There’s a brand new participant on the transthyretin amyloid cardiomyopathy (ATTR-CM) block. 4 months after greenlighting BridgeBio’s Attruby for the uncommon heart problems, the FDA approved Alnylam’s Amvuttra Thursday as the primary 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 Might 2019. Each Attruby and tafamidis are transthyretin stabilizers, whereas Amvuttra works by flattening each the wildtype and mutant types of the transthyretin RNA, in flip reducing the expression of the TTR protein. Alnylam is hoping this novel mechanism of motion will set it aside from its rivals.
“The FDA approval of AMVUTTRA for ATTR-CM marks a pivotal development for sufferers, offering a brand new and clinically differentiated therapy possibility that has been proven to enhance outcomes, together with cardiovascular mortality, and scale back development for these residing with this devastating illness,” Alnylam CEO Yvonne Greenstreet mentioned in an announcement following the approval.
That is the second approval for Amvuttra, which was approved by the FDA to deal with polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in June 2022.
Authentic article printed March 17
Alnylam’s Amvuttra Anticipated to Make Three in Crowded ATTR-CM House
A decade in the past, transthyretin amyloid cardiomyopathy was mainly a demise sentence, Neil Kumar, CEO of BridgeBio, told BioSpace final 12 months. Immediately, the outlook is far brighter. With efficient medicines from Pfizer and BridgeBio available on the market, survival charges have dramatically improved. Now, Alnylam’s vutrisiran is on the cusp of becoming a member of them.
On March 23, the FDA is broadly anticipated to approve vutrisiran—which Alnylam markets as Amvuttra for polyneuropathy of hereditary ATTR (ATTR-PN)—for the cardiovascular manifestation of the illness. The important thing query for analysts—and sure Alnylam itself—is, how a lot of the transthyretin amyloid cardiomyopathy (ATTR-CM) market—which is projected to succeed in $11.2 billion by 2030—will Amvuttra be capable of declare?
In ATTR-CM, the liver produces defective transthyretin (TTR) proteins. Clumps of those misshapen proteins then construct up within the coronary heart’s principal pumping chamber, resulting in cardiomyopathy that makes it tougher for the guts to pump blood to the physique.
Pfizer’s tafamidis—marketed as Vyndaqel and Vyndamax—got here first on this house, profitable the FDA’s first approval for transthyretin amyloid cardiomyopathy (ATTR-CM) in Might 2019. BridgeBio adopted just a little greater than 5 years later with Attruby, which got the nod in November 2024.
Alnylam believes Amvuttra’s mechanism of motion will set it aside from the competitors. Whereas tafamidis and Attruby are each transthyretin stabilizers, Alnylam’s drug is an RNAi silencer that works by flattening each the wildtype and mutant types of the transthyretin RNA, in flip reducing the expression of the TTR protein.
Amvuttra “works upstream of presently accessible therapies and, because of our distinctive expertise, delivers fast knockdown of the illness inflicting TTR protein, addressing the illness at its supply,” Tolga Tanguler, chief industrial officer at Alnylam, advised BioSpace in an electronic mail. If permitted for ATTR-CM, “Amvuttra would be the first RNAi therapeutic for this indication and the one therapeutic to deal with each hATTR-PN and ATTR-CM.”
“We imagine that the anticipated approval of Amvuttra will add one other necessary, clinically differentiated therapy possibility for sufferers with ATTR-CM, a uncommon, progressive, and lethal situation,” Tanguler continued.
Extra Aggressive Variables
The ATTR-CM house is quickly increasing. And whereas BridgeBio’s launch of Attruby has “exceeded [investor] expectations,” the market expectation is that “peak gross sales of Amvuttra will likely be greater than [Attruby],” Kostas Biliouris, director of biotech fairness analysis, BMO Capital Markets, advised BioSpace. Since its November 2024 approval, greater than 1,000 unique prescriptions have been written for Attruby.
Biliouris emphasised two key variables that would have an effect on competitors between Attruby and Amvuttra: administration and value. Amvuttra is run in “solely 4 handy, subcutaneous doses per 12 months,” Tanguler mentioned, whereas Attruby is taken orally twice a day.
Alnylam has not but introduced a price ticket for Amvuttra within the new indication, however in ATTR-PN the drug is “virtually double” the worth of Attruby and tafamidis, Biliouris mentioned.
“Alnylam might or might not determine to vary the worth, to decrease it, after they get the approval in March, however it is a crucial level to think about,” he continued. Out- of -pocket prices may play a job in affected person and prescriber selections as effectively, Biliouris mentioned. As a result of Amvuttra will likely be administered in a physician’s workplace and is due to this fact a part of Medicare Half B, most sufferers won’t pay something out of pocket, whereas each tafamidis and Attruby are Half D, carrying an as much as $2,000 out of pocket price per 12 months for sufferers, he defined.
