The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 30 November 2011

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 30 November 2011 NULOJIX 250 mg, powder for concentrate for solution for infusion B/1 (CIP code: ) B/2 (CIP code: ) Applicant: BRISTOL-MYERS SQUIBB Belatacept ATC code: L04AA28 (selective immunosuppressants) List I Date of Marketing Authorisation (centralised): 17 June 2011 The MA is accompanied by an RMP which includes pharmaco-epidemiological post-marketing studies (monitoring of the risk and consequences of lymphoproliferative syndromes, conditions of use, the outcome of exposed pregnancies) and extensions of phase III studies to three years. Ten temporary usage authorisations (TUA) in named patients have been granted for patients who are intolerant of the current immunosuppressant treatment. Medicinal product reserved for hospital use. Reason for request: Inclusion on the list of medicines approved for hospital use. Medical, Economic and Public Health Assessment Division 1/13

2 1 CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient Belatacept 1.2. Background Belatacept is a soluble fusion protein produced by recombinant DNA technology. It binds to the CD80 and CD86 receptors on the surface of antigen-presenting cells, thus blocking the co-stimulation of T lymphocytes and inhibiting their activation; T lymphocytes are the main mediators of the immunological response to the transplanted kidney Indication NULOJIX, in combination with corticosteroids and mycophenolic acid (MPA), is indicated for prophylaxis of graft rejection in adults receiving a renal transplant (see section 5.1 of the SPC for data on renal function). It is recommended to add an interleukin (IL)-2 receptor antagonist for induction therapy to this belatacept-based regimen Dosage Treatment should be prescribed and supervised by specialist physicians experienced in the management of immunosuppressive therapy and of renal transplant patients. Belatacept has not been studied in patients with Panel Reactive Antibody (PRA) titers > 30% (who often require increased immunosuppression). Because of the risk of a high total burden of immunosuppression, belatacept should only be used in these patients after consideration of alternative therapy (see section 4.4 of the SPC). Dosage: Adults: The recommended dose is based on patient body weight (kg). The dose and treatment frequency is given below. Table 1: Dose of belatacept for renal transplant recipients Dose for Initial Phase Dose Day of transplantation, prior to implantation (Day 1) 10 mg/kg Day 5, Day 14 and Day mg/kg End of Week 8 and Week 12 after transplantation 10 mg/kg Dose for Maintenance Phase Dose Every 4 weeks (± 3 days), starting at the end of week 16 after transplantation 5 mg/kg For more details on the dose calculation, see section 6.6 of the SPC. Patients do not require pre-medication prior to administration of belatacept. Infusion-related reactions have been reported with belatacept administration in clinical studies. There were no reports of anaphylaxis on belatacept. If any serious allergic or anaphylactic reaction occurs, belatacept therapy should be discontinued immediately and appropriate therapy initiated (see section 4.4 of the SPC). Therapeutic monitoring of belatacept is not required. During clinical studies, there was no dose modification of belatacept for a change in body weight of less than 10%. Elderly: No dose adjustment is required (see sections 5.1 and 5.2 of the SPC). Renal impairment: No dose adjustment is recommended in patients with renal impairment or undergoing dialysis (see section 5.2 of the SPC). 2/13

