anewoncea new once-a-day treatment for …...anewoncea new once-a-day treatment for uncomplicated...
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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!