IPD'S DRUG & CLINICAL REVIEW:
COVID-19 PODCAST EPISODES
May 18th, 2020 Update
IPD Analytics has released its fourth publicly available podcast on COVID-19. In this episode, Leslie Fish, R.Ph, Pharm.D. and Julee Oh, Pharm.D. discuss the most recent news on the coronavirus, including:
National and Global Status (2:22)
Vaccine Status (2:48)
Remdesivir from Gilead Sciences, Inc. (04:50)
Emergency Use Authorization (06:39)
Clinical Trial Updates (9:49)
Dosing and Administration (15:56)
Warnings and Precautions (17:05)
Manufacturer and Clinical Trial Impacts (20:20)
STI-1499 Antibody from Sorrento Therapeutics (23:38)
COVID-19 Update from IPD Analytics May 18th, 2020
Veronica Fowler (00:20):
Welcome to IPDs Drug and Clinical Review, the premier podcast for drug intelligence and pharmacy and therapeutic management strategy. I'm Veronica Fowler, your host, and I'm here today with Dr. Julee Oh and Dr. Leslie Fish, two of our Executive Clinical Pharmacy Team here at IPD.
Dr. Julee Oh (00:36):
Dr. Leslie Fish (00:37):
Veronica Fowler (00:39):
Welcome back. Now for our listeners today that aren't IPD subscribers, this may be your first time listening to our show. If that's the case, I encourage you to go back and listen to our previous episodes on this topic for additional context. And for those of you that aren't familiar with IPD Analytics, we provide insight, transparency, and efficiency to stakeholders across the pharmaceutical industry, including managed care organizations, hospitals and IDNs, drug manufacturers, and institutional investors.
We offer varying subscription-based products with data, analysis, and consultations – providing summarized insight covering the drug life cycle, loss-of-exclusivity projections, brand and generic financial forecasts, clinical pipeline tracking, as well as formulary management and decision-making support for payers, providers, and suppliers. Now, our show is normally available exclusively to our subscribers, but as we navigate this pandemic alongside the rest of the world, we want to do our part and allow this valuable information to be accessed by the public. So with that, for further updates from us, follow our company page on LinkedIn or check out our website at www.ipdanalytics.com.
Now, today we plan to talk primarily about remdesivir, which has recently shown promise in clinical studies and has been approved for emergency use by the FDA to treat COVID-19. But before we get into that, as usual, I'd like to start out with an update of the numbers (which will be relevant for the time of this recording), which is May 18, 2020.
Julee, can you start us off with a brief overview of confirmed cases and deaths nationally and globally?
Dr. Julee Oh (02:22):
According to Johns Hopkins university, the number of confirmed COVID-19 cases worldwide is 4,744,216 with 315,740 deaths. And in the United States, the number of confirmed cases is 1,487,447 with 89,567 deaths.
Veronica Fowler (02:48):
So, even though I read about it and hear about it constantly, whenever we do these check-ins, I'm still in shock at the number of cases. It feels like just yesterday we were recording our first episode on this topic and we weren't even sure this would be a concern for the United States population. It's just amazing how fast this has spread. So Julee, where are we with a vaccine at this point? I know some are saying this year; many are saying longer than that.
Dr. Julee Oh (03:18):
Yes, Veronica, it's still unknown. We are not sure when a vaccine for SARS-CoV-2 will be available. Scott Gottlieb says [there will be a] possible vaccine this fall and others are saying fall of 2021, or even 2022. We do know that over $3 billion of taxpayer money has been used in the development of these vaccines and drugs.
Veronica Fowler (03:25):
And just how many drugs are being tested at this point?
Dr. Julee Oh (03:45):
When it comes to COVID-19, there has never been so much information on one disease state with all sorts of data being published in medical journals, as well as the media. As we're seeing now, the number of drugs and interventions, both investigational and repurposed, being tested for the treatment or prevention of COVID-19 is unprecedented. There are over 80 drugs with some sort of antiviral activity, over 60 drugs that may have some immunomodulatory activity against [coronavirus’] direct effects and consequences, and over 70 vaccines currently being studied for COVID-19. So far, the early data has been mixed and confounded by small numbers in the studies and poor study design. But it appears in times of desperation (when the alternative is death), as long as the drugs’ benefit may outweigh the risk, physicians will try these potential therapies.
