Addressing Pediatric Needs of the Most Neglected: next steps

An updated overview of DNDi Pediatric Focus

Nathalie Strub Wourgaft (Medical Director) Janice Lee (HIV Pediatric Clinical Manager) Best science for the most neglected (1975-2004) • tuberculosis account for: Tropical diseases(including malaria)and • 12% oftheglobaldisease burden But only1.3%ofnew drugsdeveloped for other diseases 1,535 new drugs 98.7% A FatalImbalance 3 new drugs 3 new Tuberculosis: malaria) (incl. 8for drugs 18 new diseases: Tropical Source: Chirac P,Torreele E. for neglected diseases for neglected drugs 21 new 1.3% Lancet . 2006 May12; 1560-1561. Best science for the most neglected • • • observer) (permanentWHO/TDR Institut Pasteur France (MSF) Medecins SansFrontieres Brazil Foundation Cruz Oswaldo Malaysian MOH Institute (KEMRI) Kenya MedicalResearch Research (ICMR) Indian Council forMedical 7 FoundingPartners and philanthropicentities Harnessing resourcesfrompublic Addressing theneedsofmostneglectedpatients founded in2003 &developmentNon-profit drugresearch (R&D)organization A Needs-DrivenModelfor Drug Development: DNDi USA Brazil Geneva +consultants Coordination team DRC institutions, private industry Kenya 7 support offices 7 support India Malaysia Japan Best science for the most neglected portfolios” “Mini Discovery Discovery Completed; phasing outby 2014 phasing Completed; 2011 New in 2011 DND L.O. Pre-clinical i Disease Portfolio Clinical Leishmaniases Chagas HAT Helminths Paediatric HIV Reg. Malaria Access 4 Best science for the most neglected 4 3 2 1 estimation of Chagas disease in the Americas]. OPS/HDM/CD/425-06. the Americas]. in disease Chagas of estimation Pan American Health Organization (2006) Estimacio ´ncuantitat Estimacio (2006) Organization Health Pan American 31817 MSF,total: cases Source Trop.Am. J. Med. Hyg., http://www.who.int/malaria/high_r Pediatric needs forspecificdiseases • Human African Trypanosomiasis AfricanTrypanosomiasis Human • fatalifuntreated Leishmaniasis: Visceral • •Malaria: Pediatric HIV: will befully developed • Disease: Chagas • fatal if untreated 10to47%<5 years and48%to69%<15 years (dependingon – 200000deaths/ year innewborns – Accounts for20%ofpediatricmortality inAfrica – > 15000annualincidence ofcongenital – 25%arechildren <15and4%4 years old – geographical region) 84(4), 2011, pp. 543–550 2011, doi:10.4269/ajtmh.2011.10-0321 pp. 84(4), isk_groups/pregnancy/fr/index.html 2 iva de la enfermedad de Chagas en las Americas Quantitative Quantitative Americas las Chagas en de enfermedad la de iva (sleeping sickness):stage 2: 1 transmission 3 4 Best science for the most neglected Neglected Diseases &needs(for Chagas Disease (HAT) Sleeping Sickness Visceral Leishmaniasis (VL) Malaria Diseases children) No adaptedformulation( formulation basedonagebands ASAQ andASMQincludepaediatric miltefosine tablet for newborns Developed a12.5mgdispersable oral treatment are essentially basedon weight,no No ageadapted formulation,doses weight ), dosesaremostly based on Treatment except Best science for the most neglected •VL: •HAT: Chagas: • An NCEshould enterphaseIin2012 – adultco-administrationonEML - NECT: – newtreatmentforHATshould enter 1 – eziaoe10gtbe nEL–development of dispersable Benznidazole 100mg tableton EML – – PKdataonmiltefosine(on EML) inchildrenwillbecollected froman – An NCEshould enterphaseIin2012 – … 25gtbe poppk children(inclnewborns) ongoing 12.5mg tablet– ongoing study inAfrica weights/age …) weights/age …) bas children asdatabecomeavailable …, agebandgroups required PKdataindifferent (type of possible data to collect todefine) (type possibledatatocollect of More concretely … is for dosecalculationwithvariable is for Phase2/3in2012,PIPtodevelop (questions aroundtimingandtype(questions of field study datawillbeavailable , adaptivedesignwith inclusionof … Best science for the most neglected DNDI’S PAEDIATRIC

