Breaking the disease-poverty cycle, do pharmaceutical companies deliver on R&D for neglected diseases in developing countries: A perspective from

academia
Marleen Boelaert Institute Tropical Medicine, Antwerp

1. Kala-azar affects the poorest of the poor

Position of households at risk of kala-azar within the wealth distribution (quintiles) of all households in Bihar, India

Boelaert et al 2009

2. Recent breakthroughs after 70 years of pentavalent antimonials

miltefosine, the first oral drug, registered in India in 2002 (Zentaris/TDR/BHU) . (Sundar et al NEJM 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)

Illustration: history of miltefosine development

1997 Phase I/II (dose escalation) - 50 mg Alternate days to 250 mg
daily

1998-99 Three Phase II trials

I. II.

4 week study Three groups 100, 150, 200 mg daily X 28 days ( WHO Multicenter Study 50 mg daily x 6 weeks to ~ 150 mg x 4weeks Short course trial 100 mg/daily for 2, 3 & 4 weeks

III.

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

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 <1%

Miltefosine
Daily Dose: 100 mg (>25 kg); 50 mg (<25 kg); Children 2.5 mg/kg Duration: 4 weeks

Long term cure rates 94%

Studies in children (2-11 years) indicate that it is safe, results are similar to adults. Adverse events: Vomiting (mostly mild) occurs in ~40% diarrhea (mild) in ~20%. Asymptomatic transient elevation of hepatic enzymes Skin allergy, nephrotoxicity are occasionally seen Can not be used in pregnant females, and those refusing contraception (for the treatment period and another three months)

Post-registration challenges?
Phase-4 studies Access issues Affordability Monitoring clinical outcomes, surveillance of resistance, pharmacovigilance

Access. Delay from onset of symptoms till treatment (in random sample n=137)
First symptoms till presenting at Primary Health Centre (PHC) => Median 40 days (IQR 31- 59 days)
Delay between consulting community volunteer till presenting at PHC => Median 36 days (IQR 28-56 days) Presenting at PHC till start of treatment => Median 2 days (IQR 1 - 4 days)

Access. In 2008, still 48% of all kala-azar patients started on antimonials (SAG) !
Treatment regimens by month, Muzaffarpur district, 2008
100% 80% 60% 40% 20% 0% SAG Miltefosine

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Affordability in the miltefosine era

1 episode of kala-azar required 11% of household annual income in a recent household survey in Nepal (Meheus et al forthcoming) 51% of HH crossed the catastrophic threshold MOSTLY INDIRECT COSTS, as miltefosine and diagnostics was provided for free by government

Monitoring clinical outcomes

Facing a fragile health system

Treatment outcomes by regimen

(random sample, n=142)
SAG Miltefosi ne Ampho B Total

Outcome 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

Conclusions
NTDs strike the poorest, usually in very fragile health 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, implementation research required Recent data from Nepal and India indicate increasing failure rates on miltefosine.. (Sundar et al CID 2012, Rijal et al (forthcoming)