An Update on Therapeutics for COVID-19

Although the general population now has at least some immunity against COVID-19, the consequences of severe disease are frequently overlooked for certain patient populations, such as those with comorbidities or immune compromise. However, new research into COVID prophylaxis and therapeutics offers some hope that novel treatments may be on the horizon.

Is Paxlovid Still Useful?

The original phase II/III EPIC-HR trial showed that nirmatrelvir/ritonavir (Paxlovid) was nearly 89% effective for preventing COVID hospitalization and all-cause death in unvaccinated high-risk patients.

“These were remarkable findings, but this trial was conducted early on in the pandemic among unvaccinated high-risk patients and the applicability of these findings to current settings of high population immunity are not well-understood,” John McLaughlin, PhD, of Pfizer, said at this year’s IDWeek annual meeting.

Final results from the phase II/III EPIC-SR trial, published earlier this year, were not so impressive. The study, enrolling people at standard risk for severe COVID, as well as vaccinated people with at least one risk factor for severe disease, found that nirmatrelvir/ritonavir failed to shorten COVID symptom duration in those populations. There was, however, a nonsignificant trend toward fewer hospitalizations and deaths among participants who took nirmatrelvir/ritonavir versus those who took placebo.

Results such as these have “created some debate about the utility of Paxlovid therapy in the current background of high population-level SARS-CoV-2 immunity,” McLaughlin said.

To further explore this issue, McLaughlin and investigators conducted an analysis of pooled data from both of those trials. They found that nirmatrelvir-ritonavir was, in fact, effective at reducing several COVID-related outcomes in high-risk vaccinated or previously infected patients.

Most notably, the proportion of participants in the nirmatrelvir-ritonavir group who were hospitalized or died was 0.5% versus 1.9% in the placebo group, representing a relative risk reduction of 73.7% (95% CI 21.4-91.3).

There was also a 65% relative reduction in COVID-related medical visits (95% CI 24.4-83.8) with nirmatrelvir-ritonavir versus placebo, and a 46.6% relative reduction in severe COVID symptoms 7 to 28 days after treatment initiation (95% CI 22.1-63.4).

McLaughlin and colleagues also calculated the number needed to treat (NNT) to prevent one occurrence of each of these outcomes. “Even in a population with pre-existing immunity,” the NNT to prevent one hospitalization or death was 71. The NNT to prevent a COVID-related medical visit was 24, and the NNT to reduce severe COVID symptoms 7 to 28 days after starting treatment was 16.

The researchers noted that there were a limited number of Omicron infections in the study groups and the trials included no data from the 2022-2023 and 2023-2024 seasons. However, the study’s findings were consistent with real-world observational studies that have since been conducted in the Omicron era, McLaughlin pointed out.

“Taken together, these findings underscore the continued utility of Paxlovid treatment in high-risk patients, even in the context of baseline SARS-CoV-2 immunity,” he concluded.

An Unmet Need in COVID Prevention

New COVID prophylaxis and treatment options are especially needed for highly immunosuppressed people and those undergoing certain types of cancer treatment, said Dinesh De Alwis, PhD, of Generate:Biomedicines in Somerville, Massachusetts, during a presentation at IDWeek.

In particular, “there remains a significant need to treat persistent SARS-CoV-2 infection in B-cell-depleted oncology patients,” he said.

In a meta-analysis including over 7,600 patients on B-cell-depleting CAR-T therapy, “over 50% of non-relapse deaths in these patients are due to infections, of which COVID-19 is the main cause,” he noted. Infection, including COVID, is also a major cause of morbidity and mortality in patients treated with T-cell engagers in cancer immunotherapy. Moreover, vaccine responses “are suboptimal to nonexistent in these patients, and chronic COVID infection is often unresponsive to monotherapy antiviral treatments,” he said.

For people with immune compromise, monoclonal antibodies may prevent severe illness. However, their effectiveness has varied widely throughout the pandemic, depending on circulating SARS-CoV-2 variants.

GB-0669, developed by Generate:Biomedicines, is a novel monoclonal antibody that appears to be effective against diverse sarbecoviruses (i.e., the viral subgenus containing SARS-CoV and SARS-CoV-2), including multiple SARS-CoV-2 variants. Of note, GB-0669 was developed using a novel machine learning platform that focused on identifying antibodies less prone to immune escape.

The key difference between GB-0669 and other monoclonal antibodies against SARS-CoV-2 is that it binds to the S2 stem helix (S2-SH) of the virus, whereas other antibodies target the receptor-binding domain (RBD) of the virus’ spike protein. However, the RBD is highly immune-dominant, and normal antibody response drives evolution at this site, leading to resistance over time.

In contrast, lack of selective pressure at the S2-SH site “means resistance mutations have not been seen to date” with GB-0669, De Alwis said.

A small first-in-human phase I study found that the antibody was well-tolerated in healthy participants, with no serious adverse events, he reported. An analysis of pharmacokinetics demonstrated that the activity of GP-0669 had low intersubject variability and the antibody had a half-life of 55 days. The researchers identified the optimal therapeutic dose to be 1,200 mg IV, providing an approximate 10-fold increase in neutralizing titers against SARS-CoV-2 in healthy participants who had pre-existing titers (XBB.1.5 and BA.5.5).

Based on established data about passive antibody efficacy in SARS-CoV-2, a single dose of GB-0669 should provide protection against hospitalization from COVID over a period of 60 days in patients with low baseline titer levels, De Alwis said.

“This data supports advancement of GB-0669 to phase II, especially in highly immune-compromised patient populations who have the greatest need,” he concluded.

A Novel Antiviral for COVID?

Currently, nirmatrelvir-ritonavir, remdesivir (Veklury), and molnupiravir (Lagevrio) are the only available antivirals for the treatment of COVID.

Obeldesivir is an investigational antiviral with activity against SARS-CoV-2. It is an oral prodrug of the parent nucleoside GS-441524, targeting the highly conserved RNA-dependent viral RNA polymerase. The efficacy and safety of obeldesivir for the treatment of COVID in people with risk factors for severe disease was evaluated in the phase III BIRCH trial.

However, the trial was halted early because there was a lower-than-expected event rate for the primary outcome of COVID-related hospitalization or all-cause death, said Lauren Rodriguez, PhD, of Gilead Sciences, at IDWeek. (There were zero hospitalizations or deaths in the obeldesivir group [n=211] versus one in the placebo group [n=207]).

Nonetheless, some secondary and exploratory endpoints pointed to potential efficacy of the novel antiviral. Obeldesivir resulted in greater reduction in SARS-CoV-2 viral load at day 5 when compared with placebo (-0.58 log₁₀ copies/mL, P<0.0001) and also led to significantly greater reductions in infectious titers on day 3 (-0.54 log₁₀ plaque-forming units [PFU]/mL, P=0.0003) and day 5 (-0.17 log₁₀ PFU/mL, P=0.0014).

At day 3, 80% of participants in the obeldesivir group and 49% in the placebo group were negative for infectious virus (P=0.0049), and at day 5, 100% and 81%, respectively, were negative (P=0.0001). At day 10, nearly all participants were negative for infectious virus, with no differences between the two groups.

Although the BIRCH trial has been halted, the phase III OAKTREE study, evaluating obeldesivir as a COVID treatment for people without risk factors for developing severe disease, is ongoing.

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