IPD'S DRUG & CLINICAL REVIEW:
March 31st, 2020 Update
IPD Analytics has released another publicly available podcast on COVI-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
Potential Therapies, Clinical Trials, and Outcomes
FDA Approval Delays
Manufacturer Clinical Trial Delays
COVID-19 Update from IPD Analytics March 31st, 2020 Transcript
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 (00:34):
Dr. Leslie Fish (00:35)
Veronica Fowler (00:36):
Welcome to the show. Now, for those of you who aren't IPD subscribers, this may be your first time listening to our podcast. If that's the case, I urge you to go back and listen to our first public episode on this topic for better context. And if you're new to IPD Analytics altogether, we provide insight, transparency, and efficiency for stakeholders across the pharmaceutical industry, and we offer various subscription-based products with data and analysis covering many topics ranging from the drug life cycle and clinical pipeline tracking to management and strategy around clinical formulary, procurement and inventory control for payers, providers, and suppliers. Now, our show is normally syndicated exclusively to our subscribers, but in acknowledgement of the need for accurate information across the marketplace, we wanted to do our part and open up these episodes to the public. So that being said, for further updates from us, follow our company page on LinkedIn or check our website at ipdanalytics.com.
So, today will be our fourth installment of our COVID-19 coverage, and we plan to review some of the clinical trials and outcomes, immunomodulator therapy, testing, FDA—as well as manufacturer—clinical trial and approval delays, and medication shortages. I'd like to start out with an update of the numbers. Of course, all of this is changing rapidly, so all of the numbers we mentioned today will be relevant for the time of this recording, which is March 31st. So, Julee, can you start us off with a check-in on where we are nationally and globally as far as confirmed cases and deaths?
Dr. Julee Oh (02:14):
Well, Veronica, Johns Hopkins is reporting on a national level 164,610 confirmed cases in the U.S., of which 5,945 of those have recovered, with 3,170 deaths; whereas, the total world confirmed cases are reported at 101,400, of which there have been 38,743 total deaths and 172,657 recovered.
Veronica Fowler (02:53):
Well, it sounds like those numbers are par for the course. They're only continuing to rise every time we talk. I know we've got some therapies out there that are being tested. Now, Julee, can you tell us about some of the drugs that are already FDA approved but are being repurposed, starting with what's hot in the media right now—chloroquine and hydroxychloroquine—since we've heard so much about those lately.
Dr. Julee Oh (03:17):
Yes, Veronica, I'd like to start out with the fact that the FDA on Sunday, March 29th, 2020, issued an Emergency Use Authorization for hydroxychloroquine and chloroquine. Both of these are decades-old malaria drugs, championed by the president for coronavirus treatment, despite the scant evidence. The agency allowed for the drugs to be donated to the Strategic National Stockpile to be distributed and prescribed by doctors to hospitalized teen and adult patients with COVID-19 as appropriate when a clinical trial is not available or feasible.
So, I'll start with chloroquine. There've been limited clinical trial data available to date for the treatment or prevention of COVID-19. Various dosages have been recommended or are being investigated. Doses used in the chloroquine studies range from 500 milligrams twice daily for 7 to 10 days. When it comes to hydroxychloroquine, again, there's only limited clinical data available for the treatment or prevention of COVID-19. Various dosages are being studied ranging from 100 to 400 milligrams, two to three times daily for 5 to 10 days.
In a small pilot study conducted in China, 30 treatment-naive patients were randomized to receive hydroxychloroquine 400 milligrams once a day for five days with conventional treatment versus conventional treatment alone. The primary endpoint was negative conversion and pharyngeal swabs on Day 7. Negative conversion was reported at Day 7 in 13 patients (86.7%) treated with hydroxychloroquine, and 14 patients (93.3%) not treated with the drug, and the data is unclear for three patients. Median duration from hospitalization to negative conversion and to temperature normalization were similar in both groups. Evidence of radiologic progression on CT in five patients treated with the drug and some patients not treated with the drug. All patients showed improvement at follow up.
In another small study conducted in France, they used a single-arm protocol, 20 patients treated in the study. They use untreated patients from another center and cases refusing the protocol as negative controls. Azithromycin was added to treat the upper and lower respiratory tract infections. The primary endpoint was negative PCR results in nasopharyngeal samples. At Day 6, eight out of 14 (or 57%) in the hydroxychloroquine group, six out of six (or 100%) of patients in the hydroxychloroquine plus azithromycin group, and two out of 16 (or 12.5%) in the control group had negative PCR results.
Veronica Fowler (06:20):
But, I hear there were some reservations about the dependability of the outcomes of those trials. Is that right?
