ORENCIA - ORENCIA - CT 4603 - English version
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2007
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2007
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Publié le
18 juillet 2007
Licence :
Paternité, pas d'utilisation commerciale, partage des conditions initiales à l'identique
Langue
English
Introduction ORENCIA 250 mg, powder for concentrate for solution for infusion Box of 1 vial (CIP: 570 892-7) Posted on Dec 15 2009 Active substance (DCI) abatacept ATC Code L04AA24 Laboratory / Manufacturer BRISTOL-MYERS SQUIBB PHARMACEUTICALS ORENCIA 250 mg, powder for concentrate for solution for infusion Box of 1 vial (CIP: 570 892-7) Posted on Dec 15 2009
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Publié le
18 juillet 2007
Licence :
Paternité, pas d'utilisation commerciale, partage des conditions initiales à l'identique
Langue
English
The legally binding text is the original French version
TRANSPARENCY COMMITTEE OPINION 18 July 2007 ORENCIA 250 mg, powder for concentrate for solution for infusion Box of 1 vial (CIP: 570 892-7) Applicant: BRISTOL-MYERS SQUIBB PHARMACEUTICALS abatacept List I Medicine restricted for hospital use. Prescription reserved to specialists(in rheumatology or internal medicine). Date of Marketing Authorisation: May 21, 2007 Reason for request: Inclusion on the list of medicines approved for use by hospitals. Medical, Economic and Public Health Assessment Division
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1.1.
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1.4.
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CHARACTERISTICS OF THE MEDICINAL PRODUCT
Active ingredient abatacept
Background Abatacept is a selective immunosuppressant that selectively modulates the co-stimulation of T lymphocytes, by imitating the physiological activity of CTLA-4 (Cytotoxic T Lymphocyte T associated Antigen-4).
Indication ORENCIA, in combination with methotrexate (MTX), is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have had an insufficient response or intolerance to other disease-modifying anti-rheumatic drugs including at least one tumour necrosis factor (TNF) inhibitor. A reduction in the progression of joint damage and improvement of physical function have been demonstrated during combination treatment with abatacept and MTX.
Dosage
Treatment should be initiated and supervised by specialist physicians with experience in the diagnosis and treatment of RA.
ORENCIA should be administered as a 30-minute intravenous infusion at the dose specified in the table below. Following the initial administration, ORENCIA should be given 2 and 4 weeks after the first infusion, then every 4 weeks thereafter.
Body Weight of Dose Patient
<60 kg
60 to 100 kg
500 mg
750 mg
Table 1: Dose of ORENCIAa
> 100 kg 1,000 mg a approximately 10 mg/kg beach vial provides 250 mg of abatacept
Number of Vialsb
2
3
4
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2.1.
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SIMILAR MEDICINAL PRODUCTS
ATC Classification (2007) L: Antineoplastic L04: Immunosuppr L04A: Immunosuppr L04AA: Selective imm L04AA24: abatacept
s and immunomodulating agents essants essants unosuppressants
2.2. Medicines in the same pharmaceutical category 2.2.1. Comparator medicines None: To this day, there are no other medicinal products indicated in the treatment of RA following inadequate response or intolerance to anti-TNF products with the same mechanism of action as ORENCIA.
2.3.
3.1.
Medicines with a similar therapeutic aim A single medicinal product with Marketing Authorisation (MA) for the treatment of RA following inadequate response or intolerance to an anti-TNF product: MABTHERA (rituximab).
