By Deborah Borfitz

July 28, 2020 | If COVID-19 has an upside, it’s that the public health crisis has turned fierce competitors unto friendly collaborators and forged unlikely partnerships between groups who tackle problems from a different angle. The biopharmaceutical industry, charitable foundations, academia, and government agencies have come together in unprecedented ways, hoping to break time records in learning how to diagnose, prevent, and treat a new disease.

Representatives of several of those initiatives—COVID R&D, a consortium that includes leaders from 15 global pharmaceutical companies; Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), organized by the National Institutes of Health (NIH); and the COVID-19 Evidence Accelerator, a collaboration between the Food and Drug Administration (FDA) and Friends of Cancer Research (Friends)—presented at a panel session on public-private partnerships at last week’s American Association for Cancer Research virtual meeting on COVID-19 and cancer. David R. Kaufman, head of translational development at the Bill & Melinda Gates Medical Research Institute also offered some final thoughts on the importance of clinical trials that reflect the diversity of people affected by the pandemic.

“Everyone understands we can’t solve this alone,” says Ellen Sigal, Ph.D., founder of Friends. But there were plenty of missteps during the first few months, including lack of a coordinated federal effort, drug shortages, limited testing capacity, some poor-quality clinical trials, and study results that were published too soon. “I think we’re self-correcting, but in the beginning, it was really very, very chaotic.”

On the other hand, the “tremendous explosion” of open-access journals greatly accelerated scientific understanding of the virus, says Andrew Plump, president of R&D at Takeda Pharmaceutical Co. In April, after one paper on the “human interactome of the virus” published, “all of a sudden we had a couple thousand different drug candidates that could potentially be repurposed [for COVID-19].”

The big mistake happened before the pandemic, in failing to prepare for it, says Plump, citing a 2015 Nature Medicine article that drew parallels between the first Severe Acute Respiratory Syndrome (SARS) virus in Wuhan and the new SARS-CoV-2 virus. “Had we continued efforts on attacking the SARS main protease… we’d have a drug today.”

Moderna Chief Medical Officer Tal Z. Zaks, M.D., Ph.D., says he has seen no negatives from his “perch” on the vaccine front. “We’ve been fortunate from the get-go to have a relationship with the NIH, so we’re in a great position to collaborate with [the agency] and accelerate the discovery and development of a vaccine into the clinic.” A phase III clinical trial of mRNA-1273, which Moderna co-developed with the National Institute of Allergy and Infectious Diseases (NIAID), launched this week.

The common challenge ahead, Zaks says, is the level of coordination required for rapid, simultaneous testing of multiple vaccine candidates and therapeutics in large clinical trials with unmatched transparency about benefits and risks. The Department of Health and Services has been working collaboratively with different arms of the government and sponsor companies on COVID-19 vaccine development to ensure trials “can actually inform the public at large as to their relative performance and the ability to demonstrate safety and efficacy overall.”

“The good, the bad and the ugly are all the same,” according to Ramy Ibrahim, M.D., chief medical officer and vice president of clinical development at the Parker Institute for Cancer Immunotherapy, referencing the speed of response to what should have been an unsurprising pandemic. Coping with the chaos currently means trying to identify the right endpoints and patient populations and how to learn from the “flood of data generated [and being shared] in record time.”

Spontaneous Collaboration

The COVID-19 Evidence Accelerator started with a congressional mandate for the FDA to collaborate with private-sector partners, says Sigal. Through a memorandum of understanding with the FDA, Friends is providing real-world evidence (RWE) for the three-pronged initiative focused on therapeutics and diagnostics as well as holding collaborative lab meetings where scientists, vendors and other stakeholders can stay current with ongoing COVID-19 research efforts.

Work on the therapeutics side began with the lengthy process of ensuring RWE is “replicable, transparent and reliable,” she continues. More than 50 organizations helped build the first data model for hydroxychloroquine when used in a hospital setting, which involved coming up with a list of the important data elements, uniform selection parameters and repeating data analysis using different techniques. Among those collaborators are Ciox Real World Data, TriNetX, IQVIA, Aetion, Flatiron Health, Health Catalyst, Observational Health Data Sciences and Informatics (OHDSI), and the U.S. Department of Veterans Affairs.

Now that it has been confirmed that the data shells are working, Sigal says, the therapeutics collaborative is quickly pivoting to remdesivir and anticoagulants. Final results of the hydroxychloroquine analysis were presented at a lab meeting only late last week.

The diagnostics collaborative is starting with PCR tests—which ones are being used, who is using them, and their reliability—before moving into the more “massive undertaking” of antibody testing.

In early March, weeks before the COVID-19 Evidence Accelerator was announced, half a dozen R&D heads at large pharma companies had already informally met to start what would become known as the COVID R&D consortium. They were all getting pitched dozens of ideas daily from academics and biotechs about how to contribute to pandemic efforts, recalls Plump. “It became clear that we could help each other and do things differently,” motivated by nothing more than to “do the right thing.”

