Mechanisms and Selection of Disease-Modifying Therapy in hATTR Polyneuropathy

Key Takeaways:

• In the United States, the disease-modifying therapies approved for the polyneuropathy of hereditary transthyretin amyloidosis are all TTR-lowering silencers – RNA interference and antisense oligonucleotide agents – that reduce the circulating transthyretin available to form amyloid.
• TTR stabilizers are approved in the United States only for the cardiomyopathy of transthyretin amyloidosis, not for the polyneuropathy indication, so they should not be treated as hATTR-PN therapy options.
• Because available TTR-lowering therapies have similar mechanisms of action, treatment selection is often guided by route of administration, dosing schedule, monitoring requirements, and patient-specific factors.

Hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) is a progressive, multisystem disease in which destabilized transthyretin (TTR) misfolds and deposits as amyloid in peripheral nerve and other tissues. In the United States, currently approved disease-modifying therapies for hATTR-PN lower circulating TTR and fall into 2 mechanistic classes that differ in route of administration and dosing schedule.¹

Because axonal injury is often difficult to reverse, early treatment is important to preserve neurologic function.²

Silencing TTR production

Two silencer classes reduce hepatic TTR synthesis. RNA interference (RNAi) agents are small interfering RNAs (siRNAs) that promote degradation of both mutant and wild-type TTR messenger RNA, lowering serum TTR by roughly 80 percent. Antisense oligonucleotide (ASO) agents bind TTR messenger RNA and trigger its enzymatic degradation, achieving serum TTR reductions of approximately 68 to 81% depending on the agent.^3-6

Clinical trials of both RNAi and ASO therapies demonstrated significant improvement or slowing of neurologic progression compared with placebo, including benefits in mNIS+7 and Norfolk QOL-DN scores.^7-9

One trial included an active RNAi comparator rather than a concurrent placebo group, although it was not designed to directly compare efficacy between agents.⁹

Where TTR stabilization fits

A separate mechanism – TTR stabilization – binds the tetramer at its thyroxine-binding sites and slows its dissociation into the monomers that initiate amyloid formation. In the U.S., the 2 available stabilizers are approved only for the cardiomyopathy of transthyretin amyloidosis (ATTR-CM), not for the polyneuropathy indication. Although TTR stabilizers are an important treatment option for ATTR cardiomyopathy, they are not currently approved in the United States for hATTR-PN. A TTR stabilizer has received approval for polyneuropathy in some countries outside the United States.^10,11

These findings should be interpreted cautiously because benefit was demonstrated in secondary and per protocol analyses rather than the primary intention-to-treat analysis.¹²

Matching therapy to the patient

Because the silencers lower TTR to broadly similar degrees, treatment selection is often based on practical considerations, including route of administration, dosing schedule, safety profile, and monitoring requirements. Route and schedule span a weekly subcutaneous injection, a monthly subcutaneous autoinjector, a quarterly subcutaneous injection, and an intravenous (IV) infusion given every 3 weeks that requires premedication.^3-6

All TTR-lowering agents reduce serum vitamin A, so patients should take the recommended daily allowance of vitamin A and be referred to ophthalmology if ocular symptoms arise. Injection-site reactions and infusion-related reactions with the IV agent are generally mild and transient.^3-7,9

One ASO silencer carries a boxed warning for thrombocytopenia and glomerulonephritis and is available only through a Risk Evaluation and Mitigation Strategy (REMS). Appropriate use includes weekly platelet counts and regular renal surveillance. The need for ongoing laboratory monitoring should be considered when selecting therapy, especially for patients in whom frequent monitoring may be difficult. Disease stage, functional status, and the extent of cardiac or autonomic involvement should also be considered when selecting treatment.^1,2,5,8

Why timely initiation matters

Disease stage can help guide both treatment decisions and follow-up. Consensus recommendations suggest reassessment every 6 to 12 months. More frequent follow-ups are recommended in patients with more advanced disease.²

The goal of treatment is to slow disease progression. Long-term extension studies demonstrate sustained TTR reduction with preserved neurologic function over several years, supporting a disease-modifying effect.¹³

Although some patients experience improvement, neurologic deficits present before treatment may not fully recover. Early diagnosis and timely initiation of disease-modifying therapy are important to preserve long-term neurologic function.²