In August, the National Institutes of Health (NIH), the foremost medical and public health research agency in the U.S., announced a clinical trial to evaluate the efficacy and safety of potential new therapeutics for COVID-19, including monoclonal antibodies to treat the disease. The trial, known as ACTIV-2, is funded by the National Institute of Allergy and Infectious Diseases (NIAID) through “Operation Warp Speed,” a partnership led by the U.S. Department of Health and Human Services (HHS).
“Using an antibody generated by the immune system of a recovered COVID-19 patient gives us a jumpstart on finding a safe and effective therapeutic,” said NIAID Director Anthony S. Fauci, M.D., of the trial. “Investigating a variety of different therapeutics, including monoclonal antibodies, will help ensure that we advance towards an effective treatment for people suffering from COVID-19 disease as quickly as possible.”
Terri Wilder spoke with David Wohl, M.D., a professor of medicine in the Division of Infectious Diseases at the University of North Carolina at Chapel Hill (UNC), to learn more about this promising treatment trial. UNC is one of more than 25 initial sites participating in the ACTIV-2 trial being conducted by the NIH’s AIDS Clinical Trials Group to evaluate the safety and efficacy of treatments for adults with COVID-19 who do not require hospitalization.
Wohl is the site leader of the UNC Global HIV Clinical Trials Unit at Chapel Hill and an expert in HIV treatment and complications. He served two terms as a member of the HHS Antiretroviral Guidelines Panel.
In 2014, in response to the Ebola outbreak, Wohl traveled to Liberia, where he continues to conduct research with survivors to learn about chronic complications and sexual transmission of the Ebola virus disease.
In 2020, Wohl has helped lead the UNC clinical and research response to COVID-19 and is vice chair of two AIDS clinical trial group trials of SARS-CoV-2 therapeutics. He’s also the medical director of the UNC drive-through testing site. Wohl has an active clinical practice at UNC.
Terri Wilder: Dr. Wohl, thanks so much for speaking with me today. To start off, what has been the impact of COVID-19 in North Carolina?
David Wohl: It’s different from New York, that’s for sure. While New York, Seattle, and some other parts of the country were really hard hit early on, it took a while to hit here. It took a while before cases started to ramp up here. And while New York was seeing decreases in that huge surge and spike, here, we were just starting. So it’s really been this continuous upswing in the number of cases in North Carolina. Slow and steady.
We didn’t see a huge surge like we’d worried about—I think that’s a testament to our governor instituting some procedures that protected the population. But it’s been an ongoing, enduring marathon, rather than a huge mountain climb.
An ACTIV Approach to COVID
Wilder: Let’s jump right into the clinical trial ACTIV-2. What is its primary objective?
Wohl: It’s part of a group of studies. The ACTIV studies are looking at approaches to dealing with managing COVID-19. We’ve come up with a better name that’s really just a short name for what we’re trying to do, which is Rise Above COVID. So, if you visit riseabovecovid.org, you will see more about the study, and it can help you enroll in the study if you’re recently diagnosed with COVID-19.
Our study is the flagship treatment study for outpatients in the world. What we’re doing is leveraging the power of the HIV Treatment Network to answer fundamental questions like, Can we develop a good treatment that prevents people from getting hospitalized? That lessens symptoms? That prevents people from shedding the virus to others?
If you’re an outpatient diagnosed with COVID-19 and you have a really stuffy nose and a cough and you’re getting short of breath making your bed; those people want to know, “Is there a medicine I could take?” Right now they’re being told there’s not a medicine. There’s a medicine if you’re in the hospital, but there’s not a medicine for folks who are outpatients with the illness.
We need a treatment we can offer people early on, especially those who might be at higher risk of complications from COVID-19—really interrupting or aborting the infection.
Wilder: There’s been a lot of discussion about COVID-19 viral shedding—does the study address anything about that?
Wohl: One of the outcomes we’re seeking is whether or not the treatment decreases shedding of the virus. We’re going to be doing swabs in the nose, to see if it clears the virus compared to placebo. That’s an important part of what we want to do, as well.
Wilder: Can you talk about the study design and take us through that process?