3 Hepatic impairment: No patients with hepatic impairment were studied in renal transplant protocols, therefore dose modification of belatacept in hepatic impairment cannot be recommended. Paediatric population: The safety and efficacy of belatacept in children and adolescents under 18 years old have not yet been established. No data are available. Method of administration: NULOJIX is for intravenous use only. The diluted reconstituted solution must be administered as an intravenous infusion at a relatively constant rate over 30 minutes. Infusion of the first dose should be given in the immediate preoperative period or during surgery, but before completion of the transplant vascular anastomoses. For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6. of the SPC Contraindications Transplant recipients who are Epstein-Barr virus (EBV) seronegative or serostatus unknown. Hypersensitivity to the active substance or to any of the excipients (see section 4.4 of the SPC. 2 SIMILAR MEDICINAL PRODUCTS 2.1. ATC Classification (2010) L: Antineoplastic and immunomodulating agents L04: Immunosuppressants L04A: Immunosuppressants L04AA: Selective immunosuppressants L04AA28: Belatacept 2.2. Medicines in the same therapeutic category These are all medicines used in the prevention of graft rejection after renal transplantation. - Ciclosporin (CsA): NEORAL (8 April 1998: Substantial AB, IAB IV by comparison with SANDIMMUM), SANDIMMUM (8 April 1998: substantial AB, IAB I), - Tacrolimus: ADVAGRAF (6 February 2008: Substantial AB, IAB V by comparison with PROGRAF) MODIGRAF (21 December 2009: Substantial AB, IAB V by comparison with PROGRAF) PROGRAF (4 September 2002: Substantial AB, IAB III by comparison with CsA) 2.3. Medicines with a similar therapeutic aim These are other immunosuppressants indicated in the prevention of graft rejection after renal transplantation in adults, in combination with other immunosuppressants: - Mycophenolic acid: MYFORTIC, - Azathioprine: IMUREL, - Basiliximab: SIMULECT, - Everolimus: CERTICAN, - Immunoglobulin: LYMPHOGLOBULINE, THYMOGLOBULINE, - Mycophenolate mofetil: CELLCEPT, - Sirolimus: RAPAMUNE. 3/13

4 3 ANALYSIS OF AVAILABLE DATA The evaluation of the efficacity and safety of belatacept (NULOJIX) in the prevention of graft rejection in adults after renal transplantation in combination with corticosteroids and mycophenolic acid (MPA) is based on: - Two phase III clinical studies the aim of which was to assess the efficacy and safety of belatacept by comparison with ciclosporin A (CsA) in terms of patient and graft survival and the consequences of treatment for renal function at 12 months in patients with grafts from living or deceased donors using standard criteria (BENEFIT study IM ) or extended criteria (BENEFIT-EXT study IM ) and their survival at three years. - Two phase II clinical studies: o Study IM , the aim of which was to assess the efficacy and safety of belatacept by comparison with ciclosporin A in terms of the prevention of acute rejection at six months in patients with a graft from living or deceased donors. o Study IM , the aim of which was to assess the efficacy and safety of belatacept in the context of a switch in patients treated with calcineurin inhibitors; since this indication has not been validated by the MA, this study will not be discussed in this document Efficacy BENEFIT and BENEFIT-EXT studies Method: Randomised, double-blind comparative phase III study of belatacept (NULOJIX) versus CsA, administered in four-substance therapy in combination with mycophenolate mofetil, corticosteroids and basiliximab, performed in patients receiving a kidney transplant who were followed up for 12 months; the BENEFIT study included 666 patients, the BENEFIT-EXT study 543 patients. An extension phase to three years was also included in the two studies. These studies sought to compare belatacept and ciclosporin in terms of patient and graft survival, acute rejection and the impact on renal function: - non-inferiority in terms of patient and graft survival was accepted if the lower limit of the confidence interval for the difference was > -10%, - non-inferiority in terms of acute graft rejection was accepted if the upper limit of the confidence interval for the difference was < 20% (BENEFIT study only), - the superiority of betalacept by comparison with ciclosporin in terms of the impact on renal function. Inclusion criteria: Patients over 18 years of age with a renal transplant and a transplanted organ from: - living or deceased donors with an anticipated cold ischaemia time of < 24 hours (BENEFIT study), - deceased donors with extended criteria (BENEFIT-EXT study): donor age 60 years, 50 donor age 59 years and two of the following disorders: CVA, creatinine level of > 1.5 mg/dl, hypertension, an anticipated cold ischaemia time of 24 hours, donors with death of cardiac origin. Treatments: Patients were randomised to three groups in a 1:1:1 distribution. 4/13

