C&EN’s Year in Pharma 2022

Credit: Science Source

The viruses that cause polio, mpox (monkeypox), COVID-19, and respiratory syncytial virus disease (from left) all made headlines this year because of outbreaks in humans. The viruses are 25–30, 200–250, 70–90, and 150–250 nm in diameter, respectively.

The start of 2022 showed us that SARS-CoV-2 still had tricks up its sleeve as the Omicron variant of the COVID-19-causing virus flew around the globe within months, causing cases to skyrocket. Of the more than 630 million confirmed cases to date, most were caused by Omicron. But in 2022, SARS-CoV-2 wasn’t the only virus in the news.

One of the other viruses to spread in 2022 was mpox, previously called monkeypox. Bavarian Nordic, the only producer of a smallpox vaccine that can also be used to protect against mpox, received millions of dollars of orders from world governments. Smallpox antivirals received renewed research attention as possible mpox treatments.

Taking lessons from their work on COVID-19, UK-based researchers formed a consortium to develop better diagnostics, identify treatments, and study the mpox virus and vaccine effectiveness. Case numbers were falling globally as of August, but during an October press conference to announce the consortium’s launch, team members said that researchers need to be prepared for the next outbreak.

Polio also reemerged as a public health threat. British health authorities found evidence of local spread of the disease during the summer. Sewage monitoring in New York City and Jerusalem also found evidence of polio circulation in wastewater. The new cases were vaccine-derived polio. In areas of low vaccine coverage, the weakened poliovirus contained in the oral polio vaccine can begin to circulate. The UK and Israel have since been working to boost polio vaccination rates in children. The COVID-19 pandemic dramatically decreased global numbers of childhood vaccinations against many different diseases.

COVID-19 wasn’t done either, as new, faster-spreading Omicron subvariants picked up immune system–dodging mutations in the spike protein. This growing immune evasion negated the effectiveness of many monoclonal antibody treatments developed to protect the most vulnerable or help treat hospitalized patients.

In June, the US Food and Drug Administration told vaccine manufacturers that it wanted a bivalent vaccine to contain an Omicron component to target the emerging BA.5 subvariant, recalls David C. Montefiori of the Duke Human Vaccine Institute. “Two months later, they rolled out a BA.5 bivalent,” he says. “That’s phenomenal.”

A recent report by the consulting firm McKinsey says, “COVID-19 laid bare the gaps in the global vaccine supply” but also helped shift expectations of what is possible among drug developers and regulators. Messenger RNA (mRNA) vaccine technology has proved its worth and shown how quickly it can be adapted. Companies are now turning the success of the mRNA platform to many other diseases, not just flu and other virus-based illnesses but also cancer and autoimmune diseases. Montefiori, who has been working on HIV vaccines for nearly 35 years, says he thinks the mRNA platform may lead to a vaccine against HIV.

Building vaccine manufacturing capacity for new applications is a key focus for the pharmaceutical industry, the McKinsey report and Montefiori say.

Another area of pharma development is in fighting the respiratory viruses that are back after an initial retreat during the pandemic. As winter approaches in the Northern Hemisphere, influenza viruses and respiratory syncytial virus, or RSV, have returned. But the public may have reduced immunity after two winter seasons with little exposure to these viruses.

This year might be the last for severe RSV, though. While an RSV vaccine candidate from Novavax that was backed by the Bill and Melinda Gates Foundation disappointed earlier in 2022, better news came from the late-stage trials of GSK and Pfizer candidates. Phase 3 trials showed that Pfizer’s bivalent vaccine for infants has over 81% efficacy, and GSK’s vaccine for older adults has efficacy of over 82%. The firms have filed data with various regulators for approval. AstraZeneca and Sanofi’s nirsevimab, a monoclonal antibody against RSV, received a green light from European regulators in November, while Pfizer acquired ReViral, a UK company developing small-molecule RSV antivirals.

