étude de phase III dans l’asthme sévère_ autorisation FDA pour les USA 14/09/2011

source: http://www.gazettelabo.fr/breves/breves11.php?id=1831

2011-09-14
AB Science obtient de la FDA l'autorisation (IND) de démarrer son étude de phase 3 dans l’asthme sévère. Ouverture du recrutement dans cette étude aux Etats-Unis

AB Science SA (NYSE Euronext - FR0010557264 - AB), société pharmaceutique spécialisée dans la recherche, le développement et la commercialisation d'inhibiteurs de protéines kinases (IPK), annonce aujourd'hui avoir obtenu une IND (Investigational New Drug - autorisation pour une recherche clinique avec un nouveau médicament) de la part de la Food and Drug Administration (FDA) américaine pour mener aux Etats-Unis l’étude de phase 3 du masitinib dans l’asthme sévère persistant. Cette étude est déjà autorisée en Europe et le recrutement y est en cours.

Il s’agit d’une étude de phase 3, internationale, multicentrique, en double aveugle, contrôlée par placebo avec 2 groupes parallèles, comparant l’efficacité et la tolérance du masitinib à 6 mg/kg/jour au placebo dans le traitement de patients atteints d’asthme sévère persistant non contrôlé par les corticoïdes oraux.

Cette étude, qui est déjà en cours de recrutement en Europe et dans d’autres pays, recrutera environ 300 patients dans le monde.

« Cette IND pour une étude de phase 3 fait suite à une revue approfondie des données du masitinib par la FDA dans l’indication visée. Elle témoigne d’une analyse favorable de la FDA sur le potentiel du masitinib à apporter une solution thérapeutique dans l’asthme sévère persistant. Pour mémoire, l’asthme sévère persistant non contrôlé par les corticoïdes oraux est une maladie qui ne dispose pas de traitement enregistré. A ce jour tous les immunosuppresseurs et les médicaments biologiques qui ont été testés ont échoué. Le masitinib est donc le seul candidat médicament dans cette indication. De plus, le masitinib est un traitement oral et bien toléré. Cette autorisation de la part de la FDA fait suite à celle de l’EMA et des pays européens participant à l’étude.», déclare Alain Moussy, Président-Directeur Général d’AB Science.»

A propos de l’asthme sévère persistant

L’asthme est une maladie très répandue qui affecte 200 à 300 millions de personnes dans le monde, ce qui représente une prévalence de 4% à 7%. Pour environ 10% des asthmatiques (les asthmatiques sévères), cette maladie reste symptomatique malgré un traitement par inhalation de hautes doses de corticoïdes et des antagonistes b-2 longue action. Cette forme d’asthme est caractérisée par le besoin d’administrer des corticoïdes par voie systémique (non inhalée). Les patients souffrent d’exacerbations fréquentes qui peuvent conduire à une hospitalisation et qui peuvent s’avérer fatals. Cette maladie affecte la qualité de vie des patients de manière durable tout en mettant leur vie en péril. Les immunosuppresseurs comme le methotrexate ou les biologiques comme les anti-TNF alpha, qui sont efficaces dans d’autres indications inflammatoires telles la polyarthrite rhumatoïde, le psoriasis et la maladie de Crohn, n’ont démontré aucune efficacité dans l’asthme.

info etude
source: http://clinicaltrials.gov/ct2/show/NCT01449162?term=masitinib&rank=10

Asthme=anti-TyroKinase=Dégra Mastocyte
Auj. à 21:34
Asthme=Immunothérapie par anticorps monoclonaux
dans l’asthme =Anticorps anti-Tyrosine Kinase=Dégranulation des mastocytes=Nouveaux traitements: Imatinib et Masitinib=Nouveaux traitements: Les patients traités par masitinib

Variation de l’ACQ (0–7 items), en fonction du traitement par masitinib sur 16 semaines.
Humbert M et al. Allergy 2009

Ref
http://www.des-pneumo-idf.com/s/IMG/pdf/Asthme_severe_G_Garcia_janvier_2011.pdf

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Document trés bien fait et complet

Nouveau Document datant d'aujourdui.
le 23/02/2013

http://euroscan.org.uk/technologies/technology/view/2033

Source agency:
NHSC
Date of Submission:
08/10/2012
Date of Printing:
23/02/2013
Disclaimer:
This report is work in progress and should not be used for external distribution without permission from the originating agency. Users should be aware that reports are based on information available at the time of research and often on a limited literature search.
Technology, Company & Licensing

Technology name:
Masitinib (AB-101)
Technology - description:
Masitinib (AB-101) is an orally active, protein tyrosine kinase inhibitor, which selectively inhibits c-kit. Inhibition of c-kit may lead to a reduction in the number or activity of mast cells, which play a key role in inflammation. It is intended for the treatment of severe, persistent, corticosteroid-dependent asthma. In the phase III clinical trial masitinib is administered orally at 6mg/kg per day.
Company or developer:
AB Science.
Reason for database entry:
If licensed, masitinib may offer an additional treatment option for patients with severe, persistent, corticosteroid-dependant asthma.
Technology - stage in early warning process:
Assessment in progress
Technology - stage of development:
Investigational - phase III
Licensing, reimbursement and other approval:
No information available.
Technology - type(s):
Drug
Technology - use(s):
Therapeutic
Patient Indication & Setting

Patient indications:
Asthma: severe, persistent, corticosteroid-dependant.
Disease description and associated mortality and morbidity:
Asthma is a chronic disorder of the airways caused primarily by inflammatory processes and constriction of the smooth muscle in airway walls (bronchoconstriction)(1). It is characterised by airflow obstruction and increased responsiveness of the airways to various stimuli. Symptoms include recurring episodes of wheezing, breathlessness, chest tightness and coughing(1).

