As we eagerly look ahead to 2021, BioSpace spoke to four biotechs hoping to seize this opportunity in the first wave of COVID-19 vaccines and therapies – or make an impact in the second.
With the Emergency Use Authorization (EUA) of Pfizer/BioNTech’s vaccine, by all accounts an astounding accomplishment in less than a year, things seem to be on the right track to finally vanquish the villain called COVID-19. But as scientists and public health leaders keep repeating, we need to “do the math.”
“I keep hearing, ‘the vaccines are coming,’ and I just read an article that there’s 656,000 doses coming to California in December. I think we’re 44 million, so there’s still some opportunity,” said Dr. Sean Tucker, founder, and chief scientific officer of South San Francisco-based biotech Vaxart.
As we eagerly look ahead to 2021, BioSpace spoke to four biotechs hoping to seize this opportunity in the first wave of COVID-19 vaccines and therapies – or make an impact in the second. The companies’ leadership teams also reflected on the ways in which the pandemic has affected their business.
Vaccine Technology: The New and the Tried and True
On the vaccine side of the fight, Vaxart and Valneva SE are developing two very different vaccine candidates that could provide unique options down the road.
Vaxart is focused on the development of oral recombinant protein vaccines that come encased in a convenient, room temperature-stable tablet. The company is currently testing this very attractive route against the SARS-CoV-2 virus.
“There’s no device, there’s no needle, syringe or any medical things. You hand out a tablet and you take it. No learning involved. I think from the consumer standpoint, that’s a real winner,” Tucker said.
Having recently completed enrolling patients for its Phase I clinical trial, Vaxart’s oral vaccine may offer a number of important advantages.
From a scientific standpoint, Tucker explained the potential of the mucosal immune response the pill works to activate.
“We think, for COVID, there may be some advantages to having mucosal response, having antibodies and T cells working in a wet surface, and that’s not easy to address from an injected vaccine,” said Tucker. “Certainly, what we’ve seen from the standpoint of our tablet vaccine delivered to the intestine, is that we get immune responses both systemically in the blood, as well as in the intestine, and the respiratory tract as well.”
Tucker described the biological mechanism behind the oral vaccine approach.
“Most of the time, when you put a protein in the intestine, it’s considered food, so it gets degraded and nothing happens. We basically put the protein in the context that it would be considered a foreign invader, so the immune system would respond to it. We did that by co-expressing the protein of interest in the intestinal cell along with this double-stranded RNA hairpin, and that created a system where you now get immune recognition of just that protein of interest. So, whether that’s a COVID antigen like the Spike protein or the flu antigen, HA, now all of a sudden, you’ve got an immune response against the protein of interest,” Tucker said.
It just may work, too. Vaxart previously conducted an influenza challenge study with its tablet form flu vaccine candidate, and came away with these results:
“Statistically, there was no difference between our vaccine and the injected vaccine from the standpoint of preventing influenza illness. But one of the things we did see is that there is an 80% chance that we outperformed the injected vaccine for preventing shedding of influenza virus. This suggests that the tablet vaccine blocked more virus from getting into the lungs and replicating in the respiratory tract.”
The consumer-friendly nature of a pill form vaccine also has a considerable logistical upside as it does not need to be stored at ultra-cold temperatures. This could make it particularly attractive for developing nations.
Moving from the ultra-modern to the tried-and-tested, we cross the pond to visit Saint-Herblain, France, where we find specialty vaccines company, Valneva SE.
Valneva’s VLA2001, one of only a few inactivated virus vaccines in development across the world, expects to move into Phase I clinical testing before the end of December.
Inactivated vaccines, first introduced in 1945 with the influenza vaccine, are a technology that is well-established.
“One of the advantages is that you represent the whole virus to the immune system as if it was the live virus, so this means that the body can create antibodies against all different regions of the virus. Whereas, for example, the modern approach is to target a specific protein. So in the case of SARS, you target the so-called Spike protein. Which means there might be additional responses from the immune system that might be beneficial for inactivated vaccines that you don’t necessarily see with the others,” said Valneva President and Chief Executive Officer Thomas Lingelbach.
Valneva is publicly traded in the EU, and is seeking an IPO by secondary listing in the U.S., though Lingelbach explained that this was in the works long before the pandemic hit.
Lingelbach shared that the pandemic has had both negative and positive implications for Valneva’s business interests:
“On business as a whole, the pandemic of course had an impact, because our first two commercial products that we are distributing, marketing, and manufacturing, are traveler vaccines. To give you a figure, in 2019, product sales were $130 million euros and have guided the markets. In 2020, we have predicated product sales of $70 million euros. This is a major decline in commercial business.”
Lingelbach added that this same factor has aided in Valneva’s efforts against COVID-19.