The pandemic’s sway over the fortunes of certain drug companies remained in 2022. Pfizer rolled out its COVID-19 antiviral, Paxlovid, generating huge sales this year. On an earnings call Nov. 1, Pfizer CEO Albert Bourla said that while sales of the firm’s COVID-19 products may fall next year, “we believe our COVID-19 franchises will remain multibillion-dollar revenue generators for the foreseeable future.”

The biotech sector weathered a bumpy year as it maneuvered through a heavy reset after overzealous investment during the height of the COVID-19 pandemic.

Biotech stocks continued to limp along after a steep plunge in November 2021. The SPDR S&P Biotech ETF (XBI), an index that tracks biotech companies to reflect the sector as a whole, is down by about a third from a year ago, though it has crept up a bit since its low point in May.

Initial public offerings (IPOs) have also largely ground to a halt. Twenty US biotech companies have scored IPOs as of Nov. 20 this year, garnering a combined $2.2 billion—a paltry total compared with the more than 100 biotechs that filed IPOs in 2021 at a value of nearly $15 billion.

Yet against that turbulent backdrop, the crank of drug discovery and validation has continued to turn. “From an investment and stock market standpoint this has been the worst year in the history of biotech, period,” says Brad Loncar, CEO of the life sciences–focused Loncar Investments. “But fundamentally, this has probably been the year of the most progress from a clinical and regulatory standpoint that we’ve had in probably 10 years.”

Two noteworthy wins in neuroscience were the positive late-stage trial results for Biogen and Eisai’s plaque-destroying antibody lecanemab, which delayed Alzheimer’s progression; and positive results for Karuna Therapeutics’ KarXT, which if approved will be the first novel drug in decades to treat psychosis in schizophrenia. These and advances in cancer and other areas “are truly going to change how medicine is practiced,” Loncar says.

The paradox of pain during a time of progress stems from the fact that the infusion of venture capital and IPO dollars in 2020 and 2021 propelled into prime time many companies that weren’t ready for it, according to industry experts. “A lot of good companies have been dragged down with [those companies],” Loncar says. Not everyone is so pessimistic about the industry’s current status. In a recent presentation, Bruce Booth of Atlas Ventures noted that venture capital funding and dealmaking remain robust when viewed over the past decade.

A similar contradiction is reflected in the employment picture. Layoffs that began this spring have continued, with at least 43 companies trimming their workforce since June, according to Fierce Biotech’s Layoff Tracker. And yet, hiring in the sector remains strong and many in the workforce changed jobs voluntarily. Areas including gene and cell therapy have been especially robust, but opportunities exist across the sector, says Chris Clancy, associate vice president at HireMinds, a biotech recruitment firm in Cambridge, Massachusetts. “Biotech is still at zero unemployment, basically,” he says.

Credit: Associated Press

A Ukrainian flag hangs on a damaged Russian tank in Kyiv in November.

On Feb. 24, 2022, Russian forces invaded Ukraine. People watched the news in horror. Many chemists outside the country were particularly concerned for their friends and colleagues working in the Ukrainian chemical industry.

They also worried about the impact on drug discovery projects around the world as supplies from Ukraine halted. Over the past 30 years, Ukraine’s chemists have become integral to the drug discovery ecosystem, providing research services and complex molecules in the hunt for new drug leads.

When Ukrainian firms like Enamine, Life Chemicals, and OTAVAchemicals stopped operating at the time of the invasion, it created a vacuum. These contract research organizations, or CROs, were founded after the fall of the Soviet Union. Based mostly around Kyiv, they employ many chemists who provide medicinal chemistry services to the rest of the world, synthesizing and supplying large libraries of small molecules that researchers can use in early-stage research. As war broke out, around 80% of the world’s supply of screening compounds was lost, and drug discovery projects that the Ukrainian firms worked on were paused.

As the bombing of Kyiv eased in April, companies started production again.

“It was not so easy a decision; we had lots of discussion with our people from security,” says Enamine’s head of medicinal chemistry, Ivan Kondratov. Yet, he says, there was a desire from staff to return, and Ukrainian president Volodymyr Zelenskyy called on Ukrainian companies to get back to work.

