Recently, there was news that some of the world’s largest pharmaceutical companies, in partnership with the World Health Organization, have created a $1 billion fund to support small companies that are developing new antibiotics. For a detailed look at why this step is necessary, we invite you to see this article, originally published last fall.
COVID-19 has launched a storm of potential new treatments and vaccines. Our own Bill Dreitlein, Pharm.D, BCPS, is the Senior Director of the OptumRx Pipeline and Drug Surveillance team. Let him be your guide through this mass of confusing activity.
Q1: There is a lot of news around the previously approved drugs – hydroxychloroquine sulfate and chloroquine phosphate – to treat COVID-19. What do you think is important about this from a pipeline perspective?
A: There is much we still do not know about hydroxychloroquine for COVID-19, or if it even works at all. We are starting to see more data come out and the picture we are getting is that these drugs are not as effective as initially hoped.
The most recent NIH guidelines on COVID-19 say there is not enough clinical data to recommend for or against their use at this time. Now the FDA has just come out recommending against hydroxychloroquine outside of the hospital or a clinical trial due to heart rhythm problems.
In light of the rapidly evolving situation regarding hydroxychloroquine for COVID-19, we recommend watching for additional guidance from the FDA and NIH.
Expanding our view beyond just these drugs, one thing that I think gets lost in this is that the FDA is being very aggressive in supporting clinical development of drugs for COVID-19. In addition to the work around hydroxychloroquine, the FDA has announced their Coronavirus Treatment Acceleration Program (CTAP), which gives potential COVID-19 treatments priority attention. Remember, the FDA is a regulatory body; it does not develop drugs. But it can work with drug developers to provide clear guidance on what is needed to appropriately assess the balance between safety and efficacy in the current context of a pandemic.
The FDA has also joined with other government bodies as part of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program, a public –private partnership that aims to prioritize the most promising drug/vaccine candidates, streamline clinical trials and coordinate regulatory processes.
Taken together, I think these actions show that the FDA is demonstrating a willingness to do what it can from a regulatory perspective to support new treatments for COVID-19. I think that any new treatment that demonstrates some benefit will get fair and swift regulatory action.
Q2. What can you say about where the pipeline stands for drugs to treat COVID-19? For example, we know that there are existing drugs that might be re-directed toward treating COVID-19.
A: First I think we should do a basic level-set about what we can expect to see in terms of treatments. Treating a viral infection is not like treating a bacterial infection. For most bacteria, if we can match the right antibiotic against it, we can pretty much wipe out that infection completely, or near enough.
But viruses are much more elusive, and so antiviral drugs rarely give the kind of dramatic cure that antibiotics can. So most likely a new COVID-19 antiviral will be used to mitigate the effects of the disease, not cure it. This might be similar to how Tamiflu, which is used for the common flu, can only shorten the duration by a day or two. You might have fewer symptoms, but not an actual cure. But minimizing those symptoms could still make a big difference, for example, by keeping you out of the hospital, or off a ventilator.
Re-directing existing drugs
Some of the existing drugs that can make an immediate impact are those that are already being used off-label. That is, they are FDA-approved, just not specifically for COVID-19. One example is hydroxychloroquine, which we’ve mentioned.
One existing HIV medicine called Kaletra® (a combination of antiviral drugs lopinavir and ritonavir) has already been through a small study for COVID-19. While those test results were not impressive, additional studies are under way. So we expect more data to become available.
Continuing with the idea of trying to minimize the effects of the COVID-19 infection, we know that severe cases of COVID-19 infection can cause a severe immune reaction in the body called a ‘cytokine storm.’ This can lead to a kind of pneumonia and significant lung inflammation which may actually be more dangerous than the virus itself. This inflammation is one of the reasons why so many of these patients require breathing assistance with ventilators.
That’s the theory, anyway. Fortunately, the theory was tested for possible use with COVID-19 in randomized, double-blind, placebo-controlled clinical studies involving two members of the IL-6 inhibitor family: Kevzara® (sarilumab), and Actemra® (tocilizumab). These are different trials, since they are made by different manufacturers.
