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Year in pharma
It’s easy to forget that just 2 years ago most people had never heard of messenger RNA (mRNA) vaccines. Among those who had, many were skeptical that the technology would work. Even if mRNA vaccines proved to be safe and effective, manufacturing the genetic molecules in vast amounts seemed like a distant goal. COVID-19 changed all of that virtually overnight.
Before 2020, the number of people to get an experimental injection of an mRNA therapy or vaccine numbered only in the low thousands. This year, BioNTech, Pfizer, and Moderna distributed billions of their mRNA-based vaccines around the world. By late November, medical professionals had administered more than 437 million shots of an mRNA vaccine in the US alone.
No one expected the first commercial mRNA products to touch so many lives—or make their developers so much money. Moderna estimates it will sell up to $18 billion of its vaccine this year, and Pfizer pins its estimate twice as high, $36 billion. The drug industry no longer doubts mRNA’s worth. The question is now: What can mRNA do next?
For scientists working with the molecule, the applications seem nearly endless. mRNA can encode instructions that teach our cells how to make any protein. Companies are developing mRNA vaccines for influenza, respiratory syncytial virus, malaria, and more. Other firms are using mRNA to encode antibodies, cancer immunotherapies, protein replacement therapies, and CRISPR gene-editing systems. mRNA, it seems, can do it all.
“It is a totally different way of thinking about drugs,” says Diego Miralles, CEO of the RNA start-up Laronde, which raised $440 million in August. “We are entering a new era of medicine.”
Although scientists were studying many of mRNA’s potential applications before the pandemic, the companies working on them are getting more attention—and investment—thanks to the triumph of the COVID-19 vaccines. “Nothing encourages investment like success,” says Thomas Barnes, CEO of the RNA start-up Orna Therapeutics, which raised $80 million in February.
Laronde and Orna are just two of the biotech firms that emerged from stealth this year with big piles of cash to develop new versions of mRNA technology. Both start-ups are making therapies based on circular RNA molecules, which they believe will be safer and more durable than linear mRNA.
Two other start-ups, Kernal Biologics and Strand Therapeutics, are programming mRNA-based cancer therapies that activate only in certain cells. The approach could minimize side effects.
And Replicate Bioscience and VaxEquity are developing what they call self-replicating or self-amplifying RNA technology, which uses viral genes to help the RNA molecules multiply inside the body. The approach could allow the products to be administered at lower doses than traditional mRNA. “It has just been a huge amount of momentum that the field has gotten this year,” says Anna Blakney, an RNA scientist at the University of British Columbia, Vancouver, and a cofounder of VaxEquity.
The know-how and infrastructure set up to produce the mRNA COVID-19 vaccines will help second-generation versions of the technology move faster, says Nathaniel Wang, CEO and cofounder of Replicate Bioscience. “We don’t have to invent how to make mRNA,” he says. Contract manufacturing firms already solved that problem during the pandemic. That means “we can go fast. That’s why there is a lot of money coming in,” he says. “I think there is plenty of room for a lot of different winners to emerge.”
Although the effectiveness of the mRNA COVID-19 vaccines is clear, scientists debate how much of that success is due to mRNA technology itself. Although the mRNA vaccines were more effective than the adenoviral vector vaccines made by AstraZeneca and Johnson & Johnson, a protein-based vaccine from Novavax seemed about as effective as the mRNA vaccines, explains Andrew Geall, Replicate’s cofounder and chief development officer.
But slower-moving clinical trials and manufacturing delays have kept Novavax’s shot from reaching many people thus far. “The only advantage of RNA at the moment is speed,” Geall says.
Making a good mRNA vaccine requires knowing what antigen to encode in it. For the COVID-19 vaccines, the antigen was the spike protein from the SARS-CoV-2 virus. Years of work on similar proteins from other coronaviruses helped scientists design vaccines for COVID-19 quickly.
The pandemic showed that “if you have a good antigen, you can rely on mRNA to express it effectively and stimulate robust immune responses,” says Yusuf Erkul, CEO and cofounder of Kernal Biologics. “But that doesn’t mean it can’t be improved.”
Creating shots with fewer and less-intense side effects will likely be key for companies wanting to develop mRNA vaccines for common infections like the flu, Blakney says.
