PCSK9 siRNA does not affect inflammation measures or hematological parameters
Inclisiran, an siRNA against PCSK9, did not result in adverse effects on measures of inflammation, immune activation and platelets. No clinical immunogenicity AEs were observed.
Effect of inclisiran, the siRNA against PCSK9, on platelets, immune cells and immunological biomarkers - a pre-specified analysis from ORION-1Literature - Landmesser U, Haghikia A, Leiter LA et al., - Cardiovasc Res. 2020. doi: 10.1093/cvr/cvaa077.
Introduction and methods
The ORION-1 trial has demonstrated that treatment with inclisiran, a RNA-targeted therapeutic agent lowering PCSK9 levels, lowered LDL-c levels with a long-lasting effect in patients with high CV risk [1]. Previous studies with earlier RNA-based therapies have observed possible adverse effects, including thrombocytopenia [2], activation of the immune system and induction of pro-inflammatory cytokines [3, 4].
The present study was a prespecified safety analysis of the ORION-1 trial and evaluated the effects of inclisiran treatment on hematological and inflammatory parameters in patients (n=501) with high CV risk and elevated LDL-c levels. Also, an analysis of immunogenicity regarding anti-drug-antibodies (ADAs) in >6000 study samples was reported. The ORION-1 trial was part of an RNA-targeted therapy study program in humans [1], and included patients with ASCVD (LDL-c >1.8 mmol/L) or ASCVD risk equivalents (LDL-c >2.5 mmol/L) despite maximally tolerated statin therapy. They were randomly assigned to a single dose (n=252) of inclisiran sodium 200 mg, 300 mg, 500 mg or placebo on day 1, or two doses (n=248) of inclisiran sodium 100 mg, 200 mg, 300 mg or placebo on day 1 and day 90. Primary endpoint of the ORION-1 trial was percentage change in LDL-c from baseline to day 180.
Endpoints of the present analysis were effects of inclisiran on changes in TNF-α, IL-6, monocyte counts, lymphocyte counts, platelet counts and formation of anti-drug antibodies (ADAs) from baseline to 180 days.
Main results
- As compared to placebo, overall, inclisiran did not significantly affect platelet, leucocyte, monocyte, or neutrophil counts in any of the dosing groups.
- As compared to placebo, inclisiran did not significantly affect TNF-α or IL-6 levels in any of the dosing groups.
- A total of 6068 serum samples were collected and 65 samples from 39 patients were identified as potentially positives for anti-inclisiran antibodies.
- No immune system disorder AEs occurred in the inclisiran or placebo single dose groups. In the two-doses group, two AEs occurred in two subjects (3.2%) on placebo, allergy to an arthropod sting and drug hypersensitivity, and two AEs occurred in two subjects (1.1%) on inclisiran, both of seasonal allergy.
Conclusion
In this prespecified analysis of the ORION-1 trial, no significant effects were observed of 6-month treatment with inclisiran on inflammatory markers, platelets or clinical immunogenicity AEs in patients with high CV risk and elevated LDL-c levels. These findings suggest that inclisiran treatment in these patients is safe.
References
1. Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, Hall T, Troquay RPT, Turner T, Visseren FLJ, Wijngaard P, Wright RS, Kastelein JJP. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med 2017;376:1430-1440.
2. Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, Planté- Bordeneuve V, Barroso FA, Merlini G, Obici L, Scheinberg M, Brannagan TH, Litchy WJ, Whelan C, Drachman BM, Adams D, Heitner SB, Conceição I, Schmidt HH, Vita G, Campistol JM, Gamez J, Gorevic PD, Gane E, Shah AM, Solomon SD, Monia BP, Hughes SG, Kwoh TJ, McEvoy BW, et al. Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. N Engl J Med 2018;379:22-31.
3. Sioud M. Induction of inflammatory cytokines and interferon responses by double-stranded and single-stranded siRNAs is sequence-dependent and requires endosomal localization. J Mol Biol 2005;348:1079-90.
4. Meng Z, Lu M. RNA interference-induced innate immunity, off-target effect, or immune adjuvant? Front Immunol 2017;8:331.