Transcript ASAQ - MSF UK | Medical aid where it is needed most

ASAQ, a new fixed-dose
combination of artesunateamodiaquine: progress and
challenges
Ann-Marie Sevcsik on behalf of
Graciela Diap, Jean-Rene Kiechel &
FACT Partners
MSF-UK Scientific Day
London, June 2007
DNDi was created in 2003
Objective: To deliver 6 - 8 new treatments by 2014
7 Founding Partners
Indian Council for
Medical Research (ICMR)
Kenya Medical Research
Institute (KEMRI)
5 Regional Support
Liaison Offices
Coordination team
Geneva + consultants
Malaysia
Oswaldo Cruz Foundation
Brazil
USA
Medecins Sans Frontieres
(MSF)
WHO/TDR (permanent
observer)
India
Kenya
Malaysian MOH
Institut Pasteur France
Brazil
2 Project
Support Offices
Japan
RDC
2006, WHO
strengthens
recommendations.
ACTS should be:
1. first-line treatment for
falciparum malaria
everywhere
2. in fixed-dose
combinations when
possible
www.who.int/malaria/docs/TreatmentGuidelines2006.pdf
+ FACT Project partners
The product:
Artesunate-Amodiaquine Fixed-Dose Combination
« ASAQ Winthrop» / « Coarsucam »
1. Clinical results
2. Registration plans / Regulatory process
3. Possibilities for MSF
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
Simplified 3-Day ACT dose regimen of ASAQ
NEW Fixed-dose
Artesunate/amiodaquine
Co-blistered
Artesunate-amiodaquine
Fixed-dose Artemether/
lumenfrantine (Coartem®)
3 dosage strengths
available
AS: 50 mg; AQ 153 mg
AM: 20 mg; LF: 120
mg
Infants
(<8,9 kg)
<10 kg
AS: 25 mg
AQ: 67.5 mg
Not recommended*
AM
PM
10-15
kg
Young Children
(8-17,9 kg)
AS: 50 mg
AQ: 135 mg
15-25 kg
Children
(18-35,9 kg)
AS: 100 mg
AQ: 270 mg
25-35 kg
Adults
(>36 kg)
AM
AS: 100 mg
AQ: 270 mg
PM
>35 kg
* A pediatric formulation of AR/LU is currently under development by Novartis and MMV
160
Population in 31 countries where ASAQ could be considered as 1st
line treatment for uncomplicated malaria in Africa
140
=
497.3 Million
120
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
80
60
40
Principe & Sao Tome
Comorros
Zanzibar
Gabon
Mauritania
Liberia
Congo
CAR
Eritrea
Sierra Leone
Togo
Burundi
Benin
Somalia
Guinea
Chad
Senegal
Equatorial Guinea
Reference: RBM-WHOAfro, 2006.
Malawi
Burkina Faso
Mali
Niger
Angola
Cameroon
Ivory Coast
Mozambique
Ghana
Sudan
DRC
0
Madagascar
20
Nigeria
Population
100
What is known about ASAQ?
1.
2.
3.
AS+AQ: Tolerability and Drug Interaction in HNV AS vs
AQ vs AS/AQ. P.Olliaro, et al.
AS+AQ: Tolerability and PK study in HNV of non-fixed
and fixed-dose combinations, P. Olliaro et al.
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 ASAQ
A comparative clinical assessment
of fixed-dose ASAQ vs. non-fixed artesunate-amodiaquine
(AS+AQ)
-Study coordinated by
DNDi with CNFRP from
2004 to 2006
Laos
Algérie
Sénégal
Mali
Niger
Nigeria
Côte
Ghana
d’Ivoire
Bénin
-750 children < 5kg were
followed up over 28 days
-To demonstrate the noninferiority of fixed-dose
artesunate-amodiaquine
(ASAQ) versus loose
combination (AS+AQ)
-Efficacy
-Safety
Results: Primary Objective
Day-28 PCR-Corrected Cure Rate
Dataset
Fixed
Non-fixed
PP
N=342
N=340
92.11%
92.06%
D28 Cure Rate
(Δ= - 0.0005; 95% CI [-0.0345; 0.0335]
mPP
D28 Cure Rate
N=329
N=326
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)
Most frequently
reported adverse events (AEs)
•Intensity was mild to moderate
FIXED
N=375
LOOSE
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
FIXED
AS/AQ
4
NON-FIXED
AS+AQ
5
Death
1
1
Gastroenteritis
1
0
Severe malaria
Conclusions
 Comparable efficacy of fixed-dose ASAQ vs
non-fixed AS-AQ
 Non-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)
ITT
PP
ASAQ 1/D
ASAQ 2/D
AL
95.2%
94.9%
95.5%
N=310
N=315
N=311
98.9%
100%
98.6%
N=283
N=285
N=289
No unexpected AD occurred, clinical and biological
safety 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
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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