COVID therapies needed beyond vaccine: Role of monoclonal antibodies, convalescent plasma?
November 2020 was a grim time for COVID-19 in the United States, marking the beginning of a brand-new wave of infections fueled by holiday get-togethers that triggered an explosion of cases.
By the end of that month, about a third of the nation’s total cases had been reported in just the past 30 days. Hospitalizations doubled during this time, and more than 36,900 Americans died — about 51 people every hour.
However, there was one piece of positive news: On Nov. 9, the FDA issued an emergency use authorization for Eli Lilly & Co. investigational monoclonal antibody therapy, bamlanivimab, to treat mild-to-moderate COVID-19 in adults and children. That announcement, combined with several clinical trials investigating the use of high-dose human convalescent plasma and concentrated monoclonal antibodies for COVID-19, served to give hope to the idea of using these therapies to protect against severe disease following coronavirus infection.
Then, one month later, the FDA approved the first vaccine for COVID-19, thereby changing the landscape in terms of disease prevention. In light of the ongoing distribution of vaccines, what role do monoclonal antibodies and convalescent plasma now have in the management of COVID-19?
To answer this question, Healio Rheumatology sat down with Cassandra Calabrese, DO, director of the Rheumatology Infectious Disease Clinic and training program at the Cleveland Clinic, and Kevin L. Winthrop, MD, MPH, director of the Center for Infectious Disease Studies at Oregon Health & Science University.
Topics for discussion included the approved uses of monoclonal antibodies and convalescent plasma for COVID-19, their continued utility as vaccines continue their — albeit slow — national rollout, and concerns over the logistics of getting these therapies to patients.
Q: What role do monoclonal antibodies and convalescent plasma have now in the management of COVID-19?
Calabrese: At present, the role for monoclonal antibody treatments is in patients with mild-to-moderate COVID-19 who are not requiring supplementation oxygen, and most importantly who are at home, not in the hospital. The target population from the EUA is patients felt to be at risk of progression to severe COVID-19 and/or hospitalization. At our institution, patients with immune-mediated inflammatory diseases may qualify for treatment with monoclonal antibodies if they meet certain criteria, including being on prednisone equivalent of 10 mg or more daily, receiving rituximab or sulfasalazine.
These are risk factors for poor outcomes highlighted in the COVID-19 Global Rheumatology Alliance data.
In terms of convalescent plasma, the EUA is for inpatient treatment only. There are many conflicting studies on the potential benefit of convalescent plasma, with more recent studies suggesting that the effect size appears to be limited to those with symptom duration of 72 hours or less, and not on oxygen. This is in ways conflicting with the EUA, as most often patients will not be hospitalized during that symptom duration window. Also, recent studies suggest that convalescent plasma containing high titer SARS-CoV-2 IgG is most beneficial in reducing disease progression and death.
At present, the data are conflicting and both the NIH and the IDSA do not recommend use of convalescent plasma outside the use of a clinical trial.
Winthrop: Right now, they unfortunately do not play enough of a role. Not many places in the country are offering those therapies, mainly because it’s a feasibility issue. It is hard to dedicate a new space for infusions for people with COVID-19. Most infusion centers we have are keeping COVID patients out. They are receiving patients for chemotherapy, or their immunomodulators, or whatever they are getting, and those are not places where we want people with COVID to be. I know some have the necessary space, and some are trying to make space. However, I think the adoption of those therapies in the outpatient setting has been limited by that.
The monoclonal antibodies, as you know, are emergency authorized for people in outpatient settings, and there are data supporting their use in people in that setting. I think they are effective — they have been shown to decrease viral load and decrease risk for subsequent hospitalization. I suspect they will gain more of a role as more facilities are able to figure out ways to actually administer them.
The plasma is probably similar to monoclonal antibodies in that the earlier you use it, the more effect it is going to have. At least with the monoclonal antibodies, in the outpatient setting, where most people are new in their infection, it seems that they may not have mounted an antibody response yet themselves. That’s where we see the benefit. For people who are earlier in the course of their infection, there is probably some benefit whether they are in the hospital or not. However, are still waiting on the data from ongoing studies — it’s not totally sorted out yet.
Q: Are trials still examining these options as a containment option or supportive therapy for patients with COVID-19?
Calabrese: A study in U.S. nursing homes has shown that the Eli Lilly monoclonal antibody, bamlanivimab, may help protect patients from developing symptomatic COVID-19, announced in a press release on Jan 21. In the phase 3 BLAZE-2 COVID-19 prevention trial, bamlanivimab reduced the risk for COVID-19 by up to 80% in nursing home residents.
