Post on 21-Aug-2018
transcript
ASAQ Winthrop® Risk Management Plan status update
François Bompart, MD Access to Medicines
DNDi, A decade of R&D for Neglected Diseases in Africa Nairobi June 5, 2013
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ASAQ Winthrop®
Risk Management Plan Rationale Fixed-dose combination of artesunate-amodiaquine
DNDi – Sanofi partnership Made in Morocco Launched 2007, WHO prequalified 2008
2007: “ASAQ Field Monitoring Plan”, to proactively gather data on
Safety Efficacy in various settings
2008: “ASAQ Field Monitoring Plan” Formalized as a Risk Management Plan
Presented to the WHO, February 2009
1. Important identified risks: to be minimized with specific information – Intake during first trimester of pregnancy – Allergy
2. Important potential risks : to be quantified – Hepatotoxicity, neutropenia/, agranulocytosis, – Somnolence, audiometric dysfunction, extra-pyramidal symptoms – Decreased efficacy (parasite resistance)
3. Important missing information: to be documented
– Safety of repeated administrations – Specific populations (HIV/AIDS patients…) – Second and third trimester of pregnancy – Safety in non parasitemic patients – Drug interactions & Interactions with traditional drugs and remedies – Efficacy in species other than P. falciparum
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European Medicines Agency (EMA) “Risk Management Plans” format
ASAQ Winthrop® Risk Management Plan
Methods
Total : 19 studies (Sanofi, DNDi, Investigator-Sponsored studies) • Randomized clinical trials versus comparator
• Efficacy in various malaria transmission settings • Clinical safety • Biological safety, ECG data • Data in specific populations (HIV+, pregnancy) • Data in other species (P. vivax)
● Randomized cohort studies
• Efficacy / effectiveness and safety in Iterative administrations • ECG and audiometric data
● Large scale implementation study
• Effectiveness • Clinical safety in patients without parasites • Pharmacovigilance
● + Pharmacovigilance data
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Repeated treatment with ASAQ vs AL in children < 5 years, Tororo, Uganda
2-year study period 42 days follow-up 413 children: 208 ASAQ 205 AL 6027 malaria episodes treated
Number of patients per malaria episode
0
50
100
150
200
250
300
350
400
450
E1 E3 E5 E7 E9 E11 E13 E15 E17 E19 E21 E23 E25
Number of patients
Number of episodes
7
ITT population ASAQ Winthrop®
n=198
AL n=201
LCF 0 3(1.5%) LPF 5 (2.5%) 3 (1.5%)
ACPR 192 (97.0%) 194 (96.5%)
NA 1 (0.5%) 1 (0.5%)
Primary endpoint: PCR corrected treatment response at D28 for the 1st episode
Non inferiority demonstrated with an inferior limit of the
95% CI [-0.030; 0;039] of the difference of PCRs ACPR
rates between groups > 5%
PP population ASAQ Winthrop®
n=197
AL n=200
LCF 0 3(1.5%) LPF 5 (2.5%) 3 (1.5%)
ACPR 192 (97.5%) 194 (97.0%)
Non inferiority demonstrated with an inferior limit of the
95% CI [-0.028; 0;037] of the difference of PCRs ACPR
rates between groups > 5%
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Treatment Emergent Adverse Events
All malaria attacks – Safety population
* Non related to treatment One death (E16, ASAQ group) : severe malaria + severe anaemia + severe congestive heart failure
n (%) ASAQ Winthrop® (n = 208)
AL (n = 205)
Patients with any TEAE 120 (57.7%) 127 (62.0%)
Patients with any Serious TEAE 16 (7.7%) 9 (4.4%)
Patients with any TEAE leading to death 1 (0.5%) 0 (0%)
Patients with any TEAE leading to permanent treatment discontinuation
2 (1.0%) * 0 (0%)
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Reported Treatment Emergent Adverse Events, by malaria episode
31,6
%
12,4
%
9,8%
3,8%
6,4%
5,1%
2,6%
6,0%
2,6%
0,9% 1,
7% 3,0%
3,0%
2,1% 3,
0%
2,1%
1,3%
0,9%
0,4%
0,4% 0,9%
33,9
%
10,0
% 12,0
%
5,2%
4,4%
2,8% 3,
6%
6,0%
5,2%
3,6%
2,8%
2,8%
1,2%
0,8%
2,4%
0,4%
0,4% 1,
2%
0,8%
0,8%
0%
5%
10%
15%
20%
25%
30%
35%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
% AEs
Malaria attack no.
