Genta Seeks Therapeutic Product Approval

April 1, 2006 (Vol. 26, No. 7)

After a Decade of R&D, Company Hopes for the Validation of its Platform

Ten years after starting the first human trials of its lead anticancer drug Genasense (oblimersen sodium injection), Genta (www.genta.com) is seeking marketing approval for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) when Genasense is given in combination with fludarabine and cyclophosphamide. In late December, the company filed an NDA for Genasense, a pro-apoptotic drug.

The NDA, which already has both orphan drug and fast track designation, was accepted for review by the FDA and has been granted an action date in October 2006.

In January, Genta also submitted a marketing authorization application (MAA) to the European Medicines Agency for the approval of Genasense in combination with dacarbazine for the treatment of advanced malignant melanoma. &#8220Genasense is a breakthrough drug for oncology, and we look forward to getting the drug into the hands of physicians and patients as soon as possible,&#8220 says oncologist Raymond P. Warrell, Jr., M.D., the company&#8217s CEO.

Furthermore, the approval of Genasense would give economic validity to the entire therapeutic platform of drugs based on RNA and DNA technology. &#8220The scientific validity of the platform has been there for a long time,&#8220 says Dr. Warrell, but &#8220economic validation is still missing.&#8220

Based in Berkeley Heights, New Jersey, Genta was founded in San Diego in 1988 as a spinoff of GenProbe (www.genprobe.com to discover therapeutics based on the then new antisense technology. Genasense began clinical testing in 1995. Dr. Warrell joined Genta in late 1999 to guide the company&#8217s development of therapies for cancer, based on proprietary antisense and small molecule technologies.

This is Genta&#8217s second attempt to obtain FDA approval for Genasense in the U.S. The company withdrew a previous NDA for malignant melanoma in mid-2004 when the FDA&#8217s oncology drug advisory committee voted not to recommend it.

Since then, Genta scientists have completed long-term follow-up of patients enrolled in the this trial which is the basis of the current MAA in Europe. Long-term follow-up suggest that &#8220the maximum benefits of Genasense become apparent later rather than earlier,&#8220 says Dr. Warrell.

When the melanoma NDA was submitted in 2004, patients had been followed for a minimum of only seven months, and the long-term outcomes were not apparent. Recent data reveal that Genasense works best when given to patients before other drugs supervene and trigger mechanisms of drug resistance. Moreover, in the current NDA being reviewed by FDA, complete or partial remissions that occur in Genasense patients are maintained for up to 24 months, according to Dr. Warrell, whereas patients not given Genasense relapse significantly sooner.

Targets Bcl-2

Genasense inhibits the production of Bcl-2, a protein made by cancer cells that prevents chemotherapy-induced apoptosis. Bcl-2 regulates a critical pathway in apoptosis, and cancer cells often develop multiple defects in this pathway that delay or prevent cell death, leading to resistance to chemotherapy. Levels of Bcl-2 are high in hematologic cancers, such as leukemia, lymphoma, and myeloma, as well as solid tumors, such as melanoma and those in the lung, breast, colon, and prostate.

Antisense drugs are designed to block the production of specific proteins, thereby potentially minimizing side effects. Genasense consists of a small, chemically modified strand of DNA that complements and binds the messenger RNA that codes for Bcl-2.

Once Genasense binds messenger RNA, subsequent protein production stops. By reducing the amount of Bcl-2 in cancer cells, Genasense enhances the killing effects of anticancer drugs. Genasense represents &#8220a tremendous opportunity to overcome one of the fundamental major causes of the inherent resistance of cancer cells to be killed by chemotherapy,&#8220 says Dr. Warrell, and &#8220to broadly amplify the effectiveness of current cancer drugs.&#8220

Genta&#8217s antisense platform also includes a compound that targets c-myb, a gene that acts as a global regulator of cell growth and differentiation, whose function is disrupted in cancers of the blood, breast, pancreas, and colon. Known as G4460, the compound has completed early Phase I trials in patients with hematologic cancers and late Phase I development in patients with solid tumors will start soon.

Clinical Evidence

CLL is the most common form of leukemia in adults with 8,000 patients diagnosed yearly, according to the American Cancer Society. More than 60,000 people in the U.S. have CLL. A Phase III trial of 241 patients confirmed that the addition of Genasense to fludarabine and cyclophosphamide significantly increases the proportion of patients who achieve complete or nodular partial responses.

The results, which are the basis of the current U.S. NDA, showed that 17% of patients in the Genasense group experienced complete or nodular partial responses, compared to only 7% in the chemotherapy-alone group. The clinical responses in the Genasense group lasted significantly longer, explains Dr. Warrell. The complete response to Genasense included relief of disease-related symptoms and recovery of normalization of blood counts.

The advanced malignant melanoma trial was the largest randomized controlled trial ever conducted in patients with the disease. At 139 sites in nine countries, 771 patients were randomly assigned to receive the standard chemotherapy drug dacarbazine alone or in combination with Genasense.

The data from 24 months of follow-up show that about three times as many patients in the Genasense group experienced complete response compared to the dacarbazine-alone group. About twice as many patients taking Genasense achieved a durable response (lasting more than six months) as those in the dacarbazine group.

Three other randomized trials are enrolling patients to evaluate the addition of Genasense to standard chemotherapy for the treatment of small-cell-lung cancer, non-small-cell-lung cancer, and hormone refractory prostate cancer. Company researchers are developing a subcutaneous injectable form of Genasense that concentrates by fivefold the current solution used in continuous intravenous infusions. &#8220We want to establish a patient-friendly regimen to expand cancer care,&#8220 says Dr. Warrell.

While awaiting the FDA&#8217s decision about Genasense, Dr. Warrell is gearing up for sales and evaluating potential marketing partners. &#8220We have enough drug manufactured to support a worldwide launch,&#8220 he says. The company is building a commercial infrastructure and discussing partnerships with a number of firms. Genta also plans to file for regulatory approval of Genasense in Australia, where melanoma is a serious health problem.

The company&#8217s other product Ganite (gallium nitrate injection) is approved for the treatment of cancer-related hypercalcemia. This extreme bone-depleting condition, in which blood calcium levels rise to life-threatening levels, affects 20% of cancer patients. Ganite acts similarly to the bisphosphonate class of bone resorbing drugs that slow bone turnover. The current drug must be given by continuous intravenous infusion. &#8220We continue to make good progress in developing an oral formulation,&#8220 asserts Dr. Warrell.