Skip to main content Back to Top

10/18/2002

Antisense Drugs Progressing Through Product Pipelines

Kate Traynor

For four years, fomivirsen sodium has been the only antisense drug marketed in the United States.

But the product could eventually be joined by other antisense drugs—if the results of clinical testing demonstrate the worth of these rationally designed drugs as treatments for cancer and other diseases.

Antisense drugs are short chains of oligonucleotides that inhibit protein translation by specifically binding to small segments of messenger RNA (mRNA) responsible for driving the production of disease-causing proteins. The sequence of an antisense drug is designed to be complementary to its mRNA target and to render that target inactive.

The allure of antisense technology is that it inhibits the genetic processes that occur before detrimental proteins are produced. Most traditional drugs, in contrast, interfere with the action of a disease-causing protein without disrupting its production.

Clinical studies suggest that some antisense drugs may work best in combination with other therapies, particularly for the treatment of cancer. Several companies, some of which are described below, are developing antisense therapies.

Fomivirsen breaks the barrier. FDA granted marketing approval for fomivirsen in 1998 for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS who cannot tolerate or do not respond to other therapies for the ocular infection. Fomivirsen, which was developed by Carlsbad, California-based Isis Pharmaceuticals Inc., is composed of 21 nucleotides complementary to a CMV mRNA sequence that is critical to the production of infectious virus.

When injected into the eye of a patient with CMV retinitis, fomivirsen seems to inhibit the replication of the virus locally but does not cure CMV retinitis or affect viral production elsewhere in the body.

The drug is administered in two doses delivered two weeks apart, followed by an injection of fomivirsen every four weeks.

Although fomivirsen is not given in combination with other drugs to treat the ocular CMV infection, patients who are treated with the product are typically receiving antiretroviral therapy to combat HIV infection.

Also from Isis. Two other antisense drugs developed by Isis are in Phase III clinical trials. The antisense product that seems to be closest to market is a protein kinase c-alpha inhibitor that is being tested in patients with small-cell lung cancer. According to the company’s 2001 annual report, Isis has partnered with Eli Lilly & Company to develop the product, and the companies expect to file the new drug application in 2003 or 2004.

Isis’s other antisense product in Phase III trials, an intercellular adhesion molecule-1 (ICAM-1) inhibitor, is undergoing a second round of clinical testing in patients with Crohn’s disease after initial study results proved disappointing.

The ICAM-1 inhibitor is also in Phase II testing for psoriasis and ulcerative colitis. Isis has four additional products in Phase II testing for the treatment of a variety of diseases.

Most of the antisense drugs in the company’s product pipeline are delivered by injection, but Isis is exploring ways to make the medications orally active.

Genta. Genta Incorporated, of Berkeley Heights, New Jersey, is conducting Phase III studies of the antisense drug Genasense for the treatment of malignant myeloma, multiple myeloma, and chronic lymphocytic leukemia. Genasense, a Bcl-2 inhibitor, has been granted orphan drug status by FDA for the treatment of these cancers and acute myelocytic leukemia.

The company is conducting a Phase II trial of Genasense in patients with acute myelocytic leukemia.

Genta had initially expected to submit the new drug application for Genasense by the end of this year, but the company now predicts that the product will be ready for FDA review next summer. Genta signed an agreement with Aventis this past spring to develop and market Genasense.

AVI BioPharma. Oregon-based AVI BioPharma Inc. has developed what the company calls "Neugenes" Technology, in which the antisense oligonucleotide is constructed on a fully synthetic backbone.

The company claims that this design improves the stability of its antisense drugs.

AVI announced in August that it expects this year to complete a Phase I/II study examining the use of an antisense drug in patients with solid tumors. The drug, Resten-NG, was designed to block the expression of the c-myc protooncogene.

AVI is also conducting Phase II testing of Resten-NG to treat cardiovascular restenosis, a complication that occurs in some patients who undergo balloon angioplasty.

NeoPharm. NeoPharm Inc., of Lake Forest, Illinois, has begun Phase I/II testing of the antisense drug Lerafaon. The drug is designed to block the formation of raf-1, a protein that is thought to reduce cellular susceptibility to radiation.

NeoPharm hopes that the antisense drug will increase the sensitivity of cancer cells to radiation.

To increase the stability of the antisense oligonucleotide, NeoPharm uses a proprietary process to encapsulate the drug in a liposome derived from a synthetic cardiolipin. The company also uses this encapsulation process to deliver other experimental antisense and conventional drug therapies.