Wohl: This is a unique study design in that it will be open throughout the country. We’ll probably end up with 100 to 200 sites in the U.S. alone, to start. The design of the study is novel in that it’s called an adaptive design. Cancer treatment trials have done this for a while, because, for many different cancers, there are different combinations of therapies that could be given to patients; it’s usually a cocktail. Is Cocktail 1 just as good as Cocktail 2? What about three drugs instead of five drugs? Researchers are used to conducting clinical trials where new drugs come along, or where you might find out a drug isn’t looking so good, so you’re going to have to stop comparing it to the others.
That doesn’t fit here. We have a design where, as drugs become available and are promising, they can enter the trial. As drugs enter the trial and are not looking good, they can be pulled out of the trial. So we may have multiple drugs at once; we may have one drug at a time.
Wilder: I’ve been reading about what’s called COVID-19 long-haulers. Journalists like Ed Yong from The Atlantic have written a couple of pieces about it. When you’re thinking about this trial, could it help some of these long-haulers who have been ill for 30 or more days, some even approaching six months?
Wohl: If the therapies are going to work—the therapies we’re talking about are for early disease. We’re talking about within the first week or so of symptoms, where we’re trying to abort the infection. These are not therapies that would be useful for people who are really dealing with the sequelae of the infection.
In those people, it’s very unlikely that the virus itself is the problem. This is not something that’s likely to help with the longer-term complications. This is really when you get into the realm of, you know, how do we correct the immune system’s misguided response to the virus?
The COVID-19 Drugs Being Investigated in ACTIV-2
Wohl: We’re starting off with one particular agent, a monoclonal antibody, as you mentioned, that we compare to placebo. If another drug looks promising, we’ll have that added. And then participants get randomized to that Drug A, or Drug B, or placebo. If Drug A doesn’t do as well, then it’s Drug B versus placebo. That’s, I think, the most important part of the study.
The second is, some of the drugs that we’re studying—in fact, the majority of them—will really not have been studied much previously. They might have gone through some safety phase 1 evaluations, but probably not a lot is known about the drugs, unless they’re used for something else.
And so, we have two phases, where drugs will enter in a phase 2 portion of the study, where we collect data on safety and preliminary data on efficacy and how well the drug works. If it looks good after being studied in the 110 people given the drug and the 110 given placebo and based upon parameters we’ve already identified, the drug graduates to phase 3, which is the Full Monty. That’s where we really find out: Does the drug do what we want it to do, which is prevent hospitalization and death? Then we would enroll up to 1,000 people getting the drug, and another 1,000 people getting the placebo.
Again, with the adaptive design of more than one drug, it means fewer people need placebo, because drugs are compared to placebo, not to each other.
So, there are two major factors: Drugs could come in and out of the study, if they look promising or do not look promising. Then we can evaluate a drug, both through phase 2 and phase 3, all within the context of one study, rather than separating it out and drawing the study out over a longer period of time.
Wilder: My understanding is that the first therapeutic to be tested in this trial will be LY-CoV555, an investigational monoclonal antibody made by Eli Lilly and Company. What can you tell me about this therapeutic?
Wohl: It is designed based upon an antibody that was isolated from a patient who recovered from COVID-19, and his antibody profile showed that it worked very well in neutralizing the antibody. It’s directed against the protein on the surface of the virus that helps the virus get into cells, so it’s a good target.
It’s one monoclonal; some monoclonal antibody therapeutics are a combination of antibodies. This one is just one. The hope is that it’s powerful enough, and that the virus wouldn’t get around it.
The antibody is infused through an IV over a pretty short period of time. It’s gone through the phase 1 process, and now, in our study, it would enter into phase 2 and, hopefully, phase 3.
Wilder: You mentioned that the treatment would be delivered through infusion. Why is infusion being considered versus another method?
Wohl: Not all monoclonal antibodies are given by an infusion. Some are given by an injection in a muscle, or even some are being developed that are subcutaneous. The reason you can’t take it orally is because it’s a protein, similar to insulin. If you eat it, your body will digest it. Your body’s gastrointestinal tract juices will break down proteins. That’s what they’re supposed to do. So, you can’t take it as a pill. It also works quicker if it’s injected, one way or the other. So that’s why these treatments are either infused or injected.
