A New Once-a-dayA New Once a day Treatment for UncomplicatedUncomplicated Malaria: DHA/PQP

Science DayMMV Stakeholders’ Meeting

Dr. Ambrose Talisuna Former Director Global Access, MMV &Field Coordinator, African Eurartesim Registration Trial

1Defeating Malaria Together

WhereWhere are are wewe withwith DHADHA--PQP PQP todaytoday??

• In 2004, MMV and sigma-tau Pharmaceutiche , gjoined hands to develop DHA/PQP to international standards

• Today DHA/PQP is being reviewed by the• Today, DHA/PQP is being reviewed by the European Medicines Agency (EMA)

2

CurrentCurrent difficultiesdifficulties regardingregarding treatmenttreatment of of malariamalaria•Problems related to antimalarial drugs

• Widespread resistance to most available antimalarial drugs• Limited availability of new drugs (specially GMP-produced)

• Limited availability of pediatric-friendly formulations• Limited shelf-life of the artemisinin derivativesed s e e o e a e s de a es

•Access issues• Price• Price • Distribution challenges• “Counterfeit” drugs• Fragile health systems• Cultural issues

What does WHO recommend for the treatment of What does WHO recommend for the treatment of uncomplicated uncomplicated P.falciparumP.falciparum malaria?malaria?

• Use of combination therapy, preferably using artemisinin derivatives as one of the partner drugsone of the partner drugs

• Artemisinin derivatives (oral formulations) and partner medicines of ACTs should not be used as monotherapyof ACTs should not be used as monotherapy

• The following ACTs are recommended by WHO:• artemether / lumefantrine• artesunate / amodiaquine• artesunate + mefloquine• artesunate + sulfadoxine-pyrimethamine• dihydroartemisinin / piperaquine*

*Update in 2010 Guidelines

WhatWhat isis DHA/PQP?DHA/PQP?

DHA (Dihydroartemisinin): • The active metabolite of the

artemisinin compounds artesunate and artemether

PQP (Piperaquine) phosphate:

• A bisquinoline drug with PK properties i il t Chl isimilar to Chloroquine

WhatWhat waswas knownknown aboutabout DHA/PQP?DHA/PQP?

• Review of 14 studies, with up to 22 study arms• 2,636 patients treated with DHA-PQP2,636 patients treated with DHA PQP• Most studies in Southeast Asia, very few in Africa• All age groups, although mostly adult data• Efficacy assessed over 28-63 days consistently exceedingEfficacy assessed over 28 63 days consistently exceeding

95% in the treatment of multidrug resistant falciparum malaria.

• Tolerability uniformly good and no serious adverse effects• Tolerability uniformly good, and no serious adverse effects identified.

WhatWhat waswas neededneeded??

•A GMP GMP productproduct to be studiedunder GCP in the followingpopulations:populations:

• African children, theprimary target population

Ad lt (SE A i h )

278 patients

• Adults (SE Asia chosen)

301 patients223 patients

• MMV and sigma-tau designed two large multicentre RCT

447 patients304 patients

two large multicentre RCT trials (Africa and SE Asia) as part of the clinical development plan fordevelopment plan for DHA/PQP

AfricanAfrican StudyStudy outlineoutline

A large open label, randomised clinical trial (~1500 children, < 5 years),performed in 5 different African countries to assess the non-inferiority ofDHA/PQP when compared to the standard combination therapyyartemether/lumefantrine (AL), for the treatment of uncomplicated

AL (6-dose regimen):

0 8 Morning Afternoon Morning Afternoon

Day 1 Day 2 Day 3

DHA/PQP (3-dose regimen)

Day 1 Day 224h 48h

0

Day 1 Day 224h 48h

ResultsResults: D28 PCR : D28 PCR correctedcorrected ((primaryprimary endpointendpoint) ) and and uncorrecteduncorrected ACPRACPR

100 94 7 95 3100

ITTITT PPPP

87.7

76.7

90.4 90

80

90

10092

81.03

94.7 95.3

80

90

100

50

60

70

50

60

70

p<0.001p<0.001

97.5%CI>6.97.5%CI>6.8282

p<0.001p<0.001

97.5%CI>7.97.5%CI>7.66

50uncorrected PCR-corrected

50uncorrected PCR-corrected

DHA/PQPDHA/PQPALAL

In infants, PCRIn infants, PCR--corrected cure corrected cure rates > 90% and similar rates > 90% and similar between groupsbetween groupsbetween groupsbetween groups

• DHA/PQP highly efficacious at D28 (also D42) and non-inferior to ALUncorrected: DHA/PQP better than AL

ResultsResults: New : New infectionsinfections

• More new infections in the AL group• Better post treatment prophylactic effect for DHA/PQP (longer half life of p p p y ( g

partner drug?)

