Merck expands manufacturing for molnupiravir. But questions remain.

On Wednesday, Merck announced that it has signed a voluntary licensing agreement with the Medicines Patent Pool for broader access to molnupiravir — its new antiviral pill against COVID-19 — in 105 low- and middle-income countries, following local regulatory approval. This means other companies will be allowed to manufacture generic versions of the drug to broaden access to it.

The deal allows for further manufacturing of the drug outside India, where the company has voluntary licensing agreements with eight Indian generic manufacturers, the first five of which were announced in April 2021.

Molnupiravir, which was invented at Emory University with United States government funding, has since been licensed to Ridgeback Biotherapeutics, which entered into an agreement with Merck to develop the drug.

Merck, Ridgeback Biotherapeutics, and Emory University won’t be receiving royalties for sales of molnupiravir under the agreement with MPP “for as long as COVID-19 remains classified as a Public Health Emergency of International Concern by the World Health Organization,” according to a press release.

However, Merck’s deal with MPP still excludes several middle-income countries, including Latin American countries such as Brazil, Argentina, and Peru, which are currently in the top 10 of countries with confirmed deaths per million.

Merck spokesperson Melissa Moody said they are working through a “multifaceted strategy,” including voluntary licensing, tiered or differential pricing, and coordinating supply and purchase agreements and allocation processes “to ensure timely access to molnupiravir.” But Merck has not responded yet as to why certain middle-income countries are excluded from the licensing agreements.

An MPP spokesperson told Devex that even with the signing of the licensing agreement with Merck, “it does not mean we will stop there, MPP with all its licences ... will [work] on expansion of territory.”

Added to the question of access in middle-income countries, other concerns remain on the drug’s safety and efficacy. Some access advocates have also pointed out long-standing issues of weak regulatory oversight and that the manufacturing capacity in lower-income countries is still not prioritized.

Early access efforts may not be enough

Access to medicine advocates have expressed concerns over equal access to the drugs globally, fearing high-income countries will once again be prioritized for a potential COVID-19 medical intervention.

Before the Merck-MPP announcement, Brook Baker, senior policy analyst for Health GAP, told Devex that expanding manufacturing of the drug outside of India will help diversify and democratize generic manufacturing capacity, and reduce overreliance on Indian companies, especially given the Indian government’s history of imposing export controls on medical products, including, most recently, COVID-19 vaccines.

However, with Merck’s agreement with MPP, generic sales of the drug can only be done in countries where Merck has no pending or approved patent for the drug, or where a compulsory license is issued.

“The ACT Accelerator and others should demand that Merck lift its territorial restrictions and agree to not enforce its patent and regulatory data monopolies and excluded countries with blocking patents should be supported to issue compulsory licenses,” he said.

Baker is concerned that demand in middle-income countries that are not part of Merck’s licensing agreements “will not be met” and that the company will first serve the needs in the U.S. and other high-income countries.

Merck expects to produce 10 million treatment courses of molnupiravir in 2021, and 20 million in 2022, according to Reuters. The U.S. government has already closed a deal for 1.7 million courses of the drug, pending regulatory approval. Other countries have also reportedly made deals or are in negotiations with the company.

Health advocates have also called on the Bill & Melinda Gates Foundation to be bolder in its response by pushing for an intellectual property rights waiver at the World Trade Organization and demanding that Merck sign voluntary licenses including all countries.

The foundation last week announced $120 million in funding to scale up the drug’s generic production and access for lower-income countries. It is also supporting some generic manufacturers with voluntary license agreements with Merck with grants amounting to $2.4 million to help them prepare for WHO prequalification and to start manufacturing once this has been granted, a spokesperson told Devex.

But advocates say these measures do not address issues such as weak regulatory oversight or insufficient manufacturing capacity endured by recipient countries. They also don't dispel some of the doubts over the drug’s effectiveness, and may only be adding to the hype around it while solid evidence remains absent.

