Nucresiran

What is nucresiran?

Nucresiran (development code ALN-TTRSC04) is an investigational nucleic acid-based substance. It is a chemically synthesised nucleic acid, meaning it is built from the same building blocks as genetic material. The substance is being developed by Alnylam Pharmaceuticals as a potential treatment for transthyretin amyloidosis (ATTR), a condition in which a protein called transthyretin folds incorrectly and forms harmful deposits in organs and nerves.^[1]

Nucresiran has no marketing authorisation in the product records, meaning it is not yet approved as a medicine. In the trials listed in the EU registry, it appears only as the test substance.^[1][2] A paediatric investigation plan waiver has been granted, meaning the developer is not required to study the medicine in children at this stage.^[4][3]

How does nucresiran work?

Nucresiran belongs to a group of medicines known as RNA interference (RNAi) therapies. These therapies work by silencing specific genes, reducing the amount of a particular protein the body produces. In the case of transthyretin amyloidosis, the aim is to lower the production of transthyretin protein in the liver, which is the main source of this protein in the blood. Reducing transthyretin production is expected to slow or prevent the build-up of amyloid deposits that cause organ damage.^[1][2]

Which conditions is nucresiran studied for?

Nucresiran is being studied for transthyretin amyloidosis, which can affect different parts of the body. The two authorised trials cover two main forms of the disease:

• Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) — when amyloid deposits build up in the heart muscle, making it stiff and less able to pump blood. This can cause heart failure symptoms such as breathlessness and fatigue.^[1]
• Hereditary transthyretin-mediated amyloidosis with polyneuropathy (hATTR-PN) — an inherited form of the disease where amyloid damages nerves, causing numbness, tingling, pain and weakness, particularly in the arms and legs.^[2]

How is nucresiran given?

Nucresiran is given as a solution for injection in a pre-filled syringe. It is administered by subcutaneous injection, meaning it is injected under the skin. The dose reported in the cardiomyopathy trial is 1.7 mg and in the polyneuropathy trial 1.67 mg per injection.^[1][2]

What do the clinical trials show?

Two Phase 3 trials of nucresiran are authorised in the EU Clinical Trials Information System. Phase 3 is the stage of research where a potential medicine is tested in a large number of people to confirm how well it works and how safe it is. Both trials are listed as Authorised, meaning they have received regulatory approval to begin.^[1][2]

Which conditions are the trials testing?

The TRITON-CM trial (2024-519917-72-00) is studying nucresiran in people with transthyretin amyloidosis with cardiomyopathy. It plans to enrol 1,316 participants, making it the larger of the two trials.^[1] The TRITON-PN trial (2025-522544-40-00) is studying the medicine in people with hereditary transthyretin-mediated amyloidosis with polyneuropathy and plans to enrol 186 participants.^[2]

What are the trials measuring?

The cardiomyopathy trial measures a composite outcome of all-cause mortality and recurrent cardiovascular events, including cardiovascular hospitalisations and urgent heart failure visits. This means the trial looks at whether nucresiran can reduce deaths and serious heart-related events compared to placebo.^[1] The polyneuropathy trial measures the change from baseline in the Modified Neuropathy Impairment Score +7 (mNIS+7), a scoring system that assesses nerve damage, compared to an external placebo group from a previous study called APOLLO at month 9.^[2]

Who can take part in these trials?

Both trials are interventional studies, meaning participants receive the study medicine or a comparison treatment. In the cardiomyopathy trial, participants are randomised to receive either nucresiran or a placebo.^[1] In the polyneuropathy trial, participants receive either nucresiran or Amvuttra (vutrisiran) 25 mg, an existing treatment for hATTR-PN given by subcutaneous injection.^[2] The trials are open to adults with the respective forms of transthyretin amyloidosis; detailed eligibility criteria are available in the registry records.

What side effects are known?

The sources provided do not report specific side effects for nucresiran. As an investigational substance in Phase 3 trials, its safety profile is still being evaluated. Results from the ongoing trials will provide information on side effects.