Medicines Development for Global Health (MDGH) — Moxidectin WHO Pre-Qualification Grant (June 2024)

Note: This page summarizes the rationale behind a GiveWell grant to MDGH. It reflects our understanding at the time we recommended the grant in June 2024. MDGH staff reviewed this page prior to publication.

Published: November 2024

The organization

Medicines Development for Global Health (MDGH) is a non-profit pharmaceutical company with a focus on developing new medicines for diseases which disproportionately affect people living in low- and middle-income countries (LMICs).1 MDGH identifies promising drugs that are being discontinued or deprioritized for development by for-profit pharmaceutical companies,2 and obtains licenses to continue developing and testing those medicines with the aim of manufacturing at scale to bring them to market.3 Moxidectin has achieved US Food and Drug Administration approval and is currently the furthest along of the two drugs in MDGH's portfolio; MDGH’s planned moxidectin pilot field implementation project due to commence in Ghana in early 2025, will be the first time MDGH has taken a product to market.4 We are not aware of any other non-profit pharmaceutical companies with similar programs.

The intervention

Moxidectin is a new treatment for onchocerciasis, also known as “river blindness”, developed by MDGH.5 Onchocerciasis is a neglected tropical disease primarily occurring in sub-Saharan Africa that can lead to blindness and severe, debilitating skin irritation.6 Moxidectin would be an alternative to the current standard of care, ivermectin.7

This grant will enable MDGH to complete the WHO PQ process for moxidectin, which we believe will speed up the replacement of ivermectin with moxidectin in future.8 We have not investigated how a program to replace ivermectin with moxidectin would work, as those activities are significantly further along in the product development process than the activities we are funding with this grant. In addition, we are making this grant in part because we think that supporting a non-profit pharmaceutical company focused on the treatment of neglected tropical diseases that affect LMICs could be beneficial more broadly than this medicine alone, may enable us to identify other cost-effective grantmaking opportunities in future, and will help us learn how the WHO PQ process works (see more here).

That said, our brief look into moxidectin as an alternative to ivermectin indicates that moxidectin is more effective than ivermectin at reducing microfilarial load in the skin of treated patients (i.e., reducing the presence of the young worms which transmit the disease and cause symptoms for human hosts), and that moxidectin results in a larger proportion of people who have no detectable microfilariae after treatment for a longer period of time.9

The grant

Grant activities

This grant will enable MDGH to complete the WHO PQ process for moxidectin.

The PQ process is a service offered by the WHO to evaluate medicinal products on their quality, safety, and efficacy.10 Our understanding is that many countries are significantly more likely to adopt a new medicine if it has been through the WHO PQ process.11

This grant will primarily fund MDGH staff costs to prepare the application, as well as cover the PQ fees.

Budget for grant activities

The budget for the grant is $637,549, broken down as follows:12

• $438,000 for core activities, including:
  • $355,000 for preparing, writing, and publishing the WHO PQ application
  • $65,000 for PQ fees
  • $18,000 for subject matter expert consultancy
• $141,590 for grant management, overhead, and projected inflation
• $57,959 as a contingency buffer13

This grant was funded by the Kladné nuly Foundation and the All Grants Fund.

Disbursement of grant funds is conditional on the WHO issuing an invitation for an expression of interest (EOI) to apply for pre-qualification of moxidectin. (more)

