IPD'S DRUG & CLINICAL REVIEW:
COVID-19 PODCAST EPISODES
April 27th, 2020 Update
IPD Analytics has released its third 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 (2:34)
Potential Therapies, Clinical Trials, and Outcomes (3:03)
FDA Approval Delays (22:00)
Provider Impacts (24:24)
At-home Test Approval (29:53)
COVID-19 Update from IPD Analytics April 27, 2020
Veronica Fowler (00:19):
Welcome to IPD’s 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 (00:37):
Dr. Leslie Fish (00:38):
Veronica Fowler (00:40):
Welcome back. Now, for our listeners today that aren't IPD subscribers, this may even be your first time listening to our podcast. If that's the case, I encourage you to go back and listen to our first and second public episode on this topic for more information and better context. And if you aren't familiar with IPD Analytics at all, we provide insight, transparency, and efficiency for stakeholders across the pharmaceutical and biotech industries, including health plans, hospitals, drug manufacturers, and institutional investors.
We offer varying subscription-based products with data analysis and summarized insight, covering topics ranging from loss of exclusivity predictions, brand and generic financial impact forecasts, clinical pipeline tracking, as well as management and decision making support for payers, providers, and suppliers managing their clinical formularies. Now, our show is normally syndicated exclusively to our subscribers, but understanding the need for correct information across the marketplace, we continue to do our part by allowing these episodes 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 ipdanalytics.com. Now, today will be our third public episode on COVID-19, and we plan to review some of the therapies and clinical trials and their outcomes, potential FDA approval, delays, medication shortages, and impacts to the healthcare systems and patient care. 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 April 27, 2020. So, Julee, can you start us off with a brief overview of where we stand nationally and globally for confirmed cases and deaths?
Dr. Julee Oh (02:34):
According to Johns Hopkins University, the number of confirmed COVID-19 cases worldwide is 2,990,559 with 207,446 deaths, and in the United States, the number of confirmed cases is 967,585 with 54,931 deaths.
Veronica Fowler (03:03):
Well, at this point, those increases sound typical considering the short history of this pandemic. I know there have been continued clinical trials on many different medications, some of which are already FDA approved for other indications but are being repurposed here. Let's start with the drug that everyone is talking about right now, remdesivir. What kind of results are we seeing here, Julee?
Dr. Julee Oh (03:29):
Well, interestingly, with remdesivir, we're getting results that are all over the board. So, STAT News reported on April 16th, that they had heard some comments during a video discussion about trial results with University of Chicago faculty members that University of Chicago Medicine recruited the 125 people with COVID-19 in two Phase 3 clinical trials, 103 patients who are severely ill, all patients were treated with remdesivir. They found that only two of those patients died and all others were discharged. Most of the patients were severe and most were discharged at six days, which shows that patients don't even necessarily need to be treated with remdesivir for 10 days. Now, similar trials are being run at other institutions, but without a randomized, placebo-controlled trial, it's still impossible to interpret these results. Now, that said, on April 23rd, results from a long-awaited clinical trial conducted in China were accidentally released.
Supposedly, a summary of the study results was inadvertently posted to the website of the World Health Organization and seen by STAT, [who] took a picture of the conclusions before the post was removed from the WHO website. The manuscript is undergoing peer review and WHO is waiting for a final version before they comment. The post showed that 237 hospitalized COVID-19 patients underwent randomization, so this was a placebo-controlled study. One hundred fifty-eight patients received remdesivir; 79 [received] placebo. The study was meant to enroll 453 patients, but it was terminated early because they couldn't enroll enough patients in China, where the number of COVID-19 cases was decreasing, so they stopped at around half. Daily infusions of remdesivir or placebo were given for 10 days. They concluded that remdesivir use was not associated with a difference in time to clinical improvement or in time to SARS-CoV-2 PCR improvement. According to the study, after one month, 13.9% of remdesivir patients died, compared to 12.8% of patients in the control arm. This difference was not statistically significant.