Veronica Fowler (04:50):
Okay, and so to get to our main topic for today, the drug that seems to have received the most press and the most reliable clinical data is Gilead's remdesivir. Can you give us a brief overview of this medication?
Dr. Julee Oh (05:05):
Yes. Remdesivir is a broad spectrum, direct-acting antiviral, an RNA polymerase inhibitor. It's a prodrug that is converted to its active form. Remdesivir was originally developed by Gilead in 2009 to treat hepatitis C and then was tested for Ebola and Marburg virus disease, but it was not effective for these three viral infections. Remdesivir has activity in cell culture and animal models against SARS-CoV (which is the original SARS), MERS-CoV, and SARS-CoV-2.
On May 4, 2020, the Japanese Ministry of Health, Labor and Welfare granted regulatory approval of remdesivir, which goes by the trade name Veklury there, for the treatment of COVID-19. Note that Japan will also likely approve the influenza antiviral drug Avigan, or favipiravir, for treating COVID-19 by the end of May.
Remdesivir is not yet officially FDA approved in the United States. It was approved for Emergency Use Authorization on May 1st based on a review of the topline data from the randomized, double-placebo controlled trial conducted by NIAID, and the Gilead-sponsored, open-label trial that evaluated the different durations of remdesivir. The FDA felt it was reasonable to believe that the known and potential benefits of remdesivir outweigh the known and potential risks of the drug for the treatment of patients hospitalized with severe COVID-19.
Veronica Fowler (06:38):
Julee, can I stop you there for some clarification? We've all been hearing a term in the news and specifically when talking about remdesivir to treat COVID-19: EUA or Emergency Use Authorization. What exactly does that mean?
Dr. Julee Oh (06:55):
Essentially, Emergency Use Authorization, or EUA, authority allows the FDA to strengthen the nation's public health protections against chemical, biological, radiological, and nuclear (known as CBRN threats) by facilitating the availability and use of medical countermeasures needed during public health emergencies. Under Section 564 of the Federal Food, Drug, and Cosmetic Act, the FDA commissioner may allow unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases caused by CBRN threat agents when there are no adequate approved and available alternatives.
So, let's start with the criteria for the issuance of the EUA for remdesivir:
First, SARS-CoV-2 can cause serious or life-threatening disease or condition, including severe respiratory illness, to humans infected by this virus.
Second, based on the totality of scientific evidence available to the FDA, it is reasonable to believe that remdesivir may be effective in treating COVID-19, and that, when used under the conditions described in the authorization, the known and potential benefits when used to treat COVID-19 outweigh the known and potential risks of such products.
And third, there is no adequate approved and available alternatives to the emergency use of remdesivir for the treatment of COVID-19.
Veronica Fowler (08:28):
And can you describe the scope of the authorization as it relates to remdesivir?
Dr. Julee Oh (08:35):
Yes. Distribution of the authorized remdesivir will be controlled by the U.S. government for use consistent with the terms and conditions of the EUA. Gilead will supply remdesivir to authorized distributors or directly to the U.S. government, who will then distribute to hospitals and other healthcare facilities as directed by the U.S. government in collaboration with state and local government authorities as needed. Second, the remdesivir covered by the authorization will be used only to treat adults and children with suspected or laboratory-confirmed COVID-19 and severe disease. And third, the EPA requires that remdesivir be administered by a healthcare [provider] in an inpatient hospital setting via intravenous infusion, using dosages recommended in the EUA to mitigate the risks of this unapproved drug.
The EPA requires that healthcare facilities and healthcare providers administering remdesivir comply with certain mandatory requirements. These requirements include providing the patient or caregiver with information consistent with the EUA and ensuring that all medical errors and all serious adverse events related to use of the drug are reported to the FDA, as specified in the EUA.
Veronica Fowler (09:49):
And so as we've mentioned in previous episodes, remdesivir had a rocky beginning in early reports, isn't that right, Julee? I mean we've sort of been on a roller coaster as far as confirming its effectiveness.
Dr. Julee Oh (10:04):
Yes, that's correct Veronica. We can still probably say that we do not have consistent data that proves without a doubt that remdesivir will save lives. In an early trial, that was a randomized, double-blind, placebo-controlled trial in hospitalized adults with severe COVID-19, patients at multiple sites in China were randomized to receive remdesivir or placebo initiated within 12 days of symptom onset. Patients also had pneumonia confirmed by chest x-ray and oxygen saturation of 94% or lower on room air. Because of a lack of available patients, enrollment in this trial was terminated before the prespecified number of patients was attained.
