Patisiran benefits maintained over 18 months in patients with transthyretin amyloidosis

The RNAi therapeutic patisiran was able to preserve functional capacity, health status, and quality of life of patients with transthyretin amyloidosis over 18 months. These were the outcomes of the long-term extension period of the phase 3 APOLLO-B study.

Transthyretin amyloidosis (ATTR) is a progressive and fatal disease caused by a mutation of the transthyretin (TTR) gene. The disease leads to worsening heart failure (HF) and arrhythmia, with death typically occurring 2.5 to 5 years after diagnosis [1].

The IV-administered RNAi therapeutic patisiran is already approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy. After intracellular release, the small interfering RNA blocks the production of the TTR protein. During the 12-month, double-blind period of the phase 3 APOLLO-B study (NCT03997373), therapy with patisiran preserved functional capacity, health status, and quality of life in patients with ATTR amyloidosis, whereas placebo was associated with steady worsening of the disease [2]. Prof. Marianna Fontana (University College London, Royal Free Hospital, UK) presented the 18-month results of the APOLLO-B study [3].

Of the 360 participants from the double-blind phase, 334 participants entered the open-label extension (OLE) period. They had an ATTR amyloidosis with confirmed cardiomyopathy and medical history of symptomatic heart failure. Participants treated with placebo in the double-blind period were switched to patisiran therapy (0.3 mg/kg IV, once every 3 weeks) in the OLE period.

“Treatment benefits of the double-blind phase were maintained for 18 months,” Prof. Fontana said. Participants in the placebo arm that initiated patisiran in the OLE showed a slower rate of worsening in the 6-minute walking test or relative stability at 18 months compared with the double-blind period. Participants originally randomised to patisiran maintained relatively stable NT-proBNP and troponin I levels to month 18. Moreover, health status and quality of life stayed relatively stable over 18 months. However, patients randomised to placebo in the double-blind phase showed steadily rising rates of cardiac biomarker levels up to month 12, which then slowed or stabilised after initiation of patisiran.

“The study was not long enough nor powered to show treatment differences in death and hospitalisation. Despite this fact, favourable trends in all-cause mortality and all-cause hospitalisations were seen,” said Prof. Fontana. The mortality in the intervention arm was lower than in placebo from 9 months onwards.

Patisiran demonstrated an acceptable safety profile with the most common related adverse effects being infusion-related reactions in 14.1% of participants. The fact that placebo crossover patients did not recover the functional capacity, health status, or quality of life that were lost during the double-blind period compared with those in the patisiran group highlights the importance of early treatment initiation in these patients.

1. Hawkins PN, et al. Ann Med. 2015; 47:625–638.
2. Kale P, et al. Poster 354, Heart Failure 2022, 30 Sept–03 Oct, Washington DC, USA.
3. Fontana M. Patisiran treatment for ATTR cardiac amyloidosis: 18 months results of the phase 3 APOLLO-B study. Session Late breaking clinical trials: Chronic HF and cardiomyopathies, Heart Failure 2023, 20–23 May, Prague, Czechia.

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Posted on 8 August 202327 March 2024