ConclusionsConclusions: : AfricanAfrican studystudy

• The study demonstrated that DHA/PQP is non-inferior to AL on the PCR-corrected cure rate at Day 28 (primary end-point).

• Since performance of AL is consistent with expectations, this also demonstrates that DHA/PQP is efficacious.

• Efficacy among the youngest children (<1year of age) is maintained

• The study showed superiority of DHA/PQP vs AL on the uncorrected cure rate at Day 28. DHA/PQP reduced the rate of y Qnew infections in a statistically and clinically significant way as compared to AL.

• The two treatment groups showed a very similar efficacy andThe two treatment groups showed a very similar efficacy and safety profile as for the other considered end-points.

SE Asian SE Asian StudyStudy outlineoutline

A large open label, randomised clinical trial (~1,150 patients, includingchildren), conducted in Laos, Thailand and India to assess the non-inferiority of DHA/PQP when compared to artesunate + mefloquine (AS +inferiority of DHA/PQP when compared to artesunate + mefloquine (AS +MQ), for the treatment of uncomplicated malaria

AS + MQ (3-dose regimen)

24 480

Day 1 Day 2

DHA/PQP (3 dose regimen)DHA/PQP (3-dose regimen)

Day 1 Day 2

24 480

Day 1 Day 2

ResultsResults: D63 PCR : D63 PCR correctedcorrected ((primaryprimary endpointendpoint) ) and and uncorrecteduncorrected ACPRACPR

ITTITT Per ProtocolPer Protocol

AS + MQDHA/PQP

87.9 86.6

80

90

100ITTITT

75.5

98.7 97.0

80

90

100

67.3

59.660

70

CI > 1.8%0 010

%66.4

60

70%

CI > 3.1%p=0 002

50uncorrected cure rate PCR-corrected cure rate

p=0.01050

uncorrected cure rate PCR-corrected cure rate

p=0.002

• No difference in PCR corrected cure rates between treatmentsNo difference in PCR corrected cure rates between treatments

• In all the populations, the difference between the two treatment uncorrected cure rates was statistically significant

D63 lt (PP PCR t d) t th WHO it i ( 95%)• D63 results (PP, PCR corrected) met the WHO criteria (>95%)

ResultsResults: New : New infectionsinfections up up toto D63, PP D63, PP populationpopulationp pp p

• More new infections in the AS + MQ group• More new infections in the AS + MQ group• Better post treatment prophylactic effect for DHA/PQP

ConclusionsConclusions: Asian : Asian studystudy

• The study demonstrated that DHA/PQP was non-inferior to AS + MQ on the PCR-corrected cure rate at Day 63 (primary end-point).on the PCR corrected cure rate at Day 63 (primary end point).

• Since performance of AS + MQ is consistent with expectations, this also demonstrates that DHA/PQP is efficacious.The st d sho ed s periorit of DHA/PQP s AS + MQ on the• The study showed superiority of DHA/PQP vs AS + MQ on the uncorrected cure rate at Day 63. DHA/PQP reduced the rate of new infections in a statistically and clinically significant way as

d t AS MQcompared to AS + MQ. • The two treatment groups showed a very similar efficacy and safety

profile as for the other considered end-points.

