About a quarter of people risk heart attacks and strokes because they inherited a kind of cholesterol that statin drugs can’t treat.
However, Eli Lilly reported late last month that just one shot of an experimental drug eliminated most of this type of bad cholesterol, known as lipoprotein(a), for six months.
Lilly is now enrolling patients for a Phase 3 trial of its drug, lepodisiran. Amgen has already recruited its Phase 3 study of olpasiran, a rival treatment for lipoprotein(a) that is as powerful, if not quite as long-acting. Ahead of both is Novartis, whose Phase 3 trial of a monthly injection called pelacarsen could report results this year.
These drugmakers are targeting a troublesome cholesterol variant that is a risk factor for cardiovascular disease distinct from the kind of cholesterol that is treated with statins. Since one to two billion people worldwide are born with high levels of lipoprotein(a), successful drugs should have a big market.
Lipoprotein(a) levels in the blood are one of three key measures that gauge a person’s risk of cardiovascular disease. A second is an inflammation-causing molecule called C-reactive protein. The third is the well-known LDL cholesterol. Long-term studies in the U.S. and Europe have showed that a screening blood test for these factors can predict heart attack risk for decades ahead.
Diet, exercise, and statins can lower LDL cholesterol. But high levels of lipoprotein(a) are genetic. So lifestyle doesn’t much affect it. Neither can available drugs. Yet those born with the cholesterol disorder have a two-to-three fold increased risk of heart attack.
Each of the Big Pharma companies licensed their lipoprotein(a) drugs from a smaller specialist. Novartis is working with Ionis Pharmaceuticals. Amgen has teamed with Arrowhead Pharmaceuticals. Lilly is partnered with Dicerna Pharmaceuticals, which Novo Nordisk bought for $3.3 billion in 2021. The London-based biotech Silence Therapeutics is developing its lipoprotein(a) drug solo.
All these drugs work by blocking the RNA messages that tell liver cells to make lipoprotein(a). The Novartis/Ionis drug binds to the RNA and ties it up, while the other companies all use specially-crafted molecules—known as “small interfering RNA”, or siRNA—which degrade the RNA.
The siRNA molecules stay inside cells for a long time, making the shots remarkably long-acting. In the Phase 2 trial reported by Lilly on March 30, lipoprotein(a) levels were 94% reduced for six months. Amgen’s Phase 2 study dosed its drug every three months and achieved a 97% suppression of the bad cholesterol. In the Novartis study, levels fell about 80%.
All those reductions may be enough to ward off heart disease. Side effects haven’t been a problem for any of the drugs so far, either.
Now, the companies have to show that lowering the rogue cholesterol reduces heart attacks and strokes. The Phase 3 studies to prove this will take more time. With an earlier start, Novartis will be the first of these Big Pharma companies with an answer. Amgen and Lilly will require several more years.
If the drugs prove out, however, folks born with high lipoprotein(a) will finally be able to do something about it.
