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 firstname.lastname@example.org. 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.
IPD'S DRUG & CLINICAL REVIEW:
COVID-19 PODCAST EPISODES
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