New results for the Kevzara study demonstrate that the drug had no chance of showing a positive effect for severe patients (who need oxygen but not mechanical ventilation), and so that part of the trial was discontinued. Results were somewhat more positive for critical patients, those who do need a ventilator, and so that part of the trial will continue. Additionally, a second more advanced trial will shift gears slightly to focus more on critical patients. We don’t have results for the Actemra trial, which is still ongoing.
Even though the results are so far not all that positive, I still say this is useful development because it identifies a dose and subpopulation where the drug is more likely to work. The fact is that we have seen widespread use of IL-6 for treating COVID-19. These results indicate that, at least in some patients, it might actually be making things worse.
It’s a useful reminder that drug development process is often a gradual process that, while frustratingly slow, is important for identifying who may be helped and who may be harmed. We’re going to have to rely on genuinely evidence-based medicine to beat this disease, even if it doesn’t give us the answers we’d like as fast as we want them.
Q3. The COVID-19 development pipeline also contains brand new drugs; what do we know about these?
A: The closest new drug is remdesivir, which works to prevent the virus from making copies of itself. Remdesivir is not completely new, since it was developed originally against the Ebola virus some years ago. That’s good, since it means we know a lot about how it works, although obviously not specifically how it works against the COVID-19 virus.
There are multiple, randomized, double-blind placebo-controlled studies underway designed to evaluate remdesivir for the COVID-19 disease. These studies have the kind of scientific rigor we’re going to need to help us decide if this drug works for COVID-19, or not.
One trial began in February through the National Institute of Allergy and Infectious Diseases (NIAID). Early results from the NIAID trial were announced on April 29, 2020 that appeared to show that remdesivir helped patients recover more quickly from the illness caused by the coronavirus. These results indicate that remdesivir worked better than placebo, and may be more effective when given earlier in the course of illness. Infectious disease specialists who were not part of the study have been quoted as saying that while the drug does seem to have antiviral activity, it’s not yet clear how much. We can expect much more to come on remdesivir.
Two additional randomized, open-label, multicenter studies began enrolling patients in March 2020. The first of these studies will evaluate both a 5-day and a 10-day dosing duration of remdesivir, in addition to standard of care, for patients with severe forms of COVID-19. The second study will evaluate the same dosing regimens, in addition to standard of care for patients with moderate COVID-19, compared with standard of care alone.
These will enroll a total of approximately 1,000 patients in the initial phase of the studies.
These trials will be critical to determining if the drug works, and if it does, to then determine which patients are most likely to respond; what dose is most effective; and what safety risks exist.
The manufacturer is already ramping-up production to support more clinical trials and possibly, to support a launch if the data is good enough. However, it may not be physically possible to quickly produce enough to treat huge numbers of people, so access may be restricted.
One promising approach is not exactly a drug, but rather takes advantage of the immunity created in people who have been exposed to COVID-19, and recovered. Called convalescent plasma, the FDA is working with groups around the country to collect blood containing new immunity-causing antibodies from recovered patients. After being purified and concentrated, it is then give as plasma to other patients. On March 24, the FDA approved convalescent plasma on an investigational basis for use in patients with serious or immediately life-threatening COVID-19 infections.
Looking more broadly, there are over 100 compounds in development for COVID-19. Most of them are still in the pre-clinical testing phase, and have not been tested in humans. Most will probably fail, because most new drugs do. But with so many potential options there is hope that some will prove both effective and safe. We mentioned earlier that the FDA is helping as much as it can, but in the end each drug will need to earn FDA approval through its performance.
Q4. Looking at the vaccines, it’s clear that in many cases things are moving much faster than usual. What strikes you as interesting or important about how quickly this is coming together?
A: Things really are moving fast. It’s amazing to think that the genetic sequence of the virus that causes COVID-19 (SARS-CoV-2), was first published on January 11, 2020. As of April 2, two vaccines were already being studied in human trials. And a third is due to begin human trials later in April. This type of speed in drug development is unprecedented.
