14 stakeholders’ meeting critical challenges to malaria ...>1. st. gen. serc / merc >triple...

Confidential – For Celgene Internal Use Only

David Reddy, CEO; George Jagoe, EVP APM; Tim Wells, CSO

Defeating Malaria Together

14th Stakeholders’ Meeting Critical challenges to malaria elimination in S.E. Asia Bali | 11 – 12 October 2017


Defeating Malaria Together

MMV Business Plan 2017-2021


Advances in prevention, diagnostics and treatment have contributed to reversing incidence of malaria since 2000

3

Prevention** Treatment** Diagnostics**

* WHO estimates taking into account population growth ** 2014 data - Sources: WHO Global Malaria Programme (2015) World Malaria Report 2015, WHO


Yet malaria remains a public health imperative globally and vulnerable populations are particularly at risk

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Source: WHO World Malaria Report 2015

Unacceptable rates of incidence and mortality

212 million cases in 2015

429,000 deaths

3.2 billion people, almost half of the world’s population, remain at risk

Heavy burden on vulnerable populations

70% of deaths are children under 5

More than 50% of pregnant women at risk did not receive a dose of IPTp

The WHO African Region accounted for 90% of global cases of malaria in 2015


In light of this, the global malaria community has defined ambitious elimination and eradication targets

5

Source: United Nations. Transforming our world: the 2030 Agenda for Sustainable Development (2015);World Health Organization. Global Technical Strategy for Malaria 2016–2030 (2015); The Roll Back Malaria Partnership. Action and Investment to defeat Malaria 2016–2030 (AIM) – for a malaria-free world (2015); From Aspiration to Action – What will it take to end malaria? UN Secretary-General’s Special Envoy for Health in Agenda 2030 and for Malaria, Bill & Melinda Gates Foundation (2015)

Eradication

Post-2030 2026-2030 2021-2025 2016-2020

Reduce mortality rates (vs. 2015)

Reduce case incidence (vs. 2015)

Eliminate malaria from 2015 countries of

transmission

Prevent malaria re-establishment

≥40%

Renewed commitment to

eradication

At least 10 countries

Scaling-up for elimination

Elimination in low-transmission

settings

Elimination in high- transmission

settings

Achieving global eradication

Control Elimination

Re-establishment prevented in all malaria-free countries

United Nations Sustainable

Development Goals

SDG target 3.3: “By 2030, end the epidemics of AIDS, tuberculosis, malaria (…)”

RBM Action and Investment to defeat

malaria Aligned with GTS targets above

≥75% ≥90%

≥40% ≥75% ≥90%



From Aspiration to Action objectives

WHO Global Technical Strategy for malaria

The agendas of global malaria stakeholders are converging around control, elimination and eradication objectives


WHO identifies five outstanding challenge areas sustaining the malaria burden

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Source: WHO World Malaria Report 2015

Malaria burden

Program coverage Insufficient

Health systems

weaknesses

P. vivax decreasing slower than

P.f.

Weakened control efforts

Disease outbreaks

Resistance Especially in

the GMS


Failure to address these challenges will result in high human and economic costs

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If malaria reverted to 2007 levels:

Source: From Aspiration to Action – What will it take to end malaria? UN Secretary-General’s Special Envoy for Health in Agenda 2030 and for Malaria, Bill & Melinda Gates Foundation (2015)

2 billion additional

malaria cases 18 million cases

requiring hospitalization 3.7 million additional deaths

1 billion lost Working days

annually

$5.2 billion direct costs to health systems and

households

$1.2 trillion foregone in

economic output

Human cost

Economic cost


Antimalarial medicines with different profiles are needed to address these challenges

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Malaria Burden

High to

Low

Low to

Zero

Maintaining Zero

Curative combinations to reduce mortality/ morbidity in malaria-endemic settings: - Effective against

resistant parasites - Appropriate for

vulnerable populations - Ideally preventing

transmission to further reduce incidence

Combinations to protect malaria-free populations: - Different mechanism of

action from medicines used for case mgmt.

