Why new COVID-19 treatments have been so slow to develop

With Omicron looming and cases surging, researchers are racing to deliver new therapeutics. But nearly two years in, only a few have proven safe and effective.

Autopsies revealed how COVID-19 had ravaged the bodies of the first people to succumb to the virus in Bergamo, Italy: It ignited inflammation that damaged their vascular endothelial cells—the cells that cover the inner wall of blood vessels—causing blood clots that blocked their bodies’ veins and arteries and triggering multi-organ failure.

The findings gave Alessandro Rambaldi an idea. As the head of the department of oncology and hematology at Papa Giovanni XXIII Bergamo Hospital, Rambaldi had been studying a monoclonal antibody, a laboratory-made protein, as a potential treatment for damaged blood vessels that can be a deadly complication that occurs after patients receive bone marrow transplants. But as COVID-19 patients swarmed Italian hospitals in the earliest months of the pandemic, Rambaldi, like many other doctors, was drawn to the frontlines to help.

As Rambaldi reviewed the autopsies, he saw that the blood clots in COVID-19 patients looked much like those in his bone marrow transplant patients. Both types of patients’ bodies were raging with inflammation; the COVID-19 patients’ lung membranes were thick and swollen, and oxygen could no longer flow into their blood, Rambaldi says. The monoclonal antibody he was testing in transplant patients was used to tamp down the body’s inflammatory response—the body’s natural defense against infection that, when too intense, can actually lead to death.

He thought: What if that same monoclonal antibody, narsoplimab, could treat COVID-19 patients?

By late March 2020, Rambaldi had treated six COVID-19 patients—so sick that they needed a ventilator or intubation—with narsoplimab.

All six recovered.

Narsoplimab is one of hundreds of potential COVID-19 treatments being evaluated globally. These treatments—including Merck’s antiviral pill, molnupiravir, which the U.S. Food & Drug Administration authorized on November 30, and a similar one from Pfizer that the agency is expected to review soon—in combination with highly effective vaccines, could be a key component in the fight against the coronavirus, experts say. That is especially true as variants, such as the recently discovered Omicron, spread rapidly while billions remain unvaccinated globally.

The treatments are not only necessary for the unvaccinated who contract COVID-19. They are lifesaving tools for those unable to generate a robust antibody response to vaccines (such as the immunocompromised and elderly), those with waning immunity, and those with breakthrough infections. In the U.S. alone, about 25 percent of the vaccine-eligible population has not received a COVID-19 shot. Scientists are still determining how effective vaccination is against Omicron.

The importance of COVID-19 vaccines cannot be understated: “It’s always better to prevent a disease than to try to treat a disease,” says Thomas Russo, chief of the division of infectious diseases at the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo.

Ilhem Messaoudi, immunologist and chair of the department of microbiology, immunology, and molecular genetics at the University of Kentucky, adds: “The first tool that you pick is a vaccine. And then if you need other things, we want to have a full toolbox” of therapies to treat the worst cases of COVID-19.

The story of narsoplimab

Narsoplimab, the monoclonal antibody first tested in seriously ill COVID-19 patients in Italy, is now part of the U.S.-based I-SPY Covid-19 trial, a phase-two clinical trial assessing not only narsoplimab but remdesivir, pulmozyme, IC14, celecoxib famotidine, aviptadil acetate, and cyclosporine.

In the United Kingdom, the University of Cambridge is also investigating narsoplimab’s potential as a COVID-19 treatment, says Gregory Demopulos, CEO of Omeros, the biopharmaceutical company behind narsoplimab.

“Our objective was not to develop [narsoplimab] for COVID-19,” he says. But the results of Rambaldi’s compassionate use showed its unanticipated potential for treating COVID-19.

