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Announcer:
You’re listening to COVID-19: On the Frontlines on ReachMD. This episode is sponsored by Gilead Sciences. Here’s your host, Thomas Oppelt, a Doctor of Pharmacy and Senior Director in Gilead's Medical Affairs Department.

Thomas Oppelt:
Hello, and welcome to ReachMD. I’m Thomas Oppelt, and today we’ll be talking about VEKLURY, also known as remdesivir, 100 milligrams for injection which is indicated for the treatment of adult and pediatric patients 28 days and older, weighing at least 3 kilograms who are hospitalized or not hospitalized, have mild to moderate COVID-19, and are at high risk for progression to severe COVID-19 including hospitalization or death. 1 There’s a contraindication in patients with a history of clinically significant hypersensitivity reactions to VEKLURY or any of its components.1 VEKLURY, which is 100 milligrams for injection, received FDA approval in October of 2020, and it’s also the first antiviral approved by the FDA for COVID-19.1 Now in today’s discussion, we’ll also be reviewing the National Institute of Allergy and Infectious Diseases Adaptive COVID-19 Treatment Trial, also known as the NIAID ACTT-1 Trial, in patients with mild, moderate, or severe COVID-19. The information we’ll be covering today is as of [recording date]. And joining me to share all of this important data is Dr. Raj Dasgupta. He’s an Associate Professor of Clinical Medicine and a quadruple board-certified pulmonary and critical care specialist at one of the largest hospitals in Los Angeles. So, welcome to you, Dr Raj!

Dr. Raj:
Hi! It’s great to be here! I think it’s a perfect time to sit down and talk about something so relevant today.

Thomas Oppelt:
Absolutely! It’s really good to have you with us, Dr. Raj! You know, why don't we start out with you telling us a little bit about your experiences as a frontline provider during this COVID-19 pandemic?

Dr. Raj:
Yes, you know when I look back and think about this pandemic, we’ve had several variants and surges already and this will probably be going on for some time. What I remember most vividly was seeing patients in the beginning of the pandemic, seeing so many patients having very low oxygen levels around the 70s and the low 80s! Honestly initially I didn’t think this was possible. For me the bottom line here is, this experience really taught me about being humble, being a team member, and also when we talk about this, you know, communicating well with others, trying to be a good leader, and recognize that everyone is doing their best.

Thomas Oppelt:
Thank you for sharing your experiences, Dr. Raj. Now I’d like to share a bit about the mechanism of action of VEKLURY or remdesivir. VEKLURY is an antiviral medication that directly inhibits the viral replication of SARS-CoV-2. ^1,2 VEKLURY acts to inhibit the SARS-CoV-2 RNA-dependent RNA polymerase, which is essential for viral replication—and thus creation of virions that circulate in the body.^1,2

Thomas Oppelt:
Now back to you Dr. Raj, can you tell us if there are data on whether VEKLURY works against COVID-19 variants?

Dr. Raj:
The antiviral activity of VEKLURY has been tested in vitro against clinical isolates of SARS-CoV-2 variants including Alpha, Beta, Gamma, Delta, Epsilon, and Omicron. These laboratory findings demonstrated that the antiviral activity of VEKLURY against these variants is not reduced.^3,4

Thomas Oppelt:
Now if we take a moment to review the warnings and precautions in the label, Dr. Raj, are there any that we should especially note when using VEKLURY?

Dr. Raj:
Yes, hypersensitivity, including infusion-related and anaphylactic reactions, have been observed during and following the administration of VEKLURY.¹ Patients should be monitored under close medical supervision for hypersensitivity reactions during and following the administration of VEKLURY. Symptoms may include hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnea, wheezing, angioedema, rash, nausea, diaphoresis, and shivering. Slower infusion rates with a maximum infusion time of up to 120 minutes can potentially prevent these reactions. If a severe infusion-related hypersensitivity reaction occurs, immediately discontinue VEKLURY and initiate appropriate treatment. In my practice, we have slowed the infusion rate, as suggested by the Prescribing Information, and found that it did ameliorate some of the reactions. Now, continuing with the label’s warnings and precautions…¹ Transaminase elevations have been observed in healthy volunteers and in patients with COVID-19 who received VEKLURY. These elevations have also been reported as a clinical feature of COVID-19. Perform hepatic laboratory testing in all patients and consider discontinuing VEKLURY if alanine aminotransferase, or ALT levels, increase more than 10 times the upper limit of normal. Discontinue VEKLURY if ALT elevation is accompanied by signs or symptoms of liver inflammation. While hydroxychloroquine was seen more in the early days of the pandemic, we do have a warning and precaution in the label that coadministration of VEKLURY with chloroquine phosphate or hydroxychloroquine sulfate is not recommended based on data from cell culture experiments, demonstrating potential antagonism, which may lead to a decrease in the antiviral activity of VEKLURY. And for the adverse reactions, the most common, in at least 5% of patients, all grades, was nausea.¹ The most common lab abnormalities, in at least 5% of patients, all grades, were increases in ALT and aspartate aminotransferase, AST.¹ Regarding drug interactions, trials of VEKLURY and other concomitant medications have not been conducted in humans.¹