“I can’t imagine that many people would want to get a flu vaccine every year that has the same side effects as the COVID vaccine,” she says. “The day after I got my Moderna booster, I literally couldn’t move from the couch.” Blakney thinks the key to reducing these side effects lies in finding a way to dramatically decrease the dose of the shots without sacrificing their effectiveness.
One potential area for improvement is in the delivery of mRNA into the right cells, either with new lipid nanoparticles—how mRNA is currently delivered—or another delivery technology altogether. While vaccines can simply be jabbed into the arm, where they stimulate immune cells, new delivery strategies will be required for mRNA therapies that need to reach particular parts of the body, such as the brain.
Right now, targeted mRNA delivery is limited primarily to the liver, lungs, and spleen, says Kathryn Whitehead, a drug delivery scientist at Carnegie Mellon University. “Delivery is, and will continue to be, the most significant barrier to implementing mRNA therapeutics for a wide array of diseases,” she says.
The pandemic has spurred pharmaceutical firms to up their investment in mRNA. Pfizer, which partnered with BioNTech for its COVID-19 vaccine, is working on its own mRNA vaccines. Sanofi acquired its mRNA partner, Translate Bio, for $3.2 billion and said it would spend an additional $475 million annually on its newly launched mRNA Center of Excellence. And AstraZeneca struck a partnership with VaxEquity to develop therapies with the start-up’s self-amplifying RNA.
“The potential has been confirmed, and that is why we see so many start-ups and so much investment in this space,” says Michael Watson, director and executive chairman of VaxEquity.
But not every mRNA program has been successful. Translate Bio posted disappointing results in March from its early trial of an mRNA therapy for cystic fibrosis.
Sanofi also decided to terminate Translate Bio’s lagging COVID-19 vaccine program and shifted its research focus to mRNA vaccines for other diseases, including the flu. And CureVac’s mRNA vaccine for COVID-19 did not trigger as strong of an immune response as did the Moderna and Pfizer-BioNTech vaccines. The company stopped developing it and instead is focusing on a second-generation version.
Translate Bio and CureVac used a slightly different version of mRNA technology for their COVID-19 vaccines than Moderna and BioNTech. While the latter firms used chemically modified nucleotides designed to avoid triggering problematic immune responses, Translate Bio and CureVac used unmodified nucleotides.
But since the doses, lipid nanoparticles, and genetic sequences also varied among the four vaccines, some scientists say it is hard to know exactly why the Translate Bio and CureVac programs failed to impress. “It is just really hard to compare those clinical trials,” Blakney says.
mRNA companies have also been the subject of intense criticism for tightly controlling production of their vaccines and refusing to share patents and technical know-how with groups in low- and middle-income countries, where many people are still waiting for their first shots. Moderna and BioNTech both announced plans to build large mRNA vaccine manufacturing facilities in Africa, but the projects do not solve the immediate need for vaccines on the continent.
More recently, a feud between Moderna and the US National Institutes of Health over who owns Moderna’s COVID-19 vaccine has reached a boiling point. The NIH says its scientists helped design the vaccine and should share ownership of the core patents, while Moderna asserts that the vaccine that was ultimately approved for use in humans was a product of its own scientists’ design.
Despite the controversies, many scientists working on mRNA are excited about the increased attention and accelerated investment the field is experiencing. “It has become a lot more challenging to keep up with the speed of innovation in the mRNA field now,” Kernal’s Erkul says.
The potentially broad application of mRNA reminds people of the early days of protein-based therapies—which the industry calls biologics. For a long time, biologics were hard to develop, and leaders in the space were few, VaxEquity’s Watson says. “Today most pharma companies have a very significant, if not majority, activity in biologics, so I don’t see any reason why RNA can’t eventually become as significant a part of medicine.”
After nearly 2 decades with no new treatments for Alzheimer’s disease, the arrival of a new drug for the memory-robbing condition should have been a moment of celebration. It wasn’t.
The US Food and Drug Administration’s approval of Biogen’s Aduhelm was unexpected by most neurologists, many of whom were unconvinced that the drug worked. Priced at $56,000 a year, Aduhelm could bankrupt the US health-care system, some feared, for little to no benefit. But so far, interest in the drug has been minimal.
“I thought that people might flock to us when it was approved, but they haven’t,” says Jeffrey Burns, codirector of the University of Kansas Alzheimer’s Disease Research Center. Although Burns helped conduct one of the clinical trials for Aduhelm, his clinic didn’t administer its first commercial dose until the end of October, nearly 5 months after it was approved. “And actually, I don’t see that as a bad thing, because we have so much to work out in terms of who are the right patients and how it is going to be paid for,” he says.