When Rambaldi asked his hospital’s ethics committee for permission to administer narsoplimab under compassionate use to treat the sickest COVID-19 patients, it was “with the hope of minimizing their symptoms, the disease progression, and the death rate,” says Rambaldi

“Patients were so sick,” he says, “and they knew that no COVID-19 treatments were available. They were asking for something to try, [so] I told them about this possibility, which had a scientific rationale but no clinical data. We disclosed our great uncertainty with patients.”

Rambaldi recalls one COVID-19 patient who was suffering from a massive pulmonary embolism (blood clot), severe respiratory failure, and a serious shortness of breath that made the patient “very anxious with a perception of impending death,” he says. “We had the precise opinion that we were going to lose this patient in a few hours.” Instead, Rambaldi treated the patient with narsoplimab. The patient was the third to receive the monoclonal antibody—and he survived.

Narsoplimab works by inhibiting an enzyme, MASP2, that sparks inflammation in the body. This then blocks the inflammatory reaction induced by SARS-CoV-2, the virus that causes COVID-19, preventing blood clots from forming, Rambaldi explains.

The drug was well-tolerated, without any adverse reactions, Rambaldi says, and all six patients ultimately recovered and survived. Rambaldi later tested narsoplimab on 10 additional patients: eight recovered, and two died. He expects detailed study data will be published soon.

Omeros anticipates initiating its own clinical trial of narsoplimab, but manufacturing has been a hurdle: Creating monoclonal antibodies is time consuming, Demopulos says, and there are fewer opportunities to work with manufacturers, who are consumed with COVID-19 vaccine production.

Governments have “focused on vaccines, and that’s appropriate,” Demopulos says. “Where I think we have failed is that we have focused almost exclusively on vaccines. And now we’re seeing the shortcomings of that approach: that mutations could make vaccines less effective.”

What makes an effective treatment?

Initial excitement over a potential treatment can quickly wane as it works its way through the many stages of research. An effective treatment has to clear many bars, through multiple laboratory tests, and animal and human trials. It must be well absorbed and tolerated, non-toxic, and target the site of an infection, says Russo.

An effective treatment should also be safe to use, easy to produce, transport, and dispense. It should be affordable, even for the uninsured, and it would be effective in places with limited healthcare.

“What people have to realize that things often could look good at these earliest stages,” Russo explains, “and then they could flop in the very last lap.”

To fast-track development and surmount hurdles, such as safety, many scientists turned to existing drugs at the start of the pandemic—those that already have FDA approval to treat other ailments. The potential COVID-19 therapies they identified can be organized into two wide categories: antivirals and immune modulators. Antivirals keep a virus from replicating. Immune modulators enhance or tweak the immune response to infection, but they aren’t directed at the virus itself.

The newest antivirals—including those by Merck and Pfizer—have received a lot of attention, with good reason. There is only one antiviral fully approved in the U.S. to treat COVID-19, remdesivir, and it must be delivered through injection at a hospital. But the latest cohort of potential antiviral candidates can be taken orally. And pills are, of course, easier to ship and administer.

A handful of antiviral treatments and immune modulators have received emergency use authorization from the U.S. Food and Drug Administration. But hundreds of other options remain in various stages of research—with some, like narsoplimab, outside the news cycle.

If a treatment hasn’t been widely recognized in the media, “it’s probably because it doesn’t have any high-quality data to demonstrate we should be using it in humans,” Russo warns.

Reimagining COVID-19 treatment delivery

Antivirals and immune modulators are typically deployed through infusion, a process that—between treatment and observation—can take hours. “Plus, there are people who don’t want to get an injection because they are afraid of needles,” says Sam Lai, professor of pharmacoengineering and molecular pharmaceutics at the UNC Eshelman School of Pharmacy and founder of Inhalon Biopharma, a pharmaceutical startup focused on treating acute respiratory infections.

Lai is developing a version of a monoclonal antibody, regdanvimab, that can be inhaled.

The regdanvimab antibody attaches to the virus’ spike protein—the part of the virus that allows it to infect human cells—reducing its ability to infect and multiply. Results published in June from a phase-three trial showed that regdanvimab reduced the risk of hospitalization or death by 72 percent for high-risk patients and by 70 percent for all patients.