Step by step, lab by lab, CROs restarted their projects. “In summer, I think we reached up to 80%, maybe even sometimes 90% of [the capacity that] we had before Feb. 24,” Kondratov says of Enamine. But some customers have opted to go elsewhere, Kondratov says. Others have spread their contracts across different firms, leaving a smaller number of scientists contracted in Ukraine.

Credit: Enamine

Enamine chemists in the lab in Kyiv, Ukraine, before Russia invaded.

Ukrainian chemical makers also had to work out how to deliver the compounds they manufacture, devising sometimes convoluted routes to ship them, says Olga Tarkhanova, head of sales at the chemical vendor Chemspace. “In the first few months of the war, it was almost impossible to deliver anything from Ukraine,” she says. “But we, like all companies in Ukraine, worked really hard.”

Today, chemicals leave Ukraine by land and travel onward by airfreight. That takes a little longer than before the war, Tarkhanova says, but there is now a well-​developed workflow. For example, Chemspace recently shipped a delivery packed with 3 metric tons of dry ice. The shipment arrived safely in Australia.

Conference attendance has also become more arduous. Tarkhanova made several trips in 2022, but each journey involved a long drive across the continent rather than a short flight. Kondratov was able to present abroad, but it required a lot of paperwork and discussion, he says, because men are not usually allowed to leave the country under its martial law. Many of his colleagues could present talks only if a virtual option was available. And yet Ukrainian firms have continued to publish new science and develop new services.

Autumn saw renewed bombardment in Kyiv and surrounding areas, which has led to additional disruption. Chemical firms in the area say they have contingency plans, such as generators to ensure a steady power supply. Both ChemSpace and Enamine say Ukrainian chemists remain ready to work and have plans for the future.

“The company is up and running. We’re introducing new services, and we’re hiring new people,” confirms Yurii Moroz, CEO of Chemspace. “In this way we support our country to fight, and hopefully we’ll win soon.”

“There are air raid attacks. Russia still wants to occupy us,” Kondratov says. “But we’re ready to work under these circumstances.”

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  The US Food and Drug Administration is on pace to green-light a slimmer slate of drugs in 2022: just 30 new molecular entities (NMEs) were approved as of Nov. 28, compared with 50 in 2021. In addition to the NMEs, the agency approved gene therapies, vaccines, a chimeric antigen receptor T-cell (CAR-T) therapy, and drugs with already-approved ingredients that had been repurposed or reformulated to treat other patient populations.

  A lighter approval list this year doesn’t necessarily signal a decline in innovation, says Bernard Munos, a senior fellow at the think tank FasterCures. This year’s dip is within the typical fluctuations, and some of it most likely reflects a disruption in research activities due to the COVID-19 pandemic.

  A lot of the NMEs approved this year will transform the standard of care for people with the conditions those drugs treat, Munos says. It’s now easier to design drugs for diseases caused by single malfunctioning genes, he says. Increased access to free databases and free or low-cost tools has also facilitated more exploration of emerging biology, especially among smaller companies with shoestring budgets. Scientists are now also able to develop drugs and vaccines much faster once they know basic biology about an emerging disease, Munos says. He cites how quickly Moderna was able to design a vaccine prototype as soon as the structure of the SARS-CoV-2 spike protein was unveiled. That vaccine also numbers among 2022’s approvals; while the FDA granted Moderna’s COVID-19 jab an emergency use authorization (EUA) in late 2020—just a week after Pfizer and BioNTech’s EUA—its full FDA approval came in January this year.

  Big companies dominated approvals, says Sara LaFever, executive director of research and commercial support at the pharmaceutical intelligence firm Citeline. She says the biggest chunk of approvals was in oncology, followed by ophthalmology, neurology, and cardiology. But that doesn’t mean big firms discovered all those drugs. LaFever and Munos agree that the trend has held of big companies buying into smaller ones after the latter bear the risk of early discovery. Bristol Myers Squibb, Sanofi, and Novartis all had 2022 approvals for drugs that were developed by smaller firms, LaFever says.

