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This International Women’s Day, GHTC is celebrating two novel, female-initiated health technologies that have the potential to give women and girls greater control over their sexual and reproductive health, empowering them to make informed decisions about whether and when to have children and to protect themselves and their families from HIV and other sexually transmitted infections (STIs). The Women’s Condom. Photo: PATH/Glenn Austin This International Women’s Day, GHTC is celebrating two novel, female-initiated health technologies that have the potential to give women and girls greater control over their sexual and reproductive health, empowering them to make informed decisions about whether and when to have children and to protect themselves and their families from HIV and other sexually transmitted infections (STIs). GHTC members PATH and the International Partnership for Microbicides (IPM) both recently announced exciting milestones in developing and expanding access to game-changing contraceptive and HIV/STI prevention tools that help women negotiate safer sex. The Woman’s Condom, manufactured by Shanghai Dahua Medical Apparatus Co., Ltd, (DAHUA) and marketed under various brand names including O’Lavie, received World Health Organization (WHO)/United Nations Population Fund (UNFPA) prequalification last week. This approval opens the door for its purchase and distribution by United Nations (UN) agencies and other leading international organizations for distribution in the public sector. And just the week before, IPM announced the results of two large Phase 3 clinical trials—The Ring Study and ASPIRE—which showed that a monthly vaginal ring containing the antiretroviral drug (ARV) dapivirine, developed by IPM, can safely help protect women from HIV. Enduring unmet need for family planning and HIV/STI prevention methods Globally, an estimated 225 million women have an unmet need for family planning and more than 350 million new cases of curable STIs occur every year. Women's and adolescent girls' contraceptive and HIV/STI prevention needs vary across geographies and cultures and often change throughout a woman’s life. Therefore, unmet need can only be addressed through ensuring access to a range of contraceptive options. When women and adolescent girls make contraceptive decisions, they have a lot to consider: Cost Efficacy Ease of use Side effects, health concerns, and whether a hormonal or non-hormonal option is right for them Ease of access, including how often they’d have to visit a health clinic or pharmacy and the reliability of the supply of in their community Stigma(s) surrounding contraceptive use and whether they can discreetly access contraceptives Comfort and whether the product impacts pleasure during intercourse Whether they can use or administer the contraceptive themselves or must rely on a health worker or partner. Biologically and as a result of gender-based violence and discrimination, women and girls are at greater risk for HIV infection. In sub-Saharan Africa, women aged 15 to 24 are twice as likely to become infected with HIV compared to their male peers. And often, women are not empowered to negotiate safe sex with their partners, particularly the use of male condoms. The prevention methods currently available aren’t doing enough to stop the alarming rates of infection in women in sub-Saharan Africa and are often unrealistic options for them. What makes these tools so game-changing for women? The Woman’s Condom and the dapivirine ring put the power of protection in the hands of women. The Woman’s Condom was developed by PATH, CONRAD, and other partners through a user-centered design process across four countries. “This iterative process enabled the partners to create a product that truly met the needs of women and couples. The Woman’s Condom is easy to insert, use and remove; stays in place during intercourse; and is comfortable, providing good sensation for both partners,” said Patricia Coffey, head of PATH’s Health Technologies for Women and Children Team. “Unlike other female condoms on the market, the Woman’s Condom’s main pouch is compressed into a narrow, rounded capsule which women insert like a tampon. And importantly, women can insert it themselves, without relying on their partner’s cooperation. It provides another option in cases where a male partner won’t use a male condom, and it also enables a woman to bring something to the relationship…it gives the woman a chance to take a more proactive role in protecting herself and her partner,” said Coffey. The dapivirine ring (Photo: International Partnership for Microbicides) The dapivirine ring is the first long-acting HIV prevention method designed for women. It adapts a medical device commonly used to deliver hormones to women—the vaginal ring—to deliver an ARV drug. The ring is easy for a woman to insert and remove herself, can be left in for one month, and used without the knowledge of a sexual partner. In two large Phase 3 clinical trials across four countries in sub-Saharan Africa, the ring was shown to reduce HIV infection rates by 31 and 27 percent overall. This is the first time two Phase 3 studies have confirmed statistically significant efficacy for a microbicide to prevent HIV. The studies found differences in efficacy by age and level of use: For women over 21, who appeared to use the ring more consistently, the ring reduced infection by 37 and 56 percent. The dapivirine ring could “give new hope to many women at high risk who need more and different options to effectively protect themselves from HIV,” according to IPM Founding Chief Executive Officer Dr. Zeda Rosenberg. “We are also hopeful we can learn more about how to help women who want to use the ring do so consistently, which could help increase protection.” What do these announcements mean for access to these innovative new tools? WHO/UNFPA prequalification represents an important step in increasing access to the Woman’s Condom, which is currently approved for use in China, Europe, Malawi, South Africa, and Zambia. Prequalification serves as an endorsement of quality, efficacy, and safety, particularly for nations with limited regulatory capacity. It not only enables UN agencies to procure the Woman’s Condom, but the US Agency for International Development—one of the largest female condom procurers worldwide—could rely on WHO prequalification, when a product has not been reviewed by the US Food and Drug Administration. Introduction of the Woman’s Condom in new countries could also further grow the market for female condoms broadly. Because of its innovative insertion design, the Woman’s Condom has proven popular among users and some have even called the product “elegant” and “beautiful,” according to Coffey. Thus, the Woman’s Condom could help attract new users to the female condom product category and help normalize and increase regular and consistent use of female condoms. The results from the two dapivirine ring trials are a significant step forward to getting an affordable microbicide ring into the hands of women who can benefit from it. Next, IPM will submit the dapivirine ring for regulatory review while simultaneously working with partners and governments to determine how the product can best strengthen HIV prevention efforts. IPM also plans to conduct an open-label extension (OLE) study that would provide former Ring Study participants with access to the dapivirine ring and enable IPM to collect additional information on its safety and efficacy. Such a study could help IPM better understand real-world use of the dapivirine ring, and awareness of the ring’s safety and efficacy could increase adherence among participants, as was seen in follow-up OLEs of oral pre-exposure prophylaxis. The trial results also open the door to next-generation prevention products. IPM has several other microbicide products in the pipeline, including vaginal rings combining dapivirine with other ARVs and a vaginal ring containing dapivirine and a contraceptive hormone, which would last for three months and prevent both unintended pregnancy and HIV. The combination ARV rings are in Phase 1 and preclinical development, and the dapivirine-contraceptive ring is expected to enter a Phase I trial later this year.

Photo: PATH/Will BoaseLast week, GHTC convened a panel of experts to dissect and discuss a proposal for pooled funding for global health research and development (R&D). The result of many years of brainstorming and negotiating by the World Health Organization (WHO) Consultative Expert Working Group on Research and Development (CEWG), the fund would finance neglected disease R&D at WHO’s Special Program for Research and Training in Tropical Diseases (WHO-TDR).Based on the discussion, here are my five key takeaways.1. It has been a long process and the proposal has shifted over time. A pooled R&D fund and global health observatory are the end products of a decade-long debate rooted in the struggle to expand access to antiretroviral treatment in the early 2000s. This movement led to the Doha Declaration on TRIPS and Public Health—which permitted member states to circumvent patents to expand access to medicine. Rachel Cohen, Regional Executive Director at Drugs for Neglected Diseases initiative North America, noted, “There was a growing recognition in the early 2000s of the failure of the R&D system to deliver, particularly for diseases that really fell outside the market.” Cohen further remarked, “That really produced the political impulse to start the