And note that this is a small study; it was inconclusive. Results of this study will be pooled with larger studies to conduct the meta-analysis to allow for a balanced view of the efficacy of remdesivir from all randomized trials. So, again, fairly inconclusive trial, [with] small numbers, however, it was placebo-controlled. We expect Gilead’s uncontrolled, severe COVID-19 data any day now, although those results will be difficult to interpret as well, given no control. We anxiously await the large U.S. NIAID trial with remdesivir in a broad group of hospitalized patients. It enrolled quickly, as the goal was over 400 patients, and has a placebo control group that will make the results much more reliable and clear, but we don't expect the results until sometime next month in May.
Veronica Fowler (07:01):
So, if we're seeing that these controlled trials aren't having the same efficacy as that heavily picked up media story about the 125 patients at the University of Chicago hospital, what does that mean about what happened there?
Dr. Julee Oh (07:17):
The inconclusiveness results from the fact that medical practice in the United States is likely very different from that in China. We know that likely all those patients in the University of Chicago video, were sick, but they were likely all on ventilators and they likely had all the treatment options that kept them alive, unlike in China, where they probably don't have the same level of medical care as well as access to all the different medical treatments that we have here in the United States.
Veronica Fowler (07:54):
Okay, well I guess all we can do is really wait and see on that. Now, let's move on to hydroxychloroquine, what have we got going on there, Julee?
Dr. Julee Oh (08:03):
Yes, Veronica. We also have some mixed results for hydroxychloroquine as well. There was a study published on April 16th, and it was a randomized, controlled trial of 150 hospitalized patients in China who received hydroxychloroquine and found that hydroxychloroquine did not help clear the SARS-CoV-2 virus or relieve symptoms any more than standard care alone and had more adverse effects. Seventy-five patients were assigned to hydroxychloroquine, while the control group had 75 patients. The hydroxychloroquine was administered with a loading dose of 1,200 milligrams daily for three days, followed by a maintenance dose of 800 milligrams daily for the remaining days, with a total duration of two or three weeks for treatment.
The primary endpoint was the 28-day negative conversion rate of SARS-CoV-2. Now, the results showed that [the] overall 28-day negative conversion rate was not different between hydroxychloroquine and the placebo group. The negative conversion rate at Day 4, 7, 10, 14, or 21 was also similar between the two groups and there were no different 28-day symptom alleviation rates observed between the two groups. Adverse events were found in 30% of the hydroxychloroquine patients and only 8.8% of the placebo patients. The conclusion of this study was that hydroxychloroquine did not result in higher negative conversion rate and adverse events were significantly higher in hydroxychloroquine patients.
In addition, we found similar results to another study that was made public on April 21st, according to a retrospective study of Veteran's Affairs patients hospitalized with COVID-19, hydroxychloroquine, with or without azithromycin, was not associated with a lower risk of requiring mechanical ventilation. Note that the study has not been peer-reviewed and also showed an increased risk of death associated with COVID-19 patients treated with hydroxychloroquine alone.
This new data [are] not the first to suggest no benefit with hydroxychloroquine among patients with COVID-19. Again, these findings continue to emphasize the importance of waiting for results of ongoing, prospective, randomized, controlled studies for widespread adoption of these drugs.
[The] large U.S. trial of hydroxychloroquine that we're waiting for is called the ORCHID Study. It's a Phase 3, placebo-controlled trial in over 500 hospitalized patients with COVID-19, where patients will be randomized one-to-one to hydroxychloroquine or placebo. Patients will receive hydroxychloroquine 400 milligrams twice daily on the day of enrollment and then 200 milligrams twice daily for the next four days, for a total of five days. The primary endpoint will be a COVID ordinal scale for all patients on study day 15. The ordinal scale will range from death to no symptoms. Secondary endpoints will include all-cause mortality assessed on Day 15 and Day 29. Secondary end points will include all-cause mortality assessed on Day 15 and Day 29. The study actually started on April 2, 2020, is expected to complete by the end of April 2021, with published results by July 2021.