Thomas Oppelt:
Thank you very much for that important safety information, Dr. Raj. And now I’d like to turn our attention to the ACTT-1 trial. Can you give us some background and walk us through that study design?

Dr. Raj:
Sure! ACTT stands for Adaptive COVID-19 Treatment Trial.^1,5 This study was sponsored by the National Institute of Allergy and Infectious Diseases, the NIAID, part of the National Institutes of Health (NIH).⁵ ACTT-1 was the first clinical trial launched in United States to evaluate an experimental treatment for COVID-19.⁶ Now, let’s talk about the study design^1,5 ACTT-1 was a randomized, double-blinded, placebo-controlled clinical trial, the gold standard in clinical trial design. This is the kind of data I look for as a healthcare provider. 1062 hospitalized adult patients randomized 1:1 to receive VEKLURY as a 200-milligram loading dose on Day 1, followed by 100 milligrams once daily intravenously for 9 additional days, or placebo for 10 days. Patients were assessed daily during their hospitalization, from day 1 through day 29. Their clinical status was assessed on an eight-category ordinal scale which categorizes disease severity by hospitalization status, need for medical care and level of supplemental oxygen required. On this scale, a score of 1 would mean being discharged from the hospital with no limitations on activity; 8 would be death.

Recovery was defined as a 1, 2, or 3 on the ordinal scale

• 1 means not hospitalized with no limitations on activities
• a 2 means not hospitalized with limitations on activities and/or requiring home oxygen;
• and 3 means hospitalized, and not requiring supplemental oxygen – no longer requires ongoing medical care.

Now, the primary end point was time to recovery within 29 days

The inclusion criteria of ACTT-1 were:^1,5,7

• At least 18 years old
• Hospitalized with SARS-CoV-2 confirmed by reverse transcription polymerase chain reaction (PCR)
• Having COVID-19 and at least 1 of the following:
  • Infiltrates by imaging
  • Clinical assessment and oxygen saturation of 94% and below on room air
  • Requiring supplemental oxygen
  • Requiring mechanical ventilation

And the exclusion criteria were:^1,7

• Having AST or ALT levels greater than 5 times the upper limit of normal, or
• Having an estimated GFR, glomerular filtration rate less than 30 mLs per min, or being on dialysis, or
• Being pregnant or breastfeeding

Thomas Oppelt:
And can you also tell us a bit about the ACTT-1 study population and the patient baseline characteristics?

Dr. Raj:
The overall population:^1,5,7 The mean age of patients was 58.9 years, and 64.4% were male This trial had good representation across races and ethnicities: 53.3% of the patients were White, 21.3% were Black, 12.7% were Asian, and 23.5% were Hispanic or Latinx The most common prespecified coexisting conditions at enrollment were hypertension seen in 50.7% of patients, obesity with 45.4%, and type 2 diabetes mellitus with 30.6%. Also important to point out is the median time from patients’ symptoms onset to randomization was 9 days so patients did not necessarily present early or right away in their disease. Now, the distribution of comorbidities was similar between the 2 treatment groups.^1,5 26.2% of patients had one of the prespecified coexisting conditions at enrollment, and 55.2% had two or more.^1,5,7 10% of patients in both treatment groups, so 105 patients, had mild or moderate disease; 90% of patients in both treatment groups, which was 957 patients, had severe disease.^1,5,7 Now, mild/moderate means an oxygen saturation of more than 94% and a respiratory rate less than 24 breaths/minute without supplemental oxygen. Severe disease means having oxygen saturation of 94% and below on room air, a respiratory rate at least 24 breaths/minute, an oxygen requirement, or a requirement for mechanical ventilation.

