The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 4 January 2012

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 4 January 2012 VOTUBIA 2.5 mg, tablet B/30 (CIP code: ) VOTUBIA 5 mg, tablet B/30 (CIP code: ) Applicant: NOVARTIS PHARMA Everolimus ATC code: L01XE10 (antineoplastic, mtor inhibitor) List I Medicine for hospital prescription only. Medicine requiring special monitoring during treatment. Orphan drug. Date of Marketing Authorisation: 2/09/2011 (centralised conditional Marketing Authorisation) This Marketing Authorisation is accompanied by obligations and requirements including in particular the setting up of a Risk Management Plan, pharmacovigilance monitoring, long-term monitoring of the patients in the studies and the final results of the phase-iii study in progress (see annex 1). Reason for request: Inclusion on the list of medicines refundable by National Health Insurance and approved for hospital use. Medical, Economic and Public Health Assessment Division. 1/10

2 1. CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient Everolimus 1.2. Indication VOTUBIA is indicated for the treatment of patients aged 3 years and older with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) who require therapeutic intervention but are not amenable to surgery. Efficacy is based on analysis of change in SEGA volume. Further clinical benefit, such as improvement in disease-related symptoms, has not been demonstrated Dosage Treatment with VOTUBIA should be initiated by a physician experienced in the treatment of patients with TSC and therapeutic drug monitoring. Dosage: Careful titration may be required to obtain the optimal therapeutic effect. Doses that will be tolerated and effective vary between patients. Concomitant antiepileptic therapy may affect the metabolism of everolimus and may contribute to this variance (see section 4.5 of the SPC). The recommended starting dose of VOTUBIA for treatment of patients with SEGA is according to Table 1. Table 1: Recommended starting dose of VOTUBIA for treatment of patients with SEGA. Body surface area (BSA) Starting daily dose 1.2 m mg 1.3 to 2.1 m 2 5 mg 2.2 m mg Everolimus whole blood trough concentrations should be assessed approximately 2 weeks after commencing treatment. Dosing should be titrated to attain trough concentrations of 5 to 15 ng/ml. If concentrations are below 5 ng/ml, the daily dose may be increased by 2.5 mg every 2 weeks, subject to tolerability. The dose of VOTUBIA should be reduced if trough concentrations > 15 ng/ml are observed. SEGA volume should be evaluated approximately 3 months after commencing VOTUBIA therapy, with subsequent dose adjustments taking changes in SEGA volume, corresponding trough concentration, and tolerability into consideration. Management of severe or intolerable undesirable effects may require temporary dose reduction and/or interruption of therapy (see section 4.4). If dose reduction is required for patients receiving 2.5 mg daily, alternate day dosing should be considered. If a dose is missed, the patient should not take an additional dose, but take the usual prescribed next dose. Therapeutic drug monitoring: Therapeutic drug monitoring of everolimus blood concentrations is required for patients treated for SEGA using a validated assay. Trough concentrations should be assessed approximately 2 weeks after the initial dose, after any change in dose, after initiation of or change in co-administration of CYP3A4 inducers or inhibitors (see sections 4.4 and 4.5 of the SPC). Special populations: Paediatric population: The safety and efficacy of VOTUBIA in children aged 0 to less than 3 years have not been established. No data are available. The potential for growth/developmental delays with long-term treatment is unknown (see section 5.3 of the SPC). 2/10

