APOLLO-B Phase III study of Onpattro backs positive impact in transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy.- Alnylam Pharma

The results were presented at the Annual Congress of the Heart Failure Association of the European Society of Cardiology (Heart Failure 2023; May 20-23, 2023).

The Company previously announced that APOLLO-B achieved its primary endpoint and met its first secondary endpoint during the 12-month double-blind (DB) period and that it has submitted the 18-month data to the FDA as an amendment to the supplemental New Drug Application (sNDA) for patisiran for the treatment of the cardiomyopathy of ATTR amyloidosis.

The 18-month findings indicate that the favorable effects on functional capacity and health status and quality of life, as measured by the 6-Minute Walk Test (6-MWT) and the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS), respectively, observed during the DB period were sustained with continued patisiran treatment during the OLE period. Patients treated with patisiran through 18 months also appear to have maintained relative stability of NT-proBNP and Troponin I levels, measures of cardiac stress and injury, respectively. Patients who crossed over from placebo in the DB period to patisiran during the OLE period appear to show slowing of disease progression or relative stabilization across these same endpoints at Month 18. While the APOLLO-B study was not designed to show benefits in cardiac outcomes between patisiran and placebo, evidence of favorable, but non-statistically significant, trends were observed for composite all-cause death and hospitalization, and mortality analyses across the DB and OLE periods.

An analysis performed at Month 18 indicated: Favorable effects on functional capacity (6-MWT) and health status and quality of life (KCCQ-OS) were sustained in patients receiving patisiran through 18 months. In patients who received placebo during the DB period, initiation of patisiran in the OLE period was associated with a slower rate of worsening (6-MWT) or relative stability (KCCQ-OS) at Month 18 compared with the DB period. For 6-MWT, the mean change from baseline to Month 18 was -9.2 meters in patients initially randomized to patisiran, consistent with the Month 12 assessment. For patients initially randomized to placebo, the mean change from baseline to Month 12 was -25.4 meters and to Month 18 was -31.1 meters. For KCCQ-OS, the mean change from baseline to Month 18 was +0.2 points in patients initially randomized to patisiran, and -4.0 points in patients initially randomized to placebo. Continued treatment with patisiran through 18 months was also associated with relative stability in biomarker measures of cardiac stress (NT-proBNP) and cardiac injury (Troponin I). Patients who received placebo in the DB period showed steadily rising cardiac biomarker levels up to Month 12, which then appeared to slow or stabilize after initiating patisiran in the OLE period. The geometric mean fold-change from baseline at Month 18 in NT-proBNP was 1.17 for patients who continued on patisiran, and 1.53 for placebo-crossover patients. The geometric mean fold-change from baseline at Month 18 in Troponin I was 1.09 for patients who continued on patisiran, and 1.21 for placebo-crossover patients. Additionally, while the APOLLO-B study was not designed to show a treatment difference in death and hospitalizations between patisiran and placebo in the DB or OLE period, and no statistically significant differences were achieved, evidence of favorable trends were observed for these composite endpoints. The analyses of outcomes included all available data from the DB and OLE periods at the time of the Month 18 data-cut. The point estimate of hazard ratio (HR) for the composite of all-cause mortality and frequency of all-cause hospitalization and urgent heart failure visits was 0.801 (95% CI, 0.573–1.118). The HR for all-cause mortality was 0.554 (95% CI, 0.281–1.094). Patisiran demonstrated an encouraging safety profile through 18 months of treatment, consistent with the underlying disease and the known safety profile of patisiran, with no new safety concerns identified.