The good thing about the treatment is it’s a one-time deal. So it’s not like you have to take a pill every day for three, five, seven, or 14 days. The idea behind these is you get it, and that’s it.
Monoclonal Antibodies: From Ebola to HIV to COVID
Wilder: What exactly is a monoclonal antibody, and what does it do in the body?
Wohl: Monoclonal antibodies refer to antibodies that are all one type; that’s why they’re called monoclonal. They’re laboratory-made, and that’s different than what people think about when they think about, maybe, plasma. People have heard about donate plasma after surviving the disease. That plasma can be used to treat people who have the active disease. With COVID-19, I think there’s been really good press and awareness of the potential value of plasma in people who are suffering from more severe COVID-19 cases.
The whole idea of plasma is that you get a bunch of antibodies from someone who survived, and you give it to someone who’s struggling to survive, and those antibodies kickstart their response to fight the virus.
Monoclonal antibodies are even better, theoretically, because you can find the antibodies that are most effective in the lab at neutralizing the virus. Like, for instance, antibodies that attach to the outside of the virus, making it hard for the virus to get inside a cell. If you could find really effective antibodies in the lab from people who survived, you can manufacture them. Rather than a hit-or-miss, with monoclonal antibodies, we can target the best antibodies that we’ve identified, manufacture them, ramp them up into a high concentration, and give them to people.
Another nice thing about monoclonal antibodies: They work immediately. It’s not like a vaccine that your body has to make a response to—this is the response. Hopefully the idea is, it starts working right away and blocking the virus from getting into cells.
Wilder: Are there other diseases that have been treated with monoclonal antibodies?
Wohl: Not too many. Ebola happens to be one of them. People have heard about ZMapp and similar drugs—those are monoclonal antibodies that work against the Ebola virus.
This is a new technology. We’ve considered it for people with HIV. We’ve found that there are some people who make really great antibodies against HIV, and so we’ve copied those antibodies and we’ve been using them in experiments to see if we can treat HIV—or even prevent HIV.
There is some precedent, but by and large, this is really a new technology and we don’t use it often. Certainly, antibody-derived therapy is used for other diseases. Certainly in immunological diseases, it’s very common that we use antibodies that target the immune system or chemicals that the immune system makes to treat conditions like psoriasis, Crohn’s disease, or rheumatoid arthritis. So we have the same technology and same model being used here, but for an infectious disease.
Wilder: Why do you think monoclonals are a promising therapeutic class for treatment, as well as potentially prevention, of COVID-19?
Wohl: One thing I want to be clear about: We’re not restricted to monoclonals. If there’s another type or class of drug that comes along that looks promising for treatment and in outpatients, that could be clearly studied in the context of this study.
The other one thing I’d want to say is, even if we get a vaccine, a vaccine is not going to be 100% effective. No vaccine is 100% effective. There are going to be people who don’t want to take the vaccine or who don’t have a chance to get the vaccine. So that means there are going to be people getting COVID still, and we need to be able to treat those people.
Right now, we tell people to go home, don’t infect anyone, and take Tylenol. We need something that we can actually treat people with to prevent them from getting sicker. I’m taking care of people in the ICU who, if we only had something effective that we could have given them early on, we probably could have prevented this from happening. So, we need this.
The other thing is, we need people to roll up their sleeves and be part of this. Being enrolled in a study is not easy, but the reason we now have great HIV therapies is because people signed up to participate in clinical trials and phase 2 studies. The only way we’re going to get a vaccine for COVID-19, the only way we’re going to get treatment, is if people sign up. We’ve all got to do it. If we all don’t work on this treatment together, we’re not going to get back to normal.
Wilder: The ultimate goal is to stop the progression of disease to severe illness and death. Looking forward, do you think monoclonal antibodies could be used similar to PrEP [pre-exposure prophylaxis], like we have for HIV?
Wohl: There are studies happening right now where that is exactly the idea. Maybe after there’s an outbreak in a nursing home, a monoclonal antibody would be the perfect therapy for people who might have been exposed before the virus really takes root. Like, preemptive or preventative therapy.
