Correction: Macugen was erroneously referred to as an "antisense therapy" in the first version of this article. Instead, it is a RNA-based aptamer drug. It binds a protein at the cell's surface, so it does not have to enter the cell to take effect. Further, Pfizer and Eyetech Pharmaceuticals did not license Macugen from Isis. They licensed Macugen from Gilead. The paragraph containing these statements has been removed.

The FDA has agreed to review the new drug application (NDA) for Genta (NASDAQ:GNTA) and Aventis' (NYSE:AVE) Genasense, paving the way for its approval. Assuming that the FDA allows it into the marketplace, Genasense will be the first antisense-based therapy approved for cancer -- in this case, advanced melanoma. The Phase III trial showed a modest increase (two months) in survival, but the lack of any effective therapeutics for this deadly disease increases the likelihood of its final approval.

Antisense technology has been a long time in development. Always an attractive idea, researchers aim to turn off expression of problematic genes that can contribute to cancer, heart disease, and a whole assortment of maladies.

Unfortunately, treating humans is still a lot trickier than lab rats. Only one antisense drug, Isis Pharmaceuticals' (NASDAQ:ISIS) Vitravene, has been approved. The reason: It is difficult to design a drug that can survive well in the bloodstream and enter the target cells. Vitravene is injected directly into the eye, thus avoiding these problems.

Talkin' 'bout my generation
Any new technology goes through generational development. First, we had 13-inch black-and-white TV sets, then color, and now plasma TV sets that are bigger than any of the walls in my living room. The same kind of generational improvements have been going on with antisense technology.

These second-generation drugs aim to eliminate the problems experienced by the high-profile failures like Isis' Affinitak. Typically, these drug candidates have chemical modifications to the basic DNA-like structure that make them "greasier" and more likely to enter cells and avoid elimination from the blood.

Surprisingly, Genasense is a first-generation antisense molecule, and so I never gave it much chance for approval. Upon further review, it seems that some of these first-generation drug candidates may have some therapeutic benefit in certain diffuse cancers such as melanoma and leukemias. I still think, however, that the best chances for success are with the newer antisense drugs percolating through FDA trials.

Isis: the biggest pipeline
When anyone writes antisense, biotech investors automatically think "Isis Pharmaceuticals." Isis certainly has the deepest antisense pipeline of any biotech company. Its researchers are developing two second-generation compounds -- one for rheumatoid arthritis and another for type II diabetes, both in phase II. Following the lead of Amgen (NASDAQ:AMGN), Johnson & Johnson (NYSE:JNJ), and Abbott Laboratories (NYSE:ABT), Isis researchers hope to use their RA drug for psoriasis. An advantage to Isis' approach is that its candidate is a topical cream instead of an injection.

Also, Isis has a first-generation drug in phase III for Crohn's disease that has shown some promise, although the disease is a notoriously difficult target. Isis also has collaborations with several public and private companies, including such big shots as Eli Lilly (NYSE:LLY) and Amgen.

Isis trades right around $455 million in enterprise value. As W.D. Crotty wrote, Isis is not cash-rich, and it is hard to foresee it turning a profit before it needs to tap the debt or equity markets again, especially given the number of clinical trials the company is sustaining.

Genta: a one-trick pony?
Genta has diversified its pipeline beyond antisense and related siRNA technology, but Genasense and its associated drug candidates are still a major focus. Besides advanced melanoma, Genasense is in trials to treat chronic lymphocytic leukemia and multiple myeloma. As I mentioned above, these targets are probably the most promising for a first-generation antisense drug. A word of caution also applies here, though, because the company has stated that the results from the "most promising" trials would be announced first. Given the marginal survival benefit in melanoma, an investor must wonder about the benefits Genasense provides to leukemia patients.

Genta had $82.9 million in cash at the close of 2003 and burned through $50.1 million during last year. With an enterprise value north of $900 million, it's hard to argue that it is undervalued relative to its pipeline potential. It's reliant on Genasense and Ganite (a small molecule designed to prevent the bone loss in cancer patients that leads to severe pain and fractures) and doesn't have the earlier-stage candidates I'd like to see coming up the pipe.

Is Avi Biopharma ready for the big leagues?
Finally, I'd like to mention a small Portland, Ore., company, Avi Biopharma (NASDAQ:AVII), whose lead compound is a cardiovascular, not cancer, drug, for a change. The drug candidate, in phase II trials, aims to reduce restenosis, the common condition where an artery clogs up again after angioplasty. In a 57-patient trial, the addition of Resten-NG cut the restenosis rate to 8.3%. However, there is fierce competition from J&J's Cypher stent (restenosis rate ranging from 5.1% to 8.9%) and Boston Scientific (NYSE:BSX) and Angiotech Pharmaceutical's (Nasdaq ANPI) Taxus stent (7.9% restenosis rate).

Also in phase II trials for Avi Biopharma's antisense candidates include a treatment for polycystitic kidney disease (PKD), a very common genetic disorder that eventually causes kidney failure in most patients. There are no treatments for this disease, so the competitive space is wide open for the company. A drug for West Nile virus is in phase II, along with an interesting drug candidate that modifies the expression of a particular enzyme (cytochrome P450), potentially improving the pharmacological characteristics of many drugs.

Trading at an enterprise value of only $91 million with several early phase II trials in addition to a cancer vaccine program, Avi Biopharma might be the most intriguing of these three companies.

The best hope for antisense therapies lie in second- and third-generation drug candidates. This sector is not for the fainthearted, and the antisense subsector of biotech is an even riskier bet. But researchers might be turning the corner in finally fishing out the best drug candidates for the right disease targets.

Motley Fool contributor David Nierengarten, Ph.D., works with a biotechnology venture capital fund. He owns shares of Johnson & Johnson. He often contributes to Fool.com, is an active member of the TMF Community as DavidMN, and enjoys the Biotechnology discussion board.