“It has allowed us to redirect resources to COVID, specifically our manufacturing sites and infrastructure. This has given us an opportunity to leverage those resources,” he said.
Honing In on the COVID-19 Complications Culprit
To protect patients from the worst COVID-19 has to offer, La Jolla, California-based INmune Bio Inc. is going after bad actor TNF.
INmune Bio, which is focused on harnessing the patient’s immune system to treat cancer, is developing Quellor, a non-immunosuppressive, anti-inflammatory second-generation TNF inhibitor, to prevent the need for mechanical ventilation in hospitalized COVID-19 patients.
Chief Executive Officer of INmune Bio, Dr. Raymond Tesi, explained how TNF is involved in the cytokine storm, the extreme immune reaction widely believed to be associated with severe COVID-19 symptoms.
“The cytokines in the cytokine storm classically are defined as 3TNF, IL6, and IL1. The assumption in March when we began to learn about this disease was that all of these cytokines were created equal, but it turns out that’s not the case at all. It turns out that TNF is kind of a giant among men,” Tesi said.
“We’ve got two things going on here. First, it’s [TNF] the match that lights the fire. Second, it stimulates blood clots, and the third thing TNF does, it’s one of the two cytokines that is required to cause cell death. And that cell death can be gut cells, cells of the intestinal lining, cells of the brain and the heart,” Tesi said. “But most obviously, it’s causing cell death of cells in the lungs, and that’s where the respiratory problem comes. TNF is a bad actor times three. Our drug, Quellor, neutralizes TNF, and hopefully, by neutralizing TNF, we stop all of this stuff.”
INmune Bio is currently enrolling patients in a blinded, randomized Phase II trial with the target of 366 participants. Tesi said that there will be an evaluation after the first 100 patients for a Go/No-Go decision. This could potentially take place in Q1, 2021 if enrollment is high.
The development of Quellor has not come without a cost for INmune.
Tesi stated that the impact of the pandemic on its pipeline has been “huge. Because we weren’t planning to do this trial. In February, we were completely focused on cancer, on NASH [Nonalcoholic steatohepatiti], and on CNS diseases, including Alzheimer’s. That was our future. And then the pandemic started raging. We looked around the board room and we said, ‘we have a drug that might help, we should throw our hat in the ring.’ So we did that.”
For INmune Bio, the decision to push full-scale ahead on Quellor has meant delaying two of its other programs, but Tesi pointed out that the pandemic had already accomplished that.
“The practical thing is, the pandemic put some of those programs in mothballs for us. With hospitals under so much pressure with the pandemic, trials in things like NASH, even some oncology trials, just kind of went into suspended animation,” he said.
Tesi added that the pandemic has moved up his company’s thinking about commercialization:
“If you look at most of the companies that have become successful at these therapies for COVID-19, they’ve gotten Emergency Use Authorization. That means they’ve gotten approved to sell the drug probably two years faster than they had planned. So we’ve been forced to think…if by chance, our drug does what it’s supposed to do, it’s very possible we’ll start marketing this drug for COVID-19 patients probably two or three years before we expected to be in the commercial marketplace.”
While INmune Bio fights to quell TNF, its La Jolla neighbor, CalciMedica, is working to tame calcium release-activated channels (CRAC) with its lead product candidate, Auxora.
Overactivation of CRAC channels can lead to too much calcium inside the cells, causing cellular injury.
“That’s one of the issues that we’re trying to treat in diseases such as acute pancreatitis, as well as COVID-19, where the lung endothelium appears to be damaged because there’s over-activation of these CRAC channels,” said CalciMedica Chief Medical Officer Dr. Sudarshan Hebbar.
“The other thing is that these CRAC channels are actually the channel that handle the activation of T cells and other immune system cells. This overblown immune response is directly due to the CRAC channels being overactivated in T cells,” Hebbar said. “We believe that T cells in the lung that are secreting too much interferon gamma are the proximal drivers of these SARS-CoV-2 alveolitis that are occurring in patients who are infected and then develop pneumonia.”
Hebbar explained that “the CRAC channel has two components, an Orai1 and a STIM. What Auxora does is basically blocks the Orai 1 channel so you don’t get overactivation of the CRAC channels.”
Hebbar said that CalciMedica is on track to enroll patients in its Phase II trial of Auxora by the end of Q1 2021, and based on the results of this study, they intend to discuss next steps with the FDA.
For CalciMedica, the pandemic has only presented a developmental upside.
“Actually, it’s [COVID] benefited our pipeline, because we were in the process of starting our acute pancreatitis study when we pivoted to COVID-19 because we believed that we would benefit the disease. But the COVID-19 trial is informing our pancreatitis trial. I think it’s putting our whole development plan…it’s giving it a road map of where we’re going.”
