1. MMV in ACCESS-SMC 2015 - 2016 PARTNERS MEETING 18-22 JANUARY 2016 KAMPALA

2. Outline Introduction MMV deliverables 2015 achievements and challenges Looking forward for 2016

3. Introduction 3 With 60 people working towards the same mission: HOW Product development partnership Swiss Foundation / US Charity ACCESS AND PRODUCT MANAGEMENT DEPARTMENT André Tchouatieu tchouatieua@mmv.org

4. MMV Deliverables Output 1: GLOBAL PRODUCTION OF QUALITY AND ACCEPTABLE SMC PRODUCTS INCREASED  Strengthening SMC product demand forecasting  Developing business case for entry of an additional manufacturer into SP+AQ market  Providing support for additional manufacturer to develop child-friendly dispersible SP+AQ  Developing acceptable new SMC products  Developing efficacy profiles and reviewing of alternatives

5. 2015 achievements : Forecasting tool DEVELOP AND IMPLEMENT SMC PRODUCT DEMAND FORECASTING Develop standardized methodology and tools for demand forecasting Create and maintain updated 3 year rolling- forecast for supported countries Develop consolidated demand forecast for SMC products for all eligible children in all countries where SMC is recommended by WHO

6. The ACCESS-SMC Web-Based Forecasting Platform will enable users to perform 8 critical functions: View forecast needs (number of treatments & number of children per age group) at an aggregate level a)across all SMC eligible countries b)across ACCESS-SMC countries exclusively View forecast needs (number of treatments & number of children per age group) within a specific country a)at an aggregate level b)by individual districts Compare forecast needs (number of treatments & number of children per age group) a)across countries (one year) b)across years (one country) View a Manufacturing/Production forecast outlining aggregate needs (number of packs by strength) across SMC countries and across years View breakdown of forecast needs by funding partner View and export raw data and visualizations Upload forecast data Toggle between English and French versions of the platform 1 6 5 2 3 4 7 8 Web address: www.broadreachanalytics.chwww.broadreachanalytics.ch User Name + individual Password:

7. 2015 Achievements DEVELOPING BUSINESS CASE FOR ENTRY OF AN ADDITIONAL MANUFACTURER INTO SP+AQ MARKET Carry out break-even point analysis to determine number of manufacturers needed to meet the demand for SMC Develop a market entry business case for additional SMC product manufacturer Carry out research and due diligence to identify potential new manufacturers of SP+AQ Assess production capacity and required lead- in time of SMC pharmaceutical manufacturers Criteria for selecting new manufacturer: -Secured source of sulfadoxine API -Proactivity -Commitment of resources at risk -Successful development of prototype -Most favorable timelines -Strategic focus in the group of companies Price negotiations and transparency

8. 2015 achievements CONDUCT FIELD TESTING AND MARKET RESEARCH TO PROMOTE COUNTRY LEVEL UPTAKE OF CHILD FRIENDLY SMC PRODUCT FORMULATION Field test child friendly formulation: packaging Evaluate acceptability /feasibility /compliance of dispersible formulation vs tablets: Quantitative market research Identify preferences for future SMC product attributes through qualitative market research Study conducted with mapping health UK

9. Research aims and objectives Overall objective: Identify preferred attributes for future SMC medicines, to eventually replace SPAQ once resistance emerges, and potentially expand SMC into seasonal transmission areas where SPAQ is not therapeutically effective (primarily East and southern Africa). Identify the potential of existing anti ‐ malarial drugs as an alternative to SPAQ taking into account the risk/benefit ratio A Identify attributes for SMC compounds in order to inform the development of next generation SMC drugs, through in-depth qualitative discussions with global and national KOLs, policy-makers, health workers and caregivers C Cross-check SMC countries’ preferences with East and Southern Africa SMC eligible countries through discussions with NMCPs D Assess implementers and users experience with current products for SMC, identifying drivers and limitations of SPAQ B 9

