Upending the usual model of drug development, Novartis finds that focusing on a rare disease with well-understood genetics can pay off big time
On June 18 the U.S. Food & Drug Administration approved Ilaris, a biotech drug for a rare cluster of autoimmune diseases caused by a single genetic mutation. For its manufacturer, Novartis (NVS), the approval is vindication of the Swiss pharmaceutical firm's radical new approach to drug development.
Ilaris might never have made it to market if it wasn't for the efforts of Dr. Tim Wright, head of translational medicine at Novartis. Shortly after joining Novartis in 2004, Wright came up with a breakthrough idea to revive a drug that had been languishing in the company's labs. Novartis had previously tested the drug, which blocks an immune system protein known as interleukin-1 (IL-1) in rheumatoid arthritis, with disappointing results.
Taking a different tack, Wright, formerly chief of rheumatology at the University of Pittsburgh, proposed testing the drug in a disease called Muckle-Wells. It is an illness so rare that, among Novartis' staff, only Wright's boss, Dr. Trevor Mundel, was familiar with it. Mundel, who is Novartis' global head of development, understood that the inflammatory disorder, whose symptoms range from rashes and joint pain to severe kidney damage, afflicts just a few thousand patients worldwide. But he deemed it a worthy target because the cause of the disease was clearly defined: In May 2004, academic researchers had pegged it to a single rogue gene that leads the body to overproduce IL-1. Wright and Mundel believed the company needed to test only a small number of patients to prove whether the drug, known as canakinumab, was effective.
custom-tailored for these patients"
In August 2004, Wright and Mundel brought their plan to Novartis' head of global discovery, Mark Fishman, and to other senior executives within the company. "There was some disbelief, as we were proposing studying a disease only Trevor and I had ever heard of," Wright recalls. They got a green light, and the first four patients received the drug in February 2005.
Within five hours of a single injection, the patient's symptoms had visibly improved. Within a day they were gone, and by the end of the week the disease was barely detectable in the blood. Even more astonishing, the patient remained symptom-free for the next six months. This caught Wright and Mundel completely by surprise. "The reality is, many experimental drugs fail," Wright says. "This one is basically custom-tailored for these patients."
Still, the drug went nowhere for 18 months. "We sat at the table, and in principle we agreed to go ahead, but in practice nothing happened," recalls Fishman. With evidence emerging that IL-1, an inflammatory protein, could be involved in as many as 30 other indications ranging from gout to cardiovascular disease to type 2 diabetes—all much more common and potentially more lucrative—the company had problems deciding which to pursue first. "It got completely bogged down in these interminable debates around value that have paralyzed drug companies for years," explains Mundel.
By early 2006, Novartis CEO Dan Vasella, frustrated that the drug was still in limbo, intervened. He says his initial insistence on reviving the project was "met with passive resistance,—people would nod but not follow through." Some in marketing thought Muckle-Wells was too rare a disease to explore and strongly believed the company would be better off pursuing bigger markets.
It wasn't until early 2007 that development began in earnest, exploring a group of rare but potentially life-threatening autoinflammatory diseases called cryopyrin-associated periodic syndromes (CAPS), which include Muckle-Wells. That delay was a misstep that allowed Regeneron Pharmaceuticals REGN in Tarrytown, N.Y., to get to market first, in February 2008. "It took way too long, much longer than necessary" Vasella says with evident irritation.
It was a setback, but not a total loss. Novartis investigated the drug in CAPS patients and in 23 patients with systemic juvenile idiopathic arthritis (SJIA), the most severe form of arthritis in children. Through the use of computer modeling and simulation, the company was able to move directly from small proof-of-concept trials in both CAPS and SJIA directly to late-stage trials with hundreds of patients, shaving off a year of development time and tens of millions of dollars.
On June 3 the New England Journal of Medicine published important data on Novartis' phase 3 trial of the Muckle-Wells drug, now called Ilaris. Over 90% of children and adults suffering from the immune disorders that the drug was designed to treat experienced rapid, sustained remissions.
Over the next three years, Novartis hopes to file for approval to use Ilaris to treat gout, juvenile arthritis, rheumatoid arthritis, and neonatal onset multisystem inflammatory disease, which causes brain inflammation in newborns. The company is also exploring its use in chronic obstructive pulmonary disease and diabetes.