The results didn’t add up.
BridgeBio Pharma, a young biotech trying to bring its first big drug to market, followed the blueprint of one of the world’s largest pharmaceutical companies. It made a medicine meant to work like the one that company, Pfizer, had developed for a deadly, genetic heart condition. The biotech also designed a similar kind of trial to test it and expected similarly positive results.
What BridgeBio got instead was a shock.
On Dec. 27, the company said its drug, called acoramidis, improved several key markers of heart function in people with a disease known as transthyretin amyloidosis cardiomyopathy. Yet patients who received a placebo performed better on a walking test closely correlated with heart health. Those individuals were expected to do much worse over one year of study. Instead, they barely declined.
“That was a head scratcher,” said BridgeBio CEO Neil Kumar, in an interview. “There was no evidence,” based on several past trials, to suggest that would happen, he added.
BridgeBio shares lost much of their value that day, and the ripple effects of its findings are still being felt. Transthyretin amyloidosis cardiomyopathy has become a competitive field in drugmaking. Several companies, forecasting a market worth billions of dollars, are developing pills, injectable medicines and even gene editing treatments for the disease.
Leading the way is Alnylam Pharmaceuticals, a biotech that has climbed up the industry ranks but is not yet on the same level as the sector’s most successful companies, such as Regeneron or Vertex. An important Phase 3 trial of one of its medicines, Onpattro, is expected to produce results by July. Once seen as a sure bet, the study is now considered a coin toss by investors, according to Paul Matteis, a biotech analyst at Stifel.
If the trial, called APOLLO-B, succeeds, Alnylam could cement itself as one of the industry’s largest biotechs and prove BridgeBio’s study was a fluke, he said. Should the trial fail, Alnylam will lose its closest chance at a blockbuster drug, and the development plans of others in the field could change.
The trial “is pretty polarizing,” Matteis said. Both outcomes “are equally plausible.”
A not-so-rare disease
Transthyretin amyloidosis is caused by the toxic buildup of a misfolded protein, called transthyretin or TTR, that the body normally uses to transport vitamin A. The disease can be either inherited or acquired and affects patients differently. But it worsens with time, and primarily impacts the nerves, the heart or both.
For years, the only treatments were liver transplants or a generic drug that could stabilize the protein and slow nerve damage. Since 2018, though, the options for patients with nerve damage, or polyneuropathy, have improved significantly. Multiple drugs reached the market, led by Alnylam’s Onpattro, which can halt disease progression or even improve nerve function in some cases.
Progress for patients with cardiac symptoms of TTR amyloidosis has been slower. Until recently, the disease was often mistaken for other heart problems, and only diagnosed through a biopsy of heart tissue. By that point, patients typically have advanced heart failure, said Jignesh Patel, a professor of medicine at the Cedars-Sinai Smidt Heart Institute and an investigator in several TTR cardiomyopathy trials, including APOLLO-B.
Now, physicians can use a less invasive diagnostic to detect the disease without a biopsy and rule out other heart conditions. Doctors also have a treatment to offer: a Pfizer pill called Vyndamax that the Food and Drug Administration approved in 2019. “In the old days, a diagnosis would have just been an academic exercise,” Patel said.
As a result, awareness about the disease has grown, while drugmakers have realized far more people may have TTR cardiomyopathy than previously thought. Alnylam estimates 30,000 to 50,000 people in the U.S. and Europe have polyneuropathy, and about “10 times” that number have cardiac symptoms, according to chief medical officer Pushkal Garg. Pfizer’s pill generated more than $2 billion in sales last year.
The market opportunity, along with an improved understanding of how to combat the disease, has made TTR cardiomyopathy a research focus for drug companies. Over the past few years, Intellia Therapeutics, Novo Nordisk and AstraZeneca have developed or acquired prospective treatments for the disease, joining Ionis Pharmaceuticals and Alnylam.
A “baffling” result
The key trial supporting Vyndamax’s U.S. approval, published in The New England Journal of Medicine in 2018, showed a striking result: Patients who received Pfizer’s drug were 30% less likely to be hospitalized or die than those who were given a placebo.
The data were practice-changing. “We do see patients living longer,” Patel said. Still, Vyndamax isn’t perfect. It doesn’t fully stabilize the TTR protein, and treatment can’t reverse heart damage that’s already been done. Patients’ health and quality of life still worsened over the course of the trial, and the benefit that was reported wasn’t apparent immediately.
