When a person is infected with the novel coronavirus, the deadliest symptoms often show up in the lungs.
The reason is now well-understood: The virus enters through ACE2, an enzyme that is commonly found on the surface of lung cells and that, ordinarily, helps tamp down inflammation. When it’s interrupted, inflammatory forces run amok.
But ACE2 is far more than just an entryway for infection, and scientists say the enzyme could point the way to a much-needed treatment for Covid-19. Constant Therapeutics, a privately held Boston biotech company with a small staff and a threadbare website, hopes it might have just the drug to address that need.
ACE2 operates like a referee in what’s called the renin-angiotensin system, which regulates blood pressure. When angiotensin II, a peptide that constricts blood vessels, gets too high, ACE2 steps in and converts it to angiotensin-(1-7), a Gallant to its Goofus that relaxes vessels and reduces inflammation.
“The system seems to operate on a balance in which angiotensin-(1-7) is protective and angiotensin II is the bad guy,” said Salvador Moncada, a professor of clinical pharmacology at the University of Manchester who specializes in inflammatory disease.
For Concepción Peiró, a professor of pharmacology at the Autonomous University of Madrid, reading that the novel coronavirus attacked ACE2 brought angiotensin-(1-7) immediately to mind. Beyond its effects on inflammation, angiotensin-(1-7) has proved to protect against blood clots, oxidation, and premature cell death.
So she called Moncada, a longtime colleague, to confer, and the two wrote a letter to the journal Circulation, hypothesizing that boosting angiotensin-(1-7) could protect the lungs from Covid-19’s worst symptoms while the immune system did its work on the virus.
Their work appeared online April 4. On April 5, Moncada got an email from Rick Franklin, CEO of Constant Therapeutics. The company’s intravenous drug, TXA127, is a pharmaceutical version of the naturally occurring peptide angiotensin-(1-7), and the company had spent years developing it as a treatment for diseases in which the renin-angiotensin system was out of kilter.
When Covid-19 came, Franklin saw TXA127 as a potential missing puzzle piece. The industry’s focus had been on antivirals, which would fight infection, and vaccines, which would prevent it in the first place. But TXA127 could be a treatment for the host, not the virus, buying patients time by replicating the effects of ACE2 until the natural enzyme got out from under coronavirus.
“It wasn’t any genius on our part to piece this story together,” Franklin said. “It’s just that we had been looking at it for such a long time that it became obvious to us.”
The Circulation letter lent weight to Franklin’s argument, and Constant began hearing from academic centers around the world hoping to study the drug in Covid-19.
The first trial, sponsored by Columbia University, is slated to start this month, enrolling 100 patients with moderate Covid-19 and comparing a daily dose of TXA127 to placebo. The primary goals are safety and prevention of lung failure, with secondary measures of survival, inflammation, and the need for respiratory assistance.
Constant is mapping out a Phase 2 trial of its own, one that would involve about seven sites and enroll more than 200 patients who have Covid-19 but don’t yet require intensive care. It will likely take a few months to get up and running, Franklin said, meaning it would be recruiting by the fall, in time for what could be a second wave of Covid-19 cases in the U.S.
The company’s approach sounds promising, said Ankit Patel, a nephrologist at Brigham and Women’s Hospital in Boston. But ACE2 does more than just create angiotensin-(1-7), and replicating its beneficial effects may require more than just infusing more of the peptide, he said.
“It definitely seems that there’s this unopposed angiotensin II in Covid-19, and trying to reverse that seems like a good technique to address some of the lung pathology that we see,” Patel said. “But it’s going to be a fine balance, and the devil’s really in the details in terms of how these different trials are going to be set up.”
While TXA127 makes biological sense as a Covid-19 treatment, proving its benefit in clinical trials could be an arduous process, said Moncada, of the University of Manchester. A significant percentage of people who get the disease recover without developing serious lung symptoms. That means, in order to demonstrate the potential of TXA127, Constant will either need to enroll a large number of patients or figure out how to screen for the Covid-19 cases most likely benefit from the drug, Moncada said.
Franklin is confident his company can thread the needle. Constant is considering a trial design that would recruit Covid-19 patients who need oxygen but aren’t yet in the ICU, betting TXA127 can differentiate itself from placebo when it comes to preventing lung damage.
The role of ACE2 in Covid-19 is widely accepted, and the potential of angiotensin-(1-7) is clear to experts around the world, Franklin said. Constant’s task ahead is the blocking and tackling of running a clinical trial, something he believes the company is well-prepared for.
“I’d love to say that a year from now there’s no need for this drug because we’re all immune, but that’s not going to happen,” Franklin said. “I think we can provide an enormous benefit to people and to the health care system if this drug works. And my gut says that it’s going to.”