ENTRY

INTO

HIV

HIV

=

FIELD

NEGLECTED 212.23.249.141

DISEASE? Best science for the most neglected . ilo hlrn(1 r)living withHIVin2009 living withHIVin2009 2.5 million children(<15yrs) 2.5 million children(<15yrs) Paediatric Newly infected AIDS deaths Treated 260,000 355,000 370,000

HIV Best science for the most neglected oeae2%2.%22% 21.5% 28% Coverage children onART Number of children inneed Number of WHO PAWG 2011:Shaffiq Essajee more childreninfected, bettersurvival, New estimates 2010: n 09End2009 End 2009 .7mlin16 ilo 2.01million 1.66million 1.27 million more and 5,0 450,000 356,000 less coverage estimates 2010

less

children

ART data,

resulted

coverage

infected method new

in

new estimate End 2010 Best science for the most neglected •HIV …but 370,000newinfantinfections • Virtualelimination ofpaediatricHIV • treatment more Africa) with HIV/AIDS(92%in sub-Saharan each yearand2.5million children in high-incomecountries… 80% of HIV+ children will die by 5 yrs old – 50%of HIV+ children will die by 2yrsold – 1/3 ofHIV+ infantswill dieby1 yrold – > 1,000new pediatric HIVinfections – > 700deathsinHIV+children daily – daily

disease

rapid

is

than

progression

given Paediatric

in

adults

in

if

children

no

HIV

Best science for the most neglected complications •Concerns children •Aging •Effective rare •New High

A

‐ perinatal resource

cohort

Tale

treatment long

of of

‐ infections term

treatment

infected countries

of

available 2.Small paediatric conduct 1.Lack

2

are

Paediatric

of

market

paediatric

incentive

formulations •Problems started •Treatment problematic •Diagnosis each •1,000 Low

studies for

‐ day

resource manufacturers Epidemics

infants

late

with of or

when

infection

are improve

drug

countries

newly available

access

in

infected

to infants

is

12

Best science for the most neglected Scientific/Clinical Challenges Tuberculosis, malnutrition, childhood • Pharmacokinetic parameters change • Many infectedbabies/infants areexposedto • HIV concentrationinbabies andinfants10- • morbidity is part of the picture combination band dosing forcertaindrugs forfixeddose weight complicates considerably withage– resistance viral treatment orprophylaxis – nevirapine through infantormaternal aggressive therapy needed more 100 timeshigherthan inadults– Best science for the most neglected • IMPAACT P1060trial:LPV/r-basedtherapy IMPAACT • Trial, Presentedat CROI 2011) PMTCT over NVP demonstrated superior virologicalefficacy PI vs.NNRTI-based ART (Palumbo regardless ofNVP exposure for et al. IMPAACT P1060 Best science for the most neglected P1060: Palumbo HAART

P Age >

et

LPV/r 12 months al.

in IAS,

LPV/r

NVP sdNVP Capetown,

superior

South

exposed

Africa,

to

July

NVP Age <12months

2009,

children

Abs. ‐ NVP LPV/r Based

LBPEB12

Best science for the most neglected P1060: (p of 21.3% 22.0% endpoint The 15% baseline Median recommended In

<0.001 LPV/r October

24

in ( (<12 ‐ ≥ week

age 12

and

HIV

).

LPV/r differences Children

months) 2010, months)

at

21.5%

RNA primary

enrollment unblinding

the

535,632 superior

overall

in and

Data were

favor

not

Safety was copies/mL the

exposed

study 1.7

to

Monitoring

years

NVP

results.

and

(73%

CD4

‐ to Based

Board ≥

percentage sdNVP 12

months),

HAART

Best science for the most neglected • WHO GuidelinerevisedApr WHO • CHERtrial: • Med 2008;359:2233-44) symptoms (Violari immunologic declineorclinical initiate ARTimmediatelyvs. after mortality when children< 2 years 2008 and2010: – – bdfitli inhibitor (lopinavir/ritonavir) treatment, useprotease either directly or via maternal exposed toNVPor NNRTIs Infants andchildren <2 yo WHO clinical stage irrespective ofCD4countor <2 forchildren years, ART Early andimmediate diagnosis Recommendations 76% reductionof et al. Treatment N EnglJ Best science for the most neglected (ZDV, AZT)/ Retrovir Zidovudine Fumarate (TDF)/Viread Disoproxil Tenofovir Zerit (d4T)/ Stavudine Epivir (3TC)/ Lamivudine (FTC)/ Emtriva Emtricitabine EC Videx (ddI)/ Didanosine Ziagen (ABC)/ Abacavir Nucleoside Reverse Nucleoside Transcriptase Inhibitors (NRTIs) 25

