An evaluation of patisiran: a viable treatment option for transthyretin-related hereditary amyloidosis

ABSTRACT

Introduction: Hereditary transthyretin-mediated amyloidosis (ATTRv; v for variant) is a rare, progressive, fatal multi-systemic disease, autosomal dominantly inherited with heterogeneous clinical phenotype caused by mutations in the TTR gene. Mutations promoting proteolytic remodeling and tetramer dissociation result in fragmented and full-length TTR monomers that misfold, aggregate and deposit at multiple sites (mainly nerves and heart) causing peripheral neuropathy and/or cardiomyopathy.

Areas covered: The authors discuss patisiran, the first approved RNA interference-based therapeutic agent that suppresses the circulating levels of the amyloidogenic protein TTR both wild-type and mutant. This compound demonstrated a safe clinical profile in phase I and II studies and showed a significant clinical effect in a phase III (APOLLO) trial in ATTRv patients. An open-label-extension study is still underway but, based on the positive results, the regulatory agencies granted approval for the treatment of ATTRv with polyneuropathy in Stage I and II.

Expert opinion: The patisiran program has demonstrated that substantial TTR concentration reduction is associated with significant and sustained improvement in polyneuropathy scores, quality-of-life profile and several outcome measures that capture the systemic burden of the disease. The drug resulted safe also in long term follow-up studies while its efficacy for ATTR with cardiomyopathy is under investigation.

KEYWORDS:

• Patisiran
• hereditary transthyretin mediated amyloidosis
• RNA interference
• peripheral neuropathy
• cardiomiopathy

Article highlights

• Patisiran is the first RNA interfering treatment available for ATTR amyloidosis.

• Patisiran is administered intravenously once every three weeks and suppresses the circulating levels of both wild type and mutant transthyrethin.

• Treatment with patisiran is associated with a significant improvement in neurologic manifestations of hereditary TTR amyloidosis.

• Patisiran treatment was associated with an improvement in patients quality of life.

• Additional studies are investigating the role of patisiran in specific subgroup populations or in comparison with novel agent vutrisiran

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Declaration of interest

P Milani has received speaker’s honoraria from Janssen and Pfizer Inc. Meanwhile, S Perlini and R Mussinelli have both received speaker’s honoraria from Pfizer Inc. Finally, L Obici has received speaker’s and consulting honoraria from Pfizer Inc, Alnylam and Akcea. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

One referee has received consulting fees from Pfizer and Alnylam. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript has not been funded.