Three additional trials requested by EMAThree additional trials requested by EMA

1 Thorough QTc trial1. Thorough QTc trial

2. PK in Caucasian and Asian healthy bj tsubjects

3. Food Interaction

1. 1. Thorough Thorough QTcQTc trial in 268 healthy subjectstrial in 268 healthy subjects

[Full dose (three days) of AL or DHA/PQP according to body weight]

Maximum timeMaximum time--matched changes matched changes in in QTcFQTcF ((msms))

1600

1800

DHA/PQP high5 groups QTcF

1000

1200

1400

ion

(ng/

mL)

Group 1- Day 3

Group 4 - Day 3

Group 5 - Day 3

DHA/PQP high fat

DHA/PQP low fat

5 groups prolongation

Placebo (no food) + 10 ms

Riamet/ (400 Kcal

200

400

600

800

Con

cent

rat

DHA/PQP no food

Riamet/ (400 Kcal with 20g fat)

+ 20 ms

Eurartesim (no food) + 33 ms

0

200

0 4 8 12 16 20 24

Time (h)

PQP levels 24h after last (third)PQP levels 24h after last (third)

Eurartesim (400 Kcal with 20g fat)

+ 46 ms

Eurartesim (1,000 + 56 ms PQP levels, 24h after last (third) PQP levels, 24h after last (third)

administrationadministrationKcal with 75g fat)+ 56 ms

Analysis of maximum timeAnalysis of maximum time--matched actual values matched actual values and changes from baselineand changes from baseline forfor QTcFQTcF

Placebo AL DHA/PQP

gg

QTcF (ms) Placebo (N=60)

AL (N=64)

DHA/PQP (N=40)

n (%) n (%) n (%)

>450 ms 0 (0.0) 2 (3.1) 4 (10.0)

>480 ms 0 (0.0) 0 (0.0) 0 (0.0)

>500 ms 0 (0.0) 0 (0.0) 0 (0.0)

>60 ms(post vs pre) 0 (0.0) 0 (0.0) 0 (0.0)

QTcQTc study conclusionsstudy conclusions

• The effect of DHA/PQP on QTc interval is directly related to the levels of PQP in blood, which positively correlates with fat co-administration. This further supports the standard recommendation of giving DHA/PQP apartfurther supports the standard recommendation of giving DHA/PQP apart from food.

• It is equivalent to that produced by choroquine, as reported in literature.

• As for AL no subjects showed QTc >500 ms or prolongations (after- vs pre-dose) > 60 ms.

• The QTc prolongation is a “risk factor”, not an “event” and is common tomost highly effective antimalarials.

No No cardiaccardiac eventsevents werewere observedobserved duringduring thisthis trial, trial, nornorhavehave theythey everever beenbeen reportedreported at at thethe currentcurrent dosagedosage in in thethe

treatmenttreatment ofof uncomplicateduncomplicated malariamalariatreatmenttreatment of of uncomplicateduncomplicated malaria.malaria.

2. Phase I, PK trial in healthy Asian and 2. Phase I, PK trial in healthy Asian and Caucausian volunteersCaucausian volunteers

• 72 healthy subjects stratified by ethnicity, gender and body weight• Eurartesim given p.o after a light breakfast. Full dose (three days) according

t b d i htto body weight

PQPDHA

PK PK profilesprofiles similar similar betweenbetween AsiansAsians and and CaucasiansCaucasiansand and betweenbetween males and males and femalesfemales

3. Study of the effect of food on the PK of 3. Study of the effect of food on the PK of DHA/PQP after single oral administrationDHA/PQP after single oral administration

• 36 healthy Caucasian males with body weight ≥ 75 kg stratified in two groups (18+18). Standard PK procedures performed

• Two groups: 1)Fasting and 2)Fed (high fat, high calorie meal). Only one dose given.

gg

DHA PQP

TheThe observedobserved foodfood effecteffect in in thethe PK PK parametresparametres of of bothboth DHA and PQP DHA and PQP ppsupportssupports thethe recommendationrecommendation thatthat DHA/PQP DHA/PQP shouldshould be be givengiven underunder

fastingfasting conditionsconditions

ConclusionsConclusions

• A large pool of evidence supports the non-inferiority of DHA/PQP vs. g p pp yother ACTs for the treatment of acute uncomplicated P. falciparummalaria

• DHA/PQP has repeatedly shown good tolerability and safety

• Its dosing (three doses instead of six for artemether/lumefantrine) t ib t t b tt licontributes to a better compliance

• The centralized registration of DHA/PQP with EMA will bring alternatives to developing countries and also allow the availability of analternatives to developing countries and also allow the availability of an ACT (for the first time) in all the 27 EU Countries.

““You call us the future, but we are also thepresent”p

Picture of children…

Thank you!