The burgeoning field of transthyretin amyloid cardiomyopathy (ATTR-CM), which spurred excitement over a potential $20 billion market, may have just revealed the first indication of a slowdown.
For the three months ended in September, Pfizer reported a 1% sales decline year over year for its family of tafamidis products in the U.S. The $948 million haul also marked a 4% sequential decrease from the prior quarter that ended in June.
The U.S. revenue dip, though small, may raise eyebrows especially considering that the drug nearly doubled sales in the U.S. last year. At the same time, the subtle drop happened less than a year into BridgeBio’s second-to-market launch of its rival drug Attruby and just two full quarters following the entry of Alnylam’s Amvuttra, so the field is clearly evolving.
Still, Pfizer’s recent tafamidis performance may be a concerning sign for industry watchers as they’ve built considerable interest in ATTR-CM based on the assumption that the market is large enough for multiple players to thrive and grow together.
“It has to be a concern by definition,” Leerink Partners analyst Mani Foroohar, M.D., said in a recent interview with Fierce Pharma.
“If you look at the script trends, the volume trends, we have seen a little bit of a slowing from the absolutely torrid pace of growth we’ve seen the last few years and earlier this year,” Foroohar, who covers both Alnylam and BridgeBio, said.
As the current market leader, Pfizer assured investors that demand is still ticking upward for Vyndamax, which has been on the market since 2019. Since its launch, tafamadis has been sold in differing doses as Vyndaqel and Vyndamax, but the company has said it’s discontinuing the low-dose Vyndaqel by the end of the year.
The “very strong demand growth” for the product was offset by two pricing dynamics during the third quarter, Aamir Malik, Pfizer’s chief U.S. commercial officer, explained on the company’s earnings conference call in November. One factor is rebates paid under the Inflation Reduction Act, and the other is discounts offered in payer contracts. These two pullbacks will continue to play out through the end of the year, he said.
Pfizer declined Fierce Pharma’s request to quantify Vyndamax’s demand growth. That number is important, because a 20% volume growth tempered by a 21% price reduction would indicate a more prosperous overall market than a 5% volume growth marred by a 6% price concession.
Investors frequently monitor prescription volume data provided by IQVIA, but Foroohar noted that while those numbers serve well as “a directional tool,” they are not always reliable on details.
Pfizer’s opaque disclosure prevents BridgeBio CEO Neil Kumar, Ph.D., from providing precise description of Attruby’s market share. In an interview with Fierce Pharma, Kumar said that without more detailed data from Pfizer, he’s not able to update his “well in the 20s” estimate of Attruby’s new-to-brand patient share percentage offered on BridgeBio’s investor call in late October, even though he had a “more refined” understanding after Alnylam’s and Pfizer’s third-quarter reports.
Both Attruby and Vyndamax are oral ATTR stabilizers, whereas Amvuttra is an injectable gene silencer.
Kumar acknowledged that the speed of expansion of the entire ATTR-CM market—or in his words, the “growth of the growth”—appears to be flattening in the U.S. But the category’s prescription growth “continues to be profound.”
“The overall magnitude of new patients coming on drug continues to grow at a level that we haven’t seen before,” Kumar said.
Besides Pfizer’s “very strong demand growth” for Vyndamax, Alnylam reported an approximate doubling in patient demand for Amvuttra in the third quarter versus the second quarter, when the siRNA specialist recorded 1,400 ATTR-CM treatment initiations.
For its part, since Aug. 1, Attruby has added 1,508 unique patient prescriptions, reaching 5,259 as of Oct. 25, according to BridgeBio. For reference, the Vyndamax franchise has been booking about 2,500 to 2,600 total scripts—new and old—on a four-week rolling basis since July, according to IQVIA tracking data cited by Leerink.
These signals led Jefferies analyst Andrew Tsai to strike a positive note in a Nov. 4 report. He figures the ATTR-CM market is expanding on a trajectory that would enable more than $20 billion in future annual U.S. sales.
Foroohar dampened enthusiasm about the numbers by pointing out Alnylam’s “doubled” description was actually for vials shipped, raising questions of whether Amvuttra added that many new patients. To him, all signs point to one conclusion: The growth of the ATTR-CM market has moderated compared to its prior growth rate.
