This activity was funded by Alnylam Pharmaceuticals. The medical content was developed independently by M3 and Professor Violaine Planté-Bordeneuve.

Highlights from

Amyloidosis Conferences



Amyloidosis 2021 review

ATTR amyloidosis

Amyloidosis describes a group of disorders caused by protein misfolding. These misfolded proteins aggregate into insoluble fibres known as amyloid fibrils, which can accumulate in certain tissues ultimately leading to organ damage. Amyloidosis can be inherited or acquired and can be localised or systemic.1 Amyloidoses are named by their amyloid protein type, with an A (for amyloid) followed by an abbreviation of the protein type, eg ATTR for amyloid derived from transthyretin. 36 proteins are known to be amyloidogenic in humans, to date.2 Accurate classification of the amyloidogenic protein is essential, as each subtype requires a specific approach to patient management.1

In ATTR amyloidosis, instability of the transthyretin (TTR) protein's tetrameric structure results in it dissociating into monomers which misfold and aggregate into amyloid fibrils. In ATTRv, this instability is caused by mutations in the TTR gene; in ATTRwt the cause of this instability is unknown. More than 100 mutations have been linked to hereditary ATTR amyloidosis with the Val30Met substitution being the most common.3

ATTR amyloidosis is traditionally described as either ATTR with polyneuropathy (ATTRv‑PN) or ATTR with cardiomyopathy (ATTRwt‑CM or ATTRv‑CM), depending on the predominant clinical manifestation, however in clinical practice, patients often present with overlapping phenotypes.4

Mean diagnostic delays of 4 years and 8 years have been reported for ATTRv-PN and ATTRv‑CM, respectively, and, although considered rare, the prevalence of ATTR amyloidosis is likely underestimated due to its non-specific symptoms and a heavy reliance on biopsies for diagnosis.4,5 Symptomatic relief is a mainstay of ATTR amyloidosis therapy, but does not target the underlying pathophysiology.4 TTR is mainly produced in the liver and the first therapeutic option was liver transplantation, to replace the variant TTR with wildtype;6 however, this is associated with a number of risks and may not provide the desired outcome for patients.4

The landscape of ATTR amyloidosis management is evolving; there is now a range of targeted treatments for patients with ATTR amyloidosis, and a wealth of clinical trial data supporting their use,4 as well as a growing interest and understanding of ATTR-CM and a push for earlier patient diagnosis.7

Approved therapies

Tafamidis is a TTR stabiliser which prevents dissociation of the TTR tetramer, thus inhibiting amyloid formation.6

  • Tafamidis meglumine 20 mg once daily is approved for the treatment of adults with hereditary ATTR with stage 1 polyneuropathy8*
  • Tafamidis 61 mg once daily is approved for the treatment of adults with ATTRv-CM and ATTRwt-CM9

The efficacy and safety of tafamidis 20 mg was first shown in patients with ATTRv-PN in 2012 in a pivotal 18-month placebo-controlled study10 and has since been demonstrated with up to 6 years of use.11

Superiority of pooled tafamidis 20 mg and 80 mg over placebo for all‑cause mortality and frequency of CV-related death over 30 months was shown in patients with ATTR‑CM in the ATTR‑ACT phase III trial (p<0.001).12 Patients who completed ATTR‑ACT were invited to enrol in a long-term extension (LTE), with placebo-treated patients randomised 2:1 to 80 mg or 20 mg tafamidis. In ATTR‑ACT combined with the LTE, a significantly greater survival benefit was found for tafamidis 80 mg versus 20 mg (HR:0.7, 95% CI:0.501‑0.979, p=0.0374) and AE profiles for both doses that were comparable with placebo.13

Inotersen is an antisense oligonucleotide inhibitor that decreases hepatic production of TTR. Results from the phase III NEURO‑TTR double‑blind placebo‑controlled study in patients with stage 1/2 ATTRv‑PN* showed that inotersen slowed the decline of mNIS+7 and the Norfolk QOL‑DN versus placebo, irrespective of disease stage, mutation or the presence of cardiomyopathy.14

