iOWH and VL control in Bihar State, India

Antwerp, 13th November 2007

Dr. Philippe Desjeux

The Status Quo

The illnesses ofinvisiblepeople

usually stayinvisible

Our Target Population !

70% of VL patients in Bihar State of India live on less than

$1 a day

In the News

What is needed for new products ?

• There is a crucial need to:

• Improve R & D (drugs, diagnostic tests and vaccines)

• Improve access through a global strengthening of Health System

What is needed to strengthen drug R&D ?

• To strengthen R&D in emerging countries, it is urgent to:

• facilitate a massive technology transfer• make a strong local capacity building effort

• One of the options is the establishment of PD PPPs:

• to combine capacities & resources• to address field needs-driven R&D (instead of profit-

driven R&D)• to speed drug development

Why iOWH? Why a New Player?

• It provides a new creative solution by:

• Building a pharmaceutical company that has removedprofit element from its business plan

• Providing industry with a flexible and innovative partnership

• Creating a vehicle solely dedicated to drug developmentand drug access to neglected diseases!

The Institute for OneWorld Health develops safe, effective and affordable

new medicines for people with infectious diseases

in the developing world.

iOWH Mission

FundingBill & Melinda Gates Foundation

CommittedScientistsExperienced teams in Product Development

The Model

PartnersR&D, Manufacturing & Distribution

New Drug LeadsIntellectual PropertyDonated from Academia & Industry

VL: Partnership to Drive Global Health Solutions

Paromomycin for VL

BMGF iOWH

Phase III: Bihar (WHO/TDR)

Reg Approvals

IDA

Gland Gland

Indian Govt

Public and Private Health

Systems

Indian Govt South

Asia +

iOWH : Phase 4 Study - Access ModelExploring other distribution options

Visceral Leishmaniasis (VL) Project

• 62 countries• 500,000 new cases

per year:

• 62% in India• 90% of Indian cases in

Bihar State

• 1.580.000 DALYs

Facts

PAROMOMYCIN DEVELOPMENT

Paromomycin: a long story!

• Aminoglycoside antibiotic active against L. donovani, the aetiological agent for visceral leishmaniasis (VL)

• Marketed globally >40 years as parenteral for bacterial infections with extensive safety profile

• Marketed globally as an oral formulation to treat intestinal protozoal infections

• Used for 15 years in combination with Antimony in Africa by MSF

Time-line of Paromomycin in VL

1990: First report of Paromomycin activity in VL patients

1990-2000: Multiple studies in Bihar, India and East Africa demonstrating the activity of paromomycin for VL (alone & in combination)

2003: Phase 3 multi-center, randomized trial of Paromomycin IM Injection (PMI)

2006: Approval of PMI by the Government of India (GoI)

2007: Start of Phase 4 study (n= 2000 outpatients)

Phase 3 study

• Design– Multi-center, randomized trial in 667 patients with VL at

4 sites in Bihar, India

• Primary objective– Safety of paromomycin (15 mg/kg sulfate – 11 mg/kg

base) x 21 days vs. 1 mg/kg Amphotericin B x 15 doses in 30 days

• Other objectives – Initial cure rate – Efficacy at 6 months after end of treatment– Pharmacokinetics

PMI: Phase 3 – Safety data

• Ototoxicity occurred in 7/442 (1.6%), 1/7 cases within the speech range. All were transient and reversible.

• No nephrotoxicity in the paromomycin group (vs 4.2% in the amphotericin B group)

• Injection site pain - generally mild - was reported in 55% of the paromomycin treatment group

Paromomycin 11 mg/kg/day x 21 days was safe and well tolerated in the treatment of VL

Summary of Phase 3 – Safety data (2)

Serious Adverse Events– Paromomycin arm:

• 1 patient with hyperpyrexia died prior to treatment

• 3 hepatitis (1 died): possibly related• 1 deep abscess (died): not related

– Amphotericin B arm: • 1 diarrhea and gastroenteritis (died):

most probably related • 1 bacterial pneumonia, toxic hepatitis:

not related

Phase 3 – Efficacy data

Non-inferiorityParomomycinN=501

Amphotericin B

N=165upperbound

p-value1

Initial cure 98.4% 99.4% 2.8% <0.0001

Final cure 94.6%2 98.8%3 6.9% 0.00007

1One-sided 97.5% upper bound using a 10% non-inferiority margin. The analysis and margin of non-inferiority were not prospectively defined; 2: 27 failures [22 relapses, 2 SAE (deaths), 3 withdrawals with rescue] 3: 2 failures [1 lost to follow-up, 1 SAE (death)]