Dr. Julee Oh (06:27):
That's correct. And the key issues or concerns with that French study was number one, the small numbers, and it was not randomize, the control arm was from a different center, the patients were not severe patients, six were asymptomatic, 22 had either an upper respiratory tract infection or lower respiratory tract infection, six patients were lost to follow up and not included in the analysis, and there were no outcomes information, only viral load on Day 6 was the primary endpoint.
Veronica Fowler (06:59):
Yes, and as we've talked about previously, it's hard when the sample sizes are so small to make real conclusions from the data. Now, Leslie, what about off-label usage of these drugs?
Dr. Leslie Fish (07:12):
So, Oracle is working with the White House, and it's expected to be getting a project collecting information about the off-label usage of chloroquine and hydroxychloroquine. Oracle is creating that online platform. Dr. David Agus, a professor of medicine at the University of Southern California, is working with the White House and with Oracle.
Now, many experts are questioning the value and safety of a database such as this, citing too many unknown factors. Dr. Joshua Sharfstein, Vice Dean of the Johns Hopkins Bloomberg School of Public Health and a former principal deputy commissioner at the FDA, said that the only way to really know whether chloroquine works as a coronavirus treatment is through high quality clinical trials. As you just heard from Julee, this would require trials which have a larger number of patients, more controls and be randomized.
Veronica Fowler (08:07):
Well, I can definitely agree with that. Now, I've also heard that Kaletra is being tested. What can you tell us about this therapy, Julee?
Dr. Julee Oh (08:17):
Yes, Kaletra is AbbVie's protease inhibitor combination of lopinavir and ritonavir.
It was found that in the original SARS epidemic in 2002, and MERS, that there was some evidence of benefit in animal studies. However, the current data for Kaletra on SARS-CoV-2 is lacking. The study published in the New England Journal of Medicine published results on the use of Kaletra in very ill patients with COVID-19 showed no benefit. The study examined 199 patients in China. Ninety-nine patients received Kaletra in conjunction with the standard of care, while 100 patients received the standard of care alone. The primary endpoint was time to clinical improvement, time from randomization to improvement of two points on a seven-category, ordinal scale, or hospital discharge, whichever came first. In the intent-to-treat population, time to clinical improvement was not shorter with Kaletra compared with standard of care. Medium time to clinical improvement was 16 days in both groups. No significant differences in duration of oxygen therapy, duration of hospitalization and time to death.
Basically, Kaletra did not lower mortality rate, nor did it significantly shorten time to clinical improvement. It should be noted that if the patients received Kaletra within 12 days after the onset of symptoms, it was a shorter time to clinical improvement. Duration from randomization to hospital discharge was 12 days in the standard of care Kaletra group, and 14 days in the standard of care alone group. More studies are needed to determine whether earlier treatment could be beneficial, or if treatment combined with other antivirals such as arbidol or interferon alpha, which boost the immune response.
Veronica Fowler (10:19):
Okay, and now moving to oseltamivir, I hear this has been used for influenza in the past.
Dr. Julee Oh (10:27):
Yes. The neuraminidase inhibitors, which include oseltamivir, are antivirals currently active against influenza viruses. While oseltamivir is noted to have been widely used for confirmed or suspected COVID-19 cases in hospitals in China, there has been little evidence to date that oseltamivir is effective in the treatment of COVID-19. There continue to be oseltamivir clinical trials for COVID-19; however, they are just starting to recruit.
Veronica Fowler (10:59):
And what about another hot topic drug remdesivir? I understand there's been some controversy surrounding the Orphan Drug designation that was recently approved by the FDA but then rescinded by Gilead.
Dr. Julee Oh (11:13):
Yes, we've all heard about the flack Gilead received over its Orphan Drug designation for remdesivir, which would have given the drug an additional seven years of patent protection, and that's because so far, this investigational antiviral seems to have the most promise against COVID-19. Remdesivir is a broad-spectrum antiviral. It showed in vitro activity against the original SARS and MERS and active in animal models of both SARS and MERS. Safety information is already available from the Ebola trials, although it failed efficacy against Ebola. Multiple clinical trials are being conducted worldwide using remdesivir.
Veronica Fowler (11:57):
And Julee, can you tell us a little bit about some of those remdesivir trials and outcomes?
Dr. Julee Oh (12:03):
Sure, Veronica. Gilead launched two Phase 3 clinical trials in China. They were both randomized, open-label, multicenter studies in nearly 1,000 patients; 400 patients with severe symptoms and 600 patients with moderate symptoms. The dose was 200 milligrams intravenous on Day 1, followed by 100 milligrams intravenously once a day for 5 or 10 days. Primary endpoints were reduction of fever and oxygen saturation, proportion of patients discharged by Day 14.
