BridgeBio secured approval for Attruby Friday, along with the all-important mortality benefit that could give the drug a significant boost in the market against Pfizer’s tafamidis and potentially Alnylam’s Amvuttra.
BridgeBio—and people with transthyretin amyloid cardiomyopathy—have something to be thankful for after the FDA approved the company’s acoramidis Friday evening, a full week ahead of its Nov. 29 PDUFA date.
The approval of Attruby—as the drug will henceforth be known—sets up a potential three-way race in the transthyretin amyloid cardiomyopathy (ATTR-CM) market between Pfizer’s tafamidis (Vyndaqel and Vyndamax) and Alnylam’s Amvuttra, for which the company filed a label expansion for ATTR-CM in October.
Attruby’s approval was supported by positive results from the Phase III ATTRibute-CM, where the transthyretin stabilizer significantly reduced death and cardiovascular-related hospitalization, and improved quality of life.
Attruby is the “first and only approved product with a label specifying near-complete stabilization of TTR,” according to a press release issued Friday by BridgeBio. The drug’s label also states a reduction in the likelihood of both hospitalization and death—a sweetener for BridgeBio as analysts have stressed the importance of the all-cause mortality benefit, a secondary endpoint that Attruby missed in ATTRibute-CM.
This is particularly key in the larger ATTR-CM space, as both tafamidis and Amvuttra demonstrated a statistically significant benefit in all-cause mortality.
“Approval of Acoramidis with a label reflecting CV [cardiovascular] mortality renders it similar to Tafamidis . . . representing a bull case scenario,” BMO Captial Markets analyst Kostas Biliouris wrote in an investor note Friday.
BridgeBio intends to price Attruby at $18,759.12 for a 28-day supply, equating to approximately $244,500 per year, according to Endpoints News. The company will provide Attruby free for life to its U.S. clinical trial participants.
Original article published Nov. 19:
ATTR-CM Approval for BridgeBio Could Trigger Tight Race With Pfizer
The only targeted treatment option for transthyretin amyloid cardiomyopathy, Pfizer’s tafamidis—marketed as Vyndaqel and Vyndamax—may soon have competition in the form of BridgeBio’s acoramidis, which could receive FDA approval next week.
Acoramidis, which like tafamidis is a stabilizer of the transthyretin (TTR) tetramer, has an FDA action date of Nov. 29. Neil Kumar, CEO of BridgeBio, expressed confidence in the drug’s chances of approval, telling BioSpace, “This will be our third approval as a company, but our first very, very large drug.”
Indeed, the market for transthyretin amyloid cardiomyopathy (ATTR-CM), a rare but severe cardiovascular disease, was valued at $5.2 billion in 2023 and is expected to grow to $9.4 billion by 2031, according to InsightAce Analytic.
A lot is resting for BridgeBio on acoramidis’ approval and a successful market rollout, Kostas Biliouris, director of biotech equity research at BMO Capital Markets, previously told BioSpace. The drug is the primary interest for the company, he said, along with targeted cancer treatment infigratinib, which is also in development for achondroplasia.
Biliouris added that, if approved, acoramidis would be competing with Pfizer’s tafamidis, which is “very well established.” BridgeBio, a much smaller player, would be in for an uphill battle.
A survey of 30 physicians conducted by BMO Capital Markets foretells a tight race between the two drugs. Of the doctors surveyed, 50% said acoramidis and tafamidis have “similar,” efficacy, and 40% said acoramidis is “incrementally better.” Only a very small percentage of physicians said that acoramidis is significantly better, according to Biliouris.
If BridgeBio does secure approval for acoramidis, Biliouris said the company would need to exceed 2025 sales expectations of about $165 million in the U.S. “If BridgeBio can beat that number, it will be great,” he said. “It will help the stock and the story. If not, it will be challenging.”
A Decade of Progress
A potentially fatal condition affecting mostly older adults, ATTR-CM occurs when the TTR protein misfolds and amyloid deposits build up in the extracellular space of the heart’s muscle tissues. This causes the heart walls to become stiff, affecting the regular pumping of blood.
Kumar said ATTR-CM is “like Alzheimer’s of the heart.” However, “it’s one of the few diseases where, over the course of 30 years, we’ve discovered how to intervene upstream,” before too much TTR is deposited into that organ.
A decade ago, ATTR-CM was “basically . . . a death sentence,” Kumar continued. Now, “If you look at the survival rates for patients on acoramidis, they approach the survival rates that you would expect for folks without ATTR cardiomyopathy. So, it’s really neat.”
