--- title: "Nucresiran (ALN-TTRsc04): Alnylam's Next-Generation TTR Silencer Aims for Once- or Twice-Yearly Treatment of ATTR Amyloidosis (September 5, 2026) | PepTracker Pro Blog" url: https://peptrackerpro.com/blog/nucresiran-aln-ttrsc04-alnylam-next-generation-ttr-silencer-rnai-ikaria-platform-attr-amyloidosis-once-yearly-twice-yearly-dosing-triton-pn-triton-cm-vutrisiran-amvuttra-eplontersen-cardiomyopathy-polyneuropathy-september-5-2026 description: "Nucresiran (formerly ALN-TTRsc04) is Alnylam's next-generation RNAi therapeutic for transthyretin amyloidosis (ATTR). Built on the IKARIA platform, it cut serum TTR by more than 90% - and kept it down for up to a year - from a single subcutaneous dose in Phase 1, raising the prospect of an ATTR treatment given only once or twice a year. Two Phase 3 trials, TRITON-PN and TRITON-CM, are now underway." lang: en --- Skip to main content **Educational information only.** This site does not provide medical advice. Read full disclaimer (https://peptrackerpro.com/disclaimer) Research & Compounds Research & Compounds # Nucresiran (ALN-TTRsc04): Alnylam's Next-Generation TTR Silencer Aims for Once- or Twice-Yearly Treatment of ATTR Amyloidosis (September 5, 2026) PepTracker Pro Research Team September 5, 2026 9 min read ## Table of Contents - A TTR silencer built for once- or twice-a-year dosing - What ATTR amyloidosis is, and why lowering TTR matters - How nucresiran works: RNAi plus the IKARIA platform - The Phase 1 data: more than 90% knockdown, sustained for months - Safety so far: clean, but early - TRITON-PN: going head-to-head with vutrisiran in polyneuropathy - TRITON-CM: a cardiovascular outcomes trial in ATTR cardiomyopathy - Where nucresiran fits in a crowded ATTR field - Important caveats - The bottom line ## A TTR silencer built for once- or twice-a-year dosing Alnylam helped invent an entire class of medicines by turning RNA interference (RNAi) into approved drugs, and nowhere has that paid off more than in transthyretin amyloidosis (ATTR). Its infused drug patisiran and its quarterly injection vutrisiran (Amvuttra), along with Ionis and AstraZeneca's antisense drug eplontersen (Wainua/Wainzua), all work by lowering the amount of transthyretin (TTR) protein the body makes. Nucresiran - formerly known by the code ALN-TTRsc04 - is Alnylam's attempt to do that job better and far less often. In early testing, a single subcutaneous shot lowered serum TTR by more than 90% and kept it suppressed for six months to a year, opening the door to a treatment given as seldom as once or twice a year. ## What ATTR amyloidosis is, and why lowering TTR matters ATTR is a progressive, ultimately fatal disease in which misfolded TTR protein builds up as amyloid deposits in the nerves, heart and gut. It comes in two forms: hereditary ATTR (hATTR), caused by TTR gene variants and affecting roughly 50,000 people worldwide, and wild-type ATTR (wtATTR), which occurs without a gene variant and is estimated to affect 200,000-300,000 people - most of them older adults with heart disease that is increasingly recognized as a common, under-diagnosed cause of heart failure. Patients can develop polyneuropathy (nerve damage), cardiomyopathy (heart-muscle disease), or both. Because nearly all circulating TTR is made in the liver, silencing the TTR gene there cuts the supply of the very protein that forms the amyloid, addressing the disease at its source rather than just stabilizing the protein after it is made. ## How nucresiran works: RNAi plus the IKARIA platform Nucresiran is a small interfering RNA (siRNA) conjugated to a sugar molecule (GalNAc) that directs it to liver cells after a simple under-the-skin injection. Once inside, it harnesses the cell's natural RNAi machinery to destroy TTR messenger RNA, so the cell makes far less TTR - both the mutant and the normal (wild-type) forms. What is new is the chemistry: nucresiran is built on Alnylam's next-generation IKARIA platform, engineered for deeper and much longer-lasting silencing than earlier TTR drugs. That durability is the whole point - it is what could turn a quarterly or monthly treatment into a once- or twice-yearly one. ## The Phase 1 data: more than 90% knockdown, sustained for months In an ongoing randomized, double-blind, placebo-controlled Phase 1 study, 48 healthy volunteers received a single subcutaneous dose of nucresiran (5, 25, 100, 300, 600 or 900 mg) or placebo. At doses of 300 mg and above, mean serum TTR dropped by more than 90% by Day 15 and peaked at more than 96% reduction by Day 29. The effect was strikingly durable: TTR was still down by roughly 92-96% at six months, and for the 300 mg group it remained more than 70% below baseline (about 71%) a full year after that single dose. Just as notable, the response was highly consistent from person to person - roughly 96-98% knockdown across individuals at Day 29 in the higher-dose cohorts - which matters for a drug meant to be given infrequently. ## Safety so far: clean, but early In the Phase 1 study, nucresiran was well tolerated at every dose tested. Most adverse events were mild, none were judged to be treatment-related, and there were no injection-site reactions and no liver-related safety signals. Those are encouraging findings, but they come from single doses in healthy adults. As with all TTR-lowering therapies, longer-term monitoring will matter - including vitamin A levels, because TTR is the carrier that ferries retinol (vitamin A) through the blood - and