For Biogen, sales have been disappointing so far. The company sold just $300,000 of Aduhelm in the third quarter of the year. Burns believes the poor showing can be chalked up to the controversy and negative press, which has shown no signs of abating in the 6 months since the agency approved the drug.
Some major hospital systems won’t offer Aduhelm to patients. Others plan to limit its use. A few neurologists who defended the drug’s approval were lambasted for their financial ties to Biogen. Alfred Sandrock, Biogen’s head of R&D, plans to retire at the end of the year, a decision that some speculate is linked to Aduhelm’s woes. And scientists continue to criticize Biogen’s selective parsing of its clinical data on the drug and the manner in which the FDA approved it.
“The whole process was highly unusual and highly controversial,” says David A. Bennett, director of the Rush Alzheimer’s Disease Center. “Our phone is not ringing off the hook” with people asking about the drug, he adds.
Aduhelm, also known as aducanumab, is an antibody that helps remove amyloid-β plaques, which accumulate in the brains of people with Alzheimer’s disease. A theory known as the amyloid hypothesis contends that stopping the buildup of and removing these plaques could treat the disease. Amyloid-β has been the target of countless experimental drugs in recent years, yet time after time, they failed to slow the cognitive and functional decline that characterizes the disease.
At first, scientists hoped that aducanumab might buck that trend. In 2015, Biogen revealed that its antibody dramatically reduced plaques in brain scans of people with mild Alzheimer’s disease. Those promising results prompted the firm to launch two larger clinical trials to see if the drug could stave off cognitive decline.
After a preliminary analysis of data suggested that the drug wasn’t working, Biogen decided to stop the trials in March 2019. But the company reversed course that October after the last vestiges of data rolled in from the curtailed studies. A new analysis of the results suggested that the drug might be working.
In one of the two trials, people who got the highest dose of the drug had 22% slower cognitive decline than people who got a placebo. The second trial found no significant difference between the two groups, even though Aduhelm reduced plaques by more than half in both studies. “One trial suggests the amyloid hypothesis is right, and one suggests it is wrong,” says Erik S. Musiek, a neurologist at Washington University in St. Louis. “That’s why the data are so contentious.”
Biogen asked the FDA for approval despite the conflicting data. The FDA’s advisory committee for neurological drugs, composed of independent scientists and doctors who make recommendations about experimental therapies, voted against approving the drug. Many members wanted to see Biogen conduct a new study to confirm or refute the small but potentially real benefit seen in its positive trial.
The FDA unexpectedly skirted the question of whether Biogen’s positive or negative study held more weight. Instead, the agency approved Aduhelm because of the drug’s ability to significantly lower plaques in the brain. “There is no controversy about the amyloid reduction; it was there,” Bennett says. “The controversy is around the lack of any prior studies showing that amyloid reduction is reasonably associated with a clinical outcome.”
Within a week of Aduhelm’s approval, three members of the advisory committee resigned in protest, including David S. Knopman, a clinical neurologist at the Mayo Clinic. When asked how he thinks the Aduhelm controversy has shaken out since June, Knopman says, “It is too soon to tell.” European regulators look poised to reject the drug. Whether they end up doing so and whether Medicare will cover the drug’s costs in the US will have major ramifications for how widely Aduhelm is used, he says. “There are so many uncertainties.”
Musiek says that “one of the major mistakes” that the FDA made was approving Aduhelm for anyone with Alzheimer’s disease. “The trials were incredibly restrictive: you had to have extremely mild disease,” evidence of amyloid plaques in your brain, and no comorbidities, he says. “The idea that you could take the data from that trial and suddenly apply it to everyone with Alzheimer’s disease is crazy.”
The FDA later updated the drug label to indicate that Aduhelm is only for people with mild cognitive impairment or mild dementia, not moderate or severe Alzheimer’s. The agency still doesn’t require potential patients to be tested for amyloid-β plaques—which neurologists can detect in spinal fluid or on a special brain scan. “It should absolutely be required,” Musiek says. “If you don’t have amyloid plaques, you should not be getting this drug.”
