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

Highlights from

AAN 2021, EAN 2021, ESC-HF 2021 & PNS 2021

VIRTUAL, APRIL - JULY 2021

Amyloidosis Conference Highlights

Patisiran in hATTR amyloidosis: beyond the APOLLO phase III study

Take-home messages
  • Patisiran is an RNAi therapeutic licensed for the treatment of hATTR amyloidosis with stage 1/2 polyneuropathy, following positive results in the phase III placebo-controlled APOLLO study
  • Patisiran improves functional status and QOL from baseline in patients with hATTR amyloidosis versus placebo
  • Patisiran has demonstrated a positive benefit:risk profile with long-term use (≥5 years in some patients)
  • The efficacy, safety and pharmacodynamics of patisiran are not affected by the use of concomitant TTR stabilisers

The APOLLO phase III study investigated the efficacy and safety of patisiran, an RNAi therapeutic that inhibits the hepatic synthesis of transthyretin, in patients with hereditary transthyretin (hATTR) amyloidosis with polyneuropathy. At 18 months, patisiran improved neuropathy, gait speed and quality of life versus placebo.1

At the American Academy of Neurology (AAN) 2021 Virtual Annual Meeting, various speakers presented data building on the initial APOLLO results, from subgroup and post hoc analyses, to a 2-year open-label extension.

Impact of patisiran on activities of daily living and functional status in hATTR amyloidosis
Patients with hATTR amyloidosis experience progressive decline in functional status, ability to perform activities of daily living (ADL) and quality of life (QOL).2 In later stages of the disease, patients are often confined to wheelchairs or bedridden.3

Amanda Peltier, Associate Professor of Neurology, Vanderbilt University, presented ADL and functional status assessment results from APOLLO, including Rasch-built Overall Disability Scale (R-ODS; range: 0-48 points lower scores indicate greater disability), Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN; range: 0-20 points, higher scores indicate worse ADL ability) and Karnofsky Performance Status (KPS; range 0%-100%, lower scores indicate a lower ability to perform activities and a worse survival prognosis).

Over the 18-month study period, patisiran-treated patients retained a greater ability for ADL and social participation than placebo-treated patients, and a higher percentage retained or improved their baseline functioning than placebo-treated patients. On average, relative to baseline, patisiran-treated patients’ ability levels improved to a level corresponding to an ability to travel by public transportation, whereas placebo-treated patients worsened to a level corresponding to an inability to walk up a flight of stairs or do the shopping (as measured by R-ODS). A post hoc analysis estimating the odds of improvement versus worsening for R-ODS, Norfolk QOL-DN and KPS found that patisiran-treated patients were >2 times more likely than placebo-treated patients to improve or stabilise in these domains.

These results show that patisiran has the potential to ameliorate the functional decline associated with the polyneuropathy of hATTR amyloidosis.

Long-term safety and efficacy of patisiran: global open-label extension 24-month data in patients with hATTR amyloidosis
A global open-label extension (OLE) of the phase III APOLLO study was carried out to assess the long-term efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy. Eligible patients who had received placebo or patisiran for 18 months in APOLLO (n=186), or patisiran in a phase II OLE (n=25), were enrolled, and all patients received 3-weekly IV infusions of patisiran.

Interim results demonstrated a robust, sustained mean serum TRR reduction in APOLLO-placebo group patients upon patisiran treatment (79% reduction from baseline) at month 6, maintained up to 24 months, and maintenance of mean serum TRR reduction in APOLLO-patisiran and 2-year OLE groups.

The APOLLO-patisiran and 2-year OLE groups continued to demonstrate efficacy and reversal of neuropathy from their parent study baseline, as measured by modified Neuropathy Impairment Score (mNIS)+7 (-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.

Throughout the additional 24 months of 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.

Patients in the global OLE represent those with the longest treatment with an RNAi therapeutic, with some patients receiving ≥5 years of patisiran. Results from APOLLO-placebo group patients emphasise the need for early treatment, with delays in treatment resulting in the accumulation of a greater disease burden.

Evaluation of patisiran with concomitant or prior use of transthyretin stabilisers in patients with hATTR amyloidosis
Optimal patient care involves an understanding of the positioning of therapies within the therapeutic landscape. For instance, does the concomitant or prior use of TTR stabilisers affect the efficacy of patisiran?

A subgroup analysis reported the safety and efficacy of patisiran in patients with prior TTR stabiliser use in the phase III APOLLO study, and the pharmacodynamics of patisiran in patients with prior TTR stabiliser use in the phase II OLE study. The analysis found that mean change from baseline in mNIS+7 and Norfolk QOL-DN at 18 months was consistent, regardless of prior TTR stabiliser use, in the APOLLO study, and safety and tolerability was comparable across the overall APOLLO population. The median serum TRR reduction from baseline (averaged over 24 months) in the phase II OLE was also similar in patients who received patisiran alone and patients who received a concomitant TTR stabiliser.

Evidence that the efficacy and safety of patisiran is not affected by concomitant TTR stabilisers may be useful in guiding the use of patisiran in clinical practice.

IV: intravenous; RNAi: ribonucleic acid interference; TTR: transthyretin

Based on: Peltier A, Gonzales-Duarte A et al. Impact of patisiran on activities of daily living and functional status in hATTR amyloidosis. Presented at AAN Virtual Annual Meeting April 17-22, 2021; Adams D, Gonzalez-Duarte A et al. Long-term safety and efficacy of patisiran: global open-label extension 24-month data in patients with hereditary transthyretin-mediated amyloidosis. Presented at AAN Virtual Annual Meeting April 17-22, 2021; Lin H, Merkel M et al. Evaluation of patisiran with concomitant or prior use of transthyretin stabilizers in patients with hereditary transthyretin-mediated amyloidosis. Poster at AAN Virtual Annual Meeting April 17-22, 2021

  1. Adams D, Gonzalez-Duarte et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 2018;379(1):11-21
  2. Lovley A, Raymond K et al. Patient-reported burden of hereditary transthyretin amyloidosis on functioning and well-being. JPRO 2021;5:3;
  3. Adams D. Recent advances in the treatment of familial amyloid polyneuropathy. Ther Adv

Top image: Eraxion

Article image: libre de droit

The content and interpretation of these conference highlights are the views and comments of the speakers/authors.

Supported by