COVID-19 mAb developers weigh master protocols as they set clinical strategies

Master protocols haven’t yet reached prime time for novel COVID-specific mAbs

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Drugmakers developing the first crop of COVID-specific mAbs are facing the question of whether to pursue independent, company-sponsored trials or participate in master protocols that have been successful for repurposed drugs during the pandemic. So far, they’re opting for the independent route.

For Regeneron Pharmaceuticals Inc. (NASDAQ:RGEN) and Eli Lilly and Co. (NYSE:LLY), the two companies with the most advanced neutralizing antibodies, the choice was primarily a matter of timing.

While neither company is ruling out joining a master protocol for later stages of clinical development, they told BioCentury company-run trials offer the fastest path through the clinic right now, mainly because master protocols for novel mAbs are not yet ready to enroll patients.

That picture may change soon.

The Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership, in collaboration with Operation Warp Speed, is launching a pair of master protocol trials designed specifically for mAbs that could begin enrolling patients as early as this month; the mAbs that will be tested haven’t been announced (see “Warp Speed Accelerating mAbs”).

“Whether or not we join an ACTIV trial at some later point in the development plan is perpetually under discussion, but we didn’t join at the beginning because we were ready to go and they weren’t. We completed Phase I and are in Phase II, so this was a huge timing issue and we were not willing to wait,” David Weinreich, SVP and head of global clinical development at Regeneron, told BioCentury.

Regeneron’s REGN-COV2, a cocktail of two mAbs targeting the SARS-CoV-2 spike protein, started a pair of Phase I/II/III trials in mid-June and has progressed into the Phase II/III stage in both trials.

Ly-CoV555, the mAb that Lilly is developing with AbCellera Biologics Inc., began Phase I testing on June 1 and a separate Phase II trial weeks later.

“In many ways, company-sponsored trials are the more classical path for drug development. They’re familiar and there’s a lot more control in terms of execution and timing,” Ajay Nirula, VP of immunology research at Lilly, told BioCentury. “It made sense to do the first two trials ourselves from a speed and efficiency standpoint.”

Depending on timing, and on how Regeneron and Lilly weigh the risks and benefits of the trial design for novel therapies, master protocols may not get the chance to propel the first mAbs to authorization.

Still, they’ll likely offer an important tool for other mAbs in COVID-19.

According to BioCentury’s COVID-19 Resource Center, there are three neutralizing antibodies for COVID-19 in Phase I testing and more than 40 in preclinical development.

Master protocol considerations

Master protocols have emerged as the most efficient path to definitive answers on repurposed COVID-19 therapies.

The U.K.’s massive adaptive trial, RECOVERY, is responsible for much of the actionable clinical data that has led to authorizations and guided treatment decisions. It has led to the emergency use authorization of dexamethasone in the U.K., the revocation of the EUA for hydroxychloroquine in the U.S., and the discontinuation of lopinavir/ritonavir in clinical trials and treatment regimens around the globe (see “U.K. Sets the Bar”).

They have not yet been deployed for novel COVID-specific therapies, which represent the next frontier in the fight against COVID-19.

In an editorial published Friday in the New England Journal of Medicine, NIAID Director Anthony Fauci and Deputy Director of Clinical Research and Special Projects Clifford Lane praised the master protocol design and called for coordinated national and global trial platforms. However, they noted that the RECOVERY trial is most appropriate for evaluating repurposed therapies, suggesting new master protocols will be needed for novel treatments.

They wrote that large simple trials such as RECOVERY “are especially useful for addressing questions such as whether a repurposed drug or standard procedure is of value,” whereas enrolling “smaller numbers of patients into a more complex, rigid, and granular study” is more suited to studying novel therapies.

The planned ACTIV 2 trial will test mAbs in the outpatient setting, and ACTIV 3 will test them in hospitalized patients.

“Whether or not we join an ACTIV trial at some later point in the development plan is perpetually under discussion.”

David Weinreich, Regeneron

Although the trial designs for the ACTIV 2 and 3 trials haven’t been made publicly available, Weinreich told BioCentury there is some harmonization with Regeneron’s structures. “Although we didn’t participate in the planning of ACTIV 2 and 3, in looking at the study design, we see a fair degree of homology with our trials,” he said.