10. Interviewees were selected based on profiles agreed with the MMV team CategoryRespondent TypeThe GambiaBurkina Faso Community level providers Caregivers 2 Focus Groups* (12 participants) 3 Focus groups* (12 participants) Community health workers 2 Focus Group (12 participants) 3 Focus Groups (12 participants) Dispensers6 interviews8 interviews Regional decision makers Regional public health deputy & medical store pharmacist 2 interviews9 interviews Regional head and deputy2 interviews1 interview National decision makers NMCP managers, SMC coordinators3 interviews Researchers SMC researchers1 interview Implementers CRS & MC (country leads SMC coordinator, pharmacist)3 interviews2 interviews At country level41 participants46 participants WARN Managers and meeting representatives12 interviews East & Southern Africa NMCP and researchers6 interviews (phone) Global-level malaria experts Key policymakers, researchers, program managers and clinicians (WHO, MSF, various researchers)*5 interviews (phone) Total Sample 113 *No TPPs were tested with this category 10 Interviewees were selected based on profiles agreed with the MMV team

11. Repurposing and recombining current molecules seen as fastest option to replace SPAQ 11 In terms of alternatives to SPAQ, there were limited ideas, but agreement was that arguments used for choosing SPAQ would still be valid today General consensus was that a combination should still be sought Ideally, repurposed older drugs are the favorite choice of SMC experts (safety assurance) Compounds mentioned: Piperaquine  Long half life  Prolonged QT unlikely to determine clinical symptoms unless underlying disease Primaquine  Long half life  Used in elimination Large spectrum antibiotics (azithromycin, doxycycline)  Antibiotic stewardship may need to be considered as an important negative factor “Whatever it is is, we know it has to be a combination, not artemisinin based” – Global policymaker “I think we still need to define failure....resistance to the drug is not failure of SMC. Maybe if we add a 3rd drug, it could buy some more time, and work at the safety profile of other drugs. Let’s see what comes out of the SPAQ plus azithromycin study” – Researcher, Mali “Maybe before going to new molecules, we should explore mefloquine, primaquine and even chloroquine a bit more. Yes, safety is an issue, but even when giving aspirin as MDA you are still likely to have adverse events. With a good campaign, we explain the risks, and the NMCPs can prepare accordingly. But we have to have the courage to try those old molecules we dismissed initially” - Researcher, Senegal

12. 12 StrengthsWeaknesses  Combination of two well known molecules  Known safety profile  Efficacy over 70%  PQ has a long half life  DHA is an artemisinin derivative  DHA has short/limited half life  Increased risk of resistance in areas with high transmission rates OpportunitiesThreats  Consider PQ as main compound and look for other potential partners  Use DHAPQ for SMC only in countries close to elimination  Increased risk of DHAPQ included as curative treatment for uncomplicated malaria in several SMC countries DHAPQ mentioned by several papers and researchers as potential alternative to SPAQ once resistance extends 12 MSF has used DHAPQ for chemoprevention in Uganda (specific, out of ordinary situation) with similar efficacy results as SPAQ There are studies ongoing in Burkina Faso comparing DHAPQ to SPAQ for SMC suggesting the same increased efficacy NMCPs and WHO remain reluctant to consider an artemisinin-derivative as prevention strategy

13. Interviewees were also asked to provide input on three potential target product profiles 13 Product X Product Y Product Z Aim: obtain interviewees preferences in terms of product attributes for the next generation SMC Methodology: A.Interviewees were provided a base product profile (Product X) Participants were then asked to score each product attribute on a scale from 1 (no value) to 5 (highest value) Following that, the overall product value was also scored on the same scale B.Interviewees were presented with two additional scenarios (Product Z and Y) with variations on only two attributes (increased efficacy and increased administration frequency) Interviewees were asked to score again the two attributes Participants were then asked to score again the overall value of each product C.Throughout the process, interviewees were asked to also provide a qualitative rationale for each of their scores

14. In the MDA context, analysis shows four attributes are as critical for the development of new SMC products 14 Well-known, safe product (suitable for MDA) Efficacy at least equal to SPAQ Child friendly formulation Frequency of administration (able to maintain current very effective door to door campaign)

