Wednesday, July 1, 2015

Drugs in Clinical Pipeline: Vatalanib

Vatalanib [N-(4-chlorophenyl)-4-(pyridine-4-ylmethyl)phthalazin-1-amine] is an orally bioavailable anilinophthalazine compound that has potent antineoplastic activity. Vatalanib binds to and inhibits the protein kinase domain of vascular endothelial growth factor receptors 1 and 2 (VEGFR 1 and VEGFR2); both receptor tyrosine kinases are involved in angiogenesis. This agent also binds to and inhibits related receptor tyrosine kinases, including platelet-derived growth factor (PDGF) receptor, c-Kit, and c-Fms [1]. Preclinical studies demonstrated antitumor activity against a broad range of cancer types, including colorectal, prostate, renal, hepatocellular, myeloma, recurrent glioblastoma multiform and ovarian. The compound has been investigated in phase I/II studies, alone and in combination with chemotherapy.

The activity of Vatalanib is as follows:

IC50 (VEGFR2/KDR, cell-free assay) = 37 nM
IC50 (VEGFR1/FLT1, cell-free assay) = 77 nM
IC50 (VEGFR2/Flk1, cell-free assay) = 270 nM
IC50 (PDGFRB, cell-free assay) = 580 nM
IC50 (VEGFR3/FLT4, cell-free assay) = 660 nM
IC50 (c-Kit, cell-free assay) = 730 nM
IC50 (c-Fms, cell-free assay) = 1400 nM

Common Name: Vatalanib; Vatalanib dihydrochloride
Synonyms:  PTK787; PTK 787; PTK-787; ZK 222584; ZK222584; ZK-222584; CGP 79787; CGP-797870; ZK-232934; CGP79787D; PTK787/ZK 222584; CGP-79787
IUPAC Name: N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine
CAS Number: 212141-54-3; 212141-51-0 (dihydrochloride)
Mechanism of Action: Kinase Inhibitor; VEGFR-2 Inhibitor; KDR Inhibitor
Indication: Metastatic colorectal cancer and NSCLC
Development Stage: Phase II / III trials
Company: Novartis International AG/ Bayer Schering

Vascular endothelial growth factor (VEGF) is a signal protein produced by cells that stimulate vasculogenesis (formation of blood vessels occurring by de novo production of endothelial cells) and angiogenesis (formation of new blood vessels from pre-existing vessel). It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate. Its normal function is to create new blood vessels during embryonic development, new blood vessels after injury, muscle following exercise and new vessels to bypass blocked vessels. But, when VEGF is overexpressed, it can lead to disease. Solid cancers cannot grow beyond a limited size without an adequate blood supply, cancers that can express VEGF are able to grow and metastasize.

Vatalanib (INN, codenamed PTK787 or PTK/ZK) is being studied as a possible treatment for several types of cancer, particularly cancer that is at an advanced stage or has not responded to chemotherapy. Vatalanib targets all known VEGF receptors (VEGFR1, VEGFR2, VEGFR3), as well as platelet-derived growth factor receptor-beta (PDGFRB) and c-KIT, but is most selective for VEGFR-2. The compound is less potent against VEGFR1/Flt-1, 18-fold against VEGFR3/Flt-4 [1]. It is undergoing clinical trials for metastatic colorectal cancer and NSCLC.

Vatalanib was discovered through high-throughput screening. It has been extensively investigated in Phase I, II and III clinical trials. Encouraging data were obtained from phase II trials examining vatalanib monotherapy administered once or twice daily in previously treated patients with NSCLC [2]. Vatalanib was investigated in the treatment of metastatic colorectal cancer in double-blind, placebo-controlled, phase III studies: Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases in First-line (CONFIRM-1 and 2) trials. These trials investigated the effect of 5-FU, leucovorin, and oxaliplatin, (FOLFOX-4) chemotherapy with or without vatalanib as second line therapy of patients with metastatic colorectal cancer. In CONFIRM-1 trials, participants had not yet received any treatment for their cancer; and CONFIRM-2, in which participants had received first-line treatment with irinotecan and fluoropyrimidines. Both trials result showed that the progression-free survival (PFS) time was significantly longer in the vatalanib arm in patients with high levels of lactate dehydrogenase (LDH, an enzyme used as a marker of tissue breakdown) [3, 4]. However, interim results from phase III trials of vatalanib in combination with FOLFOX 4 chemotherapy as a second-line treatment in CONFIRM-2 trials, suggested no significant benefit in overall survival (OS). Thus, multitargeted TKIs are yet to show survival benefit in phase II trials when combined with chemotherapeutics.

The possible reasons for why vatalanib treatment did not show a clear benefit with FOLFOX 4 regimen in metastatic colorectal cancer patients could be the simple explanation that it is not as effective an agent at administered doses, vatalanib has a considerably shorter half-life (approx. 6 h), and the phase III trials for vatalanib used a single daily dose of the drug. Contradicting these data, however, is the fact that pharmacokinetic data suggest that an active dose of vatalanib is maintained in the blood circulation for 24 h, and that it has a rapid and pronounced anti-vascular effect [5]. Another explanation could be the off-target effects (i.e. other than on the VEGF receptor kinases). For example, vatalanib might target PDGFR-beta on perivascular cells. This action was shown in mice to be beneficial for vascular targeting, since the PDGF-B-PDGFR-beta axis is known to control vascular stabilization/maturation by recruitment of supporting perivascular cells. Blocking PDGFR-beta, however, may interfere with vascular normalization, by blocking perivascular cell recruitment and excessive vessel pruning, and thus prevent the synergistic effect of combined therapy [6]. Thus, the clinical benefit of targeting perivascular cells in addition to endothelial cells with multi-targeted TKIs in the context of chemotherapy still remains unclear.

The adverse effects of vatalanib appear similar to those of other VEGF inhibitors. The most common side effects associated with vatalanib were observed to be high blood pressure, gastrointestinal upset (diarrhea, nausea, and vomiting), fatigue, and dizziness [7, 8].

1. Wood, J. M.; et. al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res 200060(8), 2178-2189.
2.    Scagliotti, G.; Govindan, R. Targeting angiogenesis with multitargeted tyrosine kinase inhibitors in the treatment of non-small cell lung cancer. Oncologist 201015(5), 436-446.
3.    Los, M.; Roodhart, J. M.; Voest, E. E. Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer. Oncologist 200712(4), 443-450.
4.    Scott, E. N.; Meinhardt, G.; et al. Vatalanib: the clinical development of a tyrosine kinase inhibitor of angiogenesis in solid tumours. Expert Opin. Investig. Drugs 200716(3), 367-379.
5.    Morgan, B.; et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J. Clin. Oncol. 200321(21), 3955-3964.
6.    Jain, R. K. Molecular regulation of vessel maturation. Nat. Med. 20039(6), 685-693.
7.    Mross, K.; et al. Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. Eur. J. Cancer 200541(9), 1291-1299.
8.    Thomas, A. L.; et al. Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J. Clin. Oncol. 200523(18), 4162-4171.
9.    Murakami, M.; Kobayashi, S.; et. al. Tyrosine kinase inhibitor PTK/ZK enhances the antitumor effects of interferon-α/5-fluorouracil therapy for hepatocellular carcinoma cells. Ann. Surg. Oncol. 201118(2), 589-596.