process.” As a result of this movement, the CEWG was established in 2010 to look at ways to finance R&D for neglected diseases. The CEWG initially proposed establishing a global treaty requiring member states to dedicate .02 percent of their gross domestic product to health R&D with 20 percent of the amount raised through the treaty going to a pooled fund for neglected diseases. Over time the challenges of a treaty became clear, and the goal shifted to the current proposal to create a voluntary fund.2. The current proposal fulfills two distinct and separate functions—financing and coordination. While much of the public discussion has focused on the pooled fund, there are actually two components to the proposal: the pooled fund and an R&D observatory. The observatory would serve as an online compendium of all target product profiles (TPPs) for neglected disease products in the global pipeline. Given that TPPs contain comprehensive information on product candidates, including target pricing, target markets, access considerations, and other details, the observatory would give a comprehensive picture of the gaps in the global product development pipeline. Having identified these gaps, the public health community could then convene a dialogue to determine the most pressing priorities for research. Once those priorities are identified, the pooled fund would be deployed to fund R&D for products addressing the needs identified.3. Sufficient funding is not guaranteed, and the space is already crowded. WHO-TDR has modelled a variety of scenarios on what the fund could finance. Depending on the level of resources raised, the pooled fund could support R&D projects ranging from developing a limited number of simple repurposed drugs for around US$15 million per year to developing novel biologics and new chemical entities for around $500 million per year. While the hope is that a pooled fund would attract contributions from low- and middle-income countries that might not be able to fund their own freestanding R&D programs, it is unclear how much the fund could raise even with matching funds from existing donors. Furthermore, given that all contributions are voluntary, the fund would need to actively fundraise to support its work, which requires additional staff and resources purely devoted to these activities.According to Andrea Lucard, Executive Vice President of Medicines for Malaria Venture, concerns persist that “this actually may increase fragmentation” for R&D funding. Lucard asks further, “Are we at risk of siphoning off funds that exist from donors that are already there or donors that are close to being able to fund [existing] dynamic successful organizations?”Credit: WHO TRD4. The necessity of fundraising risks mixing the technical with the political. With the shift from a treaty to voluntary contributions comes growing tension between the observatory and pooled fund. The observatory must be driven by technical public health analyses such that the priorities it sets are credible, and the pooled fund must actively fundraise from individual donor nations. With fundraising comes the question of the level of influence the donor gets for its money. As we have seen in other pooled funds, the struggle between political and technical considerations is a very real problem. If the fundraising activities to support the pooled fund end up casting doubts on the observatory’s credibility, the observatory will have largely lost its ability to fill its mandate. In addition, tying the observatory to the fund runs the risk of losing the benefits of the observatory should the fund fail to raise sufficient funds and force the closure of the observatory as well through lack of funding.5. The observatory and pooled fund are only one approach to increasing access to medicines. While the pooled fund and observatory could potentially improve access to medicines by mobilizing more funds to directly finance R&D for neglected diseases, they would still operate within the existing overarching framework governing global health R&D. Rachel Cohen commented that the only way the pooled fund would be successful is if it is “based on a financing of R&D that disconnects, or de-links the cost of R&D from the pricing of final products.” This reflects the broader debate within the global health R&D community over exactly how to reform current policies to better promote access to medicines.The next step in the process is an open-ended meeting on May 2-4 where WHO-TDR will formally present its proposal for the observatory and pooled fund to WHO member states, who will then decide whether to move forward with a World Health Assembly resolution. Prior to that meeting, we expect that the full report and dataset underpinning WHO-TDR’s analysis will be published on March 17th.

