Treating ATTR-CM With Urgency: How Strength in TTR Silencing Is Helping Change the Course of Patient Care

Picture a patient in your practice who is in their late 60s and begins experiencing increasing fatigue, shortness of breath, and difficulty keeping up with the everyday activities they once handled with ease. For years, a patient may move from appointment to appointment searching for answers, and may be treated for heart failure, atrial fibrillation or simply told they are “getting older.”¹ Their physicians believe that to be true. However, this patient may have transthyretin-mediated cardiac amyloidosis, or ATTR-CM. For many individuals living with ATTR-CM, the journey to understanding what is happening can be long, frustrating and emotionally exhausting, not only for themselves, but also for their families, caregivers, and healthcare professionals (HCPs) who are watching their overall health and well-being decline over time.

These experiences reflect the broader challenges surrounding ATTR-CM today. Despite advances in diagnostic tools, the disease remains widely underrecognized due to symptom overlap with other conditions and variability in how patients present clinically. Patients may experience up to six years of symptoms before receiving an accurate diagnosis, during which disease progression continues.¹

Dr. Brett Sperry, a cardiologist at Saint Luke’s Mid America Heart Institute, says that it is critical for all members of a patient’s healthcare team to be educated on ATTR-CM to improve the patient’s diagnostic journey:

“The diagnosis doesn't begin in my office. It begins with the sonographer reading the echocardiogram or the general cardiologist flagging a patient with seemingly unrelated symptoms. All it takes is one diagnosis from a referring physician, and you've opened their mind to consider this diagnosis in future patients.”

Earlier recognition of ATTR-CM can make a difference

At its core, transthyretin-mediated amyloidosis (ATTR) is a multisystem disease caused by the misfolding of transthyretin (TTR), which aggregates into amyloid fibrils that deposit throughout the body.² With ATTR-CM, time matters. If left untreated, the life expectancy for patients is two to six years from diagnosis, underscoring the importance of identifying and treating patients as early as possible.¹

ATTR-CM is often misdiagnosed because many of its cardiac and non-cardiac manifestations are attributed to more common conditions. While left ventricular wall thickening may raise suspicion, earlier-stage disease can present more subtly. Features such as heart failure with preserved ejection fraction (HFpEF), atrial fibrillation and carpal tunnel syndrome may provide important clues, particularly when they occur together.^1,3

"General cardiologists are often the first clinicians in a position to connect the dots," said Dr. Sperry. "If a patient presents with HFpEF and has a history of carpal tunnel syndrome or atrial fibrillation, those findings together should prompt you to consider ATTR-CM. It doesn't require specialized expertise. It starts with keeping ATTR-CM on your differential and recognizing that what may look like unrelated findings could actually be telling a larger, more urgent story. Sometimes, I'll get an echocardiogram that was read as normal, and I can identify subtle features suggestive of amyloid. Sharing these specific insights back with the referring clinicians provides a compounding educational benefit.”

Detecting ATTR-CM earlier also requires careful interpretation of diagnostic imaging, including not relying on planar images alone and taking a holistic view of the cardiac pyrophosphate (PYP) scan. Earlier-stage disease may present with subtle findings that can be overlooked if clinicians rely solely on routine assessments. Incorporating advanced echocardiographic techniques and taking a comprehensive approach to image interpretation can help improve recognition before significant disease progression occurs.³

Common red flags* associated with ATTR, a progressive disease caused by the misfolding of TTR, which can accumulate as amyloid deposits throughout the body:^3-5

• Cardiac
  • Unexplained left ventricular (LV) wall thickening
  • Heart failure with preserved ejection fraction (HFpEF)
  • Conduction system disease/atrial fibrillation
  • Aortic stenosis
  • Peripheral edema
  • Signs from an echocardiogram
    • Impaired global longitudinal strain
    • Diastolic dysfunction
• Neurologic
  • Altered sensation, numbness, tingling
  • Muscle weakness, difficulty walking
  • Autonomic dysfunction (e.g., gastrointestinal symptoms, orthostatic hypotension, recurrent urinary tract infections, sexual dysfunction)
• Musculoskeletal
  • Bilateral carpal tunnel syndrome
  • Lumbar spinal stenosis
  • Biceps tendon rupture

*Not a comprehensive list of all the symptoms associated with ATTR. Patients may not experience all symptoms. AMVUTTRA^® (vutrisiran) does not treat all of the symptoms of ATTR.

RNAi: Suppressing TTR Production at the Source

Beyond diagnosis alone, advancements must be made toward identifying opportunities for earlier intervention that may meaningfully alter patient outcomes.