However, once master protocols for mAbs are up and running, it’s not clear whether mAb developers will sign up.

While adaptive master protocols offer efficiencies from shared resources, quick readouts and access to patients, both Regeneron and Lilly cited trade-offs including sacrificing control over trial design and endpoints.

“The things we would prioritize in a trial may not be the same as those on the government’s priority list. For instance, testing multiple drugs in a single trial is important if you need multiple shots on goal, but that’s not one of our priorities,” said Weinreich.

Another trade-off is the head-to-head nature of master protocols, which often line up a novel therapy against drugs that have already proven effective, rather than placebo.

Those trade-offs may matter less during the pandemic when rapid development and public health are the collective goal. Ken Kelley, executive chairman of IDBiologics Inc., told BioCentury moral obligation drove the company’s decision to develop COVID-19 countermeasures, and the company is considering master protocol trials for its mAb because they represent a rapid development path.

IDBiologics released preclinical data on its single-antibody mAb IDB003 this week and plans to begin a Phase I trial this quarter.

Kelley said the company is in discussions with ACTIV about participating in the master protocol trials.

Development plans

While neither Regeneron nor Lilly have committed to mAb master protocols, each company is accelerating clinical development with a series of studies across different treatment settings to find where their therapies will be most useful.

Lilly kicked off its program with a Phase I trial in hospitalized patients, and quickly moved to a Phase II study in the outpatient setting.

Its strategy is to start efficacy studies in the patients it thinks are most likely to benefit and layer in preclinical data to identify the lowest effective dose as quickly as possible before moving on to other treatment settings. Given the high doses of neutralizing antibodies needed to treat the infection and the high demand for treatments, using the lowest dose possible will stretch the supply.

“With a direct antiviral mechanism, we reason that the earlier we can get an antibody in the course of the disease, the better.”

Ajay Nirula, Eli Lilly

“Our design is related to our thinking about the pathophysiology of the disease. With a direct antiviral mechanism, we reason that the earlier we can get an antibody in the course of the disease, the better,” Nirula said.

Regeneron targeted the same two patient groups, using parallel Phase I/II/III trials. Its strategy is to conduct a series of clinical trials across different patient populations at once to get the fastest possible answers on where the therapy works and where it doesn’t.

Weinreich noted that Regeneron has a track record of bringing neutralizing antibodies for viruses through clinical trials -- something it’s done three times before -- so it has the infrastructure and design in place to develop REGN-COV2 quickly. 
For the Phase II trials now under way, both companies are looking at the same primary endpoint -- change in viral load -- which Nirula said is emerging as a standard endpoint in Phase II trials, particularly in the outpatient setting.

“When you’re studying an outpatient population, viral load and symptoms make sense as endpoints for Phase II. Ultimately the vision is that you could give this to someone in an outpatient setting with recent onset to prevent them from moving into the hospital, but a Phase II trial won’t be powered for endpoints like that,” said Nirula.

Both companies are using placebo controls, which hasn’t been the standard across master protocols but is becoming an FDA expectation. “It’s fair to say there isn’t an obvious standard of care for outpatients with COVID, so it’s reasonable to use a placebo control,” Nirula added.

Lilly’s randomized placebo controlled Phase II trial is testing three antibody doses with about 100 patients per arm.

Regeneron’s adaptive Phase I/II/III trials aim to enroll around 1,000 and 2,000 patients across the three phases. Its trial in hospitalized patients is split into three cohorts according to disease severity: patients on low-flow oxygen, patients on high-intensity oxygen therapy and patients on mechanical ventilation.

Regeneron also started enrolling patients in a Phase III trial in the post-exposure prophylaxis setting in individuals with household COVID-19-positive contacts, which it is running with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID). Lilly is interested in that patient group as well, but hasn’t disclosed a timeline for a trial start.

“Vaccines will be the primary mode for prophylaxis, but that’s still a little ways away and we think therapeutic antibodies are an important bridge until we get a vaccine. They may even be important after a vaccine is developed,” said Nirula.

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