A vaccine would take too long, right? So, this is exactly what’s being studied in nursing homes and in other occupational settings and households where people might have been exposed or at risk of exposure to COVID-19.
COVID-19 Study Recruitment and Prioritizing Inclusiveness
Wilder: You mentioned that overall, you’re recruiting about 100 to 200 people. Is that for your site, or overall, across all the sites?
Wohl: This is the sort of study that could go on forever—hopefully not—until we find an effective treatment. For every agent in the phase 2 of the trial, 220 people would be randomized to the drug or placebo. And then, if the drug looks good and enters into phase 3, it would be altogether 2,000 people who would be randomized to the drug or placebo. If there’s another drug that enters the study—same thing: 220 and then, overall, 2,000.
It could keep going indefinitely, depending on the number of people and drugs. So, the number of that total that could be studied in this trial could be huge.
Wilder: How are you recruiting patients for the study and making sure that people of color, specifically African Americans, are recruited?
Wohl: We feel strongly about recruiting a diverse cohort of people for the study. We feel more than strongly—we’re taking action. We want to make sure that people who are most impacted, and disproportionately impacted, by this pandemic—people of color, including African Americans and also Latinx folks—have an opportunity to participate in the study.
Wilder: That’s great to hear.
Wohl: On the one hand, we’re not saying, well, the burden of the experimentation should be borne by people of color. Yet, at the same time, we want to make sure that the research is reflective of the populations, again, that are most impacted.
There’s a balance there.
We are leaning towards making sure that the study can reach people who at least can have an opportunity to say ‘no,’ and we’ve taken a lot of measures to try to reach out. One is, we’ve formed a community advisory board, taking a page totally out of the HIV research book. The community advisory board is made up of people who’ve been active in HIV research, but have also recruited people who’ve been directly impacted by COVID-19—a very diverse group of people. We’re also reaching out to and recruiting in other groups that have also been hard hit, including Indigenous populations, and getting representation on our community advisory board that represents that constituency.
Also, all of our materials are available in English and in Spanish, whether it be our consent forms, a flip chart, or our websites, activ-2.org or riseabovecovid.org—the information is in English and in Spanish.
The website leads to a contact center, 24 hours a day, seven days a week, where someone will answer questions about whether or not you seem to be eligible for the study, in English or Spanish, and link you to a site near you in English or in Spanish so that you could be further screened and we can determine whether or not the study is a good fit for you. So we’re really trying to reach out.
Wilder: And do you have plans to further reach out?
Wohl: Yes, we’re going to reach out increasingly to organizations that need to know about the study and ask for help. We want to make sure that organizations that represent all groups of people—whether it be older people, people living in cities, farm workers, or people with disabilities—we want to make sure that the different stakeholders who really have skin in the game when it comes to COVID-19 are at least aware of our study, and can help disseminate positive messages about it.
We started a campaign that I think will be very empowering. We want everyone to think of COVID-19 as something we have to work together to overcome, the idea being you’re not a COVID-19 patient, you’re part of the solution. And you’re part of the solution by joining a study.
Wilder: I have a question about how COVID-19 testing could impact the study and enrollment. Across the country, we’re hearing that labs are overwhelmed, results are delayed, and there are people who are really sick but have negative test results. Could these factors impact trial enrollment?
Wohl: Testing has been problematic and a major complication. We’ve known that from the beginning. Despite being told anyone who wants a test can get a test, we see clearly that’s not the case. We know that there are all sorts of types of testing, which can be confusing. The one thing I’ll say is that a lot of people are getting tested now, where before, they weren’t. So there is more testing going on, which is great.
But, yes, we agree. Access to testing is a challenge as well. If you can’t find out that you’re positive, how can you join a treatment study?
The good news is most symptomatic people, even with the latest CDC recommendations, are not being turned away from testing sites. Still, I think testing confusion may be an issue we have to deal with—it is part and parcel of the landscape.
We’re hopeful that the vast testing that’s really needed will continue to ramp up, and there are some new technologies that may help with that.