5 BENEFIT study - Belatacept 10 mg/kg, More Intensive (MI), 10 mg/kg a day on D1 and D5, then every 2 weeks for 3 months, then every 4 weeks up to 6 months and 5 mg/kg every 4 weeks up to 12 months, n = 219; - Belatacept 10 mg/kg, Less Intensive (LI), 10 mg/kg a day on D1 and D5, then every 2 weeks in wk 2 and wk 4, then every 4 weeks up to 2 months and 5 mg/kg every 4 weeks up to 12 months, n = 226; - *dose regimen given in the MA - CsA, initial dose 7 ± 3 mg/kg then adjusted to achieve a blood level of 150 to 300 ng/ml during the first month then 100 to 250 ng/ml until the end of the study, n = 221. BENEFIT-EXT study - Belatacept MI, n = 184, - Belatacept LI, n = 175, - CsA, n = 184. In both studies, the treatments were administered in combination with mycophenolate mofetil (2 g/day in two doses), corticosteroids (500 mg i.v. preoperatively with a dose reduction to 2.5 mg/day orally between the 15th and the 180th day) and basiliximab (two doses i.v. as induction therapy on D1 and D5). Primary efficacy endpoints: Several primary efficacy endpoints were defined: - a composite endpoint combining the patient s global survival and survival of the graft*; - the incidence of acute rejection** at 12 months (only for the BENEFIT study), - the percentage of patients with impairment of renal function defined by a GFR of < 60 ml/min/1.73 m 2 at 12 months and/or a reduction in GFR of 10 ml/min/1.73 m 2 at 3 to 12 months; endpoint assessing renal function; *Loss of the graft was defined by: - a loss of function defined by the maintenance of a creatinine level of 6.0 mg/dl for at least four weeks or 56 consecutive days of dialysis or impairment of renal function leading to re-transplantation, - or physical loss: nephrectomy **Acute rejection was defined as a clinicopathological event defined by: - an unexplained increase in serum creatinine of 25%, - unexplained urinary excretion OR fever associated with a painful graft OR a serum creatinine level which remains elevated 14 days after transplantation, and confirmed clinically by biopsy. Results: See Tables 1 and 2 In the BENEFIT study, on inclusion the percentage of patients with a history of diabetes was higher in the CsA group (16.7%) and the belatacept MI group (17.4%) than in the belatacept LI group (14.6%). Moreover, the proportion of patients under 45 years of age included in the belatacept LI group (54.9%) was larger than in the belatacept MI (50.7%) and CsA (49.8%) groups. Finally, the percentage of men included was higher in the CsA group (74.7%) than in the belatacept groups (68.9% in MI and 64.6% in LI). In the BENEFIT-EXT study, on inclusion the percentage of patients with a history of diabetes was higher in the CsA group (28.8%) and the belatacept MI group (20.7%) than in the belatacept LI group (16%). Moreover, the percentage of men included in the belatacept LI group (73.7%) was higher than in the belatacept MI (64.7%) and CsA (63%) groups. Only the results for the dosage regimen validated by the MA (belatacept LI) will be commented on. 5/13

6 Table 1: Survival of the patients and the graft and acute rejection at 12 months (per-protocol analysis) Belatacept MI Belatacept LI CsA Survival of patients and graft: BENEFIT study - number (%) - difference vs CsA [97.3% CI] n = (95.4%) n = (96.4%) 4.1 [-0.9; 9.6] n = (92.3%) BENEFIT-EXT study - number (%) - difference vs CsA [97.3% CI] n = (85.6%) n = (87.6%) 2.4 [-5.9; 10.6] n = (85.2%) Acute rejection: BENEFIT study - number (%) - difference vs CsA [97.3% CI] 48 (22.1%) 38 (17.2%) 10.9 [4.2; 18.0] 13 (6.3%) Table 2: Impairment of renal function at 12 months (intention-to-treat analysis) Belatacept MI Belatacept LI CsA Impairment of renal function: BENEFIT study - number (%) - difference vs CsA [97.3% CI] - p vs CsA n = (55%) n = (54.2%) [-33.3; -13.7] < n = (77.9%) BENEFIT-EXT study - number (%) - difference vs CsA [97.3% CI] - p vs CsA n = (70.5%) n = (76.3%) [-18.0; 0.9] NS n = (84.8%) In the BENEFIT study, after 12 months of treatment: - patient and graft survival was 96.4% in the belatacept LI group and 92.3% in the ciclosporin A group, difference 4.1 [-0.9: 9.6]; since the lower limit of the confidence interval observed was greater than -10%, non-inferiority between belatacept LI and ciclosporin was demonstrated for this combined endpoint. - the percentage of acute rejection was 17.2% in the belatacept LI group and 6.3% in the ciclosporin A group, difference 10.9 [4.2; 18.0], RR 2.8 [1.4: 5.4]; despite a higher rejection level in the belatacept LI group, since the upper limit of the confidence interval for the difference observed was less than 20%, non-inferiority between belatacept LI and ciclosporin was demonstrated for this endpoint. These results were confirmed in the intention-to-treat analyses and confirmed after three years follow-up. As regards renal function assessed by measuring GFR (cf. primary efficacy endpoint) at 12 months, less impairment was observed with belatacept LI than with ciclosporin: 116 patients (54.2%) in the belatacept LI group versus 166 patients (77.9%) in the ciclosporin group, difference [-33.3; -13.7], p < These results were confirmed after two years follow-up: no provision was made for the measurement of GFR at three years. In the BENEFIT-EXT study, after 12 months of treatment: - patient and graft survival was 87.6% in the belatacept LI group and 85.2% in the ciclosporin A group, difference 2.4 [-5.9; 10.6]; since the lower limit of the confidence interval for the observed difference was greater than -10%, non-inferiority between belatacept LI and ciclosporin was demonstrated for this combined endpoint. These results were confirmed in the intention-to-treat analysis and confirmed after three years follow-up. 6/13