We find this interesting, however how the monoclonal antibody would be used as prophylaxis, for example during a COVID-19 outbreak in a nursing home, is not entirely clear. There are many ongoing trials investigating both convalescent plasma and the monoclonals, listed on clinicaltrials.gov.
Winthrop: There are still trials for plasma as well as for monoclonal antibodies. In terms of the latter, Regeneron is trying to figure out how to use them in inpatient settings. We are still waiting on data to come from some of those studies.
There are also studies out there looking at contact and ways to prevent new acquisition of infection. If the studies are overwhelmingly positive, there is potentially a role for prevention, too. However, I think it is harder to see how to use it in a prevention or contact setting outside of special circumstances. If you have a case around really high-risk individuals, like in a nursing home for example, then you could maybe make the case for using it. It would have to be a kind of individualized thing, or specific to the setting, where there is a lot of high risk around an individual’s case, where you could think about prophylaxis.
However, I think right now the most obvious place to use the antibody therapy — and really what our goal should be — is to be using them to prevent death and prevent progression in people who have risk factors for not doing well once infected.
Q: Are these trials still worthwhile now that vaccines have been developed?
Winthrop: I do. I think the vaccine rollout has, so far, been slower than what anyone has been hoping for. I think it’s going to take some time to vaccinate, so the monoclonal antibodies are certainly going to have their utility for a while. Even once you have widespread vaccine coverage, I feel they are going to have utility. Not everyone has an adequate vaccine response, and not everyone is going to be protected by the vaccine — they are not 100%. There are still going to be reasons to use these treatments in individuals. We also don’t know how long the vaccine lasts or offers protectiveness. So, it is important that we continue to develop these therapies.
Another issue is the arrival of new varieties of COVID-19 in the future. We are going to need the ability to adapt, I think, post-vaccine. I hope we continue developing them because I think we will need them.
Calabrese: Even with the arrival of safe and effect vaccines against COVID-19, until the majority of the population is vaccinated and circulation of SARS-CoV-2 in the community is decreased, we will always be in dire need of strategies to treat COVID-19, in particular to reduce progression to severe disease. Any means of reducing risk of infection and risk of progression to severe disease once infected will be crucial.
Q: What concerns about these treatment options have you heard from rheumatologists?
Winthrop: I have not heard any concerns. I think if there is any concern, it’s that they are not as widely available as they should be.
Calabrese: The main concern with the monoclonals is logistical — how to get this to patients who are sick at home with COVID-19. This requires presenting for an outpatient infusion. The infusion time is one hour, with one hour needed for observation after the infusion is completed. As you’d imagine, this requires some coordinating and solid safety measures, including for health care providers working these outpatient infusion centers.
Also, patients need to be infused within 10 days of symptom onset. Specific concerns regarding convalescent plasma are that the data showing benefit seem to fall outside the EUA indications — EUA for inpatients, benefit for treatment of early disease — as well as the finding that high titer convalescent plasma seems to be most effective. However, cut-offs for high-titer versus low-titer are not clearly standardized, and many different assays are being used.
Q: What are the potential side effects or conflicts with other medications?
Calabrese: None in particular at present.
Winthrop: The data that has been reported and used to support the EUA have looked quite good in terms of outpatients who have risk factors for progression being targeted with antibodies. Efficacy has been reported and, importantly, it looks very safe. There hasn’t been any safety signals in those groups of people.
The inpatient studies with these drugs — the Eli Lilly inpatient studies — were disbanded, but apparently it was not for safety reasons. However, I have not seen that data in a manuscript yet. Apparently, it was just due to a lack of efficacy. Meanwhile, Regeneron still has studies ongoing with an inpatient setting. We don’t really know about the inpatient setting yet.
However, again, if you look at the totality of the published data so far, it’s pretty clear that the people who are less sick, the ones who are earlier in their infection, and those who don’t have an antibody response yet themselves, that is where you are going to see the most benefit with these therapies, and they look safe with those groups of people.
For more information:
Cassandra Calabrese, DO, can be reached at 9500 Euclid Ave., Desk A50, Cleveland, OH 44195.
Kevin L. Winthrop, MD, can be reached at 270 Southwest Pavilion Loop OHSU Physicians Pavilion, Suite 320, Portland, OR 97239.