“While there’s tremendous excitement about the scale of the [total addressable market] and the size of the opportunity, how that translates versus the extremely high expectation is unclear,” Foroohar said.
As of mid-November, Foroohar’s team projected total ATTR drug sales of $16.7 billion in 2028 and $17.1 billion in 2035, whereas Wall Street’s consensus estimates have those numbers at $15.3 billion and $25.5 billion, respectively, according to Leerink.
Expanding patient base
ATTR-CM is a rare heart disease that’s estimated to affect about 11% to 13% of patients with heart failure with preserved ejection fraction (HFpEF), or roughly 250,000 to 300,000 patients in the U.S. For now, only about a fifth of those patients are properly diagnosed, which gives Kumar confidence that the market is on track for further growth.
The prevalent operating assumption is that with more players joining the field, awareness and diagnosis will improve. But it remains unclear how much more market penetration two biotechs can offer that Pfizer, a Big Pharma firm, has not been able to achieve in the past six years.
“First and foremost is just education and getting people to think of this condition outside of centers of excellence,” Kumar said.
As of about six months ago, the physician prescribing universe for ATTR-CM remained restricted compared with the large number of heart failure practices in the U.S., but it’s growing rapidly these days, Kumar noted.
As more clinical data are being generated by Attruby and Amvuttra, speakers bureaus are educating their peers at conferences.
“Importantly, it’s ensuring that people have different diagnostic techniques that enable them to suspect ATTR cardiomyopathy,” Kumar said.
Drugmakers are experimenting with artificial intelligence algorithms in an attempt to identify a combination of factors, such as left ventricular thickness, to help doctors screen for potential ATTR-CM patients, he noted.
“People are quickly understanding that this is a significant subpopulaton of HFpEF,” the BridgeBio CEO said. “And about how they look for it and when to look for it, I think that’s an outstanding question that is being asked and answered in the context of the care setting, and that’s the work we have to do.”
Foroohar also wouldn’t discount the commercialization power of biotechs, as evidenced by Alnyalm’s and BridgeBio’s consensus-beating results in the third quarter.
“Once upon a time, the assumption that one should ‘short’ the launch of an independent bio company was a common trade on Wall Street,” Foroohar said. “That has not proven to be true, certainly for genetically defined diseases.”
In addition, Amvuttra’s unique knockout mechanism offers doctors a new solution for patients who either have not responded to—or started to experience waning benefit from—Pfizer’s Vyndamax. The emergence of a second-line option—and a substantially more expensive one—will drive dollar growth of the market, even if it doesn’t increase patient volume, Foroohar said.
The existence of multiple players means more investment in patient awareness, which could accelerate market expansion, the Leerink analyst noted.
A fourth player could join the ATTR-CM space soon. The phase 3 CARDIO-TTRansform trial of AstraZeneca and Ionis’ antisense therapy Wainua in ATTR-CM is expected to read out in the second half of 2026. The drug is currently approved in the U.S. to treat another form of ATTR that affects the nervous system.
AZ is an established player in cardiovascular disease with a robust sales infrastructure. The Crestor inventor also sells blockbuster SGLT2 inhibitor Farxiga across multiple indications, including heart failure. So Foroohar argued that it’s plausible that AZ’s potential participation will reaccelerate growth for ATTR-CM.
What Wainua’s data will look like and whether AZ will drive class expansion or fiercer competition currently represent a key debate among ATTR-CM market watchers. But to Foroohar, there’s another more important question.
Tafamidis genericization
Pfizer’s tafamidis franchise is expected to lose U.S. patent protection in 2028. The availability of cheaper generics is expected to markedly accelerate global patient volume growth, Foroohar said. But that will almost certainly come at the cost of sales of the originator. The post-tafamidis-generic era was where Foroohar and the consensus differ in their estimates.
The task in front of Alnylam, BridgeBio and its partner Bayer, as well as potentially AZ and Ionis, is how they can differentiate themselves from generic tafamidis.
