By Nancy Volkers
Special To BioWorld Financial Watch
As the first five months of 1999 came to a close, the biotechnology industry found itself with more products in clinical trials than ever before.
Two of the many clinical trials begun recently involve antisense technology. Last month, Genta Inc., of Lexington, Mass., started a Phase I/IIa study of its lead compound, GS3139, which acts on production of the bcl-2 protein. Isis Pharmaceuticals Inc., of Carlsbad, Calif., began Phase II clinical testing of ISIS 2503 against several kinds of cancer. Phase I trials of ISIS 2503 in combination with approved chemotherapies also are planned for this year.
Antisense has been around for about a decade, but the first compound didn't break onto the U.S. market until late last year, with the approval of Isis' Vitravene (fomivirsen), a localized treatment for AIDS patients with retinitis induced by cytomegalovirus (CMV).
Isis partnered with Ciba Vision Corp., the Atlanta-based eye care unit of Swiss pharmaceutical company Novartis AG, to market Vitravene, which also recently received a positive recommendation in Europe on its marketing authorization application.
Last month Isis, Hybridon Inc. and Genta presented results of antisense compounds at the American Society for Clinical Oncology (ASCO) meeting (see chart p. 3).
Isis has six antisense drugs in its pipeline. The lead candidate, ISIS 2302, is in a pivotal trial for Crohn's disease and Phase II trials for renal transplant rejection. The compound is being also explored as a treatment for ulcerative colitis, psoriasis and asthma. Another compound, ISIS 13312, is in Phase I/II clinical trials for the treatment of CMV retinitis in AIDS patients. Other compounds are in early clinical or preclinical stages.
"It's a very rich pipeline, especially for a company that started with a technology that didn't exist," said Stanley Crooke, president and CEO of Isis. "This is a platform. There aren't many platforms; this is really one of them."
Antisense works by creating a short segment of nucleotides that complements, and therefore binds to, a specific disease-related messenger RNA, preventing it from producing proteins.
ISIS 2302 targets ICAM-1, one of a family of intercellular adhesion molecules involved in the inflammatory response.
In studies of steroid-dependent patients with Crohn's disease, Crooke said that approximately 50 percent of patients went into complete remission and were able to stop taking steroids. The results were published in Gastroenterology earlier this year.
"[ISIS 2302] produced remarkable effects and they were prolonged," he said. "This drug did something that no drug has ever been able to do get people better, get them off steroids and with no side effects. We had one patient removed from a study because his face was flushing and he was worried about it. Otherwise we actually had less side effects [in the treated group] than the placebo group."
ISIS 2302 is widely considered the next antisense candidate for FDA approval. Crooke said that if data remain positive, Isis will file an New Drug Application at the end of this year or early in 2000.
Anticancer Antisense Reveals Tumor Shrinkage
In antisense compounds being developed against cancer, a puzzle is how some of them could shrink tumors, rather than just stabilize disease. Taking into consideration the proteins that some of these drugs target, it makes sense that they would stop new cancer cells from forming, but it's unclear how they could destroy existing tumor cells.
"Based on general principles, one would think you would need to combine [an antisense compound] with something else," said Maggie Flanagan, senior director of product development for Hybridon, of Milford, Mass., which has five products in development and trials, and three others being researched by two spin-offs, MethylGene and OriGenix.
"But," Flanagan said, "every once in awhile you get a tumor cell line where you see effects on the tumor itself. So you have to wonder if, under certain conditions, you can put a cell in stasis long enough to either induce apoptosis or allow the body's immune system to act on it."
At a recent partnering conference, Hybridon presented data showing that GEM231, which is in Phase II trials, shrank tumors in a renal cell model when combined with ImClone System Inc.'s C225. Each therapy given alone produced stabilization for about 30 days, and then an increase in tumor volume. In a colon cancer model, GEM231 and paclitaxel caused tumors to grow only to 1 cm3 over 40 days, while either therapy alone produced tumors up to 3.5 cm3 over the same time period. Control tumors at 40 days, however, grew more than 5 cm3.