  Here are some of the standout US FDA approvals of 2022.

• Auvelity for major depressive disorder

  

  Axsome Therapeutics’ Auvelity is a pill for major depressive disorder (MDD) comprising two previously approved drugs: the cough suppressant dextromethorphan and the antidepressant bupropion (Wellbutrin). Among other things, dextromethorphan blocks the N-methyl-D-aspartate (NMDA) receptor, similar to the way the drug ketamine acts. Dextromethorphan is thought to modulate glutamatergic neurotransmission; research suggests that glutamate plays a role in depression. Bupropion increases dextromethorphan levels in the blood by inhibiting an enzyme involved in dextromethorphan’s biotransformation. Auvelity, which can take effect in as early as 1 week, is the first rapid-acting oral treatment for MDD and uses the first new oral mechanism of action approved to treat the disorder in over 60 years, Axsome says.

• Skysona, Zynteglo, and Hemgenix expand gene therapy’s horizons at an extraordinary price

  Skysona (elivaldogene autotemcel) and Zynteglo (betibeglogene autotemcel)—both made by Bluebird Bio—and Hemgenix (etranacogene dezaparvovec), marketed by CSL Behring, are the third, fourth, and fifth gene therapies to ever be approved by the FDA. All onetime therapies, they use viral vectors to deliver healthy copies of genes to people with conditions caused by mutated genes. Skysona treats cerebral adrenoleukodystrophy, a rare disease that allows very-long-chain fatty acids to accumulate in the brain and cause damage. Zynteglo treats β-thalassemia, an inherited blood disorder that leads the body to produce less of the oxygen-carrying protein hemoglobin. Hemgenix is a treatment for adults with the clotting disorder hemophilia B. Hemgenix has the highest price tag of any drug ever, at $3.5 million. It is followed by Skysona, at $3 million, and Zynteglo, at $2.8 million. Despite the approvals, Bluebird has had a rough year; it announced the resignation of its chief financial officer in March amid concerns that the company didn’t have enough funding to survive the next year, and it axed 30% of its workforce in April.

• Injectable diabetes drug Mounjaro also leads to weight loss

  

  Credit: Eli Lilly and Company

  Eli Lilly's Mounjaro (tirzepatide) was approved this year as a treatment for type 2 diabetes.

  Mounjaro (tirzepatide) was approved this year as a once-weekly injectable treatment for type 2 diabetes but has drawn attention because users also experienced weight loss. It binds to and activates receptors for two hormones involved in blood sugar regulation. In Phase 3 trials ranging from 40 to 52 weeks involving people with diabetes, participants lost an average of about 5 kg or 11 kg depending on the dose. The FDA has granted Eli Lilly and Company, which makes the drug, fast-track designation to evaluate tirzepatide as a treatment for adults with “obesity” or who are “overweight” with weight-related comorbidities. Novo Nordisk’s Wegovy (semaglutide), which was approved for chronic weight management last year, acts on one of the same receptors Mounjaro does. Semaglutide was originally approved under the Ozempic brand name as a type 2 diabetes treatment.

• Relyvrio gets controversial approval to treat ALS

  

  Amylyx’s Relyvrio (sodium phenylbutyrate and taurursodiol) is an oral drug approved to slow the progression of amyotrophic lateral sclerosis (ALS). It was designed to mitigate dysfunction of the mitochondria and endoplasmic reticulum, reducing the death of neurons. The controversial approval was based on a Phase 2 study with 137 participants. In a summary review document, the FDA wrote that there was some uncertainty about the evidence of the drug’s effectiveness but added that given ALS’s deadliness, ”this level of uncertainty is acceptable in this instance.” Amylyx has drawn criticism for Relyvrio’s high price—$158,000 a year before insurance.

