Gleevec maker Novartis Meets its Match in India

How good is Gleevec, the wonder-drug by Novartis that has changed the lives of those diagnosed with chronic myeloid leukemia (CML)? There's a telling moment in the rather gripping documentary Farrah's Story following the actress's losing battle against cancer, in which her partner, CML patient Ryan O'Neal, is next to her crying and saying he doesn't want to live without her, that he wants to die with her, and suddenly an otherwise incoherent Fawcett responds in a soft voice, "Stop taking your Gleevec."

O'Neal is mum, knowing that doing so would be like signing his own death warrant. Gleevec is that good.

Recently, results were published of a large Phase III clinical trial pitting Tasigna (nilotinib) against Gleevec as a first-line treatment for chronic myeloid leukemia. This so-called ENESTnd study ("Evaluating Nilotinib Efficacy and Safety in Clinical Trials of newly diagnosed Ph+ CML patients") was conducted by pharmie giant Novartis.

What immediately caught my eye about ENESTnd was the fact that it was head-to-head, drug versus drug, winner take all. You just never see this. Why not, when such a trial makes the most sense? Because the FDA doesn't require it when they're considering whether or not to approve a drug; they just want to know what kind of a shadow boxer the candidate is, how it performs against a placebo.

Novartis makes both Gleevec (aka Glivec) and Tasigna. Why would they knowingly hold a head-to-head trial and attempt to out-shine their own product?

Let's find out.

THE BIG PURPLE SCAM

Remember prescription Prilosec, the "purple pill"? AstraZeneca's heartburn drug was a wicked moneymaker when approved in 1988; at its peak it took in annual sales of $6 billion. But in 2001, as the end of their patent on the drug approached, AstraZeneca pulled Nexium out of the hat, called it "today's purple pill" and kicked Prilosec to the industry curb (i.e. Prilosec OTC).

So what—Nexium's superior, right?

Wrong. The active drug in Prilosec is omeprazole, standard dose is 20mg. The active drug in Nexium is esomeprazole, standard dose 20mg. Omeprazole and esomeprazole are almost literally the exact same thing, just a sleight of hand, chemistry-style. You don't have to understand molecular science to know that something dirty's going on; compare the drugs in the pic below:

According to AstraZeneca's own published head-to-head trials, Nexium is no better than Prilosec. In fact, some of their studies indicate that it's worse. Don't believe me? Go to purpilepill.com, open the pdf file containing the prescribing information of Nexium, and check out section 14, 'Clinical Studies'.

Schering-Plough's Claritn vs Clarinex tells a similar tale of the tape. Just as the patent on Claritin expired, along came Clarinex … but loratadine (Claritin) is a nonsedating histamine-1 receptor antagonist, and desloratadine (Clarinex) is merely that molecule's orally active metabolite—in other words, when you take Claritin your body first converts it to Clarinex.

So it's hard not to think Novartis isn't up to something dirty here. As CML patients know all too well, Gleevec is expensive—at several thousand dollars per month surely the most expensive drug they've ever encountered. But also the most important one, the one that has literally saved their lives. You can't put a price on that.

Well most of us can't, but someone has to, and Novartis does, and it's a pretty high price.

But Gleevec is that good. It's a life-saver. When it first came out, stories appeared about people across the globe selling off all their possessions in order to afford it.

So is Tasigna even better than Gleevec? And what's India got to do with this?

INDIA, A PHARMACEUTICAL WILD WEST

Novartis' thorny relationship with India dates back at least to 2001 and the arrival of Gleevec. To their credit, Novartis made a significant international effort to distribute Gleevec for free to those who needed it but couldn't afford it. By any standard, their effort was a disaster, riddled with inconsistencies and hit by all manner of ugly allegations, but they did try. Their effort came with a warning in wild-west markets like India: The moment an illegal generic appears, the Gleevec free-for-all compliments of Novartis would vanish. It didn't take long for Gleevec copycats such as Natco Pharma's Veenat to appear, priced to undercut the brand by thousands and thousands of dollars per year. Thus, Novarits made good on their warning.

India only began to comply with World Trade Organization rules regarding intellectual property in 2005 when they enacted patent legislation. Before that, it was easy-breezy to find the generic equivalent of many expensive drugs being made by local pharmaceutical companies. One aspect of that new legislation protects the public from the kind of molecular sleight of hand we saw in Nexium and Clarinex, where companies make insignificant molecular changes to a formula, patent it, and enjoy another several years of charging high prices. It's a fantastic bit of legislation that would be a brilliant addition to US patent laws but one that would never be passed here.

In 2006 Novartis tried—and failed—to patent Gleevec in India, a ruling they immediately appealed but one that they ultimately lost in 2009.

In the meantime, they've been working on Tasigna, a very similar drug to Gleevec that they've known about since at least 2001. Only in late 2007 did Novartis get FDA approval for Tasigna, but only in CML patients who are Gleevec-resistant. The Phase III head-to-head ENESTnd trial is an attempt to obtain FDA approval for Tasigna as a first-line therapy, because that's where the $$$$ is.

Just weeks ago, the FDA gave India's Sun Pharmaceutical Industries tentative approval to make a generic Gleevec, meaning it could be available to CML patients in the US sometime in 2010. When that happens, getting US insurers to pay for brand name Gleevec will be very, very hard.

Thus Novartis is hoping to avert this nightmare by pushing Tasigna as being an improvement on Gleevec even though the ENESTnd study does not bear this out, and even though it, unlike Gleevec, comes with a black box warning about potential heart problems.

TOPS VS ENESTst

In the summer of 2008, Novartis published results from the so-called TOPS study (Tyrosine Kinase Inhibitor Optimization and Selectivity Study), a Phase III, randomized, controlled clinical trial designed to evaluate the potential benefits of an 800mg starting dose of Gleevec across all risk categories of newly diagnosed, previously untreated patients with CML. The results showed that doubling the dosage of Gleevec from 400mg once daily to 800mg once daily resulted in a higher number of patients achieving a major molecular response (MMR).

If Novartis knew back in 2008 that 800mg of Gleevec was more effective than 400mg, why did the recent ENESTnd study rely on the 400mg dosage of Gleevec, unless they wanted to make sure that the resulting data stacked the deck in favor of Tasigna?

A FiercePharma story from late 2007 says it best:

• "If [Tasigna] can step into Gleevec's shoes as Novarits hopes, the Swiss drug maker may be shielded from copycats … but with generic Gleevec around, who'll need Tasigna? We'll have to tune in to Novartis' marketing materials to find out."

Exactly.

Maybe you're thinking hey, Novartis has every right to want to keep making money off such an amazing drug as Gleevec, and you would be wrong. They have had plenty of time and have made plenty of money. Big Pharma likes to cite the loss of revenue from illegal copycats as discouraging them from pursuing innovation, but don't you believe it—the pharmaceutical industry couldn't possibly be any less innovative than it is right now.

For the best example, look no further than Gleevec. Were it not for the perseverance and determination of a publicly funded medical research scientist unassociated with Novartis named Brian Druker, CML patients wouldn't even have Gleevec.

- Primary source: Marcia Angell, MD. The Truth About the Drug Companies: How They Deceive Us and What to do About it. New York: Random House, 2004.
- Read about omacetaxine, a drug in clinical trials right now for Gleevec-resistant CML patients here and here.