The case for the grant

• MDGH's model has potential to bring additional value to the issue of neglected diseases that disproportionately affect people in LMICs. We are not aware of any other non-profit pharmaceutical companies that aim to address neglected diseases by obtaining licenses of discontinued or deprioritized drugs.14 Because MDGH is addressing a neglected problem in a way that we have not seen in other organizations, we believe that they have the potential to bring significant additional value to this space.
• It is plausible that replacing ivermectin with moxidectin in areas where onchocerciasis is hyperendemic or very hyperendemic is itself above our bar for cost-effectiveness. The cost-effectiveness of replacing ivermectin with moxidectin for improving health outcomes is not the primary consideration driving this grant, but our rough cost-effectiveness model suggests that if this grant speeds up the replacement of ivermectin with moxidectin in areas with hyperendemic and very hyperendemic onchocerciasis by 1-2 years, this grant would be 8-14 times as cost-effective as unconditional cash transfers, our benchmark for evaluating grants.15 However, this model makes a few key assumptions about this rollout which are highly speculative:
  • Moxidectin replaces ivermectin in 75% of the areas where onchocerciasis is hyperendemic or very hyperendemic.
  • The DALYs averted by moxidectin compared to ivermectin is proportional to their relative efficacies at clearing microfilariae at 12 months.16
  • Funds used to pay for moxidectin have a counterfactual value equal to GiveWell's standard benchmark for government health spending, and the funds saved from reduced donations of ivermectin have a counterfactual value equal to GiveWell's standard benchmark for donated deworming drugs.

MDGH also claims that moxidectin may increase the probability of, and reduce the time to, disease elimination substantially (when compared to ivermectin).17 We have not vetted this claim nor included this benefit in our model, but MDGH sees this as a key benefit of moxidectin.18

• Supporting MDGH’s work could lead to future cost-effective funding opportunities. MDGH currently has two drugs in their portfolio, moxidectin and dovramilast,19 and they mentioned that they are considering several others for future work.20 Learning more about MDGH’s development pipeline and engaging more closely in their work could in turn lead to us learning about future cost-effective funding opportunities in this area.
• This grant is a learning opportunity that could benefit future GiveWell research on market shaping interventions. GiveWell is interested in learning more about market shaping. We think that initiatives that increase the quantity and accessibility of products that benefit people in LMICs could be highly promising. Our understanding is that many countries are substantially more likely to adopt a new medicine if it is WHO prequalified.21 The PQ process could be relevant in future market shaping projects that GiveWell investigates, and given that we are currently fairly unfamiliar with it, we expect a deeper understanding to be helpful for that future work.22 MDGH told us they are happy to help us understand how the WHO PQ process works through this grant.23
• We have a positive impression of MDGH as an organization. Based on a limited number of conversations with MDGH and with others in the field,24 we have a positive impression of MDGH’s relevant expertise and of their transparency.
• MDGH’s operating costs are sufficiently large that we do not believe that we would be creating a dependency on GiveWell funding. They informed us that their operating budget per year is in the region of AU$10-16 million (roughly $7-11 million USD),25 so this grant represents a small portion of their overall costs.

Risks and reservations

• While MDGH has been through other regulatory filing processes before, this will be their first time undergoing the WHO PQ process. We believe that this inexperience increases the chance of unanticipated difficulties that lead to a delayed or unsuccessful application. To address this, MDGH has been engaging closely with the WHO neglected tropical diseases department to lay the groundwork for the invitation to the PQ process and to better understand that process.26 Additionally, they intend to contract a specialist with experience in the WHO PQ process for consultation and support in drafting the application,27 and they have built some contingency buffer into their budget in case unexpected issues or delays arise (see the budget for grant activities). We also think that this inexperience with the WHO PQ process will increase the learning benefit to MDGH of this grant.
• It is not guaranteed that governments will in fact implement moxidectin as an alternative to ivermectin even after it is brought to market. MDGH told us that ivermectin is currently donated by Merck, a large pharmaceutical company, and so while the programmatic cost of moxidectin per round delivered will likely be similar, MDGH will need to persuade governments to incur procurement costs in switching to moxidectin or find other funders who can pay for procurement.28 If they fail to do either, it's possible that the product will not be taken up by governments even after the WHO PQ process is completed.
• There's a chance that we are funging other donors. MDGH have told us that they are also pursuing other funding sources, and in the months between our meeting in March 2024 and our recommendation of this grant in June 2024 they have secured a small amount of funding for additional moxidectin research.29 MDGH has previously relied on core funding from selling an FDA "Priority Review Voucher",30 and it is unclear whether MDGH would direct that funding toward the PQ process if not for GiveWell’s grant.31 However, we do not believe this is a major concern, as MDGH have stated that their voucher funding is for the most part no longer available.32
• We have not reviewed safety studies on moxidectin. However, we are not concerned about a risk of harm because: i) this funding is not being used directly for implementation, ii) in fact it is specifically funding a process by which the WHO will look into the safety of the product, iii) as we understand it, several safety studies have already been done, and several more are ongoing.33 It is also worth noting that moxidectin was approved for use by individuals aged 12 and over by the US Food and Drug Administration (FDA) in 2018.34
• MDGH can only begin grant activities if the WHO invites expression of interest (EOI) for pre-qualification of moxidectin.35 MDGH is in regular contact with the WHO technical unit responsible for issuing this invitation and believes that an invitation will be made soon.36 Disbursement of grant funds is conditional on MDGH receiving that invitation.

Plans for follow up

• GiveWell will have a session with MDGH to explain our cost-effectiveness analysis and our grantmaking criteria in more detail, with the intention that this will help MDGH identify future funding opportunities that may be of interest. We will aim to have that session before the end of 2024.
• We will have 6-month check-ins on the progress of the WHO PQ application.
• In addition to regular grant updates, MDGH will provide us with two workshops discussing lessons from the WHO PQ process. One workshop will be towards the beginning of the grant period (around September 2024) and one at the end of the grant period (likely near the end of 2026).

Internal forecasts

For this grant, we are recording the following forecasts:

Our process

• A GiveWell senior program officer briefly looked into MDGH and wrote a quick evidence assessment on funding acceptability studies to accelerate replacing ivermectin with moxidectin, which a GiveWell program officer reviewed in October 2023.
• GiveWell staff met with MDGH in November 2023, March 2024, and May 2024, and had further discussions about the grant opportunity with our partners at Open Philanthropy and with a market shaping expert.37
• MDGH sent an initial proposal in December 2023, and an updated proposal including responses to GiveWell questions in May 2024.
• We created a rough cost-effectiveness analysis to evaluate the impact of hastening the replacement of ivermectin with moxidectin.
• GiveWell’s director of research reviewed the case for the grant before it was approved.

Sources

• 1

  “We address health inequity by researching, developing and delivering new and improved medicines for diseases disproportionately affecting low- and middle-income countries.” MDGH, About page.

• 2

  When we spoke, MDGH told us they typically identify promising drugs through their networks in the pharmaceutical industry, as many of MDGH’s employees were formerly in the pharmaceutical industry. MDGH also has more systematic conversations with large pharmaceutical companies to understand what drugs they might be discontinuing. Conversation with MDGH, March 2024, unpublished.

• 3

  Summary of conversations with MDGH about their drug development pipeline. MDGH informed us that they currently sub-contract the manufacturing to another organization, but manage the manufacturing process. Conversation with MDGH, March 2024, unpublished.

• 4

  See MDGH’s development pipeline chart here.

• 5

  "Moxidectin is the first promising alternative treatment to ivermectin because it provides a more consistent and durable suppression of the O. volvulus microfilariae (young worms)." MDGH, Moxidectin Funding Proposal, 2024, unpublished.

• 6

  “Onchocerciasis, caused by infection with the filarial worm Onchocerca volvulus, is one of the eleven neglected tropical diseases (NTDs) recently targeted for elimination by the World Health Organization (WHO). More than 99% of all cases are concentrated in 28 countries in sub-Saharan Africa. Small foci also occurred in the Americas, but there has been successful progressive elimination in this region and infection is currently found in a single large transmission zone (the ‘Yanomani area’) which straddles the border of Venezuela and Brazil. Small foci of infection also persist in Yemen.” Murdoch 2018, p. 1

• 7

  “Ivermectin is currently the only available therapeutic option for onchocerciasis in endemic countries
  and has been used in treatment programs for ~35 years.” MDGH, Moxidectin Funding Proposal, 2024, unpublished.

