‘Really include everyone in the trial’: A Q&A with the protocol chair of the PhIII monkeypox antiviral study

On Sept. 8, the AIDS Clinical Trials Group and the National Institutes of Health began a Phase III clinical trial of tecovirimat, an antiviral approved by the FDA for smallpox. The placebo-controlled study will look at the efficacy of the drug in reducing lesions and could serve as the basis for an expanded label of the antiviral.

The US government has more than 1 million doses of the drug in its strategic national stockpile and the CDC has opened its use via an expanded access program during the monkeypox outbreak this summer.

“We currently lack efficacy data that would help us understand how well this drug may mitigate painful monkeypox symptoms and prevent serious outcomes,” Anthony Fauci, director of the NIH’s NIAID, said in a statement last Friday. “This clinical trial was designed to answer those important questions.”

Timothy Wilkin

Endpoints News spoke with Timothy Wilkin, protocol chair of the study, on Tuesday morning, shortly after the FDA updated its messaging on the drug to say that CDC scientists are “actively monitoring for changes in the monkeypox virus that could make the virus less susceptible to TPOXX,” as the antiviral is used more widely.

“Because of the potential for the virus to become resistant to TPOXX, it is important the drug be used in a judicious manner,” the FDA said.

Also Tuesday morning, the Los Angeles Department of Public Health announced that it had confirmed, with the CDC, the “first death due to monkeypox” in a resident of the local county. The person was “severely immunocompromised and had been hospitalized,” the health department said.

Wilkin, who is assistant dean of clinical research compliance at Weill Cornell Medicine, has previously conducted trials for ACTG and his main research centers around the epidemiology of HPV and anal dysplasia in people living with HIV.

The following interview has been edited for length and clarity. 

Endpoints: Let’s start by talking about how the Phase III trial came to be, and a little bit about how you got involved and what your role is in the study.

Wilkin: The National Institutes of Health and NIAID felt that there needed to be a randomized clinical trial to evaluate the efficacy of tecovirimat. The FDA has been strongly encouraging the randomized controlled trial as it’s really the only way to establish efficacy for the drug. NIAID decided to do the trial through the AIDS Clinical Trial Group because they have a huge network of sites to choose from and they asked me to develop the protocol. We had our first team meeting on July 21 and we enrolled our first participant Sept. 8, so really quite a rapid development.

Endpoints: Can you take me back to that first meeting on July 21? What that was like and who was involved?

Wilkin: So we quickly assembled a comprehensive team of people to develop the protocol, so a multidisciplinary effort of investigators, people who were treating monkeypox at the time, data managers, statisticians, pharmacologists. I really think the key question we had to wrestle with was whether we had the availability of tecovirimat through this expanded access IND and our limited clinical experience had been positive. The drug seemed to be safe. Everyone was comfortable with that, and people seemed to respond. So we developed a study with that in mind — that the risk-benefit probably favored tecovirimat for many people, including those with severe disease, people who are pregnant, and so we came up with the general design, which was the randomized portion to establish efficacy, but then to have an open-label portion of the study to treat people where we did not feel there was as much as clinical.

Endpoints: That brings me to my next question. Can you describe a bit more the setup of the STOMP study? There are multiple arms of patients receiving tecovirimat for 14 days and then a planned enrollment of a little more than 500 people.

Wilkin: For people coming into the study, we ask two questions. The first is do they have the monkeypox disease and is it symptomatic? With that first, assuming the answer is yes, let me ask the question, are they appropriate for randomization or should they just receive open-label tecovirimat? If they’re appropriate for randomization, that’s where we have the 530 people where we’re trying to show that tecovirimat leads to faster resolution of clinical symptoms than placebo. We’ve favored the randomization 2:1 for tecovirimat. The open-label portion is a detailed list of certain populations. We decided that children, people under 18, should be just provided open-label tecovirimat. We did that because we really wanted to focus on the pharmacokinetics and safety of the drug in children because we know that in different parts of the world, children are affected by this virus quite often, so we wanted to use this opportunity if there were children that were diagnosed with human monkeypox in this epidemic that we would focus on in a detailed way the pharmacokinetics. Generally, for pregnant women, the available data, the clade 1 of the virus that is endemic in parts of Africa suggests poor pregnancy outcomes and we felt it was important to offer people who are pregnant the opportunity for open-label for tecovirimat rather than randomization. Similarly, the pharmacokinetics of the drug can be altered during pregnancy so we wanted to focus on pinning the pharmacokinetics. Then there are groups of people that had serious disease already, or let me say disease that had the potential for serious long-lasting outcomes…People who are severely immunosuppressed…We developed it in collaboration with the FDA, they pushed us to really include everyone in the trial, either in the randomized portion or in the open-label portion, so there’s almost no one with symptomatic monkeypox disease that wouldn’t be eligible for our trial.

