For Novartis, the targeted chronic myeloid leukemia drug Gleevec (imatinib) has been the backbone of its oncology portfolio. The drug's launch in 2003 catapulted Novartis into a major oncology player, and with revenues for Gleevec now approaching close to $4 billion in sales annually, the drug has evolved from what was considered to be a niche treatment into Novartis' second top-selling drug.

But Gleevec's market exclusivity ends in 2015/2016 - and Novartis' ability to extend the growth of its oncology franchise beyond that timeframe depends on how successfully Novartis switches patients to a follow-up, Tasigna (nilotinib) and brings other new treatments to the market.

Like most of its Big Pharma rivals, Novartis has serious ambitions in oncology, as the industry transitions away from the traditional blockbuster marketing approach toward more targeted therapies. Novartis is facing its own steep patent cliff in the 2012 timeframe when it will lose the anti-hypertensive Diovan to generic competition.

Novartis won't be able to make up all the revenue lost from its cardiovascular bestseller - a drug that generated $5.7 billion in 2008 - from new products, but the company is looking to oncology, a market that it says is expected to grow from $75.5 billion in worldwide sales in 2009 to $109.6 billion in 2014, to make up for some of the shortfall.

Separating From The Pack Won't Be Easy

During an investor overview of its oncology pipeline Dec. 9, Pharmaceutical CEO Joseph Jimenez told investors that in oncology, Novartis is "separating from the pack," given the depth of the pipeline.

But distinguishing itself in oncology will be challenging. Novartis claims to rank number two in oncology in terms of market share, but Roche is the clear frontrunner in the space. The other players are neck and neck in a tight race for a distant second place. Roche led the market last year in dollar sales with $14.13 billion in sales, according to IMS Health data reported in December 2008, while Sanofi-Aventis was second with $5.1 billion, and AstraZeneca and Novartis were each around $4.3 billion in sales. Behind them are Lilly, Pfizer and Bristol-Myers Squibb.

Roche has built its portfolio around drugs such as Avastin and Herceptin that target large solid-tumor market opportunities like breast cancer, colorectal cancer and lung cancer, whereas Novartis has carved out a niche for itself in hematological cancers like CML.

Going forward, Novartis is looking to maintain its leadership position in hematological cancers, expand to other niche cancers like neuroendocrine tumors and, importantly, take aim at some large solid-tumor markets, including lung cancer.

"Novartis is going deep into this category," Oncology CEO David Epstein said. "This is not about just launching one therapy, but it's about launching a succession of therapies, so we can help physicians optimize care for their patients."

The oncology pipeline includes 16 new molecular entities, six in pivotal trials. Near-term growth will be driven by new indications for already marketed drugs, including Tasigna, Afinitor and Zometa .

The company is planning two regulatory submissions before the end of the year, seeking new indications for Tasigna in first-line CML and Zometa (zoledronic acid) for adjuvant use in patients with certain types of breast cancer. In terms of filings, 2010 and 2011 will be more pivotal years for Novartis in oncology. Next year, up to five additional regulatory submissions are planned, including three for NMEs.

From Gleevec To Tasigna: The Push Begins

Securing a front-line indication for Tasigna is particularly important as the company begins implementing a slow-switch strategy from Gleevec to Tasigna. The first step is securing regulatory approval for Tasigna for first-line use in patients with Philadelphia chromosome-positive CML. Tasigna received FDA approval in late 2007 for CML patients who fail prior treatment, including Gleevec. The filings for first-line CML will be based on a Phase III head-to-head clinical trial comparing Tasigna to 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.

Top-line results of the ENESTnd trial, which enrolled 846 newly diagnosed patients, already were 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 (¹ Also see "Novartis Has High Hopes For Tasigna And Predicts It Could Outpace Gleevec In CML" - Pink Sheet, 22 October, 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).

