Long-Term Treatment of Hereditary Amyloid Neuropathy with Patisiran

This is a summarized version of the full in-depth article on Relias Media.

By Norman Latov, MD, PhD. Professor of Neurology and Neuroscience, Weill Cornell Medical College; Director of the Neuropathy Center, Weill Cornell Medicine

SYNOPSIS: Hereditary transthyretin-mediated amyloidosis with polyneuropathy is effectively treated by patisiran, a lipid nanoparticle ribonucleic acid interference that binds to transthyretin (TTR) messenger RNA and inhibits TTR production in the liver, resulting in reduction of the serum TTR concentration. Treatment effect has been sustained during a five-year open-label extension study.

SOURCE: Adams D, Polydefkis M, Gonzalez-Duarte A, et al. Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study. Lancet Neurol 2021;20:49-59.

Hereditary transthyretin-mediated amyloidosis (hTTRA) is a rare, progressive disease caused by mutations in the transthyretin (TTR) gene, leading to the aggregation of TTR protein and deposition of amyloid fibrils in peripheral nerves, heart, and other tissues. This condition leads to severe neuropathy and cardiomyopathy, with a median survival of four to seven years if left untreated. Treatment options have evolved over the years, and patisiran, a lipid nanoparticle ribonucleic acid interference (RNAi) therapy, has emerged as a promising therapeutic agent, targeting the production of TTR in the liver and reducing its serum concentrations. Patisiran was approved by the Food and Drug Administration in 2018 following favorable outcomes in Phase II and III trials.

Study Overview: Long-Term Efficacy and Safety of Patisiran

In this interim analysis, researchers evaluated the long-term efficacy and safety of patisiran in patients with hTTRA who were enrolled in a five-year open-label extension trial. This study involved 211 patients from 43 clinical centers in 19 countries, all of whom had completed previous Phase II or III trials of patisiran. The goal of the extension trial was to assess the ongoing effects of patisiran, with infusions administered every three weeks.

The primary outcome measure of the trial was the modified Neuropathy Impairment Score +7 (mNIS+7), while secondary outcomes included assessments of:

• Quality of life

• Autonomic symptoms

• Nutritional status

• Disability and ambulation status

• Motor function

• Cardiac stress

Efficacy Outcomes

Among the 189 patients who completed the 12-month efficacy evaluation, the interim analysis revealed several key findings:

• Patients who had been previously treated with patisiran continued to show maintained improvements in their neuropathy scores and other outcome measures.

• Patients who were initially in the placebo group during earlier trials experienced significant improvements after transitioning to patisiran, including reductions in serum TTR concentrations and improvements in neuropathy.

• These results were consistent with earlier findings from the Phase III trials, suggesting that patisiran's therapeutic effects on neuropathy are sustained with ongoing treatment.

Safety Profile and Adverse Events

The safety profile of patisiran over the 12-month period was deemed acceptable, though adverse events were common:

• 21 patients (10%) died during the study, though these deaths were primarily related to the progression of amyloidosis-related cardiac or renal disease rather than patisiran itself.

• Nine patients withdrew due to adverse events, and 39% reported serious adverse events, which were more frequent among those with more advanced neuropathy or disease who had previously been in the placebo group.

• Despite the high rate of adverse events, 97% of patients experienced mild or moderate adverse effects, which were generally related to the infusion process.

The data indicate that while serious complications occurred, they were generally linked to the natural progression of hTTRA rather than directly caused by patisiran. Importantly, the adverse event profile was consistent with previous clinical trial findings, affirming that patisiran's safety remains manageable over a longer treatment period.

Commentary: A Promising Long-Term Treatment for hTTRA

This interim analysis provides important insights into the long-term management of hTTRA, reaffirming patisiran's efficacy in reducing serum TTR concentrations and improving neuropathy symptoms over a prolonged treatment course. Prior to the availability of patisiran and other RNA-based therapies, treatment options were limited. Historically, liver transplantation was the standard approach for slowing disease progression in hTTRA patients, though it did not fully prevent the deterioration of neuropathy. The emergence of therapies like patisiran and inotersen (an antisense nucleotide inhibitor of TTR protein synthesis) offers a major advancement, enabling sustained improvement in patients with hTTRA.

Importance of Early Diagnosis and Treatment

The study's results underscore the need for early diagnosis and treatment of hTTRA, which could prevent irreversible damage and slow disease progression. Given the significant reduction in neuropathy symptoms with patisiran, timely intervention is crucial for improving patient outcomes. hTTRA should be considered in the differential diagnosis of patients with unexplained neuropathy, particularly those with autonomic involvement or associated cardiac or renal disease. Additionally, less common presentations, such as carpal tunnel syndrome, spinal stenosis, or chronic inflammatory demyelinating polyneuropathy (CIDP) resistant to standard therapies, should raise suspicion of hTTRA.

Diagnosis typically involves DNA testing, biopsy, and amyloid typing to confirm the presence of TTR mutations and amyloid deposits. Given the progressive nature of the disease and the efficacy of patisiran in reducing serum TTR concentrations, early therapeutic intervention is likely to offer the best outcomes for patients.

Conclusion

The 12-month interim analysis of the ongoing five-year extension trial demonstrates that patisiran continues to maintain its efficacy in treating neuropathy associated with hereditary transthyretin-mediated amyloidosis. Patients previously treated with patisiran showed sustained improvement, and those transitioning from placebo also experienced significant benefits. The safety profile remains acceptable, with most adverse events linked to the underlying disease rather than the drug itself. This study highlights the importance of early diagnosis and suggests that patisiran is a valuable long-term treatment option for managing hTTRA, particularly in preventing the progression of neuropathy and improving quality of life for affected patients.

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