The approval yesterday of GlaxoSmithKline’s Votrient (pazopanib) not only adds another drug to the armoury for fighting kidney cancer, but also shows the growing influence of kinase inhibitors in fighting renal cancer, and solid tumours more generally. The drug becomes the ninth kinase inhibitor on the market, as seen by the table below, joining the likes of Gleevec and Tarceva.
Votrient may be late to the party, but the field of kinase inhibitors is growing rapidly with sales expected to ramp up from $7.6bn last year to $16.0bn in 2014, according to consensus forecasts from EvaluatePharma, representing impressive 13% compound annual growth. This rate of growth is, surprisingly, faster than cancer monoclonal antibodies, a field which is forecast to expand by 9% in the same period, to $29.3bn.
Much of the growth of the marketed products should come from follow-on indications that many of the developers of kinase inhibitors are trying to wring out of their compounds. Votrient itself is currently in a number of trials include soft tissue sarcoma, ovarian cancer, cervical and non-small cell lung cancer (NSCLC).
Market leader Gleevec, the first kinase inhibitor to gain approval back in 2001, has been approved in leukaemia, skin cancer and gastro-intestinal stromal tumours and is currently seeking marketing authorisation in melanoma and other solid tumours.
Kinases are regulatory proteins that play a major role in controlling cell growth, differentiation and cell death. They regulate a wide variety of signalling pathways and transmit biological signals from the outside of a cell to the nucleus.
In cancer cells kinase pathways can in effect get stuck in the 'on' position, leading to proliferation of cancer cells. Kinase inhibitors are designed to bind to and block the activity of gene-regulating kinases, curtailing their ability to turn on the genes that cause tumours to grow and spread.
There had been concerns that side effects seen in the Votrient clinical programme, which included increased liver enzymes, might scupper the product's chances of approval given the number of other drugs already on the market for kidney cancer (Event - Glaxo's pazopanib looking good for approval although delay possible, October 6, 2009). What appears to have impressed the regulators is the drug’s relative lack of side effects that have plagued other renal cancer drugs such as hand-foot syndrome and fatigue.
|Protein Kinase Inhibitor Market: Top 10 Products in 2014||Annual Sales WW - ($m)|
|Rank||Product||Generic Name||Company||Pharmacological Class||Phase (Current)||Patent Expiry||2008||2014||CAGR|
|1||Gleevec/Glivec||imatinib mesylate||Novartis||Tyrosine kinase inhibitor||Marketed||Jul 2015||3,670||5,312||+6%|
|2||Tarceva||erlotinib||Roche||EGFr antagonist||Marketed||Nov 2020||1,124||1,898||+9%|
|3||Nexavar||sorafenib||Bayer AG||Multi-kinase inhibitor||Marketed||Jun 2022||679||1,545||+15%|
|4||Sutent||sunitinib malate||Pfizer||Multi-kinase inhibitor||Marketed||Feb 2021||847||1,469||+10%|
|5||Sprycel||dasatinib||Bristol-Myers Squibb||Tyrosine kinase inhibitor||Marketed||Jun 2020||310||988||+21%|
|6||Tasigna||nilotinib||Novartis||Tyrosine kinase inhibitor||Marketed||Jul 2023||89||837||+45%|
|7||Tykerb||lapatinib ditosylate||GlaxoSmithKline||EGFr & HER2 (ErbB-2) dual kinase inhibitor||Marketed||Sep 2020||189||630||+22%|
|8||Iressa||gefitinib||AstraZeneca||EGFr & tyrosine kinase inhibitor||Marketed||Apr 2016||265||547||+13%|
|10||Axitinib (AG-13,736)||axitinib||Pfizer||VEGFr kinase inhibitor||Phase III||-||-||362||n/a|
Given the impressive forecast sales growth of the market it is not surprising that there are a number of kinase inhibitors currently in development. Still, the field is littered with failures; over a hundred products have either been abandoned or suspended in trials.
