One Year In: Therapeutics

This article is part of Harvard Medical School’s continuing coverage of medicine, biomedical research, medical education, and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.

At the outset of the COVID-19 pandemic, there were few answers to be had, particularly on the question of how best to treat patients at risk for life-threatening complications.

Driven by high-profile public statements, unproven medicines—most infamously the malaria drug hydroxychloroquine—quickly gained national prominence and were even touted as cures. States stockpiled millions of doses of hydroxychloroquine and, despite reservations, the FDA issued a controversial emergency use authorization based on only anecdotal reports of efficacy.

Get more HMS news here

By summer 2020, the FDA revoked its authorization as data emerged that the drug was ineffective against COVID-19 and even carried risk of harm. By fall, clinical trial data conclusively proved it had no benefit. Hydroxychloroquine reflected the country’s desperation for an effective COVID-19 treatment, even as it demonstrated the dangers of adopting drugs without evidence of safety or efficacy.

Developing safe, effective therapies is a notoriously difficult process. Today, only one drug is approved in the U.S. as a treatment for COVID-19, the antiviral remdesivir. By contrast, three highly effective vaccines have already been approved. Vaccines, however, only prevent disease, and there remains an urgent need for better, more effective interventions against COVID-19 once infection is underway.

To fill this need, Harvard scientists and physicians have devoted their research efforts over the past year to drug discovery and development as part of the Massachusetts Consortium on Pathogen Readiness, or MassCPR. Launched last March by Harvard Medical School and colleagues across Massachusetts and at the Guangzhou Institute of Respiratory Health in China, MassCPR aims to tackle every aspect of the COVID-19 pandemic and to prepare for future pandemics.

Harvard Medicine News spoke with Jonathan Abraham and Mark Namchuk, the co-leaders of MassCPR’s therapeutics working group about the challenges of developing safe, effective therapies for COVID-19, and why it is critical that we stay the course.

HM News: One year into the pandemic, what is the current state of COVID-19 therapeutics?

Namchuk: In comparison to the rapidity of vaccine development, the reality is that therapeutics have lagged. At this point, remdesivir is the only approved antiviral. There are many candidates moving forward, including numerous clinical trials for repurposed drugs. But they did not come through as quickly as one had hoped to make an immediate impact on treating patients. Therapeutics fell victim to many of the forces that were affecting the pandemic, such as the interplay between politics and science, if one thinks of what happened with hydroxychloroquine.

Abraham: I think it's been harder than many anticipated, myself included. For example, there was the idea at the beginning that we would be able to use monoclonal antibodies as a way to decrease the magnitude of the first wave, save lives, and then pass it on to vaccines for durable immunity. One of the biggest challenges, however, was how hard it is to define the therapeutic window, to know exactly how and when to intervene with antibodies.

Even for the few monoclonal antibodies that have been granted emergency use authorization, the health care system has been strained to roll out both vaccines and these therapeutics at the same time. In some situations, hospitals in major cities were running out of oxygen tanks, while the antibodies were just sitting on the shelf. The infrastructure and logistics just weren’t in place, so even if the drug was available, we weren’t necessarily able to give it at the critical time.

HM News: There are now several FDA-approved vaccines. What role do therapeutics play in this current stage of the pandemic?

Namchuk: You have to remember a vaccine is only a prophylactic measure. We still need therapeutics to intervene for seriously ill patients. Unfortunately, there's also still a lot of vaccine hesitancy. Having options for treatment, particularly for patients who decide for whatever reason to not be vaccinated, is critically important from a public health standpoint.

Thinking long-term, we're just at the beginning of the evolutionary cycle of SARS-CoV-2. The virus has arguably been propagated in hundreds of millions of human beings at this point. These initial vaccines are very effective, but we don't have a good handle yet on how quickly the viral spike proteins that vaccines target will mutate over time. It is possible that there may be cases where we’ll still need to treat patients for COVID-19 even though they’ve been vaccinated, and it’s something we have to prepare for. We absolutely have to stay the course in making sure effective therapies become available.

Abraham: With these new emerging variants, unfortunately, there's a chance therapeutics will get a second shot on goal. The genetic drift that’s happening is perhaps more significant than anticipated, and there might be room for drugs to buy more time as vaccine producers generate the relevant boosters to effectively counter these variants. There are lessons learned from the challenges we’ve faced so far that we can apply if there is a phase of the pandemic in which the virus mutates in a way that compromises vaccine efficacy, and we'll hopefully be better prepared for that.

HM News: So how do we prepare for the next outbreak?

Namchuk: SARS-CoV-2 is the third coronavirus outbreak in 19 years, after SARS and then MERS. Let’s look through the retrospect-o-meter. If we had been able to finish the development of effective drugs for SARS, we might have been able to deploy them prophylactically at the initial outbreak of SARS-CoV-2. That might have helped saved lives while work on vaccines and other therapeutics were progressing. We wouldn't have been starting from basically a standing start.

Today, we are getting better and better at identifying what common features of coronaviruses are most likely to be durable and thinking about what the next virus to jump might be. I would heavily advocate that these long-term scientific efforts shouldn't stop, even if this pandemic abates. We just can't shut down society like this nor deal with the human cost again. We have to do more to get ready.

Abraham: I agree. Remdesivir, for example, was originally developed against Ebola, but was not successful for that virus. Imagine if we had a drug effective against SARS or MERS, and that’s what we were starting with last year.

