Candidate: PAXLOVID™ (nirmatrelvir; PF-07321332)
Type: Oral SARS-CoV2-3CL protease inhibitor designed to block the activity of the main protease enzyme that the coronavirus needs to replicate. Co-administration with a low dose of ritonavir is expected to help slow the breakdown of PF-07321332 in order for it to remain active in the body for longer periods of time at higher concentrations to help combat the virus, according to Pfizer.
2022 Status: 35 Companies to Manufacture Generic Version—The Medicines Patent Pool (MPP) said March 17 that it signed agreements with 35 companies to manufacture the generic version of Pfizer’s COVID-19 pill, marketed as PAXLOVID, in 95 low- and middle-income countries.
The non-exclusive sublicence agreements result from a voluntary licensing agreement signed by MPP and Pfizer in November 2021 that was designed to enable the supply of the medicines to countries comprising approximately 53% of the world’s population. The generic manufacturers agreed to produce the raw ingredients for the Pfizer pill and/or the finished drug itself co-packaged with ritonavir.
Six companies will focus on producing the drug substance, nine companies will produce the drug product and the remainder will do both. The companies span 12 countries: Bangladesh, Brazil, China, Dominican Republic, Jordan, India, Israel, Mexico, Pakistan, Serbia, Republic of Korea, and Vietnam. A licence has also been offered to a company in Ukraine—an offer it cannot sign due to the Russian invasion, but which MPP said will remain available.
2021 Status: FDA AUTHORIZES EMERGENCY USE—The FDA on December 22 authorized the emergency use of PAXLOVID™ (nirmatrelvir [PF-07321332] tablets and ritonavir tablets) for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg [88 lbs]) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.
Treatment with PAXLOVID includes nirmatrelvir, a Pfizer-developed novel main protease (Mpro) inhibitor specifically designed to block the activity of the SARS-CoV-2 Mpro enzyme needed by the virus for replication.
Pfizer said it was prepared immediately to begin delivery of PAXLOVID in the U.S. Last month, the U.S. government agreed to buy 10 million doses of PAXLOVID for $5.29 billion beginning later this year and concluding in 2022. Also in 2022, Pfizer said, it plans to apply with the FDA for potential full regulatory approval.
CHMP Recommends PAXLOVID—The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) on December 16 recommended the use of PAXLOVID to treat adults with COVID-19 who do not require supplemental oxygen and who are at increased risk of progressing to severe disease. The European Commission has final say over a conditional marketing authorization for PAXLOVID.
Final Results Show Risk Reduction—Pfizer announced final results December 14 from an analysis of all 2,246 adults enrolled in its Phase II/III EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) trial (NCT04960202) of PAXLOVID. The results were consistent with the interim analysis announced in November 2021, showing PAXLOVID significantly reduced the risk of hospitalization or death for any cause by 89% compared to placebo in non-hospitalized, high-risk adult patients with COVID-19 treated within three days of symptom onset.
PAXLOVID also reduced the risk of hospitalization or death for any cause by 88% compared to placebo in patients treated within five days of symptom onset—a secondary endpoint, and an increase from the 85% observed in the interim analysis. Pfizer said 0.7% of patients who received PAXLOVID were hospitalized through Day 28 following randomization (5/697 hospitalized with no deaths), compared to 6.5% of patients who received placebo and were hospitalized or died (44/682 hospitalized with 9 subsequent deaths).
The EPIC-HR data has been shared with the FDA as part of an ongoing rolling submission for Emergency Use Authorization (EUA), Pfizer added.
Canada Buys 1M Initial Courses—The government of Canada said December 3 it agreed to purchase an initial 1 million courses of PAXLOVID for an undisclosed price, pending authorization by Health Canada. Pfizer submitted a rolling submission for authorization to Health Canada earlier the week of November 29, the government added.
U.S. BUYS 10M DOSES FOR $5.29B—The U.S. government agreed to buy 10 million doses of PAXLOVID for $5.29 billion beginning later this year and concluding in 2022, subject to regulatory authorization from the FDA, Pfizer said November 19. The company added that it has also entered into advance purchase agreements with several other countries and has reached out to approximately 100 countries worldwide.
Pfizer also committed to offering PAXLOVID through a tiered pricing approach based on the income level of each country “to promote equity of access across the globe,” with high- and upper-middle income countries to pay more for the COVID-19 pill than lower income countries.
PFIZER SEEKS EUA—Pfizer said November 16 that it submitted to the FDA an application for Emergency Use Authorization (EUA) for PAXLOVID for the treatment of mild to moderate COVID-19 in patients at increased risk of hospitalizations or death. The submission included clinical data from the Phase II/III EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) trial (NCT04960202) interim analysis, showing that PAXLOVID reduced the risk of hospitalization or death by 89% from any cause compared to placebo in non-hospitalized high-risk adults with COVID-19 who were treated within three days of the onset of symptoms.