Aside from sheer speed, one of the most striking things about the COVID-19 vaccine landscape is the diversity of technologies. We’re seeing the quite traditional attenuated and inactivated virus approaches; but also teams are working with DNA and RNA; with viral vectors; with recombinant protein; and more. We are really seeing all sorts of new technologies being brought to bear on this problem.
There are a couple of things we’ll be watching closely as these studies unfold.
First, there is a limit to how fast we can go without compromising on something, and this is particularly important with vaccines, because the real value of vaccines is in helping healthy individuals to prevent disease. But the risk profile of a person suffering from severe COVID-19 infection is very different from someone healthy. Someone who is sick and who feels under threat might accept a greater risk of drug toxicity if there are few or no treatment alternatives. But healthy individuals may have a much lower appetite for risk.
So before a vaccine can be given to hundreds of millions of people, the safety profile must be well understood in order to minimize the chance of causing side effects that we do not intend. This reason is why a vaccine will still be likely to take 12 – 18 months to develop, even if the initial results are positive.
Still, if a vaccine shows strong efficacy results, we could see it developed initially for more high-risk populations (elderly, patients with underlying medical conditions, first responders) and then later broadened to others.
Finally, we have to account for the complexity in the manufacturing process, what that capability is, and how to ramp it up for production on a mass scale, safely and reliably. In short, developing a workable vaccine is just the beginning. We will have a lot of work to do before we can expect to see it deployed world-wide, which in turn has implications for how we cope with the disease.
Q5. Looking longer term, do we need to be concerned that research for the coronavirus is crowding-out basic research and clinical trials on new drugs for unrelated conditions like cancer, or heart disease?
A: I think it is reasonable to believe there will be delays on a few levels.
COVID-19 is already having an impact on drugs that were otherwise expecting an FDA decision this year. Some FDA Advisory Committee meetings are going to be delayed, for example, the committee that was scheduled to meet to discuss the new NASH treatment obeticholic acid has been postponed. To compensate, the FDA may move its advisory process into the virtual setting. While these meetings have been webcast for years, going to a completely virtual setting will be new. However, when a drug is filed with the FDA, and the FDA accepts that application, they make a commitment to review that drug by a certain deadline. Those deadlines still exist. So even though COVID may be impacting the whole workflow, I think we will still see approval decisions made on time. However, those decisions may occur closer to their deadlines instead of weeks to months ahead of schedule, which was something we observed in 2019.
In addition, we have already seen one manufacturer, Bristol-Myers Squibb, delay the commercial launch of their newly approved drug for multiple sclerosis, Zeposia. Much launch activity relies on face-to-face meetings between physicians and pharmaceutical representatives which would be impossible in the current climate.
But looking longer term, I think the global drug development and testing industry is very robust. It would probably take a truly cataclysmic event to even substantially disrupt it. Just to give you a sense of it, in 2019 there were almost 319,000 registered drug trials ongoing around the world. Just by itself, Novartis has about 30,000 drug trials right now. Of those, only 240 trials had been affected by COVID-19 as of late March. And don’t forget that the manufacturers have a huge financial stake in these trials, so they can be quite resourceful. One company was able to continue a breast cancer trial right in Wuhan at the height of the epidemic. They had couriers deliver the trial treatment directly to the participating patients’ homes, and did routine patient checks using at-home monitoring by video chat or phone.
Lastly, the fact that these are global companies means that their trials often happen in multiple countries. So if testing is disrupted in certain areas (as has happened in China), there is some built-in redundancy that can help them stay on track.
All things considered, I expect a lull over the next year, but I would be surprised if we saw a significant drop-off in the number of new treatments for non-COVID-19 conditions over say, the next five years.
STATEMENT REGARDING FINANCIAL INFLUENCE:
This article is directed solely to its intended audience about important developments affecting the pharmacy benefits business. It is not intended to promote the use of any drug mentioned in the article and neither the author nor OptumRx has accepted any form of compensation for the preparation or distribution of this article.