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

Highlights from

Amyloidosis Conferences



Neurofilament light chain (NfL): a potential biomarker of disease progression and treatment response?

Take-home messages
  • NfL is a potential biomarker of neuronal damage in patients with hATTR amyloidosis
  • In the Global OLE study in patients with hATTR amyloidosis with neuropathy, NfL levels were lower in patients with less severe disease and decreased with patisiran treatment
  • NfL levels may be useful for earlier diagnosis of polyneuropathy in patients with hATTR amyloidosis and for monitoring disease and treatment response over time

Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare and fatal disease in which inherited mutations in the TTR gene cause a build-up of amyloid fibrils in organs and tissues throughout the body. This results in a multisystem disease that often manifests as a mixed phenotype of both polyneuropathy and cardiomyopathy.1,2

Disease onset and progression is difficult to predict for individual patients with hATTR amyloidosis, and existing outcome measures, such as the modified Neuropathy Impairment Score +7 (mNIS+7) can be burdensome to perform in clinical practice.3 Alternative outcome measures are needed to facilitate earlier diagnosis of hATTR and the monitoring of disease progression and treatment response. Plasma level of NfL, which is released into the circulation by damaged neurons, has been highlighted as a potential biomarker for early nerve damage in hATTR amyloidosis. An analysis of the APOLLO study suggested that an NfL level of 37 pg/mL may distinguish between healthy controls and patients with diagnosed hATTR amyloidosis with polyneuropathy, with a false-positive rate of 3.6% and true-positive rate of 84.9%.3

At the American Academy of Neurology (AAN) 2021 Virtual Annual Meeting, Michael Polydefkis, Professor of Neurology, presented an evaluation of the long-term change in NfL levels in response to treatment with patisiran at 12 and 24 months in the Global OLE study.

Patisiran, a lipid nanoparticle-delivered RNAi therapeutic that inhibits the hepatic synthesis of wildtype and variant TTR proteins,4,5 demonstrated improvements in polyneuropathy in patients with hATTR (as measured by mNIS+7) in the phase III APOLLO trial6 and a phase II OLE study.7 The Global OLE study8 enrolled patients who had received placebo or patisiran for 18 months in APOLLO (APOLLO-placebo and APOLLO-patisiran) and those who received patisiran for 24 months in the phase II OLE study (phase II OLE patisiran) to evaluate the long-term efficacy and safety of patisiran.

The APOLLO-patisiran and phase II OLE patisiran groups continued to demonstrate reversal of neuropathy from their parent study baseline (mNIS+7 of -4.9 and -5.9, respectively). Rapid polyneuropathy progression in the APOLLO-placebo group halted upon treatment with patisiran but did not return to the parent study baseline.

NfL levels were analysed:

  • in the APOLLO-placebo and APOLLO-patisiran group - at baseline and 18 months from APOLLO study, and 12 and 24 months after completion of APOLLO study
  • in the phase II OLE patisiran group - at baseline, 9, 18 and 24 months, and 12 and 24 months after completion of phase II OLE study
  • in healthy controls matched to APOLLO patients - single measurement

At Global OLE baseline, NfL levels were higher in both APOLLO groups (placebo: mean = 63.2 pg/mL; patisiran: mean = 72.1 pg/mL) than in the in the phase II OLE group (mean = 32.9 pg/mL). This correlated with disease burden which was lowest in the phase II OLE patisiran group. All patient groups had significantly higher levels of NfL than the healthy control group (mean = 16.3 pg/mL). As NfL levels were lower in patients with less severe disease (and healthy controls), these results support the potential relationship between NfL and disease activity in hATTR amyloidosis. However, the majority of patients in the phase II OLE group had NfL levels below the threshold of 37 pg/mL for distinguishing between healthy controls and patients with hATTR amyloidosis. This suggests that the threshold needs revising; further research into additional age or disease severity-dependent thresholds may be required.

During the 18-month APOLLO study, APOLLO-patisiran NfL levels decreased significantly from baseline (mean at 18 months = 48.8 pg/mL, p<0.001). A decrease was also seen in the phase II OLE patisiran group from baseline to 24 months (mean at 24 months = 29.6 pg/mL) but this was not significant (p=0.19).

After an additional 24 months of patisiran treatment in the Global OLE study, reductions in NfL levels from parent study baseline was significant for both APOLLO-patisiran and phase II OLE-patisiran groups (means at 42 months = 44.0 pg/mL, p<0.001 and 22.8 pg/mL, p<0.001, respectively).

NfL levels in the APOLLO-placebo group increased significantly during the 18-month APOLLO study (mean at 18 months = 99.5 pg/mL, p<0.001). However, when these patients were switched to patisiran in the Global OLE study, their NfL levels began to decrease. After 12 months of patisiran treatment, their NfL levels had reduced to an average of 64.0 pg/mL (p<0.001).

Interestingly, this decrease continued over the next 12 months, reaching an average of 44.2 pg/mL at 24 months of patisiran treatment, despite the mNIS+7 remaining stable over this time period. This highlights the potential variance between NfL, as a biologic indicator of nerve damage, and the clinical indicators of neurologic impairment; NfL may reflect active neuronal damage at a specific point in time, whilst mNIS+7 reflects the overall burden of neurologic impairment. That these patients may have a reduced level of active neuronal damage but still be experiencing a high burden of impairment, indicates the value of earlier intervention to prevent irreversible neuronal deficits.

OLE: open-label extension; RNAi: RNA interference

Based on: Polydefkis M, Ticau S et al. Neurofilament light chain (NfL) as a potential biomarker of treatment response in hereditary transthyretin-mediated amyloidosis: data from the patisiran Global OLE study. Presented at the American Academy of Neurology (AAN) Virtual Annual Meeting, 17-22 April, 2021

  1. 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
  2. Hawkins P N, Ando Y et al. Evolving landscape in the management of transthyretin amyloidosis. Ann Med 2015;47(8):625-638
  3. Ticau S, Sridharan G V et al. Neurofilament light chain as a biomarker of hereditary transthyretin-mediated amyloidosis. Neurology 2021;96:e412-2422
  4. Coelho T, Adams D et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med 2013;369(9):819-829
  5. Suhr O B, Coelho T et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis 2015;10:109
  6. Adams D, Gonzalez-Duarte A et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 2018;379(1):11-21
  7. Coelho T, Adams D et al. A phase II, open-label, extension study of long-term patisiran treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis. Orphanet J Rare Dis 2020;15(1):179
  8. 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

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