NIAID is also sponsoring a Phase 3 randomized placebo controlled multicenter trial to evaluate the safety and efficacy of remdesivir in hospitalized patients with laboratory confirmed COVID-19. The study will enroll 440 patients: 220 patients will receive remdesivir, 200 milligrams IV on Day 1, followed by 100 milligrams IV once a day for the duration of their hospitalization up to a total of 10 days, and 220 patients will receive placebo. Primary outcome is the percentage of subjects reporting each severity rating on an eight-point ordinal scale ranging anywhere from death, to being hospitalized on mechanical ventilation, to being not hospitalized with no limitations on activities. Conclusion, once again, safety and efficacy has not been established. However, we do expect to see results of remdesivir trials by the end of April.
Veronica Fowler (13:43):
Great. Well, we'll continue to monitor that progress as it unfolds. So now that we've covered some of the most prominent therapies, let's talk about shortages. Leslie, how are hospitals handling these issues?
Dr. Leslie Fish (13:58):
Veronica, it's not just hospitals, but when we look all over the healthcare system, there are shortages going on right now and potential ones. And I'm just going to tell you a little bit about why. So first of all, this March, the FDA did state that there are drug shortages due to manufacturing issues stemming from the coronavirus. However, the FDA has not suggested which drugs are in shortage due to the coronavirus. They do have a list of drug shortages on their website, and they actually do talk to the fact that there are drug shortages that are due to the increase in demand for other non-anti-coronavirus medications. So first of all, we have metered dose inhalers in hospitals and other healthcare facilities. The use of nebulizers is not allowed for patients infected with the coronavirus due to the potential aerosolization of the coronavirus.
So, hospitals have increased the use of metered dose inhalers so as not to use the nebulizers. Due to the increase in demand from hospitals, and increase in demand from people wanting extra supplies at home, metered dose inhalers are now in short supply. In addition to this, patients have been told that they should actually get extra medications to have at home, so people are stockpiling other chronic-use medications. In addition, health plans have actually stopped their refill too soon edits, which allow patients to get extra drug supplies, and therefore has caused more demand, causing shortages.
Another interesting issue could be the relaxation of patents. This did happen in Kaletra by AbbVie. AbbVie actually has been allowing Kaletra to be manufactured by different generic manufacturers. This could potentially allow more manufacturers to make the product, causing a strain on the supply chain for the active ingredients. And one more thing we have actually heard about, and this is really with blood products due to lack of donors, that there could be a potential lack of people donating or volunteering to donate their blood.
Veronica Fowler (16:09):
Now on another topic, I think we received a few questions from subscribers regarding immunomodulator therapy.
Dr. Julee Oh (16:18):
Yes, we received an interesting question for one of our subscribers last week, so I'll do a review of latest recommendations for patients on immunomodulator therapy such as anti-TNFs, interleukin inhibitors and JAK inhibitors. There are many organizations providing input for patients on anti-TNFs interleukins and JAK inhibitors. These organizations include Crohn's & Colitis Foundation, ACR infusion guidance during COVID-19 crisis, the Arthritis Foundation and COVID-19 Global Rheumatology Alliance on immunosuppressive medications. In summary, most guidelines say if you are stable and doing well, continue therapy. If you are considering initiation of new therapy, consider holding any change or new starts at this time. Each patient should be in consult with their physician based on individual unique circumstances.
Veronica Fowler (17:18):
Okay, and now let's move on to testing. Leslie, can you give us an update on what's happening on that front?
Dr. Leslie Fish (17:25):
Yes, and this really has been good news as far as testing. So first of all, the current PCR test for viral load relies on nasal or throat swabs. Recently, there have been new tests, which can be done in a quicker period of time. Cepheid’s Xpert Xpress SARS-CoV-2, which should take approximately 45 minutes to run. Accula’s SARS-CoV-2 tests from Mesa Biotech, which allows for an easy-use, rapid molecular SARS-CoV-2 testing with diagnostics results and about 30 minutes. This is a palm-sized system that can be used at temporary screening facilities, physician offices, urgent care and long-term care facilities.
Abbott has also stated that they have received FDA approval for their fast-acting molecular test, Abbott ID NOW COVID-19. It can diagnose a positive test result within five minutes and a negative test result within 13 minutes. Again, this test is portable and it can be used in hospital emergency rooms, urgent care centers, and physician offices. The company says it will start shipping out 50,000 tests a day by April 1st.
In clinical trials, a potential serological test to detect antibodies in patients who have had the disease, may not have shown symptoms, and if fully recovered. These tests will rely on blood samples. These tests could be used to identify patients who could donate plasma for coronavirus therapy. One thing interesting to note: that under the Stimulus Deal, manufacturers of the coronavirus tests will have to publish their cash prices.
Veronica Fowler (19:13):
Well, it's good to hear that we're going to get an increase now. Leslie, can you shed some light on what's happening as far as delays and approvals with the FDA?