More recently, results from a 3‑year open-label extension (OLE), in which all patients were treated with inotersen, supported its long‑term use. In patients who had received inotersen in NEURO-TTR, the benefit of inotersen was sustained with up to 3 more years of treatment and was greater than that observed in patients who had received placebo in NEURO‑TTR (change from baseline in mNIS+7 at Year 3: 17.2 vs 40.6). Switching from placebo to inotersen was associated with a sustained improvement in neuropathy progression versus the predicted worsening based on placebo data from NEURO-TTR.15

In the long-term safety analysis, 97.8% of patients experienced at least one treatment‑emergent adverse event (TEAE). Fatal TEAEs occurred in 11.9% of patients but none were considered treatment related.15

This study highlighted the importance of early treatment, since patients who initiated inotersen earlier in their disease course showed consistently favourable outcomes with respect to neuropathic impairment and quality of life compared with patients who were switched to inotersen after 1 year.15

Patisiran is an RNAi therapeutic that specifically inhibits hepatic synthesis of TTR. It was licensed for the treatment of hereditary ATTR amyloidosis with stage 1/2 polyneuropathy16* following positive results versus placebo for neuropathy and quality of life in the phase III placebo‑controlled APOLLO study, published in 2018.17 Since then, numerous post hoc and subgroup analyses have built upon these data.

A global OLE of the APOLLO study enrolled patients who had received placebo or patisiran for 18 months in APOLLO, or patisiran in a phase II OLE, and assigned them to 3‑weekly IV infusions of patisiran. APOLLO‑placebo group patients demonstrated a 79% reduction from baseline in mean serum TTR 6 months after switching to patisiran that was maintained for up to 24 months. Patients who had received patisiran in either parent study maintained serum TTR reductions during the OLE and continued to demonstrate reversal of neuropathy from their parent study baseline, as measured by mNIS+7. Rapid polyneuropathy progression in the APOLLO-placebo group halted upon treatment with patisiran but did not return to the APOLLO baseline level.18

Throughout the additional 24 months of patisiran treatment, no new safety concerns or signals were identified. The safety profile remained consistent with previous studies and patisiran continued to show a positive benefit-risk profile.18

Emerging therapies

Vutrisiran is an investigational RNAi therapeutic that inhibits the production of both wildtype and variant TTR. In contrast to inotersen and patisiran (which are administered weekly and 3-weekly, respectively),16,20 vutrisiran utilises an enhanced stability chemistry (ESC) GalNAc platform, meaning that it can be administered by subcutaneous injection once every 3 months. The safety and efficacy of vutrisiran in adult patients with ATTRv‑PN is currently being assessed in the phase III open label study, HELIOS-A.

At 9 months, vutrisiran showed statistically significant improvements (versus the placebo arm of APOLLO) in the mITT population for:

  • mNIS+7: LS mean change from baseline -2.24 vs 14.76; p=3.54x10-12 (primary endpoint)
  • Norfolk QOL-DN: LS mean change from baseline -3.3 vs 12.9; p=5.43x10-9 (secondary endpoint)
  • 10-MWT: LS mean change from baseline -0.001 vs -0.133; p=3.10x10-5 (secondary endpoint)

These effects were consistent with the patisiran group. Exploratory analysis demonstrated a >60% mean reduction in serum TTR levels from baseline after just 3 weeks of vutrisiran treatments, reaching a mean steady‑state serum TTR reduction of 83% (measured using samples at Day 211), similar to the reduction seen in patients receiving patisiran.

Vutrisiran demonstrated an acceptable safety profile; the majority of AEs were mild or moderate in severity and there were no drug-related discontinuations, deaths or safety signals regarding liver function tests, haematology or renal function.

The therapies described above require lifelong administration and do not fully remove amyloidogenic TTR. NTLA‑2001, a novel CRISPR/Cas‑9‑based in vivo gene editing therapy, aims to overcome these issues. NTLA-2001 comprises a lipid nanoparticle encapsulating a single guide RNA that targets TTR and a messenger RNA for Cas9 protein. Cas9 endonuclease activity induces cleavage of TTR and the resulting endogenous DNA repair introduces frameshift mutations that reduce the production of functional TTR protein.

After in vivo and in vitro studies with NTLA-2001, its safety and efficacy are now being assessed in the first ever use of CRISPR-‑based in vivo gene editing in humans. Part one of the two-part, open‑label, phase I study uses a single‑ascending dose methodology, in which a minimum of three patients per dose group will receive NTLA-2001 by IV infusion.

