Alfred Kim, MD, on COVID-19 Pre-exposure Prophylaxis for Patients with Autoimmune Disease

Dr Kim reviews the importance of PrEP in protecting patients on immune-suppressing drugs, approved formulations, and obtaining access.

Alfred Kim, MD, is an assistant professor of medicine and director of the Lupus Clinic at Barnes-Jewish Hospital at the Washington University School of Medicine in St. Louis, Missouri.

TRANSCRIPT:

Dr. Alfred Kim:  Hi. My name is Al Kim, an adult rheumatologist at Barnes-Jewish Hospital at Washington University School of Medicine in St. Louis, Missouri. Today, we'll be discussing the role, impact, and issues surrounding PrEP, or pre-exposure prophylaxis, therapy against COVID-19.

As you're all aware, the treatments used to attenuate disease activity in our rheumatic disease patients also blunt immune responses to vaccination.

This includes SARS-CoV-2 vaccination, where certain classes of medications have been associated with poor generation of antibody responses, specifically B cell-depleting therapies, such as rituximab; antimetabolites, particularly mycophenolate or mycophenolic acid; and high-dose prednisone greater or equal to 20 milligrams a day.

This is highly problematic for our patients since this increases the risk of breakthrough infections. Compounding the situation is that these medications may also increase the risk of severe manifestations of COVID-19, including death.

Unfortunately, these patients are unnecessarily bearing the brunt of the pandemic.

First, they've done everything they can to protect themselves from contracting COVID-19, including vaccination. Second, these efforts, through no fault of their own, can't confer the level of protection against COVID-19 that it should.

When you combine this with the 40% of the US population that remains unvaccinated and the certain populations that have forsaken actions to reduce the transmissions of SARS-CoV-2, the immunocompromised are placed in unnecessary risk. Of course, the mask of immunosuppression is invisible, so these others will have no idea what risk they are putting our patients at.

Fortunately, a spin on an old therapeutic concept has emerged to provide a safety net for those who are immunosuppressed. That's PrEP. The concept of PrEP has been used for decades, first, for those with immune deficiencies with intravenous immunoglobulin, or IVIG, then more recently, for HIV with antiretroviral drugs.

For COVID-19, PrEP takes the form of immunoglobulins, or antibodies, with high affinity against the spike protein of SARS-CoV-2. These antibodies are generated in mammalian cells, specifically CHO, or Chinese hamster ovary cells, that secrete the antibodies into a culture medium. Then they are purified, similar to how antibody-based biologics are purified.

Currently, one product has EUA, or early use authorization, from the FDA for use as PrEP, known by the brand name Evusheld, which is comprised of 2 monoclonal antibodies, tixagevimab and cilgavimab. This product from AstraZeneca has a wide range of medical conditions and immunosuppressive medications that make an immunosuppressed patient eligible.

Within the systemic autoimmune space, this includes 1, high-dose steroids—this is greater or equal to 20 milligrams of prednisone or equivalent a day; 2, antimetabolites— methotrexate, sulfasalazine, leflunomide, mycophenolate; 3, TNF inhibitors; and 4, biologic agents that are immunosuppressive or immunomodulatory.

Interestingly, they explicitly list B-cell-depleting therapies, but there is clearly a wide range of biologics that are included within this umbrella. Notably, treatments like hydroxychloroquine monotherapy are not eligible, largely because of the totality of data that have been generated to date demonstrate that these people generate good humoral responses following vaccination.

Also, there continues to be no role of antibody testing. If you have a qualifying condition or medication, you are eligible.

I think this is pretty smart since data generated from Mike Diamond's group with our COVaRiPAD study showed that, while those on TNF inhibitors have detectable levels of antibodies against the spike protein following vaccination, these antibodies poorly neutralize variants of concern, including Delta.

This means that, if you check antibody levels in someone who's taking anti-TNFs, and they're up high, this may actually provide a false sense of security, as they are likely not going to be protected against variants of concern. Our data, though, also highlights, though, the benefits of boosting. These people, once they got the third dose, were able to neutralize all variants tested.

These data, among others, enabled the FDA to put in very specific language about the vaccination and Evusheld within the fact sheet itself. "Pre-exposure prophylaxis of the Evusheld is not a substitute for vaccination for whom COVID-19 vaccination is recommended." Therefore, in this population, everyone should be first vaccinated if possible.

Second, the emphasis on the word recommended enables those with intolerances or allergic reactions to COVID-19 vaccination to obtain Evusheld without further doses. But the bottom line—all efforts to vaccinate or boost must be made first.