Dr. Leslie Fish (19:23):
Yes, so initially the FDA did not publish an announcement regarding delays and drug approvals. However many manufacturers believed that there would be slow downs due to a variety of reasons. Some issues include, but are not limited to, FDA advisory board meetings being postponed or canceled, challenges with working remotely, patient and physician recruitment for studies, data collection, participation in the actual COVID-19 trials, and the development of the coronavirus in patients already enrolled in other clinical trials. They also do feel that this slow down could even last after the pandemic has subsided.
Veronica Fowler (20:07):
And so that takes care of the FDA side of things. But, Leslie, before we wrap up, can you share with us what we've learned about delays from manufacturers and clinical trials? I've seen many announcements from several different manufacturers regarding this.
Dr. Leslie Fish (20:22):
Oh yes, there are many ongoing clinical trials that will be influenced by the coronavirus issues. Some companies have stated business as usual, while others have publicly acknowledged slow downs due to patient and physician enrollment and using labs for the coronavirus development to testing. In addition to ongoing studies, there'll be delays in new studies—those just starting or in development. Examples of manufacturers and announcements include Eli Lilly that announced delays to its clinical trials. It will delay new starts and pause enrolling healthy volunteers or new patients in most ongoing studies. They are also evaluating ongoing trials on a case-by-case basis. Bristol Myers Squibb has stated that their cell therapy trials are temporarily suspending screening, enrollment and apheresis. Other trial slowdowns include no new site activation, although existing sites can continue to recruit patients. Trials for their ide-cel (bb2121) and for their liso-cel (JCAR017) gene therapy will continue as normal because they would like to see the approval of these CAR T medications on time.
Dr. Leslie Fish (21:37):
Now, Sandoz is monitoring their clinical trials. Galapagos has said that they will postpone studies and their filgotinib study has been paused. ObsEva announced postponement of studies. They will not screen new patients with their two studies in linzagolix for endometriosis. Bluebird has stated that submission for Zynteglo, gene therapy for beta thalassemia could be delayed until mid-2021. Finally, Ampio Pharmaceuticals has halted patient enrollment in the late stage AP-013 of Ampion for the treatment of severe osteoarthritis of the knee. In addition to the above, the National Cancer Institute has stated that they would allow flexibility needed to continue clinical trials. And finally, the merger between Mylan and Upjohn dubbed Viatris is being pushed back into the second half of 2020.
Veronica Fowler (22:33):
Well, it sounds like no one has really been unaffected by this, and unfortunately there will likely be residual effects even after we get it all under control. Now, we're about out of time for today, but at IPD we're all working remotely and keeping our subscribers informed via our Infectious Disease pages of our Payer & Provider Insights portal, which provides formulary planning, support, clinical data, and drug information to payers, providers, and suppliers across the United States. Now, if you're not a current IPD subscriber, inquire about a subscription to IPD by emailing email@example.com. And for non-subscribers, any subsequent 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.
In order to shed light on this critical topic, IPD Analytics has made a publicly available podcast. Listen to IPD’s Executive Clinical Pharmacy Team discuss the most recent news on the coronavirus, including:
Clinical Development Pipeline and Trials
Pharmaceutical Industry Impacts
COVID-19 Update from IPD Analytics March 19th, 2020 Transcript
Veronica Fowler (00:19):
Welcome to IPD’s Drug and Clinical Review, the premier podcast for drug intelligence and pharmaceutical and therapeutic management strategy. I'm Veronica Fowler, your host, and I'm here today with Dr. Julee Oh, Dr. Leslie Fish, and Jeff Casberg, three of our Executive Clinical Pharmacy team here at IPD. Welcome to the show.
Leslie Fish (00:40):
Julee Oh (00:41):
Jeff Casberg (00:42):
Hi, Veronica. Happy to be here.
Veronica Fowler (00:43):
Today we’re covering the coronavirus, specifically potential therapies, what’s currently in clinical development, testing and where we stand with that, governmental initiatives, and impacts to the pharmaceutical industry, including impacts to payers, providers, and suppliers, as well as manufacturers.
Now, if you're new to us and this is the first time you're listening to the show, at IPD Analytics, we provide insight, transparency, and efficiency to stakeholders across the pharmaceutical industry by identifying, projecting, and quantifying the impact of brand, generic, and biosimilar launches in the marketplace. We offer various subscription-based products with data and analysis to subscribers in over 45 countries covering:
The drug life cycle, from clinical development to loss of exclusivity;
clinical formulary procurement and inventory control, insights for payers, providers, and suppliers;
brand and generic market impact forecasts;
and medical drug coding and reimbursement information.
We're headquartered in Aventura, Florida, and our team is composed of unique experts, many from the patent litigation field, many from the biosciences, and many who are clinical pharmacists, whom you'll actually be hearing from today.
