Therapeutic focus – Gleevec generic set to change the leukaemia landscape

What Gleevec gave with one hand it threatens to take away with the other. The Novartis blockbuster revolutionised the treatment of chronic myeloid leukaemia and helped create a $5bn market, but when it comes off patent in three years’ time the resulting pricing disruption could threaten all of its competitors.

The industry pipeline of CML drugs may be relatively small, but it does include four projects set to test the regulatory waters shortly (see table). Not surprisingly, the initial focus for all of these is Gleevec failures, a significant subsection of the market; whether there is any scope in first-line use – for either the later entrants or the two other drugs already approved for newly diagnosed patients – could come down to pricing economics just as much as their relative safety and efficacy.

Most recently, a rolling submission for Ariad Pharmaceuticals’ ponatinib in second-line use was made with the FDA, and the drug started a head-to-head study against Gleevec (Ariad ups the ante in battle against leukaemia competitors, July 30, 2012). Pfizer’s bosutinib, which failed against Gleevec, is already awaiting approval in second-line use.

Both of these agents use a tyrosine kinase inhibition mechanism broadly similar to that of Gleevec and the other two marketed drugs, Bristol-Myers Squibb’s Sprycel and Novartis’s own Tasigna. Slightly further behind in development are Teva’s omacetaxine, a potential first-in-class cephalotaxine that functions as a protein synthesis inhibitor, and another project from Novartis, the HDAC inhibitor panobinostat.

Mid to late-stage CML pipeline
Status  Product Company Pharmacology class Trial ID
Filed Bosutinib Pfizer Src & BCR-ABL kinase inhibitor -
Ponatinib ARIAD Pharmaceuticals BCR-ABL inhibitor & pan-FGFR inhibitor -
Omacetaxine Teva (ex-Cephalon) Cetaxine -
Phase III Panobinostat Novartis Histone deacetylase (HDAC) inhibitor NCT00451035
Phase II XL139 Exelixis/Bristol Myers Squibb Hedgehog pathway/smoothened inhibitor NCT01218477
flumatinib Jiangsu Hengrui Medicine Tyrosine kinase inhibitor NCT01503502
rebastinib Deciphera Pharmaceuticals BCR-ABL inhibitor NCT00827138
WT1 DNA Vaccine Inovio Pharmaceuticals Cancer vaccine NCT01334060
Danusertib Nerviano Medical Sciences Aurora kinase inhibitor -
PRI-724 PRISM BioLab/Eisai CBP/β-catenin inhibitor NCT01606579
GVAX Leukaemia BioSante Pharmaceuticals Cancer vaccine -
NPB-001-056 Piramal Healthcare BCR-ABL inhibitor -

CML is a cancer in which increased and unregulated growth of predominantly myeloid cells results in their accumulation in the blood. In the vast majority of cases this is caused by the Bcr-Abl tyrosine kinase enzyme being locked in an activated form.

Gleevec, which inhibits Bcr-Abl tyrosine kinase, was approved in 2001 and became the first drug that affected CML’s natural progression. The subsequent development of resistance to Gleevec spurred the development of second-generation Bcr-Abl tyrosine kinase inhibitors like Sprycel and Tasigna, and although these are now approved for first-line use that market still belongs largely to Gleevec.

First-line incentive

This situation is likely to continue; with Gleevec about to become much cheaper there might be little incentive for doctors to prescribe a more expensive alternative in newly diagnosed patients.

A narrower avenue for success could be CML patients carrying the T315I mutation that is responsible for about 15% of Gleevec resistance cases; this strategy was previously pursued by ChemGenex Pharmaceuticals with omacetaxine, which it filed as Omapro, but the drug was knocked back by the FDA citing unreliability of the test to diagnose the mutation.

The company was then acquired by Cephalon, which itself was sold to Teva, and the Israeli firm submitted a US filing in March in all patients who have failed tyrosine kinase therapy. Teva told EP Vantage that omacetaxine binds to the Bcr-Abl hybrid gene present in CML and inhibits protein synthesis; the company believes that tyrosine kinase failures represent a significant opportunity.

This appears also to be the plan for Novartis’s panobinostat, which has completed two phase III trials in resistant patients at various stages of CML progression, although no specific filing plans have been revealed. Similarly, Deciphera Pharmaceuticals’ rebastinib, one of three tyrosine kinase inhibitors in mid-stage development, targets patients resistant to the three available drugs.

Bristol-Myers Squibb and Exelixis, meanwhile, are going down the combination route of adding their smoothened inhibitor XL139 on top of Sprycel; their phase I/II trial in 36 patients will not complete until 2015. One arm of a phase I/II study of Prism Biolab/Eisai’s CBP/β-catenin antagonist PRI-724 also includes a Sprycel combination.

Another approach thought some years ago to have promise in overcoming T315I resistance was inhibition of the Aurora kinase enzyme. But while development in other cancers has progressed, the most advanced project specifically in CML appears to be Nerviano Medical Sciences’ danusertib; the private Italian company claims to be in phase II standalone and combination trials outside the US.

Driving the market

Still, given that by the time any of these earlier projects are developed successfully they will be launched into a market that will already have altered significantly, the more pressing uncertainty surrounds the late-stage pipeline.

One thing that could drive the market for patent-protected CML drugs is a strong safety or efficacy advantage, although with 95% of CML patients surviving for over five years on Gleevec this effect would need to be striking. Both Sprycel and Tasigna have been shown to have higher molecular response rates than Gleevec, while some analysts believe that ponatinib has a good shot at beating all three.

Another is a change in guidelines for what constitutes a Gleevec failure. Recently the US National Comprehensive Cancer Network recommended a more stringent definition of early response, which analysts believe could result in more patients who start on Gleevec becoming eligible to switch.

Realistically therefore, it might be this expansion of the second-line market that provides the business case for further CML drug development, and pursuit of success in the first-line setting could turn out to be something of a red herring.

With India’s Sun Pharma the first company to file for US approval of a generic version of Gleevec and receiving tentative approval three years ago the playing field is set for a shakeup. Things will become a whole lot clearer in 2015.

To contact the writer of this story email Jacob Plieth in London at [email protected]

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