ISIS Pharmaceuticals; Source: Google Maps

It's been a tough year for ISIS Pharmaceuticals (NASDAQ:IONS) investors. After a remarkable 281% return in 2013, shares have gone absolutely nowhere in 2014. That flat-line return is even more disappointing considering that the S&P 500 is up 8.9% and the Nasdaq Biotechnology index is up 19% this year.

So, what is it about ISIS that's keeping a lid firmly in place on its share price? It's certainly not a lack of development programs. The company has over 30 drugs in various clinical trials. And it's not because the company's cash spigot is tapped out. Most of those products in development are partnered with big pharmaceutical companies that are footing some of its research bill.

Instead, ISIS's unremarkable return this year may be because of its underwhelming launch of a new drug, the failure of a drug in mid-stage trials, and the fact that it may be years before drugs in its overflowing pipeline make it to market.

ISIS Chart

ISIS data by YCharts

Irons in the fire
ISIS uses its in-house technology to develop antisense RNA drugs -- single stranded molecules that can interrupt how genes work. The concept is endlessly intriguing.

In agriculture, antisense RNA has been used to alter how tomatoes mature, allowing farmers to grow firmer ripened fruit. In medicine, using antisense RNA has the potential to prevent the duplication of unwanted, faulty genes. That means that any number of genetic diseases could possibly be treated using antisense RNA.

As a result, ISIS product pipeline includes drugs that target both common disease like diabetes and uncommon indications such as TTR amyloidosis, a life-threatening disease in which proteins build up in the organs like the liver or heart.

Overall, the company lists 34 ongoing studies in its pipeline, including five that are in phase 3 trials. However, only one drug -- Kynamro -- has made it to market so far and therein may lay the problem.

Source: ISIS Pharmaceuticals

Little to cheer
Kynamro got the FDA nod for use in treating a rare form of high cholesterol in January 2013. The FDA approved Kynamro for use in homozygous familial hypercholesterolemia, or HoFH, based on studies showing Kynamro, when used alongside other approved cholesterol medication, lowered LDL levels by 25%. But the market for Kynamro has been slow to develop. In fact, sales have been so small that ISIS and its partner, Sanofi, don't even bother to break them out for investors.

Kynamro's underwhelming launch can't be blamed on HoFH's tiny patient pool. At the same time that Kynamro has failed to establish a toehold, Aegerion Pharmaceuticals' Juxtapid, which won approval a month before Kynamro, has grown into a HoFH therapy producing $36 million in second quarter sales, up 34% from the first quarter.

Instead, Kynamro's troubles may be tied to a black box warning label cautioning doctors and patients about liver toxicity and a risk evaluation and mitigation strategy that calls for patient registration and testing prior to the drug being prescribed.

Kynamro may also be struggling to win scripts due to concerns that patients develop antibodies to it, which mean that Kynamro's effectiveness may drop over time.

Kynamro's struggle is emblematic of how difficult it is to develop a delivery system that can be used to specifically target cells without exposing patients to other risks.

That challenge was evident this past summer when iCo Therapeutics and ISIS's iCo-007, a drug under development for diabetic macular edema, failed to deliver in phase 2 trials. Patients receiving iCo-007 saw no improvement in their ability to read letters on a standard eye chart and instead saw their ability to read those letters drop.

Fool-worthy final thoughts
RNA companies including ISIS were some of 2013's biggest winners, but it seems that investors are content to sit on their hands until another drug candidate establishes the billion-dollar potential of antisense technology.

There are several catalysts coming into the end of the year that could help reignite interest in ISIS shares. The company is launching phase 3 trials for ISIS-SMN, a treatment for spinal muscular atrophy, and ISIS-APOCIII, a therapy for Familial Chylomicronemia Syndrome. The company also expects to release phase 2 study data for ISIS-FXI, an anticlotting drug, and ISIS-GCCR and ISIS-PTP1B, two drugs that may help better control glucose levels in diabetics. Investors hope that those trial results will be enough to reignite shares.

Todd Campbell has no position in any stocks mentioned. Todd owns E.B. Capital Markets, LLC. E.B. Capital's clients may or may not have positions in the companies mentioned. Todd owns Gundalow Advisors, LLC. Gundalow's clients do not have positions in the companies mentioned. The Motley Fool recommends Isis Pharmaceuticals. Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.