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When it comes to developing billion-dollar blockbuster drugs, the odds are stacked against biotech companies. About 90% of drugs that enter clinical trials fail, and of those that do eventually get approved, few achieve blockbuster status. Regardless, our top Motley Fool contributors think there are three small biotech companies that can overcome the odds and eventually launch a top seller.

Cheryl Swanson: If you've heard of Enanta Pharmaceuticals (NASDAQ:ENTA), you probably know it as AbbVie's small-cap partner in the development of Viekira Pak, one of a new wave of treatments for hepatitis C. But the tiny biotech is also developing a new type of antibiotics -- the first in 30 years -- called bicyclolides.

Enanta's funding partner on that venture is none other than the National Institute of Allergy and Infectious Diseases, or NIAID. Not only does NIAID's partnership provide the possibility of up to $43 million in research, but the FDA also began special programs for such drugs through the GAIN Act. Such drugs now have a five-year exclusivity extension, as well as an expedited approval process. Those benefits, along with the urgent and growing threat of resistant strains, are nothing to be sneezed at.

Enanta is chasing another potential blockbuster in nonalcoholic steatohepatitis, or NASH, a liver-scarring disease that affects around 5% of Americans. Enanta's NASH program is in the early stage, but the company has a tidy cash hoard to fund research. Enanta has already pocketed $227 million from AbbVie for Viekira Pak, and the drug's recent EU approval will send another $80 million its way, as well as royalties on future sales.

Enanta's NASH program looks particularly promising, since it's an extension of the company's core competency in hep-C. Investing in small-cap biotechs can pay off, and I think Enanta looks promising, but remember that how investigational compounds will perform in actual trials is next to impossible to predict. Be careful out there.

Todd Campbell: Biotechnology waste bins are packed with clinical trial failures, and, as Cheryl alluded to, that means it's incredibly difficult for investors to accurately predict which of today's emerging biotech companies is likely to hit the jackpot with a billion-dollar blockbuster.

However, one company that may have what it takes to overcome the odds and deliver that kind of success is Ophthotech Corporation (NASDAQ:ISEE). I like Ophthotech's chances for a few reasons. First, Ophthotech's Fovista targets age-related macular degeneration, an indication that already supports Novartis' and Regeneron's multibillion-dollar blockbuster drugs Lucentis and Eylea, respectively.

Second, Fovista is in final phase 3 trials following phase 2 results that prompted Novartis to ink a collaboration deal for international rights to Fovista that could be worth $1 billion, plus royalties, to Ophthotech.

Third, since Fovista is being studied for use alongside Lucentis and Eylea, rather than instead of both, Ophthotech doesn't have to convince regulators that Fovista works better than them; it only has to show regulators that it improves their results. For those reasons, I think that a late-stage trial success could put Ophthotech's Fovista in a position to be a billion-dollar drug.

Brian OrelliIntercept Pharmaceuticals' (NASDAQ:ICPT) obeticholic acid, or OCA, could be a megablockbuster, but probably not in the first indication it's approved for.

The biotech has already presented positive data from a phase 3 trial testing OCA in a chronic liver disease called primary biliary cirrhosis, or PBC. The company plans to submit its marketing application to the FDA and EU regulators in the first half of this year. If approved, OCA will be used in the approximately 40% of patients with PBC who don't adequately respond to the current standard of care.

The real upside for Intercept is in NASH, a large, growing liver disease for which there aren't any approved drugs. Phase 2 data suggests that OCA is helping NASH patients, but the proper endpoints to measure efficacy are unclear. Intercept plans to start a phase 3 trial in NASH patients in the first half of this year, after working out the details of the trial with U.S. and EU regulators.

Intercept trades well off its 52-week high that was set after the phase 2 NASH trial was deemed a success, as investors are worried about some safety issues and perhaps some realizations that phase 2 success doesn't necessarily guarantee a positive phase 3 result.

I think if you're going to buy Intercept right now, you should own it for the potential in PBC and stick to treating NASH and primary sclerosing cholangitis, another liver disease that's even further behind, as potential upsides. At a market cap of $4 billion, there's already quite a bit of the sales for PBC priced in, but fortunately there's a high likelihood of approval for that indication, at least.