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In episode 3 of Over the Counter, experts weigh in on remdesivir, a potential COVID-19 treatment.
Drug Topics®: Hello and welcome to Over the Counter, the podcast from Drug Topics®. I'm Gabrielle Ientile.
Remdesivir is arguably the most prevalent top contender in treatments amidst the COVID-19 pandemic, becoming a household name for its potential to treat the virus that causes the novel coronavirus.
Hydroxychloroquine, another potential treatment, has been stripped of its emergency use authorization (EUA) status following data that pointed to the drug’s association with increased heart risk. And a COVID-19 vaccine is months away from being distributed to patients. But what is remdesivir? Here's Dr. Julie Anne Justo, infectious diseases clinical pharmacist and associate professor at the University of South Carolina College of Pharmacy, to explain what remdesivir does in the body.
Justo: But remdesivir is an interesting compound. Originally, most people will be familiar with it as it was an investigational agent in the treatment of Ebola virus. Remdesivir itself, its purported mechanism of action, it's a nucleotide analogue that is going to disrupt viral replication at the RNA polymerase.
When the virus is inside the human cell and trying to hijack and increase its own replication, remdesivir is theorized to block that replication, starting relatively early on in the disease course of the SARS CoV-2 virus.
Drug Topics®: Remdesivir was given Emergency Use Authorization status by the FDA on May 1 2020 in response to studies done by Gilead Sciences and the National Institutes of Health (NIH). Upon announcing their latest data, which focused on administering remdesivir to severely ill and hospitalized COVID-19 patients, the NIH study found that patients with severe infection who required ventilation recovered faster with remdesivir.
In fact, they recovered 31% faster than the study's control group. But that was just one study. Here's Dr. Justo again to discuss Gilead’s phase 3 SIMPLE trial, which also focused on severe COVID-19 patients and figuring out whether a 5-day or 10-day treatment course with remdesivir would be more effective.
Justo: The first thing that we noted when the full trial results were published, was that we noticed the randomization wasn't fully balanced between the 2 treatment arms, and so randomization is intending to balance the 5-day arm versus the 10-day or on all the different baseline characteristics and other potential confounders, both measured and unmeasured, that might impact the chances of clinical outcomes for these patients.
What we found, which we didn't know before, was that the 10-day group, again, this is a study of nearly 400 patients, the 10-day group was more severely ill at baseline. That's based on the score that they received on that Ordinal Scale when they were enrolled in the trial. That's very important, because while the study investigators did try to adjust for this baseline difference, it's not 100% clear if they were effective in doing so.
We think that the 5 days is just as good as the 10 days. I think we can glean that information from the trial, but we also have to take into account that we're not entirely sure what happened with the patients in the 10-day group because they started in a clinically worse position.
In addition, if we're looking at the study results, when we look at the details, about 86% of patients in the 5 day remdesivir arm completed the full 5 days of remdesivir, whereas at the point of analysis, only 44% of the patients in the 10-day group completed the full 10 days of remdesivir that was intended. Now that sounds like a big difference, which it is, and the main drivers are understandable when you look at the way the trial was designed. These investigators are pressed to get these analyses out as quickly as they can, because everyone is wondering the results of the trial. But what that results in is that the 10-day arm, a lot of the patients at that point had either been discharged from the hospital or had died, so for whatever reason, they didn't complete a full 10 days of remdesivir therapy. Some patients may have received 6 or 7, or 9 or 10 days.
Drug Topics®: Dr. Justo also discussed a small population in the Gilead trial, which started out without mechanical ventilation, but then went on to receive ventilation as their symptoms worsened, and what that could mean.
Justo: There was another important piece of information that we found. We found that they did an analysis, where they looked at where folks were at the point of day 5 of remdesivir, you would notice that the 10-day group, if you were at day 5, were on invasive mechanical ventilation. Okay, so let me take a step back. For the patients that were enrolled in this trial, mechanical ventilation at baseline was an exclusion. However, if they started off not on mechanical ventilation, but the definition of severe, and then progressed to mechanical ventilation by day five and remdesivir therapy, they were allowed to stay in the trial.