3 ANALYSIS OF AVAILABLE DATA
Efficacy The laboratory has provided three phase III clinical studies that evaluated the efficacy and safety of abatacept (ORENCIA) in the treatment of rheumatoid arthritis in patients with: - response to methotrexate (MTX) at a mean oral or infusion dose Insufficient³16 mg/week (2 studies AIM and IM 101-043) or, - Failure of at least one anti-TNF product (1 study - ATTAIN). The methodology for these studies is described in the following table:
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Table 2:methodology for the 3 studies submitted by the laboratory
Objectives
Population
Methodology
Treatments
Duration Primary endpoints
AIM IM 101-043 ATTAIN Evaluate the efficacy and Evaluate the effects of Compare the efficacy and safety of abatacept in abatacept in combination safety of abatacept + combination with MTX in with MTX on RA activity in DMARD to that of placebo the treatment of RA in patients with MTX failure. + DMARD in the treatment patients with MTX failure of RA with failure of at oAbmjeocntigv es twheer e: secondary least one anti-TNF product - to compare the effects of infliximab + MTX on RA activityversusplacebo + MTX - to compare the effects of abatacept + MTX and infliximab + MTX on DAS 28. 652 randomised patients, 431 patients with active 391 patients with active with active RA, RA progressing since an RA progressing since an progressing since an average of 7.8 years. average of 12 years. average of 9 years. - Mean DAS 28 = 6.8.- DAS 28 = 6.9. Mean - Mean DAS 28 = 6.8 Mean number of painful- number of painful Mean -- joints 31 joints: number of Mean³31. painful joints: 31-32. Mean number of swollen - Mean number of swollen-- 21 joints: 22 joints: number of Mean swollen joints: 21-22- Mean HAQ: 1.8- Mean HAQ: 1.8 - HAQ: 1.7 Mean Randomised, double-blind, Randomised, double-blind, Randomised, double-blind placebo + MTX controlled infliximab or placebo + placebo + DMARD study MTX controlled study controlled study MTX (³ (15 mg/week) MTX³ (15 mg/week) MTX³15 mg/week) combined with: combined with: combined with: - either abatacept 10- either abatacept 10- either abatacept 10 mg/kg in 30-minute mg/kg in 2-hour infusion mg/kg in 30-minute infusion at D1, D15, D29 at D1, D15, D29, D57, infusion at D1, D15, D29 then every 28 days (n= D85 then every 28 days then every 28 days (i.e., 433)* (n=156) a total of 7 infusions), - or placebo (n= 219)*- 3 mg/kg in 2- Infliximab 258) (n= hour infusion at D1,- or placebo (n= 133) D15, D43, D85 then every 8 weeks (n=165) - placebo (n= 110) or 1 year 1 year 6 months - ACR 20 at 6 months- in DAS 28 at 6 Change- 20 at 6 months ACR - HAQ response at 12 months- HAQ response at 6 months (improvement³ (improvement months 0.3 unit from baseline)³ unit from 0.3 - baseline) Genant-modified Sharp erosion score at 1 year
* Nine patients of the abatacept group and 5 of the placebo group were excluded from the efficacy analysis. Evaluation of efficacy was therefore conducted on 424 patients of the abatacept + MTX group and 214 patients of the MTX + placebo group. For the definition of the assessed criteria, refer to attachment 1
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Results:
RA with inadequate MTX response
AIM1study: The ACR 20 response rate at 6 months was greater with abatacept + MTX (68%, 288/424) than with MTX + placebo (40%, 85/214), p<0.001. Reduced progression of structural damage and improvement of functional capacity were demonstrated at 1 year in patients treated with abatacept + MTX, in effect: - of radiological effect at 1 year, assessed with Genant-modified Sharp Progression erosion score, was lower with abatacept + MTX than with MTX + placebo (0.63 vs. 1.14, p<0.029) and, The proportion of patients with HAQ response at 1 year was greater with -abatacept + MTX (64%) than with MTX + placebo (39%), p<0.001. IM 101-043 study: ITT analysis of results. After 6 months of treatment, the mean decrease in DAS 28 was significantly greater with abatacept + MTX (-2.53) and infliximab + MTX (-2.25) than with placebo + MTX(-1.48), p < 0.001. Secondary analyses, not able to conclude with a satisfactory level of evidence, compared the effects of abatacept and infliximab on DAS 28: -no difference between the two treatments (0.28, CI 6 months there was At 95% [-0.61; 0.06]). -statistically significant in favour of abatacept 1 year, the difference was At (0.62, CI 95% [-0.96; -0.29]).
Patients with failure of at least one anti-TNF product ATTAIN2study: Analysis of results in ITT. The ACR 20 response rate at 6 months was greater with abatacept + MTX (50%) than with MTX + placebo (20%), p<0.001. Furthermore, the proportion of patients with HAQ response at 6 months was greater with abatacept + MTX (47%) than with methotrexate + placebo (23%), p<0.001.
Open-label extension at 2 years In the open-label extension phase of the AIM and ATTAIN studies, the ACR 20, 50 and 70 responses were maintained over a period of 24 months in patients treated with abatacept. In the open-label extension phase of the AIM study, the rate of progression of joint damage during the second year was significantly lower than during the course of the first year in randomised patients treated with abatacept (p<0.0001). Observation Data on the proportion of patients with moderate RA in studies evaluating abatacept are not available.
