Not everyone who gets Covid-19 gets sick, but for those who do, the virus can be devastating. Here we are in the autumn of 2020, and cases are surging in many areas of the U.S. and around the world, with people continuing to die from terrible respiratory complications. Some who were hospitalized weeks or months ago have not bounced back yet; for many, the recovery is very slow.
Men have been hit harder by this virus than women. Why is that? Well, as it so happens, the answer to that is right in PCF’s research wheelhouse, and we are funding clinical trials of promising treatments.
The coronavirus SARS CoV-2 attaches itself to a receptor called ACE2: this is how the virus enters cells in the nose, airway, and lungs. So – and this is where the genomics of prostate cancer intersect with this terrible coronavirus – it turns out that a gene called TMPRSS2 is the key to allowing the virus to grab onto ACE2, and then to enter and kill lung cells. If enough lung cells are killed this way, patients die of overwhelming lung failure that is also known as fatal pneumonia. PCF and TMPRSS2 are old acquaintances; in fact, PCF-funded scientists have studied this gene in prostate cancer since 1988. TMPRSS2 is regulated by male hormones, primarily testosterone, in prostate cancer. These male hormones (androgens) activate the androgen receptor and cause more TMPRSS2 to be available on the surface of cells for the virus to enter. PCF helped to pave the way for a clinical trial, featured in Newsweek, at eleven Veterans Administration hospitals across the United States that involves temporarily blocking androgens and thus TMPRSS2 with Degarelix, a commonly used prostate cancer treatment.
Another trial under way involves a drug that directly blocks TMPRSS2. The drug is Camostat, which is already available in Asia to treat pancreatitis. It is not FDA-approved to treat pancreatitis here in the U.S., but has been safely used for many years.
Leading this trial is a physician-scientist at Yale, Joseph Vinetz, M.D., whose research is usually focused on malaria and tropical diseases. In early spring of 2020, Vinetz was part of a large team of Yale infectious disease specialists coping with an onslaught of hundreds of very sick patients. “I was frustrated, because we had nothing very useful to offer other than supportive care,” he says. “Supportive care is important, but we didn’t have any specific drugs. It reminded me of the early AIDS era, where patients were so sick with multiple opportunistic infections – we couldn’t treat it. And now here we were with Covid-19, and we couldn’t do anything.” Vinetz started doing research, and found a paper published in mid-March 2020 in Cell by German scientists showing that in the laboratory, Camostat seemed to block replication of the virus.
Although Vinetz had done clinical research in many exceptionally difficult places and circumstances for medical research – in the Amazon rainforest, for example – “I had never led a clinical trial. To come up with an idea and execute a clinical trial takes a totally different skill set; it’s a totally different ball of wax, as it were.” First, he had to design the trial, which requires experts in statistics and study design. The Yale Center for Analytic Sciences stepped up to help.
Fortunately, Camostat is not a brand-new drug. “It has a more than 30-year track record in Japan and South Korea, a very good safety record for treating pancreatitis.” The company that makes the drug, Ono Pharmaceuticals, worked with Vinetz to provide extensive safety data. “Then we had the published preliminary data from the group in Germany, and that facilitated designing a Phase 2 trial.” The FDA approval system for a new drug begins with a Phase 1 trial, which is to carry out preliminary assessments to show the drug is safe. Because this was already demonstrated, Vinetz was able to move directly to the next step. “We did our Phase 2 study in two parts,” he says. “The first was to see if there was an antiviral effect in people given the drug vs. those given placebo, using quantitative reverse transcriptase PCR (a lab test). The second, as a next step, would be to assess clinical responses to the drug. These are two very different things. I figured the FDA would want to see a measurable antiviral effect, so that was the first thing we proposed.”
This is where PCF comes in, with $900,000 to support the trial at Yale and collaborating sites around the country. “The essential design is that people who have Covid-19 infection become enrolled within a few days, get a baseline quantitative measurement of how much virus is in a nasopharyngeal swab or saliva, and then four days later – after taking the drug or placebo – we measure the virus again by swab or saliva. Our hypothesis is that the amount of virus will go down faster in the Camostat group compared to placebo. The trial is randomized and double-blind (neither investigators nor patients know whether a subject is getting placebo or Camostat).”
There are challenges with this trial. The first is simply difficulty coming in to the study site; these are people who are “by definition infectious.” Also, “a lot of our study population is people who are disadvantaged, people who can’t just drive themselves to the study site. That was a real problem when we started recruiting people.” At first, another challenge was the shortage of masks and protective equipment for patients and health care workers, although that is better now.
“Does Camostat reduce the viral load? We can’t just look at whether people feel better or not; we have to know whether the drug actually works to inhibit viral replication. The drug is not approved for use in the U.S., so we can’t just give it to hundreds of people with Covid-19 without having an inkling whether it’s actually effective to begin with. But it if proves to reduce the viral load, the next step will be to move on to testing clinical outcomes.”
What does Camostat do to the TMPRSS2 protein during the course of infection? “We just don’t know. That’s another way the PCF comes into play,” says Vinetz. “Not only is PCF interested in fighting this global pandemic and all its medical, public health, human and socioeconomic consequences – but because TMPRSS2 is a protein that is elevated in prostate cancer, and PCF-funded research is studying that protein and its oncogene, this study will also teach us about prostate cancer biology. It’s visionary what Howard Soule, Jonathan Simons and PCF are doing to fund this research.”