In BridgeBio’s Phase III ATTRibute-CM trial, treatment with acoramidis elicited an 81% survival rate compared to 74% in the placebo group. Acoramidis also cut the relative risk of cardiovascular-related hospitalizations in half, an effect that was highly statistically significant, the company reported in July 2023. Further analyses presented in May at the 2024 International Symposium on Amyloidosis showed that acoramidis-related decrease in TTR was significantly associated with higher survival.
Tafamidis stabilizes TTR by about 50%, Kumar said, while acoramidis stabilizes it by about 96%. “Our theory is that because we’re able to reduce the amount of TTR that’s depositing in the heart maximally over time . . . it should be the most efficacious drug out there.”
However, in an email to BioSpace Wednesday, a Pfizer representative said that tafamidis achieved a greater than 90% effect on both TTR stabilization and disease-relevant measures for the class.
Mortality Benefit Is Key
Biliouris agreed that acoramidis is “probably . . . incrementally better” than tafamidis but noted challenges, including that it requires twice-daily dosing compared to tafamidis’ once-daily regimen, and the fact that Pfizer was able to demonstrate a significant reduction in mortality risk whereas BridgeBio was not. Tafamidis was approved in May 2019 after showing a higher survival rate in the treated group than for their placebo comparators.
The principal controversy around the data is fueled by a lack of statistically significant all-cause mortality (ACM) benefit in the ATTRibute-CM acoramidis’ trial, Biliouris wrote in a Nov. 11 investor note. While the drug met the trial’s primary endpoint, it missed the prespecified secondary endpoint of all-cause mortality (ACM)/cardiovascular mortality (CVM). Tafamidis and Alnylam’s Amvuttra have both demonstrated a statistically significant benefit on this goal.
However, at the American Heart Association’s 2024 Scientific Sessions in Chicago this week, BridgeBio presented updated analysis from the open-label extension portion of ATTRibute-CM, showing a statistically significant ACM benefit with acoramidis.
Basing his opinion on feedback from a former clinical reviewer in the FDA’s cardiorenal division, Biliouris said in the Nov. 11 note that he believes acoramidis’ label will not include a CVM benefit, driving 20%-30% downside in the company.
In a Tuesday investor note, William Blair analysts also stressed the significance of the CVM benefit. “We continue to view a reduction in all-cause mortality as a necessary distinction to gain market share in ATTR-CM alongside Pfizer’s . . . tafamidis, which has demonstrated this benefit in ATTR-ACT with mortality claims listed on label,” they wrote.
Emerging Competition
More competition could soon be on the horizon for the two frontrunners.
RNA therapies, in particular, have recently shown promise in treating the disease. In June, Alnylam reported topline data from the Phase III HELIOS-B trial of its RNAi therapy Amuvttra (vutrisiran), demonstrating that the therapy could lower the risk of death and recurrent cardiovascular events in ATTR-CM. On the strength of these results, Alnylam submitted regulatory applications to both the FDA and European Medicines Agency in October. Amvuttra is currently approved to treat polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis. Alnylam presented further data from HELIOS-B at AHA showing a 28% reduction in the composite of ACM and recurrent CV events.
“Assuming regulatory approval, Amvuttra has the potential to be the first alternative RNAi treatment option available for these patients with an unmet need,” an Alnylam spokesperson previously told BioSpace in an email.
Mathew Maurer, a professor of cardiology at Columbia University Irving Medical Center, previously told BioSpace that while Vyndaqel and Vyndamax slow disease progression, they don’t reverse it. RNA therapies aim to stop the production of the mutated TTR protein by targeting its RNA.
Like Amvuttra, Wainua (eplontersen), developed by AstraZeneca and Ionis, is approved to treat hATTR amyloidosis. The partners are now studying the antisense RNA silencing therapy for ATTR-CM in the Phase III CARDIO-TTRansform study.
Meanwhile, Intellia Therapeutics excited analysts this weekend at AHA with Phase I data from gene editor nexiguran ziclumeran (nex-z). The biotech reported that treatment with nex-z elicited “rapid, deep and durable” reductions in serum levels of TTR. A single dose of nex-z led to a sustained decrease in serum TTR level, with the mean reduction hitting 90% at 12 months. Signals of disease-modifying effects for cardiac disease were also detected, with patients at 12 months showing signs of stabilization or improvement—despite many being enrolled with advanced or severe disease.
In a Sunday note, Biliouris called Intellia’s readout “robust,” adding that the early findings “are supportive of a strong profile, suggesting a successful PhIII outcome.”
Truist Securities’ Joon Lee called the data “impressive,” noting that nex-z elicited a stronger serum TTR reduction than Amvuttra, alongside a “faster onset of action.”
Editor’s note (Nov. 20): This story has been updated with comments from Pfizer regarding tafamidis’ efficacy.
