Monoclonal antibody, antiviral therapies struggle to keep pace with COVID-19 variants
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As the COVID-19 pandemic has moved from beta to delta to omicron, often with remarkable speed and unpredictable epidemiology, the efficacy of therapeutic approaches has risen and fallen accordingly.
Various antivirals and monoclonal antibodies have emerged, been effective, and then, ultimately, lost potency as the next variant began circulating. Meanwhile, the promise of unconventional approaches like convalescent plasma have gained significant attention but, as yet, have not quite delivered on a broad scale.
“In terms of the monoclonals that we used, things moved very quickly throughout the pandemic,” Cassandra Calabrese, DO, of the department of rheumatic and immunologic disease, and the department of infectious disease, at the Cleveland Clinic Foundation, told Healio.
At any given point in the last year to 18 months, there have been four monoclonal antibody drugs or combinations in use. These have included bamlanivimab plus etesevimab (Eli Lilly & Co.), casirivimab plus imdevimab (REGEN-COV, Regeneron), tixagevimab plus cilgavimab (Evusheld, AstraZeneca) and sotrovimab (Xevudy, GlaxoSmithKline).
As for antivirals, remdesivir (Veklury, Gilead Sciences) is currently the only drug that has full FDA approval. However, nirmatrelvir (Paxlovid, Pfizer) and molnupiravir (Merck) both carry emergency use authorization.
It is no small task for clinicians to stay up-to-date and make sense of all of this information. However, understanding the landscape can be the difference between life and death as hospitals and other health centers try to limit COVID-19 morbidity and mortality as much as possible.
One out of four ain’t bad
Despite the fact that only one of the four monoclonal antibody therapies remains in wide circulation, with similar efficacy against omicron as it had against other variants, there is still firm basis for hope in this treatment paradigm, according to Calabrese.
“I would not say that monoclonal antibodies are on their way out,” she said. “Sotrovimab is still really important for treatment of high-risk outpatients with COVID, as it is the only monoclonal antibody that maintains effectiveness against omicron.”
However, even this drug comes with some qualifications.
“We have some sotrovimab, but it is very difficult to obtain at the moment,” Kevin Winthrop, MD, MPH, director of the Center for Infectious Disease Studies at Oregon Health & Science University, said in an interview. “We really only use it in patients who are over age 65 and have multiple other risk factors, and the supply has been limited.”
The other combination currently in use is Evusheld, although it, too, is hampered by its own set of limitations.
“We suspect that it does retain some efficacy, but it is likely reduced based on the 12- to 30-fold reduction in neutralizing activity observed in in vitro experiments,” Winthrop said. “So, at the moment, we are not fully certain how efficacious it is.”
That said, the challenging nature of COVID-19 has forced clinicians to get creative in their treatment approaches, using drugs in any way that might mitigate infections. To that end, Evusheld may continue to have a role as preexposure prophylaxis (PrEP), according to Calabrese.
“High-risk immunocompromised persons, especially patients on B-cell depleting therapies, will likely benefit from PrEP with Evusheld,” she said.
As for treating high-risk patients with or exposed to COVID-19, Winthrop offered a final word on the current state of these two treatments.
“If I had the choice between Evusheld and sotrovimab, then the latter would be the pick based on the preserved neutralization capacity noted in vitro against omicron,” he said.
Regarding other monoclonal antibodies, the news is less encouraging. On Jan. 24, the FDA issued a statement limiting the use of two therapies currently in circulation.
“In light of the most recent information and data available, the FDA revised the authorizations for two monoclonal antibody treatments — bamlanivimab and etesevimab (administered together) and REGEN-COV (casirivimab and imdevimab) — to limit their use to only when the patient is likely to have been infected with or exposed to a variant that is susceptible to these treatments,” the statement read.
“Bamlanivimab and etesevimab fell off the recommendations after in vitro data,” Calabrese said. “It is not effective at treating omicron because of multiple mutations in the spiked protein.”
REGEN-COV followed a similar path, according to Calabrese. “It has neutralizing capability against delta but not against omicron,” she said.
Although clinicians are always looking ahead to the next potential agent, COVID-19 has made it difficult to predict what may come next.
A press release from Eli Lilly & Co. suggested that the novel compound LY-CoV1404, or bebtelovimab, should have activity against all variants. However, the compound has not yet received FDA emergency use approval.
