Vutrisiran: New Chapter in the Treatment of Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

The FDA has approved vutrisiran (brand name Amvuttra) for adults with transthyretin amyloid cardiomyopathy (ATTR-CM), including both wild-type and hereditary forms.

Vutrisiran is the first RNA interference (RNAi) therapy approved for ATTR-CM and also the only treatment approved for both ATTR-CM and hereditary transthyretin amyloid polyneuropathy (hATTR-PN).

This marks a leap beyond TTR stabilizers, as vutrisiran silences the TTR gene, directly targeting the disease at its molecular root.

Approval was granted based on the HELIOS-B trial, which showed reductions in cardiovascular mortality, hospitalizations, and urgent heart failure visits.

Though the therapy is expensive, manufacturer Alnylam offers patient assistance programs to improve affordability.

Dual approval for ATTR-CM and hATTR-PN reflects vutrisiran’s utility across a broad spectrum of ATTR amyloidosis.

Its unique mechanism of silencing TTR mRNA cuts across genetic origins and organ systems affected by the disease.

As a clinically differentiated treatment, vutrisiran offers a novel method to reduce toxic TTR protein buildup.

ATTR-CM is a rare disease where misfolded TTR protein builds up in the heart, leading to heart failure.

These misfolded proteins form amyloid fibrils, causing the heart muscle to stiffen and weaken over time.

There are two main forms: hereditary (hATTR-CM) due to genetic mutations, and wild-type (wATTR-CM) due to aging.

Symptoms often mimic other cardiac conditions, making early and accurate diagnosis difficult.

Common signs include shortness of breath, leg swelling, fatigue, and arrhythmias.

Historically, few treatment options existed, resulting in poor prognosis.

Without treatment, survival typically ranges from 2 to 3.5 years after diagnosis.

This underscores the urgent need for therapies that modify disease progression.

Overlapping symptoms often lead to misdiagnosis, especially in older adults.

Raising awareness among healthcare professionals is key to catching the disease earlier.

People of Black ethnicity are at higher risk for familial ATTR, indicating potential health disparities.

Vutrisiran is a small interfering RNA (siRNA) therapy that works by degrading TTR mRNA in the liver.

It uses the body’s RNA interference (RNAi) mechanism to silence TTR protein production.

After a subcutaneous injection, vutrisiran enters hepatocytes, integrating into the RNA-induced silencing complex (RISC).

The siRNA guide strand binds to TTR mRNA, leading to its cleavage and degradation.

This decreases production of both wild-type and mutated TTR, limiting amyloid formation.

A GalNAc conjugation helps liver cells absorb vutrisiran more efficiently.

This allows for a convenient quarterly injection schedule.

siRNA technology offers a direct approach, unlike TTR stabilizers which prevent misfolding.

Fewer injections could improve long-term adherence versus daily pills.

In the HELIOS-B trial, 655 patients were studied in a global, randomized, and placebo-controlled setup.

The goal was to reduce all-cause mortality and cardiovascular events.

Patients receiving vutrisiran saw a 28% reduction in these risks.

In patients not taking tafamidis, the reduction increased to 33%, and mortality alone dropped by 35%.

Those already on tafamidis still benefited, with a 41% mortality reduction at 42 months.

Participants also maintained functional ability and reported improved quality of life.

Key cardiac biomarkers like NT-proBNP and troponin I showed early improvements.

The safety profile was favorable, with similar or fewer cardiac adverse events than placebo.

Results from HELIOS-B suggest vutrisiran may become a new standard of care.

The benefits were more pronounced in monotherapy, making vutrisiran a strong first-line option.

Combining vutrisiran with tafamidis may offer added benefit, but further research is needed.

Cardiac biomarkers reinforce its disease-modifying potential.

Three FDA-approved ATTR-CM therapies now exist: vutrisiran, tafamidis, and acoramidis.

Tafamidis stabilizes the TTR tetramer, preventing monomer breakdown and amyloid buildup.

Vutrisiran, by contrast, silences the TTR gene, cutting protein production at the source.

Vutrisiran is injected every three months, while tafamidis is taken daily by mouth.

Tafamidis reduced mortality by 33% over 30 months in the ATTR-ACT trial.

Vutrisiran showed 35% mortality reduction in monotherapy over 42 months.