Over the past several years, the treatment landscape for ATTR-CM has evolved significantly. Some therapeutic strategies have increasingly focused on reducing TTR, the underlying driver of amyloid formation and disease progression.⁶

This includes RNA interference (RNAi), a therapeutic approach based on a Nobel Prize–winning discovery, which enables the targeted reduction of TTR, the protein responsible for ATTR-CM.^7,8

“When discussing RNAi with other clinicians who may not be as familiar, I try to focus on how these therapies reduce production of TTR at its source in the liver and help address the protein responsible for amyloid formation to reduce additional accumulation of deposits,” said Dr. Sperry.

While symptom management remains essential, reducing TTR production at the source may offer an opportunity to address the underlying driver of disease progression. By targeting the production of TTR at the level of gene expression, RNAi therapies aim to reduce the upstream driver of disease, supporting a treatment strategy focused on slowing disease progression.^3,7

Alnylam has been at the forefront of this shift, aiming to change the course of disease progression through its RNAi therapeutics delivery platform.⁹ ATTR amyloidosis is estimated to affect more than 500,000 people worldwide.^10,11

AMVUTTRA is the only FDA-approved silencer indicated for both the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults and the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults.¹²

Important Safety Information for AMVUTTRA can be found throughout this article and on AmvuttraHCP.com. Select Important Safety Information: AMVUTTRA treatment leads to a decrease in serum vitamin A levels. Supplement with the recommended daily allowance of vitamin A. Refer to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occur.

Silencing TTR production at its source, the liver, represents an upstream intervention strategy designed to help address the underlying cause of disease with just four HCP-administered doses per year (25 mg every 3 months). Injection site reactions may occur. The HELIOS-B Phase 3 study evaluated AMVUTTRA for the treatment of ATTR-CM. Rapid serum TTR reduction occurred as early as Week 6, and a median reduction at Month 30 was approximately 87%.¹³ In both populations, the primary endpoint was met, with a significant reduction in the composite risk of all-cause mortality and recurrent cardiovascular events in participants who received AMVUTTRA versus placebo.¹²

In the overall population (N=654), AMVUTTRA demonstrated:¹²

• A 28% relative risk reduction in the primary composite endpoint of all-cause mortality and recurrent cardiovascular events during the double-blind treatment period of up to 36 months (HR: 0.72 [95% CI, 0.55-0.93]; p=0.01)
• A number needed to treat (NNT) of four to prevent one death or cardiovascular event during the double-blind treatment period¹¹
  • The majority of deaths were cardiovascular-related (77%)¹²

In the monotherapy population (patients not taking tafamidis at baseline [60%]; n=395), AMVUTTRA demonstrated:^11,12

• A 33% relative risk reduction in the primary composite endpoint of all-cause mortality and recurrent cardiovascular events during the double-blind treatment period (HR: 0.67 [95% CI: 0.49-0.93]; p=0.02)
• An NNT of three to prevent one death or cardiovascular event during the double-blind treatment period¹¹

Further assessments included patient-reported health status and quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), and functional capacity, as measured by the 6-minute walk test (6MWT). The safety and tolerability of AMVUTTRA were established in a study of adult patients with hATTR-PN (HELIOS-A). In that study, the most common adverse reactions were pain in extremity (15%), arthralgia (11%), dyspnea (7%), and vitamin A decreased (7%). No new safety issues were identified in HELIOS-B, evaluating ATTR-CM.¹²

Together, these findings of rapid TTR reduction, clinically meaningful outcomes, and an established safety profile, support AMVUTTRA as a first-line treatment option for patients with ATTR-CM.^12,13

As with any therapy, treatment selection should be based on individual patient factors, and clinicians should consider the full Prescribing Information, including safety considerations.

Looking ahead: Advancing earlier intervention in ATTR-CM

As awareness grows and diagnostic tools sharpen, cardiologists are better positioned to identify patients sooner, when treatment may have the greatest impact. Addressing ATTR-CM at the source with therapies like AMVUTTRA offers the potential to slow disease progression and create an opportunity for meaningful treatment intervention earlier on in a patient’s journey.

“My diagnosis didn’t just explain what I was experiencing. It helped me understand a story that had impacted my family for generations,” said Kelly, who lives with ATTR-CM and receives AMVUTTRA. “Too often, patients can feel like their symptoms are being considered separately rather than as part of a larger picture. Raising awareness of ATTR-CM is so important because earlier disease recognition starts with listening, having open conversations and ensuring patients feel heard throughout their diagnostic journey.”