Doctors and hospital administrators are grappling with who, if anyone, should qualify for the drug. Some hospital systems, including Mass General Brigham in Massachusetts, the Cleveland Clinic in Ohio, and Mount Sinai Health System in New York, have decided not to use Aduhelm at all. Some hospitals are waiting to see if Medicare will cover the drug. Other groups feel they have no choice but to offer it, and they plan to do so cautiously.
“We are not a regulatory agency. FDA approved an agent, and regardless of what we think about that, it is now an FDA-approved drug,” says Bennett, who treats patients at Rush University Medical Center in Chicago. “There will be long conversations with families that want it, to make sure they understand the data, the cost, and the risk.”
The drug is not without potential side effects, including dangerous brain swelling. The FDA is investigating whether the drug was linked to brain swelling and death in a 75-year-old. Burns says the risk-benefit calculation is complicated by Aduhelm’s questionable effectiveness. “When you don’t have much on the benefit side, it’s a hard equation to solve for,” he says. “What’s clear from the Biogen data is that going after amyloid isn’t a cure.”
The FDA told Biogen that it must conduct a new trial of Aduhelm and report its data to the agency by 2030. Musiek thinks another large trial of the drug could help clarify its effectiveness, but even if the results are positive, he expects the disputes to continue. “Say you slow the disease by 25%. A lot of people would argue that isn’t enough,” he says. “There is always going to be this debate about whether it is worth the money and effort.”
Next year, doctors and investors will be closely parsing preliminary results from ongoing studies of two other experimental amyloid-targeting antibodies: Eli Lilly and Company’s donanemab and Roche’s gantenerumab.
If more studies can prove that removing plaques really does slow cognitive decline, some researchers think that amyloid-targeting drugs could become part of a multipronged approach to treating Alzheimer’s. “I don’t think anybody expects that by removing amyloid plaques you will completely stop 100% of the decline,” says Michael Weiner, a neuroimaging scientist at the University of California, San Francisco. “There should be other approaches.”
But since the immediate horizon holds little else for people with Alzheimer’s, some neurologists are taking an optimistic view of amyloid-targeting drugs. “They are not going to cure Alzheimer’s disease, but hopefully it is a first step,” Musiek says.
Burns agrees with much of the criticism of Aduhelm, but he is also excited to finally have something new to offer a small subset of his patients. “In 5 years, we will look back and either say we shouldn’t have put people on this, or we should have put a lot more people on this,” he says. “Right now, we don’t know which way it is going to break.”
COVID-19 vaccines from Moderna, Johnson & Johnson, and Pfizer and BioNTech were rolled out across the US. According to the Centers for Disease Control and Prevention, about 70.2% of the US population had received at least one dose of a COVID-19 vaccine as of Nov. 30.
On May 28, the US Food and Drug Administration approved Amgen’s Lumakras to treat lung cancers driven by KRAS G12C mutations. The drug is the first to inhibit KRAS, a common cancer driver that is notoriously difficult to overcome.
Date when the contagious Delta variant officially became the dominant form of the coronavirus in the US, according to the CDC
Amount Merck & Co. agreed to pay to acquire Acceleron Pharma, in the industry’s largest deal to date in 2021
“I am proud of all we’ve accomplished. I fundamentally believe, however, that no single person should serve in the position too long, and that it’s time to bring in a new scientist to lead the NIH into the future.”
—Francis Collins, in an Oct. 5 statement announcing his decision to step down as director of the US National Institutes of Health at the end of 2021
Number of deaths from COVID-19 worldwide as of Dec. 1
On Oct. 6, the World Health Organization recommended broad use of the malaria vaccine RTS,S. The four-dose regimen does not provide complete protection but could significantly reduce the roughly 400,000 annual deaths caused by malaria.
Annual cost of Biogen’s controversial Alzheimer’s disease drug, Aduhelm, which the FDA approved on June 7
Ending months of speculation, President Joe Biden nominated Robert Califf as FDA commissioner on Nov. 12. Califf served as commissioner in the Barack Obama administration.
On Jan. 20, the FDA approved ViiV Healthcare’s Cabenuva, the first longacting HIV therapy. The once-monthly injection is a combination of ViiV’s cabotegravir and Johnson & Johnson’s rilpivirine.
On June 4, the FDA approved Novo Nordisk’s Wegovy, a glucagon-like peptide 1 mimic that is the first new weight-loss management treatment since 2014
“The HIV vaccine story is a story of great disappointment. I think that the vaccine is the holy grail, but we haven’t found it yet.”
