Upload
harriet-tyler
View
216
Download
0
Embed Size (px)
Citation preview
ASAQ, a new fixed-dose combination of artesunate-
amodiaquine: progress and challenges
Ann-Marie Sevcsik on behalf of Graciela Diap, Jean-Rene Kiechel &
FACT PartnersMSF-UK Scientific Day
London, June 2007
DNDi was created in 2003Objective: To deliver 6 - 8 new treatments by 2014
Kenya Medical Research Institute (KEMRI)
WHO/TDR (permanent observer)
Medecins Sans Frontieres (MSF)
Malaysian MOH
Institut Pasteur France
Oswaldo Cruz FoundationBrazil
Indian Council for Medical Research (ICMR)
Kenya
7 Founding Partners
Malaysia
USA
India
Japan
Coordination team Geneva + consultants
5 Regional Support Liaison Offices
Brazil
RDC
2 Project Support Offices
www.who.int/malaria/docs/TreatmentGuidelines2006.pdf
2006, WHO strengthensrecommendations.
ACTS should be: 1. first-line treatment for
falciparum malaria everywhere
2. in fixed-dose combinations when possible
The product:
Artesunate-Amodiaquine Fixed-Dose Combination
« ASAQ Winthrop» / « Coarsucam »
1. Clinical results
2. Registration plans / Regulatory process
3. Possibilities for MSF
+ FACT Project partners
Advantages of the ASAQ Fixed-Dose Combination
• Optimized AS:AQ ratio to prevent over- and under-dosing Taylor WRJ, et al. Bulletin of the WHO. 2006; 84; 956-964.
• Easy to use: fewer tablets in once-a-day treatment regimen
drugs taken together and in correct proportions
Paediatric formulation – readily dispersible
• Affordable: <$1 for adult, $0.50 for children
• Available: no patent taken
Co-blisteredArtesunate-amiodaquine
Fixed-dose Artemether/ lumenfrantine (Coartem®)
AS: 50 mg; AQ 153 mg
AM: 20 mg; LF: 120 mg
15-25 kg
Not recommended*<10 kg
>35 kg
25-35 kg
AM PM
AS: 100 mgAQ: 270 mg
AS: 100 mgAQ: 270 mg
AS: 50 mgAQ: 135 mg
AS: 25 mgAQ: 67.5 mg
NEW Fixed-doseArtesunate/amiodaquine
3 dosage strengths available
10-15 kg
* A pediatric formulation of AR/LU is currently under development by Novartis and MMV
AM PM
Simplified 3-Day ACT dose regimen of ASAQ
Adults (>36 kg)
Children (18-35,9 kg)
Young Children(8-17,9 kg)
Infants(<8,9 kg)
Population in 31 countries where ASAQ could be considered as 1st line treatment for uncomplicated malaria in Africa
= 497.3 Million
1st priority: countries where ASAQ is adopted as 1st line
where ASAQ is one of 1st-line treatments
2nd priority: countries where ASAQ can be of benefit
Reference: RBM-WHOAfro, 2006.
What is known about ASAQ?1. AS+AQ: Tolerability and Drug Interaction in HNV AS
vs AQ vs AS/AQ. P.Olliaro, et al.
2. AS+AQ: Tolerability and PK study in HNV of non-fixed and fixed-dose combinations, P. Olliaro et al.
3. Comparative Clinical study of ASAQ vs AS+AQ in Burkina Faso – S. Sirima et al. , Ouagadougou (n=750)
4. AS+AQ for uncomplicated falciparum malaria: A systematic review of safety and efficacy data - P.Olliaro et al. (n=5000)
5. Efficacy & Tolerability of AS + AQ for falciparum malaria in Senegal. 6-year deployment of a 10-year survey field survey - P. Brasseur et al. Sénégal (n=3000),
6. Comparative Clinical study of FDC ASAQ vs. Coartem®, March to Dec.06/Cameroon, Mali, Madagascar & Senegal; (n=941) – Preliminary results presented in Amsterdam, May 07
Burkina Faso: Most relevant study to register ASAQA comparative clinical assessment
of fixed-dose ASAQ vs. non-fixed artesunate-amodiaquine (AS+AQ)
Laos
NigerMali
Côte d’IvoireGhana
Nigeria
Sénégal
Bénin
AlgérieAlgérie
-Study coordinated by DNDi with CNFRP from 2004 to 2006
-750 children < 5kg were followed up over 28 days
-To demonstrate the non-inferiority of fixed-dose artesunate-amodiaquine (ASAQ) versus loose combination (AS+AQ)
-Efficacy-Safety
Results: Primary ObjectiveDay-28 PCR-Corrected Cure Rate
PP N=342 N=340
D28 Cure Rate 92.11% 92.06%
(Δ= - 0.0005; 95% CI [-0.0345; 0.0335]
mPP N=329 N=326
D28 Cure Rate 95.74% 96.01%
(Δ= - 0.0005; 95% CI [-0.0345; 0.0335]
Non-inferiority of fixed-dose AS/AQ versus non-fixed AS+AQ demonstrated (P<0.05) in all datasets (ITT included)
Dataset Fixed Non-fixed
Most frequently reported adverse events (AEs)
•Intensity was mild to moderate
FIXED LOOSEN=375 N=374
– Pyrexia (fever) 18.1 % 18.7 %– Anaemia 5.3 % 6.4 %– Diarrhea 1.9 % 2.7 %
•Nausea and vomiting, typically seen, were <2% over course of study (Days 1-28)
Serious adverse events FIXEDAS/AQ
NON-FIXEDAS+AQ
Severe malaria 4 5
Death 1 1
Gastroenteritis 1 0