Evusheld has several important properties that allows it to work as PrEP. First, it's a combination of 2 monoclonal antibodies derived from convalescent COVID-19 patients. Second, these antibodies have broad neutralizing activity against most variants of concern. I say most since it has roughly 150, 200-fold higher titers that are needed to neutralize Omicron based off of data generated from the FDA, Oxford University, and Washington University School of Medicine. I'll come back to this issue of whether we think this is a problem or not.

Third, the half-life of both the antibodies and Evusheld is extraordinarily long for an IgG1. Typically, IgG1 molecules have a half-life of 23 days. Modifications to the Fc domain increases the half-life to over 80 days. This dramatically increases the time interval between doses, in this case, for Evusheld, 6 months.

These modifications to the Fc domain also reduce antibody effector functions to minimize the risk of antibody-dependent enhancement of disease. This is essentially where the antibody actually increases the infectivity of the virus. This has been observed with dengue virus, but this is not a concern here.

Two clinical trials, PROVENT and STORM CHASER, were done to examine the safety and efficacy of Evusheld for the prophylaxis against SARS-CoV-2 symptomatic illness. PROVENT used Evusheld as PrEP, where a 77% relative risk reduction was observed compared to placebo.

In STORM CHASER, Evusheld was tested as post-exposure prophylaxis. There, a 32% reduction within the first 3 days after randomization was observed, which was not statistically significant. Therefore, the lone indication for Evusheld is for PrEP.

The safety profile of Evusheld looked quite good to me. Most common adverse events included headache, fatigue, and cough, and these frequencies were similar to those in the placebo arm. Anaphylaxis is very rare. In over 1,200 study patients given Evusheld, only 1 had an anaphylactic reaction.

Peculiarly, there was a cardiac signal that was noted. Specifically, 0.6% of Evusheld recipients had a serious cardiac adverse event — angina, elevated troponin, acute myocardial infarction. This is compared to 0.2% of placebo participants.

Per the fact sheet, all of these adverse events were in those with "cardiac risk factors and/or a prior history of cardiovascular disease at baseline." Therefore, shared decision-making will be obviously important for these particular individuals.

Let's go back to the issue with Omicron. I had mentioned before that about 150- to 200-fold more Evusheld is needed to neutralize Omicron in vitro compared to other variants of concern. This sounds terrible at first glance, and there are anecdotal reports of breakthrough infections on social media following Evusheld administration.

There are a couple things to note, though. First, remember that the reduction in relative risk of symptomatic COVID-19 with Evusheld was 77%. It wasn't 100%. Of course, this was pre-Omicron. People could easily say, "This is going to increase because of Omicron's presence."

Then, second, when you work the numbers out, it still may not be an issue. Using IC, or inhibitory concentration 50s, or IC50s, as the endpoint, which is a commonly accepted endpoint in the SARS-CoV-2 neutralization antibody literature, the IC50s for the antibodies in Evusheld is somewhere between 170 to 275 ng/ml.

Based on pharmacokinetic data in the fact sheet, serum levels of both antibodies is 4,000 ng/ml, and this is 7 months after administration. Remember, 150 milligrams of each antibody is injected intramuscularly, which is a huge load of monoclonal antibodies. Therefore, at the 7-month time point, serum levels are 14 to 23 times higher than the IC50 for Omicron.

Of course, this medication is administered every 6 months. While this is a theoretical argument that this is going to be effective against Omicron, time will tell whether or not Evusheld is protective against Omicron infection. The potential is there that it can.

You may wonder, "How do I access Evusheld?" Doses are highly constrained right now. Where I'm practicing, at Barnes-Jewish Hospital in St. Louis, Missouri, we only have received a small handful of doses initially.

Thus, we have had to prioritize patients into a top tier that'll have access to the first round of doses. Before they can get those doses, they are then selected from a lottery system. Then we are able to identify who can get Evusheld.

Much like everything else COVID-19, this rollout will just amplify health disparities. For example, this lottery system I just described will tilt things in the favor of those who already engage with the health care system, leaving the vulnerable more vulnerable.

There are other antibodies, such as sotrovimab by Vir Biotechnologies and GlaxoSmithKline, that's likely to obtain FDA EUA for PrEP, and supply chain is increasing. Things will get better, but this is the unfortunate reality we have to deal with in the US for the short term.

In summary, PrEP for COVID-19 is going to be a critical part of the arsenal for providers who treat the immunosuppressed. Finally, our patients can start to experience what it was like pre-COVID.