Now, our show is normally syndicated exclusively to our subscribers, but since this epidemic is so rapidly changing and information dissemination is key, we decided that we would open up this episode to the public. For further updates from us, follow us on LinkedIn or check out our website at ipdanalytics.com.
And for press inquiries, contact firstname.lastname@example.org.
So, all of that being said, today will actually be our third installment of the COVID-19 update, and, of course, we're watching the numbers very closely. Understanding that they're changing rapidly, all of the facts and figures that we mention here today are relevant for the time of this recording, which is March 19, 2020.
That being said, Julee, can you start us off with an update on where we stand nationally as well as globally?
Julee Oh (3:02):
Sure, Veronica. Since we last spoke, the CDC website has updated the numbers in the U.S. that total cases now number 7,038 and total deaths number 97. And the WHO (World Health Organization) website keeps us updated on what's happening globally across the world. There've been total cases of 191,127 with deaths numbering 7,807.
Veronica Fowler (03:36):
So, yes, Julee, as you've said, since our last talk, those numbers have definitely grown dramatically. And, of course, the thought on everyone's mind is where are we on a vaccine for this. Leslie?
Leslie Fish (03:48):
Yes, so therapies for the coronavirus can be divided into prevention and treatment. Vaccines will be the most effective therapy for prevention. Please note, a vaccine for the coronavirus could take well over a year to come to market. However, on March 17, the National Institute of Health (or the NIH) announced that the first human vaccine trial for the COVID-19 was started. Even though as I just stated, a commercial coronavirus vaccine is likely more than a year away, the trial was started to assess the efficacy and the safety of the vaccine. The efficacy portion of the vaccine will be looking at whether the vaccine can stimulate the patient's immune system to make antibodies that can stop the virus from replicating and thereby preventing illness. This trial is very early. We call that a Phase 1 trial. ‘
The trial is going to enroll 45 healthy adults ages 18 to 55 years. Each will receive two shots 28 days apart. They're actually looking at three different doses (those are being tested). The vaccine itself was developed by the NIH and Moderna. Moderna is a biotechnology company. Interestingly, the first recipient of the NIH/Moderna vaccine told MSNBC that she signed up for the clinical trial because she was eager to help scientists with the response.
Veronica Fowler (05:18):
And so, Julee, we're hearing a lot of terms out there, including antivirals, antibodies, and anti-inflammatory agents. Can you just give us a rundown on what each of these are and how they work?
Julee Oh (05:32):
Sure, Veronica. Antivirals are drugs that actually kill or prevent replication of the virus, while antibodies are proteins that are made by a patient's immune system after an antigen enters the body. In this case, the antigen is the coronavirus. The antibody then destroys the antigen. Anti-inflammatory drugs do not necessarily impact the coronavirus itself, but impact the symptoms of the disease. One of the major complications of COVID-19 is acute respiratory distress syndrome (ARDS), where fluid leaks into the lungs making breathing difficult or impossible. Anti-inflammatories can help prevent the body's immune and inflammatory response, which occurs when the immune system overreacts and attacks healthy tissue and organs.
Veronica Fowler (06:27):
And I understand there are many of these therapies currently in clinical trials, can you take us through those?
Julee Oh (06:35):
Yes, Veronica. There are numerous drugs in clinical trials. Some of these drugs include antimalarials, such as hydroxychloroquine and chloroquine phosphate, those trials should begin fairly soon.
Other drugs include sildenafil citrate, a lipoic acid, Ebastine-Lopinavir-Interferon alpha combination or a combination of Danoprevir, Ritonavir, and Interferon, also mesenchymal STEM cells are being studied. A combination of Dipyridamole and remdesivir is being studied, and also remdesivir alone is being studied. We expect to know results by early April.
Washed microbiota transplantation is being studied. Even Avastin plus recombinant ACE2 is being studied. Bromhexine hydrochloride plus Arbidol umifenovir, favipiravir, and interferon a2b, a combination of those four products is being studied. Favipiravir alone is being studied. Methylprednisilone and thalidomide are also being studied. So there are a slew of different drugs with different mechanisms of action that are being studied right now.
Veronica Fowler (07:55):
Okay, and so since vaccines are still out about a year to a year and a half, I've read that antibody therapy maybe a quicker solve. Are those also being studied now?
Julee Oh (08:06):
That's correct, Veronica. Antibodies can actually be used as prophylaxis or prevention before exposure to the SARS-CoV-2 virus or as treatment for those already infected. And another term that we've been hearing is called hyperimmune globulins, and they're basically the same thing as antibody treatment. It's a plasma-derived therapy that has previously been shown to be effective in the treatment of severe acute respiratory viral infections, and now they may be an option for COVID-19. Hyperimmune globulins, as well as antibodies, work by concentrating the pathogen-specific antibodies from plasma collected from recovered patients or vaccinated donors in the future. Again, by transferring the antibodies to a new patient, it may help that person's immune system respond to the infection and increase their chance of recovery.
