Breakthroughs Blog: Guest post

Malaria in pregnancy threatens the health of mothers and babiesWhen a woman finds out she is pregnant, it is often an exciting, emotional, and nerve-racking time. For women in malaria-endemic countries, however, there is an additional concern: the risk of contracting malaria during pregnancy. This was a major worry for Kenyan mother Elyne Kaingu. Fortunately, during her second pregnancy, she received intermittent preventive treatment of malaria in pregnancy (IPTp) at the health clinic, enabling her to have a malaria-free pregnancy. However, not all women are as fortunate as Kaingu.According to the World Health Organization’s (WHO’s) 2021 World Malaria Report, 34 percent of the more than 33 million pregnancies worldwide in 2020 were exposed to malaria, meaning more than 11 million women and babies were at risk for the serious complications that malaria in pregnancy (MiP) may entail, including anemia, the development of severe malaria, and risk of miscarriage or low infant birth weight. Insufficient prevention and treatment options for MiP Despite the urgent need, options for preventing and treating MiP are currently limited. Pregnant women are usually excluded from clinical trials to protect them and their babies from potential adverse effects of new drugs in development, making it difficult to determine the safety and appropriate dose to guide recommendations of new and existing drugs for use in pregnant women. While WHO recommends artemisinin-based combination therapies (ACTs) to treat uncomplicated malaria and sulfadoxine-pyrimethamine (SP) for IPTp for women in their second and third trimesters, these treatments fall short in some critical areas: neither is recommended for use in the first trimester of pregnancy1 and SP should not be used by pregnant women with HIV/AIDS receiving prophylaxis against opportunistic infections or by women in areas where SP drug resistance is reported.Protecting and treating pregnant women: Researching, repurposing and recombining antimalarials  To improve the availability of well-tolerated and effective antimalarials for pregnant women, changes in drug development approaches are urgently needed. Through MMV’s MiMBa strategy, the product development partnership is advocating for and advancing several innovative research approaches.What has first been required is a mindset shift—a clear agreement to change the way we approach de-risking of compounds so that there is robust data on pregnancy as soon as possible in the drug development process. Starting at the earliest phase (discovery), MMV is prioritizing new antimalarials for progression to development based on their low-risk profile for birth defects. In addition, MMV is using translational pregnancy models to optimize and accelerate their clinical development by providing information on the potential need to adjust drug dosing for pregnant women, as well as the possibility of fetal exposure. Further, MMV performs developmental and reproductive toxicity studies that evaluate the effects of potential drugs on one complete life cycle (from conception in one generation through the following generation) earlier in the development process. Compounds which are shown to be well-tolerated in developmental and reproductive toxicity studies will be evaluated in pregnant women. It is hoped that if compounds can be appropriately de-risked, then in future dedicated clinical trials in pregnancy might be conducted in parallel to phase 3 trials, also known as confirmatory studies, which “aim to confirm the efficacy and safety of the candidate compound in a large patient population.” This approach would allow for the collection of information to establish the benefit/risk balance of a new antimalarial at an earlier stage and will help ensure that the needs of pregnant women are addressed in a more timely and equitable manner in the future.Existing antimalarials: Filling the data gapMMV has undertaken research on existing drugs for their potential use in pregnant women. With its pharmaceutical partner Shin Poong and other research partners, MMV conducted a real-life study (CANTAM) on pyronaridine-artesunate (Pyramax®) in five countries in Africa with results indicating high safety, tolerability, and efficacy for the 11 women who were unknowingly pregnant. Finally, MMV is currently providing input in an ongoing study, PYRAPREG, led by the University of Sciences, Techniques and Technologies of Bamako, which is looking at the efficacy and safety of four ACTs, including Pyramax, in the second and third trimesters of pregnancy. Further, MMV is supporting follow-up studies on ACTs already on the market. For example, MMV and the Liverpool School of Tropical Medicine’s Timika facility in Indonesia continues to monitor women during and after their pregnancies.Finally, MMV has set up a pregnancy registry, launched last year in Kenya with the Liverpool School of Tropical Medicine and extended to Burkina Faso at the beginning of 2022. Through this registry, MMV aims to obtain robust data on the use of a range of ACTs for the treatment of uncomplicated malaria in pregnancy. The information generated will serve to better understand the benefit/risk ratio and contribute to informing policymakers, regulators, clinicians, and pregnant women on the use of ACTs, particularly during the first trimester. According to Hellen Barsosio, a senior clinical research scientist based in Kenya, “Pregnancy registries are vital in providing safety information on drugs and vaccines used during pregnancy, particularly within the first trimester, a critical period for the growing baby due to the limited safety data available by the time drugs reach the market.”Facilitating access to antimalarialsFor antimalarials to be useful in preventing and treating MiP, healthcare workers and patients must be aware of their protective effects and be able to access them. MMV works with governments, pharmaceutical