A rolling submission of non-clinical data for PAXLOVID was initiated with the FDA in October 2021, Pfizer said.
The company added that it has signed a voluntary licensing agreement with the Medicines Patent Pool (MPP) to help expand access, pending regulatory authorization or approval, in 95 low- and middle-income countries that account for approximately 53% of the world’s population.
POSITIVE PHASE II/III RESULTS; EUA SUBMISSION “ASAP”–Pfizer reported strong positive Phase II/III results November 5 showing that its oral antiviral, renamed PAXLOVID™ (PF-07321332) reduced the risk of hospitalization or death by 89% from any cause compared to placebo in non-hospitalized high-risk adults with COVID-19 who were treated within three days of the onset of symptoms.
Pfizer also reported that 0.8% of patients who received PAXLOVID™ were hospitalized through Day 28 following randomization (3/389 hospitalized with no deaths), compared to 7.0% of patients who received placebo and were hospitalized or died (27/385 hospitalized with 7 subsequent deaths).
Similar reductions in COVID-19-related hospitalization or death were observed in patients treated within five days of symptom onset, according to Pfizer: 1% of patients who received PAXLOVID™ were hospitalized through Day 28 following randomization (6/607 hospitalized, with no deaths), compared to 6.7% of patients who received a placebo (41/612 hospitalized with 10 subsequent deaths).
Pfizer said that based on the positive results, it will end further enrollment into EPIC-HR—a decision recommended by the study’s independent Data Monitoring Committee, and FDA consultation. The pharma giant said it plans to submit data from EPIC-HR as part of its ongoing rolling submission to the FDA for an EUA “as soon as possible.”
Global Phase II/III Trial Launches—Pfizer said September 27 that it launched the Phase II/III EPIC-PEP (Evaluation of Protease Inhibition for COVID-19 in Post-Exposure Prophylaxis) trial, designed to evaluate PF-07321332 plus a low dose of ritonavir for the prevention of COVID-19 infection. The trial is enrolling individuals who are at least 18 years old and live in the same household as someone with a confirmed symptomatic SARS-CoV-2 infection.
The randomized, double-blind, placebo-controlled study plans to enroll up to 2,660 healthy adults who will be randomly assigned (1:1:1) to receive PF-07321332/ritonavir or placebo orally twice daily for 5 or 10 days. The primary objective will assess safety and efficacy for the prevention of confirmed SARS-CoV-2 infection and its symptoms through Day 14.
EPIC-PEP is the third study launched in the EPIC global clinical research program assessing PF-07321332. EPIC includes a Phase III trial (NCT04960202) in SARS-CoV-2 infected patients who are at high risk of severe illness (including hospitalization or death), which began in July 2021, and another trial (NCT05011513) in infected patients who are at standard risk (i.e., do not have risk factors for severe illness), which began in August 2021.
Results from the Phase I trial showed that PF-07321332 was safe and well tolerated, Pfizer said.
Phase I Trial Begins—Pfizer said March 23 that it had progressed to multiple ascending doses after completing the dosing of single ascending doses in a Phase I trial (NCT04756531) in healthy adults to evaluate the safety, tolerability, and pharmacokinetics of PF-07321332. The randomized, double-blind, sponsor-open, placebo-controlled, single- and multiple-dose escalation study is being conducted in the U.S. after in-vitro studies showed that PF-07321332 was a potent protease inhibitor with potent anti-viral activity against SARS-CoV-2.
The structure of PF-07321332, together with the preclinical data, was set to be shared in a COVID-19 session of the Spring American Chemical Society meeting on April 6.
2020 Status: Pfizer on March 13 restated earlier plans to develop its own antivirals against COVID-19 as well as collaborate with BioNTech on an mRNA vaccine to prevent the disease. The pharma giant also articulated five principles it said would govern its drug and vaccine development activity: Sharing tools and insights; creating “a SWAT team” of experts focused solely on fighting the pandemic; applying its drug development expertise; offering any excess manufacturing capacity to support other drug and vaccine developers; and building a “cross-industry rapid response team of scientists, clinicians and technicians” to improve response to future epidemics.
Earlier in March, Pfizer said it completed a preliminary assessment of antiviral compounds that were previously in development and that inhibited the replication of coronaviruses similar to the one causing COVID-19 in cultured cells. Pfizer said it was engaging with a third party to screen these compounds under an accelerated timeline and expected to have results back by the end of March.
“Toxicology studies would then need to be completed prior to any clinical development, but if successful, Pfizer hopes to be in the clinic by no later than the end of 2020,” the company added.
COVID-19: 300 Candidates and Counting
To navigate through the >300 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
● TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.
GEN has also tagged the most common treatment types: