Novartis files globally for approval of Glivec

Swiss pharmaceutical giant submitting applications worldwide

Novartis is submitting applications with health authorities globally seeking marketing authorization for Glivec (STI571) for the treatment of patients with chronic myeloid leukemia (CML) in the blast crisis, accelerated phase or in chronic phase after failure of interferon-alpha therapy.

These filings, announced March 1 and occurring within approximately one week of each other, continue the company's efforts to accelerate the rapid pace of this novel agent's global development.

Submissions have taken place in the U.S. and the European Union, and the filing for Switzerland was expected as of this writing (March 8). The filing will be submitted in Japan and other countries shortly as well.

Based on early study results, the FDA gave Glivec fast track status during development for the myeloid blast crisis phase indication of CML. Typically, such designations are given to drugs with potential to address unmet medical needs or improve upon available therapy for the treatment of a serious or life-threatening condition. In addition, Glivec was granted orphan drug designation by the U.S., the European Union and Japan.

The applications come in less than three years after the initiation of clinical trials with the agent, ahead of an industry average of nearly five years.

The filing is based on study results from approximately 1,230 patients in 32 centers located in five countries. To date, Glivec has been studied in more than 5,000 patients in 30 countries.

"We believe that Glivec marks the beginning of a new stage in cancer therapeutics development," said Dr. David Parkinson, vice president of clinical research, Novartis Oncology. "By understanding the molecular abnormality causing the cancer — CML in this case — we can design drugs like Glivec that target the fundamental biochemical abnormalities associated with cancers, with better treatment results and fewer toxic effects on normal cells."

About CML and Glivec

CML is one of the four most common types of leukemia. Worldwide, the disease occurs in one to two cases per 100,000 people per year and is responsible for 15 to 20 percent of all adult leukemias.

Glivec represents a new type of antiproliferative agent called a signal transduction inhibitor (STI), which has been shown to have the potential to interfere with intracellular signaling pathways that have implications in tumor development.

Glivec molecularly targets an abnormal protein produced by the specific chromosomal abnormality called the Philadelphia chromosome, which is present in a majority of patients with CML.

The filing is supported by data from three Phase II studies. The endpoints of the studies included both hematologic and cytogenetic response rates. A cytogenetic response indicates the disappearance or reduction of Philadelphia chromosome-positive cells.

"The development of Glivec has been a tremendous experience for the investigator community," said Dr. Brian Druker, professor of medicine at Oregon Health Sciences University in Portland and principal investigator for the Phase I CML study. "Glivec has offered us not just an opportunity to provide a drug to patients that has truly changed the course of their lives, but has allowed us to evaluate a drug that may be the first of many that may radically change how cancer is treated."

In clinical trials, Glivec has been generally well tolerated, with side effects including nausea, muscle cramps, edemas, skin rash, diarrhea, heartburn, and headache, which have been largely mild or moderate in intensity.

Fewer than 3 percent of patients have experienced serious side effects such as the potential for liver toxicity, fluid retention syndrome, and hemorrhages.

Additional research underway

The Philadelphia chromosome involved in CML is present less commonly in patients with acute lymphocytic leukemia (ALL). Some patients with these rare forms of leukemia were included in the Glivec clinical trials.

Additionally, in a program of smallscale, proof-of-concept studies, Novartis recently began investigating the role of Glivec in select types of solid tumors where the biological mechanisms suggest potential activity. These pilot studies are intended to establish the basis for further clinical trial study.

Novartis accelerated development

As a result of the highly promising Phase I results, which eventually drew widespread demand for Glivec (STI571 at that time) by CML patients, Novartis recognized the potential impact this agent could have on the CML community and prioritized and accelerated the compound's development with all diligence. Additional resources were devoted to supporting, expediting and expanding the clinical program. Novartis also increased the technical resources and capacities devoted to the product, transferring production of Glivec directly to large, commercial-scale manufacturing facilities.

Manufacturing Glivec entails many processes to ensure a high purity and reproducible drug substance, and the company initiated measures that decreased the complex procedures to a production time of approximately 9 to 12 months.

"Since the first promising data emerged on Glivec, Novartis began taking extraordinary steps to expedite the development program," said David Epstein, president of Novartis Oncology. "The enthusiasm surrounding this drug has been incredible.

"Filing the registration package in just 32 months after the first human dosing demonstrates the dedication of Novartis employees and investigators who have devoted themselves to making Glivec available to patients in need," Epstein added. "The outpouring of support from the patient community has provided a real boost to all of us."

In the U.S., patients and physicians interested in more information on these studies can contact the Novartis Oncology Clinical Trials Hotline at 1- 800-340-6843, or the company's Web site, www.novartisoncology.com.

The company did qualify its "forward-looking statements," pointing out the use of such terminology as "believe," "highly promising," "potential impact," "may drastically change" or similar expressions. "Such statements," said the company's press release, "reflect the current views of the company with respect to future events and are subject to certain risks, uncertainties and assumptions. Many factors could cause the actual results, performance or achievements of Glivec to be materially different ..."