Alnylam has talked about tafamidis genericization as a positive for Amvuttra. That’s because the company's drug has shown some cardiovascular benefits in patients who are already on background tafamidis, according to data from the phase 3 Helios-B trial.
Without a combination-specific label, using two branded drugs together is not a strategy expected to gain much traction with payers. But the company sees the prospect of broader uptake once tafamidis generics relieve the financial burden of a combo. Under that scenario, Amvuttra could reap the benefit of the patient volume expansion without having to compete with generics for market share.
Leerink’s Foroohar agrees that the combination approach could drive ATTR-CM market growth, but he’s not as upbeat about the dynamic as some of his analyst peers. There could be a combination opportunity in the U.S., but the situation is less promising elsewhere, Foroohar said.
An effective and safe generic drug is “typically a headwind to reimbursement, especially in European markets, where you have comparability pricing,” Foroohar noted.
Alnylam is already experiencing slower-than-expected initial launch of Amvuttra in Europe. Because Amvuttra is the only physician-administered option for ATTR-CM, the “buy and bill” model of reimbursement in the U.S. offers practices a financial incentive derived from the differences between the drug’s acquisition cost and the payer reimbursement rate. This incentive, however, is not present outside the U.S.
Amvuttra’s combination dream may also depend on data from Wainua’s phase 3. The trial, which is so far the largest and longest study in the indication, might give AZ the first clean combination label, Foroohar noted.
For its part, BridgeBio has been focused on differentiating Attruby as a best-in-class, first-line stabilizer and a more potent drug than Vyndamax, Kumar said.
Because patients’ out-of-pocket costs likely won’t change much after Vyndamax goes generic, Kumar said he doesn’t expect a difference in pricing will be a determining factor in the choice between tafamidis generic and Attruby.
“If they were super concerned about cost, we would own the category right now, since we are, by far and away, the cheapest drug, and there wouldn’t be a whole lot of Alnylam being prescribed,” Kumar said.
Attruby’s twice-daily dosing schedule also puts it at a disadvantage against Vyndamax’s once daily regimen. But Kumar argued that the concern about dosing frequency “comes down to what’s the differential efficacy you’re getting.”
BridgeBio made Attruby a twice-daily medicine to keep TTR stabilization levels well above 90% during all hours of the day. And ATTR-CM is a severe enough life-threatening condition in which convenience is not necessarily the top priority, the CEO said. Besides, almost 80% of ATTR-CM patients are already on other twice-daily drugs anyway, Kumar noted.
ATTR-CM should not be treated as a monolithic market, the BridgeBio exec argued, as doctors and patients are looking for different benefits out of their treatment options. A patient who has failed on another treatment and needs to get the disease quickly under control may choose Attruby, Kumar argued, because the drug’s effects can show as early as three months.
“That’s really where we’re focused, is the uniqueness of our brand in the context of a lot of these different subpopulations,” Kumar said.
BridgeBio is targeting about 30% to 40% of the overall ATTR-CM market share. Eventually, Attruby’s position will depend on the data that it can produce, Foroohar said. For now, Foroohar said he does not model that kind of penetration percentage for Attruby, and he’s projecting the drug’s share to flatten out upon tamifidis genericization.
“The larger question for us is not just how can they achieve that market share, but what data they would need to do [it],” the Leerink analyst said.
At least according to Kumar, a head-to-head trial against tafamidis is unrealistic for a small company like BridgeBio. Given that both therapies are effective in lowering hospitalization and death, it would take a very long and large trial to differentiate the event rates between the two meds. According to Kumar’s estimate, such a study would cost about $400 million.
Meanwhile, improvements in ATTR-CM patient outcomes after the first wave of drug launches could spell some trouble for Alnylam’s next-generation candidate nucresiran, Foroohar said.
Alnylam has guided to a potential launch of nucresiran in 2030 based on a phase 3 trial that, according to Foroohar, could plausibly show a combination benefit with tafamidis. The diagnosis push among drugmakers will instead be a detriment to clinical trials of newer ATTR-CM prospects, Foroohar argued. As patients are diagnosed earlier with milder disease, it would be even more difficult for newer agents like nucresiran to demonstrate a treatment effect.