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iStock/ magicmine The FDA approval of Alnylam’s Amvuttra sets up a three-way race with Pfizer and BridgeBio, which both market transthyretin stabilizers for transthyretin amyloid cardiomyopathy. There’s a new player on the transthyretin amyloid cardiomyopathy (ATTR-CM) block. Four months after greenlighting BridgeBio’s Attruby for the rare cardiovascular disease, the FDA approved Alnylam’s Amvuttra Thursday as the first RNAi silencer for ATTR-CM. Amvuttra’s approval ignites a three-way race with Attruby and Pfizer’s tafamidis, which won the FDA’s first approval for ATTR-CM in May 2019. Both Attruby and tafamidis are transthyretin stabilizers, while Amvuttra works by knocking down both the wildtype and mutant forms of the transthyretin RNA, in turn lowering the expression of the TTR protein. Alnylam is hoping this novel mechanism of action will set it apart from its competitors. “The FDA approval of AMVUTTRA for ATTR-CM marks a pivotal advancement for patients, providing a new and clinically differentiated treatment option that has been shown to improve outcomes, including cardiovascular mortality, and reduce progression for those living with this devastating disease,” Alnylam CEO Yvonne Greenstreet said in a statement following the approval. This is the second approval for Amvuttra, which was approved by the FDA to treat polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in June 2022. Original article published March 17 Alnylam’s Amvuttra Expected to Make Three in Crowded ATTR-CM Space A decade ago, transthyretin amyloid cardiomyopathy was basically a death sentence, Neil Kumar, CEO of BridgeBio, told BioSpace last year. Today, the outlook is much brighter. With effective medicines from Pfizer and BridgeBio on the market, survival rates have dramatically improved. Now, Alnylam’s vutrisiran is on the cusp of joining them. On March 23, the FDA is widely expected to approve vutrisiran—which Alnylam markets as Amvuttra for polyneuropathy of hereditary ATTR (ATTR-PN)—for the cardiovascular manifestation of the disease. The key question for analysts—and likely Alnylam itself—is, how much of the transthyretin amyloid cardiomyopathy (ATTR-CM) market—which is projected to reach $11.2 billion by 2030—will Amvuttra be able to claim? In ATTR-CM, the liver produces faulty transthyretin (TTR) proteins. Clumps of these misshapen proteins then build up in the heart’s main pumping chamber, leading to cardiomyopathy that makes it more difficult for the heart to pump blood to the body. Pfizer’s tafamidis —marketed as Vyndaqel and Vyndamax—came first in this space, winning the FDA’s first approval for transthyretin amyloid cardiomyopathy (ATTR-CM) in May 2019. BridgeBio followed a little more than five years later with Attruby, which got the nod in November 2024. Alnylam believes Amvuttra’s mechanism of action will set it apart from the competition. While tafamidis and Attruby are both transthyretin stabilizers, Alnylam’s drug is an RNAi silencer that works by knocking down both the wildtype and mutant forms of the transthyretin RNA, in turn lowering the expression of the TTR protein. Amvuttra “works upstream of currently available therapies and, thanks to our unique technology, delivers rapid knockdown of the disease causing TTR protein, addressing the disease at its source,” Tolga Tanguler, chief commercial officer at Alnylam, told BioSpace in an email. If approved for ATTR-CM, “Amvuttra will be the first RNAi therapeutic for this indication and the only therapeutic to address both hATTR-PN and ATTR-CM.” “We believe that the anticipated approval of Amvuttra will add another important, clinically differentiated treatment option for patients with ATTR-CM, a rare, progressive, and deadly condition,” Tanguler continued. More Competitive Variables The ATTR-CM space is rapidly expanding. And while BridgeBio’s launch of Attruby has “exceeded [investor] expectations,” the market expectation is that “peak sales of Amvuttra will be higher than [Attruby],” Kostas Biliouris, director of biotech equity research, BMO Capital Markets, told BioSpace. Since its November 2024 approval, more than 1,000 unique prescriptions have been written for Attruby. Biliouris emphasized two key variables that could affect competition between Attruby and Amvuttra: administration and price. Amvuttra is administered in “only four convenient, subcutaneous doses per year,” Tanguler said, while Attruby is taken orally twice a day . Alnylam has not yet announced a price tag for Amvuttra in the new indication, but in ATTR-PN the drug is “almost double” the price of Attruby and tafamidis, Biliouris said. “Alnylam may or may not decide to change the price, to lower it, when they get the approval in March, but this is a very important point to consider,” he continued. Out- of -pocket costs could play a role in patient and prescriber decisions as well, Biliouris said. Because Amvuttra will be administered in a doctor’s