The long-term extension of the phase 3 APOLLO-B study confirmed the efficacy and safety of patisiran in patients with transthyretin (ATTR) amyloidosis and highlights the importance of early treatment. Functional capacity, health status, and quality of life were preserved throughout the follow-up period.

ATTR amyloidosis is a progressive and fatal disease caused by a variant of the transthyretin (TTR) gene. Pathogenic variants cause TTR protein to misfold and accumulate as amyloid fibrils in the heart, among other organs. The disease leads to worsening heart failure (HF) and arrhythmia, with death typically occurring 2.5 to 5 years after diagnosis.

The IV-administered RNAi therapeutic patisiran is 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. Marianna Fontana, MD, PhD, presented the 18-month results of the APOLLO-B study.

Of the 360 participants from the double-blind phase 3 study, 334 participants continued in the open-label extension (OLE) period. They had ATTR amyloidosis with confirmed cardiomyopathy and a medical history of symptomatic HF. 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,” Dr. Fontana said. Moreover, functional capacity, health status, and quality of life were sustained through 18 months of treatment. Participants in the placebo arm that initiated patisiran in the OLE showed a slower rate of worsening in the 6-minute walk test or relative stability at 18 months compared with the double-blind period. Participants originally randomized to patisiran maintained relatively stable NT-proBNP and troponin I levels to month 18. Moreover, there was relative stability in health status and quality of life over 18 months. However, patients randomized to placebo in the double-blind phase showed steadily rising rates of cardiac biomarker levels up to month 12, which then slowed or stabilized after initiation of patisiran.

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

Patisiran demonstrated an acceptable safety profile; the most common treatment-related adverse effects were infusion-related reactions in 14.1% of participants, and 52% of participants had cardiac adverse events consistent with their underlying disease and with those reported during the double-blind period. The study highlights the importance of early treatment given that placebo crossover patients did not recover the functional capacity, health status, and quality of life that were lost during the double-blind period relative to those in the patisiran group.

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