—Warner Greene, director, Gladstone Institutes’ Michael Hulton Center for HIV Cure Research, on news that Johnson & Johnson’s HIV vaccine had failed in a Phase 2 trial in Africa
Valuation of synthetic biology company Ginkgo Bioworks when it began trading on the New York Stock Exchange on Sept. 17 under the ticker symbol “DNA”
At this time last year, COVID-19 vaccines were becoming available in the US and parts of Europe—a scientific triumph that had the world wondering if the pandemic would soon be behind us. But a year later, those vaccines aren’t widely available in many parts of the world, and even in places where they are plentiful, some people refuse them. Meanwhile, the highly contagious Delta variant of SARS-CoV-2, the virus that causes COVID-19, caused cases to spike, and a troubling new Omicron variant has been detected around the world. In mid-November, more than 1,000 people still died daily from COVID-19 in the US alone.
As we head into a third pandemic year, many are pinning their hopes on a new tool for bringing the virus under control: pills. Oral antiviral candidates from Merck & Co. and Pfizer performed well in clinical trials and, if approved, could soon be widely available. Many hope these medications will be what doctors need to crush the pandemic.
Remdesivir, marketed by Gilead Sciences as Veklury, was the first COVID-19 antiviral approved by the US Food and Drug Administration. But that drug must be given intravenously, which limits its use to hospitals. By the time someone with COVID-19 is hospitalized, the disease has usually advanced too far for an antiviral to have much of an effect.
An antiviral pill could be taken when someone experiences the first symptoms of COVID-19. “An oral antiviral would have an enormous impact on this pandemic,” says Jeffrey Pearson, a clinical pharmacy specialist in infectious diseases at Brigham and Women’s Hospital. A pill could help treat the disease earlier and keep people out of the hospital altogether.
“Vaccines are still the first line of defense,” says Namandjé N. Bumpus, director of the Department of Pharmacology and Molecular Sciences at Johns Hopkins University School of Medicine. Antiviral pills, she says, “are not replacements, but they’re an important part of the tool kit.”
Efforts to make such medicines are finally bearing fruit.
In October, Merck & Co. and Ridgeback Biotherapeutics reported promising results for molnupiravir, which, like remdesivir, targets SARS-CoV-2’s RNA-dependent RNA polymerase—an enzyme that the virus needs to make copies of itself. Interim analysis of a Phase 3 study showed the compound cut the risk of hospitalization and death from COVID-19 by about 50% in unvaccinated people who are at higher risk of developing severe forms of the disease because of their age or other health conditions. The companies informed regulators about the positive results.
Molnupiravir was approved by the UK’s Medicines and Healthcare Products Regulatory Agency in early November, and later that month European regulators allowed its emergency use to stem a rising wave of infections. In late November, Merck and Ridgeback updated their analysis, reporting a drop in molnupiravir’s ability to reduce the risk of hospitalization and death from COVID-19 from 50% to 30%. Despite the slip, on Nov. 30, the FDA’s Antimicrobial Drugs Advisory Committee voted to recommend emergency use authorization of molnupiravir.
There was also good news about Pfizer’s oral COVID-19 antiviral, PF-07321332, in November. PF-07321332 blocks SARS-CoV-2’s 3CL protease (also known as the main protease). The drug candidate is used in combination with a low dose of the HIV antiviral ritonavir, which prevents the body from metabolizing PF-07321332 before it does its job. The experimental antiviral dramatically reduced the risk of hospitalization or death from COVID-19, according to a press release from Pfizer.
Pfizer’s Phase 2/3 trial enrolled more than 1,200 unvaccinated adults with mild to moderate symptoms who tested positive for the virus within 5 days of experiencing symptoms and who had at least one risk factor for developing severe COVID-19.
An interim analysis of the study showed that people who took the drug candidate within 3 days of experiencing COVID-19 symptoms were 89% less likely to be hospitalized or die than those who took a placebo. That reduced risk was 85% for people who took PF-07321332 within 5 days of experiencing symptoms. No patients who received PF-07321332 died, while 10 people who received a placebo died.
Pfizer developed PF-07321332 with breathtaking speed. Although remdesivir and molnupiravir had been around for years as possible treatments for other RNA viruses, Pfizer designed its compound specifically for SARS-CoV-2.