Endpoints: The US stockpile of tecovirimat includes both oral and IV formulations, but this study is focusing on the oral drug, correct? Can you expand on the reasoning behind that?

Wilkin: We do not have intravenous tecovirimat in this trial. It’s been quite rare that anyone needs to receive the drug intravenously.

Endpoints: A recent CDC study with data as of Aug. 20 looking at the expanded access to tecovirimat reported that about 46.3 of the patients who received the antiviral were living with HIV. And you talked about this a little bit earlier, but can you talk about including the AIDS Clinical Trials Group in the study, as well as your own research experience studying the epidemiology of HPV as well as people living with HIV? Can you talk about bringing together all those different areas?

Wilkin: The AIDS Clinical Trials Group is an incredibly experienced cooperative research group, and because of our broad reach, we were asked to conduct the study. However, we are advocating enrolling people with HIV and people without. People with HIV are affected by a number of sexually transmitted infections, and we don’t completely understand why they are so susceptible to certain infections. For human monkeypox virus, we don’t have an adequate explanation yet of why they seem to be infected more often than their counterparts without HIV. This study will not answer that question, but we will be able to look at the interactions of tecovirimat and certain medications to treat HIV to better understand whether any of these interactions are relevant.

Endpoints: And also in that CDC study, it’s found about 3.5% of 340 patients with data, had adverse events. That’s a relatively low percentage if viewed by clinical trial standards. Can you talk about what the STOMP trial will look for in terms of safety?

Wilkin: For the STOMP trial, we’re focused on more serious adverse events, so grades 3 or 4 adverse events. We’re not focused on the low-level mild or moderate side effects. We’ve done that to simplify the study to encourage rapid enrollment. It’s difficult to interpret adverse event data in the absence of a control group, specifically in the absence of a placebo group, so it can be difficult to sort out what adverse events are in fact related to tecovirimat and what adverse events are related to the underlying infection, so STOMP will help to sort that out in a way that the expanded access IND studies cannot.

Endpoints: On the topic of rapid enrollment, how long do you expect the study to last? I know on Clinicaltrials.gov, that there’s a primary completion date anticipated for April 30 of next year.

Wilkin: Originally we planned to enroll this study over eight weeks. However, the epidemic is receding in the US, which is terrific, so it may take longer to enroll for the randomized portion of the study. The portion of the study for children and pregnant people will likely take much longer to be able to get that pharmacokinetic and safety data. We are also pursuing international sites. Those have not been confirmed, but that’s an additional option open to the AIDS Clinical Trials Group to enroll patients.

Endpoints: I was going to ask about the international lens because there’s been a lot of criticism that a lot of countries don’t have access to either the antivirals or vaccines, so I was going to ask if there are any plans for international sites, as well.

Wilkin: Yeah, I mean, personally, I would love for international sites to participate. Often the regulatory landscape can be very challenging in these countries for clinical trials with an investigational agent; however, several of the countries’ regulatory bodies and health authorities have pushed the sites to participate in the study. Ideally, they’ll be able to approve the study in expedited fashion to really bring access to the drug to the areas that desperately need it. I do want to point out that it will be very difficult to really provide tecovirimat on a worldwide scale in the absence of efficacy data. That’s a major reason why we need a randomized clinical trial so that we can have the justification to scale up and provide access around the world, like we’ve done for HIV.

Endpoints: If it were to expand to other countries, would that mean that enrollment would be larger then?

Wilkin: The randomized portion we think will still be what we planned. That wouldn’t change by adding international sites. There have been no randomized clinical trials of human monkeypox virus, so no sites have clinical experience with attaining these particular endpoints, so given the uncertainty around that, we have built-in evaluations with the database monitoring board and clinical sites needed to accurately power this study.

Endpoints: This morning or maybe last night, the FDA updated the emergency preparedness website on monkeypox saying that CDC scientists are monitoring for changes in the virus, particularly around the VP37 protein since Tpoxx’s label includes a low barrier to viral resistance and they recommend the “drug be used in a judicious manner.” Can you talk a little bit more about how this trial will be observing changes in the virus? That’s something that people became very familiar with during the different lineages of SARS-CoV-2.

