Pfizer has so far refused an invitation from the Geneva-based Drugs for Neglected Diseases Initiative (DNDi) to cooperate on a study exploring whether the treatment window of its successful antiviral drug, Paxlovid, could be extended from 5-7 days using another drug compound in addition, Dr Nathalie Strub-Wourgaft, Director of DNDi’s COVID-19 Response, told Health Policy Watch. 

DNDi wants to test if the key active ingredient of Paxlovid, nirmatrelvir, could be offered in combination with an inhaled corticosteroid, budesonide, in order to extend the treatment window of the life-saving COVID treatment by two more days, Strub-Wourgaft said in an interview. 

Extending the treatment window is critical for patients in low-income countries because the currently-approved formulation of Paxlovid must be commenced within 3-5 days of COVID symptoms. 

Meanwhile ANTICOV, a major DNDi-sponsored trial of COVID treatments underway in ten African countries, has revealed that one-half of COVID patients present for treatment after the five day cut-off date.  

That makes the current Paxlovid combination less than suitable for low- and middle-income country (LMIC) conditions, said Strub-Wourgaft. She is one of the coordinators of the ANTICOV Consortium, a group of 26 African and global research organizations engaged in the clinical trial research on novel COVID drugs for LMICs.  

On 15 March, DNDi issued a  public statement expressing its concern that “efforts to conduct urgently needed studies in low- and middle-income countries (LMICs) utilizing the novel oral antiviral, nirmatrelvir/ritonavir (Paxlovid), are being blocked by Pfizer, which developed the drug.

Paxlovid, which uses the common HIV drug ritonavir in combination with nirmatrelvir, has been found to reduce the risk of hospitalization or death by a stunning 89% in patients at high risk of severe COVID-19 disease. But the treatment needs to be taken within three to five days of patients developing symptoms.

According to DNDi, “an interim analysis done in the context of the ongoing ANTICOV clinical trial conducted in 10 African countries showed that of the 1180 patients enrolled, more than half present for care after day 5.

“To overcome this challenge, it is necessary to explore whether using Paxlovid with other drugs could widen the ‘treatment window’ to at least seven days,” DNDi said in its statement.

DNDi also wants to investigate if the drug could be “beneficial for immune-suppressed patients who are the most vulnerable to disease progression but were excluded from phase 3 trials.” 

DNDi, a Geneva-based not-for-profit research and development organisation, works to deliver new treatments on neglected diseases and serving neglected groups in low- and middle-income countries.

Still looking for ways to access nirmatrelvir

Strub, in her comments to Health Policy Watch, suggested that DNDi, which has a good track record of building cooperation with the pharma industry, was still trying to obtain the drug somehow – or even persuade Pfizer to collaborate. 

“We would like to test nirmatrelvir/ritonavir in combination, as well, with inhaled budesonide or maybe fluoxetine (brand name Prozac),” said Strub-Wourgaft. 

“We issued a statement to say that we had asked Pfizer to get access to nirmatrelvir, to work with us on this trial. They denied. We’re continuing to try to get access to this drug.”

“We think this [combination] would extend the window of treatment to seven days of symptoms. In the study that they [Pfizer] have done, which is a great study showing really fantastic results, they looked at patients who had five days of symptoms before they were enrolled. 

“And we have seen for now, in our study in Africa, that half of the patients come after five days of symptoms,” she said. 

Such delays are typical because COVID diagnosis and treatment services are less widely available and it thus takes people longer to get diagnosed, even if they are symptomatically ill.  

“There are critically important public health research questions that must be answered quickly – particularly in low- and middle-income countries where access to vaccines remains low,” added Strub-Wourgaft, in the DNDi statement. 

“It is difficult to understand any rationale for refusing to cooperate in the midst of a global pandemic, and this sets a dangerous precedent since there are many other promising antivirals in the pipeline and these novel treatments will also require follow-on research to determine their optimal use in resource-limited settings.”

MPP deal with Pfizer – not enough 

Pfizer recently signed a deal  with another Geneva-based group, the non-profit Medicines Patent Pool, that will allow  35 new manufacturers to produce and supply generic versions of Paxlovid to some 95 low- and middle income countries – in what the company has said is a move to lower the drug’s cost and expand access in low-income countries. 