Reported AEs (%) according to malaria attack and treatment group
Coarsucam®/ASAQ Winthrop® (n = 234 AEs)
Coartem®(n = 251 AEs)
ASAQ ASA
ASAQ Winthrop® n=234 AEs
AL n=251 AEs
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Adverse Events of Special Interest increased ALAT in ASAQ treatment group
47
430
80
3020 32 30
70
7
77
37 32
39
0
50
100
150
200
250
300
350
400
450
500
D0 / EPISODE 1 D7 / EPISODE 1 D14 / EPISODE 1 D28 / EPISODE 1D0 / EPISODE 2 D7 / EPISODE 2 D21 / EPISODE 2
D0 / EPISODE 3 D7 / EPISODE 3 D28 / EPISODE 3D0 / EPISODE 4 D7 / EPISODE 4 D28 / EPISODE 4
D0 / EPISODE 5 D7 / EPISODE 5 D28 / EPISODE 5
Episodes 1 to 5: Coarsucam®/ASAQ Winthrop® administered from D0 to D3
Patient no. 347 - attack no.1ALAT (IU/L)UNL = 45 IU/L
study product administration (D0-D3)
4029 34
28
388
91
22 26 29 27
0
50
100
150
200
250
300
350
400
450
D0 / EPISODE 7 D7 / EPISODE 7 D28 / EPISODE 7 D0 / EPISODE 8 D7 / EPISODE 8 D14 / EPISODE 8 D28 / EPISODE8 D42 / EPISODE8D0 / EPISODE 9 D7 / EPISODE 9 D28 / EPISODE 9
Episodes 7 to 9: Coarsucam®/ASAQ Winthrop® administered from D0 to D3
Patient no. 038 - attack no.8ALAT (IU/L)UNL = 45 IU/L
study product administration (D0-D3)
59
2722 26
182
39 35
12
2214
0
20
40
60
80
100
120
140
160
180
200
D0 / EPISODE 10 D7 / EPISODE 10 D28 / EPISODE 10D0 / EPISODE 11 D7 / EPISODE 11 D21 / EPISODE 11
D0 / EPISODE 12 D7 / EPISODE 12 D28 / EPISODE 12 D81 / EPISODE 12D0 / EPISODE 13 D7 / EPISODE 13 D28 / EPISODE 13
Episodes 10 to 13: Coarsucam®/ASAQ Winthrop® administered from D0 to D3
Patient no. 110 attack no.11ALAT (IU/L)UNL = 45 IU/L
study product administration (D0-D3)
28 32 42 26 43
495
99
27
0
100
200
300
400
500
600
D0 / EPISODE 5 D7 / EPISODE 5 D21 / EPISODE 5D0 / EPISODE 6 D7 / EPISODE 6 D28 / EPISODE 6 D42 / EPISODE 6
D0 / EPISODE 7 D7 / EPISODE 7 D28 / EPISODE 7
Episodes 5, 6 & 7: Coarsucam®/ASAQ Winthrop® administered from D0 to D3
Patient no. 171 - attack no.6ALAT (IU/L)UNL = 45 …
study product administration (D0-D3)
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Adverse Events of Special Interest increased ALAT in AL treatment group
35 4426 30
624
204
82
47
0
100
200
300
400
500
600
700
D0 / EPISODE 6 D7 / EPISODE 6 D22 / EPISODE 6D0 / EPISODE 7 D7 / EPISODE 7 D19 / EPISODE 7
D0 / EPISODE 8 D7 / EPISODE 8 D26 / EPISODE 8D0 / EPISODE 9 D7 / EPISODE 9
Episodes 6, 7, 8 & 9: Coartem® administered from D0 to D3
Patient no. 139 - attack no.7ALAT (IU/L)UNL = 45 IU/L
study product administration (D0-D3)
49 51 50 4516
563
33
0
100
200
300
400
500
600
D0 / EPISODE 4 D7 / EPISODE 4 D28 / EPISODE 4 D42 / EPISODE 4D0 / EPISODE 5 D7 / EPISODE 5 D28 / EPISODE 5 D42 / EPISODE 5
Episodes 4 & 5: Coartem® administered from D0 to D3
Patient no. 317 - attack no.5ALAT (IU/L)UNL = 45 IU/L
