Safety of PCSK9 siRNA demonstrated in pooled data analysis

Effect of inclisiran on haematological and immunological biomarkers: A pooled analysis of ORION-9, 10 and 11 trial data

Presented at the virtual EAS 2021 by Ulf Landmesser (Berlin, Germany)

Introduction and methods

The novel small interfering RNA (siRNA)-based drug inclisiran specifically targets PCSK9 mRNA in the liver to prevent production of PCSK9, resulting in increased LDL receptor expression and reduced LDL-c levels. Inclisiran is conjugated with the GalNAc molecule, which facilitates delivery to the liver. Earlier, some hematological and immunological adverse events were reported for undirected antisense-based therapies.

Safety analysis of the phase II ORION-1 trial has shown that inclisiran did not result in changes in inflammatory, immune or hematology makers, but this trial had a small size and short study period.

Therefore, in this study it was examined whether inclisiran resulted in changes in hematological and immunological biomarkers using pooled data from phase 3 ORION-9, 10 and 11 trials (n=3655). 1833 Patients had been randomized to inclisiran and 1827 to placebo. Inclisiran or placebo was administered on day 1, day 90 and 6 months. Patients had ASCVD, a risk-equivalent or heterozygous FH. Patients were on a background of maximally tolerated statin therapy.

White blood cell counts, platelet counts were assessed at baseline, day 150 and day 540 and hsCRP levels were assessed at baseline, day 150, 330 and 540.

Main results

• Over the treatment period of 540 days, there was no change in hematological markers, including no change in platelet count, with inclisiran or placebo.
• There was no change in median hsCRP levels with inclisiran or placebo.
• Local injection site reactions were more frequently observed in the inclisiran group compared to the placebo group, but were mild or moderate.
• In those who experienced treatment-emergent adverse events(TEAEs), there was no change in median hsCRP levels from baseline to day 540 in the inclisiran-treated patients, suggesting that the TEAES were not associated with chronic systemic inflammation.

Conclusion

Administration of inclisiran was not associated with adverse changes in hematological markers or hsCRP levels over 540 days. TEAEs at the injection site were more frequently observed with inclisiran compared to placebo, but there was no change in hsCRP, indicating no sign of systemic immune activation. These findings support the safety of inclisiran to lower PCSK9 and subsequently LDL-c in patients with HeFH, ASCVD or ASCD risk equivalent.

-Our reporting is based upon the information provided at the EAS 2021 congress-