office and is therefore part of Medicare Part B, most patients will not pay anything out of pocket, while both tafamidis and Attruby are Part D, carrying an up to $2,000 out of pocket cost per year for patients, he explained. While Alnylam declined to comment on the potential pricing of Amvuttra in ATTR-CM, Tanguler said, “We believe that our science can only impact human health if patients have access to their medicines. . . . As such, we will measure our success by broad patient access to Amvuttra.” Alnylam could also benefit from its experience and infrastructure in ATTR-PN, Biliouris said. In addition to Amvuttra, the company markets Onpattro for polyneuropathy caused by hereditary ATTR (hATTR). Together, the franchise brought in more than $1.2 billion in 2024, “and it’s been growing every year, which shows you they know how to do it,” Biliouris said. “They have done it before successfully.” Alnylam is aiming for Amvuttra to be a first-line treatment choice for ATTR-CM, according to Tanguler. The data from the company’s Phase III HELIOS-B study —in which Amvuttra led to a 36% risk reduction in all-cause mortality—positions the drug for this role, he said. The Label While Biliouris believes Amvuttra will be approved in ATTR-CM, one factor he is watching closely is the drug’s label. Currently, the labels for tafamidis and Attruby are “pretty similar,” he said, listing improvement in cardiovascular mortality and hospitalization. Amvuttra, however, has a chance to secure the much-coveted all-cause mortality benefit, according to Biliouris. While Attruby missed this secondary endpoint in the Phase III ATTRibute-CM trial, Amvuttra was successful in this metric in HELIOS-B, leading to a lower risk of death from any cause and recurrent cardiovascular events compared to placebo. However, Biliouris said, “this can be just incremental, and it may not have a big impact on physicians and the uptake.” The second item Biliouris is watching for on the label is the possibility of a combination benefit with tafamidis. In HELIOS-B , “[Alnylam] saw that there is a benefit from the combination of the two drugs . . . but the improvement was not statistically significant,” he noted. Importantly, the trial was not designed to measure statistical significance on this metric. BMO’s “bull case” is that the label will include an all-cause mortality benefit as opposed to only cardiovascular mortality and a possible mention of a combination benefit between Amvuttra and a transthyretin stabilizer, Biliouris said. On Deck in ATTR-CM While Alnylam is in the spotlight this week, there are more therapies waiting in the wings for ATTR-CM, including another RNA silencer being developed by AstraZeneca and Ionis. Wainua, which is approved to treat hATTR amyloidosis, is currently being studied in the Phase III CARDIO-TTRansform study for ATTR-CM, which is expected to be completed in April 2026. Meanwhile, gene editing leader Intellia is working on what it calls a “one and done” treatment for ATTR-CM. The biotech presented Phase I data from nexiguran ziclumeran (nex-z), a gene editor, in November at the American Heart Association’s 2024 Scientific Sessions, showing “rapid, deep and durable” reductions in serum levels of TTR, according to a press release. In patients with ATTR-CM, the mean TTR reduction was 90% at 12 months. Nex-z could have the advantage of reducing treatment burden, an Intellia spokesperson told BioSpace in an email. “Many patients experience anxiety from going to infusion centers frequently, spending time away from their families and work [to receive] repeated injections. A one-time option would eliminate that burden.” The investigational treatment could also ultimately be more effective, the spokesperson continued. “Dosing every few months produces a cyclic rise and fall of TTR levels over time, with peaks and troughs. Our data show that a one-time dose can reduce TTR to very low levels and keep it there, maintaining treatment benefit at its maximum.” Intellia is currently enrolling the Phase III MAGNITUDE trial and is “ahead of [its] internal target projections,” according to the spokesperson. The company expects the trial to be fully enrolled by early 2027. For its part, Alnylam isn’t stopping with Amvuttra. The company is developing a third-generation TTR-targeting RNAi therapeutic called nucresiran, which is expected to elicit deeper and faster TTR knockdown and carries the potential for biannual dosing. Alnylam reported data from a Phase I trial of nucresiran in November 2024 showing “rapid knockdown of TTR that is sustained at six months following a single dose.” A Phase III study of the candidate is expected to begin in the first half of this year, Tanguler said. Tanguler stressed the importance of continued progress in this space, noting that ATTR-CM rates have increased approximately tenfold since 2019. Despite this, approximately 80% of patients remain undiagnosed globally, he said. “This is a large and growing category with significant unmet need.”