7 - no significant difference was observed between belatacept LI and ciclosporin in terms of the impairment of renal function assessed by measuring the GFR: 129 patients (76.3%) in the belatacept LI group versus 151 patients (84.8%) in the ciclosporin group, difference -8.5 [-18.0; 0.9], NS. These results were confirmed after two years follow-up: no provision was made for the measurement of GFR at three years Study Method: Open, randomised, comparative phase II study of belatacept (NULOJIX) in multiple doses versus ciclosporin A, administered in four-drug therapy in combination with mycophenolate mofetil, corticosteroids and basiliximab, performed in 218 patients receiving a kidney transplant and followed up for six months. This study sought to demonstrate the non-inferiority of belatacept by comparison with ciclosporin in terms of acute rejection of the transplant within six months after transplantation; non-inferiority was admitted if the upper limit of the confidence interval for the difference was < 20%. Inclusion criteria: Patients over 18 years of age with a renal transplant from living or deceased donors. Treatments: Patients were randomised to three groups in a 1:1:1 distribution. - Belatacept, More Intensive (MI), dosage allowing the achievement of concentrations of 20 µg/ml until D99 then 5 µg/ml until D183. After D169, patients were divided into two treatment groups of 5 mg/kg every four weeks for the first group and every eight weeks for the second, n = Belatacept 10 mg/kg, Less Intensive (LI), dosage allowing the achievement of concentrations of 20 µg/ml until D29 then 5 µg/ml until D99. After D85, patients were divided into two treatment groups of 5 mg/kg every four weeks for the first group and every eight weeks for the second, n = Ciclosporin, initial dose 7 ± 3 mg/kg then adjusted to achieve a blood level of 150 to 400 ng/ml during the first month then 150 to 300 ng/ml until the end of the study, n = 73. Primary efficacy endpoint: Number of acute rejections observed in the six months after transplantation. Results: cf. Table 3 (per-protocol analysis) On inclusion, the percentage of patients with a history of diabetes was higher in the CsA group (18%) than in the belatacept groups (9% in the LI group and 10% in the MI group). Moreover, the patients included in the belatacept LI group (mean = 42.1 years) were slightly younger than in the belatacept MI (46.5 years) and CsA (46.1 years) groups. Only the results for the dosage regimen validated by the MA (belatacept LI) will be commented on. Table 3: Acute rejection at 12 months (per-protocol analysis) Belatacept MI n = 71 Acute rejection: - number (%) - difference vs CsA [CI 95%] Belatacept LI n = 69 5 (7.0%) 4 (5.8%) -1.4 [-9.7; 6.8] Ciclosporin (CsA): n = 73 5 (7.2%) The percentage of acute rejection in the six months after transplantation was 5.8% in the belatacept LI group and 7.2% in the ciclosporin A group, difference -1.4 [-9.7; 6.8]; since the 7/13

