The Drugs for Neglected Diseases initiative (DNDi), on behalf of a consortium of 26 African and global research organizations, expressed concern today 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.
Nirmatrelvir/ritonavir has emerged as one of the most promising antiviral treatments for outpatients with mild-to-moderate COVID-19, reducing the risk of hospitalization or death by up to 89% in patients at high risk of severe disease. This and other novel oral antiviral treatments will be a critical part of the therapeutic arsenal to treat patients today and prepare for future waves. However, the treatment must be taken within 3-5 days of symptom onset to be effective and reaching patients this early in the course of their infection is challenging.
But an interim analysis done in the context of the ongoing ANTICOV clinical trial conducted in 10 African countries showed that of the 1,180 patients enrolled, more than half present for care after day 5 (mean 5.1 days, median 5.0 days). This means that even in a clinical trial setting, more than half of patients would not benefit from nirmatrelvir/ritonavir.
To overcome this challenge, it is necessary to explore whether using nirmatrelvir/ritonavir with other drugs could widen the ‘treatment window’ to at least 7 days and be beneficial for immune-suppressed patients who are the most vulnerable to disease progression but were excluded from phase 3 trials (as such, there is no robust evidence available to guide the therapeutic strategies).
DNDi and academic investigators from large university hospitals in Europe have separately approached Pfizer about potential collaborations on combination studies in LMICs but Pfizer has declined to provide access to the drug for research purposes.
‘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,’ said Dr Nathalie Strub-Wourgaft, Director of DNDi’s COVID-19 Response and one of the coordinators of the ANTICOV Consortium. ‘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.’
DNDi is also concerned about additional hurdles in obtaining generic versions of the drug to conduct the relevant combination studies via ANTICOV. For example:
- The terms of the Pfizer/Medicines Patent Pool (MPP) licensing agreement 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.
‘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, Leader, Global Health and Infectious Diseases Research Group, 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.’
DNDi, the ANTICOV Consortium, and other clinical researchers therefore ask Pfizer to:
- Agree to provide access to nirmatrelvir/ritonavir (Paxlovid) for the DNDi-coordinated ANTICOV trial and other relevant clinical trials;
- 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.
A not-for-profit research and development organization, DNDi works to deliver new treatments for neglected patients, those living with Chagas disease, sleeping sickness (human African trypanosomiasis), leishmaniasis, filarial infections, mycetoma, paediatric HIV, hepatitis C, and dengue. DNDi is also coordinating the ANTICOV clinical trial to find treatments for mild-to-moderate COVID-19 cases in low- and middle-income countries. Since its inception in 2003, DNDi has delivered nine new treatments to date, including new drug combinations for kala-azar, two fixed-dose antimalarials, and DNDi’s first successfully developed new chemical entity, fexinidazole, approved in 2018 for the treatment of both stages of sleeping sickness. dndi.org
Frédéric Ojardias (Geneva)
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Ilan Moss (New York)
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 See FDA News Release, December 22, 2021: Coronavirus (COVID-19) Update: FDA Authorizes First Oral Antiviral for Treatment of COVID-19 | FDA
 Pfizer-MPP License and Sublicense (Execution Version), November 2021.