As scientific understanding continues to evolve, cardiologists have an opportunity not only to rethink how ATTR-CM is managed, but also to play a critical role in recognizing the disease earlier, connecting symptoms that may otherwise appear unrelated and ensuring all patients are identified before significant disease progression.

“There are still areas of the country that don't have major centers with doctors focused on amyloidosis, and in those regions, many patients may not be receiving a timely diagnosis,” Dr. Sperry shared. “That's why I feel it is so important to spend time reaching out to cardiologists in other health systems, whether it's a call, a visit, or simply following up after a referral. The goal is to make sure ATTR-CM stays on their radar, so we continue to make progress toward earlier diagnosis and, ultimately, earlier intervention that can help slow disease progression.”

To learn more about AMVUTTRA as a treatment option for ATTR-CM, visit: https://www.amvuttraHCP.com/ 

Indications and Important Safety Information

Indications

AMVUTTRA^® (vutrisiran) is indicated for the treatment of:

• cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality, cardiovascular hospitalizations and urgent heart failure visits.
• polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults.

Important Safety Information

Reduced Serum Vitamin A Levels and Recommended Supplementation

AMVUTTRA treatment leads to a decrease in serum vitamin A levels.

Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking AMVUTTRA. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with AMVUTTRA, as serum vitamin A levels do not reflect the total vitamin A in the body.

Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness).

Adverse Reactions

In a study of patients with hATTR-PN, the most common adverse reactions that occurred in patients treated with AMVUTTRA were pain in extremity (15%), arthralgia (11%), dyspnea (7%), and vitamin A decreased (7%). In a study of patients with ATTR-CM, no new safety issues were identified.

For additional information about AMVUTTRA, please see the full U.S. Prescribing Information

References

1. Rozenbaum MH, Large S, Bhambri R, et al. Impact of delayed diagnosis and misdiagnosis for patients with transthyretin amyloid cardiomyopathy (ATTR-CM): a targeted literature review. Cardiol Ther. 2021;10(1):141-159. https://doi.org/10.1007/s40119-021-00219-5
2. Jain A, Zahra F. Transthyretin amyloid cardiomyopathy (ATTR-CM) [Updated 2023 Apr 27]. StatPearls. StatPearls Publishing; 2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK574531/.
3. Kittleson M, Ambardekar A, Cheng R. et al. Transthyretin cardiac amyloidosis evaluation and management: 2025 ACC concise clinical guidance. J Am Coll Cardiol. 2026;87(5):549-565.https://doi.org/10.1016/j.jacc.2025.09.004
4. Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012;126(10):1286-1300. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.078915
5. Conceição I, Gonzalez-Duarte A, Obici L. et al. Red-flag symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2016;21(1):5-9. https://doi.org/10.1111/jns.12153
6. Fontana M, Berk, JL, Drachman B, et al. Changing treatment landscape in transthyretin cardiac amyloidosis. Circ Heart Fail. 2025;18(8):e012112. https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.124.012112
7. Grogan M, Sheikh FH, Sperry BW, et al. Realizing the therapeutic potential of rapid knockdown of transthyretin via RNA interference in transthyretin amyloidosis. Mol Ther Nucleic Acids. 2025;36(3):102590. https://doi.org/10.1016/j.omtn.2025.102590
8. The Nobel Prize in Physiology or Medicine 2006. (n.d.). NobelPrize.org. https://www.nobelprize.org/prizes/medicine/2006/popular-information/
9. Jadhav V, Vaishnaw A, Fitzgerald K, Maier MA. RNA interference in the era of nucleic acid therapeutics. Nat Biotechnol. 2024;42(3):394-405. https://doi.org/10.1038/s41587-023-02105-y
10. Delgado D, Dabbous F, Shivappa N, et al. Epidemiology of transthyretin (ATTR) amyloidosis: a systematic literature review. Orphanet J Rare Dis. 2025;20(1):29. https://doi.org/10.1186/s13023-025-03547-0
11. Data on file. Alnylam Pharmaceuticals, Inc.
12. AMVUTTRA (vutrisiran) Prescribing Information. Cambridge, MA: Alnylam Pharmaceuticals, Inc.
13. Fontana M, Algalarrondo V, Garcia-Pavia P, et al. Vutrisiran-mediated knockdown of transthyretin in patients with ATTR amyloidosis. Clin Pharmacokinet. 2026;65(7):1073-1085. https://doi.org/10.1007/s40262-026-01651-3