GARDP and Neonatal Sepsis Programme

Sally Ellis, Neonatal Sepsis Project Leader

July 2018

Focus: • Drug-resistant bacterial infections for which

adequate treatment is not available. • Address global health priorities that reflect

the realities of clinical practice.

Global scope: Low-, middle- and high-income countries

Joint initiative:• World Health Organization• Drugs for Neglected Diseases initiative

Priorities:• Neonatal sepsis• Sexually transmitted infections• Memory recovery and exploratory• Paediatric antibiotics

GARDP – a not-for-profit R&D organization

2023 objectives

Develop 4 new treatments through:

• Improving existing antibiotics

• Developing new chemical entities

Build a robust pipeline of pre-clinical and clinical candidates end to end

Actively support appropriate use of and access to new antibiotic treatments

Business model and operating principles

GARDP Programmes to date

Diseases & Syndromes

Neonatal Sepsis: develop treatments for highly drug-resistant infections

Sexually-Transmitted Infections: develop a new treatment for drug-resistant gonorrhea and other STIs

Paediatric Antibiotics: optimize current and develop new antibiotics for children

Memory Recovery & Exploratory: revive old knowledge and abandoned projects; support early research

Treatment of neonatal sepsis – 2017 WHO guidelines

New Antibiotics • Among paediatric-specific studies,

• 18 evaluate safety and efficacy of new compounds,

• 4 are pharmacokinetic studies, but only 2 focus on neonates.

• For most antibiotics, despite adult phase 3 studies being completed, it will take

another 5-10 years before adequate prescribing information becomes available for

children.

• New antibiotics will cost around $100/day

• No new antibiotic neonatal program currently being conducted or actively planned.

Old antibiotics – Extremely limited data• Only 6 of the antibiotics identified in a recent ECCMID review of 33 antibiotics

have a licensed neonatal indication and of these only tobramycin and fosfomycin

have significant MDRGN activity.

• Colistin – 2 pharmacokinetic studies in neonates 1 in 1967 and second in 2016

each with less than 10 patients – 90% had sub-therapeutic levels

• Polymyxin B – has paediatric label in the USA but very little if any published

Pharmacokinetic data in children

New/old antibiotics for use in neonates

Primary objectives: Develop 1-2 new treatments within

the 6 years.

1.An empirical treatment for babies with possible serious

bacterial infection in areas where drug-resistant Gram-

negative (ESBL) pathogens are suspected (TPP1)

2.A treatment for babies where MDR Gram-negative

pathogens is confirmed (e.g. carbapenem-resistant K.

pneumoniae, or Acinetobacter spp), TPP2.

Neonatal Sepsis Program

NeoAMR - A global consortium to develop two new treatments for neonatal sepsis

Program

WP1: Pre-selection of potential agents Advisory Role for study conduct

WP6: Project Management

Target PopulationWP 2: Clinical Observational study of

neonatal sepsis in target settings

Bacterial EpidemiologyWP3: Microbiological study of neonatal

sepsis in target settings

Therapeutic Options

WP4: Pharmacokinetic study(ies)

WP4: PK /PD modelling

WP4: Formulation

WP5: Clinical

Trial(s)

Empiric

treatment

Confirmed

MDR

resistant

treatment

Aim: By 2023,

deliver one

combination

treatment for the

empiric

management and

one combination

treatment targeted

for MDR cases

NeoFosfoObjectives

• estimate the PK of IV fosfomycin in

neonates

• estimate the oral bioavailability of

fosfomycin in neonates

• assess the safety of IV fosfomycin with

regard to possible elevation of sodium

at 48 hours in neonates

Treatment

• Randomised to Amp/Gent (SoC) vs

Amp/Gent plus a 7-day course of

fosfomycin

• 48 hours (or more) IV fosfomycin,

followed by up to 5 days of oral

fosfomycin.

• Neonates will move to oral fosfomycin

once they are tolerating oral feeds.

Baseline Assessments including:Electrolytes, blood culture, Lumbar Puncture (if

indicated)

Randomisation

Standard of care aloneStandard of care + Fosfomycin

Early & Late PK sample after IV dose

Day 2: Electrolytes and CMP (48h) Electrolytes and CMP (48h)

Early and Late PK sample after IV dose

Day 7: Electrolytes

Start Ampicillin and GentamicinDay 1: Start Ampicillin and Gentamicin

Day 1 & 2: Start intravenous Fosfomycin

If tolerating oral meds / clinical improved:stop IV fosfomycin start Oral Fosfomycin Day 3-7

Day 7: Trough PK sample

Day 28: Follow-up

Day 7: Electrolytes

Day 28: Follow-up

• Expedite development of new & late stage pipeline drugs by collaborating with companies

• Extending use / Improve or optimize formulations of existing antibiotics for use in childhood infections

Accelerate the development of

paediatricantibiotics

• Support the update of guidelines with evidence, taking into account an evolving epidemiology globally

Evidence-based treatment guidelines

• Build on existing clinical trial networks to develop an international neonatal and paediatric network, including regulatory

Paediatric CT Network

6

Strategy for paediatric/ neonatal

programme

0.

1.3

2.5

3.8

5.

6.3

Category 1 Category 2 Category 3 Category 4

Chart Title

Series 1 Series 2 Series 3

www.gardp.org

Thank youGlobal Antibiotic R&D Partnership (GARDP)

Drugs for Neglected Diseases initiative15 Chemin Louis-Dunant | 1202 Geneva | Switzerland