.9 % Table 2: Results of study MBL 0405 INT for the primary endpoint (controlled disease) Number of patients with controlled disease/number of patients included (ITT) % of patients with XAMIOL Betamethasone Calcipotriol Placebo 385/ / /272 31/136 controlled disease Odds ratio 1.41 * 4.13** 95 CI ( ) ( ) p < < * comparison of Xamiol vs betamethasone ** comparison of Xamiol vs calcipotriol *** comparison of Xamiol vs placebo 8.65*** ( ) XAMIOL is more effective than betamethasone (OR 1.41; 95 CI ), calcipotriol (OR 4.13; 95 CI ), and placebo (OR 8.65; 95 CI ), on the primary endpoint (percentage of patients with controlled scalp psoriasis in week 8). XAMIOL does not differ from betamethasone on the secondary endpoints in week 8; the only difference in secondary endpoints is in regard to the percentage of patients with controlled disease in the view of the investigator in week 2 and week 4, on which parameters XAMIOL is superior to betamethasone. XAMIOL is superior to calcipotriol and placebo on all the secondary endpoints. To sum up, XAMIOL was more effective than each of its active ingredients used on their own and more effective than placebo. 4

5 However: - on the primary endpoint, the size of the effect of XAMIOL relative to betamethasone is small, - this difference was not confirmed by the analysis of the secondary efficacy endpoints, - the pharmaceutical presentations of the comparators used were made for the study and are not marketed in this form. However, a corticosteroid can have greater or lesser efficacy depending on the excipient used in conjunction with the active ingredient. - calcipotriol is used at a dosage 2 times weaker than that in the MA Study MBL 0406 INT This was a 3-arm randomised double-blind multicentre study of efficacy. The patients were treated with XAMIOL or betamethasone or calcipotriol applied once daily. The betamethasone and calcipotriol were prepared ad hoc for the study in a non-commercial pharmaceutical form comprising a paraffin-based gel, identical to that of XAMIOL. The score used to measure the patients psoriasis at the time of inclusion was the global scalp psoriasis severity score, on a 6-point scale 1. The treatment duration was of 8 weeks. The primary endpoint was the percentage of patients with controlled disease in week 8 of the study (no clinical symptoms or very mild symptoms on the global severity score 1 ). The secondary endpoints were: - the percentage of patients with controlled disease, in the view of the investigator, in week 2 and week 4, - the percentage of patients who regard the treatment as successful (level 0 or 1 on a 7-level scale), - the week 8 scores for erythema, skin thickening, and desquamation, - the total severity score in week 8 (addition of the scores for each of the abovementioned symptoms). The Cochran-Mantel-Haenszel test, which allows adjustment for centre, was used for the statistical analysis in regard to the primary endpoint. Results: Mean age of the patients: 48 years, 55% were women. The length of time for which the psoriasis had been present and the extent of the scalp lesions were comparable between the groups. On inclusion, 53 % of the patients had moderate scalp psoriasis and 36% had severe or very severe psoriasis. 5

6 Table 3: Distribution of the patients according to global severity score on inclusion Disease XAMIOL Betamethasone Calcipotriol Mild 9.9 % 8.0 % 12.2 % Moderate 54.8% 53.6 % 51.4 % Severe 29.9 % 33.6 % 32.9 % Very severe 5.5 % 4.8 % 3.5 % Table 4: Results of study MBL 0406 INT for the percentage of patients with controlled disease in week 8 (primary endpoint) Number of patients with controlled disease/number of patients included (ITT) % of patients with XAMIOL Betamethasone Calcipotriol 388/ / /286 controlled disease Odds ratio 1.41* 3.13** 95 CI ( ) ( ) p < * comparison of Xamiol vs betamethasone ** comparison of Xamiol vs calcipotriol XAMIOL was more effective than betamethasone (OR 1.41; 95 CI ) and calcipotriol (OR 3.13; 95 CI ) on the primary endpoint (percentage of patients with controlled scalp psoriasis in week 8). The results for the secondary endpoints were as follows: XAMIOL is superior to betamethasone on all the secondary endpoints except in regard to the percentage of patients with controlled disease in the view of the investigator in week 4 and the desquamation score in week 8, on which XAMIOL does not differ from betamethasone. - XAMIOL is superior to calcipotriol on all the secondary endpoints. To sum up, in this second study, XAMIOL was more effective than its 2 active ingredients (betamethasone and calcipotriol) used on their own. However: - on the primary endpoint, the size of the effect of XAMIOL relative to betamethasone is small, - the pharmaceutical forms used as comparators were made for the study and are not marketed in this pharmaceutical form. However, a corticosteroid can have greater or lesser efficacy depending on the excipient used in conjunction with the active ingredient, - calcipotriol is used at a dosage 2 times weaker than that in the MA Study MBL 0503 INT This was a 2-arm randomised double-blind international multicentre efficacy study versus DAIVONEX (calcipotriol). The dosage was one application of XAMIOL per day and two applications of DAIVONEX per day. The treatment duration was of 8 weeks with an 8-week follow-up period after the end of the treatment. 6