From the standpoint of quickly creating a drug against one coronavirus, the spike protein is the logical target. But from the standpoint of having something on hand that could have activity against multiple coronaviruses, even those that haven't emerged yet, viral enzymes would be the target to aim for.

Namchuk: I did an analysis of the most successful near-term repurposing of drugs for SARS-CoV-2, and routinely they targeted critical enzymes for replication or targeted shared components of critical enzymes across coronaviruses. I don't think it's a fluke, and I think that teaches us where we need to go with future chemical matter to prepare more diligently for the next pandemic.

HM News: What are some of the major scientific challenges that need to be considered?

Abraham: We’ve been able to develop antivirals that are extremely efficacious against viruses that cause chronic infections like HIV and hepatitis C. But we haven’t figured out yet how to treat acute viral infections. Even for remdesivir, the benefits are unclear, from the standpoint of when to use it, how to use it, and its overall impact on COVID-19. So how do we overcome that? How do we develop agents that we know how to use, when to use, and how often to use for an acute viral infection? I think it would be a big advance moving forward, independent of SARS-CoV-2.

Namchuk: That window for an intervention point is critical for respiratory viruses. Even when we invent drugs, figuring out how to use them is critical.

Abraham: I’ve always imagined an antiviral drug you could take when you first start to get a sore throat from maybe just a regular common cold coronavirus, which stops the virus before you ever get sick, similar to antibiotics and how quickly they work against bacterial infections. If we want to develop a drug like that, we need to answer these questions.

HM News: The cure for the common cold?

Abraham: That’s right [laughs].

HM News: Is this amplified focus on virology and therapeutic science a kind of silver lining?

Abraham: I think so. As someone who since freshman year of college has been working on emerging viruses, I used to have to convince people of the value of research on these viruses—and to remind people that as a consequence of international travel, we’re all closely connected on this planet. Because of current circumstances, I feel like emerging virus research won't have to be justified anymore for a while.

Namchuk: The other part, and one of most rewarding aspects of being in MassCPR, was collaborating with so many scientists who did not previously work on virology. The number of extraordinarily talented researchers who took their diverse skill sets and areas of expertise and applied it to SARS-CoV-2, I don't think we've ever seen anything like it. Getting that many people from that many different perspectives engaged on the same problem was remarkable, and I think a lot of them are going to stay on for the foreseeable future. It'll enrich the scientific endeavor on emerging pathogens, and I think that's a good thing.

HM News: What’s been your experience with MassCPR over the past year?

Namchuk: For me personally, being involved in MassCPR was one of the most rewarding experiences of my professional career. Just seeing so many people from different places committed to solving the same problem, you don’t see it very often. Taking a year’s look back, I just have this enormous respect for, and awe of, the scientists I work with. It was an amazing experience.

Abraham: Very quickly we realized that the work we were doing was very well intertwined with work of other MassCPR working groups. Communications within and outside MassCPR, and the interconnectedness of all the working groups, was a big theme. Being able to bounce ideas and discuss findings that were emerging was critical. So many collaborations were created, and what we learned was that we function best as a whole group, as opposed to these disparate parts.

Namchuk: In addition, as some of the science matured, we started going through a route that was more similar to what was going on with vaccines, in terms of partnering with companies more intimately as time went on. For example, Jonathan and I are both involved with the AbbVie research alliance on emerging pathogens.

What’s different with a vaccine is that you can take a vaccine quite a bit further at the laboratory scale than you can with a small molecule or an antibody. If we were going to do something with therapeutic relevance for the outbreak, we realized we needed to partner up with people with the skill set and, frankly, the resources to move at a pace where that kind of work can be impactful.

That was an evolution we saw with many of the people in the therapeutics working group, that they ended up working with different entities to take ideas and accelerate development, which I think ultimately is a good thing. If MassCPR lit the candle, and that ultimately allowed those larger scale efforts to move more quickly, then that’s terrific.

Abraham: I completely agree. A greater alliance between government, academia, philanthropic entities, and industry is critical. But this would have to be sustainable. One would hope as well given the significance of this pandemic, that perhaps memory will be less short-lived with SARS-CoV-2 than it was with SARS or MERS.

HM News: What should the public understand or expect regarding therapeutics for COVID-19 moving forward?

Namchuk: There are a lot of groups still working on therapeutics. I expect that therapies for SARS-CoV-2 will follow the path that other successful antivirals did. The idea is that we're going to be going after multiple magic bullets over time, not just one. I don't see numerous magic bullets in a year. I think it's going to take a little longer than that. But as we accumulate an understanding of more mechanisms that we can combine, we will see better efficacy. I believe that will be the case.

Ultimately, the development of antivirals for SARS-CoV-2 is moving faster than anything I've seen previously. We just have to keep going. We have to keep our attention on it.

Abraham: I would just add that there’s probably going to be a phase in which we have to factor in other steps beyond discovery of new drugs. Rolling out new therapeutics involves many aspects, such as the logistics of administering monoclonal antibodies, which will need to be sorted out.

Also, making it convenient for people to take antiviral drugs quickly when they get sick. For example, if you’re diagnosed with COVID-19 right now, you might call your doctor, you might be placed in a lottery, and then get an appointment a few days later at an infusion center to get a monoclonal antibody, which is way too slow.

Hopefully what we’ll have soon is the ability for your doctor to call your pharmacy, and you can just get the drug on the same day, like you do with antibiotics, and then take it right away. Once we can clearly prove that early treatment with antivirals is highly effective, I think making things convenient for patients will be a critical next step.