So, unfortunately, the results of this large-scale study are a bit far off. Novartis, the maker of Plaquenil, is planning its own Phase 3 trial of hydroxychloroquine for COVID-19 as well. They will start enrolling next month in May, and the trial will be conducted at more than a dozen sites in the U.S. Patients will be randomized into three groups. The first group will receive hydroxychloroquine. The second group will receive hydroxychloroquine in combination with azithromycin. The third group will receive placebo. Again, this study is not expected to complete until later this year. We will have to wait for the results from these more reliable hydroxychloroquine studies.
Veronica Fowler (12:27):
Well, again, it sounds like the media has picked up these small tidbits of information and run with them, but we're going to have to wait a while to get some reliable results from well-designed hydroxychloroquine studies. Now, I've also heard that galidesivir is being tested, which is a broad-spectrum antiviral. What can you tell us about this therapy from BioCryst Pharmaceuticals, Julee?
Dr. Julee Oh (12:52):
Yes, on April 9th, BioCryst Pharmaceuticals began enrollment into a randomized, double-blind, placebo-controlled clinical trial to assess the safety, clinical impact, and antiviral effects of galidesivir in patients with COVID-19. The trial is being funded by the National Institute of Allergy and Infectious Diseases, which is part of the National Institute of Health. Galidesivir is a broad-spectrum antiviral drug that was safe and well-tolerated in previously reported Phase 1 trials in healthy subjects. Galidesivir is an identity nucleoside analog that acts to block viral RNA polymerase.
Galidesivir has demonstrated broad-spectrum activity in vitro against more than 20 RNA viruses in nine different families, including the coronaviruses that cause MERS and SARS. In the COVID-19 trial, efficacy measures include time to clinical improvement, time to hospital discharge, time to undetectable levels as measured by PCR in respiratory specimens of SARS-CoV-2, and all-cause mortality. In part one of the trial, it will enroll 24 hospitalized adults diagnosed with moderate to severe COVID-19, confirmed by PCR and in part two of the trial, up to 42 hospitalized patients with COVID-19 will be randomized 2-to-1 to receive the IV galidesivir or placebo after treatment. The patients will remain hospitalized until resolution of COVID-19 symptoms allows release. All patients will be followed for mortality through day 56. We don't expect results of the study until May 2021.
Veronica Fowler (14:42):
Wow, May 2021 seems really far away. Now, moving to favipiravir, which I understand is approved for flu in Japan under the name Avigan. I hear these trials are a little closer to completion, is that right, Julee?
Dr. Julee Oh (15:00):
That's correct, Veronica. One study of favipiravir showed that it shortened the time to viral clearance in patients who took the medication, and 91% of the patients who took favipiravir had lung improvement, versus 62% of patients who did not get the medication. Note that these outcomes may only apply for patients with no symptoms or mild symptoms of COVID-19. The Japanese Health Ministry suggests that favipiravir is not as effective in patients with more severe symptoms.
Veronica Fowler (15:35):
Okay, and I also understand there's a whole slew of drugs being tested for their anti-inflammatory or immunomodulatory effects. Let's start with Farxiga, which is normally used to treat adult type two diabetes.
Dr. Julee Oh (15:53):
Yes, AstraZeneca and St Luke's Mid-America Heart Institute have initiated a randomized, global, Phase 3 trial to assess Farxiga, an SGLT2 inhibitor, dapagliflozin, as a treatment in patients hospitalized with COVID-19 who are at risk of developing serious complications, such as organ failure. The goal of the trial, called DARE-19, is to assess whether Farxiga can reduce the risk of disease progression, clinical complications, and death due to COVID-19 in patients who also have cardiovascular, metabolic, or kidney risk factors.
