Pilot study shows sustained LDL-c reduction with PCSK9-siRNA in hoFH patients

Introduction and methods

News - May 28, 2019

Pilot ORION-2 study with inclisiran, a novel anti-PCSK9 treatment, shows promise in homozygous familial hypercholesterolemia

Presented at EAS 2019 in Maastricht, The Netherlands, by Frederick Raal (University of the Witwatersrand, Johannesburg, South Africa)

Established LDL-c lowering therapies are not sufficiently effective in patients with homozygous familial hypercholesterolemia (hoFH), or the agents are not ideal because of a risk of hepatotxicity (mipomersen), or they require frequent injections.

Inclisiran is a drug in the RNA interference class. It targets the PCSK9 gene, and prevents synthesis of the protein in the liver. As a result, LDL receptors on the hepatic cell surface are not broken down, which leads to increased clearance of LDL by the liver, thus lower cholesterol levels. This mode of action at the level of PCSK9 protein production, gives inclisiran a longer dosing interval than the PCSK9 monoclonal antibodies, which need to be given every 2 or 4 weeks. Chemical modifications minimize RNAse action and enable hepatic uptake.

The ORION-2 study showed that treatment with inclisiran showed sustained LDL-c reduction in patients with elevated cholesterol, most of whom received statin therapy. The LDL-c reduction was on average >50% with two subcutaneous 300 mg doses. This effect persisted for several months.

This pilot study tested inclisiran in four patients with hoFH. All four patients were homozygous or compound heterozygous for mutations in the gene coding for the LDL receptor, and all had defective LDL receptor function. Inclisiran 300 mg was administered as a subcutaneous injection on day 1 and also on day 90 or 104 (if serum PCSK9 levels at day 60 or 90, respectively, were not higher than 70% lower than baseline levels). Treatment was 180 days, followed by an extended follow-up, until LDL-c reduction as <20% of absolute reduction from baseline to day 90 (day 180-300).

Main results

  • Three patients showed a decrease in LDL-c levels at day 90, namely -11.7%, -33.1% and -18.5% change in LDL-c. At day 180, the LDL-c levels were -32.7%, -37.0% and -17.5% in the respective patients.
  • In one patient, an increase in LDL-c of 14.3% was seen at day 90, and of 3.3% at day 180. This patient had a history of minimal response to evolocumab and alirocumab (<20% reduction in LDL-c).
  • PCSK9 levels were decreased in all four patients, by about 50% in three patients, and by -83.6% in one, at day 90. At day 180, PCSK9 levels were decreased in the range from 40% to 80%.
  • Reductions in other atherogenic lipoproteins, including apolipoprotein B (ranging from -15% to -46% at day 90, and from -7% to -38% at day 180) and lipoprotein(a) (ranging from -25% and +10% at day 90 and from -25% to +3.7%) were also seen.
  • No drug-related adverse events or treatment discontinuations were seen, nor were injection-site reactions reported, or laboratory abnormalities of clinical relevance.


Treatment with inclisiran, an injectable siRNA agent directed against PCSK9, lowered LDL-c in people with hoFH, with different underlying genetic variants. The LDL-c reduction was sustained and lasted for up to 6 months in three out of four subjects in the study. The data also show that despite comparable effects on PCSK9 reduction, different degrees of LDL-c reduction may be seen in hoFH patients with the same causal mutations.

In a press release, professor Raal compared inclisiran to PCSK9 antibodies: ‘Monoclonal antibody therapy directed against PCSK9 is effective in homozygous FH, at least in those subjects with some residual LDL receptor activity. However, as production of PCSK9 by the liver is not inhibited, these agents needs to be administered fortnightly in order to maintain the reduction in PCSK9. Inclisiran, by inhibiting the production of PCSK9 by the liver, “turns off the tap” and this effect is sustained for several months. This allows inclisiran to be administered much less frequently, only every 3 to 6 months, in these difficult-to-treat patients.’

Our reporting is based on the information provided at the EAS 2019 congress

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