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Mar 05, 2012
 |  BioCentury  |  Product Development

Kalydescopic vision

Vertex's Kalydeco for cystic fibrosis validates venture philanthropy model

FDA'sapproval of Kalydeco ivacaftor for a small subset of cystic fibrosis patients - three months ahead of the PDUFA goal and five and a half years after Vertex Pharmaceuticals Inc. started the first clinical trial of the molecule - is powerful proof that the alignment of venture philanthropy; smart, aggressive drug development; and efficient regulatory oversight can accelerate the creation of a breakthrough therapy.

Some aspects of the story are unique to Kalydeco, but many of the lessons learned could be broadly applied, according to FDA officials, senior managers at Vertex and the Cystic Fibrosis Foundation (CFF).

CFF, which pioneered the venture philanthropy concept, propelled Kalydeco from a scientific hypothesis into a life-enhancing product, financing the high throughput screening that led to the discovery of the compound and funding its early development.

Work the foundation did to prepare the way for Kalydeco and other therapies, such as collecting data for decades in patient registries to elucidate the natural history of CF, and creating a clinical trials network to efficiently test investigational agents, was at least as important as the funding it provided.

Once Vertex gained control of the molecule by acquiring Aurora Biosciences Corp. in April 2001, the biotech matched CFF's pace and commitment. Vertex took scientific and financial risks, starting with a decision to accept the opportunity cost associated with a product targeted at only a few thousand patients, and then betting it could collapse the standard development cycle by going straight from a Phase IIa trial to Phase III.

FDA did its part to sprint over the finish line, approving the Kalydeco application just in time for Commissioner Margaret Hamburg to present it at a congressional hearing as an example of its support for biomedical innovation.

Industrializing development

The key to translating scientific discoveries about CF into therapies has been "industrializing" the process, Robert Beall, CFF president and CEO, told BioCentury.

Identification of the mutant gene that causes CF in 1989 - research that was partly funded by CFF - created tremendous excitement, with initial attention focused on academic efforts to cure the disease using gene therapy.

The first human gene therapy trial for CF was conducted in 1993. It generated newspaper headlines, but almost 20 years later the technology hasn't come close to providing a viable treatment.

When it became clear that gene therapy wasn't going to produce a quick cure, CF advocates started exploring other approaches, including the possibility of creating drugs to address the underlying cause of the disease.

The genetic mutations that cause CF prevent normal functioning of the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel that helps keep the lung epithelium hydrated and prevents mucus buildup that leads to airway obstruction and infection.

"We knew the basic defect was that chloride couldn't get out of the cell and felt that if we could get chloride out of the cells by whatever chemical means, maybe we could develop a new therapeutic strategy," Beall said.

By the mid-1990s, he told BioCentury, he was getting anxious that there wasn't a pathway for efficiently exploiting the potential created by breakthroughs in understanding the biology of CF: "The academic pace was just too slow, and academic labs were not as automated as we'd like. I said, 'Guys, we need to change our model - we need to get industry engaged in cystic fibrosis.'"

Beall's idea was to use an "industrialized approach to screening for chemical compounds to get chloride out of the airway cells."

He contacted seven companies he thought might have the technical capacity, but only two returned his calls - Aurora and Genzyme Corp. (now part of Sanofi).

"The person from Aurora who called had worked in a CF lab as a...

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