PMI: Manufacturing Details

• Paromomycin is manufactured by Gland Pharma Limited, Hyderabad, India

• Stable at tropical temperatures:

• 2-year shelf life when stored below 30ºC and protected from light;

• Stable to at least 6 months at 40ºC

• Affordable ($10-15 per patient)

Outcomes of PMI phase 3

• Good safety profile

• 94,6% efficacy (6 month follow up)

• 2006: Approval by GOI as new antileishmanial drug

• 2007: Inclusion into WHO Essential Medicines List

PMI R & D: What is still needed for GoI policy?

• Phase 4 clinical trial data in outpatient setting (ongoing)

• Submission of data to GoI

• Review by National Expert Committee

• Recommendation by WHO/SEARO RTAG

Official inclusion of PMI into VL treatment National Policy

What is Still Needed? IMPROVED ACCESS! • Sustainable, scalable & transferable access model

– Reinforcement of human resources– Institutional strengthening– Decentralization of treatment from clinic to village– Validation of an innovative supply management & delivery system– Implementation of a strict monitoring & evaluation

• Global strengthening of Health System!

What is Needed? (cont.)

PMI SHOULD BE:

• Affordable (local production, low price)• Acceptable (quality control)

• Available ( supply, proc. chain, delivery,….) • Accessible (limited distance, good coverage)

iOWH Confidential 25

Phase 4 Program Overview

1. Collect additional safety data for PMI when given in the outpatient setting in an expanded patient population

2. Develop and test a sustainable, scalable & transferable social delivery access model in increasingly rural settings

The ongoing Phase 4 Program is an innovative protocol with 2 main goals:

Phase 4: Study Design and Plan• Open-label, multi-center, single-arm study enrolling

up to 2000 VL patients. Objectives are to:

– Fulfill pharmacovigilance requirements for the GoI– Provide confirmatory safety data in an expanded population– Progressively extend network of treatment centers– Progressively extend the number of well trained staff

– Strengthen VL treatment capacity in rural Bihar (+++)

Field Research Studiesconducted by:

The Patna Rajendra Memorial Research InstituteIndian Council of Medical Research

(RMRI/ICMR) and

the Institute for One world Health (iOWH)

Principal Investigator: Dr. P. Das, Director of RMRI/ICMR

(September 2006 to May 2007)with assistance of SRI/IMRB-Delhi)

Four Field StudiesFour epidemiological and economic field studiesconducted in one kala-azar endemic districtof Bihar:

• 12 month prevalence of kala azar (disease burden)

• Household KAP survey• Healthcare provider KAP survey• Economic impact assessment of kala-azar on

household (no results yet)

Criteria for district selection*

• Kala-azar endemic district • Increasing number of reported kala-azar cases • No other major concurrent kala-azar studies• Adequate road connections to Patna and

Muzaffarpur urban centers• Presence of Janani clinics (our key NGO

partner)

*At the time of selection

Field Research District

Preparatory district assessmentVisit of 20 Block PHCs

- To review:

• Number of kala-azar cases listed in clinic registers

• Villages location of kala-azar cases• Clinic catchment areas• Recorded vs. reported case numbers

- To field test Provider and Household KAP survey instruments

Selection of 7 administrative blocks• 27 district blocks were stratified into high,

medium, and low incidence areas

• Seven blocks were randomly selected from the 3 strata to include:

– All 3 high incidence blocks

– 2 (of the 13) medium incidence blocks

– 2 (of the 11) low incidence blocks

iOWH Confidential

Sampled blocks in study district

Sampling Methodology

7Administrative

Blocks 80 Villages 14, 223

Households 91,009Individuals

Seven administrative blocks were randomly selected to represent low, medium and high incidence areas to allow for generalization to the district level.

“The enormity of the challenge

has also the enormity of the opportunity”

Aziz Premji(CEO of WIPRO)

To secure all together long-term access to life-saving medicines