GEM231 targets protein kinase A Type I, which is produced by some tumors.
Genta's G3139 is its sole antisense compound, and is targeted to the bcl-2 protein, which is produced by some tumors. The drug is in eight Phase I/II studies, both as a single agent and in combination with chemotherapy. According to Robert Klem, chief technical officer, the National Cancer Institute also will be starting three trials of the compound.
"Our goal is to evaluate this compound in as many cancers as we can," Klem said. "We are now generating data that support that [G3139] is a specific downregulator of the bcl-2 protein. It does appear that the mechanism is working according to the mechanism we've supposed."
According to Klem, the bcl-2 protein stops the normal apoptotic process that would destroy cancer cells. By preventing the protein's production, G3139 allows apoptosis to resume, reducing tumor size.
Genta recently moved its headquarters from San Diego to Lexington, Mass.
Obstacles And The Next Generation
Oral drug delivery has been an obstacle in the past, though Klem said that in the case of G3139, oral delivery is not a goal.
"[Oral delivery] has not turned out to be an issue as far as we're concerned," he said, because cancer patients are usually already in the hospital or receiving other intravenous therapies. "For other therapies, it would be an issue."
Hybridon and Isis both are working toward oral formulations. Hybridon's GEM92 (HIV) and GEM231, and Isis' 2302 and 13312 have produced bioavailability when given orally.
The development of oral formulations is leading antisense technology into its second stage. The first stage making compounds with minimal toxicity and efficacy has given way to compounds with improved chemistries that last longer, produce fewer side effects, and which may be able to be administered orally, topically and via aerosol.
"Hybridon was the first to take an antisense compound to the clinic through the FDA, and the first to experience the very significant side effects of first-generation oligonucleotides," Flanagan said. "That has been a great impetus for us to study what those effects were due to, and to design molecules to prevent that."
GEM92, Hybridon "new chemistry" antisense compound against HIV, recently went through Phase I trials in Europe in which oral and intravenous administrations were given. According to Flanagan, Hybridon estimated a whole-body bioavailability of about 25 percent in the oral formulation.
ISIS 13312 is that company's first member of the "next generation" of product chemistries, which Crooke refers to as methoxyethylgapmers.
"We've found an increase in potency" with the new chemistry, Crooke said. "Instead of having to give it once every two days, we can dose once a week or even once every two weeks. There are also fewer nuisance side effects."
ISIS 13312, a "backup" to Vitravene, may only have to be given a few times a year, Crooke said. In trials, "we haven't had to give a second dose yet. The eye has very little nuclease activity, so the drug isn't degraded for a long time."
Crooke said ISIS 2302 has been given orally in animal studies with 25 percent to 30 percent bioavailability.
"We now need to convert what we've done and make a capsule or tablet," he said. "That's not basic research, but it's still plenty tough. That's why we did the deal with Elan."
The April deal gave Isis approximately $25 million from Dublin-based Elan Corp plc, Crooke said, including $15 million in equity at a premium and "a budget to get to oral delivery. In addition," Crooke said, "Elan has a lot of expertise in exactly the areas we need it." (See BioWorld Today, April 14, 1999, p. 1.)
Overall, the outlook for antisense is good, though the technology remains concentrated in a dozen or so companies. Flanagan cited several reasons for the specialization.
"The field is still relatively new," she said. "Also, it had some really bad press in the early 1990s. People naively thought that the side-effect profile would be nonexistent because of the specificity, but it's the entire molecule that interacts with the body. Those not working in the field thought it would be squeaky-clean medicine, and no medicine is squeaky clean."
Isis (NASDAQ:ISIP) has a market cap of approximately $280 million. Hybridon (OTC:HYBN) has a market capitalization of approximately $7.2 million, while Genta (NASDAQ:GNTA) has a market cap of about $37.7 million.