San Francisco Chronicle - (Sunday)
Quest still on for drugs to beat COVID
Even with powerful vaccines in hand and the coronavirus waning across most of the United States, there’s still an urgent need for drugs to treat COVID19 — and that could lay the foundation for the next generation of therapies for pandemics, say Bay Area scientists conducting such research.
Drug therapies were an early focus in the pandemic, when it wasn’t clear how long it would take to develop effective vaccines. But while vaccine development has been enormously successful, thanks in large part to the federal government’s $18 billion investment, drug treatments have been disappointingly elusive.
The Biden administration announced this month that it would invest $3.2 billion into research on COVID therapies, in particular antivirals that attack the virus and stop it from replicating early in the infection, before people become seriously ill. That was cause for celebration, Bay Area scientists said, though it was unclear how much local research would be funded.
Just one drug therapy —
remdesivir — that directly targets the virus has been federally approved in the U.S. since the start of the pandemic almost a year and a half ago, and it’s only marginally successful. Antibody therapies that help the body fend off the virus are effective but expensive and difficult to administer. A few other treatments have helped prevent deaths among people hospitalized with COVID.
These are all critical components of battling COVID, but they don’t fit a particular need that could help crush this pandemic and potentially the next one, too: a drug that comes in a pill, is simply and cheaply distributed, and prevents serious illness or stops people from getting sick at all.
“The vaccine is a medical miracle. But the reality is that you need multiple arsenals against a disease like this,” said Dr. Upinder Singh, an infectious disease expert at Stanford. “What we really need is something you can just get at your pharmacy.”
The need for such a treatment is especially critical in parts of the world where almost no one has been vaccinated and the coronavirus is still killing thousands of people a day. But doctors also are desperate for therapies in the U.S., where more than half the population is still not fully vaccinated and the highly infectious delta variant has a foothold.
The Biden administration funding partly is meant to address the immediate crisis: to propel promising drugs toward clinical trials and federal approval, ideally by the end of the year. But it’s also supposed to go toward research that builds the biological scaffolding for therapies that may take years to develop.
“I was happy to see the administration is not sitting back and saying this is cured now — we have a vaccine and we’re done,” said Dr. Vinit Mahajan, a Stanford ophthalmologist who turned his lab over to COVID research during the pandemic. “The vaccines are heroes, but there are still patients who need treatments. It’s clear that this is something that’s going to be around for a long time, and there will be some other future pandemic.”
Scientists from all the Bay Area’s major research institutions have been involved in developing therapeutics since the start of the pandemic. Many labs like Mahajan’s switched overnight to studying the new virus — diverting entire staffs from investigating therapies for other infectious diseases, or for cancer or Parkinson’s or diabetes, into fulltime COVID research. At UCSF, a collaboration of about 200 scientists from more than 20 labs came together within weeks.
Early in the pandemic many scientists around the globe pored through libraries of known drugs — some still experimental, some federally approved — to see if any could be repurposed for COVID. They hoped to shave billions of dollars and years off otherwise costly development, but those drugs have mostly failed.
Remdesivir, which had been developed as a potential treatment for Ebola, is the only therapy to come out of that process that is now standard COVID care. Early research at UCSF identified more than 50 drugs for possible repurposing. Last week, scientists involved in that work published a paper in Science exploring why many of those drugs didn’t work out, though one recently entered clinical trials.
“Repurposing is great if you need to be fast. But it’s like life: If you want something quick and easy, it’s usually not that great,” said Charles Craik, a professor of pharmaceutical chemistry at UCSF who was involved in the early efforts to identify drug candidates. “I want the repurposed drugs for the short term, but I want the true antivirals that have been developed against this target for the long run. Then we can repurpose them later for the next pandemic.”
Craik named about half a dozen potential COVID drugs that are in advanced stages of development and are either already being studied in human clinical trials or are expected to be soon. They include a drug made by Pfizer that was developed to fight the coronavirus that caused the 2003 outbreak of severe acute respiratory syndrome, or SARS, but was shelved when that epidemic ended abruptly.
There aren’t as many options as he had expected in the early months of the pandemic, Craik said. But in hindsight it’s not that surprising.
The U.S. placed almost all its early bets on vaccine development ahead of therapeutics — a gamble that has paid off, infectious disease experts say, but at the expense of finding new drugs. Meanwhile, this coronavirus is proving a deceptively tricky target.
Like many other viruses, it lacks the genetic equipment to damage the body all on its own. Instead, the coronavirus infiltrates human cells and hijacks them, using a cell’s own machinery to replicate more virus. That alone is enough to cause illness, but this coronavirus does even more damage by sometimes triggering the immune system to overreact and attack itself, which is what happens in severe cases.
Doctors would like to stop the virus from taking over the human cells to begin with. Scientists have broadly focused on two ways to do that: by disabling the virus itself or by turning off parts of the human cell that enable the hijacking. They’re looking for molecules that incapacitate the parts of the virus or cell that are necessary for a viral takeover.
“It would be even better to have a whole shelf of molecules we can pick and choose from, targeting many different mechanisms,” said James Fraser, a bioengineering professor at UCSF’s School of Pharmacy.
That’s how HIV drugs are so effective — they’re delivered as molecular cocktails that attack the virus on several fronts. Not only does that make the drugs more powerful, but it also makes it more difficult for the rapidly mutating virus to develop resistance. If HIV finds a way to evade one molecule, there are several more to get the job done.
“That would be ideal if we can get there,” said Andreas Puschnik, an infectious disease fellow at the Chan Zuckerberg Biohub in San Francisco. “But just getting one good compound is already hard enough.”
Craik’s lab at UCSF was involved in research developing the first drugs to be effective against HIV: protease inhibitors, which block a key enzyme, or protease, that breaks down proteins and allows the virus to infiltrate cells. There are different kinds of proteases, and they’re found in the virus as well as human cells.
Many other viruses, including coronaviruses, similarly rely on proteases. The dream, Craik said, would be a “broad spectrum, panCOVID therapeutic” — like the powerful antibiotics that can knock out all kinds of bacteria.
Developing a drug usually takes more than a decade, from finding a molecule to finetuning it for humans and testing in clinical trials. Most drugs fail along the way: What looks good in a petri dish or in a mouse does nothing in humans, or comes with unbearable side effects. Sometimes a drug works, a little or in some people, but the results aren’t considered worth the investment.
Scientists are hopeful the process will be sped up for this coronavirus and future pathogens with pandemic potential. The Biden administration funding will help, along with the global sense of urgency.
Although the main goal of current COVID research is to develop therapies that could be used in this pandemic, “what we need to be working on is COVID24,” said Brian Shoichet, a computational chemist at UCSF.
Like others, he noted that the world had multiple warnings that a pandemic of this scale was on the horizon, and opportunities had emerged to start working on drug platforms that could be quickly revised to match new pathogens.
Two earlier coronaviruses had caused concerning but ultimately easily contained global outbreaks: SARS in 2003 and MERS (Middle East respiratory syndrome), which arrived in 2012. The world would have been in a much better place in early 2020 if scientists had started chasing down antivirals and other drugs to battle those viruses years ago.
“If $3 billion had been thrown at the problem 20 years ago, we wouldn’t be in this situation,” Shoichet said. “The next one could be worse. That’s what the people at the CDC mumble in their dark dreams. This wasn’t the big one, actually.”