How a surprise finding made an Alnylam study one of biotech’s most ‘polarizing’ trials
The outcome, no longer seen as a sure bet, could influence how future drugs for a deadly heart disease are developed.
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.”
The outcome, no longer seen as a sure bet, could influence how future drugs for a deadly heart disease are developed.
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.”