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