Thomas Oppelt:
Thank you for giving us that really detailed breakdown, Dr. Raj. Now earlier, you mentioned that the primary outcome was time to recovery by Day 29, and you described recovery being defined as a level 1, 2, or 3 on an 8-point ordinal scale. So how did VEKLURY perform on this metric?

Dr. Raj:
The 541 patients randomized to the VEKLURY arm had a median time to recovery that was 5 days shorter compared with the 521 patients in the placebo arm. Median time to recovery was 10 days in the VEKLURY arm and 15 days in the placebo arm. The recovery rate ratio or RRR was 1.29 with a 95% confidence interval or a CI of 1.12 to 1.49.^1,5,7 A prespecified subgroup analysis showed that 676 patients with symptoms onset of 10 days or less, the median time to recovery was 9 days with VEKLURY versus 15 days with placebo, which translated into a recovery rate ratio of 1.37 with a 95% confidence interval of 1.14 to 1.64. In the 383 patients with symptom onset of greater than 10 days, the median time to recovery was 11 days with VEKLURY versus 15 days with placebo, with a recovery rate ratio of 1.20 and a 95% confidence interval of 0.94 to 1.52.^1,5 Keep in mind that the FDA label doesn’t contain any restrictions on this, and VEKLURY is indicated for hospitalized patients independent of time since symptom onset.¹ The data showed that patients who were treated earlier had the greatest benefit. In my practice and experience, I also found treating earlier, once a patient has been hospitalized, is a good strategy. Now, regarding the ACTT-1 trial, the FDA noted that, “The most compelling evidence for effectiveness of VEKLURY was provided by NIAID-sponsored ACTT-1 trial, with this rigorous trial design.”⁸ And I’d like to just say some personal thoughts on the primary endpoint. Time to recovery was an important endpoint. In the ACTT-1 trial, we wanted to see these hospitalized patients improve in a clinically meaningful way, and the ACTT-1 was able to show this. As a pulmonologist, I work with clinicians across the hospital and see the results of shorter or longer recovery times. The 5-day shorter recovery time is a clinically meaningful endpoint..

Thomas Oppelt:
Thanks for that, Dr. Raj, and I completely agree. Now, let’s talk a bit about the additional secondary endpoints and outcomes in ACTT-1. What can you tell us about the data there?

Dr. Raj:
In a key secondary endpoint in ACTT-1, patients receiving VEKLURY were 54% more likely to have improvement in clinical status by Day 15 versus placebo, with an odds ratio of 1.54 and a 95% confidence interval of 1.25 to 1.91, and that was maintained out to Day 29.^1,5,7 In terms of the additional secondary endpoints,^1,5,7 A 1-point improvement on the ordinal scale was seen in a median of 7 days with VEKLURY versus 9 days with placebo. The RRR was 1.23 with a 95% confidence interval of 1.08 to 1.41. A 2-point improvement was observed in a median of 11 days with VEKLURY versus 14 days with placebo. The RRR was 1.29 with a 95% confidence interval of 1.12 to 1.48. Time on oxygen support from baseline was a median of 13 days for VEKLURY arm versus 21 days for placebo arm, a median difference of around 8 days. Discharge or a National Early Warning Score of less than or equal to 2 for 24 hours was a median of 8 days for VEKLURY versus 12 days for placebo, and a 95% confidence interval of 1.10 to 1.46. And finally, initial hospitalization was a median of 12 days for patients in the VEKLURY group and 17 days for patients in the placebo group with a 95% confidence interval of a -7.7 to -2.3. Then there are also some additional secondary outcomes on oxygen support progression in the ACTT-1 that are especially near and dear to me as a pulmonologist. The NIAID ACTT-1 showed that VEKLURY helped reduce progression to new oxygen support.^1,5,7 The incidence of new use of noninvasive ventilation or high-flow oxygen among 573 patients who were not receiving these interventions at enrollment was 29% lower in the VEKLURY group than in the placebo group: 17% progressing in the VEKLURY arm versus 24% in the placebo arm. This corresponds to a rate ratio of -7 with a 95% confidence interval of -14 to -1. The incidence of new mechanical ventilation or ECMO use among the 766 patients who were not receiving these interventions at enrollment was 43% lower in the VEKLURY arm than in placebo group, with 13% progressing in the VEKLURY arm versus 23% in the placebo arm. The rate ratio was -10 with a 95% confidence interval of -15 to -4. These data on disease progression are as interesting as the time to recovery endpoint; my fellow clinicians and I want to see both. Also, patients requiring high-flow or mechanical ventilation are often treated in the medical ICU. We want to avoid that step up to the ICU. In my experience, a reduced risk of mechanical ventilation and ECMO translates to fewer patients in the ICU. And as I said earlier, my strategy is to start treatment early.

