Novartis AG is paying $9.7 billion to buy The Medicines Company. For what? Its medicines, of course. Actually make that medicine singular. Yes, Novartis Chief Executive Officer Vas Narasimhan pulled the trigger on a deal to get one particular type of medicine that’s not quite reached the market yet. It’s name is inclisiran.
Do you have an inkling of what inclisiran is or what it can be? The drug recently went through Phase 3 clinical studies for the treatment of familial hypercholesterolemia. “Familial” in medicine-speak usually means “runs in families” or inherited. “Hyper” means high. “Cholesterol” means cholesterol, and “emia” means in the blood. Thus, familial hypercholesterolemia is an inherited disorder that can result in you having very high levels of cholesterol in your blood.
The high levels are of not just any cholesterol but low density lipoprotein (LDL) cholesterol. To remember that LDL cholesterol is bad cholesterol, just consider LDL to be the opposite of LOL. As the U.S. National Library of Medicine Medline Plus website describes, in familial hypercholesterolemia, a defect in your chromosome 19 prevents your body from adequately getting rid of LDL from your blood. Higher LDL levels make you more likely to have a heart attack, other types of heart disease, a stroke, and peripheral vascular disease, even at quite early ages, like as a kid.
Until recently, the mainstay of treatment, besides a diet low in cholesterol and saturated fats and getting plenty of exercise, has been statins. Statins are a class of cholesterol-lowering drugs that all end in the suffix -statin. Examples include lovastatin, known better by its stage name Mevacor, pravastatin otherwise known as Pravachol, simvastatin which goes by Zocor, and atorvastatin, famously called Lipitor. You’ve probably heard of these drugs, because many of them are blockbusters, earning lots of money for their makers. That’s because while familiar hypercholesterolnemia may occur in one out of 200 to 500 people, according to a publication in Current Atherosclerosis Reports, having high cholesterol in general is much more common.
Statins, of course, are not the miracle cure for high lipids and cholesterol. It’s not as if you can take statins and then eat endless amounts of mayonnaise sandwiches or even a lower fat diet and expect the statins to always correct everything. Statins do reduce the amount of cholesterol that your liver produces by inhibiting an enzyme called HMG-CoA reductase. However, your liver is not the only source of cholesterol. A lot of it comes from what you eat as this video from the Cleveland Clinic shows:
That’s why you need a clean-up crew to periodically pick up LDL from your blood. As you can see in the video, your liver has LDL receptors on the surface of its cells that bind excess LDL in the blood and bring the LDL into your liver to be broken down. The liver then returns the empty LDL receptors back to the cell surfaces to do their thing again. Consider these LDL receptors as little garbage trucks that pick up the LDL trash and gets rid of it, circling back and forth. If there aren’t enough LDL receptors to clean up the mess, the result can be high cholesterol and lipids.
That’s why PCSK9 is a problem. This vowel-less name refers to a protein in your body that also binds to LDL receptors. Ah, but when the liver absorbs the PCSK9-LDL receptor combination, it destroys both. PCSK9 essentially tells the liver to “kill us both,” which is not a good thing if it happens too often, leaving your body depleted of LDL receptors. So not only does PCSK9 have no vowels, it can also kind of suck.
If there were only a way to stop this PCSK9 BS. Well, 2015 saw the approval of not one but two monoclonal antibodies that can bind to and inhibit the action of PCSK9. That year Regeneron/Sanofi brought Praulent (alirocumab) to market while Amgen did the same with Repatha (evolocumab). Take that PCSK9. Score one for the LDL receptors.
While effectively muzzling PCSK9 sounds good, could you do one better by stopping the production of PCSK9 in the first place? In other words, is there some way of “interfering” with PCSK9? You may have an inkling that there is.
RNA interference may sound like a penalty in football or an interruption in your cell phone call, but it is a way to turn off a gene. Genes produce messenger RNA, which then essentially provides the instructions or blueprints for what proteins to be produced. RNA interference or RNAi for short is a method to silence this gene, which sounds very mafia-esque but essentially means negating the messenger RNA produced by the gene. If RNAi is too simple for you to say, you can use the equivalent term Post-Transcriptional Gene Silencing (PTGS). Post-transcriptional means after the gene has produced or transcribed messenger RNA. Your cells naturally use RNAi to turn off certain genes at various times, because you wouldn’t want all of your genes to be on and essentially sending chatter all the time. That would be a cacophony and a mess.
Here is a Nature video describing the natural RNAi process:
As you can see, the RNAi process begins when your cells produce these double-stranded RNA that can then combine with the enzyme mentioned in the video. These RNA-enzyme complexes can then bind to matching messenger RNA produced by the gene of interest, resulting in that messenger RNA being cleaved or slice apart, effectively silencing that gene. Think of the gene as a person who wants to send messages (e.g., emails, tweets, or semaphors) to others as instructions to get something done. You could silence that person by intercepting every email, tweet, or waving flag and slicing them apart so that no one will ever be able to read them.
RNAi is what occurs naturally. Could scientists then synthesize certain types of double-stranded RNA to use RNAi to silence certain genes that need to shut the bleep up, like the ones that produce PCSK9? Indeed, that’s what inclisiran is supposed to do. And based on results from the recently completed ORION-10 clinical trial, inclisiran seems to be be pretty good at silencing. In this American Heart Association (AHA) video, R. Scott Wright, MD, the Principal Investigator of ORION-10 and Professor of Medicine at the Mayo Clinic, described the trial and results:
And here Karol E. Watson, MD, PhD, Professor of Medicine at the David Geffen School of Medicine at UCLA, offered her assessment of the trial and its results:
The AHA website includes more detailed results from the trial, which were first announced at the AHA meeting earlier this month. The trial randomly assigned 1561 patients with high LDL levels to receive either inclisiran or a placebo. Inclisiran administration included an initial injection, a second one three months later, and then subsequent twice a year injections. After 18 months, those receiving inclisiran on average experienced significant reductions in their LDL levels while not experiencing major side effects.
Therefore, things do look promising for inclisiran. If it is indeed another way to effectively lower bad cholesterol, it could very well be another blockbuster drug. This then would give Novartis AG the medicine that it wanted when it takes The Medicines Company.