An alternative to Paxlovid, the only antiviral pills approved by the US Food and Drug Administration to treat COVID-19, is on the horizon. Pfizer—the maker of Paxlovid—has begun Phase 3 clinical trials of a next-generation coronavirus antiviral, ibuzatrelvir.
Ibuzatrelvir offers several advantages over its predecessor. It doesn’t have the drug-drug interactions that prevent many people with COVID-19 from taking Paxlovid. And participants in ibuzatrelvir’s Phase 2 clinical trial didn’t report “Paxlovid mouth,” an unpleasant side effect of the drug in which people experience a lingering taste described as metallic or, more colorfully, like grapefruit mixed with soap.
Despite its drawbacks, Paxlovid is a marvel of modern medicinal chemistry. Experts says its discovery and development show what a well-resourced anti-infective program can produce. The drug, which combines the compounds nirmatrelvir and ritonavir, entered human clinical trials in March 2021, just 12 months after its first synthesis—stunning speed for making a new bespoke drug. At the time, vaccines for COVID-19 were just becoming widely available in the US, and the prospect of an antiviral pill offered another avenue for avoiding hospitalization or death from the disease. By early 2022, Paxlovid was available under emergency use authorization, and it had received full FDA approval by May of 2023.
A molecule bound within an enzyme's active site.
Credit: RCSB Protein Data Bank
X-ray crystal structure of ibuzatrelvir bound to the SARS-CoV-2 main protease active site.
Still, the drug’s side effects, along with a high list price—nearly $1,400, although that’s usually covered by insurance or US government programs—have contributed to its underutilization. A retrospective study published in January 2024 found that out of 309,755 people who were eligible to receive Paxlovid when they were treated for COVID-19 by the US Department of Veterans Affairs health-care system in 2022, only 12.2% received the drug. And even though that percentage climbed over the course of the study, it was only at 23.2% in December of 2022.
One factor that prevents doctors from prescribing Paxlovid is drug-drug interactions related to its ritonavir component. Ritonavir doesn’t do anything to fight SARS-CoV-2, the coronavirus that causes COVID-19. That’s the job of Paxlovid’s nirmatrelvir component, which works by blocking SARS-CoV-2’s main protease (Mpro, also known as the 3CL protease), thereby preventing the virus from replicating. But nirmatrelvir is susceptible to metabolism, so to get it to stick around long enough to block Mpro, Pfizer scientists added ritonavir to the mix.
Ibuzatrelvir is coming forward to make sure we can reach more patients.
Charlotte Allerton, head of preclinical and translational sciences, Pfizer
People who take Paxlovid consume two 150 mg doses of nirmatrelvir and one 100 mg dose of ritonavir twice a day for 5 days. Ritonavir binds with CYP3A4 enzymes, which are responsible for metabolism, and gives nirmatrelvir a pharmacokinetic, or PK, boost. Unfortunately, ritonavir can also boost the lifetime of other medications in dangerous ways. This means people who take any of a long list of other drugs, including the immunosuppressant voclosporin and the sedative midazolam, can’t take Paxlovid.
Because of this, says Northwell Health chief pharmacy officer Lisa Mulloy, ibuzatrelvir could be an important therapy for people at high risk of developing severe complications from COVID-19, such as those who have undergone organ transplants or are undergoing cancer treatment.
Charlotte Allerton, Pfizer’s head of preclinical and translational sciences, says the drugmaker “wanted to bring forward a second-generation molecule that didn’t require that PK boosting and wouldn’t have inherent drug-drug interactions that would preclude it from being widely prescribed to patients.”
To do this, the Pfizer scientists focused on making a molecule that was less susceptible to metabolism. One spot they quickly identified for modification was the geminal dimethyl group on nirmatrelvir’s rigid fused bicyclic ring system. It’s prone to oxidation by CYP3A4 enzymes.
“As part of optimizing the substituents in that position and the overall molecule, we were looking at balancing lipophilicity,” Allerton says. The fused bicyclic ring with a geminal dimethyl group was lipophilic.
“We know that if we take down lipophilicity—we make it less greasy—that it will likely be less easily metabolized. But of course, that has to be balanced,” Allerton says. Make the molecule too polar, and it won’t be taken up by the body when it’s swallowed. “It won’t cross the gut wall, and also we won’t get the good antiviral cellular activity that we required,” she says.
Structure of ibuzatrelvir.
The team’s solution was to replace that fused bicyclic ring system with a proline that has a pendant trifluoromethyl group. This change also makes ibuzatrelvir less rigid than nirmatrelvir. There is a lower barrier to rotation around the amide bond of that proline group. The Pfizer scientists propose that this rotation makes the crystalline form of ibuzatrelvir easier to dissolve and boosts its oral bioavailability compared with that of nirmatrelvir.