companies, and implementing partners to ensure that antimalarials are available as quickly as possible after launch, especially in hard-to-reach areas. A recent success in facilitating access to antimalarials for pregnant women is the achievement of WHO prequalification for SP by Universal Corporation Ltd, a Kenyan pharmaceutical company, supported by Unitaid and MMV. Universal Corporation Ltd is the first pharmaceutical company in Africa to achieve prequalification for SP. As alternatives to SP advance, it will be crucial to enable manufacturers in endemic countries to produce quality-assured medicines so that they are readily available for pregnant women. The World Health Summit serves as a reminder that those who are the most vulnerable to diseases must be at the center of drug discovery and development efforts. Developing antimalarials to address the needs of pregnant women is vital to achieving malaria eradication by ensuring that everyone can access the care they need. 1. On 25 November, WHO released its updated guidelines for malaria, which include a strong recommendation for the use of an ACT, artemether-lumefantrine, to treat uncomplicated malaria in women in their first trimester

International Women’s Day calls for action to address biases, discrimination, and inequities that continue to impact the quality of life of women and girls, including their access to healthcare, such as malaria prevention and treatment. Pregnant women and their babies are among the most at risk from malaria, and this is exacerbated by their limited access to antimalarial medicines. According to the World Health Organization (WHO), in 2020, nearly 12 million pregnant women were exposed to malaria, and they are particularly vulnerable as pregnancy can weaken their immune system. Malaria can have devastating effects on pregnant women and infants, from mothers with severe anemia and babies born with low birth weight to, in the worst case, the death of the mother and/or baby. According to research from 2020, one in ten maternal deaths in malaria-endemic countries is the result of malaria. WHO recommends intermittent preventive treatment in pregnancy (IPTp) to prevent malaria in pregnancy. Ideally, eligible pregnant women should receive three doses of sulfadoxine-pyrimethamine (SP) to prevent malaria in their second and third trimesters for optimal protection. Due to several factors, only 32 percent of eligible pregnant women received all three recommended doses of IPTp in the 33 sub-Saharan African countries assessed by WHO’s 2021 World Malaria Report. A 2019 review that looked at determinants of IPTp uptake in 18 sub-Saharan African countries found that poor policy implementation resulting from weak coordination between national malaria control and reproductive health programs and stockout of quality SP were the main barriers. The review also mentioned the pivotal role played by health providers in delivering IPTp, highlighting the correlation between their awareness of the policy and the IPTp coverage. In sub-Saharan Africa, between 70 and 90 percent of pharmaceuticals are imported, making it difficult to ensure a steady supply of treatments like SP. To help remedy this access gap, Medicines for Malaria Venture (MMV) is currently leading a UNITAID-funded project to enable the pharmaceutical companies Universal Corporation Ltd (Kenya), Swipha/Biogaran (Nigeria) and Emzor (Nigeria) to manufacture quality SP, not only for domestic use, but also for other countries in Africa. Community IPTp (C-IPTp) is another solution to help address the access gap, in which pregnant women visit “purposely trained and supervised, easily accessible community health workers” close to their homes to receive IPTp. C-IPTp is being explored by many countries with promising results in improving SP uptake. MMV is also involved in Transforming Intermittent Preventive Treatment for Optimal Pregnancy, otherwise known as TIPTOP, a Jhpiego-led project to increase the number of women able to benefit from C-IPTp.Under the umbrella of the Roll Back Malaria Partnership, MMV is participating in a signature campaign calling for global leaders to Speed Up Scale-Up IPTp through an open letter that asks for increased funding to address malaria in pregnancy, proper training for health care workers and the removal of the previously mentioned barriers to seeking care. Beyond statistics: Surviving malaria in pregnancy The need for new options for medicines is underscored by Eileen Buxton’s experience. Eileen, a Ghanaian nurse, was already aware of the risks of malaria in pregnancy as a health care worker in an endemic country. After falling ill while pregnant herself, Eileen “was scared… I knew how being sick during pregnancy could affect the mother and the child too.” She was admitted to a hospital for treatment. After her release, however, the fever came back within a couple of days. Eileen was experiencing severe malaria and had to be admitted to the hospital again, this time for about three weeks. “It took a long time for me to recover some strength,” she recalls. Despite this harrowing experience, Eileen can be described as one of the fortunate ones: after her recovery, she gave birth to healthy twin babies. Millions of women are not so lucky. Scaling up IPTp-SP access will prevent millions of women from going through experiences like Eileen’s. While International Women’s Day highlights women’s achievements, it is also a reminder of the existing challenges they face. When it comes to health and malaria specifically, it is also a reminder that we have not yet reached equity. Ending malaria means working to provide access to antimalarial prevention and scaling up access to IPTp and other treatment methods that are effective and safe for all people—like Eileen Buxton—who are most at risk. Ultimately, that’s a win for everyone. We urge you to add your name to the open letter and help protect more mothers and babies from malaria.