FDA Edurant Intelence Etravirine (ETR)/ Viramune (NVP)/ Nevirapine (ETR)/ Intelence Etravirine (EFV)/ Sustiva Efavirenz (DLV)/ Rescriptor Delavirdine Non-Nucleoside Non-Nucleoside Rilpivirine (RPV)/ Transcriptase ‐ Inhibitors (NNRTIs) Reverse Reverse Approved (ATV)/ Reyataz Atazanavir (TPV)/ Aptivus (TPV)/ Tipranavir (SQV)/ Invirase Saquinavir (RTV)/ Norvir Ritonavir (NFV)/ Viracept Nelfinavir (LPV/r)/ Kaletra Lopinavir+Ritonavir (IDV)/ Crixivan Indinavir Lexiva** (FPV)/ Fosamprenavir (DRV)/ Prezista Darunavir Inhibitors Protease (PIs)

ARVs (RAL)/ Isentress (RAL)/ Raltegravir Integrase Inhibitor

(as

of (T20)/ Fuzeon (T20)/ Enfuvirtide Inhibitor Fusion

Nov 2011) (MVC) Selzentry Maraviroc Antagonist CCR5 Best science for the most neglected Fumarate (TDF)/Viread Disoproxil Tenofovir Zerit (d4T)/ Stavudine Epivir (3TC)/ Lamivudine (FTC)/ Emtriva Emtricitabine EC Videx (ddI)/ Didanosine Ziagen (ABC)/ Abacavir (ZDV, AZT)/ Retrovir Zidovudine Nucleoside Reverse Nucleoside Inhibitors (NRTIs) Transcriptase 25 FDAApprovedARVs -9Approved -- Edurant Intelence Etravirine (ETR)/ Viramune (NVP)/ Nevirapine (ETR)/ Intelence Etravirine (EFV)/ Sustiva Efavirenz (DLV)/ Rescriptor Delavirdine Non-Nucleoside Non-Nucleoside Rilpivirine (RPV)/ Transcriptase Inhibitors (NNRTIs) Reverse Reverse for NeonatesandInfants (ATV)/ Reyataz Atazanavir (TPV)/ Aptivus (TPV)/ Tipranavir (SQV)/ Invirase Saquinavir (RTV)/ Norvir Ritonavir (NFV)/ Viracept Nelfinavir (LPV/r)/ Kaletra Ritonavir Lopinavir+ (IDV)/ Crixivan Indinavir Lexiva** (FPV)/ Fosamprenavir (DRV)/ Prezista Darunavir Inhibitors (PIs) Protease (RAL)/ Isentress (RAL)/ Raltegravir Integrase Inhibitor (as ofNov2011) (T20)/ Fuzeon (T20)/ Enfuvirtide Inhibitor Fusion -- (MVC) Selzentry Maraviroc infants and neonates in Not approved Antagonist CCR5 Best science for the most neglected Implementation Challenges lack ofco-formulations malaria requiringtreatment, Multiple co-infections eg.TB, 1 day stability at >25°C dispensing Require refrigerationuntil 40% alcohol Horrible tastingsolution 6 monthsshelflife Horrible tastingsolution Best science for the most neglected Scope •First •Short Guided • (<5 developed advisors

yr) ‐

of line ‐

term projects

by DNDi

ART

target in

(<3

consultation

for

Pediatric yr)

product under

and

medium

3 ‐

profile

year HIV with ‐

olds ‐ Projects expert term

(TPP)

Best science for the most neglected Drug Palatability Safety/tolerability Target Dosing Formulation ‐ Pill Durability drug Stability Efficacy Profile (TB

Cost population

burden frequency

interaction

Rx)

(taste) d Water < 50 medicines, 1 amount No No Well form

(scored)

Target USD/patient/year ‐

taste weight soluble, drug

tolerated that Both monitoring

of ‐

or drug

pill

particularly

can liquid months bands adult

Once nice NVP dispersible rifabutin ‐

interaction Ideal usable be

and High

‐

taste

(suitable minimum ART) exposed

daily (WHO used

needed Product old)

no (consistent

genetic

b across for rifampicin

laboratory

with tablet

table)

children

with and for

2 No

small

broad barrier years

2

dosage

non cold ‐ TB

36 with Same

or

‐

shelf

exposed

chain

(PI

as

‐ Profile like).

