By admin 
However, Alnylam Pharmaceuticals is now aggressively pushing back against this narrative. In a series of briefings and communications, the Cambridge-based biotech is making a forceful case that the failure of eplontersen is a reflection of specific trial design choices and the inherent properties of that specific molecule, rather than a systemic failure of RNA interference (RNAi) or antisense oligonucleotide (ASO) technology. Alnylam’s leadership argues that their own recent success with Amvuttra (vutrisiran) in the HELIOS-B trial provides the definitive proof-of-concept that silencers not only work but are essential for the long-term management of ATTR-CM, even in patients already receiving Pfizer’s stabilizer therapy.
To understand the stakes of this debate, one must first look at the underlying pathology of ATTR-CM. The disease is characterized by the buildup of misfolded transthyretin (TTR) proteins, which form amyloid fibrils that deposit in the heart muscle. Over time, these deposits cause the heart to become stiff and thick, leading to progressive heart failure and, eventually, death. For years, the gold standard of care has been Pfizer’s tafamidis, a small molecule that binds to the TTR protein and "stabilizes" it, preventing it from breaking apart and forming those dangerous fibrils. While tafamidis has been a life-saving breakthrough, it does not stop the liver from producing the TTR protein in the first place.
This is where the "silencers" come in. Drugs like Alnylam’s Amvuttra and AstraZeneca’s Wainua use different genetic technologies—RNAi and ASO, respectively—to intercept the genetic instructions for TTR production. By "silencing" the gene, these drugs drastically reduce the amount of TTR protein circulating in the blood, often by 80% or more. The central question for the medical and investment communities has been whether adding a silencer to a stabilizer provides enough additional benefit to justify the high cost and potential complexity of dual therapy.
The failure of AstraZeneca’s CARDIO-TTRansform trial appeared to provide a pessimistic answer. The study was massive, involving over 1,400 patients, and was designed to show that eplontersen could reduce a composite of cardiovascular mortality and recurrent cardiovascular events. When the trial missed the mark, the immediate takeaway for some was that stabilizers like tafamidis are "good enough," and that silencers might be redundant.
Alnylam, however, views the situation through a different lens. They point to the HELIOS-B trial of Amvuttra as the true benchmark. In that study, Amvuttra achieved a highly significant 28% reduction in the risk of the primary composite endpoint in the overall population and a 33% reduction in patients who were not taking tafamidis at baseline. Crucially, even in the "add-on" group—patients who were already taking tafamidis—vutrisiran showed a consistent trend toward benefit.
"The results of HELIOS-B were unambiguous," Alnylam executives have noted in recent discussions. They argue that the difference between their success and AstraZeneca’s failure lies in three key areas: the potency and consistency of the drug, the duration of the trial, and the specific statistical handling of the "background" use of tafamidis.
First, there is the matter of the drugs themselves. While both are silencers, they utilize different platforms. Amvuttra is an RNAi therapeutic, while Wainua is an antisense oligonucleotide. Alnylam has long maintained that its RNAi platform offers more consistent and durable knockdown of the target protein. If a silencer allows too much "leakage"—meaning the TTR protein levels fluctuate or remain high enough to continue forming fibrils—the clinical benefit may be lost over a multi-year trial.
Second, the design of the CARDIO-TTRansform trial may have been its undoing. AstraZeneca’s trial was one of the largest ever conducted in ATTR-CM, but size does not always equate to success. Alnylam has suggested that the patient population in the AstraZeneca trial might have been "too healthy" or too well-managed on background therapies at the start, making it difficult to show a statistically significant improvement over the placebo group (which was also receiving standard care, including tafamidis in many cases). In contrast, the HELIOS-B trial was meticulously calibrated to ensure it captured a population where the disease was likely to progress, allowing the drug’s effect to become visible.
Furthermore, the duration of follow-up is critical in amyloidosis. Because the amyloid fibrils clear very slowly from the heart, it takes time for the reduction in protein production to translate into improved cardiac function and lower mortality. Alnylam argues that their trial design allowed for a sufficient window of observation to see the "separation of the curves" between the treated and placebo groups.
The implications of this biotech defense extend far beyond the current competition. Alnylam is currently preparing for a potential supplemental New Drug Application (sNDA) for Amvuttra in ATTR-CM, aiming for a 2025 launch in that indication. If the market perceives silencers as secondary to stabilizers, Alnylam’s commercial potential could be capped. By framing the AstraZeneca failure as a "trial design failure" rather than a "class failure," Alnylam is protecting the multi-billion dollar valuation of its RNAi franchise.
Moreover, Alnylam is already looking toward the next generation of treatment. The company is developing nucresiran (formerly known as ALN-TTRsc04), a next-generation RNAi therapeutic designed for even greater potency and infrequent dosing—potentially once or twice a year. Alnylam’s argument is that as the field moves toward earlier diagnosis, the goal will be to shut down protein production as early as possible to prevent any amyloid from ever forming. In this vision of the future, silencers are not "add-ons"; they are the foundational therapy, and stabilizers might eventually become the secondary option.
Industry analysts remain divided. Some, like those at Goldman Sachs and B. Riley, have noted that the AstraZeneca miss creates a clearer runway for Alnylam, essentially removing a major competitor from the "silencer" space for several years. Others caution that the failure of a major pharmaceutical player like AstraZeneca to prove the benefit of a silencer in a large trial could make payers—the insurance companies and national health systems—more skeptical of covering these expensive treatments when tafamidis is available.
The debate also touches on the shifting demographics of ATTR-CM patients. As awareness of the disease grows, more patients are being diagnosed earlier. These patients often have fewer symptoms and better outcomes, which is good for the patients but challenging for clinical trials that rely on "events" (like hospitalizations or deaths) to prove a drug works. Alnylam’s defense hinges on the idea that they have mastered the nuances of this evolving patient landscape better than their rivals.
Beyond the clinical data, there is a strategic element to Alnylam’s stance. The company has spent decades and billions of dollars proving the viability of RNAi. To have the value of that technology questioned because of a competitor’s failed trial is a challenge they are not willing to let stand. They are positioning Amvuttra not just as a drug, but as a superior technological solution to a complex biological problem.
As the medical community awaits the full data presentation from AstraZeneca’s failed trial, which is expected at an upcoming medical congress, Alnylam’s "defense of the silencers" will continue. The company is betting that when physicians look at the totality of the evidence—the success of HELIOS-B versus the failure of CARDIO-TTRansform—they will conclude that the choice of molecule and the rigor of the trial design are what truly matter.
In the high-stakes world of cardiovascular medicine, where the difference between a blockbuster and a failure can rest on a few percentage points of hazard ratio, Alnylam is doubling down on its expertise. They are arguing that their medicines maintain their value because they were built on a deeper understanding of the disease’s biology and a more precise clinical execution. Whether the FDA and the broader medical community agree will determine the future of ATTR-CM treatment for the next decade. For now, Alnylam remains confident that the silencer class is not only alive but poised to become the dominant force in treating this devastating heart condition.
