Almost four years after starting a research collaboration with Novartis Pharma AG, Vertex Pharmaceuticals Inc. secured another $100 million in funding as it nears the clinic with small-molecule kinase inhibitors.

The companies came together in May 2000 and since have worked to find targets in the protein kinase gene family. They amended the agreement on Tuesday, giving Vertex another $100 million in research revenue through 2006, as well as potential milestone payments.

"It allows us to deliver drug candidates to Novartis at an earlier stage for development, essentially relieving Vertex of an obligation to conduct early clinical development," said Michael Partridge, director of corporate communications at Cambridge, Mass.-based Vertex. "And also it is giving us an opportunity for milestones in association with product advancements."

In 2000, when the original deal was formed, it potentially was worth $800 million for Vertex. The collaboration allowed for an additional two years beyond 2004 of early development work for drugs discovered late in the research phase of the collaboration. (See BioWorld Today, May 10, 2000.)

"There was an option to terminate the collaboration, but now it's committed research funding through 2006," Partridge said.

While Vertex continues to be responsible for drug discovery, the revised agreement allows for a more rapid transfer of a candidate in the research phase at Vertex to clinical development in the hands of Basel, Switzerland-based Novartis. Vertex will nominate preclinical drug candidates. If accepted, Novartis will cover all preclinical and clinical development of such candidates and would continue to cover research funding until 2006. Vertex would receive up to $35 million in license fees and milestones for each preclinical drug candidate accepted by Novartis, if the candidate is successfully developed. About $10 million of this money will be granted to Vertex up front.

In addition to milestone payments, Vertex would be entitled to royalties as laid out in the original agreement.

"In all of Vertex's agreements with any company our royalties are in the double digits," Partridge told BioWorld Today.

Novartis, which gains exclusive worldwide development, manufacturing and marketing rights to the preclinical candidates it accepts from Vertex, can pursue research in the kinase field independently of Vertex. And under terms of the original agreement, Vertex may opt for a set period of time to continue development with Novartis of two kinase inhibitors for oncology indications, VX-680 and VX-528, or it may choose to develop and commercialize the candidates on its own. Under the terms of the amended agreement, Novartis also has an option to develop another kinase inhibitor, VX-608, for neurological disease.

Vertex plans to advance several compounds into preclinical development this year for indications such as cancer, inflammation and autoimmune disease.

"We're definitely moving toward having multiple products in the clinic and that's a reflection of the research progress we've made," Partridge said. "We have VX-680, which is really on the cusp of beginning clinical development."

Partridge said a clinical trial of VX-680 could begin in the first half of this year in multiple cancer indications. Preclinically, the drug candidate has been studied in leukemia, colon cancer and pancreatic cancer.

"We have the option at any time to continue it under the collaboration or to choose to develop it ourselves," he said.

All three of the lead kinase inhibitors - VX-680, VX-528 and VX-608 - were developed as part of the collaboration between Vertex and Novartis.

Protein kinases are enzymes that help to propagate biochemical signals in many biological pathways. Vertex groups protein targets according to structural similarity, in order to leverage medicinal chemistry and develop drugs more efficiently. The company's researchers have determined the atomic structure of more than 20 kinase drug targets and more than 300 kinase inhibitor co-complexes. The researchers have published interpretations of how mutations in kinases, like Flt-3, can lead to uncontrolled cellular proliferation and cancer. Vertex has filed for more than 90 patents covering hundreds of distinct chemical scaffolds as a result of its library of kinase inhibitors.

Aside from its collaboration with Novartis, Vertex and partner GlaxoSmithKline plc, of London, recently won FDA approval of the HIV protease inhibitor Lexiva. (See BioWorld Today, Oct. 22, 2003.)

Vertex's stock plunged in November on news that the company and partner Aventis SA, of Strasbourg, France, stopped a Phase IIb trial of pralnacasan for rheumatoid arthritis due to liver abnormalities in an animal toxicology study. The drug also did not meet its endpoint in a Phase II study treating patients with osteoarthritis, the company said in January. (See BioWorld Today, Nov. 12, 2003.)

Vertex's stock (NASDAQ:VRTX) fell 38 cents Wednesday to close at $9.42.