Structure of nirmatrelvir.
The other key difference between nirmatrelvir and ibuzatrelvir is that the trifluoroacetate group in nirmatrelvir has been replaced with a methylcarbamate in ibuzatrelvir.
Both molecules are alike in all other respects: both have structures that look like short peptides, and they both contain a nitrile group that reacts with a cysteine in SARS-CoV-2’s Mpro. The Pfizer scientists described ibuzatrelvir’s medicinal chemistry campaign in a Journal of Medicinal Chemistry paper that was published in April 2024 (DOI: 10.1021/acs.jmedchem.3c02469).
Artificial intelligence, machine learning, and computational chemistry influenced ibuzatrelvir’s design, Allerton says. Such capabilities expedite the company’s drug discovery process and help them get to molecules that are most likely to meet the criteria they want, she says, instead of making lots of compounds and profiling them in the laboratory, which is a slower process.
For example, Allerton says, their models can predict a molecule’s absorption, distribution, metabolism, and excretion properties. “We can predict them on virtual molecules before we make them, and it really helps us move much more quickly to the molecules that we should be making,” she says.
While drugmakers sometimes create next-generation antivirals to address viruses’ resistance to their predecessors, Allerton emphasizes that this is not the case with the development of ibuzatrelvir. Authors of a study published in Sept. 2024 concluded that it was rare for drug-resistant strains of SARS-CoV-2 to emerge after nirmatrelvir treatment (JAMA Network Open, DOI: 10.1001/jamanetworkopen.2024.35431). “Ibuzatrelvir is coming forward to make sure we can reach more patients,” Allerton says.
Like nirmatrelvir, ibuzatrelvir binds tightly to the Mpro active site. Because of that, and because it’s dosed at high concentrations, Allerton and her team think that the second-generation antiviral will also have a low risk of clinical resistance.
University of Oxford medicinal chemist Lennart Brewitz says he was impressed by the way Pfizer modified nirmatrelvir to arrive at ibuzatrelvir. “Just looking at the structures, they don’t differ massively,” he says. And yet, Brewitz says, the Pfizer team made this molecule much more useful because it doesn’t need to be dosed with ritonavir.
This work showed how focused, properly funded medicinal chemistry can deliver new medicines within a very short time frame, at least for infectious disease.
Christopher J. Schofield, medicinal chemist, University of Oxford
Paxlovid “was developed under intense time pressure and extremely difficult conditions for them to work in, and it wasn’t perfect,” says Christopher J. Schofield, who is also a medicinal chemist at Oxford. Under normal circumstances, Schofield says, he’s confident that “the follow-up compound would likely have been the one they actually took forward.”
Brewitz and Schofield wrote a commentary about ibuzatrelvir that also appeared in the Journal of Medicinal Chemistry (2024, DOI: 10.1021/acs.jmedchem.4c01342). They say there’s a larger lesson to be learned from Pfizer’s development of Paxlovid and ibuzatrelvir.
“This work showed how focused, properly funded medicinal chemistry can deliver new medicines within a very short time frame, at least for infectious disease,” Schofield says. Similarly focused efforts could lead to treatments for other infectious diseases, including malaria and tuberculosis (TB), Schofield says. “It can be done. It does not take 15 years to make a new anti-infective medicine.”
Mel Spigelman, president and CEO of the TB Alliance, a nonprofit that develops tuberculosis drugs, agrees. He tells C&EN in an email, “There is no question in my mind that if we had even a fraction of the resources available for TB that were put to work on Covid, we could not only achieve even greater breakthroughs than have already been achieved but could get to the point of eradicating TB.”
What's in the pipeline
A handful of manufacturers still have antivirals for SARS-CoV-2 in development.
By: Rowan Walrath
Fujian Akeylink Biotechnologya
Mpro
Approved in China
Shionogi
Mpro
3 ongoing
Pfizer
Mpro
3 ongoing
Enanta Pharmaceuticalsb
Mpro
2 complete
Aligos Therapeautics
ALG-097558d
Mpro
2 ongoing
Red Queen Therapeutics
RQ-01e
Heptad repeat 1 domain
1 complete
Insilico Medicinec
ISM3312d
Mpro
1 complete
Shionogi
Mpro
1 ongoing
Sources: Manufacturers.
a Atilotrelvir is approved to treat COVID-19 in China. Fujian Akeylink Biotechnology is seeking partners to codevelop the drug outside China.
b Enanta Pharmaceuticals is seeking partners to continue developing EDP-235.
c Insilico Medicine is seeking partners to continue developing ISM3312.
d Structure undisclosed.
e Lipopeptide.
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