The following article is adapted from "Lenacapavir全球普及惹争议，是否应该探索强制许可？" [https://mp.weixin.qq.com/s/T7QA2TpFBsqBRITcI_q4yg]

Lenacapavir, a well-known drug since its rise to fame in June 2024, has been the focus of attention due to its groundbreaking results in achieving zero HIV infections with just one injection every six months. In the medical field, it is rare to find a new drug trial report with a 100% efficacy rate.

In the PURPOSE 1 study conducted on young women in South Africa and Uganda, the Lenacapavir group had a 100% lower HIV infection rate compared to the PrEP drug group. Similarly, in the PURPOSE 2 study targeting gay, bisexual, and gender-diverse populations, the infection rate was 89% lower. The superior performance of these injectable PrEP drugs compared to daily oral PrEP medications is likely due to people finding them easier to use rather than the drugs themselves being more potent. Given the severity of the global HIV epidemic, there is a growing demand for either immediate sale of the drug or its generic production.

In response to this issue, Gilead, the company that developed the drug, has made a statement expressing its commitment to "ensuring broad and sustainable access to Lenacapavir for PrEP globally" and "ending new HIV infections worldwide." While this has generated enthusiasm among the public, actual progress has been limited. Critics argue that if the voluntary licensing system for generic drug manufacturers does not improve, countries should explore compulsory licensing.

In April 2025, the journal "Clinical Infectious Diseases" published two opinion articles presenting contrasting viewpoints on this matter.

Gilead: Faster Progress Than Any Other HIV Drug

Dr. Jared Baeten, Senior Vice President of Clinical Development at Gilead Sciences and former academic researcher for HIV prevention in African countries, elaborated on Gilead's stance in developing Lenacapavir. Dr. Baeten takes pride in various aspects of the Lenacapavir research process, which focused on populations most in need of improved HIV prevention and involved interactions with advocates, scientists, regulators, and policymakers. The uniqueness of the PURPOSE 1 study lies in its inclusion of adolescents, pregnant women, and breastfeeding mothers, while the PURPOSE 2 study features a more diverse sample, including transgender men and non-binary individuals.

Lenacapavir's global accessibility planning began in 2022 and involved extensive consultations. "Our plans for low- and lower-middle-income countries follow four key priorities: rapidly providing Lenacapavir, ensuring sufficient quantities to meet demand, pricing for broad availability, and collaborating with a multi-sector ecosystem upon approval," stated Dr. Baeten.

Lenacapavir has been swiftly submitted for approval to drug regulatory authorities in the United States and Europe. In addition to considering whether Lenacapavir should be marketed in the European Union, the European Medicines Agency will provide regulatory advice on the use of Lenacapavir in the global south. They will follow the same procedure as with the dapivirine vaginal ring, which facilitates subsequent approvals by the World Health Organization and regulatory agencies in low- and middle-income countries, as many of these countries lack the capacity to review all new drugs independently.

Voluntary licensing agreements have been signed with six generic drug manufacturers, which, according to Dr. Baeten, is faster than the progress made with any previous HIV medication.

Critics: Licensing Agreements Harm Broad Drug Accessibility

Another commentary comes from Dr. Andrew Hill, Dr. Mark Siedner, Dr. Cassandra Fairhead, and Dr. François Venter, whose analysis was supported by the International Treatment Preparedness Coalition. Dr. Andrew Hill and his colleagues argue that the terms of the licensing agreements will harm broad accessibility of the drug.

Under the licensing agreement, six generic drug manufacturers will receive support to develop technical expertise to independently produce Lenacapavir and market it to 120 countries. These generic companies will not have to pay patent fees to Gilead and can determine the price of Lenacapavir themselves. In the rest of the world, Gilead will have exclusive marketing rights for Lenacapavir and will decide its price.

Gilead has listed 120 high-burden and resource-limited countries, but Hill points out that they have not yet explained their criteria. These countries are mostly located in Africa, Asia, the Caribbean, and Eastern Europe. While almost all countries classified as low-income or lower-middle-income by the World Bank are included, the approach for upper-middle-income countries is inconsistent. Sub-Saharan African countries will be included in the agreement, but most Latin American countries are excluded. Thailand is included, but Malaysia and China are not. Hill notes that Brazil, Colombia, Guatemala, and Algeria will not have access to generic Lenacapavir, despite having lower average incomes than some countries included in the agreement, such as Guyana and Kazakhstan.

According to estimates by Hill, by 2023, the excluded middle-income countries will account for over 200,000 new HIV infections, representing 23% of the global total. In many of these countries, the incidence rates among key populations are particularly high. For example, in Brazil, the incidence rate among men who have sex with men (MSM) and transgender women is estimated to be 9.2%, while in Peru, it is 11.9% and 2.9%, respectively. Among people who inject drugs, the annual incidence rate is 8.1% in China, 6.9% in Bulgaria, 4.5% in Iran, and 3.5% in Mexico.

Despite over half of the participants in the PURPOSE 2 study being recruited from Brazil, Peru, Argentina, and Mexico, these countries do not have access to generic PrEP. Hill argues that unless Gilead sets a cost-effective price for its proprietary Lenacapavir product in these countries, the company may be in violation of the Helsinki Declaration's ethical guidelines for conducting research. The declaration states that vulnerable populations should only be included in research if they "stand to benefit from the knowledge, practices or interventions that result from the research."