The most advanced novel drug still in the pipeline (see table below) is AstraZeneca’s Zactima, which has had a less than smooth development pathway in lung cancer given that the drug failed to meet its primary endpoint in two phase III clinical trials. Still, the drug generated highly significant data in progression free survival and more importantly has impressed observers with its quality of life measures, which could play well with the regulator, given that doctors put great score on this measure in these very sick patients (ASCO - AstraZeneca's Zactima looks stronger with quality of life data, June 4, 2009).
European approval for the drug could come by February and a decision by the US regulator is expected in May.
Teva and Mylan’s eriotinib is a generic version of Pfizer and OSI Pharmaceuticals Tarceva. In March Mylan confirmed that it had been sued by Pfizer and OSI over its generic challenge to the 25mg, 100mg and 150mg versions of the drug.
Still reeling from a phase III failure in pancreatic cancer, Pfizer’s Axtinib has seen 2012 sales forecasts cut by 58% over the last 12 months to $154m; late stage research in kidney and thyroid cancer is ongoing (Pfizer suffers fresh late-stage disappointment, February 2, 2009).
Full data from a phase III renal cancer trial is expected in 2010, and will be vital in providing assurance that the drug does have efficacy in other cancer types.
One of the few janus kinase inhibitors (JAK) in advanced studies is Incyte’s INCB1844. The company has taken a departure from the usual kinase field of cancer, and the drug is instead being developed as both a topical treatment for psoriasis and as a treatment for orphan indication myelofibrosis, where the main opportunity is seen (Event – JAK inhibitor data may help Incyte address financial concerns, August 13, 2009).
Of the earlier stage drugs one that many people have their eye on is Boehringer Ingelheim’s Tovok, which in August entered phase III trials as a front line treatment for non-small cell lung cancer in patients with EGFR mutations. If successful the drug would be the first oral inhibitor of both EGFR and HER 2 to reach the market in this indication.
|Pipeline of kinase inhibitors|
|Product||Generic Name||Company||Pharmacological Class||WW sales in 2014 ($m)|
|Filed||Zactima||vandetanib||AstraZeneca||EGFr & VEGFr inhibitor||282|
|Erlotinib||erlotinib||Mylan/Teva Pharmaceutical Industries||EGFr antagonist||17|
|Phase III||Axitinib (AG-13,736)||axitinib||Pfizer||VEGFr kinase inhibitor||362|
|INCB18424||-||Incyte||Janus kinase-2 (JAK-2) inhibitor||254|
|Aflibercept (VEGF Trap)||aflibercept||Sanofi-Aventis/Regeneron Pharmaceuticals||VEGFr kinase inhibitor||152|
|Recentin||cediranib||AstraZeneca||VEGFr kinase inhibitor||115|
|SKI-606||bosutinib||Wyeth||Tyrosine kinase inhibitor||80|
|Neratinib (HKI-272)||neratinib||Wyeth||HER2 (ErbB-2) inhibitor||78|
|BMS-582664||brivanib||Bristol-Myers Squibb||FGFR & VEGFr kinase inhibitor||70|
|PKC412||midostaurin||Novartis||Flt-3 kinase inhibitor||48|
|Enzastaurin||enzastaurin||Eli Lilly||Protein kinase C (PKC) inhibitor||39|
|CEP-701||lestaurtinib||Cephalon/Kyowa Hakko Kirin||Trk tyrosine kinase inhibitor||3|
|XL184||-||Exelixis/Bristol-Myers Squibb||VEGFr2, RET & Met tyrosine kinase inhibitor||-|
|AMG 706||motesanib||Amgen/Takeda||VEGF, platelet-derived growth factor (PDGF) & c-kit inhibitor||-|
|Vargatef||-||Boehringer Ingelheim||Triple angiokinase inhibitor||-|
|Tovok||-||Boehringer Ingelheim||EGFr & HER2 (ErbB-2) dual kinase inhibitor||-|
|Hypericin||-||Hy Biopharma||Kinase inhibitor||-|
|AB1010||masitinib||AB Science||KIT tyrosine kinase & platelet-derived growth factor receptor (PDGFr) inhibitor||-|