- Vaccine-level safety for use in entire populations

Curative combinations to block transmission from symptomatic and asymptomatic individuals in malaria-endemic settings: - Improved convenience

(ideally single dose) - Safe and cost-effective

for population-wide use

Control Elimination Eradication

Global Malaria Agenda

Optimize current medicines

Single-Exposure Radical Cure (SERC)

Single-Exposure Chemoprotection (SEC)


MMV partnership is better equipped today to address these challenges

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1 More launched products saving more lives

2 First new P. vivax drug in 60 years approaching the market

3 NCEs and compounds with novel mechanisms of action in clinical development

4 Translational medicine platforms to de-risk & accelerate early development

5 Consolidated lessons learned and adapting structurally

6 Assumed convening role on regulatory reform


1 Intensified Discovery effort

2 Increased emphasis on medicines for chemo-prevention / protection

3 More deliberate approach to product launch, including post approval evidence generation and equitable access

4 Translational medicine applied to combination drug development (SCID mouse, CHMI, modelling & simulation, regulatory strategy)

5 Policy and advocacy - leveraging external partners to maintain a fertile and supportive external environment

Some realignment in focus is required

10


MMV’s 5-year strategy: 3 clear programmatic areas

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Case management of relapsing malaria

Case management of severe malaria

Case management of uncomplicated malaria

Clearance of the human reservoir

Chemoprevention for vulnerable populations

Chemoprotection of malaria-free populations

2nd generation SERC compounds with transmission blocking

>1st gen. SERC / MERC >Triple ACT >DHA-PQP pediatric

Pre-filled artesunate syringes

Tafenoquine (with G6PD PoC diagnostic)

>Injectable artesunate >Rectal artesunate

ACTs (adults and children)

SPAQ / SP

ACTs + low-dose primaquine

2 with chemoprotection

10-15 clearly differentiated NCE candidates, including:

1-2 with transmission blocking

1 with relapse prevention

2022 + 2017-2021 Deploy

APM Delivery of medicines that MMV helps bring to market facilitated to reach those in need

2027 +

Long acting chemoprotection

Timeline to registration

>Pediatric SPAQ (SMC) >Enhanced SPAQ (SMC) >DHA-PQP (IPTp)

1. Facilitate equitable access to quality antimalarial medicines

2. Develop better antimalarial medicines for clinical case mgmt. and vulnerable populations

3. Bring forward new tools for containing resistance and eliminating malaria Discovery

New classes of molecules supporting

the elimination agenda discovered

Development New antimalarial

medicines developed and registered

Translational Proof-of-concept and

safety of new molecules in human

subjects demonstrated

New injectable


Equitable access to quality medicines

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1 AREA

Ensure equitable access to existing products by vulnerable populations in malaria endemic countries

• Best deployment of all five ACTs slowing the spread of drug-resistant parasites

• New paediatric treatments for uncomplicated malaria

• Suppositories for pre-referral management of severe malaria in children

• Chemoprevention regimens for small children (SMC1) and pregnant women (IPTp2)

