Gene silencing therapies for hereditary ATTR amyloidosis: what do we know and what can we expect?

Take-home messages:

  • Gene silencers have proven to be an effective therapeutic approach for hereditary ATTR-PN
  • Exploratory analysis shows preliminary secondary cardiac benefits with patisiran
  • A phase III trial with patisiran for ATTR-CM is ongoing
  • A second generation of GalNAc-conjugated gene silencers show increased metabolic stability and hepatic specificity, with clinical trial results expected in the near future

Transthyretin-mediated amyloidosis (ATTR amyloidosis) is caused when transthyretin (TTR) tetramers secreted from the liver dissociate into monomers that aggregate into amyloid fibrils which are deposited, and accumulate, in different parts of the body.1

As Dr Pablo Garcia-Pavia, Consultant Cardiologist, Hospital Universitario Puerta de Hierro, explained during a talk at ESC Heart Failure & World Congress on Acute Heart Failure 2022, understanding this pathology provides a number of steps that can be targeted when designing treatments for ATTR amyloidosis: synthesis of TTR tetramers, dissociation of the tetramers and accumulation of amyloid fibrils.2 Dr Garcia-Pavia's talk focused on the first of these steps and the current and future therapies designed to suppress the production of TTR.

“There are two types of therapies that are being developed, RNA [interference] [RNAi] and antisense oligonucleotides [ASOs],” Dr Garcia-Pavia explained. Both RNAi and ASO have already been proven to be effective in hereditary ATTR amyloidosis with polyneuropathy (ATTR-PN), and Dr Garcia-Pavia shared some of these results with the audience:

  • In the APOLLO trial, 3-weekly administration of patisiran, an RNAi therapeutic, was shown to reduce the mean serum TTR levels from baseline by ~80% from first administration.3 An open-label extension (OLE) showed consistent reduction in neurological symptoms (mNIS+7) from baseline with up to 42 months of patisiran treatment4
  • In the NEURO-TTR trial, once-weekly administration of inotersen, an ASO, reduced the mean serum TTR levels from baseline by ~70% at Week 13 and this was maintained up to 65 weeks.5 Extension of inotersen administration to 104 weeks total treatment in an OLE showed improvement in progression of neurological symptoms (mNIS+7) from baseline compared with placebo5,6

But what about ATTR amyloidosis with cardiomyopathy (ATTR-CM)? "In these trials," Dr Garcia-Pavia said, "there were patients who also had cardiac disease, and we are able to gather some information from these drugs regarding cardiac parameters." Inotersen treatment did not show any changes in cardiac parameters in the cardiac subpopulation (patients with LV wall thickness >13 mm and no history of hypertension or aortic stenosis) of NEURO-TTR.5 Patisiran, however, did show some cardiac benefits in the APOLLO trial.7

APOLLO cardiac subgroup: exploratory analysis

In the cardiac subgroup (n=126) at 18 months, patisiran versus placebo reduced:7

  • V wall thickness
    • LSM change from baseline: -1.0 mm vs 0.1 mm, p=0.017
  • LV mass
    • LSM change from baseline: -15.1 g vs 0.6 g, p=0.15
  • global longitudinal strain
    • LSM change from baseline: 0.1% vs 1.5%, p=0.015

The exploratory analysis also found a 45% lower rate of cardiac hospitalisation and all-cause mortality with patisiran versus placebo:7

  • all-cause hospitalisation/ mortality
    • negative binomial regression RR: 0.49 (95% CI: 0.30-0.79);
      Andersen-Gill HR: 0.48 (95% CI: 0.34-0.69)
  • cardiac hospitalisation/ mortality
    • negative binomial regression RR: 0.54 (95% CI: 0.25-1.16);
      Andersen-Gill HR: 0.54 (95% CI: 0.28-1.01)

"It has been hypothesised that these molecules could benefit cardiac parameters, not only by suppressing further TTR molecules, but also by promoting, somehow, amyloid clearance. And this has already been shown in several patient reports that have been published lately," Dr Garcia-Pavia went on.

In a case report of a patient with hereditary ATTR amyloidosis and a mixed phenotype of cardiomyopathy and polyneuropathy (ATTR-CM/PN), patisiran treatment caused regression of cardiac amyloid load, as detected by cardiovascular magnetic resonance, with the LV wall thickness dropping from 17 mm in 2018 to 13 mm in 2020. Native T1 mapping confirmed this finding with a drop from 1,120 ms to 948 ms across the 2 years.8

A group in London found that treatment of patients with ATTR-CM/PN and patisiran (with or without diflunisal; n=16) resulted in stable or improved ECV values versus patients with ATTR-CM/PN treated with diflunisal only.9

These results suggest that these agents may be effective in ATTR-CM but, as Dr Garcia-Pavia emphasised, clinical randomised trials in this population, such as the APOLLO-B trial, are needed to confirm this.

APOLLO-B is a phase III trial comparing patisiran with placebo in patients with ATTR-CM with or without polyneuropathy, with a medical history of HF, and who are tafamidis-naive or have evidence of disease progression after ≥6 months of tafamidis treatment.10

The primary endpoint of the study is the change in 6MWT from baseline at 12 months. Secondary endpoints include change in KCCQ-OS and a composite of all-cause mortality and frequency of cardiovascular events.10

The results of APOLLO-B are expected later this year.10

Dr Garcia-Pavia finished his talk by discussing a second generation of gene silencers, the ongoing development of which he described as 'good news'. ALN-TTRSC02 and TTR-LRX are GalNAc-conjugated molecules targeting hepatocyte-specific asialoglycoprotein receptors. Such targeting affords them:

  • increased metabolic stability11
  • increased potency that enables monthly or 3-monthly subcutaneous administration12-14
  • high hepatocyte distribution and low levels of non-specific, systemic exposure12

ALN-TTRSC02 is currently being tested versus placebo in the HELIOS-B phase III trial and recruitment is underway for the CARDIO-TTRansform phase III trial, which will compare TTR-LRX with placebo. "We will [wait], anxiously," Dr Garcia-Pavia said as a final remark, "to see the results of these trials that are ongoing."

6MWT: 6-minute walking test; CI: confidence interval; ECV: extracellular volume; ESC: European Society of Cardiology; GalNAc: N-Acetylgalactosamine; HR: hazard ratio; KCCQ-OS: Kansas City Cardiomyopathy Questionnaire Overall Summary Score; LSM: least squares mean; LV: left ventricular; mNIS+7: modified neuropathic impairment score; RR: rate ratio

Based on: Garcia-Pavia, P. Update on RNAi therapy in hATTR amyloidosis. Presented at Heart Failure & World Congress on Acute Heart Failure, 21-24 May 2022, Madrid, Spain; oral presentation

Top image: Design Cells
The content and interpretation of these conference highlights are the views and comments of the speakers/ authors.


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