the safety of repeated dosing over years has not yet been established. ## TRITON-PN: going head-to-head with vutrisiran in polyneuropathy Alnylam has moved nucresiran into a Phase 3 program called TRITON. The first pivotal study, TRITON-PN (NCT07223203), is a global, randomized, open-label trial of about 125 patients with hereditary ATTR with polyneuropathy. In an unusual and telling design, it uses Alnylam's own approved drug vutrisiran as the active comparator: the study is built to show that nucresiran is superior to vutrisiran at lowering serum TTR, while also tracking neurologic impairment, quality of life, disability, nutritional status and gait speed. The goal is to reach patients as quickly as possible, with Alnylam targeting a potential launch around 2028. ## TRITON-CM: a cardiovascular outcomes trial in ATTR cardiomyopathy The second pivotal study, TRITON-CM (NCT07052903), is much larger and aimed at the biggest ATTR population: the heart. It is an event-driven cardiovascular outcomes trial enrolling roughly 1,200 patients with ATTR cardiomyopathy - wild-type or any TTR variant, including those already taking a stabilizer drug - and it doses nucresiran at 300 mg subcutaneously once every six months. Because it is designed to measure hard clinical outcomes rather than just a biomarker, it is a longer, more definitive study; if successful, it could support approval around 2030. ## Where nucresiran fits in a crowded ATTR field ATTR has quickly become one of the most competitive areas in medicine. Nucresiran would compete not only with TTR silencers vutrisiran, patisiran and eplontersen, but also with oral stabilizer pills such as tafamidis (Vyndaqel/Vyndamax) and acoramidis (Attruby) that hold TTR together rather than reducing it, and with a one-time gene-editing approach, NTLA-2001 (nexiguran ziclumeran), that aims to knock out TTR production for good. Nucresiran's pitch in that crowd is convenience plus depth: near-complete TTR knockdown from an injection given only once or twice a year. Its role also protects Alnylam's flagship Amvuttra franchise as competition intensifies. ## Important caveats The excitement around nucresiran rests, for now, on a small Phase 1 study in healthy volunteers that measured a biomarker - serum TTR - not clinical outcomes in patients. Deep TTR knockdown is strongly expected to translate into clinical benefit based on the track record of vutrisiran and patisiran, but that has to be proven for nucresiran in the ongoing TRITON-PN and TRITON-CM trials, which have not yet reported results. The durability and safety of dosing every six to twelve months over many years are unproven, and cross-trial comparisons with other ATTR drugs are not head-to-head. Nucresiran is investigational and not approved by the FDA, EMA or any regulator; it is not a supplement or research chemical, and any product sold under its name outside a clinical trial is unverified. ## The bottom line Nucresiran represents the next step in RNAi for ATTR amyloidosis: the same validated strategy of silencing the TTR gene, but engineered for such deep and durable effect that treatment could shrink to one or two injections a year. Early Phase 1 data delivered more than 90% TTR knockdown lasting up to a year from a single dose, with a clean safety profile, and Alnylam has committed to two Phase 3 trials - a fast vutrisiran-controlled study in polyneuropathy and a large cardiovascular outcomes study in cardiomyopathy. If those trials confirm that low-frequency dosing preserves the clinical benefit already shown by earlier TTR silencers, nucresiran could meaningfully change how often ATTR patients need treatment. As always, the definitive answers will come from the pivotal trials, not the biomarker data that opened the door. Ready to track your peptide research? Open PepTracker Pro (https://app.peptrackerpro.com/) PepTracker Pro Research Team The PepTracker Pro Research Team is an editorial group of science writers, pharmacologists, and clinical researchers dedicated to making peptide science accessible. Every article is reviewed for accuracy against peer-reviewed sources and updated as new evidence emerges. ## Citations 1. [1] Alnylam Announces Interim Phase 1 Data of Nucresiran (ALN-TTRsc04) Showing Rapid Knockdown of TTR that is Sustained at Six Months Following a Single Dose - Alnylam (November 17, 2024) Source (https://investors.alnylam.com/press-release?id=28541) 2. [2] Alnylam Announces Interim Phase 1 Data of Nucresiran (ALN-TTRsc04) - BioSpace (November 2024) Source (https://www.biospace.com/press-releases/alnylam-announces-interim-phase-1-data-of-nucresiran-aln-ttrsc04-showing-rapid-knockdown-of-ttr-that-is-sustained-at-six-months-following-a-single-dose) 3. [3] TRITON-PN Phase 3 Study Design and Rationale Presented at the 2026 American Academy of Neurology (AAN) Meeting - Alnylam Capella Source (https://capella.alnylam.com/2026/04/20/aan-2026) 4. [4] TRITON-PN (NCT07223203) - ClinicalTrials.gov Source (https://clinicaltrials.gov/study/NCT07223203) 5. [5] TRITON-CM (NCT07052903) - ClinicalTrials.gov Source (https://clinicaltrials.gov/study/NCT07052903) 6. [6] Alnylam R&D Day: pipeline progress and platform innovation (nucresiran twice-annual dosing) Source (https://investors.alnylam.com/press-release?id=28716) **Disclaimer:** This article is for educational purposes only and does not constitute medical advice. Always consult a licensed healthcare provider. 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