Whereas Alnylam declined to touch upon the potential pricing of Amvuttra in ATTR-CM, Tanguler mentioned, “We imagine that our science can solely influence human well being if sufferers have entry to their medicines. . . . As such, we’ll measure our success by broad affected person entry to Amvuttra.”
Alnylam may additionally profit from its expertise and infrastructure in ATTR-PN, Biliouris mentioned. Along with Amvuttra, the corporate markets Onpattro for polyneuropathy attributable to hereditary ATTR (hATTR). Collectively, the franchise introduced in more than $1.2 billion in 2024, “and it’s been rising yearly, which reveals you they know do it,” Biliouris mentioned. “They’ve achieved it earlier than efficiently.”
Alnylam is aiming for Amvuttra to be a first-line therapy alternative for ATTR-CM, in line with Tanguler. The information from the corporate’s Part III HELIOS-B study—wherein Amvuttra led to a 36% threat discount in all-cause mortality—positions the drug for this position, he mentioned.
The Label
Whereas Biliouris believes Amvuttra will likely be permitted in ATTR-CM, one issue he’s watching intently is the drug’s label. Presently, the labels for tafamidis and Attruby are “fairly related,” he mentioned, itemizing enchancment in cardiovascular mortality and hospitalization. Amvuttra, nevertheless, has an opportunity to safe the much-coveted all-cause mortality profit, in line with Biliouris.
Whereas Attruby missed this secondary endpoint within the Part III ATTRibute-CM trial, Amvuttra was profitable on this metric in HELIOS-B, resulting in a decrease threat of demise from any trigger and recurrent cardiovascular occasions in comparison with placebo. Nonetheless, Biliouris mentioned, “this may be simply incremental, and it might not have a huge impact on physicians and the uptake.”
The second merchandise Biliouris is looking forward to on the label is the potential of a mixture profit with tafamidis. In HELIOS-B, “[Alnylam] noticed that there’s a profit from the mix of the 2 medicine . . . however the enchancment was not statistically important,” he famous. Importantly, the trial was not designed to measure statistical significance on this metric.
BMO’s “bull case” is that the label will embody an all-cause mortality profit versus solely cardiovascular mortality and a potential point out of a mixture profit between Amvuttra and a transthyretin stabilizer, Biliouris mentioned.
On Deck in ATTR-CM
Whereas Alnylam is within the highlight this week, there are extra therapies ready within the wings for ATTR-CM, together with one other RNA silencer being developed by AstraZeneca and Ionis. Wainua, which is permitted to deal with hATTR amyloidosis, is presently being studied within the Part III CARDIO-TTRansform study for ATTR-CM, which is predicted to be accomplished in April 2026.
In the meantime, gene modifying chief Intellia is engaged on what it calls a “one and achieved” therapy for ATTR-CM. The biotech presented Part I information from nexiguran ziclumeran (nex-z), a gene editor, in November on the American Coronary heart Affiliation’s 2024 Scientific Periods, exhibiting “fast, deep and sturdy” reductions in serum ranges of TTR, in line with a press launch. In sufferers with ATTR-CM, the imply TTR discount was 90% at 12 months.
Nex-z may have the benefit of decreasing therapy burden, an Intellia spokesperson advised BioSpace in an electronic mail. “Many sufferers expertise nervousness from going to infusion facilities steadily, spending time away from their households and work [to receive] repeated injections. A one-time possibility would remove that burden.” The investigational therapy may additionally finally be more practical, the spokesperson continued. “Dosing each few months produces a cyclic rise and fall of TTR ranges over time, with peaks and troughs. Our information present {that a} one-time dose can scale back TTR to very low ranges and maintain it there, sustaining therapy profit at its most.”
Intellia is presently enrolling the Part III MAGNITUDE trial and is “forward of [its] inside goal projections,” in line with the spokesperson. The corporate expects the trial to be absolutely enrolled by early 2027.
For its half, Alnylam isn’t stopping with Amvuttra. The corporate is creating a third-generation TTR-targeting RNAi therapeutic referred to as nucresiran, which is expected to elicit deeper and sooner TTR knockdown and carries the potential for biannual dosing. Alnylam reported information from a Part I trial of nucresiran in November 2024 exhibiting “fast knockdown of TTR that’s sustained at six months following a single dose.” A Part III examine of the candidate is predicted to start within the first half of this 12 months, Tanguler mentioned.
Tanguler burdened the significance of continued progress on this house, noting that ATTR-CM charges have elevated roughly tenfold since 2019. Regardless of this, roughly 80% of sufferers stay undiagnosed globally, he mentioned. “This can be a giant and rising class with important unmet want.”
