publication date: May. 1, 2020

Remdesivir established as standard of care for COVID-19, Fauci declares

FDA issues Emergency Use Authorization

By Matthew Bin Han Ong and Paul Goldberg

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Credit: Sundry Photography / Shutterstock.com

This story is part of The Cancer Letter’s ongoing coverage of COVID-19’s impact on oncology. A full list of our coverage, as well as the latest meeting cancellations, is available here.

Early data from two randomized phase III studies of the antiviral drug remdesivir make it a viable treatment for COVID-19.

FDA May 1 issued an Emergency Use Authorization for remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.

The investigational drug was shown in a clinical trial to shorten the time to recovery in some patients.

“Whenever you have clear-cut evidence that a drug works, you have an ethical obligation to immediately let the people who are in the placebo group know, so that they could have access. And all of the other trials that are taking place, now have a new standard of care,” Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said in a press conference at the White House April 29, when the two positive studies were reported.

In one of the two studies, an NIH-sponsored randomized, placebo-controlled trial involving over 1,000 hospitalized patients with advanced COVID-19 and lung involvement, patients who received remdesivir recovered faster than similar patients who received placebo (The Cancer Letter, April 24, 2020).

“I do believe that there is most likely a two-step process, with potentially the EUA being granted, and then moving onto the full approval,” Daniel O’Day, Gilead’s CEO and chairman of the board of directors, said in an earnings call April 30.

In another study, conducted by the drug’s sponsor, Gilead Sciences Inc., patients with severe manifestations of COVID-19 receiving a 10-day treatment course of remdesivir achieved similar improvement in clinical status compared with those taking a five-day treatment course. The study enrolled 397 patients.

However, in a third trial, conducted in China, remdesivir didn’t produce an advantage in time to clinical improvement in patients with severe COVID-19. The study, in which 237 patients were randomized 2:1 to remdesivir vs. placebo, was published in The Lancet on April 29.

“Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early,” the study states, pointing to accrual problems. “Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less.”

According to an update published on ClinicalTrials.gov, the China trial is one of two remdesivir trials by the Capital Medical University in Beijing that were ended or halted, because “the epidemic of COVID-19 has been controlled well in China, [and] no eligible patients can be enrolled at present.”

The NIH trial, called the Adaptive COVID-19 Treatment Trial, or ACTT, is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID).

An independent data and safety monitoring board overseeing ACTT met on April 27 to review the data, concluding that remdesivir was better than the standard of care from the perspective of the primary endpoint, time to recovery.

Recovery, a metric often used in influenza trials, was defined as being well enough for hospital discharge or returning to normal activity level.

According to preliminary results, patients who received remdesivir had a 31% faster time to recovery than those who received placebo (p<0.001). The median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group (p=0.059).

“That’s sort of good. All I saw in the report was that there was no difference, but that meant no statistical difference,” said Don Berry, professor in the Department of Biostatistics and founding chair of that department at MD Anderson Cancer Center, said to The Cancer Letter. “In fact, it was a 3%-point difference in mortality, which is suggestive.”

According to NIAID, FDA has been engaged in sustained and ongoing discussions with Gilead regarding making remdesivir available to patients.

“It’s strong enough for what FDA would approve it for,” said Berry, who is also senior statistical scientist and founder of Berry Consultants, a company that is playing a key role in providing statistical guidance for multiple COVID-19 trials. “They would say this extends or this shortens the time to recovery, and it’s based on the statistical significance of shortening the time to recovery.

“It’s all depending on the indication. It won’t say, ‘Take this if you don’t want to die.’”

The ACTT trial is designed to incorporate additional arms.

“Unlike traditional drug development, we are attempting to evaluate an investigational agent alongside an evolving global pandemic,” Merdad Parsey, Gilead’s chief medical officer, said in a statement. “Multiple concurrent studies are helping inform whether remdesivir is a safe and effective treatment for COVID-19 and how to best utilize the drug.

“These study results complement data from the placebo-controlled study of remdesivir conducted by the National Institute for Allergy and Infectious Diseases and help to determine the optimal duration of treatment with remdesivir.