3 Dosing recommendations for paediatric patients aged 3 years and older with SEGA are consistent with those for the adult SEGA population. The safety and efficacy of VOTUBIA in paediatric cancer patients have not been established. No data are available. Elderly patients ( 65 years) No dosage adjustment is required (see section 5.2 of the SPC). Renal impairment: No dosage adjustment is required (see section 5.2 of the SPC). Hepatic impairment: The dose should be reduced by approximately 50% to maintain the target trough concentrations between 5 and 15 ng/ml. Patients with severe hepatic impairment (Child-Pugh C): Everolimus has not been evaluated in patients with severe hepatic impairment (Child-Pugh C) and its use is not recommended in this population (see sections 4.4 and 5.2 of the SPC). Method of administration: VOTUBIA must be administered orally once daily at the same time each day, consistently either with or without food (see section 5.2 of the SPC). VOTUBIA tablets are to be swallowed whole with a glass of water. The tablets must not be chewed or crushed. For patients unable to swallow tablets, VOTUBIA tablet(s) can be dispersed completely in a glass with approximately 30 ml of water, by gently stirring, immediately prior to drinking. After the dispersion has been swallowed, any residue must be re-dispersed in the same volume of water and swallowed (see section 5.2 of the SPC). 2. SIMILAR MEDICINAL PRODUCTS 2.1. ATC Classification (2011) L Antineoplastic and immunomodulating agents L01 Antineoplastic agents L01X Other antineoplastic agents L01XE Protein tyrosine kinase inhibitors L01XE10 Everolimus 2.2. Medicines in the same therapeutic category VOTUBIA is the first treatment available in the specific indication subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex 2.3. Medicines with a similar therapeutic aim The non-drug reference alternative consists of surgical resection of the astrocytomas. 3/10

4 3. ANALYSIS OF AVAILABLE DATA 3.1. Efficacy Assessment of the efficacy and tolerance of VOTUBIA (everolimus) is based on: - a (pivotal) non-comparative, phase-ii study (C2485), which evaluated everolimus efficacy in terms of volume of the subependymal giant cell astrocytoma (SEGA) in 28 patients with Bourneville s tuberous sclerosis after 6 months of treatment, - the intermediate results of a phase-iii study (Exist-1), which compared everolimus with placebo in terms of tumour response rate in 117 patients with SEGA associated with Bourneville s tuberous sclerosis Phase-II study: C2485 Methodology: open-label, non-comparative, phase-ii study, carried out on 28 patients with SEGA associated with Bourneville s tuberous sclerosis monitored for 6 months. Inclusion criteria: patients aged 3 years and older with subependymal giant cell astrocytoma (SEGA) associated with Bourneville s tuberous sclerosis defined in accordance with the Gomez criteria or by searching for genomic mutations. SEGAs had to be active and confirmed by two MRI scans. Treatment: everolimus, n=28: starting dose of 3 mg/m 2 /day, then adjusted to achieve a blood level of between 5 and 15 ng/ml. Primary efficacy endpoint: change in SEGA volume 6 months after commencing the treatment (or at the time of the last assessment available in patients who stopped treatment before 6 months) compared with inclusion; this development was determined by radiography with independent central reading. A reduction 30% in SEGA volume was considered to be clinically relevant. RESULTS: analysis on an intention-to-treat basis (see Tables 1 and 2). The median age of the patients included was 11. Table 1: Change in median SEGA volume t at 3, 6, 12, 18 and 24 months Inclusion N=28 3 months N=26 6 months N=27 12 months N=26 Median SEGA volume (cm 3 ) [0.49; 14.23] [0.25; 8.32] [0.31; 7.98] [0.29; 8.18] Reduction compared with [-0.12; 5.91] [0.06; 6.25] [0.02; 6.05] inclusion p< months N= [0.33; 5.20] 0.74 [-0.24; 9.03] 24 months N= [0.33; 3.66] 0.46 [0.12; 3.79] A significant reduction in median SEGA volume was therefore observed compared with inclusion after 6 months of treatment with everolimus (Primary efficacy endpoint): reduction of 0.83 cm 3 [0.06; 6.25], p< Taking into account the methodology of this study (no comparator, small number) these results should be interpreted carefully. 4/10

