Antisense and Sensibility in RNA Therapeutics - RNAi

STAYING THE COURSE
In light of these obstacles, several companies have abandoned their antisense efforts. Yet some are forging ahead. Recent clinical results, though largely preliminary, suggest their persistence could be paying off.
"I'm hopeful that there will be multiple antisense drugs on the market," says Frank Bennett, vice president of antisense research at Isis. Along with licensees including Eli Lilly & Co., Vancouver-based OncoGenex, and Australia-based Antisense Therapeutics, Isis has several ASOs in clinical trials. In August 2004 the company announced promising results from a Phase I trial using an ASO to silence expression of apoB-100, which plays a role in elevating cholesterol levels. The drug caused significant decreases in low-density lipoproteins, very-low-density lipoproteins, and total cholesterol levels, as well as lowered apoB-100 levels.[2]
Also conducting clinical trials is Genta of Berkeley Heights, NJ, a pharmaceutical company developing both RNAi and antisense therapies. At the American Society of Hematology meeting last December, Genta announced results from a Phase III trial of its antisense drug Genasense, which targets Bcl-2, in patients with advanced chronic lymphocytic leukemia. According to a company press release the drug "significantly increased the proportion of patients who achieved a major response, which was the primary end-point of the trial."[3] The news came just one week after the company announced disappointing data from a Phase III trial of Genasense in patients with multiple myeloma.[4]
The news for Isis has likewise been mixed. The company announced December 2 that in two Phase III trials of patients with Crohn disease, alicaforsen, an antisense molecule against ICAM-1, "did not demonstrate statistically significant induction of clinical remissions compared to placebo."[5] But the company intends to stick with the drug for ulcerative colitis, based on positive Phase II studies.
"What has largely been viewed [in the pharmaceutical industry] as a disappointment for antisense therapeutics is something that's going to turn around," says Scott Cormack, CEO of OncoGenex, whose ASO candidate to target the expression of clusterin, a protein that inhibits cells from responding to chemotherapy, recently completed a Phase I clinical trial.
Cormack compares the progress of antisense technology to that of other highly hyped technologies. After the excitement and fanfare fade, "the realization of implementing and making it a commercial reality" sets in, he says. "If you asked seven years ago if monoclonal antibodies would ever be a success, people would say that it would be a failure. It didn't deliver on being the [touted] magic bullet, but then there was an inflection point in the technology to make monoclonal antibodies a major opportunity for novel medicines."
ALTERNATE AVENUES
Silencing gene expression posttranscription is not the exclusive domain of ASOs and RNAi. Others are developing drugs based on catalytic RNAs called ribozymes. Like RNAi, these sequences target and destroy specific mRNAs. But where RNAi relies on a protein-RNA complex to do its work, the ribozyme cleaves the RNA itself.
Facing the same kind of difficulties as ASOs, ribozyme therapeutics have made progress toward the clinic. Boulder, Colo.-based Sirna Therapeutics (formerly Ribozyme Pharmaceuticals) has tested some of its ribozyme candidates in human clinical trials, including Angiozyme, an anticancer drug that targets vascular endothelial growth factor, and Herzyme, which targets human epidermal growth factor 2 in patients with breast cancer. Neither trial has released results yet. Johnson & Johnson is currently recruiting patients for a Phase II trial of its anti-HIV ribozyme OZ1.
Another strategy involves microRNAs, which operate in a fashion akin to RNAi. In October Isis Pharmaceuticals and RNAi therapeutics company Alnylam Pharmaceuticals of Cambridge, Mass., announced they had licensed key patents from the Max Planck Society to develop therapeutic applications of microRNAs.
Whether microRNAs or any other transcript-targeting strategy will ultimately prove successful in the clinic is uncertain. What is certain, however, is that all this R&D will surely advance future development efforts, by teaching researchers how to stabilize and deliver their drugs more effectively. Says Raymond P. Warrell, Jr, chairman and CEO at Genta: with "the richness of the antisense experience," the development timeline for RNAi will be "markedly accelerated."