As we know, cardiac, renal, and metabolic comorbidities have been associated with poor outcomes and death in COVID-19 patients. And the trial design is supported by extensive data on the protective effect of Farxiga in patients with heart failure, with reduced ejection fraction, chronic kidney disease, or type two diabetes. DARE-19 is an international, parallel, group-randomized, double-blind, placebo-controlled, investigator-sponsored Phase 3 trial, evaluating the safety and efficacy of Farxiga. In addition to standard-of-care therapy, on the risk of all-cause death or disease progression and complications in adults who are hospitalized with COVID-19 at the time of enrollment. The primary efficacy outcome of the trial is time to first occurrence of death from any cause, or new or worsened organ dysfunction through 30 days of follow up.
Veronica Fowler (17:32):
And how about ivermectin, an old antiparasitic drug used in the past to treat head lice, but may have some antiviral activity?
Dr. Julee Oh (17:42):
Yeah, Veronica. Researchers at Melbourne's Monash University Biomedicine Discovery Institute found that ivermectin inhibited activity of COVID-19 in vitro, causing about a 5,000-fold reduction in viral RNA after 48 hours. A small observational study from the University of Utah found that critically ill patients with lung injury requiring mechanical ventilation benefit from administration of ivermectin. So, a Phase 1 study is ongoing to recruit 50 patients to compare ivermectin plus hydroxychloroquine in COVID-19 patients with pneumonia to hydroxychloroquine alone. That recruitment started on April 8th. Ivermectin 0.2 milligrams per kilogram plus hydroxychloroquine 400 milligrams daily will be the dose. We expect the study completion to be somewhere around August of this year.
Veronica Fowler (18:44):
Great, well we'll continue to track that progress and see what comes in August. Now, how about leronlimab, which is actually currently being studied for HIV and triple-negative breast cancer.
Dr. Julee Oh (18:58):
Leronlimab is a CCR5 antagonist. It's a humanized IgG4 monoclonal antibody that blocks CCR5, and we found that the CCR5 receptor may play a key role in modulating immune cell trafficking to sites of inflammation. CytoDyn’s Phase 2 randomized clinical trials started enrolling patients in early April for those patients with mild to moderate COVID-19, they are collaborating with Novant Health test sites in Virginia, North Carolina, South Carolina, and Georgia. CytoDyn also initiated a Phase 2b/3 trial on April 6th, with leronlimab for severely ill COVID-19 patients. This will be a 342 patient, double-blind, placebo-controlled trial, where patients will receive leronlimab placebo for two weeks. The primary endpoint will be mortality at 28 days, with the secondary endpoint [being] mortality rate at 14 days.
Veronica Fowler (19:36):
Okay, and Julee, last therapy we’re covering today, cholecalciferol, which is really just vitamin D3, is that correct?
Dr. Julee Oh (20:06):
That's correct. So, there's an ongoing Phase 3 study with 260 patients randomized to either high dose of vitamin D3, compared to the standard dose of vitamin D3. The primary outcome is number of deaths from any cause during the 14 days following inclusion intervention. The inclusion criteria will require that the patient be 70 years or older and diagnosed with COVID-19. The premise is that COVID-19 has seasonality, with outbreaks during winter, since the pandemic is more severe above winter latitudes of 20 degrees, while it remains less severe in the Southern hemisphere. The clinical research suggests that SARS-CoV-2 virus enters cells via the angiotensin converting enzyme 2 (ACE-2) [receptor]. Viral replication down-regulates ACE-2, thereby dysregulating the renin angiotensin system and leading to a cytokine storm in the host, causing acute respiratory distress syndrome. Research also shows vitamin D plays a role in balancing the renin angiotensin system and reduces lung damage. Research also shows that chronic lack of vitamin D induces pulmonary fibrosis through activation of the renin angiotensin system. Lack of vitamin D is also associated with ARDS or Acute Respiratory Distress Syndrome. Vitamin D supplementation has been reported to increase immunity and reduce inflammatory responses and the risk of acute respiratory tract infections. This first vitamin D study is expected to complete this July.
Veronica Fowler (22:00):
Okay. Thank you, Julee, for that overview of some of the current clinical trials. There seems to be a lot going on. So now that we've covered most of the prominent therapies, let's switch gears and talk about the impacts to various stakeholders in the market. Leslie, what have you been hearing about potential delays at the FDA on current clinical trials for medications not being tested for COVID-19, but for other indications?