So if we look at that interesting, small, but severely ill subgroup of patients, what we found is that patients on 5 days of remdesivir, about 40% of those patients that were on mechanical ventilation at day 5 ended up dying versus 17% of the patients in the 10-day group and then ended up dying. So 40% death versus 17% of death.
Those numbers are small and it's just a numerical difference, however, that's enough information for a lot of clinicians at this point of time to suggest for patients that are mechanically ventilated on remdesivir, they probably need to have consideration for extension from 5 days to 10 days of therapy.
So that's an important thing that we learned from the full published trial results in the severe trial. So again, just to summarize, patients that are mechanically ventilated with severe COVID-19 10 days may be better for them than 5 days. That's a lot of where that information came out in the FDA EUA that had that recommendation for 10 days duration of therapy specifically for patients with mechanical ventilation.
Drug Topics®: Gilead is also pursuing trials for moderate COVID-19 symptoms and is even planning to engage in clinical trials for pediatric COVID-19 patients. Here's Dr. Justo again.
Justo: Now we have a new press release from Gilead that talks about preliminary results from the SIMPLE moderate trial, which is patients that have oxygen saturations of above 94%. So if you're looking at all this data, in summary, what it's suggesting is that it does the best for patients that are early in their hospital admissions, and not yet to the point where they're requiring life support care in the form of mechanical ventilation, or other things like that.
Taking that into account, I’m still interested in seeing further information about whether or not remdesivir will provide any help for patients with mechanical ventilation. As I suggested, there's some limitations to how we design the study. We also have only just been looking at remdesivir in monotherapy form right now. A lot of clinicians are very interested in seeing if remdesivir could help even more severely ill patients, like mechanically ventilated folks, if it's used in combination with other agents such as convalescent plasma, or immunotherapies, such as tocilizumab or sarilumab, all agents that are currently being considered as experimental agents in actual bedside situations.
Drug Topics®: As of this podcast posting remdesivir has not been approved by the FDA for any use, and clinical trials are still ongoing. But the EUA is only 1 of 4 ways that hospitals can receive remdesivir to treat COVID-19.
Thomas Lombardi, PharmD, systems director of pharmacy and chair of the Institutional Review Board at St. Peter's Health Partners in Albany, New York, explains the 4 ways that patients can be treated with remdesivir for their COVID-19 symptoms.
Lombardi: There's actually numerous ways that a hospital can receive remdesivir. The first and probably the most complicated way is to be enrolled into a clinical trial through Gilead. This requires primary investigators, it involves enrolling into a specific study, and it tends to be some of the larger organizations that are enrolled. Most of the studies are not enrolling additional sites at this point in time, so it's difficult to achieve it that way.
A second way is through a compassionate use program from Gilead. This is very limited. It's only limited to pregnant women and children less than 18 years of age. In that situation, the provider and the physician would have to contact Gilead directly and request compassionate use for that individual patient, so it's an individual request.
The third way is through an expanded access program. The hospital has to apply by identifying a primary investigator physician, who will then apply to the protocol. The protocol would have to be reviewed by their review board. They have to go through that process. In that case, only that 1 individual provider would be able to prescribe the drug for any patient with COVID. There's very specific inclusion criteria.
The most recent way is through the emergency use authorization which the FDA approved just on May 1.
Drug Topics®: On May 7, a week after the FDA EUA, Gilead donated 607,000 vials of remdesivir to the federal government. Rather than implementing a centrally focused strategy and executed by the national government, the US Department of Health and Human Services instead almost entirely left i up to state health departments to allocate the drug to their hospitals. Compared to past epidemics, the federal government has been decidedly hands off. By mid-May, some organizations, including the American Society of Health-System Pharmacists, urged more transparency and orderly allocation of remdesivir supplies in hospitals.