“The study demonstrates the potential for some patients to be treated with a 5-day regimen, which could significantly expand the number of patients who could be treated with our current supply of remdesivir. This is particularly important in the setting of a pandemic, to help hospitals and health care workers treat more patients in urgent need of care.”

The Gilead trial sought to determine whether a 5-day course is similar to the 10-day regimen. Secondary endpoints were the rates of adverse events and additional measures of clinical response. The trial, which focused solely on patients who had severe manifestations of COVID-19, did not randomize patients to a control arm, with only placebo or standard of care treatment.

“I guess they felt they couldn’t give placebo, so they were looking at a dose effect or a dose duration effect,” Berry said.

Patients had evidence of pneumonia and reduced oxygen levels that did not require mechanical ventilation at the time of study entry. Clinical improvement was defined as an improvement of two or more points from baseline on a predefined seven-point scale, ranging from hospital discharge to increasing levels of oxygen support to death. Patients achieved clinical recovery if they no longer required oxygen support and medical care or were discharged from the hospital.

“So, we are, and the team is, in constant information exchange with the agency right now and they’re getting information from us, obviously from NIH on the NIAID trial,” O’Day said. “There���s a big sense of urgency here, I think. FDA understands the importance of reacting quickly to this. And so, it’s intense right now. We think the FDA will move quite quickly on their decision-making on the labeling side.

“We made a decision to donate 1.5 million vials, which was the entirety of our supply through the early summer.”

The time to clinical improvement for 50 percent of patients was 10 days in the 5-day treatment group and 11 days in the 10-day treatment group. More than half of patients in both treatment groups were discharged from the hospital by Day 14 (5-day: 60.0%, n=120/200 vs.10-day: 52.3% n=103/197; p=0.14). At Day 14, 64.5 percent (n=129/200) of patients in the 5-day treatment group and 53.8 percent (n=106/197) of patients in the 10-day treatment group achieved clinical recovery.

Clinical outcomes varied by geography. Outside of Italy, the overall mortality rate at Day 14 was 7% (n=23/320) across both treatment groups, with 64 percent (n=205/320) of patients experiencing clinical improvement at Day 14 and 61% (n=196/320) of patients discharged from the hospital.

Key efficacy and safety results from Gilead’s phase III SIMPLE trial for patients with severe manifestations of COVID-19 are included in the table below.

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This is one of two randomized, open-label, multi-center phase III trials by Gilead for remdesivir in countries with high prevalence of COVID-19 infection.

In this study, an expansion phase of the study was recently added and will enroll an additional 5,600 patients, including patients on mechanical ventilation. The study is being conducted at 180 trial sites around the world, including sites in the United States, China, France, Germany, Hong Kong, Italy, Japan, Korea, the Netherlands, Singapore, Spain, Sweden, Switzerland, Taiwan and the United Kingdom.

A second SIMPLE trial is evaluating the safety and efficacy of 5-day and 10-day dosing durations of remdesivir administered intravenously in patients with moderate manifestations of COVID-19, compared with standard of care.The results from the first 600 patients of this study are expected at the end of May.

 

Fauci’s April 29 remarks in the Oval Office follow:

A trial that the National Institute of Allergy and Infectious Diseases—which is the institute I direct—sponsored, called the Adaptive COVID-19 Treatment Trial, was started in Feb. 21 of this year, and it was a randomized placebo-controlled trial, comparing the Gilead drug remdesivir with a placebo.

It was highly powered, with about 1,090-plus individuals, so it is the first truly high-powered, randomized, placebo-controlled trial. It was an international trial involving multiple sites. The primary endpoint was the “time to recovery,” mainly the ability to be discharged.

The data and safety monitoring board … notified the study team, namely the multiple investigators who are doing the study throughout the world, that the data shows that remdesivir has a clear-cut significant positive effect in diminishing the time to recovery. This is really quite important, for a number of reasons, and I’ll give you the data.

It’s highly significant. If you look at the time to recovery, being shorter in the remdesivir arm, it was 11 days, compared to 15 days. And that’s a p-value, for the scientists who are listening, of 0.001. So, that’s something that, although with 31% improvement—doesn’t seem like a knockout, 100%—it is a very important proof of concept. Because what it is proving, is that a drug can block this virus.