7 The score used to measure the patients psoriasis at the time of inclusion was the global scalp psoriasis severity score, on a 6-point scale 1. The primary endpoint was the percentage of patients with controlled disease in week 8 of the study (no clinical symptoms or very mild symptoms on the global severity score 1 ). The secondary endpoints were: - the percentage of patients with controlled disease in week 2 and week 4, - the percentage of patients who regard their scalp psoriasis as controlled (level 0 or 1 on a 5-level scale), - the total severity score in week 8, - the time to relapse and the incidence of relapse in an 8-week follow-up period after the end of the treatment, - the incidence of rebound, - tolerance, - quality of life. The Cochran-Mantel-Haenszel test, which allows adjustment for centre, was used for the statistical analysis in regard to the primary endpoint. Results: Mean age of the patients: 51 years, 56% were women. The length of time for which the psoriasis had been present and the extent of the scalp lesions were comparable between the groups. The majority of the patients had moderate scalp psoriasis on inclusion. Table 6: Results of study MBL 0503 INT for the percentage of patients with controlled disease in week 8 (primary endpoint) Number of patients with controlled disease/number of patients included (ITT) XAMIOL once daily DAIVONEX twice daily 142/207 33/105 % of patients with controlled disease ,4 Odds ratio, 95 CI 5.4 ( ) p <0.001 XAMIOL was more effective than DAIVONEX (OR 5.4; 95 CI ) in terms of the percentage of patients with controlled scalp psoriasis in week 8 (primary endpoint). The results for the secondary endpoints confirm the superior efficacy of XAMIOL, showing in particular in week 2 and week 4 that XAMIOL is more rapidly effective than DAIVONEX. Table 7: controlled disease in week 2 and week 4 % of patients with controlled disease (ITT) XAMIOL once daily DAIVONEX twice daily In week In week Odds ratio 95 CI 14.3 ( ) 5.8 ( ) p XAMIOL is more rapidly effective than DAIVONEX in week 2 and week 4. However, observation of the time to relapse in an 8-week follow-up period shows that patients relapsed sooner after the end of the treatment with XAMIOL (35 days) than after DAIVONEX (58 days). 7

8 To sum up, this study showed that XAMIOL applied once daily was more effective (OR 5.4; CI ) than DAIVONEX at the MA dosage of 2 applications per day over a period of 8 weeks, in the control of scalp psoriasis Study MBL 0502 US This was a 2-arm randomised double-blind multicentre efficacy study versus placebo carried out in the United States. The dosage was one application per day. The placebo was a gel identical to the excipient of XAMIOL. The duration of treatment was 8 weeks. The score used to measure the patients psoriasis at the time of inclusion was the global scalp psoriasis severity score, on a 6-point scale 1. The primary endpoint was identical to that of the preceding studies: the percentage of patients with controlled disease in week 8 of the study (no clinical symptoms or very mild symptoms on the global severity score 1 ). The Cochran-Mantel-Haenszel test, which allows adjustment for centre, was used for the statistical analysis in regard to the primary endpoint. Results: Mean age of the patients: 45 years. 66% were men. The length of time for which the psoriasis had been present and the extent of the scalp lesions were comparable between the groups. The majority of the patients (70%) had mild or moderate scalp psoriasis. Table 8: Results of study MBL 0502 US for the primary endpoint (controlled disease) Number of patients with controlled disease/number of patients included (ITT) XAMIOL Placebo 96/135 17/42 % of patients with controlled disease ,5 Odds ratio, 95 CI 3.23 ( ) p <0.001 In this study, XAMIOL proved more effective than placebo in terms of the percentage of patients with controlled disease (OR 3.23; 95 CI ). 8

