Discussion about Covid-19 antiviral pills has focused on recently authorized Pfizer and Merck drugs, which now give patients oral alternatives to injectable or infused therapies. Other companies are in pursuit of more convenient oral formulations as well, including Pardes Biosciences, which now has $274 million to support clinical development of a pill that goes after the same virus target as Pfizer, but with a potential dosing advantage.

Just prior to the Christmas holiday, shareholders of FS Development Corp. II approved the merger of that special purpose acquisition company with Carlsbad, California-based Pardes, setting the stage for the newly combined company to begin trading on the Nasdaq this week under the stock symbol “PRDS.” The SPAC merger comes less than two years after the company formed in the early days of the Covid-19 pandemic. Since then, the biotech has advanced a development of a lead antiviral candidate, PBI-0451, which is currently in human testing.

The Pardes drug belongs to a class of medicines called protease inhibitors. Proteases are enzymes that break down proteins. Acting like a pair of scissors, they cut up a long chain of proteins and enable different enzymes from that chain to become functional in the viral replication process. By binding to proteases, protease inhibitors block them from performing their cutting work, which in turn stops this key step of the viral replication process.

The concept of stopping viruses by targeting proteases is an old one. The first protease inhibitors to reach the market were HIV drugs approved in the mid-1990s. Drugs from this class are also approved for treating hepatitis B and C. PBI-0452 is designed to target main protease, or Mpro. If that protease sounds familiar, it might be because it’s the same target addressed by newly authorized Pfizer antiviral Paxlovid. In results from Phase 2/3 testing Pfizer reported that its drug reduced the risk of hospitalization or death, compared to a placebo, by 89% when given within three days of symptom onset. When given within five days, the risk reduction was 88%.

The protease inhibitor in the Pfizer drug is called nirmatrelvir. It must be given in combination with another drug, ritonavir. That drug is commonly combined with HIV medicines to help them work better. In the treatment of Covid-19, ritonavir slows the breakdown of Paxlovid, helping it to remain in the body for a longer period of time and at higher levels of concentration. But getting this benefit means that patients need to take an extra ritonavir tablet with every two-pill dose of Paxlovid. For a five-day course of treatment, patients need to take 30 pills total.

Pardes is pitching its protease inhibitor as a way to target Mpro without needing an additional boosting agent. The efficacy of this approach still needs to be demonstrated in clinical trials, but if it works, it could mean patients won’t need to take as many pills. Pardes has not, however, specified how many pills make up a single dose of PBI-0451.

Pardes was founded by biotech industry veteran Uri Lopatin, whose experience includes executive roles at Gilead Sciences, Roche, and Assembly Pharmaceuticals. The biotech was formed as a direct response to the pandemic, Lopatin told MedCity News in a September interview.

“I’m an infectious disease doctor and when a new pandemic virus starts spreading, one of the reflexes is that we’re going to need a new oral antiviral as well as a vaccine—multiple [products],” Lopatin said. “Unfortunately, that prediction has turned out to be correct.”

Pardes is built on protease inhibitor science in HIV that dates back decades, Lopatin added. For nearly as long as coronaviruses have been known, Mpro stood out as a promising protease target. When a virus enters a cell, RNA from the virus is translated into a chain of proteins called a polypeptide. That chain is cleaved by Mpro 11 times. Lopatin said that Mpro’s role doing the lion’s share of the cutting work means it’s important to the virus, and thus, a valuable drug target. Other features also make Mpro a good target. For one, it does its work early on in the viral replication cycle.

“The further upstream you can break the pathogen life cycle, the more attractive that target becomes,” Lopatin said. “There’s fewer opportunities for the virus to do bad things.”

In addition, Mpro is a conserved protease—it doesn’t change much even as viruses mutate—so it’s likely to continue to be a valid target for new variants. This protease is required for every known coronavirus, which Pardes said broadens the potential for its drug to address coronavirus infections beyond Covid-19. In preclinical research, the company has said its drug has shown activity against a range of coronaviruses including SARS-CoV-2. Also, Mpro isn’t found in humans, so targeting it is less likely to spark adverse effects.

The features of Mpro that make it an attractive target for Pfizer and Pardes have also drawn the research interest of other companies. Exscientia is developing Mpro-targeting small molecules under a partnership with the Bill & Melinda Gates Foundation; others include Cortexyme and Arbutus Biopharma. So far, those research efforts are in preclinical development.

The Phase 1 test of PBI-0451 is a dose-ascending study designed to enroll about 120 healthy adult volunteers. Enrollment began in August. According to a November investor presentation, the Pardes drug has been well tolerated so far with no known discontinuations from the study. Trial investigators have reported that adverse effects have been mild. Pardes expects to have preliminary Phase 1 data in the first quarter of 2022. Those results will determine the dose to advance to the next stage of clinical testing, which could begin in the middle of 2022, the company said. That Phase 2/3 test will enroll patients with mild-to-moderate Covid-19.

Pardes does not yet have data on PBI-0451’s effect on omicron, but Lopatin said via email that the company will explore it. He added that the active site of the viral protein is highly similar across all known coronaviruses, so the company expects the drug’s activity against them will be retained. “Future clinical trials would be anticipated to evaluate the effect of PBI-0451 on whichever variants are circulating at the time,” Lopatin wrote.

Pardes’s cash haul from the SPAC merger breaks down to $199 million from FS Development Corp. II’s trust accounts, plus a $75 million private investment from Foresite Capital, RA Capital Management, Frazier Life Sciences, funds and accounts advised by T. Rowe Price Associates, GMF Capital, EcoR1 Capital, Monashee Investment, and Gilead Sciences. The money will be used to continue the Phase 1 test of PBI-0451, start the Phase 2/3 study, and manufacture the drug for the clinical trial. Pardes also plans to further develop its pipeline, including applications of its technology to viral targets beyond coronaviruses as well as non-virology applications.

Photo by Pardes Biosciences