Biopoharma is working to restock the COVID-19 medicine chest. And its next wave of therapies could shift the standard of care, provided their clinical data pan out.
The current coronavirus treatment paradigm, according to NIH, calls for use of the monoclonal antibodies, such as Eli Lilly’s bebtelovimab and GlaxoSmithKline’s sotrovimab, as first-line agents for high-risk patients. AstraZeneca’s Evusheld antibody cocktail has FDA approval for pre-exposure prophylaxis.
Gilead’s Veklury (remdesivir) has the go-ahead in those with mild-to-moderate infections. Physicians expect small-molecule drugs, like Pfizer’s Paxlovid (nirmatrelvir/ritonavir) and Merck’s Lagevrio (molnupiravir), to eventually become mainstays in the mild-to-moderate setting.
But each of these COVID-19 treatments has its drawbacks.
Veklury has a cumbersome three-day-long IV treatment duration. As for the oral antivirals, Paxlovid must be taken twice a day and has a high pill burden (30 pills over a five-day course); one of its key ingredients, ritonavir, is notorious for having drug/drug interactions. The knock on molnupiravir (40 pills over a five-day course) has been worse trial outcomes and concerns over potential mutagenicity and fetal harm.
The Merck and Pfizer pills must be administered to patients as soon after diagnosis as possible, which can be challenging when they’re not available at the pharmacy counter. Because prescribers have had so much trouble tracking them down, HHS recently launched a COVID-19 Therapeutics Locator.
Meanwhile, the now-dominant Omicron variant, which has largely relegated other monoclonal antibodies to the sidelines (think Regeneron’s REGEN-COV and Eli Lilly’s bamlanivimab/etesevimab cocktails), has raised questions about the durability of this entire drug class against emerging strains. Based on just-released data, the FDA said Thursday that Evusheld and GSK’s sotrovimab don’t perform as well against Omicron’s subvariants as they did against the original version.
Next-gen antivirals could address many of these drawbacks, say analysts from investment bank Leerink. The analysts believe these agents promise to transform the COVID-19 treatment landscape by bringing additional convenience and/or potency advantages over the two oral antivirals. Having more options on the market could ease supply issues as well.
Here, then, we present the drugs in development that are angling to restock the coronavirus armamentarium. While in the early-to-late stages of clinical (and, in one case, pre-clinical) testing, they could shift the treatment paradigm in the next couple of years as COVID-19 becomes more endemic.
Shionogi’s S-217622 is one of a number of oral antivirals advancing in the clinic for COVID-19 treatment. Like some others on this list, S-217622 is in the oral protease inhibitor class of medicines and doesn’t need to be taken with ritonavir for a boosting effect. The drug is orally administered once daily for five days.
A global Phase 3 study of S-217622 is due to get underway this month and the company has already filed for Japanese regulatory approval. Analysts are expecting it to be granted by next month, given the drug’s Phase 2/3 data. The company has said it will make the drug available to a million people by the end of March.
In the Phase 2/3 clinical trials among mostly Japanese patients, S-217622 demonstrated a significant antiviral effect (after the third dose) versus placebo, as well as rapid reduction in viral titer and good clinical symptom improvement and safety.
While S-217622 seems to have lower in vitro potency, per Leerink, it may offer the highest oral bioavailability (97%), a measure of the amount of the drug entering circulation upon ingestion.
Enanta’s EDP-235 is the biotech’s own once-daily, oral protease inhibitor. The company is planning for its first-in-human Phase 1 trial of EDP-235 in healthy volunteers to start this month and Leerink estimates a readout later this year.
According to Leerink, EDP-235 thus far seems to exhibit the most potent in vitro activity against the Omicron variant of these other protease inhibitors, although it cautions that more clinical data are needed in order to be certain.
Enanta CEO Jay Luly hasn’t been shy about trumpeting that potential differentiation. The drug’s combination of “potent antiviral activity and a favorable pharmacokinetic profile positions EDP-235 to potentially be a best-in-class,” he said.
Another oral antiviral being developed as a standalone therapy, Pardes’ PBI-0451 is currently under evaluation in a Phase 1 study in New Zealand. The Phase 1 readout of PBI-0451 in healthy volunteers is due by March, followed by initiation of a Phase 2/3 study in mid-2022.
PBI-0451, which is being tested in once- and twice-daily dosing, seems to confer the highest in vitro potency level against the Delta variant, Leerink points out.
Analysts called out protease inhibitors as the “class to watch.” But much like Merck’s molnupiravir, Atea’s bemnifosbuvir/AT-527 is a nucleoside inhibitor, with a uniquely dual-target mechanism (against RdRp and NiRAN).
After failing to meet the primary endpoint in its prior Phase 2 trial, Atea terminated its pivotal Phase 3 study of AT-527. Instead, the company is moving ahead with testing a combination regimen with one or more undisclosed protease inhibitors and AT-527 as the backbone, Leerink reports.
Atea’s new Phase 2 outpatient study of 200 high-risk patients is designed to support this new and improved formulation for use in future combination trials. The biotech, which still believes in the drug as a single-agent treatment for COVID-19, is expected to report topline data in late 2022.
In the preclinical area, Aligos’ ALG-097431 shows the potential for being broad-acting across variants while still maintaining strong potency, according to Leerink.
A preclinical toxicology study of the protease inhibitor is set to start later this year, with a subsequent filing in late 2022. Analysts expect ALG-097431 will need to be taken twice daily for five days but will not need ritonavir boosting.
Are these agents real contenders? Multiple data readouts, due over the next six to 12 months, should answer that question .
Analysts will be assessing how broadly they cover SARS-CoV-2 variants (and potentially other coronaviruses). Along with once-daily dosing, and without the need for ritonavir boosting, such a profile would differentiate the agents from either Pfizer’s or Merck’s antivirals.
“While it’s early days, these data suggest to us that ‘not all protease inhibitors are created equal’ and subsequent clinical data should widen the gap between these in-class competitors,” Leerink analyst Roanna Ruiz wrote in an investor note. “And, while Pfizer’s Paxlovid has set a high clinical bar, we believe even somewhat lower efficacy plus safety/dosing/administration advantages still presents a competitive clinical profile.”
Elsewhere in the COVID-19 pipeline, there’s Gilead’s oral antiviral GS-5245, a nucleoside analogue with a similar mechanism to Veklury. Its Phase 1 trial is underway and a registrational trial for GS-5245 is expected to begin before year’s end.
Other promising approaches include Novartis/Molecular Partners’ ensovibep, part of a new class of custom-built protein drugs known as DARPin therapeutics. The companies have applied for emergency use authorization based on positive Phase 2 results.