• Daxxify challenges Botox for smoothing frown lines

  Daxxify (daxibotulinumtoxinA-lanm) is the first frown-line injection treatment to pose a significant threat to the reign of Botox (onabotulinumtoxinA). Like Botox, it consists of a tiny amount of botulinum toxin. But while the toxin in Botox is stabilized with animal proteins or human serum albumin, Revance Therapeutics’ Daxxify uses a 35-amino-acid peptide as a stabilizer. Both drugs prevent muscle contraction by blocking the release of the neurotransmitter acetylcholine. Botox has been approved since 1989; Daxxify, which can last months longer than Botox, is poised to be its first major challenger.

• A flurry of new treatments for psoriasis

  

  Vtama (tapinarof), Spevigo (spesolimab-sbzo), and Sotyktu (deucravacitinib) are three drugs approved this year to treat different forms of psoriasis. Dermavant Sciences’ Vtama, the first steroid-free cream for plaque psoriasis, binds to and activates a protein that plays a role in maintaining the skin barrier. Boehringer Ingelheim’s Spevigo is a monoclonal antibody that blocks a receptor involved in immune signaling. It is the first drug approved to treat adults with generalized pustular psoriasis flares. Bristol Myers Squibb’s Sotyktu treats adults with moderate to severe plaque psoriasis. It inhibits tyrosine kinase 2, an enzyme involved in immune and inflammatory signaling pathways. It’s the first oral treatment approved in almost 10 years and the first that only needs to be taken once a day, according to BMS. It was more effective than Amgen’s twice-daily competitor Otezla in Phase 3 trials.

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Two drugs that the US Food and Drug Administration deemed safe and effective 20 years ago were in the news in 2022. Mifepristone and misoprostol—a drug combination for terminating pregnancies up to 10 weeks of gestation—made headlines, not because of any new scientific findings but because the US Supreme Court’s decision in Dobbs v. Jackson Women’s Health Organization overturned Roe v. Wade, the case codifying the right to abortion.

The ruling in Dobbs gave states the ability to restrict and even outlaw abortion at a time when the majority of people who terminate a pregnancy in the US do so using mifepristone and misoprostol—roughly 54% in 2020, according to a survey of abortion providers by the Guttmacher Institute. That’s up from 39% in 2017.

The percentage of medication abortions has most likely been higher in 2022, as the FDA decided late last year that doctors no longer had to dispense the pills in person for people to take in a clinic. Doctors could instead prescribe mifepristone via telemedicine and have it delivered by a mail-order pharmacy. People could use the drug in the privacy of their home—if their state didn’t impose further restrictions.

The Dobbs decision “has thrown medication abortion into the center of the debate” over abortion legislation, says Alina Salganicoff, director of Women’s Health Policy at the Kaiser Family Foundation (KFF). States led by antiabortion legislators have tried to limit the use of telemedicine or ban the distribution of mifepristone by mail.

The strict regulations around medication abortions can confuse people. “When folks see something that is highly regulated, they often think that it must be unsafe and that is why the government is stepping in,” Jamila Perritt, CEO of Physicians for Reproductive Health, said during a KFF webinar in July. “That is not true for medication abortion.” In fact, she said, it is safer than many medications that are available over the counter. Medication abortion is tightly regulated because of political ideology, she said.

People who choose medication abortion first take mifepristone, which binds to progesterone receptors. Progesterone plays an important role in keeping the lining of the uterus thick in early pregnancy. When progesterone is blocked, the lining of the uterus thins so that it can’t support the pregnancy.

Misoprostol, which is taken 24–48 h after mifepristone, is a prostaglandin that opens the cervix and causes uterine contractions to expel the pregnancy. The drug is also used in cases of miscarriage. Studies have shown that misoprostol alone can be effective at terminating pregnancies, although the FDA has not approved the drug on its own for that purpose.

The stigma around abortion means many people don’t know about pharmaceutical options for it, Salganicoff says. A KFF survey conducted in May found that 73% of adults and 60% of women aged 18–49 had not heard of mifepristone or medication abortion. “There’s a lot of confusion around how to get this medication, how to get it safely,” Salganicoff says.