BridgeBio believes it can do better with acoramidis. In preclinical testing, the drug stopped TTR proteins from misfolding more effectively than Vyndamax, raising expectations that it would have a stronger effect on the disease. Kumar said the company designed a “very similar” trial to Pfizer’s, though he acknowledged some differences in the types of patients who were enrolled.
There were other differences, too. The main goal of BridgeBio’s study was a difference in scores after one year on a test measuring how far patients can walk in six minutes. The test is a well-established way to judge the impact experimental medicines have on heart failure symptoms and — importantly for drugmakers — faster data to collect than hospitalizations or deaths. (The six-minute walk test, as it’s known, was a secondary goal in Pfizer’s trial.)
Though comparing trials can be difficult, the difference between the performance of the placebo groups in the two studies is “incredibly confusing,” said Matteis, of Stifel. After one year in BridgeBio’s trial, placebo patients walked seven meters fewer than they did at the study’s start, a break from what researchers anticipated based on historical data. The six-minute walk scores of placebo patients in Pfizer’s trial, by comparison, declined by nearly 60 meters over that time.
BridgeBio can still salvage some success should acoramidis prove it can keep patients alive and out of the hospital. Those results are expected next year. “I think the drug still has significant potential,” said Patel, of Cedars-Sinai.
In the meantime, the findings have implications for Alnylam, as well as others developing TTR cardiomyopathy drugs. The performance of the placebo group “is terribly important,” said Intellia CEO John Leonard in an interview earlier this year. “We are absolutely paying deep attention to that.”
Searching for answers
Kumar gave two explanations for BridgeBio’s surprise outcome. One is “training bias,” he said. Study participants are aware that TTR stabilizers are proven to help, so they might have performed better on the walking test as a result. Such a phenomenon has occurred in studies of other drugs for pulmonary arterial hypertension, according to Kumar.
The other possible explanation, Kumar said, is that the standard of care for TTR cardiomyopathy patients improved significantly between Pfizer’s and BridgeBio’s studies, making it harder to see a drug’s effect quickly.
“Probably both [factors] contributed,” he said.
Patel, the investigator in BridgeBio’s trial, has another idea. According to him, the placebo group’s performance likely indicates they weren’t as sick as those enrolled in Pfizer’s trial. If Alnylam sees the same thing, companies may need to focus on enrolling sicker patients, or enlarging their studies and running them for longer, he said.
There is also some discussion that the six-minute walk test might no longer be a useful study goal in TTR cardiomyopathy. The outcomes of such assessments can vary widely because of the other ailments, like spinal stenosis, that patients may have. Current studies might be too small to overcome that variability, Patel said.
The walking test is also “effort dependent” and involves some coaching from study investigators, noted Stifel’s Matteis. Patients could be more motivated if they know that the test is the primary goal of a study.
“If the Alnylam trial fails the way the BridgeBio trial failed, that would probably be the primary takeaway,” Matteis said.
BridgeBio’s findings led Alnylam to examine its trial “with a fine-toothed comb,” Garg, Alnylam’s chief medical officer, acknowledged. Although Alnylam’s drug will also succeed or fail based on walking test results, the company remains optimistic for several reasons, he said.
For one, the drug being tested, Onpattro, differs from acoramidis. Instead of fixing a protein that’s already made, Onpattro “silences” the gene that produces it. This approach appeared to result in a much stronger impact on polyneuropathy in clinical trials. In those studies, Onpattro showed signs of an effect on heart damage, too.
Garg also pushed back against criticism of the six-minute walk test, as well as the idea that Onpattro’s benefits might be harder to prove in healthier patients. In polyneuropathy trials, promising findings were observed in patients with even earlier heart disease than those enrolled in BridgeBio’s trial, he said.
“My inference is [BridgeBio’s result] is somehow related to the way the six-minute walk test was administered or performed in the clinical trial,” Garg said.
Patel expects the outcome will come down to which patients Alnylam enrolled. Given Onpattro’s effects on neuropathy, Alnylam’s chances of showing a benefit on the walking test might be higher if study participants had nerve symptoms as well as heart damage at the start of the trial.
“It’s hard to know until we see the data,” Patel said.
The stakes are high. Alnylam is a pioneer in a drugmaking method known as RNA interference, and has brought four medicines to market since 2018. But none are blockbusters, and Alnylam still isn’t profitable. The company recorded a net loss of nearly $853 million last year.
Success in APOLLO-B could change that, which is why Matteis expects a big swing in Alnylam’s stock price based on the trial’s outcome. But the results will be just as important for others, too.
“That trial will tell us a lot,” Kumar said. Was what BridgeBio saw “a spurious outcome, or is it suggestive of the future?”