According to the National Institutes of Health, there are 163,000 clinical studies currently under way throughout 185 countries. This is why it can sometimes be difficult to get the attention of investors when a revolutionary new treatment pathway prevents itself.  

But what if I told you that the leading cause of death in the United States is heart disease and there was a very promising new treatment pathway in the works by a number of top pharmaceutical companies that had the potential to significantly lower the risk of cardiovascular disease? Might that get your attention?

This latest experimental drug class that's demanding your attention is PCSK9 inhibitors.

The 411 on PCSK9 inhibitors versus statins
The first thing you need to know about PCSK9 inhibitors is that they're a completely different beast than statins, which are the front-line treatment for most high-cholesterol suffers. Without getting overly technical, statins work within the liver by inhibiting the enzyme HMG-CoA reductase, which plays a role in cholesterol production. But statins also can have rare serious adverse side effects, such as muscle degradation, so they're not for everyone.

PCSK9 inhibitors work by targeting PCSK9 proteins. These proteins bind with low-density lipoprotein receptors, or LDLRs, on the liver and prevent those receptors from removing LDL-cholesterol (the so-called "bad kind") from a person's blood, leading to high cholesterol levels. And as we know, high cholesterol levels can lead to more serious complications, such as cardiovascular disease. By binding with PCSK9 proteins these inhibitors free up LDLRs to remove more LDL-cholesterol from a person's blood. Furthermore, statins tend to activate PCSK9 proteins, thus minimizing their effectiveness.

Source: Daniel Paquet, Flickr.

What we're seeing through the handful of ongoing studies involving PCSK9 inhibitors is that they serve a solid purpose as a second line of treatment where either statins didn't produce the desired LDL reduction in a patient, the patient can't tolerate statins due to serious adverse events, or the patient possesses a genetic condition involving extremely high cholesterol levels that necessitates PCSK9 inhibitors. Also, for those patients who can tolerate statins, PCSK9 can actually be administered in combination with statins, or statins and cholesterol-absorption inhibitors, to produce improved LDL-reducing results. Perhaps the most intriguing aspect of all is that PCSK9 inhibitors are given as a once or twice-monthly injection as opposed to taking statin pills on a daily basis. 

Of course, PCSK9 inhibitors aren't risk-free, either -- but what drug is?

Last month Regeneron Pharmaceuticals (REGN 1.78%), one of the many biopharmaceutical companies engaged in the development of PCSK9 inhibitors, advised investors that the Food and Drug Administration had "become aware of neurocognitive adverse events in the PCSK9 inhibitor class" and requested it and partner Sanofi (SNY 0.96%) assess the potential for neurocognitive AEs across their development program. If PCSK9 inhibitors are eventually linked to neurocognitive degeneration then it'd be the equivalent of suffering a tire blowout doing 90 mph on the freeway! We should, though, keep in context that this is merely a request from the FDA to investigate the safety of this new treatment pathway further and not something of a full-blown investigation.

The key players worth watching
With that in mind, let's have a look at some of the key players.

  • alirocumab: Obviously we have Regeneron and Sanofi's alirocumab under development. Currently in phase 3 clinical studies, the duo of Regeneron and Sanofi reported positive top-line data from its initial phase 3 study (ODYSSEY MONO) in October showing that its PCSK9 therapy reduced LDL-cholesterol levels at the 24-week mark from baseline by 47.2% compared to just 15.6% for the control arm taking Merck's Zetia. Investors will really want to pay attention this week as the duo is presenting its ODYSSEY MONO full data after 52 weeks at the American College of Cardiology's scientific session on Monday.  
  • bococizumab: Also known as RN316, bococizumab is Pfizer's (PFE 0.82%) prospective PCSK9 inhibitor targeting hyperlipidemia. Although phase 3 studies of bococizumab are under way, it was yesterday's phase 2b study data that stole the show. Its 354-patient double-blind, placebo-controlled study examined the effects of bococizumab being administered once or twice subcutaneously per month compared to a placebo with primary efficacy analysis measuring the placebo-adjusted change in baseline LDL-cholesterol at week 12. Based on the results, the 150 mg twice monthly dose led to a mean reduction in baseline LDL-cholesterol of 53.4 mg/dL while the once monthly 300 mg injection led to a mean reduction of 44.9 mg/dL. 
  • RG7652: Listed as a mid-stage therapy in Roche's monstrous list of ongoing clinical studies on its website, RG7652 provided intriguing early stage results via an abstract released in November that studied the therapy in combination with Pfizer's Lipitor. The phase 1 arm involving RG7652 resulted in dose-related reductions in serum apoliprotein B and oxidized-LDL by up to 50% from baseline.
  • evolocumab: This mammoth experimental therapy being developed by Amgen (AMGN 1.13%) is being studied through 14 separate trials and indications that will involve about 30,000 people. The hope is that evolocumab can attain numerous approved indications, as well as demonstrate its safety across a wide moat of patients -- and with Amgen now six for six in its study of the drug I'd say it's well on its way. The most recent data we received was actually from its TESLA phase 2/3 study involving evolocumab as a treatment for homozygous familial hypercholesterolemia (HoFH), a rare genetic condition. In results released last week from its initial phase 3 study, we learned that evolocumab met its primary endpoint of a clinically meaningful and statistically significant reduction in LDL-cholesterol at week 12 from baseline. Possibly best of all, current HoFH patients either undergo one injection of Isis Pharmaceuticals and Sanofi's Kynamro each week, take a pill therapy known as Juxtapid from Aegerion Pharmaceuticals each day, or merely get nine total injections in a 24-week period from Amgen. In other words, the convenience and interval factor certainly favors evolocumab. One tidbit worth keeping in mind, though, not all HoFH patients will respond to evolocumab, but for those that do it could become the clear choice if approved.
  • ALN-PCS: Developed by Alnylam Pharmaceuticals (ALNY -1.68%) and licensed out to The Medicines Co. for what seems like pennies on the dollar -- $25 million upfront, $180 million in potential milestone payments, and a double-digit royalty if approved -- ALN-PCS is a therapy that will attack PCSK9 inhibition through RNA-interference for the treatment of hypercholesterolemia. Preclinical data presented in November showed that subcutaneous injections of ALN-PCS "led to an up to 95% knockdown of plasma PCSK9 and an up to 67% reduction in low-density lipoprotein cholesterol." RNAi therapies are still very wet behind the ears, but this new approach is one that deserves monitoring.

Long story short, there's a lot going on with PCSK9 inhibitors and I didn't even hit every company involved! It's an exciting new treatment pathway that has the opportunity to revolutionize the way we treat high-cholesterol patients and it could be your ticket to big gains.