Justo: Paramavir was approved a couple of years ago to address the H1N1 pandemic. It was issued an emergency use authorization. At the same time the FDA coordinated to develop a web page that had an online form that a clinician could complete if they felt that they had a patient that was eligible to receive the drug.
Unfortunately, when the FDA recently issued the A for remdesivir, there was no associated mechanism, website, phone line, email, there was no way to request the medication through this supply mechanism from the federal government. That led to a lot of confusion and additional time and sleuthing on a lot of pharmacists’ parts to try to find ways to access this remdesivir.
We knew it was out there, but we didn't necessarily know how to get it or how to advocate for our hospitals to receive some of that allocation. Now fortunately, we fast forward a couple of days and we have a bit more information about how to get it. We've learned since that AmerisourceBergen is going to be the sole distributor, the drug is coming from the donated supply of Gilead. It is still a very fluid process, but instead of having the process outline on day 1, it seemed to take a couple of days to get that going.
Drug Topics®: So now that remdesivir is authorized to treat COVID-19 in hospitalized patients, the expected next step would be to set a price. Developed countries can expect to pay $390 per vial of remdesivir based on a 5-day treatment course, which the majority of COVID-19 patients are receiving, remdesivir is expected to cost each patient around $2400.
And while Gilead has set their price, they've asserted that they intend to continue to explore earlier treatment courses, outpatient settings, inhaled formulation, and additional patient groups in combination with other therapies.
The COVID-19 pandemic itself is also far from over. The end of June brought in surges of COVID-19 cases across the US, with states such as California, Florida and Texas, seeing upticks and their infection curves when they should have been flattening out. New Jersey halted the reopening of indoor restaurant dining for a lack of mask-wearing and social distancing amid the summer weather. As of July 1, European countries have decided to bar Americans from entering due to their failure to control the virus. Dr. Justo encourages people to continue to take precautions such as mask wearing and social distancing, and to seek medical attention if you feel you might have COVID-19 and not to wait.
Justo: Time is of the essence. If patients feel that they have any symptoms and maybe at risk of having COVID-19, I strongly encourage them to seek medical attention as soon as possible and not wait until they're very severely ill. We have seen some patients that have waited quite a bit of time and then they come into the hospital, and essentially, we have to go straight into the ICU, which is a much more difficult situation for remdesivir to actually exert some positive effect on the treatment course.
That's 1 thing that I would encourage patients to know: if you feel like you have symptoms and you might have COVID-19, make sure that you isolate yourself, follow good infection control practices, and get medical attention.
Drug Topics®: For the medical community, Justo underlined the importance of providing benefit to patients.
Justo: For clinicians: remdesivir does seem to provide some benefit, and so we are incorporating it early in the treatment course for patients that are eligible. There are a couple of criteria; you have to make sure that their kidneys are working well, that their liver is working well. There's not an absolute contraindication if they have some multi-organ failure, but it has to be done. taken in careful consideration with all the information that we know about the drug.
The next thing that I would say is that we still have a lot of questions that we have to answer. As a healthcare system and medical community, we can't step off the gas in terms of trying to do research. I personally have a lot of questions about whether or not remdesivir can be used on patients that are on dialysis, whether or not remdesivir can be used in combination with other agents. What's the right sequence? Should we be doing 5 days or 10 days for ventilated patients? Should we be abandoning that therapy for that level of severity of illness at all?
As you can see, there's still a lot of questions that need to be answered when it comes to use of remdesivir, but I'm much more hopeful, I think now, than I was even 2 months ago. We’ve started to get a clearer picture about the treatment options that are available for COVID-19.
Drug Topics®: That's it for this episode of Over the Counter.
Want to learn more about remdesivir or other potential COVID-19 treatments? Check out drugtopics.com for Dr. Justo’s full interviews, plus more content on remdesivir and other COVID-19 topics, like pharmacy-provided COVID-19 testing and vaccinations; and weekly roundups of the latest coronavirus-related news.
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