Is Remdesivir a Viable Option for Treating COVID-19?

Segment description: Matthew Davis, PharmD, infectious diseases clinical pharmacist at UCLA Ronald Reagan Medical Center, provides an overview on the agent remdesivir.

Interview transcript: (modified slightly for readability)

Contagion®: Thanks for joining us for another Contagion coronavirus video. Today we're joined by Dr. Matt Davis. We'll be talking about a presentation that he gave on behalf of SIDP, regarding remdesivir. Thanks so much for joining us.

Davis: Yeah, absolutely. Thanks for having me.

Contagion®: So, can you discuss the mechanism of action of remdesivir?

Davis: Yeah, absolutely. Remdesivir is a nucleoside analog. It works through inhibiting viral replication through competitively inhibiting viral RNA polymerase, kind of similar to acyclovir and ganciclovir. The interesting thing about remdesivir is that it has this phosphoramidate attachment to the ribostring, which is essentially a nice way to deliver a monophosphorylated nucleoside analog intracellularly. Once it's inside the cell, the phosphoramidate is cleaved by esterases to the monophosphate form, which then is subsequently phosphorylated to the triphosphate compounds, which is the pharmacologically active version. So it is a nice way to kind of circumvent the rate limiting phosphorylation step that we see with ganciclovir or acyclovir in the other nucleoside analogs.

Contagion®: So, let's talk about pharmacokinetics. What do we know so far?

Davis: Yeah, that's a great question. Remdesivir pk is a little bit tricky because we really are tracking the concentrations of a number of different metabolites. So the remdesivir compound itself, the prodrug phosphoramidate compound, that doesn't really matter all that much. It has a very rapid clearance from the plasma. Once it enters the cell, it's rapidly converted by esterases to the various nucleoside metabolites. The thing that we actually care about the most is the pharmacologically active triphosphate form and the intracellular concentrations of that one. It has a relatively long half-life intracellularly, it's about 11 hours. So that's sufficiently long enough to allow for once daily dosing. There's a second nucleoside metabolite that we look at, which is the dephosphorylated form, which has a really long half-life as well, about 20 to 25 hours. So that allows us to administer remdesivir once daily dosing. From a metabolism standpoint, like I said, the prodrug is cleaved by intracellular esterases. Then from an elimination standpoint, it's partially excreted, renally, and then also hepatobiliary.

Contagion®: So safety is obviously really important. So looking at the data that we have right now, what do we know about safety?

Davis: Yeah, that's a that's a great question. I think we need a little bit more data before we can make a final judgment call on safety of remdesivir. So far in the preclinical studies, it seems to be generally well tolerated. The most notable adverse events that has been reported is obviously transaminitis, which has led to the exclusion criteria. [In] the ongoing clinical trials with contaminates values it seems to be generally mild grade 1, grade 2 transaminase elevations, and then also self limiting. The resolution usually occurs days to weeks after cessation of therapy. Other adverse events that have been reported, are what we would normally expect in any clinical trial or any studies is gi intolerances. It is intravenous, so there is some proportion of patients who experience phlebitis. But all in all so far, it seems to be generally well tolerated.

Contagion®: So I know that remdesivir has been studied for other viruses. So can you summarize a little bit about what we know about the activity against these other viruses?

Davis: Yeah, that's a that's a great question. There's been a lot of interests looking at remdesivirs activity for a number of different RNA viral families. Pretty much across the board, from what it's been studied in, it seems to have relatively high in vitro potency for some notable viruses like Ebola, some of the pneumo-viruses like RSV, and human metapneumovirus, and also the human and zoonotic coronaviruses.

One thing I do want to make sure that the audience remains cognizant of is this is all in vitro potency data. It's really important that we operate with a healthy dose of skepticism because this is not necessarily translatable to clinical efficacy. What we've seen historically for hydroxychloroquine and chloroquine in a number of different viruses, leading up to SARS-CoV-2 is that there can be a disconnect between in vitro potency and also clinical efficacy. So it's important to know that although remdesivir does seem to have very potent in vitro activity, that doesn't necessarily mean that it's going to be successful and treating disease.

Contagion®: So you mentioned Ebola, and I know that remdesivir was evaluated in a study in the DRC. for Ebola. So what happened in that trial?

Davis: Yeah, that's the that's the million-dollar question, right? So just briefly for the audience. There was a there's a trial conducted in the DRC in 2018, during the Ebola outbreak. It was a forum study, so it was an active competitor trial. ZMapp, which was a triple monoclonal that had previously been studied in the treatment of Ebola served as the active comparator. Remdesivir was one of the included arms and then there were2 additional treatment arms. One was an alternative triple monoclonal and one was a single monoclonal that was harvested from an Ebola survivor.

The trial had equal enrollment in each of the 5 arms. Patients were stratified at baseline by viral load. And they studied the primary endpoint of 28 day mortality. When the trial was actually conducted, they conducted an interim analysis and they found a pretty significant signal that there was increased mortality in both the ZMapp and the remdesivir arms. So these 2 arms had around a 50 to 53% mortality rate compared to the other 2 options, which were around 29 to 33%. So a pretty big split.

