M Boelaert
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Transcript of M Boelaert
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Breaking the disease-poverty cycle, dopharmaceutical companies deliver on
R&D for neglected diseases in developingcountries:A perspective from academia
Marleen Boelaert
Institute Tropical Medicine, Antwerp
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1. Kala-azar affects the poorest of the poor
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2. Recent breakthroughs after 70 years ofpentavalent antimonials
miltefosine, the first oral drug, registered in Indiain 2002 (Zentaris/TDR/BHU) . (Sundar et alNEJM 2002)
paromomycin registered in Indian in 2006(IOWH/BHU) (Sundar et al NEJM 2007)
liposomal amphotericin B, single dose 10 mg/kg(BHU) (Sundar et al, NEJM 2010)
several short course combination regimens(DNDI/BHU) (Sundar et al, Lancet 2011)
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Illustration: history of miltefosinedevelopment
1997 Phase I/II (dose escalation) - 50 mg Alternate days to 250 mg
daily
1998-99 Three Phase II trials
I. 4 week study Three groups 100, 150, 200 mg daily X 28 days (
II. WHO Multicenter Study 50 mg daily x 6 weeks to ~ 150 mg x4weeks
III. Short course trial 100 mg/daily for 2, 3 & 4 weeks
2000 - Multicenter Phase III
100 mg (> 25 kg) or 50 mg (< 25 kg) daily x 4 weeks
Paediatric Studies -
1999 - Pilot trial - 1.5 and 2.5 mg/kg x 4 weeks
2001- Phase II 2.5 mg/kg x 4 weeks
2001-2 Phase IV
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Adverse Events - Miltefosine
Vomiting was the chief side-effects in 38% patients(Ampho B 20%).
Duration 1- 2 Days 27%
3- 4 Days
8%> 4 Days 3%
Diarrhea occurred in 20% patients (Ampho B 6%)
Duration 1- 2 Days 15%
3- 4 Days 5%
> 4 Days
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MiltefosineDaily Dose: 100 mg (>25 kg); 50 mg (
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Post-registration challenges?
Phase-4 studies
Access issues
Affordability
Monitoring clinical outcomes, surveillance ofresistance, pharmacovigilance
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Access. Delay from onset of symptoms
till treatment (in random sample n=137)
First symptoms till presenting at Primary HealthCentre (PHC) =>Median 40 days (IQR 31- 59 days)
Delay between consulting community volunteer tillpresenting at PHC =>Median 36 days (IQR 28-56 days)
Presenting at PHC till start of treatment =>Median 2 days (IQR 1 - 4 days)
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Access. In 2008, still 48% of all kala-azarpatients started on antimonials (SAG) !
Treatment regimens by month,
Muzaffarpur district, 2008
0%
20%
40%
60%
80%
100%
jan
feb
mar ap
rmay ju
n jul
aug
sep
oct
nov
dec
SAG
Miltefosine
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Affordability in the miltefosine era
1 episode of kala-azar required 11% ofhousehold annual income in a recent householdsurvey in Nepal (Meheus et al forthcoming)
51% of HH crossed the catastrophic threshold MOSTLY INDIRECT COSTS, as miltefosine
and diagnostics was provided for free bygovernment
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Monitoring clinical outcomes
Facing a fragile health system
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Treatment outcomes by regimen(random sample, n=142)
Outcome
SAG Miltefosine
Ampho B Total
Cured 51 (75%) 37 (86%) 29 (94%) 117 (82%)
Failure 2 (3%) 0 0 2 (1%)
Defaulted 4 (6%) 3 (7%) 1 (3%) 8 (6%)
Died 1 (1%) 1 (2%) 0 2 (1%)
Referred 8 (12%) 2 (5%) 1 (3%) 11 (8%)
Transf. out 2 (3%) 0 0 2 (1%)
Total 68 43 31 142
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Conclusions
NTDs strike the poorest, usually in very fragilehealth system context
Innovation cannot stop now, better products
needed PDP model delivers, opportunities in endemic
countries
Many challenges post-registration, need to take
health system into account, implementationresearch required
Recent data from Nepal and India indicate
increasing failure rates on miltefosine.. (Sundaret al CID 2012 Ri al et al forthcomin
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