Asthma usually develops in childhood but may start at any age. There is no cure for asthma, although people may experience long periods of remission. Poorly controlled asthma can have a significant impact on the quality of life of the affected person and their family, though there may be variation in an individual’s perception of the symptoms and how they adapt to the condition over time (1,2). Clinical measures such as lung function may not correlate well with an individual’s quality of life, but if asthma is well controlled, near maximal scores on quality of life instruments can be achieved . The diagnosis of asthma is a clinical one; there is no standardised definition of the type, severity or frequency of symptoms, nor of the findings on investigation(3).

It is estimated that there are 5.2 million people with asthma in the UK, of whom approximately 2.9 million are women and girls, 2.3 million are men and boys, 0.7 million people are older than 65 years, and 0.6 million are teenagers. The Health Survey for England (2010) estimated the lifetime prevalence of diagnosed asthma to be 17% in women and 16% in men(4). NICE estimates the prevalence of severe persistent asthma to be 47 per 100,000 population(1,2). Mortality from asthma is rare, with 999 asthma-related deaths reported in 2010(5). Although mortality from asthma is rare, expert opinion suggests that it still accounts for nearly 3 potentially eminently preventable deaths, sometimes in young persons, every day.
Number of Patients:
In 2010-11, there were 62,961 hospital admissions for asthma (ICD-10 J45) in England, resulting in 148,497 bed-days and 82,253 finished consultant episodes(6).
Technology - specialities(s):
Respiratory disease & thoracic surgery
Technology - setting(s):
General hospital and ambulatory care
Setting - further information:

Impact

Alternative and/or complementary technology:
Additive or complementary technology
Current Technology:
The management of asthma aims to control the disease; this includes no daytime symptoms, no night-time awakening due to asthma, no need for rescue medication, no exacerbations, and no limitations on activity including exercise(1,2). The SIGN/BTS(7) guideline recommends a ‘stepwise approach’ to treatment in both adults and children. Treatment is started at the step most appropriate to the initial severity of the asthma with the aim of achieving early control of symptoms and optimising respiratory function. Control is maintained by stepping up treatment as necessary and stepping down when control is good(1,2).

The following stepwise and additive approach is recommended(6):
• Inhaled short-acting beta2-agonist (step 1).
• Inhaled corticosteroid (ICS) 200-400µg/day (children aged 5-12), 200-800µg/day (adults) or other preventer drug if inhaled steroid cannot be used (step 2).
• Inhaled long-acting beta2-agonist (LABA) (step 3).
- Benefit from LABA but inadequate control – increase ICS dose to 400µg/day (children aged 5-12), 800µg/day (adults).
- No response to LABA - stop use and increase ICS dose to 400µg/day (children aged 5-12), 800µg/day (adults).
- Control still inadequate - consider leukotriene receptor agonist or modified release theophylline.
• Increase ICS up to 800µg/day (children aged 5-12), or trials of increasing ICS up to 2000µg/day, or addition of a fourth drug e.g leukotriene receptor antagonist, modified release theophylline, β2 agonist tablet (adults) (step 4).
• Daily oral, corticosteroids (lowest dose) and ICS at 800µg/day (step 5)

NICE guidelines also recommend the use of omalizumab for severe persistent allergic asthma(.
Health Impact:
No information available.
Diffusion:
No information available.
Cost, infrastructure and economic consequences:
The cost of masitinib is unknown. The cost of selected inhaled corticosteroids and other treatments for the treatment of asthma is (8,9):
Drug: Beclometasone dipropionate
Dose: 100 - 400µg twice daily; children under 12 years, 100-200µg twice daily.
Cost: 200µg/metered inhalation (100-dose unit): £9.89

Drug: Budesonide
Dose: 100 - 400µg twice daily; children under 12 years, 100-200µg twice daily.
Cost: 200µg/metered inhalation (200-dose unit): £17.71

Drug: Ciclesonide
Dose: 160µg daily as a single dose.
Cost: 160µg/metered inhalation (60-dose unit): £19.31

Drug: Fluticasone propionate (Flixotide; Accuhaler)
Dose: 50 - 200µg twice daily; children aged 4-12yrs, 50–100µg twice daily.
Cost: 100µg/blister with Accuhaler: £8.93

Drug: Mometasone fuorate (Asmanex; Twisthaler)
Dose: 400µg as a single dose in the evening or in 2 divided doses. Not recommended for children under 12.
Cost: 200µg/metered inhalation (30-dose unit): £15.70