The mortality rate trended towards being better, in the sense of less deaths in the remdesivir group—8% vs. 11% in the placebo group. It has not yet reached statistical significance, but the data needs to be further analyzed.

The reason why we’re making the announcement now, is something that, I believe, people don’t fully appreciate. Whenever you have clear-cut evidence that a drug works, you have an ethical obligation to immediately let the people who are in the placebo group know, so that they could have access. And all of the other trials that are taking place, now have a new standard of care.

So, we would’ve normally waited several days to dot the i’s and cross the t’s, but the data are not going to change. Some of the numbers may change a little, but the conclusion will not change.

When I was looking at this data with our team the other night, it was reminiscent of 34 years ago, in 1986, when we were struggling for drugs for HIV, and we had nothing. And there were a lot of anecdotal reports about things that maybe it did work, and maybe not, and people were taking different kinds of drugs.

And we did the first randomized placebo-controlled trial of AZT, which turned out to give an effect that was modest, but that was not the endgame, because building on that every year after, we did better and better. We had better drugs of the same type, and we had drugs against different targets.

This drug happens to be blocking an enzyme that the virus uses, and that’s an RNA polymerase. But there are a lot of other enzymes that the viruses uses that are now going to be targets for this.

This will be the standard of care. And, in fact, when we look at the other trials we’re doing, we’re going to do trials with another anti-inflammatory, a monoclonal antibody. We’re going to now compare the combination of remdesivir with this.

So, as drugs come in, we’re going to see if we can add on that. So, bottom line, you’re going to be hearing more details about this; this will be submitted to a peer-reviewed journal and will be peer-reviewed appropriately.

But we think it’s really opening the door to the fact that we now have the capability of treating [COVID-19], and I guarantee you, as more people, more companies, more investigators get involved, it’s going to get better and better.

 

Excerpts of remarks by Gilead CEO O’Day and CMO Parsey in the April 30 earnings conference call follow:

Dan O’Day:

I’ll just make a couple of comments, which was also echoed by Dr. [Anthony] Fauci yesterday, which is, with the NIAID results and the highly statistically significant reduction in “time to recovery,” this now changes the landscape for drug development within COVID-19, being that one has to now think about comparing to remdesivir and/or looking at adding to remdesivir, which I think is exactly what the NIH trial is going to do now, and I’m sure all of our collaborators within the drug development space.

We have been working with them, we’re going to continue to work with them on the possible hypotheses around how we might be able to consider, just as one reflects upon HIV decades ago, that remdesivir becomes the base therapy, and one looks to try to improve symptomatology improvement, mortality improvement, expanding patient populations, and so, that is yet another factor that will go into how we determine how best to create a sustainable solution for remdesivir.

But, clearly, all those things, we have been thinking about and now we have to accelerate, now that we have these trial results. More to come on that.

Merdad Parsey:

Thanks, Dan. The concentration [of remdesivir] that we’re looking for, we think our AC50 in human cells is in the tens of nanomolar range, and we know our serum concentration gets in the micromolar range. And so, we should be more than adequately covered by achieving those levels with the current dosing paradigm that we have, probably by an order of magnitude, or two.

Certainly, in the serum and based on modeled data in non-human primates as well as mice, we see more than adequate concentrations getting into the lungs of those animals and in vivo efficacy in those animals. And I think the clinical benefits we’re seeing suggest that that’s exactly what’s happening in humans as well. I think we’re pretty comfortable with where we are in terms of both dosing and exposure, including in the lung.

DO:

There’s been a surprising consistency across all the different data elements in our clinical program, from compassionate use to interrogating what we know about the China trial, to the [Gilead] severe trial, to the NIAID trial.

 

In anticipation of more data

MP:

We all were using the parallel construct of influenza for our thinking around remdesivir, which was you got to get in really early, given the viral kinetics in influenza, and getting in too late probably won’t have much of an impact. That was certainly our expectation.