Wilkin: Very limited data suggest that there can be changes in the virus that perhaps make tecovirimat less effective. That’s part of the reason why we favor randomization 2:1 so that we would have more people exposed to tecovirimat and more opportunities to observe participants for development of resistance or development of changes in the virus. In addition, the inclusion of people who are severely immunosuppressed will be important for evaluating resistance because just like Covid, we would expect people with a suppressed immune system to be the most at risk to develop resistance or changes to the virus. This study will be important to characterize how commonly this occurs. Even if we document it, what the study won’t answer is how often the mutated virus, or resistant virus, is transmitted.

Endpoints: Take me through the decision-making a little bit more in terms of having ACTG and the NIH leading the study versus the drug manufacturer, SIGA.

Wilkin: AIDS Clinical Trials Group has a vast array of sites within the US and around the world that are incredibly experienced at performing clinical trials. During Covid, this network was used to rapidly implement Covid therapeutics trials. It’s not clear that SIGA would in fact have the resources to conduct these clinical trials and because the US government was heavily involved in the development of tecovirimat, there may be issues around that.

Endpoints: This is worst-case scenario, but drug development is a difficult path and clinical trials are meant to test the robustness of treatments, so what happens if the STOMP study finds that tecovirimat is not better than placebo? The US stockpile has more than a million doses, albeit originally intended for smallpox, so what happens to that EA-IND for monkeypox or what happens in terms of treatment going forward?

Wilkin: Well, then it becomes critical to develop new therapies or to study new therapies. That’s data that we needed to know. It’s not acceptable to provide ineffective drugs to thousands of people. In addition, we need an effective therapy both for the current strain of the epidemic but also for areas of the world where it’s endemic and there’s a high mortality rate and a public health issue that needs to be addressed. We’ve learned many times over the years that infectious disease problems in other parts of the world can affect us in the US, and we are safer in the US if we help to solve these problems before they become problems in the US.

Endpoints: In that vein, ACTG Judith Currier mentioned the study will also evaluate markers “that may tell us that the drug is working so we can identify future promising drugs.” Can you expand on that thought a little bit, what you’ll be looking for in terms of various markers?

Wilkin: Currently, our primary endpoint is a clinical endpoint, a resolution of skin lesions, and it’s subjective and it requires participants and study staff accurately access skin lesions. So we would like a surrogate marker that is objective, laboratory-based to be able to accurately access whether an antiviral is working for this infection. We can think of analogies in HIV studies where we can look at the changes in viral load and its relationship to outcomes to be able to identify biomarkers such as blood levels of human monkeypox or skin lesion levels to be a surrogate marker for efficacy.

Endpoints: BARDA recently signed a procurement agreement for another smallpox drug, Chimerix’s Tembexxa (brincidofovir). Are you aware of any plans at NIH, ACTG or elsewhere to also study the efficacy of that drug when it comes to monkeypox?

Wilkin: I don’t know that any studies have been planned. Some investigators have proposed looking at combinations of tecovirimat and brincidofovir to more effectively treat human monkeypox virus. I would say that we need controlled efficacy data of tecovirimat first before we investigate combinations, but I do think that combinations of antivirals are attractive for people who have severe immune suppression and are at the highest risk for poor outcomes. I think STOMP will provide a foundation for future trials of combinations of antivirals or alternatives.

Endpoints: As more and more data come to light, the number of cases is increasingly being reported in people of color. Clinical trials, in general, they struggle to be representative of demographics in the US. Can you talk about how this trial will work to ensure that patients are representative?

Wilkin: The AIDS Clinical Trials Group has a long history of enrolling people of color and populations representative of the HIV epidemic, so all our sites in the US have strong community partners to really help engage those affected to get into clinical research. It’s something that we prioritize. It’s something that we monitor. It’s something that we frankly select our sites based on, their ability to enroll people of color in our clinical trials.

Endpoints: Is there anything else you would like to highlight or add?

Wilkin: One thing that we’ve had a few sites that have really not felt comfortable in this study because they just think that everyone should get drug through the expanded access program or really that there’s not a need for controlled data, so obviously we feel different and the FDA disagrees with that strongly. They think that controlled data is absolutely required. So the drug isn’t going to be readily or more easily accessible until there’s controlled clinical trial data that would allow first emergency use authorization and then FDA approval based on the safety data.

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