1 Seasonal Malaria Chemoprevention 2 Intermittent Preventive Treatment in pregnancy


MMV-supported projects July 31 2017

Translational Product development Access Preclinical Patient

confirmatory Post approval Human volunteers

Patient exploratory

Regulatory review

Research Candidate Profiling

Lead optimisation

Tafenoquine GlaxoSmithKline

Dihydroartemisinin piperaquine Paediatric Sigma-Tau/Pierre Fabre

Rectal artesunate Cipla/Strides/WHO-TDR

Dihydroartemisinin- piperaquine Sigma-Tau /Pierre Fabre

Artesunate for Injection Guilin

Pyronaridine- artesunate Shin Poong

Artesunate- amodiaquine Sanofi/DNDi

Pyronaridine- artesunate granules Shin Poong

3

2

4

Artemether- lumefantrine Dispersible Novartis

6

Sulfadoxine pyrimethamine+ amodiaquine Guilin

4

1

3

Artesunate- mefloquine Cipla/DNDi/ Farmanguinhos

5

Footnotes: Included in MMV portfolio after product approval; Global Fund Expert Review Panel (ERP) reviewed product – permitted for time-limited procurement, while regulatory/WHO prequalification review is ongoing. WHO Prequalified OR approved/positive opinion by regulatory bodies who are ICH members/observers. MMV support to projects may include financial, in-kind, and advisory activities Brand names 1: Coartem® Dispersible; 2: Artesun®; 3: Eurartesim®; 4: Pyramax® tablets or granules; 5: ASAQ/Winthrop®; 6: SPAQ-COTM; * For infants 3 – 12 months, ** for children 13-60 months

Rectal artesunate Cipla/Strides/WHO-TDR

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Sulfadoxine pyrimethamine+ amodiaquine ** Guilin


Target deliverables 2017-2021

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1 AREA

Uncomp. malaria

• All MMV-supported ACTs included in WHO treatment guidance for malaria endemic countries

• Increased manufacturing capacity for paediatric and adult prequalified DHA-PQP

Severe Malaria

• Rectal artesunate prequalified and deployed in 10 countries • Global information clearinghouse to support best practices for

management of severe malaria • At least two prequalified suppliers of injectable artesunate,

and development of simplified injection requirements

Chemo-prevention

• Prequalification of a second child friendly SPAQ for SMC, and inclusion in paediatric Essential Medicines List

• Diversification of upstream API suppliers of quality assured sulfadoxine and pyrimethamine


MMV’s 5-year strategy: 3 clear programmatic areas

15

Case management of relapsing malaria

Case management of severe malaria

Case management of uncomplicated malaria

Clearance of the human reservoir

Chemoprevention for vulnerable populations

Chemoprotection of malaria-free populations

2nd generation SERC compounds with transmission blocking

>1st gen. SERC / MERC >Triple ACT >DHA-PQP pediatric

Pre-filled artesunate syringes

Tafenoquine (with G6PD PoC diagnostic)

>Injectable artesunate >Rectal artesunate

ACTs (adults and children)

SPAQ / SP

ACTs + low-dose primaquine

2 with chemoprotection

10-15 clearly differentiated NCE candidates, including:

1-2 with transmission blocking

1 with relapse prevention

2022 + 2017-2021 Deploy

APM Delivery of medicines that MMV helps bring to market facilitated to reach those in need

2027 +

Long acting chemoprotection

Timeline to registration

>Pediatric SPAQ (SMC) >Enhanced SPAQ (SMC) >DHA-PQP (IPTp)

1. Facilitate equitable access to quality antimalarial medicines

2. Develop better antimalarial medicines for clinical case mgmt. and vulnerable populations

3. Bring forward new tools for containing resistance and eliminating malaria Discovery

New classes of molecules supporting

the elimination agenda discovered

Development New antimalarial

medicines developed and registered

Translational Proof-of-concept and

safety of new molecules in human

subjects demonstrated

New injectable


Better medicines for case management and vulnerable populations

16

2 AREA

MMV will work with partners to develop a new generation of antimalarial medicines that will overcome resistance, facilitate deployment with shorter treatment courses, and prevent malaria episodes in vulnerable populations.

• Launch of single-dose cure for relapsing P. vivax malaria (tafenoquine)

• Development of improved regimens effective against resistant parasites

• Development of new medicines capable of simplifying therapy

1 Single Encounter Radical Cure / Multiple Encounter Radical Cure


Discovery and Early Translational



Patient exploratory

Regulatory review


Lead optimisation

P218 Janssen, (Biotec Thailand)

MMV253 Zydus Cadila

M5717 Merck KGaA

AN13762 (Anacor)

UCT943 H3D Cape Town

SJ733 Kentucky/Eisai

MMV048 (UCT)

Artefenomel/ Ferroquine Sanofi

Cipargamin Novartis

KAF156/ Lumefantrine Novartis

SAR121 Sanofi

DSM265 Takeda (UTSW/UW/ Monash)


