From ‘lost cause’ to gold rush: Biotechs swarm to cure AATD

Highlights Rarely has a new technology so squarely lent itself to one disease. Here’s why. Major biotechs, including Beam, Wave Life Sciences, Korro Bio, Tessera, and Yoltech are targeting a single misspelled letter of DNA. Analysts see a multibillion-dollar potential market. Biotechs are spending billions to cure a rare liver disorder most Americans have never heard of. The contentious race features dueling technologies, patent wars, a broken alliance, and a boiling competition between the U.S. and Chinese drug industries. The disease, known as alpha-1 antitrypsin deficiency (AATD), is a slow-moving disaster for patients. Thanks to a single misspelled letter of DNA, their livers produce a mutant version of a protein that normally travels through the bloodstream and protects the lung from damage. These mutant proteins both leave the lungs undefended and can form toxic buildups inside the liver, damaging two vital organs at once. Beginning in early adulthood, a constellation of often misdiagnosed symptoms can emerge — coughing, fatigue, jaundice. Either or both organs can slowly fail. Scott Exton was diagnosed in his early 30s, after a chest infection landed him in the hospital for five days and revealed his lungs were severely damaged. “You think your life’s kind of over,” said Exton, who has now enrolled in a gene-editing trial. The earliest gene therapy research dates back four decades. But only in the last five years have efforts spun into a frenzy, as executives at more than a half dozen companies realized the condition is the perfect application for new technologies capable of changing individual letters of DNA or RNA. The disease is caused by cells in the liver, the only organ that companies can reliably deliver gene-editing tools to today. About 200,000 people are believed to have the disease in North America and Europe, although the vast majority are either asymptomatic or misdiagnosed with a more common lung disease. (The mutation is thought to have possibly been spread by Viking conquest and is not widely found elsewhere.) From a business standpoint, that’s more than twice the market of cystic fibrosis, a disease that earns Vertex Pharmaceuticals $12 billion a year. And patients all have almost the same mutation, meaning they can be covered by one treatment. Commercially, there’s no opportunity like it. “It checks all of the boxes, right?” said Eric Schmidt, an analyst at Cantor Fitzgerald. “I’m sure all of the different internal project managers in these companies, as they come across their potential opportunities and disease indications — this would probably smoke to the top of any list.” Beam Therapeutics has the most advanced program for gene editing. It could file for an approval in 2028. Three other Boston-area gene-editing companies are behind them, along with a Shanghai-based biotech co-founded by a former Beam scientist, and a slate of startups that target RNA. At least five groups are pursuing other gene therapies or protein-based or pill-based approaches. It is not a quiet fight. Executives, founders, and investors have accused each other of violating a long-standing agreement, copying technology, or even acting against their countrymen. Amid a prolonged downturn for gene-editing companies and growing anxiety in the U.S. about the rise of Chinese biotech, the stakes — and tempers — are high. For patients, though, the competition amounts to a long-awaited moment, when thousands of scientists are working on a long-invisible and misdiagnosed disease. Jon Hagstrom, chair of the Alpha-1 Foundation, can scarcely believe it. He was diagnosed a decade ago, at 39, when there were few options besides the double-lung transplant he would eventually receive. “I was sort of a lost cause,” he said. And now there’s “this incredible pipeline.” ‘No real hope’ For 40 years, there has been one treatment for AATD: replacement protein. Companies like Grifols take donor blood and purify out the key protein, called AAT. Patients receive infusions weekly. Such treatments cost around $100,000 per year and come with significant drawbacks. Patients must receive infusions for life. They don’t receive enough AAT to fully protect their lungs. And the treatment does nothing to protect the liver. Because AATD progresses so slowly, it’s been difficult to prove the treatment substantially slows patients’ decline. The Food and Drug Administration approved it based on laboratory evidence that the replacement protein did its job: blocking a bacteria-shredding enzyme on immune cells from also shredding lung tissue. But it remains unavailable in the U.K. and many other countries. Even in the U.S., conversations with patients were difficult. “They’re always asking, what is coming? What should I be excited about?” said Andrew Wilson, head of the Alpha-1 Center at Boston University and scientific director of the Alpha-1 Foundation. “And the answer for the longest time was basically nothing. I had no real hope in the form of new possible therapies.” Before 2020, two other treatment ideas percolated. Ron Crystal, the National Institutes of Health pulmonologist who first devised AAT protein replacement therapy, spent decades trying to build a gene therapy, to little avail. (He began a trial only last year.) In the late 2010s, Vertex tried to design small molecule “correctors” for AATD, hoping to reproduce its life-changing medicines for cystic fibrosis. A series of different molecules disappointed in trials, and Vertex quietly removed Alpha-1 from its pipeline last year. By then, though, patients’ and doctors’ focus had shifted dramatically. ‘The holy grail’ In December 2016, longtime biotech executive John Evans visited David Liu’s lab at the Broad Institute to learn about his latest invention: Gene editors capable of changing individual DNA letters. Evans knew immediately how to use it. “I did immediately