14 stakeholders’ meeting critical challenges to malaria ...>1. st. gen. serc / merc >triple...
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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
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Defeating Malaria Together
MMV Business Plan 2017-2021
Confidential – For Celgene Internal Use Only
Advances in prevention, diagnostics and treatment have contributed to reversing incidence of malaria since 2000
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Prevention** Treatment** Diagnostics**
* WHO estimates taking into account population growth ** 2014 data - Sources: WHO Global Malaria Programme (2015) World Malaria Report 2015, WHO
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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
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In light of this, the global malaria community has defined ambitious elimination and eradication targets
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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%
At least 20 countries
At least 35 countries
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
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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
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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
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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)
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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
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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
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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
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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
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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
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2
4
Artemether- lumefantrine Dispersible Novartis
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Sulfadoxine pyrimethamine+ amodiaquine Guilin
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1
3
Artesunate- mefloquine Cipla/DNDi/ Farmanguinhos
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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
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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
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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
Confidential – For Celgene Internal Use Only
Better medicines for case management and vulnerable populations
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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
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Discovery and Early Translational
Translational Product development Access Preclinical Patient
confirmatory Post approval Human volunteers
Patient exploratory
Regulatory review
Research Candidate Profiling
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)
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
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
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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
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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
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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
Combination section tool (in silico) Symcyp: drug interations
Combinations in SCID: one per month through 2018 Combinations in human challenge model
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Strength in discovery
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Translational Product development Access Preclinical Patient
confirmatory Post approval Human volunteers
Patient exploratory
Regulatory review
Research Candidate Profiling
Lead optimisation
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
OZ609 Nebraska, Monash, STPHI
FAR797 Novartis
UCT944 H3D Cape Town
JPC3210 Jacobus
mCBK068 Calibr
MMV253 Zydus Cadila
M5717 Merck KGaA
AN13762 (Anacor)
UCT943 H3D Cape Town
SAR121 Sanofi
2-3 new candidates per year
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New tools for containing resistance and eliminating malaria
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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
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Discovery priorities: 2017-2021
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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 …
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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
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If you want to go fast, go alone If you want to go far, go together
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