One hundred fifty-eight patients were treated with remdesivir and 78 with placebo. Thirty-two percent had also received interferon alfa-2b. Twenty-eight percent also received the fixed combination of lopinavir-ritonavir and 66% also received corticosteroids during hospitalization.
The primary outcome [measure] was time to clinical improvement within 28 days after randomization or hospital discharge, whichever came first. The median time to clinical improvement was not significantly different in the remdesivir group, which was 21 days versus the placebo group, which was 23 days. And the 28-day mortality was similar in both groups, 14% for remdesivir and 13% for placebo. The conclusion of this study was that because of the low enrollment, the trial was insufficiently powered to detect differences in clinical outcome.
Veronica Fowler (11:47):
Okay, and I understand that in the recent weeks we've had some more positive results?
Dr. Julee Oh (11:53):
Yes, Veronica. On April 29, 2020, the results of the Adaptive COVID-19 Treatment trial were released. This is the data upon which the FDA approved the EUA for remdesivir, although we haven't seen trial details published yet. This was an NIAID (which is the U.S. National Institute of Allergy and Infectious Diseases) sponsored, placebo-controlled trial in severe COVID-19 patients. The conclusion was that hospitalized patients with advanced COVID-19 and lung involvement who received remdesivir recovered faster than similar patients on placebo.
This was a randomized, control trial involving 1,063 patients showing that remdesivir patients had a 31% faster time to recovery than those who received placebo. This had a p-value of less than 0.001. The median time to recovery with remdesivir was 11 days versus 15 days for placebo.
The study has received some criticism as the primary endpoint was changed halfway through the trial. Instead of measuring patients on an eight-point ordinal scale that ranged from death to not hospitalized on day 15, the study would measure the time until patients scored one of the best three outcomes on the scale. There were 1,063 patients in this study, but only 480 had recovered at the time of the analysis. If the study went longer, researchers could have collected more data and perhaps have learned if remdesivir saves lives.
The decision to end the trial stemmed early from the moral decision that placebo patients should be offered active drug. The results did, however, suggest a survival benefit with the mortality rate of 8% for remdesivir and 11.6% for the placebo group resulting in a p-value of 0.059. In order to obtain the highly significant p-value of 0.01, more patients would be put at risk of dying, and the investigators felt that would be unethical. Plus, in the world of statistical analysis, a p-value less than 0.05 is still considered significant and they felt they were close enough.
Also on April 29th, Gilead announced topline results for one of its Phase 3 SIMPLE trials, an international study that compared a 5-day to a 10-day course of remdesivir to determine whether a shorter duration of therapy may have the same efficacy and safety as the longer duration. There was no placebo control in this study. There was no significant difference in clinical improvement between the 5-day and the 10-day group on day 14 in hospitalized, but not ventilator-dependent, COVID-19 patients.
More than half the patients in both groups were discharged from the hospital by Day 14, and by Day 14, 65% of the 5-day group and 54% of the 10-day group achieved clinical recovery. In addition, improved outcome was seen for patients receiving remdesivir within 10 days of symptom onset, compared to those who had started treatment later. An elevation of liver function tests was seen in 7% of the remdesivir patients. We expect to know within a few weeks (by early to mid-June of 2020) the results of a similar clinical trial studying remdesivir on patients with moderate cases of COVID-19, again comparing improvement with 5- or 10-day treatment courses.
So, we can tell by this study, like all viral diseases including influenza, initiation of therapy is critical and it appears that COVID-19 is no exception. It appears that there is a 5 to 10-day window where treatment response is better, thus reinforcing importance of early testing upon symptom onset.
Veronica Fowler (15:56):
Yes, it sounds like early testing and starting the medication within the treatment window is key here. Now can you tell us about the dosing and administration of remdesivir?