Drug: Omalizumab (Xolair)
Dose: Subcutaneous injection. The appropriate dose and frequency of omalizumab is determined by baseline IgE (IU/ml), measured before the start of treatment, and body weight (kg). The maximum recommended dose is 600 mg every two weeks(10).
Cost: £15,400 per patient, per year.
Ethical, social, legal, political and cultural impact:
No information available.
Evidence & Policy

Clinical evidence and safety:
Trial: NCT01449162, AB07015; masitinib vs placebo; phase III.
Sponsor: AB Science.
Status: Ongoing.
Source of information: Trial registry(11).
Location: France.
Design: Randomised, placebo-controlled.
Participants: n=300 (planned); aged 18 years and older; severe persistent asthma despite treatment.
Schedule: Randomised to masitinib, oral, 6mg/kg once a day vs placebo, oral, both for 36 weeks.
Follow-up: Active treatment period 36 weeks.
Primary outcome/s: Asthma exacerbation rate.
Secondary outcome/s: Asthma control questionnaire (ACQ) score, moderate and severe asthma exacerbation rate.
Key results: -
Adverse effects (AEs): -
Expected reporting date: Primary completion date reported as Dec 2013.

Trial: NCT00842270, AB04026; masitinib vs placebo; phase II.
Sponsor: AB Science.
Status: Completed and published.
Source of information: Trial registry(12) and publication(13).
Location: France.
Design: Randomised, placebo-controlled.
Participants: n=44; aged 18 years and older; severe persistent asthma; disease duration >1 year.
Schedule: Randomised to masitinib, oral, 3mg/kg, 4.5mg/kg, 6mg/kg, or placebo, all once a day for 16 weeks.
Follow-up: Active treatment period 16 weeks, follow-up 3 months.
Primary outcome/s: Decrease in oral corticosteroid therapy.
Secondary outcome/s: Asthma control improvement assessed by the ACQ (asthma exacerbation rate).
Key results: Patients weaned from oral corticosteroids: 35.7% (masitinib group), 27.3% (placebo group); number of patients experiencing at least one exacerbation during the study: 42.4% (masitinib group), and 54.5% (placebo group); improvement in asthma control score (assessed by ACQ), 0.56, 1.57 and 0.89 units in patients treated with 3, 4.5 and 6mg/kg masitinib respectively, improvement of 0.43 units in the placebo group.
Adverse effects (AEs): Common AEs include nausea (30.3%), skin rash (30.3%), peripheral oedema (18.2%), diarrhoea (18.2%), vomiting (12.1%), fatigue (12.1%) and pruritus (12.1%).
Expected reporting date: -
Economic evaluation:
No further information available.
Ongoing research:
None.
Ongoing or planned HTA:
No further information available.
Web link:

References and sources:
1) National Institute for Health and Clinical Excellence. Inhaled corticosteroids for the treatment of chronic asthma in children under the age of 12 years. Technology appraisal TA131. London: NICE; Nov 2007.
2) National Institute for Health and Clinical Excellence. Inhaled corticosteroids for the treatment of chronic asthma in children aged 12 years and over. Technology appraisal TA138. London: NICE; March 2008.
3) National Institute for Health and Clinical Excellence. Guidance on the use of inhaler systems (devices) in children under the age of 5 years with chronic asthma. Technology appraisal TA10. London: NICE; August 2000.
4) The Health Survey for England. Respiratory Health: Summary of key findings. Leeds: The NHS information centre. 2010.
5) Office for National Statistics. Mortality statistics: deaths registered in England and Wales (Series DR) 2010. http://www.ons.gov.uk
6) NHS Hospital episode statistics. NHS Englnad 2010-11. 2011. www.hesonline.co.uk
7) Scottish Intercollegiate Guidelines Network. Managing asthma in adults: A booklet for patients and their families and carers. Edinburgh: SIGN; Dec 2011.
National Institute for Health and Clinical Excellence. Omalizumab for the treatment of severe persistent allergic asthma in children ages 6 to 11 years. Technology appraisal TA201. London: NICE; Oct 2010.
9) British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BNF. London: BMJ Group and RPS Publishing, Mar 2012.
10) The electronic Medicines Compendium (eMC). Summary of Product Characteristics, Xolair. Novartis Pharmaceuticals UK Ltd. Accessed 24 Sept 2012.
11) ClinicalTrials.gov. A prospective, multicentre, randomised, double-blind, placebo-controlled, 2-parallel groups, phase 3 study to compare the efficacy and the safety of masitinib at 6mg/kg/day versus placebo in the treatment of patients with severe persistent asthma treated with oral corticosteroids. http://clinicaltrials.gov/ct2/show/NCT01449162?term=masitinib&rank=9 Accessed 24 July 2012
12)ClinicalTrials.gov A multicentre, double-blind, placebo-controlled, randomised, parallel-group study to evaluate the efficacy of oral AB1010 in adult patients with severe persistent corticosteroid dependent asthma. http://clinicaltrials.gov/ct2/show/NCT00842270?term=masitinib&rank=5 Accessed 24 July 2012.
13) Humbert M, De Blay F, Garcia G et al. Masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid-dependent asthmatics. Allergy 2009;64(:1194-201.