The Dobbs ruling has made the legal landscape for medication abortion tough to navigate across the country, both for providers and for people seeking abortions. Websites like Plan C Pills are trying to fill the information gap. Preliminary data suggest more people are requesting mifepristone and misoprostol from Aid Access, a nonprofit organization that provides these drugs via mail outside a clinic.

It’s early days for trying to understand all the implications of the Dobbs ruling on the use and availability of these drugs, Salganicoff says. How will limited access to mifepristone and misoprostol affect people who need them for other conditions, like miscarriage? Will insurance cover travel for people who can’t receive the drugs by mail in their state? “There’s just all sorts of issues that have just kind of popped up in a very short period of time,” she says.

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Brain imaging allows doctors to evaluate people with Alzheimer's disease, including monitoring brain degradation and looking for bleeding and swelling which are associated with monoclonal antibody treatments.

A tumultuous sequence of events in 2021 and 2022 surrounded Biogen and Eisai’s Alzheimer’s drug aducanumab. But in September, the companies reported positive clinical trial results for lecanemab, a second amyloid-eliminating monoclonal antibody. In spite of the clinical failure of yet another anti-amyloid drug from Roche 2 months later, experts hail 2022 as an exciting year for Alzheimer’s treatment.

During lecanemab’s Phase 3 trial, the compound slowed cognitive decline by 27% among participants with early Alzheimer’s symptoms. The drug candidate is currently under priority review by the US Food and Drug Administration, with a decision slated for Jan. 6.

The positive results were a counterpoint to developments with aducanumab. Late last year it became the first anti-amyloid therapy to receive approval from the FDA, but the decision was controversial because the drug had conflicting clinical outcomes during two Phase 3 trials. Aducanumab was a commercial failure, generating low sales after the Centers for Medicare and Medicaid Services refused to cover its cost for people with Alzheimer’s outside clinical trials.

While lecanemab’s benefits are the largest yet among its class, they are still modest. And the trial’s 18-month duration is not long enough to reveal whether the drug candidate leads to meaningful clinical benefit in the long term. Further complicating the picture, Stat and Science each published news reports of separate deaths of a participant in lecanemab’s Phase 3 trial. Investigators in both cases believe the deaths were linked to the drug, according to the news reports.

In addition, in November, Roche announced that its anti-amyloid antibody gantenerumab slowed cognitive decline by 6–8%, which was not statistically significant. The company will halt development of the drug for people with early Alzheimer’s and pause another preventive study.

Experts are quick to point out key differences in the mechanisms of action of lecanemab and gantenerumab that could explain their different clinical outcomes. Gantenerumab removes the fibril form of the amyloid-β protein, whereas lecanemab targets the protein before it forms fibrils.

The aducanumab fiasco, combined with decades of other failed treatments, had led to a reckoning for the amyloid hypothesis, which claims that the accumulation of amyloid-β plaque in the brain is the main driver of Alzheimer’s disease. According to this theory, ridding the brain of amyloid should slow disease progression. But some experts point out that even with gantenerumab’s flop, lecanemab’s positive clinical results mean pursuing treatments that target amyloid is worthwhile.

The hypothesis will once again face scrutiny next year when Eli Lilly and Company reveals Phase 3 clinical data for donanemab, another anti-amyloid antibody.

“Each drug has different characteristics,” says Laura Nisenbaum, the executive director of drug development at the Alzheimer’s Drug Discovery Foundation, which funds Alzheimer’s research projects. “So we really do need to look at each of the drugs and drug trials independently.”

For all the industry attention they have received, amyloid plaques are just one hallmark of Alzheimer’s, Nisenbaum says. Busting plaque is not a catchall treatment for this multifaceted disease.

Researchers are investigating strategies that have other modes of action, Nisenbaum says. She expects that combination therapies tailored to the individual will be the best approach to treat Alzheimer’s in the future. For now, she says, the field is moving forward on all fronts.