5 Table 2: Percentage response at 3, 6, 12, 18 and 24 months 3 months 6 months N=26 N=27 n (%) n (%) 12 months N=26 n (%) 18 months N=18 n (%) 24 months N=8 n (%) Reduction 50% 10 (38.5) 9 (33.3) 9 (34.6) 8 (44.4) 3 (37.5) Reduction 30% 17 (65.4) 21 (77.8) 20 (76.9) 12 (66.7) 6 (75.0) Reduction > 0% 25 (96.2) 27 (100.0) 26 (100.0) 16 (88.9) 8 (100.0) No change (5.6) 0 Increase 1 (3.8) (5.6) 0 A reduction 30% in SEGA volume, considered to be clinically relevant, was observed in 21/28 patients (75%) included after 6 months of treatment Study Exist-1: Preliminary results Methodology: A comparative, randomised, double-blind phase-iii study of everolimus (VOTUBIA) versus placebo, carried out on 117 patients with SEGA associated with tuberous sclerosis complex ; the patients were monitored until there was a progression in the SEGAs, unacceptable toxicity or discontinuation of treatment whatever the cause observed. (The study protocol was requested from the Pharmaceutical company to clarify these points, but was not available at the time of the examination; a summary was however sent to us). To date, only the preliminary results, 6 months after the end of randomisation (conclusion of the analysis on 02/03/2011), are available and set out below. Inclusion criteria: patients aged 3 years and older with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex defined in accordance with the Gomez criteria or by genetic tests and: - the presence of at least one SEGA lesion 1.0 cm in diameter, - an increase in SEGA volume of at least 10% or the presence of a new lesion 5 mm in diameter, or ventriculomegaly defined by an increase in at least 10% of the volume of each of the lateral ventricles identified through a comparison of the MRI at inclusion and a previous MRI. Treatments: - Everolimus 4.5 mg/m 2 /day then adjusted to attain a blood level of between 10 and 15 ng/ml n=78, - Placebo, n=39. Primary efficacy endpoint: response rate (percentage of responders) with independent central reading defined by: - a reduction in initial SEGA volume 50%, - no aggravation of lesions other than the SEGA referred to, - no development of new SEGA 1 cm in length, - no new hydrocephaly or sign of aggravation. Control MRIs were carried out at 12 and 24 weeks then every 24 weeks. RESULTS: analysis on an intention-to-treat basis (see Table 3). The median age of the patients included was 9.46 years [0.6; 26.6]. 5/10

6 Table 3: Response rate, 6 months after the end of randomisation (analysis on 02/03/2011) Everolimus n=78 Placebo n=39 Responders Percentage [95% CI] N= % [24.2; 46.2] N=0 0% [0.0; 9.0] Difference vs placebo [95% CI] p versus placebo Non-responders - No clinical development - SEGA progression - Not documented 34.6 [15.1; 52.4] <0, (62.8%) 0 2 (2.6%) 36 (92.3%) 3 (7.7%) 0 Six months after the end of randomisation (preliminary analysis on 02/03/2011), a significant reduction in the responder rate was observed with everolimus versus placebo : 34.6% versus 0, difference 34.6 [15.1; 52.4], p< No clinically relevant development (> 50%) was observed in 62.8% of the patients of the everolimus group and 92.3% of the placebo group (statistical test not available). These intermediate results should be interpreted carefully and confirmed by the final analysis of the results scheduled for September Adverse effects In the C2485 phase-ii study, adverse effects were observed in all the patients treated with everolimus. The most common adverse effects (> 10%) were: stomatitis and upper respiratory tract infections (78.6%), sinusitis, otitis, fever, acne, cellulite, diarrhoea, gastro-enteritis, hypertriglyceridaemia, cough, gastric infection, skin infection and a reduction in leucocytes. The majority of these effects were mild to moderate intensity; 5 serious adverse effects were observed (pneumonia, bronchitis, convulsions (2) and vomiting). No death was observed. In the Exist-1 phase-iii study, after 6 months of monitoring, adverse effects were observed in 82/117 (70%) of the patients: 65/78 (83.3%) patients of the everolimus group and 17/39 (43.6%) of the placebo group. The most common adverse effects were (> 6%): - mouth ulcers: 30.8% vs 2.6%, - stomatitis: 30.8% vs 12.8%, - hypercholesterolaemia: 6.4% vs 2.6%, - asthenia: 6.4% vs 0. 6/10