COVID R&D set out to share best practices in the labs and offices of its members, says Plump. One set of activities is related to amplifying and simplifying data-sharing efforts, particularly for clinical trials, which has “never really been done before.” Among the therapeutic-directed activities are using the companies’ capabilities and expertise in running trials to aid drug repurposing efforts, as opposed to the “signal-seeking kind of trials that were really gumming up the system.”

A longer-term venture of COVID R&D is best-practice sharing around how to make new therapies, Plump continues. “Many of us, like Takeda, decided to focus on partner trials. We’re very engaged with the NIH ACTIV efforts and in the next several weeks will stand up an ICU-based trial, a master protocol out of UCSF… a collaboration with about five companies.” Takeda will also have its own master protocol, called “Community,” which will include drugs from several different pharmaceutical companies, he says.

Spontaneous collaboration was likewise the case for the Parker Institute for Cancer Immunotherapy, starting with a “no agenda” telephone call with nearly 60 scientists on the line, says Ibrahim. The group quickly realized that COVID-19 would need to be tackled with more than a single modality or approach.

“The call morphed from a group of immunologists who were just sharing data and knowledge [to one also including] infectious disease doctors, cardiologists, pulmonologists and virologists, Ibrahim says. “We started to see early IL-6 [interleukin 6] data that was encouraging but not enough and it wasn’t helping old patients. We realized our approach had to rely more on combinations versus… repurposing available drugs.”

Data emerging from the initial flurry of investigator-sponsored studies raised questions and concerns, says Ibrahim. What are the appropriate endpoints that should be used to assess a single agent or drug combo? How could populations by divvied up into relevant subsets and not just the broad outpatient versus inpatient categories?

In recent weeks, the focus at the Parker Institute has been on “combining different [drug] modalities, using appropriate endpoints and being able to make quick decisions about what is working and what is not, and leveraging existing data.” Multiple groups are working on solutions to at least one of these problems, Ibrahim says, and many “impactful,” adaptively designed clinical trials are underway.

The combined modalities being tested don’t necessarily have different mechanisms of action, adds Ibrahim. “There might be some situations where you have two antivirals and just rethinking the route of administration. We want to make sure whatever we’re doing is not redundant with ongoing efforts but is more complementary.”

Moderna’s Head Start

The NIAID recognized the potential of Moderna’s mRNA vaccine platform for pandemic threats years ago, points out Zaks. “Our first-ever vaccine was against pandemic strains of flu.”

Moderna started its COVID-19 work on Sept. 29, 2019, following a meeting with Anthony Fauci, M.D., head of the NIAID, about a demonstration project to time out how long it would take to get a vaccine against a novel virus to the clinic. Coincidentally, a few months later SARS-CoV-2 emerged in China and that became the test case. The company had already done some mRNA work with the NIAID against Middle Eastern respiratory syndrome in pre-clinical models, he notes.

In the second phase of its relationship, Moderna worked hand-in-hand with clinicians within the NIAID to launch a phase I clinical trial. “When we started the trial, we couldn’t know if we were successful or not because we didn’t have any immunogenicity assays yet,” says Zaks, noting that the institute spearheaded efforts to develop diagnostics. Figuring out dose response and building the assays had to happen in parallel.

Moderna was already talking to the FDA about a phase III trial by the time federal efforts around Operation Warp Speed escalated to a discussion about how to “harmonize” such studies, continues Zak, adding that the company received a “lot of flak for being the first to test the waters.” In fact, some elements of the guidance document issued by the agency were contributed by Moderna. “It’s no mistake that our [harmonized] protocol actually fits the guidance. Other teams coming up behind us have a somewhat easier job since a lot of that initial back-and-forth was already clarified.”

Zak called out Moderna’s strategic collaboration with PPD, “one of the premier and best CROs [contract research organizations] I’ve ever worked with. As a company, it has run more clinical trials than Pfizer ever will.”

Fewer companies in the business of vaccine development are sharing data in real time due to competitive pressures, comments Plump. He specifically cited “simple things like sharing endpoints and protocols to even more proprietary things like immune correlates to protection, which could be massive in terms of stimulating additional vaccine efforts.”

With the launch of Moderna’s phase III trial with the NIAID, information about the assays and correlates of protection—both of which have been “completely harmonized” across labs—entered the public domain. The design element of the study was shared earlier with participants in the effort, including Takeda, Zak says.

Question of Trust

Once an effective vaccine has been developed, there is still no guarantee that the most at-risk people will want to take it, which Zak says is the “one real challenge that keeps me up at night. We all tend to fall into the typical physician’s trap, which is [to say] “No, no, you don’t understand; let me explain.”

Zak’s view is that “people have honest concerns that are valid in many cases, whether it is having enough safety [data] to launch a vaccine or enough data in minority populations and how you treat them in clinical trials through deployment, and those are fair challenges that all of us [including industry and government] need to be very closely attuned to and clear-eyed about our answers to them.