Dr. Julee Oh (16:09):
Yes. For hospitalized adults not requiring invasive mechanical ventilation and or ECMO (which is extracorporeal membrane oxygenation, a remdesivir loading dose of 200 mg IV infusion on day one, followed by maintenance dose of 100 mg IV infusion once daily on Days 2 through 5. It's the recommendation, if there is no clinical improvement, youth may be continued at the 100 mg daily dose for up to five additional days to a total of 10 days. Treatment for hospitalized adults requiring invasive mechanical ventilation and/or ECMO [is a] remdesivir loading dose of 200 mg IV infusion on Day 1, followed by a maintenance dose of 100 mg once daily on Days 2 through 10. It's recommended dosing in pediatric patients is based on weight.
Veronica Fowler (17:05):
And Julee, any warnings or precautions people should be aware of with this medication?
Dr. Julee Oh (17:10):
Both renal and hepatic function must be assessed prior to remdesivir administration. Remdesivir has not been studied in patients with hepatic or renal impairment, and use in these patients is not recommended unless potential benefit outweighs the risk.
Veronica Fowler (17:25):
And, so what are we hearing about cost? How will this be covered?
Dr. Julee Oh (17:11):
We really don't know yet, but remdesivir is expected to cost anywhere from $1,000 to $4,500 per course of treatment. ICER’s pricing model for remdesivir states that preliminary cost recovery pricing for a 10-day course of remdesivir is estimated at about $10, or $5 for a 5-day treatment course. But, the cost effectiveness pricing at a commonly used threshold for treatments of large patient populations is estimated at a ceiling of $4,500.
ICER also states that “policy makers and the public will need to debate most appropriate development and pricing paradigms to be used to achieve rapid development and distribution of affordable treatments for a global pandemic.” Payers, however, will have no choice to cover remdesivir if it gets approved. The government is not talking to pharma about costs at this point. Some companies are saying that there will be two levels of pricing: during the pandemic and post pandemic, where theoretically, the sky's the limit.
Veronica Fowler (18:38):
Yes, it'll definitely be interesting to see what they do post pandemic. So how available is remdesivir currently? Is Gilead ready for this flurry of demand coming?
Dr. Julee Oh (18:51):
Gilead is currently donating all initial supply of remdesivir, but the federal government is in charge of coordinating where it will be shipped, with hospitals in cities most heavily impacted by COVID-19 receiving top priority. However, distribution seems to be somewhat challenging right now according to some hospitals.
Dr. Leslie Fish (19:11):
And you know, Julee, I saw a few announcements over the last week that included some pharmaceutical companies and their need to outsource production of some medications so they can concentrate on the production of the coronavirus therapies. In addition, in order to allow for enough doses of the approved remdesivir, Gilead has also outsourced some of the production of it.
So Gilead has signed nonexclusive licensing agreements with five generic makers to manufacture the active ingredient for remdesivir. And according to a publication, one of the drugs manufacturers, Cipla, will make the active ingredient as well as the finished product for remdesivir.
Under the agreements, Gilead will share its manufacturing know-how with the five companies to help them gear up for the production of it. Each company will be allowed to set its price for its own generic version of the drug. The licensed drug makers will not be paying royalties to Gilead until the World Health Organization calls off the novel coronavirus public health emergency or until another therapy for COVID-19 is approved.
Veronica Fowler (20:20):
So Leslie, you had said a few announcements. Are there other companies doing the same thing?
Dr. Leslie Fish (20:07):
Yes. At the beginning of May 2020, Pfizer stated it plans to outsource production of some of its drug portfolio to make way for a rapidly growing vaccine manufacturing effort. It will use its 200-strong network of contractors as part of a plan to build a robust U.S.-based supply chain as well as one based in Europe. Pfizer said it came to that outsourcing decision after determining its COVID-19 rollout would heavily tax its ability to produce 1.5 billion doses of sterile injectables each year. Pfizer is also working to build up inventory for the sterile injectables before manufacturing of the potential vaccine launches at scale. Pfizer is developing a candidate with partner BioNTech.
Veronica Fowler (21:19):
So Leslie, in previous podcasts we've talked about the downstream effects of the pandemic on other clinical trials and studies. Do we have any updates now on that?
Dr. Leslie Fish (21:31):
So, as stated before in podcasts, clinical trials have been delayed, slowed down, and postponed because of the coronavirus. How long these will be postponed remains uncertain. There is a possibility that some studies may never restart. One article in the Wall Street Journal estimated that as many as 200,000 clinical trials across the world may have been affected involving many different types of diseases, from cancer to Alzheimer's, to heart disease and stroke. The writer from Yale University stated that about 500 research projects, just at Yale, had been placed on hold. These included both industry-sponsored trials and federally funded ones from the NIH.