7 3.3. Conclusion Efficacy and tolerance of everolimus (VOTUBIA) have been assessed in a non-comparative, phase-ii (study 2485) and a phase-iii study versus placebo (Exist-1), in patients with subependymal giant cell astrocytomas (SEGA) associated with tuberous sclerosis complex In the non-comparative study after 6 months of treatment, a significant reduction in median of SEGA volume was observed with everolimus compared with inclusion (main primary efficacy endpoint): reduction of 0.83 cm 3 [0.06; 6.25], p< A reduction 30% in SEGA volume considered to be clinically relevant was observed in 21 of the 28 patients (75%) included after 6 months of treatment. Taking into account the methodology of this study (no comparator, small number) these results should be interpreted carefully. In the study versus placebo, after six months of treatment (preliminary analysis), the percentage of responders was higher with everolimus than with placebo: 34.6% versus 0, i.e. a difference of 34.6 [15.1; 52.4], < No clinically relevant development (> 50%) was observed in 62.8% of the patients of the everolimus group and 92.3% of the placebo group (statistical test not available). These intermediate results should be interpreted carefully and confirmed by the final analysis of the results scheduled for September Everolimus efficacy was demonstrated only in the change in SEGA volume but in no other clinical endpoint, such as an improvement in disease-related symptoms. On the other hand, although everolimus reduces the volume of the subependymal giant cell astrocytomas (SEGA), it does not destroy them completely; discontinuation of treatment leads to resumed tumour growth. Chronic treatment with everolimus is therefore necessary whilst the tolerance of a cumulative high dosage is unknown. The most common adverse effects observed during these studies were: stomatitis and upper respiratory tract infections, sinusitis, otitis, fever, acne, cellulite, diarrhoea, gastro-enteritis, hypertriglyceridaemia, cough, gastric infection, asthenia, skin infection and a reduction in leucocytes. 7/10

8 4. TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit Subependymal giant cell astrocytomas (SEGA) are one of the symptoms of tuberous sclerosis complex. These are cerebral tumours that are benign in nature but which can induce functional deficits and mental retardation. The increase in the volume of these astrocytomas may, in some cases, lead to obstruction of the cerebrospinal fluid circulation pathways (hydrocephaly) and threaten patients survival as a result of complications. Everolimus, which reduces SEGA volume without destroying it completely, is a palliative treatment. These medicinal products are first-line treatments in patients who are not immediately eligible for surgical resection of SEGA. To date, there is no alternative medicinal product but surgical removal is usually, recommended. The efficacy/tolerance ratio for these medicinal products is high. Public health benefit: Tuberous sclerosis complex is a rare genetic disease, the most serious complication of which is the development of subependymal giant cell astrocytomas (SEGA). Because of its rarity, the burden represented by this pathology is low, including in patients aged 3 years and older who are not amenable to surgery. In view of the preliminary results of the trial carried out versus placebo and the palliative nature of this treatment on SEGA development, VOTUBIA s effect on morbidity can be considered moderate, owing to its efficacy in reducing SEGA volume. It is acceptable to apply the trial data to standard practice. The medium- and long-term impact on mortality and quality of life, in the absence of data, cannot be quantified. The impact of this medical treatment on organisation of care also cannot be quantified. All things considered, no public health benefit is expected for VOTUBIA in this indication. The actual benefit of these medicinal products is substantial Improvement in actual benefit (IAB) Taking into account the efficacy of VOTUBIA (everolimus) in reducing the volume of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex in patients aged 3 years and older, VOTUBIA provides a substantial improvement in actual benefit (IAB II) in the treatment of patients who are not immediately eligible for surgical resection of SEGA Therapeutic use 1,2 Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disease characterised by benign tumours (hamartomas), due to irregularities in some embryonic cells, in various organs. The disorder is multi-tissular, preferentially affecting the central nervous system, skin, kidneys, heart and lungs. Neurological signs such as epileptic attacks, mental disorders and intellectual retardation dominate the clinical picture. 1 Dr Wolkenstein Sclérose tubéreuse de Bourneville ( Bourneville s tuberous sclerosis ) Orphanet, February D Andon et al. Gliomes de bas grade ou astrocytomes ( Low-grade gliomas or astrocytomas ) IGR, March /10

