TMC’s inclisiran impresses at ESC, but will it surpass PCSK9 rivals?

Cardiologists only had to wait a few days after The Medicines Company teased top-line results with its cholesterol-lowering drug inclisiran before they got a good look at the data – and it looks positive.

Just last week, TMC said the phase 3 ORION-11 trial of met all its objectives, with the twice-yearly gene-silencing drug effective at reducing LDL cholesterol from baseline as well as other lipid biomarkers in patients with atherosclerotic cardiovascular disease (ASCVD).

Yesterday at the European Society of Cardiology (ESC) in Paris the ORION-11 added in the detail – a 54% reduction in LDL cholesterol with inclisiran compared to placebo that looks competitive with Amgen and Sanofi/Regeneron’s PCSK9 inhibitor antibodies, the new drug’s main rivals.

Most importantly, the small, interfering RNA (siRNA) drug appeared to be safe in the 1,617-patient trial, which was a relief to investors as inclisiran is based on an RNA scaffold developed by Alnylam that has raised concerns about possible liver toxicity in the past.

There were no treatment-related liver or renal abnormalities seen in the trial, so TMC should now be able to position inclisiran as being safe, as effective as Amgen’s Repatha (evolocumab) and Sanofi/Regeneron’s Praluent (alirocumab), and with a more convenient dosing schedule.

The two PCSK9 antibodies are generally given once a month, while inclisiran required three doses in the first year (at three, six and 12 months) and is given every six months thereafter.

Inclisiran also targets PCSK9, but switches off production of the protein at the RNA expression level rather than inhibiting the protein itself, and so has a longer duration of action. TMC is hoping that the dosing advantage will help inclisiran leapfrog Repatha and Praluent in the market, tackling adherence problems with cholesterol-lowering drugs.

Like the two antibodies it could face payer resistance, however. All three drugs are aimed at patients struggling to manage cholesterol levels using older oral medicines like statins, but Repatha and Praluent got off to a very slow start, forcing their manufacturers to slash prices from $14,000 to around $6,000 a year.

There are some signs sales have started to pick up for the two antibodies, and that is likely because they now have cardiovascular outcomes data to back up their activity on LDL cholesterol.

TMC won’t have data strong enough for a label claim in hand until the ORION-4 reads out in 2024, although there were encouraging signs from ORION-11, including a statistically significant reduction compared to placebo in heart attacks and strokes.

The company is confident prescribers will turn to its drug before the outcomes data is available, however, and says it is now planning to submit marketing applications in the US before the end of the year and in Europe in early 2020.

Between now and then it should have results from ORION-10, a confirmatory trial of the drug in ASCVD, as well as the ORION-9 trial in heterozygous familial hypercholesterolaemia (HeFH), a genetic form of high cholesterol.