However, the wild card here, and what I think we’re still learning is, what are the viral kinetics in patients with this virus? How long does that last and how quickly does it go up and how quickly can we have an impact on it?

I think the data, essentially, we are seeing efficacy across both patient populations, but also across trials that are really all tracking in the same direction, as Dan alluded to, so, even if you look at the China data, the hazard ratios for improvement are consistently positive. The study was underpowered, and I think the hazard ratios we’ll probably see from the NIAID study are going to be in the same ballpark, but with an appropriate sample size—they’re highly statistically significant.

Similarly, I think when we look at the mortality data and when we look at all of those different factors, this virus seems to be behaving differently. Remdesivir seems to be having efficacy in a relatively broad patient population, so I think we’re learning as we go.

We’ll learn as more and more data are generated; right? We have our moderate data coming up, where we’ll be looking at an even less severely ill patient population, so there’ll be more data coming out in that population, that they may add to our knowledge base here to understand the spectrum.

And, as we talked about earlier, understanding the efficacy in the subgroups and the NIAID study will be really interesting in this, and we don’t have that information yet, so I think all those data will contribute to our overall understanding of, how early do you need to be in? Do patients who have symptoms for less time do better?

Those are certainly the trends, but there are certainly things to be benefited even in patients who have longer duration of symptoms right now.

DO:

To clarify the EUA, under an Emergency Use Authorization, one could charge for the product. We made a decision to donate 1.5 million vials, which was the entirety of our supply through the early summer, and that’s for a variety of uses, right? I mean that’s for clinical trials, as one would expect not to charge for those, of course; compassionate use, EIT in other countries.

But also available is that supply for regulatory approvals around the world, and then we’ll allocate accordingly until its regulatory approvals come online.

So, yes, it is possible to charge. I would just say that our goal here is to get a full approval for remdesivir. We feel the data supports that and an EUA, therefore, is a step to a more formalized approval.

The reason—the agency and we are talking about that—is that these are extraordinary times; right? So, weeks would make a difference to being able to get medicine to patients by enacting an EUA, if that’s what the FDA chooses to do prior to another form of approval.

And so, it’s a stepwise approach, which allows us to immediately address the humanitarian need, while still pursuing all the aspects of a normal approval, which we are doing with the FDA. So, I think that’s probably the most important point.

We will be answering your questions on the sustainable model for remdesivir in the future, in the near future. We just don’t have the answers yet, but we deeply respect and appreciate the fact that when we get into millions of doses, we have to have a sustainable economic model that works here, and that achieves access to affordability for patients around the world. So, more to come on that, if I could turn it over to Merdad on the ventilated treatment approach.

 

Remdesivir in patients on ventilators

MP:

The criticality, this comes down to a timing question; right? It really comes down to how long is viral replication ongoing in the lungs of patients, and how quickly do patients deteriorate to needing mechanical ventilation. Certainly, what we’re seeing is that patients are very rapidly deteriorating. Some patients deteriorate rapidly.

And so, getting them antiviral therapy in that timeframe, where it seems that there’s still viral replication going on, certainly seems to be benefiting those patients. And probably what’s going on, and this is speculation on my part, is by limiting the viral replication, you’re going to limit the inflammation, you’re going to reduce the number of people who develop lung injury, and you’re going to get them off the ventilator faster.

So, the discharge rates that we’re seeing, where people are being discharged four days earlier, for example, in the NIAID study, underlying that are patients who are deescalating or need oxygenation and that leads them to getting onto room air more quickly. So, there’s a time element in all of this that I think is probably where we’re benefiting these patients.

Certainly, if you talk about people who’ve been ventilated for a week or two weeks, there, the question of whether an antiviral would be beneficial, I think, seems more difficult to tie into what’s going on. But again, it comes down to understanding the viral kinetics here. And that’s a work in progress, I think, for all of us.

 

Washington, and drug pricing

DO:

I think people have come together in a variety of ways and, certainly, that’s also occurred to a certain degree in Washington.

I’ve spent a decent amount of time in Washington over the past several months, certainly before the shelter-in-place, and I think, even then, there is some change in the rhetoric [about drug pricing].