Lai, through Inhalon Biopharma, is using an approved vibrating mesh nebulizer that dispenses protein drugs to distribute the aerosol version of regdanvimab. “We know that the concept of being able to inhale a protein-based treatment—which is what antibodies are—is not a scientific fantasy,” Lai says. “It is readily achievable.”

The challenge will be reformulating regdanvimab so that it stays stable through the nebulizer, enabling a patient to “inhale an effective drug,” Lai says.

The first patient was dosed in October with the nebulized version of regdanvimab, IN-006.

Using a nebulizer comes with a learning curve, warns Russo, and patients with typical COVID-19 symptoms like shortness of breath may have trouble using one. But the delivery system could be more practical for patients who are wary of treatment or unable to go a hospital, he adds.

Immune modulators as potential COVID-19 treatments 

Infliximab is an immune modulator that blocks levels of a substance called tumor necrosis factor alpha from spiking and triggering inflammation.

Immune modulators, including infliximab, have been used to control autoimmune diseases such as Crohn’s disease and rheumatoid arthritis. Some scientists hope infliximab can help COVID-19 patients who experience an extreme inflammatory response, which can lead to acute respiratory distress syndrome and multiple organ failure.

In August, the World Health Organization announced a new phase of its Solidarity PLUS trial, a global effort to test promising COVID-19 treatments. On the lineup are three drugs: artesunate, which is used for severe malaria; imatinib, which is used for certain cancers; and infliximab.

An independent panel of experts narrowed down hundreds of potential treatments to these three, says Tarik Jašarević, WHO spokesperson, because “they were considered to have the largest” life-saving potential. The first patient entered the trial on Aug. 6, he says.

Separately, the ACTIV-1 trial, which is a randomized and double-blind trial in phase three, also includes infliximab. (A double-blind clinical trial is one in which neither the researchers nor the participants know which treatment a patient is receiving.)

Infliximab is intended for the sickest adult COVID-19 patients—those who have already been hospitalized, and either need supplemental oxygen or have evidence of pneumonia on an X-ray, says Brian Smith, Samuel L. Katz professor of pediatrics at Duke University and the faculty lead at the Duke Clinical Research Institute, which oversees the U.S. sites of the ACTIV-1 trial.

Another immune modulator, tocilizumab—a repurposed drug used to treat arthritis—is also administered to tamp down inflammation for late-stage COVID-19 patients. In June, the FDA gave the drug emergency use authorization in the U.S. after it was shown to improve outcomes for patients who’d also received corticosteroids.

Tocilizumab’s impact on COVID-19 continues to be studied, says Ivan Rosas, professor and section chief of pulmonary, critical care and sleep medicine at Baylor College of Medicine, who led a study on the immune modulator that showed its use did not result in significantly better clinical status or lower mortality than a placebo. (Smith’s study predated those that included patients who had been treated with corticosteroids, which appear to be a key to tocilizumab’s early success.) Rosas says he’s confident tocilizumab will be fully approved.

But tocilizumab, like other potential COVID-19 treatments, will face a challenge in future evaluations: As more people are vaccinated, there are dwindling numbers of ill people to evaluate.

“We’ve been challenged with recruiting to these studies,” Rosas says, “because the number of COVID-19 patients has significantly dropped. We were happy to see that vaccination can prevent severe COVID-19 in most cases. But doing clinical trials is going to be much more complicated.”

Whatever comes, Rosas says important lessons have already been learned from testing potential COVID-19 treatments.

“One of the things we’ve learned is that patients who have developed severe respiratory failure from [any] viruses can be treated with these medications,” Rosas says. “There will be future pandemics—at least, this is what the forecast unfortunately predicts. I think we’ve learned how treatments that inhibit viral replication and systemic inflammation can respond to these infections. We’ll be able to apply [these lessons] when we have a future pandemic.”

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