think of A1AT,” Evans wrote to Liu two days later, using another acronym for AATD. Rarely has a new technology so squarely lent itself to one disease. When the first three CRISPR gene-editing companies emerged in the early 2010s, each considered pursuing AATD. Two started programs. But CRISPR 1.0 was much better at breaking genes than fixing them. Base editing, as Liu called his creation, offered far greater finesse. It could change only certain DNA letters, but among those was the error — an “A” where there should be a “G” — that causes AATD. With a single dose, you could fix the misspelling in most patients, at once protecting their lungs and lowering the toxic protein accumulating in their livers. “That’s the holy grail in this disease,” said Gerry McElvaney, a longtime AATD researcher at Beaumont Hospital in Ireland. In 2018, Beam launched, with Evans as its CEO. But creating the drug took years. Beam had to engineer the editor to work efficiently in human cells and design lipid nanoparticles, tiny soap bubbles, to ferry the editors into the liver. Beam didn’t dose its first AATD patient until June 2024. One night that October, Scott Exton finished his shift at a truck maintenance shop in Derbyshire, England, and hailed a taxi for the three-hour drive to London. It had been a brutal two-and-a-half years for Exton. Many people born with the mutation never develop symptoms, but Exton smoked and worked in construction for a decade, inhaling dust eight hours a day. He was diagnosed with chronic obstructive pulmonary disease, before a senior doctor noticed that 33 was awfully young for COPD and ordered a genetic test. Exton saw it as a death sentence. The only options were inhalers and steroids. Google search turned up worst-case scenarios. When physicians at an AATD clinic offered him a chance at clinical trials, he took it only because it might benefit his two young children and other patients. They offered him a new roughly monthly treatment, being developed by Sanofi. Or Beam’s one-and-done gene-editing drug. He asked if he would grow a third arm and, assured he wouldn’t, said, “So put me down for the gene one if it’s a single dose.” After a day of tests in London, he was hooked up to a clear IV bag and waited for 45 minutes, as a warm feeling passed through his body. He felt no different on the cab home, he said, and yet a small, profound change had occurred. Beam later announced that volunteers in its trial saw their blood levels of properly folded AAT, called M-AAT, increase and the percentage of mutant, misfolded AAT, called Z-AAT, decline. The effect was modest in low-dose patients like Exton but striking in the high dose. “It’s the first time in human history that we were able to correct a mutation,” Evans said. A ‘super secret’ program Beam has now treated 29 patients. At high doses, patients’ levels of Z-AAT almost disappeared while levels of total AAT more than doubled. When one patient got an infection, AAT levels soared to protect the lung. “It’s doing what it says on the tin, essentially,” said Alice Turner, an investigator on the study and Exton’s doctor at the University of Birmingham. Yet Beam faces immense competition. Inspired by a discovery in squids, several companies are developing “RNA editors” for AATD. These biweekly or monthly drugs don’t touch DNA and may be attractive to patients hesitant to alter their genomes. Clinical data, from Wave Life Sciences and Korro Bio, have so far been lackluster compared with Beam’s. But several candidates are still in development. Beam is also competing with four different gene-editing companies, three that may be poised for a legal battle with Beam and one founded by a former Beam scientist. A year after Beam launched, Liu founded another startup, Prime Medicine, around a new tool called prime editing. Prime editing is capable of changing any DNA letter into any other letter. Early on, Prime and Beam struck an agreement that gave Beam the rights to use prime editing for any mutations that could already be corrected with base editing — such as AATD. Liu believed the deal would prevent Beam and Prime from competing, freeing up each to divide and conquer the thousands of rare diseases that might be treated with their technology. The deal is “designed to maximize patients’ interests,” Liu told STAT at the time. Although Beam has never publicly advanced prime editing for any disease, including AATD, in principle it could be assured Prime would not try to undercut any of its programs. Practically speaking, though, there weren’t thousands of diseases to pursue. Although prime editing could theoretically correct almost any disease-causing mutation, most of those mutations were exquisitely rare and affected hard-to-reach organs like the brain. Prime’s leadership soon realized it had handed away rights to one of the most lucrative diseases. By 2022, it had started a “hush-hush” AATD program, according to a person familiar with Prime’s internal operations. Even internally, it wasn’t referred to by name. In 2025, as investors lost faith in its other efforts, Prime publicly unveiled the AATD program. Beam took Prime to arbitration, demanding damages. (Liu’s thoughts on the clash are unclear. Though he holds equity in both companies, he is not on either’s board and did not respond to requests to speak on-record about the matter. Prime CEO Allan Reine has said the company didn’t disclose earlier because it was waiting until it had generated more data.) Other competitors emerged. That fall, CRISPR Therapeutics unveiled its own AATD program, and Regeneron paid $150 million to collaborate on an AATD program with Tessera Therapeutics. Prime has accused both companies of using its technology. This month, an arbitrator decided in Prime’s favor, for technical reasons. Beam immediately sent investors a note promising to “aggressively defend” its patents, including against other companies working on