Interim data from the first six patients (three patients receiving 0.1 mg/kg and three patients receiving 0.3 mg/kg) observed a dose-dependent reduction in serum TTR concentrations by Day 7 which continued through to Day 28. At Day 28 the mean (range) reductions in TTR concentration from baseline were:

  • 0.1 mg/kg group - 52% (47%-56%)
  • 0.3 mg/kg group - 87% (80%-96%)

A knockdown of 87%, as shown in the 0.3 mg/kg group, would be expected to produce a positive outcome in terms of neuropathy.

NTLA-2001 was generally well‑tolerated in the acute phase and no serious AEs were reported. All reported AEs were grade 1 and mainly unrelated to treatment. No liver toxicity or coagulopathy was observed.

Further dose escalation is ongoing to identify the optimum dose, which will be given to an expanded cohort of patients in part two of the study.

Considerations for patient management

Early diagnosis
While these studies have shown good efficacy with targeted therapies, they have also shown that efficacy is greater in earlier stages of disease, meaning that early diagnosis is essential for optimising patient outcomes.4,11 This has been reflected in recent guidelines that aim to improve the diagnosis of ATTR amyloidosis.5,7

An expert consensus for the diagnosis of hereditary ATTR‑PN highlighted the diversity and non‑specificity of clinical manifestations of the disease, which include neuropathic pain, loss of balance, carpal tunnel syndrome and unexpected weight loss. The authors provided suspicion indexes for the diagnosis of ATTR-PN in endemic and non‑endemic areas, stating that disease should be considered in patients with neuropathy and at least one red flag symptom.5

A similar approach is suggested for ATTR‑CM. A scientific statement from the AHA emphasised the importance of identifying patients before they experience significant cardiac dysfunction, and the need for a high suspicion index when faced with the non‑specific presenting symptoms of ATTR‑CM. A recent emergence of imaging techniques that allow accurate, non‑invasive diagnosis of ATTR-CM, such as echocardiography, CMR imaging, and bone scintigraphy, may help improve the rate of early diagnoses without the need for confirmatory biopsies7 as well as having the potential to predict prognosis and evaluate response to therapy.23

Multidisciplinary approach
For patients with hereditary ATTR, the systemic nature of their disease, and a frequent overlap in cardiomyopathy and polyneuropathy phenotypes, mean they may present to a variety of different specialties and an MDT should be involved in their management.7 It is recommended that evaluation of the spread of disease, essential for detecting accompanying organ damage, should involve an MDT which may consist of a neurologist, a cardiologist, and ophthalmologist, a nephrologist and a GP.5

Future landscape

The advances in ATTR amyloidosis treatment look set to continue; the positive outcomes with vutrisiran and NTLA-2001 provide hope that they can be used in clinical practice in the future, while trials are underway to expand the indications of the currently approved therapies. Patisiran for patients with ATTR-CM is being investigated in the APOLLO‑B placebo‑controlled phase III trial24 and the use of inotersen in this patient group is being assessed in a 24-month open-label study.25 Acoramidis is a new TTR stabiliser that is not yet licensed for use but is being compared with placebo for the treatment of ATTR‑CM in the 30‑month phase III ATTRibute‑CM study. After the 12‑month analysis, eligible patients will be able to receive tafamidis, which may allow for a direct comparison between acoramidis and the current standard of care.26

With the advent of readily available non-invasive diagnostic tests for ATTR‑CM, increasing the number of treatment options available may be an important direction for the future.7

*Polyneuropathy staging: 0 ‑ asymptomatic; 1 ‑ mild, ambulatory symptoms limited to the lower limbs; 2 ‑ moderate symptoms and further neuropathic deterioration -patients are ambulatory but require assistance; 3 ‑ severe symptoms ‑ patients are bedridden/ wheelchair-bound with generalised weakness.27
†61 mg tafamidis free acid is bioequivalent to 80 mg tafamidis meglumine.