For the second time, the World Health Assembly took place in the midst of an ongoing pandemic that is widening health inequities across and within regions. More than a year after the first wave of the pandemic, health systems in many parts of the world continue to battle waves of infection amid shortages of oxygen, vaccines, and health care workers. Yet among the numerous challenges posed by the pandemic, there were positive signals that with coordinated and focused action, health innovation in record pace is possible, particularly if that action can be built on a firm foundation of existing research and development (R&D). Our next challenge—as we continue the battle against COVID-19 and other health threats—is to channel similar coordinated, focused action to ensure the benefits of innovation are distributed equally across both geography and gender. What happens when years of existing research systematically exclude certain populations, denying them or delaying access to the benefits of health innovation? How can we address the underlying causes and accelerate shifts to make clinical research more inclusive? A recent side event at the 74th World Health Assembly, co-organized by Deutsche Stiftung Weltbevölkerung, Global Health Technologies Coalition, and Medicines for Malaria Venture (MMV), explored the above questions by highlighting the specific issue of gender inequity in health innovation. The panelists at the event discussed how gender biases have resulted in women’s underrepresentation in preclinical and clinical research, leading to downstream gaps in therapeutic options for them. Though gender inequity in health innovation is not limited to malaria, this article builds upon MMV’s presentation at the event, focusing on gender equity in malaria R&D to meet unmet needs. Unlike COVID-19, malaria is a disease that we have known for centuries. Despite the vast amount of scientific and epidemiological knowledge on malaria, a quick glance at the historical trajectory of malaria research reveals that it has been embedded in a larger context of gender bias in medical research. During the clinical development of most new medicines, including antimalarial drugs, pregnant people are actively excluded from trials and, if pregnancy occurs during the trial, treatment is discontinued and follow-up on the pregnancy outcomes is ensured. While this practice aims to protect the pregnant person and the fetus, it also prevents the generation of data and in doing so it has created knowledge gaps in the treatment of malaria in pregnant people. In addition to delaying the benefits of new treatments to these populations, the knowledge gaps also hinder the creation and implementation of gender-sensitive policies to fight the disease.Malaria in pregnancy, and more broadly in people of reproductive potential, remains a major public health challenge today. The World Health Organization estimates that 12 million pregnancies are at risk annually, resulting in nearly 822,000 children being born with low birth weight. Though preventive tools like vector control (for example insecticide-treated bednets and indoor residual spraying) and intermittent preventive treatment in pregnancy exist, there are very few treatment options for pregnant and lactating people in their first trimester. The longer we wait to change our course, not only do we risk losing thousands of pregnant people and babies to a treatable disease, but we also widen the existing knowledge gaps that urgently need to be bridged. In other words, if we delay the process of integrating a gender lens as an essential element of the drug development process, the journey to catch up will be steep and could jeopardize efforts to eliminate and eradicate malaria. Fortunately, there is a growing determination within the malaria community to rectify gender-related data gaps. At MMV, we are doing so through our Malaria in Mothers and Babies (MiMBa) strategy, which aims to systematically prioritize and address the needs of pregnant people and newborns, right from target product profiling at the outset of drug development through to ensuring a stable supply of recommended medicines to treat and protect these populations from malaria. In one example, recognizing the lack of safety and tolerability data for antimalarials used during pregnancy, we have teamed up with the Liverpool School of Tropical Medicine to develop a pregnancy registry to help fill the data gaps with the objective of eventually establishing standard protocols in the treatment of malaria during pregnancy in all endemic regions.Other organizations, like the WorldWide Antimalarial Resistance Network, are building online repositories of published and unpublished literature on malaria in pregnancy, contributing to the methodical archiving of data on this topic. Furthermore, awareness campaigns like “Zero malaria starts with me” are also placing a strong focus on the need for inclusive innovation to treat malaria in pregnancy.In an important step forward, high-level decision-making bodies like the G7 are also taking note of this issue. We welcome the G7 health ministers’ Therapeutics and Vaccines Clinical Trials Charter to pave the way for “stronger collaboration in large-scale international trials to enable greater diversity of participants, including pregnant people and children.” This is an important step forward toward more equitable clinical research.While great strides are being made in advancing health innovation to better represent and account for the needs of all genders in health care, much critical work remains to be done. Decades of exclusion from clinical research will not disappear overnight. The need of the hour is gender mainstreaming supported by significant investments into R&D, as well as moving policymaking forward, to ensure a fairer and more inclusive health care system for all. Most importantly, while organizations like MMV commit to extend the benefits of our innovation equitably to all populations affected by malaria, we firmly believe that the road to achieving gender equity in clinical research will be paved by the inclusion and support of patients, health workers, researchers, policymakers, as well as the champions and advocates for health equity in the global health system. Much like for the COVID-19 pandemic, catalyzing this transition to a gender-sensitive malaria eradication strategy will require focused and coordinated action and all voices have a part to play.

