New drugs for ATTR amyloidosis

In recent years effective new drugs for ATTR amyloidosis have become available. These drugs can improve symptoms and delay disease progression in suitable patients. Several other drugs are in various stages of development, offering yet more hope for the future. The trials discussed below are ongoing at the London National Amyloidosis Centre. For more details on each trial, see

Genetic based therapies

In 2019, regulatory authorities in the UK and the US approved patisiran (a small interfering RNA drug) and inotersen (an antisense oligonucleotide drug) for treating neuropathy caused by hereditary ATTR amyloidosis. These two approaches aim to “switch off” the gene for TTR in the liver cells, so that TTR (both mutant and wild-type) is simply not produced. Recent clinical trials of these drugs in patients with hereditary ATTR amyloidosis and symptomatic neuropathy had very encouraging results, serving as a landmark in the field of amyloidosis treatment and leading to regulatory approval.

The early trials only assessed the impact of these drugs on nerve damage caused by ATTR amyloidosis. Effects on cardiac ATTR amyloidosis (also known as cardiomyopathy) were not formally assessed and patients with wild-type ATTR amyloidosis were not included in the drug trials.

Some of the ongoing clinical trials of patisiran, and of other, newer genetic therapies include patients with both hereditary and wild type cardiac ATTR amyloidosis.

The APOLLO-B study is evaluating the efficacy and safety of patisiran in patients with ATTR amyloidosis (hereditary or wild type) with cardiomyopathy.

The small Patisiran in Patients With Hereditary Transthyretin-mediated Amyloidosis (hATTR Amyloidosis) Disease Progression Post-Liver Transplant study is evaluating the effect of patisiran in a patient group who were not included in the early trials.

Vutrisiran (AL-YTTRSCO2) is a second generation RNA inhibitor belonging to the small interfering RNA drug class. It is currently being assessed in the HELIOS clinical trials. The HELIOS-A study is comparing vutrisiran (administered by subcutaneous injection) to patisiran (administered by intravenous infusion) in patients with hereditary ATTR amyloidosis with neuropathy. The HELIOS-B study is comparing vutrisiran with placebo in patients with ATTR amyloidosis (hereditary or wild type) with cardiomyopathy.

AKCEA-TTR-LRx is a second generation RNA inhibitor, belonging to the antisense oligonucleotide drug class.  The NEURO-TTRansform study is comparing AKCEA-TTR-LRx to inotersen (both administered subcutaneously) in patients with hereditary ATTR amyloidosis polyneuropathy. The CARDIO-TTRansform trial is evaluating the efficacy and safety of AKCEA-TTR-LRx in patients with ATTR cardiomyopathy (hereditary or wild type).

TTR stabilizer

Destabilization, misfolding and aggregation of TTR leads to ATTR amyloid tissue deposits. Several small molecules have been shown to bind to and stabilize TTR, potentially preventing the initiating event in ATTR amyloidogenesis. AG10 is a new selective TTR stabilizer drug being developed to treat ATTR amyloidosis.. It is hoped that AG10 will halt or slow ATTR disease progression.

The Eidos AG10-301 study is evaluating the efficacy and safety of AG-10 in patients with symptomatic ATTR amyloidosis cardiomyopathy (hereditary and wild type).

CRISPR/cas gene editing therapy

NTLA-2001 is an experimental therapy that could potentially be the first curative treatment for ATTR amyloidosis.

CRISPR/cas9 technology is a novel gene editing tool that allows scientists to alter genes very precisely and efficiently.  The protein Cas9 (or CRISPR- associated) is an enzyme that functions like a pair of molecular scissors, so that specific sections of the DNA can be removed, altered or added.

NTLA-2001 is the first CRISPR therapy to be administered systemically (intravenously) to edit genes inside the body.  Almost all the TTR in the body is made in the liver;  NTLA-2001 uses a lipid nanoparticle delivery system to deliver the gene editing CRISPR protein to the liver.  The goal is to permanently delete the gene for TTR in a single course of treatment. 

Preclinical data has shown promising results, and this phase 1 trial, starting in late 2020 is the first time the therapy has been administered to humans.

Clinical Trials at the National Amyloidosis Centre

The NAC can now offer patients with ATTR amyloidosis, subject to various eligibility criteria demanded by the pharmaceutical companies, various opportunities for treatment with the new drugs or for participation in clinical trials. For details of ongoing trials at the NAC see here.