9 3.2. Adverse effects SPC data The clinical studies included over 1900 patients treated with XAMIOL, approximately 8% of whom experienced a non-serious adverse effect. The only common effect is pruritus; the uncommon and rare effects reported are local cutaneous effects or ocular irritation. The use of the 2 active ingredients on their own, which goes back a long way, reveals more severe local effects and rare or very rare systemic effects: - photosensitivity and hypersensitivity, and impaired calcium metabolism for calcipotriol, - systemic effects due to topical corticosteroid application: suppression of the hypothalamus-pituitary axis, infections, cataracts, and increased intraocular pressure Study MBL 0407 INT (long-term tolerance study over a period of 52 weeks) This was a randomised double-blind international multicentre tolerance study which compared 2 arms of patients treated with XAMIOL or calcipotriol, which were used as needed, at a dosage of one application per day. The calcipotriol was prepared ad hoc for the study in a non-commercial gel form, which was, however, identical to that of XAMIOL. The duration of treatment was 52 weeks. Follow-up visits every 4 weeks were planned. The primary endpoints were tolerance criteria: - incidence of adverse effects of any kind, - incidence of adverse effects connected with long-term use of a corticosteroid: ocular hypertension, infected dermatitis, folliculitis, impetiginisation, pustular rash, acne, rosacea, dermatitis. The statistical test used for the analysis of tolerance was the chi 2 test. Results: Mean age of the patients: 49 years, 56% were women. The length of time for which the psoriasis had been present and the extent of the scalp lesions were comparable between the groups. The majority of the patients had moderate scalp psoriasis and 38% had severe psoriasis. The severity of the disease on inclusion was identical in the 2 groups. 9

10 Table 9: Results of study MBL 0407 INT for the primary tolerance endpoints (ITT analysis) XAMIOL Calcipotriol Number of patients having at least one adverse effect 72/ /431 % of patients having at least one adverse effect (ITT) Odds ratio, CI ( ) p <0.001 Number of patients having had at least 1 adverse effect 11/419 13/431 connected with long-term use of a corticosteroid % of patients having had at least 1 adverse effect connected with long-term use of a corticosteroid Odds ratio, 95 CI ( ) p 0.73 After 52 weeks, adverse effects of any kind were significantly less common with XAMIOL than with calcipotriol (OR: 0.50; CI ). There no was difference between XAMIOL and calcipotriol in terms of the incidence of adverse effects connected with long-term use of a corticosteroid Conclusion The two randomised double-blind efficacy studies comparing XAMIOL with each of the 2 active ingredients used on their own in a gel form identical to that of the excipient of XAMIOL showed, in regard to the percentage of patients with controlled scalp psoriasis in week 8, - the superiority of XAMIOL relative to calcipotriol in gel form, administered once daily (OR 4.13; CI and OR 3.13; CI ), - the superiority of XAMIOL relative to betamethasone (OR 1.41; CI and OR 1.41; CI ). An efficacy study versus DAIVONEX (calcipotriol) showed XAMIOL's superiority to DAIVOINEX at the MA dosage of 2 applications per day in terms of the percentage of patients with controlled scalp psoriasis in week 8. The efficacy of XAMIOL relative to the active comparators was demonstrated mainly in moderate to severe scalp psoriasis. A tolerance study showed that adverse effects of any kind were less common with XAMIOL than with calcipotriol (OR: 0.50; CI ). This study found no difference between XAMIOL and calcipotriol in terms of the incidence of adverse effects connected with longterm use of a corticosteroid. However, a negative clinical trial does not mean that it is possible to rule out the risk of a rare adverse effect such as a systemic effect connected with dermocorticosteroids. The Committee notes that XAMIOL s superiority to betamethasone in regard to efficacy is small. No study comparing XAMIOL with a commercial product based on betamethasone has been performed. This is because betamethasone is marketed with various excipients, the formulation of which can affect the efficacy of the product. The Committee is thus of the opinion that XAMIOL s superior efficacy to commercial proprietary products based on betamethasone has not been demonstrated. Furthermore, the Committee regrets the fact there is no study comparing XAMIOL with successive application of calcipotriol and betamethasone to demonstrate the benefit of the fixed combination. 10

