ISIS Pharmaceuticals (NASDAQ:IONS) is a drug developer that is most famous for its RNA interference (RNAi) technology. Although early clinical progress in RNAi was slow due to crippling toxicity and delivery issues, ISIS Pharma (and its peers) have truly refined the delivery of RNAi into an art form. Using novel technologies that significantly improve the efficiency of RNAi delivery through the cell membrane, these companies are now developing "FDA-approvable" products that are good enough to compete with traditional drugs for market share.
The FDA's approval of Kynamro (mipomersen) in 2013 – the first RNAi therapy on the market – also helped to convince investors of the technology's viability. And despite some lingering concerns over toxicity, it seems that Kynamro and RNAi are here to stay.
Whats so great about RNAi?
What makes RNAi so interesting to the pharmaceutical industry is its potential to knock out an unwanted protein production at the genetic level, which gives pharmaceutical companies the power to eliminate proteins that are directly or indirectly associated with disease. Because of their mechanism, RNAi drugs can be used against untreatable diseases like amyloidosis that are based upon the buildup of harmful proteins.
Because we don't know what every protein actually does in the body, the RNAi field is still very open-ended righ tnow. But there are a few targets that have already demonstrated promise in early and mid-stage clinical trials.
Perhaps the most promising target in the ISIS pipeline is ApoCIII – a protein that is responsible for transporting triglycerides in the blood.
ApoCIII inhibition could make a blockbuster
Through years of research, the medical community found a strong link between a protein called ApoCIII and high tryglyceride levels, which are associated with heart disease.
ISIS is the first company that is developing an RNA interference-based drug that is designed to knock out production of ApoCIII. The product – currently referred to as ISIS-APOCIIIRx – recently produced two sets of phase 2 data for hypertriglyceridemia and for a very rare genetic disease known as familial chylomicronemia syndrome (FCS). Both diseases induce elevated triglyceride levels, which elevate cardiovascular risk.
In the Phase II trial for FCS, ISIS-APOCIIIRx lowered triglycerides by 69% in three patients. While that population is way too small to make an actual drug efficacy claim, its important to consider that there are only ~300 patients with FCS in the United States. It will be very hard to determine the extent of ISIS-APOCIIIRx's efficacy against the disease, but I believe the FDA would be very lenient toward this program.
The figures from the hypertriglyceridemia trial, on the other hand, do show us that ISIS-APOCIIIRx lowered triglycerides in high triglyceride diabetics by 69% with a p-value of 0.02 after 13 weeks. This p-value proves that the triglyceride-lowering effect is statistically significant (aka - the math checks out), and that ISIS-APOCIIIRx has a good chance of becoming the most efficacious triglyceride-lowering drug currently known.
That will be a big deal for the millions of patients who struggle to lower triglyceride levels in their bloodstream.
Also consider that ISIS-APOCIIIRx also increased HDL-C (aka "good cholesterol") by 42%, which is another sign that the drug could do wonders against heart disease.
Because we don't have Phase III trial data yet, it's hard to say whether ISIS-APOCIIIRx truly is ISIS Pharma's best overall program at this point. But we can say is that this drug has the potential to become the absolute best option for ~4 million patients with "very high" (>500 mg/dL) triglyceride levels who have heightened risk for heart disease.
Refined fish oil pills, like Glaxo's Lovaza and Amarin's Vascepa, are also very popular for patients with very high triglyceride levels, but they can only lower triglycerides by about 20-30% after three or four months of therapy along with a statin. Many over these patients need something far more potent to bring their triglycerides to a reasonable level.
ISIS is also way ahead of the RNAi competition – at least in terms of ApoCIII. Alnylam has an ApoCIII program, but it would probably take a number of years to catch up to ISIS in hypertriglyceridemia.
ISIS intends to start Phase III trials for ISIS-APOCIIIRx before the end of this year, so any investors who own this company should pay close attention to the drug that could become this company's staple product five years from now.