Some currently in development are Takeda's TAK-888. Emergent BioSolutions has initiated development of 2 hyperimmune polyclonal antibody products for the treatment and prevention of COVID-19. [Eli] Lilly and AbCellera Biologics are partnering to co-develop a therapy to treat and prevent the virus as well.
Veronica Fowler (09:10):
But since these antibody treatments will rely heavily on human donor blood, which we've seen in other therapies and isn't wholly uncommon, won't that pose potential issues with supply as we've seen with IVIG because of the reliance on voluntary donations? So I guess the real question is, do we have any other therapies that aren't dependent on these human blood donations?
Julee Oh (09:53):
Yes. In addition to using human plasma to obtain antibodies, recombinant technology is also on the horizon that avoids the need for human plasma. Monoclonal antibodies are proteins produced by the immune system that can neutralize pathogens. Antibodies are typically made in mice that have been genetically modified to have human-like immune systems, which means that when they're given to a patient, his or her immune system will not attack the antibody there. Vir Biotechnology and Biogen are partnering to develop and manufacture human monoclonal antibodies for COVID-19, as well as Regeneron, who's developing an investigational 2-antibody therapeutic, as well as a 3-antibody therapeutic, both of which have shown promise in treating other viral infections in the past.
In addition to that, Actemra and Kevzara, which are both IL-6 inhibitors are being studied. Normally the response helps fight infections, but if the immune system overreacts, it can attack healthy tissue and organs. In some COVID-19 patients, the immune response may be accelerating and damaging the lungs even after significantly diminishing the amount of virus in the body and blocking IL-6 may prevent the immune system to keep the body from attacking itself.
Veronica Fowler (11:12):
Well that sounds interesting, but have any of these drugs been proven yet?
Julee Oh (11:19):
And the answer is no. There is very little to no evidence, and we have not seen any results of the trials yet. We've seen numerous anecdotal reports, but note that case reports are not controlled clinical trials that can be validated. In fact, the World Health Organization said on March 18th that it would launch a multi-arm, multi-country clinical trial for potential coronavirus therapies in order to validate the current numerous small studies currently ongoing. And the study, which the World Health Organization hopes other countries will join, has been named the Solidarity Trial. Countries that have already signed on are Argentina, Bahrain, Canada, France, Iran, Norway, South Africa, Spain, Switzerland, and Thailand. The WHO also goes on to state that multiple small trials with different methodologies may not provide clear, strong evidence that we really need to save lives. The drugs to be tested are the antiviral drugs remdesivir, combination of the two HIV drugs, lopinavir and ritonavir, plus or minus interferon b and the anti-malarial drug, chloroquine.
Veronica Fowler (12:34):
But, we're seeing all of these news reports and things in the media saying that there are drugs out there that have shown clinical benefit. What can you say about that?
Leslie Fish (12:45):
So I can take this one, Julee. A recent news article stated that the HIV medications ritonavir and lopinavir showed a little benefit. The data from this was published in the new England journal of medicine on March 18th. The new England journal of medicine article stated that there was no benefit from these medications compared to standard of care. It is important to make sure that we are getting the information from a credible source, and just as importantly, what the data really shows.
Veronica Fowler (13:19):
And I think your point is such a good one – people should be reading the sources of this information rather than the stories referencing the information. The writers of these additional articles may be putting their own spin on it. That changes the meaning – little benefit versus no benefit.
Leslie Fish (13:36):
Yes. So let me discuss some of the information that has been in the news articles. There has been data regarding favipiravir shortening recovery time in patients with no symptoms or mild symptoms, data regarding favipiravir shortening, fever duration and more data regarding lung function, X-rays. Some issues with this data is that there was no definition of what a mild or regular case is. Definitions have to be made clear as far as the chest X-rays are concerned. It looks like in patients who received the medication, there was improvement in 91% of patients; in patients who did not get the medication, there was improvement in 62% of those patients. Again, we don't even know what improvement is defined as. Is it clinically significant? There are no published studies on this yet, just articles and reports. Could this particular medication be approved for mild or standard cases when first diagnosed? Maybe.
We also get news about remdesivir and it's very mixed. Some of the data looks like it could be moderately beneficial. However, there are concerns over increases in liver enzymes and other side effects. We don't have data on this either. What we also don't have data on is whether the virus itself can increase liver enzymes. Like the other medications, we need to see if this can be beneficial from mild or severe cases of the COVID-19 virus.
Veronica Fowler (15:16):
And so we've also been seeing in the news reports that there are medications that patients are currently on that are putting them at a higher or a greater risk. Is that true Leslie?