Photo: PATH/Map Photo Agency Gilead Sciences, a California-based biopharmaceutical company, has received US Food and Drug Administration (FDA) approval for Odefsey®, a complete, single-pill regimen for HIV and AIDS. Odefsey® contains tenofovir alafenamide (TAF), a modified version of the antiviral tenofovir, used to treat HIV and AIDS and hepatitis B. TAF is highly effective at entering HIV cells, and thus can be administered in doses a mere ten percent of that required for tenofovir-based medicines. Gilead also recently received a positive opinion from the European Medicines Agency (EMA) on Descovy, another TAF-based treatment. The EMA’s recommendation will be evaluated by the European Commission, which can grant regulatory approval for the 28 European Union member states. Prior to the 2014 Ebola outbreak, the experimental therapy ZMapp had only been tested in non-human primates. The therapy, which is comprised of three antibodies against the virus, is particularly difficult to manufacture, and thus only seven patients received ZMapp during the outbreak. Now, results of the first human clinical trial of ZMapp affirms that the treatment could be an important tool in fighting Ebola. The randomized control trial was conducted by the US National Institute of Allergy and Infectious Diseases (NIAID) in partnership with the governments of Guinea, Liberia, and Sierra Leone. As the spread of Ebola slowed, so too did new cases, and thus the partners could only enroll 72 patients, one-third of the 200 for which they had planned. In the study, all patients received supportive care, including provision of fluids and electrolytes, and half of patients received three doses of ZMapp. Patients receiving ZMapp recovered much faster, in terms of symptoms and presence of the virus in the blood, and the fatality rate was lower for ZMapp recipients: 22 versus 37 percent. Despite the small trial size, NIAID Director Dr. Tony Fauci is optimistic that the FDA will “favorably consider” the results, in light of the dearth of approved Ebola treatments and positive animal study results, in which the drug was 100 percent effective. A team of Google engineers is working with the United Nations Children’s Fund (UNICEF) to develop a platform to track and predict the spread of Zika, a mosquito-borne virus linked to birth defects that was recently declared a Public Health Emergency in Latin America. The platform uses data such as weather and travel patterns to anticipate communities at-risk for Zika, and will be adaptable for use in other outbreaks. Google is also providing a US$1 million grant to UNICEF for mosquito control and behavior change efforts, with the goal of reaching 200 million people throughout the Americas. The company is also working to ensure that helpful, accurate information is readily available to all using the search engine, adding detailed information in 16 languages on Zika prevention and symptoms as well as government public health alerts.

The dapivirine ring (Photo: International Partnership for Microbicides) GHTC member the International Partnership for Microbicides (IPM) announced last week the results of two phase 3 clinical trials demonstrating that a monthly vaginal ring filled with the antiretroviral drug dapivirine can reduce the risk of HIV infection in women. The dapivirine ring is the first long-acting HIV prevention method designed for women, and IPM plans to seek regulatory approval for the product. The trials, conducted by IPM and the Microbicide Trials Network (MTN), enrolled 1,959 and 2,629 HIV-negative women and reduced infection rates by 31 and 27 percent, respectively. Efficacy rates were affected by participant age and adherence: for women over 21—who reportedly used the ring more consistently—the dapivirine ring reduced HIV infections by 37 and 56 percent in the trials led by IPM and MTN, respectively. As IPM Founding Chief Executive Officer Dr. Zeda Rosenberg stated, “These findings give new hope to many women at high risk who need more and different options to effectively protect themselves from HIV.” Researchers at the Scripps Research Institute (TSRI) and the US Army Medical Research Institute of Infectious Diseases have discovered potent antibodies against Ebola that could play a critical role in the research and development (R&D) of Ebola vaccines and treatment. The team identified 300 different antibodies against Ebola in the blood of a survivor, using molecules developed by TSRI to hunt for antibodies. Seventy-seven percent of the antibodies were able to combat the virus in mice, providing protection rates ranging from 60 to 100 percent. The three strongest antibodies all targeted distinct vulnerable spots on a certain protein found on the virus’ surface. Anti-Ebola antibodies have been used before, including in ZMapp™, an experimental treatment deployed during the 2014 Ebola outbreak. However, the number of known, effective antibodies was previously limited. This research also revealed a weak spot on the base of the aforementioned Ebola surface protein. As the virus mutates, so do the surface proteins. However, the base of these proteins remains largely the same, and thus, a weak spot on the base of the protein could be a potential target for manifold strains of the virus. US President Barack Obama is calling on Congress to allocate an additional US$200 million for the President’s Malaria Initiative (PMI), a 30 percent increase that would bring the Initiative’s budget to US$874 million. The funding would enable PMI to expand into three new countries—Sierra Leone, Cote D’Ivoire, and Cameroon; eliminate malaria in Zambia and Cambodia; scale up the use of bed nets; and advance R&D for vaccines, drugs, diagnostics, and vector control methods. As resistance grows to both malaria treatments and insecticides, the need for R&D remains critical. Further, resistance to the leading antimalarial was first reported in Cambodia and the most virulent strains are found on the border between Cambodia and Thailand. Thus, eliminating malaria in Cambodia would impede the global spread of drug resistance. With this new funding, PMI would be able to reach an additional 70 million people, ultimately reaching 92 percent of those in malaria endemic regions.