8 upper limit of the confidence interval for the observed difference was less than 20%, non-inferiority between belatacept LI and ciclosporin was demonstrated for this endpoint Adverse effects In the BENEFIT study, 401/666 patients (60.2%) exhibited adverse effects: 115/219 (52.5%) in the belatacept MI group, 123/226 (54.4%) in the belatacept LI group and 163/221 (73.8%) in the ciclosporin group. The most frequently observed adverse effects (> 5%) were: - urinary infections: 5.9% versus 4.9% versus 5.4%, - dyslipidaemia: 4.6% vs 5.8% vs 14%, - leucopenia: 5.9% vs 8% vs 4.5%, - anaemia: 3.7% vs 5.8% vs 2.3%, - increased creatinine: 1.4% vs 3.1% vs 10%. Autoimmune adverse effects were observed in two patients in the belatacept LI group (one uveitis and one psoriasis) and three patients in the ciclosporin group (one hyperthyroidism, one rheumatoid arthritis and one myasthenic syndrome). In the BENEFIT-EXT study, 320/543 patients (58.9%) exhibited adverse effects: 97/184 (52.7%) in the belatacept MI group, 93/175 (53.1%) in the belatacept LI group and 130/184 (70.7%) in the ciclosporin group. The most frequently observed adverse effects (> 5%) were: - urinary infections: 8.2% versus 9.1% versus 6%, - CMV infection: 4.3% vs 5.1% vs 4.9%, - leucopenia: 10.3% vs 5.7% vs 5.4%, - anaemia: 8.7% vs 9.1% vs 4.9%, - allograft nephropathy: 2.7% vs 1.1% vs 5.4%. Autoimmune adverse effects were observed in four patients in the belatacept LI group (one autoimmune thyroidism, one Crohn s disease, one angiooedema and one psoriasis) and two patients in the ciclosporin group (one hyperthyroidism and one optic neuritis). In study , 133/216 patients (61.6%) exhibited adverse effects: 43/74 (58.1%) in the belatacept MI group, 40/71 (56.3%) in the belatacept LI group and 50/71 (70.4%) in the ciclosporin group. The most frequently observed adverse events (> 5%) were: - vomiting: 1.4% versus 5.6% versus 0%, - fever: 5.4% vs 7% vs 5.6%, - urinary infections: 9.5% versus 7% versus 9.9%. According to the SPC, the commonest adverse effects (> 10%) are: urinary tract infection, upper respiratory infection, cytomegalovirus infection, bronchitis, anaemia, leucopenia, insomnia, anxiety, headache, hypertension, hypotension, dyspnoea, cough, diarrhoea, constipation, nausea, vomiting, abdominal pain, arthralgia, proteinuria, increased blood creatinine, dysuria, haematuria, peripheral oedema, fever and graft dysfunction. As regards malignant tumours and post-transplantation lymphoproliferative syndromes (PTLD), the SPC states that: The Year 3 frequency of malignant neoplasms, excluding non-melanoma skin cancers, was similar in the belatacept LI and ciclosporin groups and higher in the belatacept MI group. PTLD occurred at a higher rate in both belatacept treatment groups versus ciclosporin. Non-melanoma skin cancers occurred less frequently with the belatacept LI regimen than with the ciclosporin or belatacept MI regimens. In the three studies (one phase II and two phase III studies, Study 1 and Study 2), the cumulative frequency of PTLD was higher in belatacept-treated patients at the recommended dosing regimen (LI) (1.3%; 6/472) than in the ciclosporin group (0.6%; 3/476), and was 8/13