An estimated 125 million pregnancies around the world are at risk from malaria annually.[1] For both mother and baby, the disease is potentially life-threatening and babies that do survive are often born with low birth weight, which is associated with negative impact on development.[2] These mothers-to-be need medicines to both protect them from getting infected with malaria and to treat them should they fall ill. Yet, these needs remain inadequately addressed.Medicines for Malaria Venture (MMV) is working with partners to improve the quality of global supplies of the World Health Organization (WHO)-recommended medicine sulphadoxine-pyrimethamine (SP) for use as intermittent preventive treatment in pregnancy (IPTp). As a partner in the Unitaid-funded Jhpiego-led consortium TIPTOP, MMV is supporting improved coverage of SP for IPTp in Africa through community health workers by strengthening the supply side for WHO-prequalified SP. For women who become infected with malaria during pregnancy, WHO currently recommends artemisinin combination therapies (ACTs) for the treatment of malaria in the second or third trimesters, and quinine with the antibiotic clindamycin in the first trimester. Angela Kangulumais is a primary school teacher in Zambia. She is 6 months pregnant with her second child.  Angela is no stranger to malaria—she fell ill just before her first pregnancy and was treated with an ACT. Pregnant women at risk of malaria like Angela benefit from IPTp to protect themselves and their unborn babies from malaria. Photo: Medicines for Malaria VentureBased on meta-analyses comparing treatment outcomes using the ACT artemether-lumefantrine (AL) versus quinine in first trimester pregnancies and following a recommendation for policy change from an Expert Review Group, WHO is considering whether to recommend the use of all ACTs in all trimesters of pregnancy. That said, the data set regarding the use ACTs other than AL in the first trimester is comparatively small. MMV is working with the Liverpool School of Tropical Medicine’s Timika Research Facility in Indonesia to analyse historical data and to capture new evidence regarding the use of the ACT dihydroartemisinin-piperaquine (DHA-PQP) in the first trimester of pregnancy. These new analyses will contribute to the evidence base regarding safety and tolerability of this ACT during pregnancy.In addition to expanded use of ACTs for treatment in pregnancy, the malaria research community is also focused on exploring the use of DHA-PQP as a potential substitute for SP for IPTp in the future, should SP’s preventive efficacy decline. MMV is working with the London School of Hygiene and Tropical Medicine in Tanzania on a study to evaluate the cardiac safety of a single course of IPTp with DHA-PQP in pregnant women with and without asymptomatic infection.For the future, we are also looking at the medicines we have in development and how they might be used for pregnant women. Traditionally, most drugs are tested for safety in pregnancy quite late in development (if at all), since in many therapeutic areas, a product that cannot be used in pregnancy can still have enormous therapeutic value. However, in the case of malaria, the needs of pregnant women are clear and compelling. MMV thus focuses early on in its drug development process to identify molecules that may have an acceptable safety profile in pregnancy. This focus includes conducting standard embryo-foetal development studies in parallel with other non-clinical safety assessment or phase I studies. A favorable safety report early on means that these molecules could be prioritized for development. In addition, with MMV’s support, a review was carried out and published to help guide the prioritization of antimalarial drugs for development. It detailed the non-clinical safety of all non-artemisinin antimalarial drugs. [3] The article summarized data that was previously not easily accessible to health experts and is helping to guide the development of next-generation antimalarial medicines that could have an appropriate safety profile in pregnant women. With our partners, MMV is committed to investigating all the avenues to improve pregnancy outcomes for women at risk of malaria. By focusing on protecting and treating pregnant women at risk, we safeguard two lives, not just one.[1] Dellicour S et al. “Quantifying the Number of Pregnancies at Risk of Malaria in 2007: A Demographic Study”. PLos Med; 7(1): e1000221 (2010).[2] Schantz-Dunn J & Nour NM. “Malaria and Pregnancy: a global health perspective”. Rev Obstet Gynecol; 2(3):186–192 (2009).[3] Clark RL. “Animal Embryotoxicity Studies of Key Non-Artemisinin Antimalarials and Use in Women in the First Trimester.” Birth Defects Res. 109(14):1075-1126 (2017).