• 8

  MDGH has indicated that moxidectin is likely to be used in hyperendemic settings where alternative strategies are required to reach elimination or in settings where recrudescence (reoccurrence of disease when it was thought eliminated) has occurred, although for the purposes of our modeling we have assumed that moxidectin will replace ivermectin in a portion (75%) of hyperendemic settings.

• 9
  • “All three moxidectin doses (2, 4, and 8 mg) achieved both faster and considerably more complete skin microfilarial clearance than ivermectin. For all three moxidectin doses, the number of patients with undetectable levels of skin microfilariae was statistically significantly greater than with ivermectin, with the difference reaching significance as soon as 8 days after treatment with 4 and 8 mg moxidectin.” Milton et al., 2020, p. 1072
  • “Significantly more participants maintained undetectable skin microfilariae in the moxidectin group (360/938 = 38%) than in the ivermectin group (7/478 = 1.5%) (p &lt 0.0001) between 1 and 12 months after treatment.” Milton et al., 2020, p. 1072

• 10

  "WHO prequalification of medicines is a service provided by WHO to assess the quality, safety and efficacy of medicinal products." WHO, Prequalification of medicines.

• 11

  “WHO's list of prequalified medicinal products is used by international procurement agencies and increasingly by countries to guide bulk purchasing of medicines.” WHO, Prequalification of medicines.

• 12

  MDGH, Responses to GiveWell Questions, 2024, unpublished.

• 13

  MDGH have told us that they build in a contingency buffer of an additional 10% of total costs to account for overoptimism in the budgeting process. $438,000+$141,590=$579,590. Then $579,590*0.1=$57,959. Conversation with MDGH, May 2024, unpublished.

• 14

  The most similar organization we have come across is DNDi.

• 15

  Note that a) our cost-effectiveness analyses are simplified models that are highly uncertain, and b) our cost-effectiveness threshold for directing funding to particular programs changes periodically. See GiveWell’s Cost-Effectiveness Analyses webpage for more information about how we use cost-effectiveness estimates in our grantmaking.

• 16

  MDGH told us (by email) that no data or modeling exists yet quantifying the potential impact of moxidectin on DALYs.

• 17

  "Due to its longer half-life (20-30 days), a single dose of moxidectin will likely interrupt the chain of infection transmission compared to ivermectin (half-life &lt 1 day), thus requiring fewer rounds of mass drug administration (MDA). Mathematical modellers predict that moxidectin will increase the probability of, and accelerate the time to, disease elimination in affected countries." MDGH, Moxidectin Funding Proposal, unpublished.

• 18
  • “Despite this, there are still many areas where prevalence is high, and elimination of disease transmission is a long way off which is why new medicines, like moxidectin, are required.” MDGH, 2022-2023 Annual Report, p. 7.
  • “Projections from this modeling indicate that 6-monthly administration of moxidectin could reduce by half the number of years needed to achieve elimination of transmission in areas with moderate endemicity (mesoendemic) of river blindness and may be the only strategy that can achieve elimination of transmission in hyperendemic regions.” MDGH, 2022-2023 Annual Report, p. 13.

• 19
  • “MDGH is developing two medicines: moxidectin and dovramilast.” MDGH, Our Pipeline.
  • “Dovramilast modifies the host’s immune response to infection and is being studied for the treatment of tuberculosis and leprosy type 2 reactions.” MDGH, Our Pipeline.

• 20

  Conversation with MDGH, March 2024, unpublished.

• 21

  “WHO's list of prequalified medicinal products is used by international procurement agencies and increasingly by countries to guide bulk purchasing of medicines.” WHO, Prequalification of medicines.

• 22

  Open Philanthropy previously commissioned Rethink Priorities to do a shallow investigation of the WHO PQ process, but we believe that we can learn more by speaking with MDGH as they go through the process.

• 23

  "MDGH would be very happy to provide regular progress updates, to field questions, and share lessons learned as we progress through the PQ process. Additionally, MDGH would be delighted to conduct an online session with you to share our experience and understanding of the PQ procedure." MDGH, GiveWell Questions and Responses, unpublished.