Conclusions
Comparable efficacy of fixed-dose ASAQ vs non-fixed AS-AQNon-inferiority demonstrated
Easy to use
Well tolerated
AS + AQ Meta-Analyses
• Meta-analysis on safety and efficacy of AS + AQ studies around the world (P. Olliaro et al.)– N ≥5000 patients– 31 Studies conducted between 1999-2006
• 27 comparative, 3 non-comparative, 1 PK only
– 18 African countries– Most following WHO guidelines – Patients largely children (<5 yr in 18 studies);
• only 5 enrolled also adults
– Preliminary results presented at ASTMH 2006, Atlanta
Conclusions Efficacy & Safety
• Efficacy generally >90% after genotyping correction
• AS+AQ:– more effective than monotherapy and non-ACTs– similar to AS+SP– compares well with AM+LF, DH+PQ after PCR
correction but more re-infections
• Safety: crudely comparable safety profiles– Broader safety data needed
AS+AQ Individual Patient Meta-Analysis
Julien Zwang (Nosten + Olliaro)
AS+AQ Efficacy in the Treatment of Uncomplicated falciparum malaria
• > 4000 patients treated with AS+AQ 66% under 5 y.o. • 24 African sites 12 African Countries (Uganda 1283, Senegal 966)• 28 to 63 days follow up• AS+AQ efficacy PCR corrected 91%• Median time of parasite recrudescence 21 days• Tolerability analysis pending full compilation• Revision by PI’s June 2007• Publication December 2007
A multinational, randomized Phase III study to assess the efficacy and tolerability of FDC
AS+AQ once or twice daily vs. AL for uncomplicated falciparum malaria
- To demonstrate the non-inferiority of ASAQ versus AL in Cameroon, Mali, Senegal & Madagascar, from Mar to Dec 2006
- 941 patients including 437 children
- Preliminary results*:- >95% PCR-corrected cure rate at D28 for all groups- Good clinical & biological safety seen among all treatment
arms
*Presented at 5th ECTMIH, Amsterdam, 24-28 May 2007
AS+AQ once or twice daily vs. AL PCR-corrected adequate clinical and
parasitological response (2)
ASAQ 1/D ASAQ 2/D AL
ITT 95.2%N=310
94.9%N=315
95.5%N=311
PP 98.9%N=283
100%N=285
98.6%N=289
No unexpected AD occurred, clinical and biologicalsafety was good in the 3 arms
Registration File – Fixed-Dose Formulation
International CTD format• Approved in Morocco, February 2007
• Submitted to the WHO prequalification process, February 2007
• Registration process undertaken in 23 sub-Saharan African countries
• Approved in 14 sub-Saharan African countries – Benin, Burkina Faso, Congo, Côte d’Ivoire, Gabon,
Guinea, Kenya, Mali, Mauritania, Democratic Republic of the Congo, Togo, Zanzibar, Ghana & Madagascar
How can ASAQ be ordered?
• In many countries, Coarsucam® needs to be registered before ArteSunate AmodiaQuine Winthrop® can be submitted to national regulatory agencies.
• Until Artesunate Amodiaquine Winthrop® is available, NGOs and other non-for profit institutions interested in obtaining ASAQ can purchase Coarsucam® Impact Malaria at a “no profit-no loss” price under the following conditions :– Coarsucam® Impact Malaria is registered in the country of interest– Minimum order of 5000€– Qualified person (“pharmacist responsible") required– Storage facility available at country level
How can MSF contribute?
- Anticipate orders: estimate ASAQ needs for use in the field considering the 4 different presentations
- Get special authorisation to use ASAQ in countries out of the s-a 1st priority (Liberia, Sierra Leone, Malawi, South Sudan)
- Document and analyse the use of ASAQ in the field- Tolerability- Adherence- Efficacy- Drug interaction- Special group of patients
- Share experience and knowledge as part of the MSF advocacy
Thank you!
Looking forward to
more partners who could
help to deliver innovation to the patients!
Acknowledgements• EC INCO-Dev Program• FACT Consortium and Team Members
– Fondation Médecins Sans Frontières
– Tropival, Université de Bordeaux 2
– Centre for Tropical Medicine, University of Oxford
– Centre for Drug Research, Universiti Sains Malaysia
– Faculty of Tropical Medicine, Mahidol University
– Instituto de Technologia em Farmacos, Farmanguinhos
– WHO Special Programme on Research & Training in Tropical Diseases
– Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso)
• P. Olliaro, W.R.J. Taylor (WHO/TDR)
• Colleagues from DNDi and MSF
• Ellipse, Cardinal Systems, Quintiles, Cardinal Health…
• Abbott (Knoll); Pfizer (Parke-Davis); Roche; sanofi-aventis