Credit: Intellia

A researcher from Intellia Therapeutics, a CRISPR-based gene-editing company

Genetic therapies, which aim to treat genetic conditions once and for all by rewriting or overwriting mutated DNA, started to come of age this year, though recent stumbles show they are not fully mature.

Gene editing technologies, in particular, marched toward commercialization. “We’re finally seeing these gene-editing clinical readouts potentially translating all of this groundbreaking science into actual marketed products,” says Amanda Micklus, a managing consultant at the pharmaceutical business intelligence firm Citeline. “They’re really powerful products” for people with diseases that had few or no treatment options, she says.

The sickle cell disease and β-thalassemia treatment exa-cel is poised to be the first CRISPR therapy to receive US Food and Drug Administration approval, Micklus says. The treatment’s developers, Vertex Pharmaceuticals and CRISPR Therapeutics, jointly initiated their submission of a biologics licensing application to the FDA last November and expect to complete the submission by the end of the first quarter of next year.

Previously, a lot of work focused on editing genes outside the human body and then transferring cells with the new genes into the person who needs them. Exa-cel is an example of this ex vivo approach. This year, in vivo gene editing—in which genes are edited within cells in the body—generated several big-name partnerships, including Precision BioSciences with Novartis, Bayer with Mammoth Biosciences, and Pfizer with Beam Therapeutics.

“In vivo is clearly the future of gene editing,” says David R. Liu, a chemist at the Broad Institute of MIT and Harvard and a cofounder of Beam. Only bone marrow, which can be removed and tinkered with before being returned to the body for the treatment of blood diseases, is amenable to ex vivo procedures. “It’s very hard to imagine editing other major organs outside of the body,” Liu says.

CRISPR treated humans in vivo for the first time in a clinical trial that began in late 2020. The therapy’s developers, Intellia Therapeutics and Regeneron Pharmaceuticals, revealed promising results from this trial in August 2021 for treating transthyretin amyloidosis. This year, the partners reported another positive Phase 1 trial for their in vivo CRISPR-based therapy for hereditary angioedema.

New gene-editing technologies that are potentially more accurate than CRISPR are also on the rise. The gene-editing start-up Prime Medicine, which Liu also cofounded, is developing a “search-and-replace” genome-tweaking technique called prime editing. In October, the company raised $175 million in an initial public offering as many other biotech companies were struggling to raise funds from public investors, Micklus says.

Another novel gene-editing method made its clinical debut this year. Three trials started for therapies that use base editing, a gene-correction method that changes single spelling errors in the DNA rather than longer snippets of the genetic code.

In August, Beam began trials on a treatment for sickle cell disease that employs base-editing technology. Researchers at University College London are testing a T-cell leukemia treatment using base-edited chimeric antigen receptor T cells. And Verve Therapeutics delivered a base-editing therapy to treat heterozygous familial hypercholesterolemia, an artery-clogging heart disease, to the first participants in its clinical trial. Verve’s technology is licensed from Beam.

All has not been smooth for gene therapy in 2022, however. The FDA put Verve’s therapy on clinical hold for undisclosed reasons, and Beam delayed plans to move a second sickle cell treatment into the clinic.

The safety of gene-editing therapies is an ongoing concern, as well. Perhaps the industry’s largest setback was the death of Terry Horgan, the first and only participant in a clinical trial for an in vivo CRISPR treatment for Duchenne muscular dystrophy. The developer of the experimental treatment, the nonprofit Cure Rare Diseases, did not release any information about the cause of death.

On the gene therapy front, after a slew of approvals for first-generation treatments this year, sticker shock is settling in. Bluebird Bio received back-to-back FDA approvals for Zynteglo and Skysona, one-time therapies based on DNA-shuttling viruses. A month later, the FDA approved CSL Behring’s Hemgenix for treating hemophilia B. But all three treatments come with record-breaking, multimillion-dollar price tags. Micklus says discussion in the industry is underway to improve gene therapy manufacturing methods and reduce costs.