Dr. Leslie Fish (22:26):
So throughout the pandemic, the FDA has given mixed messages about whether or not they feel that there will be delays in approving new medications and about new clinical studies. Mid-April, the FDA acknowledged that the postponement of advisory meetings, the number of new applications for drugs, diagnostics, and vaccines for COVID-19, and staffing issues will impact incoming submissions. It also said that it would be reprioritizing work if necessary.
Additionally, the FDA reported that many trials, at least 440, have been suspended since March 1, 2020. Drug manufacturers, university medical centers, hospitals, and community research centers have all suspended various research products. However, on April 17, there were two new FDA drug approvals: Tukysa and Penzyre. They're both oncology medications and both ahead of their upcoming PDUFA times. On April 19th, Richard Pazdur, the CDER’s oncology official, stated that “the continued approval of oncology medications demonstrate that while the FDA continues to focus our efforts on addressing the COVID-19 pandemic, the FDA remains committed to the important work of reviewing treatments for patients with cancer and other serious conditions.”
To give you an idea of FDA approvals since February of this year, we have Nurtec ODT, Sarclisa, Isturisa, Zeposia, Koselugo, Tukysa, and Penzyre. What we may see this year is a lot of the near-term approvals on track or even ahead of time, but a delay much later on in the year due to the stalled or delayed clinical trials.
Veronica Fowler (24:24):
And of course, from the healthcare system standpoint, there must be substantial impacts, including changes to current patient care, medical shortages. Can you tell us what you're hearing here?
Dr. Leslie Fish (24:37):
So yes, throughout the pandemic there have been many acknowledgements about the increase in telemedicine. Although telemedicine has been around for a while, the pandemic really catapulted it ahead. One thing to note is that the providers are now understanding what telemedicine really means and what changes will have to take place in order for it to work more efficiently. This is in terms of both software and clinical diagnoses. One question to think about is, will this have lasting results? Will telemedicine continue to grow even after social distancing subsides? Another thing to think of, or another offshoot of the pandemic, is the increase in the Medicaid population. Payers may see patients leaving commercial plans due to unemployment and enrolling in either Medicaid or ACA options. This could mean changes to state Medicaid plans, retail pharmacies, PBMs, and changing business trends in revenues.
Veronica Fowler (25:38):
And I understand that outside of increased use of telemedicine, there's been a dramatic increase in home infusions.
Dr. Leslie Fish (25:48):
So yes, the impact of COVID-19 pandemic continues to reach into all areas of healthcare that are not directly related to the virus, including treatment of cancer patients and the possibility of replacing visits to infusion centers with home-based chemotherapy. There are many successful models of home-based infusion programs for other medications and extending those models to oncology has been discussed for many years. However, it has yet to be widely accepted due to several barriers. Though there have been small trials of oncology home infusion, there are limited published data. However, recently, the University of Pennsylvania in Philadelphia developed and executed a home-based chemotherapy program for two treatment regimens with Hematologist-Oncologist, Amy Laughlin, leading the study. The program, Cancer Care at Home, enrolled 40 patients who were referred to the program from fall 2019 to the winter 2020.
The COVID-19 pandemic triggered a swift rise in enrollment and within a four-week period (that's March 10 to April 17, 2020), UPenn received another 135 referrals to the program. With the increased enrollment, the trial has expanded available medications from two to seven products. UPenn also started the program by offering leuprolide for prostate cancer or breast cancer, and treatment for lymphoma, which included etoposide, vincristine, doxorubicin, cyclophosphamide, prednisone, and if needed, rituximab. Following the recent spike in enrollment, the study now includes Velcade (bortezomid), Somatuline Depot (lanreotide), zoledronic acid and denosumab. UPenn is also planning on adding rituximab and Keytruda (pembrolizumab) for lung cancer and head and neck cancer.