Thomas Oppelt:
I completely agree with you on the early strategy, especially when dealing with patients hospitalized with COVID-19. And while mortality was not the primary endpoint of ACTT-1, it was a pre-specified secondary endpoint. So with that in mind, what can you tell us about the mortality findings in this study?

Dr. Raj:
At day 29, the overall 29-day mortality was 11% for the VEKLURY group versus 15% for the placebo group. These results were not statistically significant with a hazard ratio of 0.73 and a 95% confidence interval of 0.52 to 1.03.^1,5,7 The ACTT-1 study was not powered to evaluate the difference in mortality in the overall population.^1,5,6 After observing the overall results, a post-hoc analysis was conducted to evaluate mortality in patient subgroups by baseline oxygen status.^1,5,7 In ACTT-1, the largest patient population enrolled at baseline were on low-flow oxygen, ordinal group 5, (which was 40% of the study population, equating to, you know, 435 patients). Patients on low-flow oxygen at baseline (which was ordinal scale 5) treated with VEKLURY had 72% reduction in mortality at Day 15 with a 95% confidence interval of 0.12 to 0.66, with a 70% reduction at Day 29 compared to placebo with a 95% confidence interval of 0.14 to 0.64. These results do represent a significant difference versus placebo for this patient subpopulation only.^1,5,7 Patients who were not on supplemental oxygen (ordinal group 4), which represented 138 patients and those who were on either high-flow oxygen (ordinal 6), which represented 193 patients or mechanical ventilation/ECMO (ordinal 7), which represented 285 patients at baseline were much smaller cohorts of patients in ACTT-1. A reduction in mortality was not seen in these ordinal groups.^1,5,7 Also, note that there was no adjustment to control for multiple testing in the post hoc analysis.^1,5 Additionally, mortality benefit with VEKLURY has not been demonstrated in some other studies.^9,10

Thomas Oppelt:
And in terms of safety and adverse events, Dr. Raj, what do clinicians need to know?

Dr. Raj:
Well, the frequency of adverse events was comparable between remdesivir, also known as VEKLURY, and placebo.¹ Adverse events with grades ≥3 occurred in 41 out of the 532, or 8% of patients who received VEKLURY and in 46 out of 516 patients, or 9% of those who received placebo. 2 patients, or 0.4% of those on VEKLURY experienced serious adverse events versus 3 patients or 0.6% on the placebo arm. 11 patients or 2% of those given VEKLURY had adverse reactions leading to treatment discontinuation while this was observed in 15 patients or 3% of those who received placebo. These results were similar to what I've seen in my use of VEKLURY. Lab abnormalities were also comparable between VEKLURY and placebo.¹ For example, increased ALT was observed in 3% of patients in the VEKLURY arm, and in 6% of patients in the placebo arm.¹ Similarly, increased AST was observed in 6% of patients in the VEKLURY arm versus 8% of patients in the placebo arm.¹ Decreased estimated glomerular filtration rate was also observed in 18% of patients who received VEKLURY and 24% of patients who received placebo.¹ Also, an increased prothrombin time was noted in 9% of patients given VEKLURY and in 4% of patients given placebo.¹