iStock/ magicmine The approval of Alnylam’s Amvuttra sets up a three-way race with Pfizer and BridgeBio, which both market transthyretin stabilizers for transthyretin amyloid cardiomyopathy. There’s a new player on the transthyretin amyloid cardiomyopathy (ATTR-CM) block. Four months after greenlighting BridgeBio’s Attruby for the rare cardiovascular disease, the FDA approved Alnylam’s Amvuttra Thursday as the first RNAi silencer for ATTR-CM. Amvuttra’s approval ignites a three-way race with Attruby and Pfizer’s tafamidis, which won the FDA’s first approval for ATTR-CM in May 2019. Both Attruby and tafamidis are transthyretin stabilizers, while Amvuttra works by knocking down both the wildtype and mutant forms of the transthyretin RNA, in turn lowering the expression of the TTR protein. Alnylam is hoping this novel mechanism of action will set it apart from its competitors. “The FDA approval of AMVUTTRA for ATTR-CM marks a pivotal advancement for patients, providing a new and clinically differentiated treatment option that has been shown to improve outcomes, including cardiovascular mortality, and reduce progression for those living with this devastating disease,” Alnylam CEO Yvonne Greenstreet said in a statement following the approval. This is the second approval for Amvuttra, which was approved by the FDA to treat polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in June 2022. Original article published March 17 Alnylam’s Amvuttra Expected to Make Three in Crowded ATTR-CM Space A decade ago, transthyretin amyloid cardiomyopathy was basically a death sentence, Neil Kumar, CEO of BridgeBio, told BioSpace last year. Today, the outlook is much brighter. With effective medicines from Pfizer and BridgeBio on the market, survival rates have dramatically improved. Now, Alnylam’s vutrisiran is on the cusp of joining them. On March 23, the FDA is widely expected to approve vutrisiran—which Alnylam markets as Amvuttra for polyneuropathy of hereditary ATTR (ATTR-PN)—for the cardiovascular manifestation of the disease. The key question for analysts—and likely Alnylam itself—is, how much of the transthyretin amyloid cardiomyopathy (ATTR-CM) market—which is projected to reach $11.2 billion by 2030—will Amvuttra be able to claim? In ATTR-CM, the liver produces faulty transthyretin (TTR) proteins. Clumps of these misshapen proteins then build up in the heart’s main pumping chamber, leading to cardiomyopathy that makes it more difficult for the heart to pump blood to the body. Pfizer’s tafamidis —marketed as Vyndaqel and Vyndamax—came first in this space, winning the FDA’s first approval for transthyretin amyloid cardiomyopathy (ATTR-CM) in May 2019. BridgeBio followed a little more than five years later with Attruby, which got the nod in November 2024. Alnylam believes Amvuttra’s mechanism of action will set it apart from the competition. While tafamidis and Attruby are both transthyretin stabilizers, Alnylam’s drug is an RNAi silencer that works by knocking down both the wildtype and mutant forms of the transthyretin RNA, in turn lowering the expression of the TTR protein. Amvuttra “works upstream of currently available therapies and, thanks to our unique technology, delivers rapid knockdown of the disease causing TTR protein, addressing the disease at its source,” Tolga Tanguler, chief commercial officer at Alnylam, told BioSpace in an email. If approved for ATTR-CM, “Amvuttra will be the first RNAi therapeutic for this indication and the only therapeutic to address both hATTR-PN and ATTR-CM.” “We believe that the anticipated approval of Amvuttra will add another important, clinically differentiated treatment option for patients with ATTR-CM, a rare, progressive, and deadly condition,” Tanguler continued. More Competitive Variables The ATTR-CM space is rapidly expanding. And while BridgeBio’s launch of Attruby has “exceeded [investor] expectations,” the market expectation is that “peak sales of Amvuttra will be higher than [Attruby],” Kostas Biliouris, director of biotech equity research, BMO Capital Markets, told BioSpace. Since its November 2024 approval, more than 1,000 unique prescriptions have been written for Attruby. Biliouris emphasized two key variables that could affect competition between Attruby and Amvuttra: administration and price. Amvuttra is administered in “only four convenient, subcutaneous doses per year,” Tanguler said, while Attruby is taken orally twice a day . Alnylam has not yet announced a price tag for Amvuttra in the new indication, but in ATTR-PN the drug is “almost double” the price of Attruby and tafamidis, Biliouris said. “Alnylam may or may not decide to change the price, to lower it, when they get the approval in March, but this is a very important point to consider,” he continued. Out- of -pocket costs could play a role in patient and prescriber decisions as well, Biliouris said. Because Amvuttra will be administered in a doctor’s office and is therefore part