In hATTR-PN, vutrisiran may improve polyneuropathy symptoms more than tafamidis.

Because vutrisiran lowers Vitamin A, supplementation is required.

Different mechanisms enable a personalized treatment approach for ATTR-CM.

Acoramidis (Attruby), like tafamidis, is a TTR stabilizer.

It binds to thyroxine sites, slowing tetramer dissociation and mimicking a protective mutation.

Acoramidis is taken twice daily, unlike quarterly-injected vutrisiran.

In ATTRibute-CM, acoramidis reduced mortality and hospitalizations by up to 48.2% at 42 months.

Vutrisiran showed 28% reduction in the general population in HELIOS-B.

Acoramidis also improved functional and biomarker outcomes.

It raises serum TTR, indicating its stabilizing effect.

Acoramidis is generally well-tolerated, with some GI side effects.

Its higher potency may translate to better clinical benefit.

Vutrisiran’s injection schedule may be preferable for some patients.

High TTR levels post-treatment reflect protein preservation, not disease worsening.

Vutrisiran is priced at $477,000/year, tafamidis at $268,000, and acoramidis at $244,000.

ICER recommends prices closer to $13,600–$39,000 for cost-effectiveness.

Still, vutrisiran earned an ICER "A" rating for clinical benefit.

Alnylam Assist offers copay, free drug, and insurance help.

Pfizer’s VyndaLink and BridgeBio’s ForgingBridges offer similar support for tafamidis and acoramidis.

High prices raise concerns about long-term healthcare sustainability.

Manufacturers aim to ensure broad coverage and access through support programs.

Next-gen therapies are on the horizon, including eplontersen, another siRNA therapy.

Eplontersen, under study in the CARDIO-TTRansform trial, is given monthly and already approved for hATTR-PN.

Other future treatments include NTLA-2001 (CRISPR gene editing) and monoclonal antibodies.

Fibril depleters like ALXN2220 and coramitug are also being tested.

This reflects a vibrant pipeline of diverse therapeutic strategies.

Eplontersen’s monthly dosing offers an alternative to vutrisiran’s quarterly schedule.

Gene editing technologies could lead to curative options for hereditary ATTR.

In summary, vutrisiran (Amvuttra) is a groundbreaking advance for ATTR-CM treatment.

It expands therapy beyond TTR stabilizers with a gene-silencing mechanism.

The HELIOS-B trial proved its ability to reduce mortality and cardiac events.

With both TTR silencers and stabilizers, clinicians can now personalize care.

Despite its high cost, access programs aim to help eligible patients.

The future looks promising with siRNA, gene editing, and other emerging approaches.

Vutrisiran represents a bold stride forward in conquering ATTR-CM. 

🔑 Key Take-Home Points: Vutrisiran for ATTR-CM

• Vutrisiran (Amvuttra) is the first FDA-approved RNA interference (RNAi) therapy for ATTR-CM, targeting both wild-type and hereditary forms.

• It works by silencing the TTR gene, reducing the production of amyloid-forming transthyretin (TTR) protein at its source.

• Administered as a subcutaneous injection every 3 months, vutrisiran offers a convenient alternative to daily oral therapies like tafamidis.

• The HELIOS-B trial showed vutrisiran significantly reduces all-cause mortality and cardiovascular events, especially in patients not on tafamidis.

• Patients experienced improved functional capacity, quality of life, and lower levels of key cardiac biomarkers (e.g., NT-proBNP, troponin I).

• Compared to TTR stabilizers (tafamidis, acoramidis), vutrisiran offers a distinct mechanism—a true gene-silencing approach.

• Vitamin A supplementation is required during therapy, as vutrisiran can reduce serum vitamin A levels.

• The therapy’s high annual cost (~$477,000) raises cost-effectiveness concerns, but robust patient assistance programs help improve access.

• Acoramidis and tafamidis are oral TTR stabilizers, while vutrisiran and emerging eplontersen are siRNA-based TTR silencers.

• The future of ATTR-CM treatment is expanding, with gene editing (CRISPR) and fibril-depleting therapies in clinical development.

• Vutrisiran represents a paradigm shift in managing ATTR-CM, offering disease modification and improved outcomes for a historically devastating disease.