Pelacarsen Cut Lp(a) by 78 Per Cent but Not Heart Attacks, Strokes or Deaths in the Lp(a)HORIZON Trial

It was the cleanest possible test of a promising idea, and it came back empty. A drug that cut lipoprotein(a), a genetic blood fat linked to heart disease, by nearly four fifths made no difference to heart attacks, strokes or deaths in more than 8,300 people followed for years.

The result of the Lp(a)HORIZON trial of pelacarsen, funded by Novartis, was presented on Saturday at the American Heart Association's Scientific Sessions in Chicago and published in The New England Journal of Medicine. The AHA's release describes the cardiovascular outcomes as unexpectedly neutral. The meeting runs until Monday. The outcome itself was not a surprise: Novartis had said in a top-line announcement on 4 September that the trial had missed its primary endpoint, and Saturday supplied the numbers.

What did the Lp(a)HORIZON trial find?

Lipoprotein(a), or Lp(a), is largely inherited and barely moves with diet, exercise or statins. The trial enrolled 8,323 adults with established cardiovascular disease and Lp(a) of at least 70 mg/dL at 797 sites in 42 countries, according to the AHA. Participants received either monthly pelacarsen injections or placebo, on top of well-managed background care: about 75 per cent already met blood pressure and cholesterol targets and nearly four in five were on high-intensity statins.

Lp(a) fell by about 78 per cent on the drug. Over a median of 4.7 years, Healio reports, major adverse cardiovascular events occurred in 12.3 per cent of the pelacarsen group and 12.1 per cent of the placebo group, a hazard ratio of 1.02 with a 95 per cent confidence interval of 0.90 to 1.15. Patients with the highest starting levels, 90 mg/dL or more, showed no benefit either, and the individual components of the main outcome showed no meaningful difference.

What about safety?

The AHA release says serious adverse events were reported in 37.3 per cent of the pelacarsen group and 41.1 per cent of the placebo group. The drug was linked to more flu-like symptoms, injection-site reactions and acute allergic reactions. Nineteen patients on pelacarsen had anaphylaxis, against none on placebo, with no deaths from allergic reactions. About 21 per cent of the drug group stopped treatment because of adverse reactions, compared with more than 7 per cent of those on placebo.

Is the Lp(a) idea finished?

The trial's senior author, Steven Nissen of the Cleveland Clinic, was blunt in the release: "it didn't work". But he added that the result does not make Lp(a) irrelevant. In comments to Healio he said it is not the end of the story, and that the near-optimal background therapy may have left less room for a benefit. He also pointed to limits: the trial included only people who had already had cardiovascular events, and 78 per cent of participants were white, while people of African ancestry, who have on average about twice the Lp(a), made up under 4 per cent.