Home infusion offers many potential benefits for patients, including the ability to stay in a safe and protected environment without having to travel or risk exposure to infectious diseases, one-on-one care and close monitoring by the home care health provider throughout the entire infusion period, and the convenience of scheduling treatments around their personal schedules.
Opinions among the oncology leaders are mixed. The National Comprehensive Cancer Network endorsed the concept, stating that there are several chemotherapy agents that have the potential to be administered at home. The American Society of Clinical Oncology has also stated that they are monitoring the program and advise considering whether home infusion is both medically and logistically feasible. However, the Community Oncology Alliance has indicated that while home infusion of some medications during the COVID-19 pandemic may be reasonable, the oncology setting entails specific factors for patients, and it cautions against broadly applying this kind of site-of-care management. The COE issued a statement that fundamentally opposes home infusion of oncology agents due to safety issues.
Veronica Fowler (28:57):
Well, Leslie, those sound like important shifts to make considering these patients need uninterrupted treatment. And speaking of uninterrupted treatment, that brings us to medication shortages. What are you seeing there?
Dr. Leslie Fish (29:10):
So since the last podcast, the increase of medications needed for the ventilators including fentanyl, morphine, hydromorphone coding, ephedrine, and pseudoephedrine, also including ketamine, diazepam, midazolam, lorazepam, phenobarbital, and rocuronium have been in shortage. There was also potential for dialysis supply shortages due to the number of patients in hospitals with the COVID-19 virus that are developing renal failure. It is estimated that 20% of the patients in the ICU need kidney treatment, and that could go on for longer periods of time.
Veronica Fowler (29:53):
Okay. Leslie, we're about out of time for today, but before we wrap up, do you have any final thoughts here?
Dr. Leslie Fish (30:00):
So, one thing I'd like to mention is something that they're now calling the Accelerating COVID-19 Therapeutic Interventions and Vaccines partnership. You'll be seeing it as ACTIV. The U.S. National Institute of Health, or NIH, announced a new public-private partnership, which brings together more than a dozen biopharmaceutical companies and various government bodies, including the FDA and the European Medicines Agency. The goal of this endeavor is to speed up the response to the COVID-19 pandemic. The partnership will work on building a framework to prioritize vaccine and drug candidates, streamline clinical testing, coordinate regulatory processes, and leverage the use of assets among all partners to rapidly respond to COVID-19 and future pandemics.
Another thing I would like to note is, the FDA authorized the first COVID-19 diagnostic at-home test. The test, by LabCorp, allows patients to self-swab nasal passages using the company's Pixel test kits. LabCorp plans to make the kit available to consumers in the coming weeks, however, will allow healthcare workers and first responders to get them first. LabCorp has stated that the price of the test, including the kit, by way of overnight shipping, physician services, and the test in LabCorp’s laboratory, will be $119. Samples can be collected and tested from the patient's nose using the test kits, nasal swabs, and saline. Once collected, patients can mail in their sample to LabCorp in an insulated package. Because of sterility and cross reactivity risks, the FDA has emphasized that cotton swabs other than those included in the test kit should not be used to collect at-home samples.
Veronica Fowler (32:01):
Well that at-home kit sounds really interesting and it also sounds like everyone is really coming together to work on this, which has crossed competitive boundaries in many cases. So, kudos to all of the manufacturers and governmental agencies for that. And Julee, Leslie, thank you so much for coming on and talking to us today. At IPD, I know we're all working hard to keep our subscribers informed, and the best way to get up-to- date information on this is to check our infectious disease pages of our Payer & Provider Insights platform. Here, you'll find vast amounts of COVID-19 information, as well as a formulary planning strategy, clinical data, and drug information for payers, providers, and suppliers who need to make tactical decisions. If you're not a current IPD subscriber who can access our Payer & Provider Insights platform, inquire about a subscription to IPD by emailing firstname.lastname@example.org. And that said, any subsequent public episodes will be posted to our LinkedIn page, so be sure to follow our company there as well. Thank you for listening and stay healthy!