9 highest in the belatacept MI group (1.7%; 8/477). Nine of 14 cases of PTLD in belatacepttreated patients were located in the CNS; within the observation period, 8 of 14 cases were fatal Conclusion Belatacept was evaluated in three comparative studies versus ciclosporin A (CsA) as part of a four-drug therapy in combination with mycophenolate mofetil, corticosteroids and basiliximab. Two double-blind studies (BENEFIT and BENEFIT-EXT) were carried out in patients who received a transplanted kidney and were followed up for 12 months, then in a three-year extension phase. The transplants used in these studies differed: standard transplant in the BENEFIT study (living or deceased donors with an anticipated cold ischaemia time of < 24 hours) and transplant with extended criteria in the BENEFIT-EXT study. The third study ( ) was randomised, open, and carried out in patients who received a transplanted kidney taken from living or deceased donors and who were followed up for six months. In the BENEFIT study, after 12 months of treatment: - survival of the patients and the transplant (combined endpoint) was 96.4% in the belatacept LI group and 92.3% in the ciclosporin A group, i.e. a difference of 4.1 [-0.9: 9,6] in favour of belatacept. Since the lower limit of the confidence interval for that difference observed was greater than -10%, non-inferiority between belatacept LI and ciclosporin was demonstrated for this combined endpoint. - the percentage of acute transplant rejection was 17.2% in the belatacept LI group and 6.3% in the ciclosporin A group, i.e. a difference of 10.9 [4.2; 18.0] to the detriment of belatacept. Despite a higher rejection level in the belatacept LI group, since the upper limit of the confidence interval for that difference was less than 20%, non-inferiority between belatacept LI and ciclosporin was demonstrated for this endpoint. These results were confirmed after three years follow-up. The deterioration in renal function (GFR < 60 ml/min/1.73 m 2 at 12 months and/or reduction of 10 ml/min/1.73 m 2 from 3 to 12 months) was less common with belatacept LI than with ciclosporin (54.2% vs 77.9%), i.e. a difference of [-33.3; -13.7]. Although deterioration of renal function was defined as a primary efficacy endpoint, no provision was made in the protocol for the measurement of GFR at three years; only the calculated GFR is available. In the BENEFIT-EXT study, after 12 months of treatment: - patient and graft survival (combined endpoint) was 87.6% in the belatacept LI group and 85.2% in the ciclosporin A group, difference 2.4 [-5.9; 10.6] in favour of belatacept. Since the lower limit of the confidence interval for the difference observed was greater than -10%, non-inferiority between belatacept LI and ciclosporin was demonstrated for this combined endpoint. These results were confirmed in the intention-to-treat analysis and confirmed after three years follow-up. - no significant difference was observed between belatacept LI and ciclosporin in terms of the impairment of renal function assessed by measuring the GFR: 129 patients (76.3%) in the belatacept LI group versus 151 patients (84.8%) in the ciclosporin group, difference -8.5 [-18.0; 0.9], NS. Although the impairment of renal function was defined as a primary endpoint, no provision was made in the protocol for the measurement of GFR at three years; only the calculated GFR is available. Thus, the study results show the value of belatacept versus ciclosporin in the impairment of renal function only in young patients who received a transplant with standard criteria (living or deceased donors with an anticipated cold ischaemia time of < 24 hours). 9/13

10 In study , the percentage of acute rejection observed in the six months after transplantation was 5.8% in the belatacept LI group and 7.2% in the ciclosporin A group, a difference of -1.4 [-9.7; 6.8] in favour of belatacept. Since the upper limit of the confidence interval for the difference observed was less than 20%, non-inferiority between belatacept LI and ciclosporin was demonstrated for this endpoint. No comparative study versus tacrolimus is currently available. According to the SPC, the commonest adverse effects (> 10%) are: urinary tract infection, upper respiratory infection, cytomegalovirus infection, bronchitis, anaemia, leucopenia, insomnia, anxiety, headache, hypertension, hypotension, dyspnoea, cough, diarrhoea, constipation, nausea, vomiting, abdominal pain, arthralgia, proteinuria, increased blood creatinine, dysuria, haematuria, peripheral oedema, fever and graft dysfunction. In these three studies, the cumulative frequency of lymphoproliferative syndromes was higher in patients treated with belatacept LI and MI than in the ciclosporin group (1.3%, 1.7% and 0.6%). These syndromes were followed up as part of the RMP. Finally, the use of belatacept must be restricted to transplanted patients with serology positive for Epstein-Barr virus (EBV) (cf. Contraindications in the SPC). 10/13