study product administration (D0-D3)
50
22
136
436
103
40 31 38
0
50
100
150
200
250
300
350
400
450
500
D0 / EPISODE 8 D7 / EPISODE 8 D28 / EPISODE 8D0 / EPISODE 9 D7 / EPISODE 9 D14 / EPISODE 9 D28 / EPISODE 9
D0 / EPISODE 10 D7 / EPISODE 10 D28 / EPISODE 10
Episodes 8 , 9 & 10: Coartem® administered from D0 to D3
Patient no. 056 - attack no.9ALAT (IU/L)UNL = 45 IU/L
study product administration (D0-D3)
69 63
25 24 27
479
176
44
0
100
200
300
400
500
600
D0 / EPISODE 7 D7 / EPISODE 7 D21 / EPISODE 7D0 / EPISODE 8 D7 / EPISODE 8 D28 / EPISODE 8 D42 / EPISODE 8
D0 / EPISODE 9 D7 / EPISODE 9 D28 / EPISODE 9
Episodes 7, 8 & 9: Coartem® administered from D0 to D3
Patient no. 301 - attack no.8ALAT (IU/L)UNL = 45 IU/L
study product administration (D0-D3)
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Malaria attacks over time Insecticide-Treated Nets distribution
In spite of supervised distribution of bednets during summer 2009, no decrease in malaria incidence was observed
*
150
200
250
300
350
400
juin-08
juil-08
aug2008
sept-08
oct-08
nov-08
dec2008
janv-09
fev2009
mars-09
april2009
may2009
juin-09
juil-09
aug2009
sept-09
oct-09
nov-09
dec2009
janv-10
feb2010
mars-10
apr2010
Inclusion period
number of malaria attacks
months
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Repeated treatment with ASAQ vs AL in children < 5 years, Tororo, Uganda
Paper to be submitted Adoke Yeka,1 Valerie Lameyre,2 Ambrose Talisuna,3 Kibuka Afizi4, Mudhanga Fredrick4, Robinson Lukwago4, Moses Kamya5 1 Department of Disease Control and Environmental Health, School of Public Health, College of Health Sciences, Makerere, Kampala, Uganda 2 Sanofi Access to Medicines, Gentilly, France 3 Uganda Malaria Surveillance Program 4 Department of Medicine, Makerere University College of Health Sciences 5 East Africa WWARN, Kenyatta Hospital Estate, Nairobi, Kenya Scientific Committee: MV Kombila, Ph Brasseur, M Danis, Ogobara Doumbo,
Laurence Adonis, P Ambroise-Thomas Other collaborations: Marielle Boyou (Libreville) , Hervé Bogreau (Marseille)
ASAQ Winthrop® Risk Management Plan Summary
Completed trials: 8,058 patients treated with ASAQ Winthrop
EFFICACY : Day 28 efficacy rates consistently > 95%
SAFETY ▫ Similar to comparators
- No unexpected clinical adverse events - Asymptomatic, transient increases in liver transaminases and neutropenia
▫ No impact of repeated administrations on safety in children
▫ Extrapyramidal syndromes added to Summary of Product Characteristics Ongoing trials: > 17,000 patients treated with ASAQ Winthrop
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Internal source: Commercial Operations ATM
Registered in 32 countries (30 in Africa, Colombia, India) > 200 million treatments distributed
ASAQ Winthrop® availability 2013