1. Kremer JM et al. Effect of abatacept in patients with methrotrexate resistant active rheumatoid arthritis - A randomized trial. Ann Int Med 2006 ; 144: 865 - 876. 2. Genovese MC et al. Abatacept for Rheumatoid Arthritis Refractory to Tumor Necrosis Factorα Inhibition. N Engl J Med 2005; 353:1114-23.
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3.2.
3.3.
Adverse effects The safety profile for abatacept (ORENCIA) was evaluated in placebo-controlled clinical studies (1955 patients treated with abatacept and 989 treated with placebo) and particularly in the ASSURE study (n=1441, 959 of which were treated with abatacept), which objective was to evaluate the safety of abatacept (10 mg/kg) compared to placebo in patients with active RA and receiving 1 or more conventional or biological DMARDs. In placebo-controlled studies, the incidence of adverse events was 52.2% with abatacept and 46.1% with placebo. The most frequently observed events (³5%) were headache and nausea. The proportion of patients discontinuing treatment due to adverse events was 3.4% with abatacept and 2.2% with placebo. Other adverse events reported with a frequency (>2%) were mainly: upper respiratory tract and urinary tract infections, dizziness, diarrhoea, rash, cough and arterial hypertension. Infusion site reactions were observed in 9.8 % of patients treated with abatacept and 6.7% patients treated with placebo. These consisted mainly of light-headedness, headache, and increased blood pressure / hypertension. Furthermore, in the 54 included patients with COPD, 51.4% of patients treated with abatacept and 47.1% of those receiving placebo experienced adverse events (in particular: worsening of COPD, cough, bronchial rales and dyspnoea). The incidence of possibly treatment-related infections was 23.2% with abatacept and 19.5% with placebo. The frequency of malignant neoplasia was 1.4% with abatacept and 1.1% with placebo. The European risk management plan includes follow-up of infections and cancers.
Conclusion The efficacy of abatacept 10 mg/kg (ORENCIA) combined with MTX (15 mg/week) in the treatment of active RA with failure of MTX (2 studies) or at least 1 anti-TNF product (1 study) was demonstrated for ACR 20 (2 studies) and DAS 28 (1 study) criteria. In the AIM study, conducted on patients with inadequate MTX response, the ACR 20 response at 6 months was greater with abatacept + MTX (68%) than with MTX alone + placebo (40%), p<0.001. In the ATTAIN study conducted on patients with failure of at least one anti-TNF product, the ACR 20 response rate at 6 months was greater with abatacept + MTX (50%) than with MTX + placebo (20%), p<0.001. Finally, in the IM 101-043 study, conducted on patients with inadequate response to MTX, the mean decrease in DAS 28 after 6 months of treatment was significantly greater with abatacept + MTX (-2.53) and with infliximab + MTX (-2.25) than with MTX + placebo(-1.48), p < 0.001. Secondary exploratory analyses without a satisfactory level of evidence did not demonstrate any difference between abatacept and infliximab at 6 months, but did show a significant change in favour of abatacept at 1 year. Studies comparing abatacept to an anti-TNF product in patients with failure of at least one anti-TNF therapy were not conducted. Reduction in the progression of joint damage and improvement of physical function were demonstrated in patients treated with abatacept + MTX.
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TRANSPARENCY COMMITTEE CONCLUSIONS
Actual benefit Rheumatoid arthritis is a chronic and debilitating disease. The efficacy/adverse effects ratio is high. Public health benefit: The burden caused by rheumatoid arthritis, a serious chronic and debilitating disease, is substantial. The burden imposed by the sub-population likely to benefit from this treatment is moderate. Improving management for the treatment of rheumatoid arthritis is a necessity falling within the scope of a GTNDO** identified public health priority. In light of the size of the expected impact on morbidity and quality of life (moderate), but also of the small size of the affected population, and the uncertainty regarding long-term safety, a public health benefit is expected for this medicinal product. However, this benefit, as that for MABTHERA, is low. There is only one alternative treatment with a MA in the rheumatoid arthritis with inadequate response or intolerance to other disease-modifying drugs including at least one anti-TNF product (rituximab- MABTHERA). The actual benefit of ORENCIA is substantial.
