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

2

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

3

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

4

ASAQ: CLINICAL STUDIES SITES

+ Brazil

Colombia India

Myanmar Vietnam

6

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%

8

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%)

9

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

10

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)

11

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)

12

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

13

14

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

15

| 16

Internal source: Commercial Operations ATM

Registered in 32 countries (30 in Africa, Colombia, India) > 200 million treatments distributed

ASAQ Winthrop® availability 2013

Partnerships ▪ DNDi

▪ National Malaria Control Programs

▪ Academic teams

▪ Medicines for Malaria Venture

▪ Morocco and Ghana WHO collaborative Centres for

Pharmacovigilance

▪ WWARN : efficacy data

▪ ACT Consortium :safety data

▪ Sanofi teams in Africa

17