of Medicare Part B, most patients will not pay anything out of pocket, while both tafamidis and Attruby are Part D, carrying an up to $2,000 out of pocket cost per year for patients, he explained. While Alnylam declined to comment on the potential pricing of Amvuttra in ATTR-CM, Tanguler said, “We believe that our science can only impact human health if patients have access to their medicines. . . . As such, we will measure our success by broad patient access to Amvuttra.” Alnylam could also benefit from its experience and infrastructure in ATTR-PN, Biliouris said. In addition to Amvuttra, the company markets Onpattro for polyneuropathy caused by hereditary ATTR (hATTR). Together, the franchise brought in more than $1.2 billion in 2024, “and it’s been growing every year, which shows you they know how to do it,” Biliouris said. “They have done it before successfully.” Alnylam is aiming for Amvuttra to be a first-line treatment choice for ATTR-CM, according to Tanguler. The data from the company’s Phase III HELIOS-B study —in which Amvuttra led to a 36% risk reduction in all-cause mortality—positions the drug for this role, he said. The Label While Biliouris believes Amvuttra will be approved in ATTR-CM, one factor he is watching closely is the drug’s label. Currently, the labels for tafamidis and Attruby are “pretty similar,” he said, listing improvement in cardiovascular mortality and hospitalization. Amvuttra, however, has a chance to secure the much-coveted all-cause mortality benefit, according to Biliouris. While Attruby missed this secondary endpoint in the Phase III ATTRibute-CM trial, Amvuttra was successful in this metric in HELIOS-B, leading to a lower risk of death from any cause and recurrent cardiovascular events compared to placebo. However, Biliouris said, “this can be just incremental, and it may not have a big impact on physicians and the uptake.” The second item Biliouris is watching for on the label is the possibility of a combination benefit with tafamidis. In HELIOS-B , “[Alnylam] saw that there is a benefit from the combination of the two drugs . . . but the improvement was not statistically significant,” he noted. Importantly, the trial was not designed to measure statistical significance on this metric. BMO’s “bull case” is that the label will include an all-cause mortality benefit as opposed to only cardiovascular mortality and a possible mention of a combination benefit between Amvuttra and a transthyretin stabilizer, Biliouris said. On Deck in ATTR-CM While Alnylam is in the spotlight this week, there are more therapies waiting in the wings for ATTR-CM, including another RNA silencer being developed by AstraZeneca and Ionis. Wainua, which is approved to treat hATTR amyloidosis, is currently being studied in the Phase III CARDIO-TTRansform study for ATTR-CM, which is expected to be completed in April 2026. Meanwhile, gene editing leader Intellia is working on what it calls a “one and done” treatment for ATTR-CM. The biotech presented Phase I data from nexiguran ziclumeran (nex-z), a gene editor, in November at the American Heart Association’s 2024 Scientific Sessions, showing “rapid, deep and durable” reductions in serum levels of TTR, according to a press release. In patients with ATTR-CM, the mean TTR reduction was 90% at 12 months. Nex-z could have the advantage of reducing treatment burden, an Intellia spokesperson told BioSpace in an email. “Many patients experience anxiety from going to infusion centers frequently, spending time away from their families and work [to receive] repeated injections. A one-time option would eliminate that burden.” The investigational treatment could also ultimately be more effective, the spokesperson continued. “Dosing every few months produces a cyclic rise and fall of TTR levels over time, with peaks and troughs. Our data show that a one-time dose can reduce TTR to very low levels and keep it there, maintaining treatment benefit at its maximum.” Intellia is currently enrolling the Phase III MAGNITUDE trial and is “ahead of [its] internal target projections,” according to the spokesperson. The company expects the trial to be fully enrolled by early 2027. For its part, Alnylam isn’t stopping with Amvuttra. The company is developing a third-generation TTR-targeting RNAi therapeutic called nucresiran, which is expected to elicit deeper and faster TTR knockdown and carries the potential for biannual dosing. Alnylam reported data from a Phase I trial of nucresiran in November 2024 showing “rapid knockdown of TTR that is sustained at six months following a single dose.” A Phase III study of the candidate is expected to begin in the first half of this year, Tanguler said. Tanguler stressed the importance of continued progress in this space, noting that ATTR-CM rates have increased approximately tenfold since 2019. Despite this, approximately 80% of patients remain undiagnosed globally, he said. “This is a large and growing category with significant unmet need.”