“As for the pipeline for monoclonal antibodies, I am not aware of much public information on agents that are active against omicron,” Winthrop said. “I suspect they exist, but omicron is too new, and I have not seen any data.”
Whatever happened to antivirals?
The ongoing use of remdesivir has been a bright spot in the pandemic, according to most experts. Winthrop noted that clinical trial findings have supported the continued use of the drug.
“We really have better data more recently for early remdesivir now,” he said.
However, sourcing certain antivirals can pose another challenge for clinicians in some areas. Although Calabrese noted that the Cleveland Clinic has made significant use of them — “I would not suggest that antivirals are too hard to get to be helpful,” she said —
for Winthrop, the story is a bit different.
“Paxlovid, in particular, can still be very hard to find for us,” he said.
The good news is that help may be on the way.
“The U.S. is expected to get a lot more of both Paxlovid and molnupiravir in the coming months, so hopefully they will be easier to attain for patients,” Calabrese said. “We think that these drugs will be key in management of high-risk outpatients.”
As both drugs maintain effectiveness against omicron, the hope is that they will be used widely over the coming year.
“It is really important to make the Pfizer antiviral more available,” Winthrop said. “That will become the ‘Tamiflu-like’ solution to this. The drug is unlikely to be affected by variants now or in the future.”
That said, Winthrop acknowledged that COVID-19’s unpredictability thus far has left clinicians feeling as though anything is possible.
“The efficacy of Paxlovid could vary depending on the variant, I suppose, but that is unlikely to occur without a major shift in the virus,” Winthrop said.
Meanwhile, despite the attention that convalescent plasma has received, this approach has largely been left by the wayside in routine COVID-19 care.
“I am not sure convalescent plasma is worthy of a whole story,” Calabrese said. “On occasion, high-titer convalescent plasma is used in-house to treat severely immunocompromised persons fighting COVID-19, like those on rituximab (Rituxan, Genentech), but it is not recommended for inpatient use by national societies such as the Infectious Disease Society of America."
One other consideration for both antivirals and monoclonal antibodies is the timing of intervention.
“These approaches are optimized if we get to the patient early, within 10 days of exposure for monoclonals and 5 days for the oral antivirals,” Calabrese said.
‘Strained’ resources
Beyond the neutralizing activity of specific therapies, staffing has been an additional challenge in delivering care.
“We are strained,” Calabrese said, noting that a lack of personnel and infusion centers has forced the Cleveland Clinic Foundation to muster as many resources as possible to deliver monoclonal antibodies.
“We are hoping that the workforce can manage the high demand of omicron,” she added.
Attempting to alleviate these shortages, the FDA has stressed that such treatments are just one component of the battle against COVID-19.
“While it’s critical that we have ways to treat those who contract COVID-19, the authorized treatments are not a substitute for vaccination in individuals for whom COVID-19 vaccination and a booster dose are recommended,” read the FDA’s Jan. 24 statement. “Data has clearly demonstrated that the available, safe and effective vaccines can lower your risk of developing COVID-19 and experiencing the potential associated serious disease progression, including hospitalization and death.”
However, apart from the vaccine recommendation, individual centers have interpreted the language of FDA communications pertaining to treatment in different ways, depending on their staffing, patient population, circulating strains and other factors, according to Calabrese.
“Centers have taken creative liberties depending on whether they have a lot of high-risk patients with heart or lung disease, or patients taking immunosuppressive drugs or high-dose steroids, or those who are over 65,” she said.
In short, hospitals have had to be pragmatic.
“You have to save as much drug as you can for your patients who are most at-risk for complications or death,” Calabrese said.
Omicron has shown significant transmissibility but, fortunately, less capacity for complications or death. However, that does not mean clinicians can rest easy just yet.
“We stand at a crossroads, because COVID-19 has morphed into two pandemics,” Calabrese said. “Vaccinated, immunocompetent people will likely do just fine if or when they get omicron. But then there are the unvaccinated and those who are immunocompromised to different degrees. They might not do fine.”
Education about all available therapies and preventative approaches is critical, according to Calabrese.
“If you are unvaccinated or immunocompromised, you should be careful about your activities and be aware when you might have been exposed,” she said. “We are working as hard as we can to protect and treat these vulnerable patients, and we will use both antivirals and monoclonal antibodies to the best of our ability.”
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