Leslie Fish (15:28):
Thank you for asking that Veronica. It’s an important question because there have been some circulated reports in a few different medications. So the first one I'm going to talk about are antihypertensives. They're known as ACE inhibitors or ARBs. So again, one of the circulating reports we saw that ACEs cause a greater risk for the coronavirus. To dispel these reports, the Heart Failure Society of America (AHFS), the American College of Cardiology (ACC), and the American Heart Association (AHA) published a statement that addressed these concerns.
The three organizations recommend continuation of the antihypertensive medications for those patients who are currently prescribed such agents for the indications for which they're known to be beneficial. These are heart failure, hypertension, and ischemic heart disease. The white paper also mentions that ARBs have been shown to reduce severe lung injury and certain viral pneumonias. Again, the recommendation is to continue the use of these important antihypertensive agents.
The second thing that I'd like to mention (in addition to the antihypertensive issues) is that there are also discrepancies as to if nonsteroidal anti-inflammatory drugs or insets are harmful in patients with the virus. French officials had suggested that the use of these agents should be avoided and that acetaminophen should be used in place. However, many physicians, both inside France and outside of France, countered that there is insufficient evidence to state this. Physicians can recommend treatment with acetaminophen. Instead, Dr. Gregory Poland, a Professor of Medicine and Infectious Disease and Director of the Vaccine Research Group at the Mayo Clinic in Rochester, Minnesota, said that without clarification of any new detailing effects, additional risks from nonsteroidal anti-inflammatories related to COVID-19 are questionable.
Veronica Fowler (17:33):
Well, now that we've covered therapies, let's turn now to testing. Leslie, where are we with that?
Leslie Fish (17:42):
So Veronica, we do have a lot going on as far as testing is concerned. On March 17, the FDA began allowing states to authorize laboratories to develop their own diagnostic tests for the COVID-19 virus without the government. The FDA Commissioner Steven Hahn said during a press conference that the State Department of Health can act as a surrogate for the FDA. In addition, labs will not have to pursue the emergency use authorization from the FDA, which is usually required. This will hopefully speed up the number of tests that are available.
Currently, the United States has capacity to run about 175,000 tests per week. Some other notes of interest: Roche announced it received emergency approval from the FDA for a new, much faster test. The tests can be run in high volumes on fully automated equipment; thus it could provide more results far faster than others. Roche says it can run 96 tests in about three hours for 24 hours, which means it can run up to 4,100 tests.
Other companies including Co-Diagnostics, Laboratory Corp of America, Quest Diagnostics, Denmark Diagnostics, and Becton Dickinson have either launched or are preparing to launch their tests. And finally, Opko Health’s BioReference Laboratories has partnered with the New York State Department of Health to provide further tests.
Veronica Fowler (19:16):
And Leslie, what can we say about the accuracy of these tests?
Leslie Fish (19:20):
So it is PCR testing, which is for viral load, which should mean that it should be accurate. What could impact test results are poor swabs or not enough viral presence.
Veronica Fowler (19:33):
And as far as the expense for all of this, I know the government has put together a coronavirus package to help financially. Jeff, can you touch on that?
Jeff Casberg (19:44):
Sure, Veronica. So as you stated, the U.S. government is implementing a comprehensive financial coronavirus stimulus package and most of the components are unrelated to the pharmaceutical industry, such as, you know, paid emergency leave, enhanced unemployment insurance, and food subsidies. But there are a couple specific items directly related to the pharmaceutical industry. First one is free COVID-19 testing for everybody who needs it, including the uninsured, so the payers will have to implement that. And, secondly, increased federal funds for Medicaid. These are the two items in this coronavirus stimulus package directly related to the pharmaceutical industry.
Veronica Fowler (20:27):
And, Leslie, I've heard that there have been many other actions taken on a state level. What do we know about that?
Leslie Fish (20:34):
Yeah, so first of all, the governors have been reducing the number of people gathering together. They do this by closing bars and restaurants and are only allowing for pickup at the restaurants. They're closing schools and they're really trying to reduce the amount of contact between people to slow or flatten the curve. Recently, Governor Andy Beshear from Kentucky expanded prescribing rights to pharmacists in light of the coronavirus. So, the law allows for Kentucky pharmacists to fill prescriptions for 30 days, including an emergency refill if they're not able to make contact with the patient's physician. In addition, if there is a need, pharmacists can operate temporarily in an area that is not designated by the pharmacy’s permit. And this actually means that they can assist with and set up mobile stations for the COVID-19 efforts. Finally, pharmacists can dispense needed medications to treat COVID-19 when they are FDA approved and indicated, as long as they followed the protocols by the CDC or the NIH or other public health officials.
Veronica Fowler (21:42):
Okay. So we've been talking a lot about potential therapies and government and state initiatives regarding the public. But, Jeff, what are the impacts that you're seeing to the pharma industry as a whole?