10-MWT: 10 metre walk test; AE: adverse event; AHA: American Heart Association; ATTRv-CM: hereditary transthyretin-mediated amyloidosis with cardiomyopathy; ATTRwt‑CM: non-hereditary transthyretin-mediated amyloidosis with cardiomyopathy; ATTRv‑PN: hereditary transthyretin-mediated amyloidosis with polyneuropathy; CI: confidence interval; CMR: cardiac magnetic resonance; CRISPR: clustered regularly interspaced short palindromic repeats; CV: cardiovascular; HR: hazard ratio; LS: least squares; MDT: multidisciplinary team; mITT: modified intention-to-treat; mNIS+7: modified neuropathy impairment score +7 neurophysiologic tests composite score; Norfolk QOL‑DN: Norfolk Quality of Life‑Diabetic Neuropathy; RNAi: RNA interference.

  1. Muchtar E, Dispenzieri A et al. Systemic amyloidosis from A (AA) to T (ATTR): a review. J Intern Med 2021;289(3):268-292
  2. Picken M M. The pathology of amyloidosis in classification: a review. Acta Haematol 2020;143(4):322-334
  3. Ruberg F L, Grogan M et al. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol 2019;73(22):2872-2891
  4. Hawkins P N, Ando Y et al. Evolving landscape in the management of transthyretin amyloidosis. Ann Med 2015;47(8):625-638
  5. Adams D, Ando Y et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol 2021;268(6):2109-2122
  6. Luigetti M, Romano A et al. Diagnosis and treatment of hereditary transthyretin amyloidosis (hATTR) polyneuropathy: current perspectives on improving patient care. Ther Clin Risk Manag 2020;16:109-123
  7. Kittleson M M, Maurer M S et al. Cardiac amyloidosis: evolving diagnosis and management: a scientific statement from the American Heart Association. Circulation 2020;142(1):e7-e22
  8. Tafamidis meglumine Summary of Product Characteristics. Available at: Accessed November 2021
  9. Tafamidis Summary of Product Characteristics. Available at: Accessed November 2021
  10. Coelho T, Maia L F et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology 2012;79(8):785-792
  11. Barroso F A, Judge D P et al. Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years. Amyloid 2017;24(3):194-204
  12. Maurer M S, Schwartz J H et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 2018;379(11):1007-1016
  13. Damy T, Garcia-Pavia P et al. Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study. Eur J Heart Fail 2021;23(2):277-285
  14. Benson M D, Waddington-Cruz M et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med 2018;379(1):22-31
  15. Coelho T, Whelan C et al. Efficacy and safety with >3 years of inotersen treatment for the polyneuropathy of hereditary transthyretin amyloidosis. Oral presentation 015 presented at the 7th Congress of the European Academy of Neurology – Virtual 2021, 19-22 June 2021
  16. Patisiran Summary of Product Characteristics. Available at: Accessed November 2021
  17. Adams D, Gonzalez-Duarte A et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 2018;379(1):11-21
  18. Adams D, Polydefkis M 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(1):49-59
  19. Adams D, Tournev I L et al. HELIOS-A: 9-month results from the phase 3 study of vutrisiran in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Presented at the American Academy of Neurology (AAN) Virtual Annual Meeting, 17-22 April 2021
  20. Inotersen Summary of Product Characteristics. Available at: Accessed November 2021
  21. Gillmore J D, Gane E et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N Engl J Med 2021;385(6):493-502
  22. Gillmore J D, Taubel J et al. In vivo CRISPR/Cas 9 editing of the TTR gene by NTLA-2001 in patients with transthyretin amyloidosis. Presented at the 3rd European ATTR amyloidosis meeting for patients and doctors, 6-8 September 2021
  23. Fontana M. Cardiac imaging in ATTR amyloidosis. Presented at the 3rd European ATTR amyloidosis meeting for patients and doctors, 6-8 September 2021
  24. APOLLO-B: a study to evaluate patisiran in participants with transthyretin amyloidosis with cardiomyopathy (ATTR amyloidosis with cardiomyopathy). Available at: Accessed November 2021
  25. 24 month open label study of the tolerability and efficacy of inotersen in TTR amyloid cardiomyopathy patients. Available at: Accessed November 2021
  26. Efficacy and safety of AG10 in subjects with transthyretin amyloid cardiomyopathy. Available at: Accessed November 2021
  27. Adams D, Suhr O B et al. First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr Opin Neurol 2016;29 Suppl 1:S14-26

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