11 4 TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit Immunosuppressant treatments, associated with organ transplants, are administered in clinical situations of a serious nature. NULOJIX is intended as a preventive treatment combining other immunosuppressants. Its efficacy/safety ratio in EBV+ patients and in combination is high. This proprietary medicinal product is a first-line therapy. There are treatment alternatives, particularly ciclosporin and tacrolimus. Public health benefit: The public health burden of graft rejection after renal transplantation is low. Improving the prevention and treatment of transplant rejection is a public health need that is an established priority (GTNDO priorities*). Given the current preventive management of graft rejection, the results of studies of noninferiority versus ciclosporin and the absence of comparative data versus tacrolimus, NULOJIX is not expected to have any impact in terms of morbidity and mortality in this indication. Moreover, a negative impact cannot be ruled out because of the tolerability problem, in particular lymphoproliferative syndromes. The transferability of these results to current practice is acceptable. In the absence of data, the impact on the quality of life cannot be determined. Because of its mode of administration (intravenously whereas tacrolimus is taken orally), a negative impact on the organisation of care can be expected (need for additional consultations in order to receive the product), but in the absence of data, that impact is not quantifiable. Therefore the medicinal product NULOJIX does not provide a response to an identified public health need. Consequently, in view of the current management of graft rejection after renal transplantation, there is not expected to be any public health interest in the medicinal product NULOJIX in this indication. * Groupe Technique National de Définition des Objectifs [National technical group for setting of public-health objectives] (DGS [Department of Health]-2003) The actual benefit of these proprietary medicinal products is substantial Improvement in actual benefit (IAB) NULOJIX (belatacept) provides a minor improvement in actual benefit (IAB IV) in terms of less impairment of renal function, in the management of young patients who have an immunological status positive for Epstein-Barr virus and have had received a transplanted kidney from living or deceased donors in accordance with standard criteria. In other populations of transplanted patients, NULOJIX does not provide any improvement in actual benefit (IAB V). 11/13

12 4.3. Therapeutic use 1,2 Renal transplantation necessitates life-long immunouppressant anti-rejection treatment. Treatment protocols are constantly evolving and treatment combinations largely depend on the habits of the centres and the profiles of the recipient (age, pre-sensitisation) and the donor (borderline transplanted organ, compatibility with the recipient, etc.). The optimal immunosuppressant treatment combines several types of immunosuppressants with complementary pharmacotherapeutic targets, so as to be able, by reducing their respective doses, to limit the adverse effects of each one without at the same time losing efficacy. Immunosuppressant protocols are based on an initial induction phase with stronger immunosuppression followed by a maintenance phase. The induction phase includes the use of monoclonal or polyclonal antibodies. Two types of antibodies are available: - depleting antibodies directed against all T lymphocytes, either polyclonal (anti-lymphocytic serum) or monoclonal (anti-cd3), - non-depleting antibodies directed against precise immunological targets (anti-il2 receptor) such as basixilimab or daclizumab. In the maintenance phase, the immunosuppressant treatments used are in four therapeutic classes: - corticosteroids; - calcineurin inhibitors: ciclosporin and tacrolimus; - mtor inhibitors: sirolimus and everolimus; - antimetabolites: azathioprine, mycophenolate mofetil and mycophenolic acid. The maintenance phase of immunosuppression in most cases combines one, two or three immunosuppressant medications. The most commonly used protocol combines a calcineurin inhibitor and an antimetabolite. Immunosuppression protocols are prescribed on the basis of numerous immunological parameters, particularly initial compatibility, the onset of rejection or infection and the age of the recipient. In view of the results observed in the BENEFIT and BENEFIT-EXT studies, NULOJIX (belatacept) is an alternative to ciclosporin in particular in young patients who have an immunological status positive for Epstein-Barr virus and have received a renal transplant taken from living or deceased donors in accordance with standard criteria Target population The target population for NULOJIX is represented by the adult population who has received a renal transplant (de novo) and consequently requires treatment to prevent rejection of the transplant. According to data from the Biomedicine Agency 3, 2826 patients received a kidney transplant in For information, on 1 January 2010, 7511 adult patients were on the register of patients waiting for a kidney transplant. According to that agency, the EBV negative population is of the order of 10%. 1 HAS. Outpatient follow-up of adult renal transplant recipients more than 3 months after transplantation. Professional guidelines November Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, et al. Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study. Health Technol Assess 2005; 9 (21): 1-179, iii-iv. 3 Biomedicine Agency. Medical and scientific report /13

13 It is not possible to give a precise estimate of the adult target population because of the fact that immunosuppressant treatment is given life-long and thus concerns all patients with renal transplants Transparency Committee recommendations The Transparency Committee recommends inclusion on the list of medicines approved for hospital use and various public services in the indication and dosages in the Marketing Authorisation. The Transparency Committee wishes to re-examine this dossier in 18 months. 13/13