Jeff Casberg (21:55):
So within the pharmaceutical industry, I see three particular impacted areas. First impacted area would be to the payers or the health insurers. Next would be impacts to the pharmaceutical manufacturers themselves. And then lastly, I see impacts to the supply chain, people who produce and distribute the pharmaceuticals.
So, first let me start with impacts to the payers and the health insurers. A few moments back, we spoke about the requirements contained in the U.S. government stimulus package of COVID-19 testing coverage at no cost to members of health insurance companies and also at no cost to patients who don't have insurance at all, so that would be the first impact to the payers. Then there's likely to be increased physician office and hospitalization cost in 2020 and beyond for treatment of these patients that have COVID-19.
Telehealth. Telehealth is an area that is going to have needed increased coverage and access. Telehealth includes services such as tele-doctor visits, online monitoring of diabetes, and other conditions, so that's definitely an area of expanded coverage and growth in the health care industry.
Next would be prescription refill impacts to the payers. There's going to be increased requests for early refills or even expanding the window for refills to avoid patients going without their medications, especially for those patients who may be quarantined and cannot return to their homes. Most payers traditionally allow refills once about 60% to 75% of the days’ supply of a prescription that has passed. It's likely that may be relaxed during this period of COVID-19 crisis.
Also, off-label use. So off-label use is when prescriptions are approved by the FDA, they're approved for a specific indication. Off-label uses are when medications are used outside their FDA-approved indications, payers will likely see an increase requests for off-label use of medications. Especially for patients who have advanced disease and require, you know, high-cost medication for products like Actemra, Kevzara, interferon, and Avastin.
Julee also discussed investigational products. The payers will see increased use for coverage of investigational products and their associated medical service costs. And, lastly, out-of-network coverage. So when you have health insurance, many times you're required to stay in particular network of physicians or hospitals. During this time of COVID-19, there could be increased requests for out-of-network coverage due to, you know, lack of access for needed services in network or being stuck outside the network where your current insurance doesn't cover. So that covers the payer impacts.
Veronica Fowler (24:56):
And, Jeff, you also mentioned manufacturer impacts. Can you go through some of those?
Jeff Casberg (25:02):
Sure. There are going to be many impacts in the pharmaceutical manufacturers, but I'll just touch on a few of them. First would be especially to new drug approvals and new drug launches. So currently there are not as many, or very few at all, representatives out in the field visiting physicians, which is common practice in the industry. With this COVID-19, the representatives are staying out of the office, and this change can have a lasting impact on the pharmaceutical sales, moving representatives away from face-to-face promotion and a movement towards electronic pharmaceutical sales.
Another impact could be potential FDA approval delays. So, the FDA supplies manufacturers with anticipated approval dates; it's called PDUFA dates. The FDA has not announced that there will be delays, but there could be delays due to the FDA being shut down for periods of time.
And then, lastly, FDA advisory committee delays. The FDA also has these committees and they gather groups of experts from across the country to discuss the safety and efficacy of potential drugs for approval. These committee meetings usually occur a month or two in advance of the FDA's approval or denial decisions for approval of the drug. These committees could be delayed and cause delay in the future approval of those drugs. Currently, a couple important therapeutic areas, such as NASH and Alzheimer's, have scheduled FDA advisory committee meetings, and these meetings may be delayed.
Veronica Fowler (26:40):
Okay, and before we wrap up, Jeff, I know you mentioned also there may be some supply chain impacts. What are those?
Jeff Casberg (26:48):
No, you're correct. There could be significant impacts to the supply chain, which is the production and distribution of pharmaceuticals in the world. There may be shortages of these products due to unforeseen problems with the transportation along the supply lines such as raw material shipping, wholesaler- and retailer-based transportation delays. And the supplies of the drugs may also be temporarily curtailed due to manufacturing shutdowns or delays in the manufacturing process in countries facing COVID-19, although we have been hearing that in the generic industry, especially in India, there is decent stockpile of raw materials. Therefore, in the short term, we hope the manufacturing and supplies may not be a major concern.
Veronica Fowler (27:36):
Thanks, Jeff. Well, we've gone through many topics surrounding this coronavirus, including potential therapies, testing, governmental initiatives, and impacts to stakeholders in the pharmaceutical industry. And, of course, we'll continue to monitor the virus and the development of these and the stakeholder impacts as they unfold. Now for us here at IPD, we're all hunkered down and remotely working hard at keeping our subscribers informed, and any information that we're able to share will be provided on our infectious disease pages of our Payer and Provider Insights Portal, which provides pharmacy and therapeutic management support and drug information to payers, providers, and suppliers across the United States. Now, if you're not a current IPD subscriber, inquire about a subscription by emailing email@example.com. And any subsequent episodes will be posted to our LinkedIn page, so be sure to follow us there as well. Thank you for listening and stay healthy.