Alnylam Pharmaceuticals announced new interim results from an exploratory data analysis evaluating its Onpattro (patisiran). Onpattro was tested in APOLLO-B Phase III trial open-label extension period in patients with transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy.
Onpattro is an RNAi therapeutic targeting transthyretin (TTR) that is designed to target and silence TTR messenger RNA, as such reducing the production of TTR protein before it is made.
The 18-month findings demonstrated sustained and favourable effects on the functional capacity, and health status and quality of life (QoL), measured by a 6-minute walk test (6-MWT) and the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS), respectively.
The mean change in 6-MWT from baseline to month 18 was -9.2 meters initially randomised into the treatment cohort and the findings were consistent with the assessment in month 12. The mean change from baseline to month 18 in KCCQ-OS was +0.2 points in patients treated with Onpattro.
The continued treatment was also associated with relative stability in biomarker measures of cardiac stress (NT-proBNP) and cardiac injury (Troponin I). The geometric mean fold-change from baseline at month 18 was 1.17 in NT-proBNP and 1.09 in Troponin.
Subjects who were initially randomised to the placebo cohort during the DB period were eligible to receive Onpattro in the open-label extension. The initiation of treatment was associated with a slower rate of worsening (6-MWT) or relative stability (KCCQ-OS) at month 18 compared with the DB period.
The interim analysis showed that the mean change from baseline in 6-MWT was -25.4 meters at month 12 and -31.1 meters at month 18. The mean change in KCCQ-OS was -4 points in this cohort.
The geometric mean fold-change from baseline at month 18 was 1.53 in NT-proBNP and 1.21 in Troponin for placebo-crossover patients.
The Phase III trial (NCT03997383) enrolled 360 adults with hereditary or wild-type ATTR amyloidosis with cardiomyopathy. Patients were randomised 1:1 to receive 0.3mg/kg of Onpattro or placebo intravenously administered every three weeks over a 12-month DB treatment period. Alnylam launched the study in September 2019.
The majority of adverse events (AEs) were mild or moderate in severity, and the most common treatment-related AE was infusion-related reactions.
Next steps for Onpattro
Alnylam has submitted the 18-month data from the open-label period to the US Food and Drug Administration (FDA) as an amendment to the supplemental New Drug Application (sNDA) for Onpattro.
The FDA has set an action date on 8 October 2023 under the Prescription Drug User Fee Act (PDUFA). The agency noted that they are planning to convene a meeting of the Cardiovascular and Renal Drugs Advisory Committee to discuss the application.
In September 2022, Alnylam announced that the APOLLO-B trial met its primary and first secondary endpoint during the 12-month double-blind (DB) period. Onpattro was approved for polyneuropathy of hereditary ATTR amyloidosis in adults by the FDA in 2018.
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