“The pandemic allowed us to do drug development at speed and with rigor,” says Saye Khoo, an expert in antiviral pharmacology at the University of Liverpool, who was not involved with the development of Pfizer’s antiviral. He says the speed is in part due to creative clinical trial designs that allowed several antiviral candidates to be tested simultaneously. Had it not been for the pressure of the pandemic, he says, “it would have taken us years to get to where we are.”
Scientists were always going to go after a small-molecule antiviral for COVID-19, Khoo says. Small molecules transformed HIV and hepatitis C treatment, so it makes sense that scientists would look for a small-molecule antiviral that is specific to SARS-CoV-2. Even with the promising results for molnupiravir and PF-07321332, Khoo says, there’s still a need for antivirals that are effective at lower doses.
Not all the news about COVID-19 antivirals has been good. In October, Atea Pharmaceuticals announced that its antiviral candidate, AT-527, which also blocks the viral RNA polymerase, did not clear the virus in people with mild to moderate infections. The company is now rethinking how to proceed with a Phase 3 study, and its development partner, Roche, has returned the rights to the compound.
Unlike the patients in the trials for molnupiravir and PF-07321332, who were unvaccinated and had other risk factors for developing severe COVID-19, the patients in the trial for AT-527 needed only a positive COVID-19 test and mild symptoms. The reason that no significant effects were seen could be that those patients were generally at lower risk of being hospitalized in the first place.
Another goal of researchers is to find other therapies that can fight the virus in its early stages. “The more antivirals we have, the better,” Brigham and Women’s Pearson says.
Viruses tend to mutate to develop resistance to antivirals. HIV, hepatitis C virus, and influenza viruses have all shown they can outmaneuver medicines. Having antivirals that have different mechanisms of action and that can be given together is a good strategy for combating resistance. That way, Pearson says, “one mutation wouldn’t knock out multiple antiviral candidates.”
Because combination therapies have been so powerful in treating HIV, tuberculosis, and hepatitis C, scientists wonder if it makes sense to pursue a combination of molnupiravir and PF-07321332.
From a scientific perspective, the two antivirals should complement each other, says Daria Hazuda, Merck’s vice president of infectious disease and vaccines. Molnupiravir and PF-07321332 “have distinct mechanisms of action, hitting two different critical proteins in the coronavirus life cycle,” she says. But because both therapies have been shown to be effective, she says, it would be tough to demonstrate that combining them makes a difference in the clinic.
Hazuda notes that in other infectious diseases, combination antivirals are good at helping keep drug-resistant strains of those viruses from developing. “We have not seen any evidence of resistance to date in the clinical trials with molnupiravir,” she says. “Given what we’ve seen, both with respect to resistance and efficacy, it would be very challenging to show that two drugs have added benefit.”
Oral antivirals have the potential to curtail the pandemic in places where people don’t have access to vaccines. But some doctors and scientists wonder if the same forces that have prevented vaccines from reaching everyone, such as cost and availability, will be the same for antivirals. “Will an antiviral become widely available in those places?” Johns Hopkins’s Bumpus asks. “Some of the challenges that we see as far as access and availability would be similar, at least early on for an antiviral,” she says.
Merck announced in October that it granted a royalty-free license for molnupiravir to the Medicines Patent Pool (MPP)—a United Nations–backed nonprofit that increases access to medical treatments and technologies. Pfizer announced a similar deal with the MPP for PF-07321332 in November.
The agreements allow companies in about 100 low- and middle-income countries to sell molnupiravir or PF-07321332 at a reduced price. For example, while the US will pay $712 for a 5-day course of molnupiravir, generic-drug makers could sell the same 5-day course for as little as $20, according to global health policy researchers.
But some say the agreements don’t go far enough. Doctors without Borders’ Access Campaign has expressed disappointment with the licenses because they exclude middle-income countries with robust manufacturing capabilities, including Brazil and China.
For resource-limited countries, small-molecule antivirals are attractive because they’re easier to produce at scale than the monoclonal antibodies that have been approved to treat COVID-19, says Márcio Silveira da Fonseca, an infectious disease doctor and adviser to the Access Campaign. “It is an important advance, particularly for the areas where vaccination coverage is low,” he says.
Nevertheless, da Fonseca says antivirals will not solve the problem of lack of access to vaccines, which should be the first line of defense against the virus. And antiviral use should be accompanied by testing, he says. “Just like vaccines, just like treatments, in the poorer countries, that’s where we have the least access to diagnostic tests.”