AATD. Regeneron, Tessera, and CRISPR declined requests for an interview. Tessera and CRISPR have denied they copied Prime’s or Beam’s technology. A Shanghai competitor Beam’s rivals believe they can build a better drug. Beam’s drug still doesn’t restore patients’ AAT levels to the healthy range of 20 to 50 micromolars. The company’s scientists aren’t sure why. But Evans dismissed the concern as “somewhat academic.” Historically, just 11 micromolars has been considered “protective.” And people who inherit just one copy of the AATD mutation often live symptom-free lives, despite often carrying AAT levels in the teens. Beam averaged around 14 to 16 micromolars. “The beautiful thing about Alpha-1 … is we have so much information from clinical genetics,” he said. “Nature has done the experiment for us.” Experts note, however, that carriers are still at heightened risk for lung disease if they smoke. One theory for why Beam may be struggling is that its editor is prone to mistakes. When the CRISPR enzymes go into a cell to flip that mutant A to a G, they sometimes flip other nearby As, too. Beam argues so-called bystander edits don’t affect the resulting protein, but not everyone is convinced. Companies that use prime editing won’t face those challenges. And there is a hair of data suggesting that fewer bystander edits may provide benefit. In 2022, Emma Wang, a young scientist who had worked at Beam and Tessera, left to build one of the first Chinese gene-editing companies, alongside a Shanghai-based academic named Yuxuan Wu. Initially, Wu told STAT, they weren’t sure whether to pursue AATD. Beam was too far ahead. Yet their own molecular analysis suggested that bystander edits were detrimental. They set out to build a more specific base editor that avoided Beam’s patents. By 2025, it was in the clinic, thanks to a pathway that allows Chinese companies to start trials without regulatory oversight. (Because AATD is vanishingly rare in China, the company flew patients in from Europe.) That year, the company announced it had exceeded Beam’s efficacy in one of two patients. Though early, it caught the eye of investors at RA Capital and RTW, who struck a deal this month to license the drug and roll it into a new company. “The drug looked like it really could be potentially best in class,” said Laura Tadvalkar, a managing director at RA Capital. The backlash was swift. The deal came at a moment of existential anxiety over the fate of U.S. biotech. Cheap labor, cheap manufacturing, and cheap clinical trials were enabling Chinese companies to spin up molecules at a rapid clip, enticing investors and big pharmas to pass over U.S. startups. Yoltech — having almost caught up to the leading U.S. company, just a few years after being founded by a junior scientist at that company — seemed to exemplify those fears. Jason Kelly, a prominent biotech executive, accused RTW and RA Capital of “working against US startups and US biotech scientists.” Bob Nelsen, an investor behind Beam and Prime, said he didn’t want to ban drugs but there had to be some method to disincentivize “blatant copies like this and incentivize U.S. companies” that take risks. RTW and RA leaders have argued that the medicine could benefit U.S. patients. “I do think that it was relatively narrow-minded to just say that this is a simple copycat, and to not think that there could be genuine innovation that was coming out of China,” RTW’s Samantha Larsen said. Though still at Yoltech, Emma Wang has now deleted her LinkedIn and scrubbed her name from the website. She wanted “to encourage the field to focus on the science,” she said via email. Next: finding the patients The fight may only heat up in the next couple of years. The next drug to win approval is likely to be the new protein replacement therapy from Sanofi, which it purchased for up to $2.2 billion in 2024. Takeda also has an RNAi drug designed just to address liver symptoms. If Beam can reach market by 2028, analysts expect it should have a first-mover advantage. But Tessera, Yoltech, Prime, and CRISPR won’t be far behind. “I think those trials are not going to be struggling to recruit,” said Turner, the Birmingham physician. “Patients are hearing what’s going on with Beam.” Typically in drug development, lawsuits only come after drugs reach market. The biggest hurdles may lie beyond approval. Turner expects that the U.K. may not pay for these medicines until companies demonstrate clearly that they stop the disease — which could take years, given its slow-moving nature. And once drugs are available, companies and doctors will need to find patients among the thousands who are asymptomatic or think they have COPD. The Alpha-1 Foundation has launched an effort to provide clinics with free genetic testing. Sanofi plans to comb health records with AI. Once patients are found, doctors will face an even tougher question: When to treat? Editing a patient’s DNA early could prevent them from experiencing irreversible lung or liver damage. But doctors don’t want to expose someone to side effects if they might never develop symptoms. Scott Exton, now 39, in Derbyshire, still struggles to breathe sometimes. But doctors tell him his lungs have at least stopped deteriorating, though he thinks that’s both from the drug and because he stopped smoking and quit his job in construction. Occasionally, he’ll get messaged on Facebook by another patient or the hospital will call him back down, to talk to a volunteer having second thoughts. He’s still waiting to get a full dose, as Beam has promised it will offer before approval. In the meantime, he takes things day by day. He no longer thinks he has a death sentence. Twice a year, he takes his family abroad, even if it hurts his savings. Recently, he bought a new motorcycle for the first time in 15 years. He cites an old Scottish proverb about savoring each day. “You’re a long time dead, aren’t you?” he said.