• 24
  • GiveWell staff met Mark Sullivan (Managing Director) and Danielle Smith (Global Head of Regulatory Affairs) in London, and Caroline Cahill (Associate Director, Development Management, Onchocerciasis) and George Rugarabamu (Principal, Corporate Development) virtually. They have extensive relevant expertise (e.g., previous work for corporate pharmaceutical companies) and seemed to be transparent about how they work and how they source new opportunities.
  • GiveWell staff spoke with partners at Open Philanthropy who had briefly looked into MDGH for drug research and development in the past and had a positive impression of them as an organization. Conversation with Open Philanthropy, June 2024, unpublished.

• 25

  Conversation with MDGH, May 2024, unpublished.

• 26

  Conversation with MDGH, May 2024, unpublished.

• 27

  Conversation with MDGH, May 2024, unpublished.

• 28

  Conversation with MDGH, March 2024, unpublished.

• 29

  MDGH, Responses to GiveWell Questions, unpublished.

• 30

  The FDA provides companies who register a drug for treatment of a neglected tropical disease a voucher that can be used to accelerate that drug’s review and thereby its entry to market (see the Tropical Disease Priority Review Voucher Program). MDGH was able to sell this voucher to a commercial pharmaceutical company, and relied on the proceeds of that sale to fund further moxidectin development. Conversation with MDGH, May 2024, unpublished.

• 31
  • Vouchers typically sell for between US$90 and $110M (see here) MDGH sold its voucher in 2018. MDGH mentioned that a large proportion of the proceeds were used to provide a return to the Gates Foundation backed Global Health Investment Fund, among others, who provided MDGH the capital to complete moxidectin development. The remainder was retained by MDGH as an endowment and has been invested into its global health medicines. It seems plausible that it has spent the majority of those funds because their operating costs are 10m AUS$ or more per year and it has been 6 years since the sale. Conversation with MDGH, May 2024, unpublished
  • We understand that $13m USD was spent on the final stages of moxidectin development: "Moxidectin is the first new FDA-approved treatment for onchocerciasis in more than 20 years, and the $13 million of financing required for the final stages of development was enabled entirely as a result of the PRV incentive program." MDGH, MDGH discloses Novo Nordisk as purchaser of its PRV, 2019.

• 32

  Conversation with MDGH, May 2024, unpublished.

• 33
  • "There are many ongoing and planned studies that will complement and expand upon the existing evidence base. Of particular relevance is a large MDGH-sponsored safety study (protocol number: MDGH-MOX-3002; NCT04311671) which is nearing completion. This study has enrolled and dosed more than 12,500 participants with moxidectin, including children down to 4 years of age, across two sites in Africa. The main purpose of this study is to provide data in people with all levels of disease (including undetectable) living in onchocerciasis and LF co-endemic areas, to inform treatment guideline recommendations. The inclusion of participants in zones co-endemic for onchocerciasis and LF should benefit both programmes and enable treatment recommendations in both settings. Data from this study is expected to be available in early 2025 during the WHO treatment guideline development process." MDGH, GiveWell Questions and Responses, unpublished.
  • “As of 15 December 2022, safety data are available from 7,521 subjects enrolled in twelve clinical trials. Specifically, 243 healthy volunteers received moxidectin at doses of 3 to 36 mg (183 subjects at moxidectin doses between 8 and 10 mg) and 16 healthy volunteers received placebo in six completed studies.” MDGH, Moxidectin Investigator’s Brochure, unpublished.

• 34

  "Five years ago, the United States Food and Drug Administration (US FDA) approved moxidectin for the treatment of river blindness (onchocerciasis) in people aged 12 and older.” MDGH, FDA approval of Moxidectin, 2023.

• 35

  Note that the WHO EOI will be a public notice inviting organizations to submit applications for PQ. As the only organization with a registered moxidectin product MDGH is the only organization that is well placed to respond to the call.

• 36

  MDGH, GiveWell Questions and Responses, unpublished.

• 37

  GiveWell staff also had an introductory meeting with MDGH in March 2021.