Improvement in actual benefit With an efficacy comparable to that of MABTHERA for severe forms, ORENCIA (abatacept) combined with methotrexate provides a significant (level II) improvement in actual benefit within the context of its indications (moderate to severe active RA in adult patients who have had an insufficient response or intolerance to other disease-modifying anti-rheumatic drugs including at least one tumour necrosis factor (TNF) inhibitor, in the treatment of RA.
Therapeutic use The usual management of RA includes prescription of immediate anti-inflammatory activity products (NSAIDs, corticosteroids) and a disease-modifying drug to induce clinical and biological remission. MTX is one of the most effective disease-modifying treatments in RA. It may be combined with other disease-modifying drugs under strict clinical and biological supervision. In case of inadequate response to or contraindication of MTX use, another traditional disease-modifying drug or anti-TNF product may be administered, according to the clinicobiological manifestation of the disease and the patient’s physiopathological profile. However, according to specialist opinion, approximately 30% of patients have an inadequate or insufficient response to anti-TNF products after 2 years.
*Technical Objective Definition Group (DGS) 2003GTNDO: National
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4.4.
4.5.
The efficacy of ORENCIA® combined with MTX has been demonstrated in the treatment of active RA in patients who have had an inadequate response or intolerance to disease-modifying drugs including at least one anti-TNF product. However, data on abatacept safety is still limited (small duration of treatment and low number of exposed patients). Caution is recommended in light of the activity of ORENCIA on T lymphocyte response, the insufficiency of long-term data, in particular with regards to the risk of opportunistic infections and lymphomas.
Target population The prevalence of RA is between 130,000 and 240,000 patients. According to specialist opinion, 45% to 60% of these patients are currently treated with MTX. Approximately 18% of patients treated with MTX experience treatment failure. The target population of anti-TNF products in this indication is approximately between 10,000 and 26,000patients. According to the specialists, 1/3 of patients treated with anti-TNF products experience an inadequate response or intolerance, i.e., 3,500 to 8,000patients. According to its indication description, the use of ORENCIA is restricted to patients who have had an inadequate response or intolerance to other disease-modifying drugs including at least anti-TNF product, i.e., a target population comprising between 3,500 and 8,000 patients.
Transparency Committee recommendations The Transparency Committee recommends inclusion on the list of medicines approved for use by hospitals and various public services for the indication and dosage indicated in the Marketing Authorisation.
The Transparency Committee wants that a long-term follow-up study be conducted for ORENCIA in patients with RA, in addition to the long-term study for the medicinal products Enbrel, Humira, Remicade and MabThera®according to a similar methodology and protocol. The Transparency Committee points out that the aims of such a study are to: - the prescription modalities (indication, posology, coprescriptions, describe etc.) and the treated patients (sociodemographic data, patient’s medical history, disease history, comorbidities, etc.); - assess the impact of the treatment on the concerned population‘s health in terms of morbidity and mortality (particularly disease progression, patient quality of life, monitoring of drug resistance appearance, onset of long-term adverse events, etc.); -describe the treatment strategy and the use of healthcare services.
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ATTACHMENT 1 Definition of endpoints assessed in the clinical studies ACR 20 response corresponds to a 20% reduction in the number of swollen and tender joints since baseline, and a 20% reduction in three of the following parameters: o ESR or CRP (C-Reactive Protein) o global assessment of disease activity on VAS, Patient o global assessment of disease activity on VAS, Physician o assessment of pain on VAS, Patient o Degree of disability
DAS 28 score (Disease activity score) is a validated measure of the activity of RA. It includes 28 joint counts and takes into account the number of painful joints, the number of synovitis, the patient’s assessment of pain intensity, and ESR or CRP. The disease is very active if the score is greater than 5.1 and inactive if the score is less than 2.6. Furthermore, it is used as a criterion of clinical remission. RA is considered in remission when DAS 28< 2.6. Disability index HAQ (Health Assessment Questionnaire) assesses physical functional restrictions in RA patients. The patient completes this questionnaire. HAQ >2: severe handicap, <1: slight handicap. Genant-modified Sharp score 14 joint sites are rated for joint erosion in hands, 6 in feet, with a score range from 0 to 98. 13 joint sites are rated for narrowing of joint space in the hands with a score range from 0 to 104. Total score ranges from 0 to 200.
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