Crushable If

medicines, life for

requirement, 2

pills, at HIV+ adults

Some Long Sprinkles No

room

must laboratory children

plasma pill drug

but

temperature To

fraction)

that be

dosage can ‐

be be drug adjustments Acceptable Twice

same Palatable under half

acceptable can

investigated be

monitoring

interaction ‐

used life.

be form

for daily tablet

3

used

years both

with may

count

in

c

needed old

proper with work.

fo”may “food”

(or

TB a

same dose

Best science for the most neglected .Investigate “induction-maintenance” 4. Assess feasibilityof resolving 3. EvaluatedifferentNRTI backbone 2. Developanimproved PIformulation 1. concept (integrase inhibitors) and medicines incompatibility betweenPIs andTB TDF) options forusein firstline(ABC& (LPV/r) p Summary otential for s

of p ecial re

Actions g imen for infants

Planned Best science for the most neglected • Improved formsofLPV/r Improved • Projects –Consider Uncertainties: – –Improved Prodrugs: – •Nanoparticles •IP •Cost •Taste Nanodispersion • •Characterization Synthesis • atazanavir

formulation for

Under commissioned

ritonavir

at

formulation

WuXi planned

(ATV)

with (RTV) Consideration

(PK,

as

at existing

stability

&

IOTA alternative

lopinavir

formulation, LPV

(LPV) and

RTV

etc.)

(1)

API Best science for the most neglected •TB •ARV Incompatibility Projects ¾ ¾ ¾ ¾ ¾ • • • •

To To Rifabutin RTV Raltegravir (Merck (IMPAACT) medicine Extra RTV PIs Rifampicin

regimen

facilitate hold

and

inhibits

for RTV

expert

some

or ‐

Gilead/ANRS),

super (superboosting)

that

induced

rifapentine the that

CYP3A4, Under

NNRTIs between meeting

+ development

is

is TDF/3TC ‐

compatible CYP3A4

boosting compatible

thus are

as with

metabolized

alternative

ARV is enhances Consideration

expression

TB required

(long

adult

planned Alliance

& with

with ‐

term)

TB PI

when for

mainly

exposure trial ARVs

TB medicine rifampicin

rifampicin in

treatment

in by

children

CYP3A4 Brazil

is

given

(2)

25 Best science for the most neglected Field • •Improved l ti Alt Projects Nanoparticles – Nanodispersion – Prodrug – Technology • Potential • •Involves

soluble solid evaluation

blend

forms of

matrix

chemical bt

ritonavir for

of Under

is

dispersible

insoluble

based without

of of formulation

modification

super ritonavir

(RTV) on

(biitt)

chemical material

the tablet

Consideration ‐

formation boosting

of

for

within modification

RTV

super

of

a

a

dry, ‐ boosting

(3) Best science for the most neglected •“Induction Projects –Merck –Adding –Integrase Proof – –HIV+ yet below progression integrase reduction regimen

approved

children of

detection drug

an

concept during

‐ inhibitor) inhibitors in

extra aneac”scheme maintenance”

Under raltegravir

is viral

for

have more

idcin phase “induction”

ARV

at

infants study load,

a higher

are aggressive

more drug

which

(RAL) now? known

(also Consideration

viral (from rapid

is may

need

to load, the

rate new

achieve

result should

furthest to

and

class)

explore

in

disease

lead HIV

patient

to along,

RNA ViiV 1 to st

‐

rapid line

but benefit

levels

(4)

not

Best science for the most neglected Conclusions Policy pre-conditions: • collaborative, not-for-profit Innovative, • Appropriately adapted andaffordable • Children with HIV/AIDSdonotconstitute • infants But utopia will notarrivetomorrow – • effortmustbemadeto“eliminate” Every • can fillgap pediatric formulations models fordeveloping treatments are urgentlyneeded pharmaceutical R&Dagenda soare excluded from the lucrative “market” will continuetofallthroughcracks MTCT New incentives – regulatory Innovative pathways – openinnovation Access IPandfacilitation of to – utial financing Sustainable