14 new candidates, 9 new targets

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Target deliverables 2017-2021

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2 AREA

Relapsing

malaria

• Tafenoquine registered for prevention of relapses of P. vivax in adults and children, with full WHO policy recommendation for tafenoquine

• Multi-country implementation: simultaneous deployment of tafenoquine and point-of-care G6PD screening

Uncomp. malaria

• Combination medicine with at least one new chemical entity submitted for stringent regulatory authority approval

• Compounds against three new molecular targets, advanced into clinical studies

Severe malaria

• Data supporting potential for parenteral administration of a new fast-acting chemical entity in pipeline

Chemo-

prevention

• Launch second generation chemoprevention option • Completion of clinical study of DHA-PQP assessing its safety

and efficacy during pregnancy


Translational Sciences: 2017-2021

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3 AREA

Uncomp. malaria

• 5 new molecules tested in the blood stage infection models

Chemo-protection

• 2 molecules proposed for advancement into late-stage clinical development for a new chemoprotection medicine

• Chemoprotection data obtained for 3 new molecules in controlled human infection models

Clearance of human reservoir

• Transmission blocking data obtained for 5 new molecules

Trans. models

• New Controlled Human Malaria Infection (CHMI) models validated for transmission blocking and for chemoprotection


Putting the combination together

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SINGLE STUDY: PHASE 2a/2b Drug A / Drug B Combination

Limited Dose

Finding in 2-5y

Ph2a Highest Combo

Doses in adults

Exposure Ranging

In > 12 y**

Safety Satellite in

2–12y

Safety Satellite in

0.5–2y

Drug A – Individual Agent

Phase 1a SAD + FE

Phase 1b Challenge

Drug B – Individual Agent

Phase 1a SAD + FE

Phase 1b Challenge

Satellite Study

PopPK & PKPD

Ph2b Healthy Volunteers Pre-Clinical

Ph1a: What is the maximum well tolerated dose (& dose ratio)?

Ph1b Mono: What is the initial estimated active dose range?

Ph2a Combo: Confirm minimum efficacy at maximum feasible* dose

PONV: No Go if probability of combination efficacy >95% ACPR is low at maximum feasible* dose

Ph2b: Confirm tolerability & efficacious doses/exposures across age / weight range & dosing weight bands

Ph3: Pivotal efficacy for filing

Go/No Go

Phase 1a Combo safety

SCID mouse P.f. individual

agents & combo

Phase 1b Combo

challenge

Ph1b Combo: How do individual agents work together? Demonstrate the contribution of the individual agents to overall effect of the combo. What is the initial estimated active dose range?

Dose selection rationale for Phase 3 Ph3/4: Safety & Efficacy on re-dosing

Pre-clinical Mono: & Combo Demonstrate antimalarial activity (kill rate & time to recrudescence) & contribution of individual agents to the overall effect of the combo., including potential PD interaction. Rank potential combination partners

Go/No Go (or Combination selection)

*Highest clinically feasible dose includes tolerability, Toxicology margins, dose size and potential for commercial formulation ** alternative age minimum depending on local regulations *** Dose with optimal balance of efficacy, duration & tolerabiliy PONV – Proof of non-viability

Test multiple combination partner & select best

Rank combination partners

Phase 3 Studies in Africa, Asia &

LATAM Optimal

Combination Dose vs SOC in adults

& children

Ph 3 / 4 Multiple exposures study

Ph3


Putting the combination together

21

SINGLE STUDY: PHASE 2a/2b Drug A / Drug B Combination

Limited Dose

Finding in 2-5y

Ph2a Highest Combo

Doses in adults

Exposure Ranging

In > 12 y**

Safety Satellite in

2–12y

Safety Satellite in

0.5–2y

Drug A – Individual Agent

Phase 1a SAD + FE

Phase 1b Challenge

Drug B – Individual Agent

Phase 1a SAD + FE

Phase 1b Challenge

Satellite Study

PopPK & PKPD

Ph2b Healthy Volunteers Pre-Clinical

Ph1a: What is the maximum well tolerated dose (& dose ratio)?