A few more announcements include:
On April 28th, IQVIA released its first-quarter financials stating what is happening to its research and development business. It announced that 80% of its clinical research sites were inaccessible due to limitations on the ability to travel and access sites.
Also in April, another research organization, Icon, stated that 65% of its global sites were impacted in some way by the pandemic, and as more companies report this week and next, expect to see the same pattern.
Many of these R&D companies are stating that they feel the slowdown will continue until the end of the third quarter and then turn around during the fourth quarter.
Another one, Novartis has announced that they have paused enrollments in the UK clinical trial ORION-4, which is studying inclisiran.
And finally, a survey of the American Cancer Society Grantees finds more than half report their cancer research has been halted as a result of the COVID-19 pandemic. In addition, the American Cancer Society stated that due to the temporary closing of many research labs, it will delay the start date of its next round of grants from July 1 to September 1, 2020.
Veronica Fowler (23:38):
Well, it's obvious that this has interrupted many of the efforts previously a priority for drug manufacturers. And speaking of interruptions, Leslie, how are manufacturers handling marketing in these unprecedented times? I know visits to doctor's offices and hospitals where the main tactic for marketing before this all started.
Dr. Leslie Fish (23:59):
So Veronica, this is actually a really good question, because there's quite a variety in the way that pharmaceutical companies have decided to handle the newly-approved medications. Zeposia, a medication for multiple sclerosis was approved on March 25th. However, BMS has decided to wait to launch until later in the year when some of the restrictions on travel and business has relaxed.
On the other hand, other manufacturers have decided to use emails, teleconferences, and video calls to introduce and launch newly-approved medications. An example of this is Lily's recently approved oncology medication, Retevmo, [which] will be launched and marketed by emails and video calls.
A company called Veeva systems, which is a company that sells software to drug companies, has seen an increase in use of the software it sells to facilitate online interactions with doctors. In April, companies conducted more than 316,000 remote meetings with doctors and sent about 7 million emails to them globally, and this compares with 4,900 remote meetings and 1.2 million emails in January.
Veronica Fowler (25:18):
And, I wonder just how many of those operational changes will be permanently adopted once this is all over. Now Leslie, before we wrap up, I know that over the weekend we had sort of a late breaking announcement from Sorrento Therapeutics, which has announced that they're working on an antibody called STI-1499, could you provide some more information about that?
Dr. Leslie Fish (25:43):
Yes. Over the weekend, Sorrento Therapeutics has announced that an antibody called STI-1499 could provide 100% inhibition. The company has stated that they have screened and tested billions of antibodies that they have collected over the past decade. They have found that a dozen of these antibodies demonstrated the ability to block the spike proteins from attaching itself to the human enzyme ACE2, which is the receptor the virus uses to enter the cell. One of these antibodies, again, the STI-1499, seems to block the [corona]virus from infecting the cell by 100% and at a low antibody dose. Sorrento, in partnership with New York Mount Sinai Health System, is working on creating a cocktail dubbed COVI-SHIELD, which would consist of three antibodies. They also may pursue a standalone STI-1499 product called COVI-GUARD. Sorrento plans to request prior evaluation and accelerated review from regulators to determine the best pathway to make any potential treatment available as soon as possible. In addition, Sorrento is seeking potential government support and pharmaceutical partners to further scale up the STI-1499 manufacturing capacity with a goal of potentially providing tens of millions of doses in a short period of time to meet what they really feel is a vast projected demand. The results of the preclinical experiments will be submitted to a peer review publication shortly. If approved, this could be used as both prophylactic therapy and for people exposed to the virus.
Veronica Fowler (27:27):
Well, Julee, Leslie, that covers the agenda for today's discussion. I thank you both for coming on and sharing your knowledge with us. As always at IPD, we'll continue to monitor the situation and any information that we're able to share will be provided on our Infectious Disease pages of our Payer & Provider Insights portal, which provides formulary management decision-making support and drug information to payers, providers, and suppliers across the United States. Now, if you're not a current IPD subscriber, and would like to be, inquire about a subscription by emailing email@example.com. Any subsequent episodes will be posted to our LinkedIn page and also our website, so be sure to follow us there. Thank you for listening and stay healthy!