From Gleevec to Tasigna: Novartis' Switch Push Kicks Off With Front-Line CML

2009 Dec 9, J Merrill

The launch of Gleevec (imatinib) for the treatment of chronic myeloid leukemia in 2003 catapulted Novartis into a major oncology player and made the company into a poster child for oncologic success: an expensive, targeted therapy that payers point to as a treatment worthy of its price tag. But Gleevec's market exclusivity ends in 2015/2016 - and Novartis' ability to extend the growth of its oncology franchise beyond that timeframe depends largely on its success in switching patients to a follow up, Tasigna (nilotinib).

Novartis is starting to implement its switch strategy. The first step is securing regulatory approval for Tasigna for first-line use in patients with Philadelphia chromosome-positive CML. Novartis is planning to file regulatory submissions in the U.S. and EU by the end of this year based on the results of a Phase III head-to-head clinical trial comparing Tasigna to Gleevec. Tasigna received FDA approval in late 2007 for CML patients who fail prior treatment, including Gleevec.

In the Phase III trial, presented as a late-breaker abstract at the American Society of Hematology meeting Dec. 8, Tasigna demonstrated greater efficacy over Gleevec in the first-line treatment of Ph+ CML, as measured by major molecular response, complete cytogenetic response and prevention of progression to accelerated or blastic phase. MMR measured the reduction in the level of abnormal Bcr-Abl protein - an indicator of CML - in the blood. CCyR measured CML cells containing the diagnostic Ph chromosome in bone marrow samples. Top-line results of the ENESTnd trial, which enrolled 846 patients, were already presented in October. The trial compared Tasigna at its approved 400 mg twice daily dose as well as at a 300 mg twice daily dose versus Gleevec 400 mg daily ('The Pink Sheet' DAILY, Oct. 22, 2009). At 12 months, significantly fewer patients progressed to accelerated or blastic phase on Tasigna 300 mg twice daily than on Gleevec 400 mg daily (2 patients versus 11).

Management Assures Investors Switch Strategy Is In Place

Novartis management highlighted the data during an investor update on the oncology pipeline Dec. 9, while also discussing several of its other most promising candidates and the potential for seven registration filings in 2010. The company is anxious to assure investors that Tasigna will replace Gleevec as the standard of care because billions of dollars are at stake. Gleevec generated $3.7 billion in 2008, while in its first full year on the market, Tasigna generated $89 million.

"When we speak about a faster and deeper response, it's not just data," Chief Commercial Officer Herve Hoppenot said. "We are speaking of patients who have been diagnosed with cancer...and where the choice is whether you can have your cancer for a little bit longer or we can eradicate it faster. When you give them that choice, you know exactly which direction they will go if they have the choice between the two."

While Tasigna is likely to compete eventually against a low cost generic version of Gleevec, sales of the drug will hold up, predicted President and CEO of Novartis Oncology and Molecular Diagnostics David Epstein.

Responding to an analyst's question, he added, "By 2015/2016 either the medical community has decided that Tasigna is standard of care, in which case I don't think they will switch back to some older, less effective agent, or they will have not decided that, in which case the question is moot."

"In our opinion, based on the data we have now, the clinical program yet to come, and what we have heard from the investigators who worked on this trial, it is highly likely Tasigna will be the standard of care," he added. "If that's the case, the product will keep growing as the number of patients on the brand continues to build, as their lifespan continues to increase."

Novartis is also conducting four clinical trials involving Tasigna in patients categorized as "suboptimal" responders to Gleevec. That data could answer questions about when it would be the best time to switch patients who start on Gleevec to Tasigna. Data from those trials will be available in the 2012-2014 timeframe and will drive continued switches beyond newly diagnosed patients, Hoppenot said. Newly-diagnosed patients account for about 10 to 12 percent of Gleevec's CML sales, he added. CML accounts for about 75 percent of Gleevec sales.

BMS Also Has An Eye On Front-Line CML With Sprycel

The Tasigna data puts additional pressure on Bristol-Myers Squibb, which is also looking to become an oncology powerhouse, based in part on its presence in the CML market, and which also faces a steep patent cliff in 2012 (see 'Bristol-Myers' Grand Ambitions in Oncology, IN VIVO, November 2009). Bristol sells Sprycel (dasatinib), which currently competes against Tasigna in the second-line setting for CML. The FDA approved Sprycel, which also inhibits Bcr-Abl and other kinases, for CML patients resistant or intolerant to Gleevec in 2006. The drug generated sales of $310 million in 2008.

All three drugs work in similar ways by blocking Bcr-Abl, although Sprycel and Tasigna target more variations of the protein.

Bristol is conducting its own head-to-head trial comparing Sprycel to Gleevec, with data expected in the first half of 2010. Gleevec's strong presence in hematology gives Novartis a tremendous competitive advantage, but one clear differentiator between Sprycel and Tasigna has been in the area of safety. Tasigna carries a black box warning related to cardiovascular risks associated with QT prolongation, including sudden death, while Sprycel carries no black box warnings.

In the latest trial, however, Novartis reported that no patients in the study had prolongation of QT interval of greater than 500 milliseconds and no sudden deaths occurred with either treatment. Additionally, the company plans to file the lower 300 mg dose due to a slight safety advantage over the 400 mg dose, the firm said.

How the safety profiles between Tasigna and Sprycel stack up could be a significant factor in how the market unfolds.

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