Ph1b Mono: What is the initial estimated active dose range?

Ph2a Combo: Confirm minimum efficacy at maximum feasible* dose

PONV: No Go if probability of combination efficacy >95% ACPR is low at maximum feasible* dose

Ph2b: Confirm tolerability & efficacious doses/exposures across age / weight range & dosing weight bands

Ph3: Pivotal efficacy for filing

Go/No Go

Phase 1a Combo safety

SCID mouse P.f. individual

agents & combo

Phase 1b Combo

challenge

Ph1b Combo: How do individual agents work together? Demonstrate the contribution of the individual agents to overall effect of the combo. What is the initial estimated active dose range?

Dose selection rationale for Phase 3 Ph3/4: Safety & Efficacy on re-dosing

Pre-clinical Mono: & Combo Demonstrate antimalarial activity (kill rate & time to recrudescence) & contribution of individual agents to the overall effect of the combo., including potential PD interaction. Rank potential combination partners

Go/No Go (or Combination selection)

*Highest clinically feasible dose includes tolerability, Toxicology margins, dose size and potential for commercial formulation ** alternative age minimum depending on local regulations *** Dose with optimal balance of efficacy, duration & tolerabiliy PONV – Proof of non-viability

Test multiple combination partner & select best

Rank combination partners

Phase 3 Studies in Africa, Asia &

LATAM Optimal

Combination Dose vs SOC in adults

& children

Ph 3 / 4 Multiple exposures study

Ph3

Combination section tool (in silico) Symcyp: drug interations

Combinations in SCID: one per month through 2018 Combinations in human challenge model


Strength in discovery

22



Patient exploratory

Regulatory review


Lead optimisation


OZ609 Nebraska, Monash, STPHI

FAR797 Novartis


JPC3210 Jacobus

mCBK068 Calibr

MMV253 Zydus Cadila

M5717 Merck KGaA

AN13762 (Anacor)


SAR121 Sanofi

2-3 new candidates per year


New tools for containing resistance and eliminating malaria

23

3 AREA

We need new molecules which novel mechanisms of action to: • Address drug resistance, including resistance emerging in the future • Block human-to-mosquito transmission; breaking the infection cycle • Provide single-exposure chemoprotection to protect malaria-free

populations

MMV will further invest in new translational models and discovery platforms enabling the development of molecules targeting: • Transmission of the malaria parasite • Reactivation of the dormant P. vivax hypnozoite • Liver schizonts to give new chemoprotection medicines


Discovery priorities: 2017-2021

24

3 AREA

Chemo-protection

• 2 new long acting formulations for injectable SEC proposed for preclinical testing

Clearance of human reservoir

• One candidate with transmission blocking activity, and • One with anti-relapse activity

Discovery platforms

& Field

building

• Steady pipeline of new molecules: • 2 per year entering preclinical development from MMV

funded projects • 1 additional per year from projects where MMV is advising,

and not funding • First preclinical candidate MMVopen

Of these …


Discovery priorities 2017- 2021

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3 AREA

Priority

P. Vivax assay and candidates

Target-based discovery

Backup strategy

Next-gen tech and platforms

Data sharing

Near-term needs for MMV and partners • Increased access sporozoites • Build-up of HTS capabilities and assays • New focused compound libraries

• Focus medicinal chemistry on irresistible compounds • Active management of target database: screening, highest priority

targets with GHDDI, IMI

• Additional resourcing for high priority targets • New scaffolds if liabilities cannot be addressed with existing candidates

• Up front screening of Pf liver stage and transmission blocking • Intramuscular formulations delivering long duration chemoprevention • Finalise endectocide TCP6 and road map

• Complete due diligence of IT solutions vs. needs • Improved curation, data views, and integration partner tools • Processes for facilitating publication of MMVOpen data


If you want to go fast, go alone If you want to go far, go together

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14 stakeholders’ meeting critical challenges to malaria ...>1. st. gen. serc / merc >triple...

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