9 Subependymal giant-cell astrocytomas (SEGA) are made up of a specific cell of tuberous sclerosis complex: the giant astrocyte. SEGAs are low-grade, glial brain tumours (WHO classification) pathognomonic of BTS. Exclusively localised at the level of the Monro s holes, their benign character is constant but they have the potential to develop with a risk of hydrocephaly which is the source of severe complications and is life-threatening. Although their potential to develop is slow, these tumours should be removed so that their effect is not added to the disease s pre-existing functional deficits. Their treatment is based mainly on surgical resection. In 90% to 95% of cases, the surgeon is able to perform complete or almost complete ablation and also cure the child. Unlike curative surgery, treatment with VOTUBIA (everolimus) is a palliative treatment which enables SEGA volume to be reduced but does not destroy it completely. However, discontinuation of the treatment leads to resumed tumour growth, making chronic treatment necessary, whilst the tolerance of a high cumulative dosage is unknown. For this reason, according to the experts, everolimus should be reserved for preparation of the surgical approach, which makes it simpler and more complete in some developed cases of SEGA. Everolimus should not dispense with the chance of surgical cure; it is therefore not an alternative to surgery but a temporary treatment preparing for this Target population 1,2 VOTUBIA s target population is patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex who are unable to benefit from surgical resection of SEGA. It can be estimated on the basis of the following data: - according to the Orphanet data 1, the prevalence of BTS in the general population is estimated at 8.8/100,000 in Europe, which, placed in the context of the French population amounts to approximately 5,800 patients, - approximately 15% of them are likely to develop astrocytomas, i.e. approximately 900 patients. - according to the experts, 90% of these patients are able to benefit from surgical intervention. In view of the aforementioned details, the VOTUBIA (everolimus) target population can be estimated at about one hundred patients Transparency Committee recommendations The transparency Committee recommends inclusion on the list of medicines refundable by National Health Insurance and on the list of medicines approved for hospital use and various public services in the indication in the Marketing Authorisation. 9/10

10 ANNEX 1 OBLIGATIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION Pharmacovigilance system The Marketing Authorisation holder should ensure that the pharmacovigilance system, presented in Module of the Marketing Authorisation, is set up and operational before and during the marketing of the medicinal product. Risk Management Plan (RMP) The Marketing Authorisation holder should carry out the pharmacovigilance activities described in the pharmacovigilance plan, included in the risk management plan, adopted and presented in Module of the Marketing Authorisation request, as well as all subsequent updates of the RMP adopted by the Committee for Medicinal Products for Human Use (CHMP). In accordance with the CHMP recommendation concerning the risk management systems of medicinal products for human use, the updated RMP should be submitted at the same time as the next periodic pharmacovigilance report. Furthermore, an updated RMP should be submitted: - when new information is received which may have an impact on the medicinal product s safety profile, the pharmacovigilance plan or the risk minimisation activities, - within 60 days following the date on which an important stage (pharmacovigilance or risk minimisation) is passed, - at the request of the European Medicines Agency. PSURs The timetable for submitting PSURs should follow the timetable for submitting the Afinitor PSURs. Conditions or restrictions for safe and effective use of the medicine Not applicable Specific Obligations to be complied with for post-authorisation procedures in the context of a conditional Marketing Authorisation As this Marketing Authorisation is conditional and in accordance with article 14(7) of regulation (EC) No 726/2004, the Marketing Authorisation holder should carry out, in accordance with the timetable indicated, the following procedures: Description The requester should undertake to submit a long-term follow-up concerning the duration of response and the time before progression for the C2485 and M2301 studies. The Marketing Authorisation holder should bring to a successful conclusion the pivotal clinical study M2301 currently in progress and submit the preliminary and finalised safety and efficacy results, in accordance with the timetable indicated. At the time of the intermediate analysis, the Marketing Authorisation holder should: Analyse the incidence of the adverse effects according to the medicine s plasma concentration, with or without inducer, stratified by age, Re-evaluate the starting dose strategy, using the knowledge of the relationship between the Cmin and the dose in this patient population, as well as the experience acquired on the need to adjust doses during study C2485, Submit a new simulation predicting the Cmin mean and confidence interval, resulting from the dosage recommended in the appropriate patient sub-groups, bearing in mind that the pharmacokinetic analysis of everolimus in children may lead the requester to define different stratifications depending on the age in relation to the current analyses (i.e. a 10-year limit might not be optimal). Expiry date 31/03/2015 Intermediate clinical study report due by: 30/12/2011 Final clinical study report due by: 30/09/ /10