How will the success of the Merck and Pfizer drug candidates affect antiviral development in the future? “There will be more resources, more effort put into antivirals,” Johns Hopkins’s Bumpus says. If another pandemic threat emerges, “we need to be able to act very quickly,” she says.
“The pandemic has changed drug development forever,” the University of Liverpool’s Khoo says. Many of the drug candidates being developed today were born out of the severe acute respiratory syndrome (SARS) epidemic of 2003. “We put those drugs into the fridge,” he says. “I don’t think that should ever happen again.”
Although COVID-19 continued to dominate headlines in 2021, biotech firms didn’t stop pushing their therapies forward this year. Psychedelic drugs, stem cell therapies, and multiple gene-editing technologies showed promise for treating mental illnesses, chronic diseases, and genetic conditions.
The data behind these new approaches are preliminary at best. In some instances, the therapies were tested in just a few people. And it’s too soon to know how safe or effective these therapies will be in larger populations. But if any of them prove successful, the implications could be huge. These are just a few of the emerging approaches that C&EN will be watching in the years to come.
A growing number of academic groups and biotech companies are betting that psychedelic drugs, still illegal in most of the US, could help people with serious mental illnesses. Initial trials are testing these drugs in conjunction with intensive therapy sessions, often in people who have not responded to more traditional treatments. This year, two studies provided some of the best evidence yet that two psychedelic drugs could gain medical legitimacy.
In May, doctors hailed MDMA, commonly known as ecstasy or Molly, as a potential breakthrough for people living with severe posttraumatic stress disorder (PTSD). Researchers from several academic institutions conducted a Phase 3 study, published in Nature Medicine, of 90 people who got either MDMA or a placebo during multiple talk therapy sessions.
After three sessions, 67% of those who got MDMA and just 32% of people who got the placebo improved to the point where they no longer met the standard diagnostic criteria for PTSD. The researchers will need to conduct another study before seeking regulatory approval for the treatment.
In November, the British biotech firm Compass Pathways announced that its synthetic formulation of psilocybin, a hallucinogen found in magic mushrooms, may help some people with depression who haven’t responded to traditional antidepressants. The company tested three doses of the drug, taken during talk therapy, in a Phase 2b study of 233 people. People who got the highest dose of psilocybin scored lower on a common test of depression and were more likely to have significant improvement through the 12 weeks of the study than people who got a medium or low dose of the drug.
Psychedelic treatments are not without risks. More than 80% of people who got Compass’s high dose of psilocybin experienced at least one side effect, such as headache, nausea, or fatigue. A few people experienced suicidal behavior, suicidal ideation, or intentional self-injury, although it’s not clear whether or how much the drug contributed to these events.
A plethora of companies are beginning to test psilocybin, MDMA, and other psychedelic compounds as potential treatments for a wide range of mental illnesses and substance use disorders. And some firms are hoping to synthesize psychedelic-inspired compounds that retain the therapeutic benefits without potentially dangerous side effects.
Nine years after the 2012 publication that ignited the CRISPR craze, scientists are finally getting an idea of how well the gene-editing technology works when used as a therapy to alter DNA in people.
In recent years, multiple groups have used CRISPR-Cas9 as a tool to edit the DNA of cells removed from the body. The technique is called ex vivo gene editing, and it has applications in cancer and genetic blood diseases. This year brought the first data from an in vivo CRISPR treatment, in which the gene-editing system does its work inside the body.
In June, Intellia Therapeutics and Regeneron Pharmaceuticals revealed the first data from a clinical trial that used CRISPR-Cas9 to treat transthyretin amyloidosis, a genetic disease in which misfolded transthyretin protein builds up in the body and damages organs. Intellia’s therapy, a single injection delivered in lipid nanoparticles, contains messenger RNA with instructions for CRISPR gene-editing machinery. Once inside the liver, CRISPR acts like a pair of molecular scissors and cuts the gene for transthyretin to inactivate it.
After 4 weeks, transthyretin levels decreased an average of 52% in three people who got the lowest dose and 87% in people who got a medium dose, according to the company’s study, published in the New England Journal of Medicine. Although Intellia still needs to prove that those benefits last, scientists were stunned by the remarkably clear data showing, for the first time, that in vivo CRISPR gene editing could work.