They decided to stop enrolling patients in those 2 arms because of the significant difference in mortality. It kind of left a lot of people scratching their heads because in the PREVAIL study leading up to this trial ZMapp had a much lower mortality rate, around 22%. Also in the animal data and the in vitro data for remdesivir, it seemed to be a really promising agent. Having mortality rate around 50 to 53% was very unexpected and underwhelming.

So, a couple of points from that study. The baseline characteristics in each of the arms were relatively well match. However, there was a numerically higher serum creatinine values in the remdesivir and ZMapp arms. So that could potentially be a signal that maybe these patients were sicker at baseline there were already manifesting and organ effects of Ebola.

Another thing that the authors mentioned in the discussion was that the 2 arms that perform really well, the triple monoclonal and the single monoclonal they were administered as a single daily dose, just a 1 treatment dose, and that was the full course. Whereas both ZMapp and remdesivir required multiple infusions to get the whole treatment course. Then in a disease that progresses as rapidly as Ebola, that might have had some effects on the overall outcomes of the trial. But at the end of the day, ZMapp and remdesivir didn't perform anywhere near as well as we were hoping, hoping them to perform.

Contagion®: Thank you. So now that we've kind of worked our way through what we know already, why don't we just get into what we're seeing right now with COVID-19. So can you talk a little bit about how remdesivir is being evaluated right now?

Davis: Yeah, there are several ongoing clinical trials right now. It's actually a little difficult to keep track of everything that's going on for remdesivir. In the United States there are a few clinical trials. There's the ADAPTIVE study, which is being sponsored by the NIAID. It is structured initially as a placebo-controlled trial with remdesivir being administered for 10 days. The intent of this study, if there is a, good enough signal for efficacy and safety, is to shift from this initial placebo-controlled methodology to an active comparator with remdesivir serving as the active control and comparing it to other antivirals for COVID. So that's one study. Gilead, the manufacturer of remdesivir is sponsoring 2 different studies. One for severe disease and then another for mild, moderate disease. They're really trying to figure out what the optimal duration of therapy is. They're comparing 5 days versus 10 days.

There are a few ongoing clinical trials in China right now. One for severe disease and then one, also for mild moderate disease as well. There's a couple of international studies. So there's the SOLIDARITY trial which is sponsored by the WHO, and that's currently, remdesivir versus hydroxychloroquine versus standard of care. There's also the DISCOVERY trial, which is a multinational trial being conducted in Europe, which is sponsored by Inserm, the French Institute of Research. That's actually a 4 active arm study, which remdesivir is 1 of those arms and then there's also a standard of care arm as well. So a number of ongoing clinical trials currently. We are hoping to see some at least preliminary results maybe by the end of May, or maybe even a little earlier. But, there's definitely a lot kind of going on right now.

Contagion®: Absolutely. So my next question for you is actually one that was submitted by a Contagion reader. And that person asks: how is Gilead providing access to remdesivir for clinicians within the US?

Davis: Yeah, that's another great question. It seems like the answer is rapidly changing. By the time this video goes live, there's going to be some new information. Historically, there was the compassionate use option for patients who were not eligible for clinical trials. Because of just the global demand for remdesivir, currently, Gilead has essentially shut down their compassionate use portal.

They're only accepting new requests for patients who are pregnant, or patients who are less than the age of 18 years old with severe disease, because those 2 patient groups are excluded from the ongoing clinical trials. They're transitioning, compassionate use access to this expanded access program. The protocol is now live on clinicaltrials.gov. There are I think seven enrolling sites already. They are going to be assessing eligibility for enrollment as a site for the expand access program based off a couple of criteria.

Really, it's going to come down to whether or not you can access remdesivir through other means. So enrollment and clinical trials; the surge of your of your local area and your overall burden of COVID cases; the local reach of your institution; and then also regulatory compliance. But yeah, this is rapidly changing. I think I would, I'd like to direct the audience just to the the rdvcu.gilead.com website, which is our compassionate use portal for probably the most updated information or also clinical trials.gov.

Contagion®: Thank you. So my last question for you is what are your tips for staying engaged and informed in the face of a pandemic?

Davis: Oh, that was really tough to figure out. A couple of strategies that we've been doing over at UCLA... So myself and a few of our ID physicians are doing this somewhat of a round robin journal club. We have a literature team basically, and every couple of days, we'll take turns, just getting one of the newest articles that comes out and just doing a deep dive into the methodology, the results, the limitations, and then providing a summary to our division at large. So that's, that's one way that we're trying to stay on top of the literature. It's essentially just drinking from a firehose. There's new studies coming out constantly, there's new agents being recommended. So I think, getting a group of people that you trust, and trying to do deep dives. Also, acknowledge the fact that no single person can read every single thing that's coming out. So you really do need A team of folks around you doing literature evaluation as well.

That's one avenue we're doing at UCLA. Another thing is just basically reading anything that Erin McCreary and Jason Pogue, put out. Tweets, review articles, looking at SIDP there's a lot of great summary material, all the webinars and videos. I think that those are kind of the the strategies that we've been taking.

Contagion®: Those are great. Thank you so much. So thanks so much for joining us today. We really appreciate your overview of remdesivir and your helpful tips. For anyone that's interested in viewing Dr. Davis's presentation you can do so on the SIDP website, and a link is included below this video.

Davis: Thanks for having me.

Davis's webinar is accessible here.