Thomas Oppelt:
Thanks so much for breaking all of that down for us, Dr. Raj. And now, I’d like to take a moment to walk us through how VEKLURY is dosed and the label’s guidance on pregnancy and lactation. Dosage for adult and pediatric patients weighing 40 kilograms or more is 200 milligrams on Day 1, followed by once-daily maintenance doses of 100 milligrams from Day 2, administered only via intravenous infusion over 30 to 120 minutes.¹ Dosage for pediatric patients at least 28 days old and weighing three or more kilograms to less than 40 kilograms is 5 milligrams per kilogram on day 1 followed by once-daily maintenance doses of 2.5 milligrams per kilogram from day 2 administered by intravenous infusion over 30 to 120 minutes. For patients who are hospitalized and require invasive mechanical ventilation and/or ECMO, the recommended total treatment duration is 10 days. VEKLURY should be initiated as soon as possible after diagnosis of symptomatic COVID-19. Treatment duration for patients not requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation, or ECMO, is 5 days, and may be extended up to an additional 5 days (10 days total) if clinical improvement is not observed. For patients who are not hospitalized, diagnosed with mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19, including hospitalization or death, the recommended total treatment duration is 3 days. VEKLURY should be initiated as soon as possible after diagnosis of symptomatic COVID-19 and within 7 days of symptom onset. Testing prior to initiating VEKLURY and during use includes performing estimated GFR, hepatic laboratory, and prothrombin time testing as clinically appropriate.¹ For patients with renal impairment, VEKLURY is not recommended in individuals with an estimated GFR of less than 30 mLs per minute.¹ There are two different formulations of VEKLURY: VEKLURY for injection (supplied as 100 mg lyophilized powder in vial), the only approved dosage form of VEKLURY for pediatric patients weighing 3 kg to <40 kg; and VEKLURY injection (supplied as 100 mg/20 ml [5mg/ml] solution in vial.) To see full Prescribing Information for VEKLURY, please click on the link on the ReachMD landing page or visit www.vekluryhcp.com.¹ Administration should take place under conditions where management of severe hypersensitivity reactions, such as anaphylaxis, is possible.¹ And as for Pregnancy and Lactation:¹

A pregnancy registry has been established. There are insufficient human data on the use of VEKLURY during pregnancy. COVID-19 is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death. VEKLURY should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus. It is not known whether VEKLURY can pass into breast milk. Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19.

Now coming back to you, Dr. Raj, we’ve clearly covered a lot of ground today, so what would you say are the key takeaways from our discussion?

Dr. Raj:
COVID-19 is still an ongoing public health threat, and as I said we are still continuing to see surges happening two years in and arrival of new variants.¹¹ Although we have therapeutic tools for our hospitalized patients with COVID-19, VEKLURY is the first antiviral approved by the FDA for COVID-19.¹

Thomas Oppelt:
And as a friendly reminder to our listeners, VEKLURY is indicated for the treatment of adult and pediatric patients who are 28 days old and older, weighing at least 3 kilograms who are hospitalized or not hospitalized, have mild to moderate COVID-19 and are at high risk for progression to severe COVID -19.¹ Dr. Raj, please continue.

Dr. Raj:
And as a friendly reminder to our listeners, VEKLURY is indicated for the treatment of adult and pediatric patients who are 28 days old and older, weighing at least 3 kilograms who are hospitalized or not hospitalized, have mild to moderate COVID-19 and are at high risk for progression to severe COVID -19.^1,5 Safety data were comparable between patients taking VEKLURY and patients taking placebo. 41 out of 532 patients given VEKLURY, or 8%, had an adverse reaction with Grade 3 or greater compared with 46 out of the 516 patients, or 9% of those given placebo.^1,5 2 patients in the VEKLURY arm had a serious adverse event while this occurred in 3 patients in the placebo arm. Adverse events leading to treatment discontinuation was observed in 11 patients, or 2% of those given VEKLURY, and in 15 patients or 3% of those in the placebo arm. I just want to point out again that VEKLURY is contraindicated in patients with a history of clinically significant hypersensitivity reactions to VEKLURY or any of its components. This is the only contraindication in the label.¹ To see full Prescribing Information for VEKLURY, please click on the link on the ReachMD landing page or visit www.vekluryhcp.com.

Thomas Oppelt:
Well, this has really been a great overview. Thanks so much, Dr. Raj, for walking us through the VEKLURY ACTT-1 clinical data in such detail and for sharing your perspectives. I hope our listeners have also enjoyed our podcast and picked up some new insights on VEKLURY today.

Dr. Raj:
Thank you, Thomas and Gilead. This is a topic I’m truly passionate about! I’ve seen and cared for a lot of patients throughout this pandemic, and I’ve used a lot of VEKLURY, which is remdesivir 100 milligrams for injection, so I’m happy that I could share my thoughts and experiences on this topic.¹ Thank you again everyone and stay safe!

Announcer:
This episode of COVID-19: On the Frontlines was sponsored by Gilead. If you missed any part of this discussion, visit reachmd.com/industry-feature. This is ReachMD. Be Part of the Knowledge.

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