In September, Editas Medicine announced long-awaited early results from a study of six people who got its gene-editing therapy for Leber congenital amaurosis 10, a genetic form of blindness. CRISPR-Cas9 was encoded in viral vectors and injected under the retina to remove a disease-causing stretch of DNA.
The low dose of the therapy didn’t affect vision much. Editas says two of the three people who got the medium dose of the therapy had improved vision, but they were still considered legally blind. Some individuals developed retinal tears and hemorrhaging after the injection as well. The lackluster results suggest there is room for improvement and that not all applications of CRISPR will work equally well. Editas and Intellia both plan to test their therapies at higher doses.
After more than a decade on the back burner, experimental therapies based on stem cells are beginning to make a comeback. Scientists have learned how to coax stem cells into becoming specialists such as insulin-producing cells in the pancreas or dopamine-producing cells in the brain. Early studies suggest that implanting those specialized cells into people could provide a new way to treat some chronic diseases.
One of the most exciting announcements in the field came from Vertex Pharmaceuticals, which in October revealed data on its experimental therapy for type 1 diabetes. Although the results were for a single person, they astounded: Just 90 days after an infusion of insulin-producing islet cells made from stem cells, the individual was making their own insulin. The person, who had been dependent on insulin therapy for 40 years, needs only about one-tenth as much insulin as before the treatment.
Also in June, the stem cell company ViaCyte also announced promising preliminary results from its own stem cell–derived therapy for type 1 diabetes.
In June, BlueRock Therapeutics, a stem cell subsidiary of Bayer, announced that it had begun a Phase 1 clinical trial to test its experimental cell therapy in people with advanced Parkinson’s disease. The neurodegenerative condition is characterized by a loss of dopamine-producing brain cells. BlueRock is converting human embryonic stem cells into dopamine-producing neurons that surgeons will implant in a region of the brain called the putamen, where cell death is common in Parkinson’s.
Going forward, scientists expect to see a greater emphasis on induced pluripotent stem cells (iPSCs). In this technology, human skin cells are transformed into stem cells, which are further transformed into a specialist such as islet cells or neurons. iPSCs could provide a more steady source of stem cells without the controversy tied to embryonic stem cells.
In November, Neurona Therapeutics got a green light from the US Food and Drug Administration to begin a clinical trial in which inhibitory neurons made from iPSCs will be implanted into people with a form of epilepsy that doesn’t respond to conventional drugs. Other companies are developing iPSC-derived therapies for a long list of conditions, including eye diseases, hair loss, heart disease, muscular dystrophies, osteoarthritis, and spinal cord injury.
A second-generation version of CRISPR gene editing called base editing will soon be tested in clinical studies for the first time. Unlike CRISPR-Cas9, which cuts DNA like a pair of scissors to turn off a problematic gene or insert a new piece of DNA, base editors are akin to pencils that change one nucleotide of DNA into another. Just 5 years after the first publication describing the technology, Beam Therapeutics has an OK from the FDA to test base editing as a therapy for sickle cell disease.
Sickle cell disease is caused by a single mutation in the gene for hemoglobin. The mutation restricts hemoglobin’s oxygen-carrying capacity and deforms red blood cells into sickle shapes that clump together and clog small blood vessels. Base editors can’t change all nucleotides—including the ones that cause the broken hemoglobin gene—but Beam has developed a clever workaround.
Beam will use its base editors to introduce a protective mutation that causes blood cells to produce fetal hemoglobin, a protein that will act as a substitute for the normal hemoglobin that adults make. Beam will make the edit in hematopoietic cells removed from a person’s body and then reinfuse the cells. The upcoming Phase 1/2 trial will test the safety and efficacy of the therapy.
Another base-editing company, Verve Therapeutics, is also on track to begin its first clinical trials in 2022 after publishing promising preclinical data in monkeys in Nature earlier this year. The therapy uses base editors to target the gene for PCSK9, a protein important for controlling cholesterol levels.
In monkeys, slightly changing the gene decreased levels of PCSK9, which in turn lowered low-density lipoprotein cholesterol—often called “bad” cholesterol—by about 60% for at least 8 months. Verve plans to first test the therapy in people with an inherited disease that causes high cholesterol levels and increases the risk of heart disease. It hopes to eventually use the therapy in the much bigger population of any adult at risk of developing atherosclerotic cardiovascular disease.
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