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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