Switch Strategy Is In Place, Management Says

Novartis management highlighted the data during the oncology update, anxious to assure investors that Tasigna will replace Gleevec as the standard of care given the billions of dollars 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 eventually will compete against a low-cost generic version of Gleevec, sales of the drug will hold up, predicted 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."

Novartis also is conducting four clinical trials involving Tasigna in patients categorized as "suboptimal" responders to Gleevec. Those data could answer questions about when 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 percent to 12 percent of Gleevec's CML sales, he added. CML accounts for about 75 percent of Gleevec sales.

The Tasigna data put additional pressure on Bristol-Myers Squibb, which also is looking to become an oncology powerhouse, based in part on its presence in the CML market (² IN VIVO, November 2009). Bristol's Sprycel (dasatinib) currently competes against Tasigna in the second-line setting for CML. FDA approved Sprycel, which also inhibits Bcr-Abl and other kinases, for CML patients resistant or intolerant to Gleevec in 2006. Sprycel generated sales of $310 million in 2008.

Bristol is conducting its own head-to-head trial comparing Sprycel to Gleevec, with data expected in the first half of 2010.

Novartis recently added a late-stage asset to its hematology franchise through a deal with InCyte. The company paid $210 million in upfront and retroactive payments for ex-U.S. rights to INCB18424, a Phase III JAK1/JAK2 inhibitor in development for myelofibrosis (³ Also see "Two-Compound Partnership With Novartis Brings Incyte $210 Million Immediately" - Pink Sheet, 25 November, 2009.). Novartis is targeting 2011 for a regulatory filing.

Outside Hematology, ASA404 Is One To Watch

Expansion of Afinitor (everolimus) beyond its current indication for advanced renal cell carcinoma is a cornerstone of Novartis' near-term oncology growth strategy. The mTor inhibitor was approved in March (⁴ Also see "Afinitor Wins FDA Nod For Kidney Cancer" - Pink Sheet, 30 March, 2009.). The company is conducting a Phase III program studying Afinitor in advanced pancreatic neuroendocrine tumors, with data expected in mid-2010 and potential regulatory filings later in the year.

The tumors are ones for which there are no effective treatments other than the somatostatin analog octreotide (Novartis' Sandostatin and generics), which controls hormonal symptoms, according to James Yao, University of Texas M.D. Anderson Cancer Center, who addressed investors during the update meeting. Prevalence of the tumors - somewhere around 35 per 100,000 patients in the U.S. - is increasing, he added. Novartis is studying Afinitor in a wide range of other cancers as well, including breast, gastric and liver.

Other filings planned for 2010 are SOM230 (pasireotide) for the treatment of the rare disorder Cushing's disease (a Phase III trial of the drug in carcinoid tumors also is ongoing) and EPO906 (patupilone) in ovarian cancer.

One of the most significant near-term opportunities for Novartis to establish a stronghold in the solid-tumor space is ASA404 (vadimezan), a potentially first-in-class tumor vascular disrupting agent in development for non-small cell lung cancer. It is being studied in two Phase III trials in combination with chemotherapy: ATTRACT-1 as first-line therapy and ATTRACT-2 as second-line therapy. Pending those outcomes, a regulatory submission is planned for 2011.

The mechanisms of action for the drug are different from angiogenesis inhibitors like Avastin, so it could offer better control of the disease and work synergistically with those drugs, Oncology Global Development Head Alessandro Riva said.

"ASA404 in the field of lung cancer is what many would consider a risky field because in fact many agents have failed in lung cancer over time," Epstein said. "We think that the Phase II data are very solid. The program has enrolled rapidly, and should this drug get approved, it could become one of the biggest products in our portfolio."

Having a first-in-class agent for a major solid tumor would go a long way toward protecting Novartis' position in the oncology market, especially one coming to market in time to supplant some of the sales that will be lost to Gleevec generics.

- Jessica Merrill ( ⁵ j.merrill@elsevier.com )

Beyond Gleevec: What's Next For Novartis Oncology?

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