We don’t normally update stock recommendations from our various services in the Daily Journal, but from time to time something happens that’s important enough to discuss with the entire audience.

On Friday, Porter & Co. Biotechnology recommendation Novartis (NVS) announced that its heart and cholesterol drug pelacarsen failed in a Food And Drug Administration (“FDA”) Phase III trial to reduce cardiovascular events despite lowering the harmful cholesterol Lp(a).

One of our main themes in Porter & Co Biotechnology is a technology called RNA interference. It can prevent harmful proteins from being produced inside cells, before they cause harm in your body. As this intervention occurs earlier in the pathology of disease and inside cells, it has a good safety profile and can be extremely effective. We believe it’s going to become a dominant new approach to treating chronic disease.

One of the biggest potential market opportunities for RNA interference is preventing the production of certain kinds of cholesterol that are linked to cardiovascular disease (heart attack, stroke). Cardiovascular disease is a leading cause of death, so there are potentially huge markets for these drugs – if they’re safe, and if they can prevent disease.

Novartis has been conducting a six-year-long, huge (8,323 people) clinical trial (“HORIZON”) using an older form of RNA interference (antisense) to target lipoprotein(a). Lp(a) is a cholesterol-carrying particle found in the blood. It resembles an LDL particle, the type commonly called “bad cholesterol,” with an additional protein called apolipoprotein(a) attached to it.

Your genes determine most of your Lp(a) level. Diet, exercise, and statins generally do little to change it. People born with high Lp(a) experience more heart attacks, strokes, and aortic-valve disease over their lifetimes. And currently there’s no FDA-approved treatment to reduce Lp(a), which makes it one of the most valuable potential drug targets in medicine.

Novartis’ Lp(a) drug is called pelacarsen. On Friday afternoon, Novartis announced that pelacarsen did not lower the risk of cardiovascular events in the treatment population of the clinical trial. We don’t have complete data from the trial, so we don’t know exactly how it failed. We do know that Pelacarsen did what an antisense drug is supposed to do: it lowered the protein it was designed to lower. The problem is that patients did not suffer fewer cardiovascular events as a result.

There’s a lot of controversy about cholesterol drugs (statins) already. Many people claim that LDL isn’t the cause of heart attacks. While cardiovascular disease is multi-faceted, there’s no question that lowering LDL, especially before cardiovascular disease has begun, can dramatically reduce the risk of heart attack and stroke. We know this because some people have natural mutations that result in much lower levels of LDL and they have much less (88% less, in one landmark study) incidence of heart disease. Likewise, some people have natural mutations that lead to much higher levels of LDL – they get heart disease when they’re still very young.

Using drugs to replicate lower levels of LDL improves cardiovascular health: The Cholesterol Treatment Trialists combined 26 randomized trials containing 170,000 participants. Each 38.7 milligram-per-deciliter (“mg/dL”) reduction in LDL produced a 22% reduction in major vascular events and a 10% reduction in overall mortality. A meta-analysis of patients beginning at very low LDL levels found a 21% reduction in major vascular events for every 38.7 mg/dL reduction, combining statins and nonstatin drugs.

I’m explaining all of this because I suspect there will be a lot of people (especially on the internet) who point to this clinical-trial failure and then claim that cholesterol isn’t a factor in heart disease. But that isn’t what this trial means. LDL has bidirectional genetic evidence and repeated outcome benefits from several mechanistically different drugs.

Still, if high Lp(a) leads to heart attack, then why didn’t lowering it reduce heart attacks?