I think for highly innovative, research-based companies that have immediately shifted their efforts to solutions for the coronavirus—it’s pretty impressive, actually, to many of the peers in the industry that I stay in very close touch with—have spared no expense to pivot and shift.

I think at the end of the day, I think this will certainly help the industry’s reputation. I think the ability to solve a human crisis like this, because of the decades of investment and the at-risk investment that’s done by so many companies, people and the general public will see that. And whether that’s treatment, different types of treatments or vaccines, I think that’ll be the case.

But I think the tone is different in Washington. I think people are very appreciative and concerned about finding solutions here, and it’s brought us all together, which I think is a good thing. I’m not suggesting that there won’t continue to be focus and pressure on drug pricing.

Of course, there will be, and we continue to work appropriately to make sure that, in particular, the patients that are bearing the brunt, sometimes, of some of the pharmaceutical pricing that legislation has put into place that supports that, and improves that for patients. And that we lean in as an industry and as a company to give more that flows through to patients.

So, all of those principles, I think, still apply, but it’s being done now in a way where we can have an appreciation for the innovation the industry brings. So, more to come and a lot still to happen this year, with the election coming up, and with other things.

But I think, from a Gilead perspective, we stay focused on innovative medicines and making sure we have access programs, on leaning into legislation that supports the innovative industry and that supports reducing patient out-of-pocket costs. And that would be our focus, accordingly. I hope that gives a little bit of an insight.

 

FDA approval for remdesivir?

DO:

We’ve been in constant dialogue with [FDA] on remdesivir. We have been working with them on the submission.

They’ve been open to receiving parts of the submission, which has been very helpful under a normal process. Plus, there’s the whole EUA process that kind of goes on top of that. So, yes, the answer is, and you can imagine that, obviously, that’s been going on for weeks, and, actually, a couple of months now, but in the past 48 hours is increased in intensity.

We are, and the team is, in constant information exchange with the agency right now and they’re getting information from us, obviously from NIH on the NIAID trial. There’s a big sense of urgency here, I think.

FDA understands the importance of reacting quickly to this. And so, it’s intense right now. We think the FDA will move quite quickly on their decision-making on the labeling side.

MP:

This has been an unprecedented time in terms of our interactions with the regulators, both here in the U.S. As well as outside the U.S. It’s been really impressive and truly collaborative, working with the NIH and the FDA in parallel over the past couple of months. We talk constantly and the same is true with the EMA. Same is true with Japan. We’re talking to all the regulators in parallel. It’s been a pretty unique situation and I think everyone understands the gravity. That’s been very helpful in moving forward collaboratively.

DO:

The discussions are still ongoing in terms of what’s required for a formal approval, but I meant to infer that the NIAID data demonstrate safety and efficacy at a highly statistical level, which is usually the barrier for a full approval. So, that’s what we’re working with them on.

I don’t want to get ahead of the agency on that. But again, I do believe that there is most likely a two-step process, with potentially the EUA being granted, and then moving onto the full approval.

 

Clinical trial endpoints

Diana Brainard [senior vice president of clinical research at Gilead]:

In terms of end points, the NIAID study looked at time to clinical recovery, using a seven-point ordinal scale. The ordinal scale is really tracking throughout most of the major clinical trials right now. But as our understanding of the disease has evolved, the types of endpoints using that scale has evolved.

So, NIAID changed to time to clinical recovery, which basically means no longer requiring medical care within the hospital, getting off of oxygen, or discharge. In our moderate study, we’re using the ordinal scale as well, but we’re looking at the day 11 distribution along that ordinal scale.

So, similar to what we did in our severe study, but looking at day 11 instead of day 14, recognizing that we’re looking at a population that’s less sick.

The moderate study is looking at patients who are hospitalized, but they’re not hypoxic, they’re not requiring oxygen. The NIAID study enrolled patients from starting there, but all the way through mechanical ventilation. So, slightly different endpoints for slightly different patient populations, and, most importantly, really looking at different questions.

We’re looking at treatment duration. They’re looking at primary safety and efficacy with a placebo control.

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