While 2028 is considered the most likely date for widespread availability of generic Lenacapavir, Hill believes that reaching agreements with more than six generic manufacturers could enable faster, large-scale production. Although three of these generic companies are based in India, other experienced Indian manufacturers have been excluded. The remaining three companies are located in Pakistan, Egypt, and the United States. Many experts argue that not including any manufacturers from sub-Saharan Africa is a missed opportunity to support self-sufficiency in the region.

Affordability is Key to Accessing Medical Services

The pricing of Lenacapavir will be a crucial factor in determining the impact of the twice-yearly PrEP medication on the global epidemic. Jared Baeten from Gilead Sciences provided some general information about the company's pricing strategy but did not give any specific figures. He stated that in the 120 countries/regions covered by the voluntary license, the pricing of Lenacapavir will not bring any profit to the company. This policy will apply during the period between the approval by drug regulatory authorities and the actual launch of generic drugs, making Gilead's pricing potentially most critical in 2026 and 2027. After that, the prices will be determined by each generic drug manufacturer, and he hopes that the prices will decrease over time, as has been the case with generic PrEP pills.

However, in countries excluded from the licensing agreement, Gilead will continue to set prices independently. Baeten indicated that the company is "exploring a range of innovative strategies to support access to Lenacapavir for PrEP in upper-middle-income countries, including tiered pricing" - a strategy where the same drug is sold at different prices in different countries, usually based on income levels or market conditions. He mentioned that consultations and planning are underway in Latin American countries participating in the PURPOSE 2 study.

Lenacapavir, was initially designed to treat HIV, particularly in patients with resistance to existing antiretroviral medications. Currently, the drug has received approval from regulatory authorities for the treatment of heavily treatment-experienced patients with multidrug-resistant HIV. In high-income countries, Gilead charges approximately $40,000 per year for this niche product. However, Baeten has explicitly stated that this pricing will not serve as a reference point for the cost of Lenacapavir as PrEP in any country. Lower prices would facilitate the development of a larger market for injectable PrEP, but the extent to which Gilead is prepared to reduce the price remains unclear.

According to calculations by Hill, generic manufacturers could produce Lenacapavir at a price of approximately $95 per year, assuming a market of 1 million PrEP users. If the market size expands to 10 million PrEP users, the price could drop to $40 per year. These projections are based on the assumptions that voluntary licensing agreements are in place and that there is fierce competition among generic manufacturers. A modeling study has found that for Lenacapavir to be cost-effective in South Africa, an upper-middle-income country, its annual cost would need to be less than $106. In contrast, for Zimbabwe, a lower-middle-income country, the annual cost should not exceed $21.

Baeten has also stated that the company is committed to supplying its own manufactured Lenacapavir in low- and middle-income countries until generic manufacturers are ready to produce the drug. During this period, Gilead will be able to provide the medication for up to 2 million people. Furthermore, patients participating in the PURPOSE 1 and 2 studies will continue to receive Lenacapavir until the drug becomes available for routine use.

Baeten primarily focuses on the work done by the company under licensing agreements to cover the period until the production of generic Lenacapavir. However, the article does not directly address the criticisms of the licensing agreements themselves, many of which have been previously raised by advocacy groups and the Joint United Nations Programme on HIV/AIDS (UNAIDS).

Both articles were written before Donald Trump's return to the White House, when most of the United States' global health programs were invested in this funding. This will have profound implications for the prospects of Lenacapavir, as it removes key players who might have been prepared to place large orders for the product with generic manufacturers, which would give manufacturers the confidence to invest in production and help lower prices.

Over the past decade, more than 90% of PrEP in the rollout of oral PrEP has been funded by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR). However, PrEP programs have been explicitly excluded from any continuation of PEPFAR, and other major players such as the Global Fund have been weakened by recent events, as a significant portion of their funding comes from the U.S. government. It remains unclear whether national governments are willing or able to step in and pay for PrEP pills themselves, let alone injectable PrEP.

Compulsory Licensing May Be Necessary to Eliminate HIV Transmission

According to Hill, compulsory licensing may be required if Gilead does not modify its voluntary licensing agreement for Lenacapavir. Compulsory licensing is a legal mechanism that allows governments to authorize companies to produce or import patented medicines without the consent of the patent holder. It is typically invoked in cases of public health emergencies, anti-competitive behavior, or when the prices of patented medicines are high or unavailable. Between 2001 and 2007, several countries, including Brazil, Thailand, and Malaysia, used compulsory licensing to force access to antiretroviral drugs. However, in recent years, few countries have dared to take such action. A notable exception is Colombia, an upper-middle-income country that was excluded from the voluntary licensing agreement for dolutegravir. In 2024, Colombia issued a compulsory license for this critical HIV treatment drug. The threat of compulsory licensing can also serve to lower prices.

Hill and colleagues emphasized the urgency of collaboration among various stakeholders to guarantee the widespread availability of Lenacapavir. They stressed that without this coordinated approach, it may be challenging to eliminate HIV transmission on a global scale. The authors also suggested that significant modifications to the existing licensing agreements might be necessary, and compulsory licensing could be required if these changes are not implemented.

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