11 4 TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit Psoriasis is a chronic, non-infectious, non-contagious and usually benign, inflammatory dermatosis, but one which in its severe forms can have a major psychosocial impact. XAMIOL is a symptomatic treatment. The efficacy/adverse effects ratio of XAMIOL in scalp psoriasis is high. This proprietary product is to be used mainly after failure of local monotherapy. There are treatment alternatives. The public health burden arising from psoriasis is substantial on account of its frequency and its potential seriousness. It is moderate in the population to whom the indication applies. The management of patients with scalp psoriasis is not a public-health need. On the basis of the data from the clinical trials, this proprietary product is not expected to have an impact on morbidity or quality of life. Consequently, it is not expected that the proprietary product XAMIOL will benefit public health. The actual benefit of XAMIOL is substantial Improvement in actual benefit (IAB) XAMIOL does not provide an improvement in actual benefit (level V) in the therapeutic strategy for scalp psoriasis Therapeutic use Treatment for psoriasis depends not only on the severity and extent of the lesions, but also on the impairment of function and cosmetic appearance and the harm to work and relationships, on the psychological impact of the disease, and on the patient s desire for remission. As a general rule, patients with psoriasis which is very limited and/or psychologically well accepted are not always treated. Current treatments do not produce a permanent cure for the disorder, but result in the temporary disappearance of the lesions, more or less completely. There are few topical treatments indicated in scalp psoriasis: dermocorticosteroids and vitamin D3 analogues or a combination of these products. The emulsion, gel, lotion, and shampoo forms are particularly suitable for treating the scalp disorder. Scalp psoriasis can be divided into 3 classes on the basis of severity: mild, moderate, and severe. XAMIOL has demonstrated its efficacy in moderate and severe scalp psoriasis. XAMIOL is to be used mainly after failure of local monotherapy (with a dermocorticosteroid in particular) and only in moderate or severe scalp psoriasis. The recommended duration of treatment with XAMIOL is 4 weeks. After this period, if no clearance has occurred, the initial treatment may be extended under medical supervision. If 11

12 clearance has occurred, treatment with XAMIOL is to be followed on by maintenance therapy. If this fails, another form of treatment must be considered. In the case of long-term maintenance treatment, XAMIOL is likely to produce the adverse effects of corticosteroids Target population In France the prevalence of psoriasis, treated or untreated, is 2 to 3% of the general population. In the United Kingdom, a large epidemiological study 2 carried out in 2005 which was based on the medical files of 8 million people estimated the prevalence of treated psoriasis at 1.5% of the general population. A fairly large proportion of patients do not need treatment as their quality of life is not affected. In France, the percentage of patients treated is probably higher than in the United Kingdom, as there is easier access to dermatologists. The prevalence of psoriasis in France may thus be estimated at between 1.5 and 3% depending on whether the treated population or the population that may be treated is being considered. According to a 1974 study 3 in 5600 patients, among the patients with psoriasis, the proportion in whom the disease was located on the scalp was approximately 54%. The number of individuals with moderate or severe psoriasis is estimated at about 20 to 24% 2,4. As regards psoriasis affecting the scalp, the proportion of individuals with moderate or severe disease is apparently, according to expert opinion, 1/3. Calculating on this basis, the target population of XAMIOL, corresponding to the number of patients to be treated for moderate or severe scalp psoriasis, is in the range 170,000 to 350,000 persons Transparency Committee recommendations The Transparency Committee recommends inclusion on the list of medicines reimbursed by National Health Insurance and on the list of medicines approved for use by hospitals and various public services in the indications and at the dosages in the Marketing Authorisation Packaging: Appropriate for the prescription conditions Reimbursement rate: 65 % 2 Gelfand J.M. Prevalence and treatment of psoriasis in the United Kingdom, a population-based study. Arch Dermatol 2005 ; V14 : Farber EM, Nall ML. The natural history of psoriasis in 5,600 patients. Dermatologica 1974;148: Medline plus/psoriasis/national Foundation Psoriasis site consulted on 1 April