“My concern is mainly about a hype about a given product without evidence of added-therapeutic value. We already had a craze around remdesivir only to acknowledge a more limited effectiveness later on,” Jaume Vidal, senior policy adviser for Health Action International, told Devex via email in response to the Gates Foundation announcement.

“Again, we see how public announcements that ignore very basic information, such as the actual cost of producing Molnupiravir or geographical limitations on any MPP-brokered license, are being taken at face value only to be nuanced, corrected, or simply withdrawn with much less fanfare,” he added.

Safety concerns and other lingering questions

Apart from issues around accessibility, some experts have raised questions about the drug’s safety and efficacy. Merck’s press release this month said the drug halved the risk of hospitalization and death among mild to moderate, nonhospitalized COVID-19 patients based on an interim analysis of its phase 3 clinical trial, but scientists want more peer-reviewed data.

“They all keep saying it is safe, but not much has been published (and peer reviewed) yet by researchers that don't have a conflict of interest. I'd like to see results from independent researchers. Of course, I hope it is safe and effective, but again, I'd like to see more independent data,” Dr. Katherine Seley-Radtke, professor of chemistry and biochemistry at the University of Maryland, Baltimore County, and president-elect of the International Society for Antiviral Research, told Devex via email.

Merck’s Moody didn’t specify when exactly the company will be publishing full results of the study, only mentioning to Devex the interim analysis of its phase 3 trial and that findings will be presented in an “upcoming medical meeting.”

A key safety concern is that the drug could cause mutations that could result in birth defects. Merck has responded to these concerns, saying that “we’re very comfortable that the drug will be safe if used as intended.”

Additionally, Moody said that safety and laboratory data from trials to date have “have provided no evidence for unexpected findings or trends observed at any of the doses studied.” She said precautions were made to ensure pregnant women and those planning to get pregnant were not enrolled in the drug’s clinical study “due to the unknown effects of new drugs on pregnancy.” Women enrolled in the study were also asked to use birth control during the study’s duration to “guard against becoming pregnant while taking an investigational drug.”

“We are assessing the developmental and reproductive toxicity of molnupiravir in animal studies and will report all necessary information in the prescribing information to ensure the safe use of molnupiravir for the treatment of COVID-19,” she said.

Meanwhile, two Indian drug manufacturers have requested approval to end late-stage trials of the drug for moderate COVID-19 patients earlier this month after reportedly not showing “significant efficacy” for this particular population.

Moody said the company cannot speak for the results of the studies in India, but pointed out the difference in definitions of moderate disease in India and the U.S. As per guidance from India’s COVID-19 National Taskforce, moderate disease “reflects more advanced respiratory symptoms requiring hospitalization,” she said.

Cautious optimism

Seley-Radtke said the attention the drug is receiving worldwide isn’t surprising given everyone’s desperation to “get back to normal,” in addition to how the parties involved in the drug’s development “are hyping it big time.” But she said it remains to be seen how safe and effective the drug will be and how much impact it will have.

“At this point, I'm cautiously optimistic, but again, it is too early to tell for sure,” she said.

Meanwhile, Unitaid is reportedly eyeing to purchase the drug at $10 per course of treatment — although the organization has yet to confirm anything — to distribute to low- and middle-income countries in 2022, pending regulatory approvals and WHO’s recommendation.

Unitaid spokesperson Herve Verhoosel told Devex in an email that preparatory work in making the drug widely available is being done even at the risk that the product may not be recommended for use. But “such risk, while mitigated, is in any case only at market level, not clinical, as [the] product would not be deployed if not recommended.”

“But, in a pandemic like this one, we cannot afford to wait until such a potential treatment (and other promising ones already in last clinical stages) are recommended for use to start addressing access barriers, because then we would need months before the product can be made available in low and middle-income countries,” he added.

And while the product is currently not widely present in the market — because it’s an investigational product unlike hydroxychloroquine and ivermectin — once authorities approve molnupiravir, “one could indeed expect to see hoarding procurement and that is precisely why we cannot wait to anticipate and prepare some interventions, conditional to recommendation, if we are to avoid the inequity gap,” Verhoosel said.