“The safety question is always the fair one,” he continues. “If and when these vaccines work, we expect adoption to be at a pace that’s not been seen in our professional lives but is driven by the unmet need… we should think about deploying it [first] in the populations who need it the most, where the benefit-risk proposition is favorable based on data we have at the time.”

Among minority populations and people with comorbid conditions, mistrust started with historic clinical trial abuses that Moderna will be actively addressing in the way it approaches outreach and enrollment for the phase III vaccine trial, says Zak. “I want to make sure our trial ends up with a representative population inclusive of those minorities we’re trying to protect because they’re at increased risk of [adverse] outcomes from this disease. A multi-faceted answer to a multi-faceted problem requires us to listen carefully and understand what’s behind people’s concerns because they vary.”

This means working with people where they live, which prior to the pandemic happened at brick-and-mortar churches, says Zak. Recruitment and enrollment efforts for the vaccine trial will rely heavily on the participation of trusted representatives in minority communities. Under-enrollment of minority groups in the trial would be “very problematic for trust.”

Trust, as Plump later remarks, is “inextricably linked” to reputation. “Let’s admit that the reputation of the pharmaceutical industry is just deplorable and in many places for the right reasons but oftentimes for the wrong reasons. I think we have an opportunity here to really alter the trajectory of our ecosystem and change the nature of our reputation.” If the industry doesn’t leave COVID-19 with an improved status it will have “failed immensely,” he says.

Partners Required

For more than a century, convalescent plasma has been used either prophylactically or as a disease treatment, says Plump. Efficacy has been demonstrated predominantly on the prophylactic side, but in the more recent past shown morbidity and mortality benefit in treating severe H1M1 infection. Two COVID-19 studies published earlier this year, one conducted at Mt. Sinai and the other in China, suggest that convalescent serum may have a role in reducing morbidity, he adds. Early indicators from an ongoing convalescent plasma study at the Mayo Clinic likewise look promising.

“With convalescent plasma, the problem is scale and also it’s a little bit messy,” continues Plump. “The safety measures put in place when you transfuse plasma from one patient to another are not quite as significant as when you do purification and concentration, which is what we do.”

Most companies would also be limited in terms of supply and manufacturing, Plump says. Takeda, on the other hand, has built “deep infrastructure” for both plasma collection and production over the years.

But even Takeda can’t go it alone, he says, because its collection facilities are geographically limited so as not to overlap with some of its competitors. And the company’s manufacturing capabilities couldn’t meet demand “if [convalescent plasma] works for every patient who is going to need it.”

Cancer-COVID Connection

Like cancer, COVID-19 can be a fatal disease if doctors don’t intervene appropriately and with the proper drugs, says Ibrahim. The biology of both diseases is highly complex with a lot of unanswered questions—in the case of the novel coronavirus, the pathogenicity of the infection.

“One of the problems early on was that many [COVID-19] patients presented with severe disease, which really prevented us from being able to collect any biospecimens,” he says. Doctors were either busy trying to prevent them from needing a ventilator or weaning them off one. “Now, our understanding of the disease and complexity of the infection is better. Many of the institutions we’re working with already established a means where they can safely bring patients in so we can collect blood, serum or other biospecimens… but for the longest time we couldn’t touch outpatients. If they tested positive, they were sent home to try to minimize exposure.”

Current efforts at the Parker Institute go toward “supporting scientists trying to understand what is happening to those patients, how the virus is damaging tissue, and what is permanent and what is reversible,” Ibrahim says. “A lot from the cancer realm can be applied to COVID-19,” at least the less severe cases.

Seeking Equity

Panel participants were uniformly positive about the prospects of finding an effective vaccine and treatments for COVID-19. They also expressed hope that stakeholders will “capitalize” on the crisis to permanently delete inefficiencies baked into research and development.

They were more pessimistic and concerned about social unrest tied to systemic racism, and the lack of diversity and equity that negatively impacts clinical trials and human lives. “The unmet need has never been as big, and that comes with responsibility,” says Zak. “My fear is the lasting effects on society because [the pandemic] is disproportionately hitting those who are most vulnerable in the population both in terms of health effects and economic effects.”

Ensuring equitable distribution of therapeutics, vaccines, and diagnostics to the world’s most vulnerable populations is the focus of the Gates Foundation and its subsidiary, Gates Medical Research Institute, says Kaufman. “One critical point learned in the global health field is that you can’t separate research from serving the vulnerable populations that you work with.

“As researchers,” Kaufman continues, “we should remember that we are learning disproportionately from the vulnerable populations disproportionately affected by the pandemic. We have a specific obligation to ensure we create holistic interactions, which goes beyond studying populations and enrolling them in clinical trials” to include community engagement and assistance with long-term pandemic preparedness.