But that deal has also been criticised for failing to cover dozens of other middle-income and upper-middle income countries that will have to purchase patented versions of the drug.  

Although Pfizer had also said that it would create a tiered pricing system for Paxlovid, drug price advocates say that the price remains too high in many settings. In the United States, the government pays Pfizer about $530 for a five day course, although the pills also are in short supply in some US communities.   

In addition, most  of Pfizer’s Paxlovid supply for the first half of 2022 has already been bought up by rich countries, meaning that LMICs will only be able to get about 10 million doses of the drug in the near term.   

Pfizer’s Paxlovid Goes Generic in 95 Countries – Too Little, Too Late, say Access Advocates

However, even considering the MPP deal and other preferential pricing mechanisms, the fact remains that the version of Paxlovid currently being produced is not an optimal fit for many LMICs, Strub-Wourgaft said.  

“So  for now, if we were to be able to give them Paxlovid, under the current conditions, half of them would not even have access,” she told Health Policy Watch.

MPP deals with generic manufacturers may not enable supplies to ANTICOV 

DNDi is also concerned about the potential difficulty of obtaining generic versions of Paxlovid  to conduct the new ANTICOV combination studies, the company has said. 

“The terms of the Pfizer/Medicines Patent Pool (MPP) licensing agreement to the new generics manufacturers could be interpreted to mean that sub-licensees cannot provide nirmatrelvir/ritonavir for use in the sorts of combination studies that DNDi and others wish to conduct, unless they have explicit written approval from Pfizer.

“Some generic manufacturers are also encountering difficulties obtaining Paxlovid as a ‘reference drug’ so that they can conduct the necessary bioequivalence studies to show regulators that their generic version has the same effect in the body, effectively blocking availability of generics for both research and clinical use”, DNDi added in its statement. It has therefore asked Pfizer to not only provide access to nirmatrelvir/ritonavir (Paxlovid) for the DNDi-coordinated ANTICOV trial and other relevant clinical trials, but also to:

• Remove any ambiguities or restrictions in the Pfizer-MPP licensing agreement that could prevent sub-licensees from supplying such research studies (or publicly clarify that no such restrictions exist);
• Provide access to Pfizer’s originator product as a ‘reference drug’ so that any interested generic manufacturer can conduct the necessary bioequivalence studies for regulatory approval; and
• Allocate sufficient quantities of Paxlovid specifically for LMICs and remove all barriers to access to generic nirmatrelvir/ritonavir to enable scale up for care and treatment in LMICs.

“Every effort should be made to ensure that clinical studies for COVID-19 treatment are conducted in low- and middle-income countries, and that any products developed reach vulnerable populations,” said Dr John Amuasi, head of the Global Health and Infectious Diseases Research Grou at Kumasi Center for Collaborative Research in Tropical Medicine in Ghana and a principal investigator for ANTICOV. 

“We must not arrive at a situation where research priorities are determined by the actions or inactions of any company.”

Pfizer response – committed to well-controlled trials

In response to a request from Health Policy Watch, a Pfizer spokesperson did not provide any clarification of the reasons behind the company’s refusal to participate in the DNDi trial – aimed a making the treatment more suitable to low-income settings.

“Pfizer appreciates the importance of gathering additional data and information for governments to help maximize the public health response to the COVID-19 pandemic,” said the spokesperson, adding that the company is committed to “well-controlled, hypothesis-driven clinical studies that can provide data that will be accepted by global regulatory agencies.

“Additional studies of PAXLOVID are underway or are being explored, and we will continue to share information as we have it,” the spokesperson added.

In addition, “Right now, we are focusing our efforts and resources in a way that maximizes availability of our overall supply, to help ensure access to patients as quickly as possible,” the spokesperson said, noting that the company remains “confident” in the clinical trial results, which showed an 88-89% efficacy rate for the drug, when it was administered to non-hospitalized, high-risk patients within 3-5 days of symptom onset.

-Updated 9 April with correction on the price of Paxlovid paid by the US government for patients in the USA and on 11 April with details of Pfizer response.

Image Credits: Bobbi-Jean MacKinnon, DNDI/Twitter, DNDi.