15. Other Main Findings Conclusions & Recommendations 15 SMC acceptability is high among all stakeholders, including eligible countries not implementing it Increased interest likely to translate into faster adoption if a new product becomes available Even in current “non SMC countries”, door-to- door campaign format considered the most appropriate one for MDA A different campaign format would have to ensure / demonstrate similar adherence levels (e.g. polio or measles like campaigns) Drivers for SPAQ as SMC drug: efficacy, long half life, known safety, two different MoA, availability and affordability Similar arguments are likely to be considered when evaluating the new proposed drugs Increased willingness to use (repurposed) well known drugs rather than new compounds which may require country pilots Repurposing and recombining current molecules may still be the fastest option to replace SPAQ Injection generally considered more effective (by the general population) If the frequency is low (e.g. one injection per season), consider developing an injectable rather than an oral Full and summary reports are being prepared Specific country reports will be sent to Burkina Faso and The Gambia

16. Already done in 2016 INVESTIGATE PREFERENCES AND POSSIBLE OPTIONS FOR REPLACEMENT TO SP+AQ Convene SMC Expert Consultation Group ◦Meeting convened in London 13 and 14 of January ◦24 participants from various institutions ◦Meeting report in preparation OBJECTIVES  Refine MMV’s target product profiles for future chemoprevention treatments  Consider perspectives on existing medicines that may be re-purposed in the short- and medium-term to support development of chemoprevention medicines  Understand evidence required for normative policy change and regulatory pathways for chemoprevention medicines.

17. Topics discussed Need to have a gradual approach ◦Medium term by repurposing existing drugs ◦Long term with new compound A dosing schedule favoring a door to door distribution Injection of a depo for 3 four months feasible but safety issues to be considered No place for artemisinin derivatives Make available piperaquine monotherapy for chemoprevention studies Possibility of associating a new compound with an established antimalarial drug Which drug to repurpose? Piperaquine ? Pyronaridine ? Choroquine ? Back to “chloroquinization” ? Development of new compound for chemoprevention: regulatory considerations not clear, need to discuss with RA Drug should consider preserving premunition to form: no liver stage action Effectiveness analysis in a multi intervention context? A formal report of the meeting is being written and will be available in two weeks

18. PROVIDE INFORMATION AND SUPPORT TO ADDITIONAL MANUFACTURERS OF CHILD FRIENDLY DISPERSIBLE SP+AQ Provide information on market opportunity and support to new potential manufacturers Support additional manufacturers to develop and register a prequalified dispersible SP+AQ Signature of the partnership on going with a fairly acceptable price Prototype development done (video) Protocol for BE studies validated with WHO PQ Secure AQ comparator stock with MC Nigeria Sulfadoxine API prequalified CMC specialist consultant already identified Pyrimethamine API method development as per WHO – PQ requirement Timelines for file submission to WHO PQ: 12 months Looking forward for 2016

19. To be done in 2016? CONDUCT FIELD TESTING AND MARKET RESEARCH TO PROMOTE COUNTRY LEVEL UPTAKE OF CHILD FRIENDLY SMC PRODUCT FORMULATION Field test child friendly formulation: packaging Evaluate acceptability /feasibility /compliance of dispersible formulation vs tablets: Quantitative market research Identify preferences for future SMC product attributes through qualitative market research To be planned with the new manufacturer Experience with AL dispersible showing good uptake of the product Child friendly formulation recognized as a key attribute in recent survey is another research being required to confirm the need for a dispersible formulation vs hard tablets ? Looking forward for 2016

20. 2016 production / supply ERP Pyrimethamine + sulfadoxine + amodiaquine dipersible dossiers for both strengths: manufacturer requested for new documentation that was submitted on Dec 25, 2015, Decision awaited Production capacity SP+ AQ 12.5/250 + 75mg : 2.1 million blisters per month SP+AQ 25/500 + 153 mg : 4.2 million blisters per month 10 million treatments already produced for the 2016 campaign SP+ AQ 12.5/250 + 75mg : 2.1 million blisters per month SP+AQ 25/500 + 153 mg : 4.2 million blisters per month 10 million treatments already produced for the 2016 campaign Sulfadoxin pyrimethamine API Sulfadoxine API from Guilin Pharma with ERP approval running up to July 2016: 30 tons Sulfadoxine API from Anuh Pharma recently prequalified: 50 tons Anuh Pharma working on APIMF for Pyrimethamine PQ

21. Questions Is there a need for a third dosage for kids 59 – 120 months ? What is the practice in Senegal? Are scored tablets a solution ? What regulatory synergies (partners and countries) could be put in place for filing the dossier for submission to country regulatory while filling dossier for PQ?

22. Thank you