Sample Record from Pharmaprojects (File 128)
1/19/1
DIALOG(R)File 128: PHARMAPROJECTS
(c) 2007 INFORMA UK LTD. All rights reserved.
0030985 ** Image available **
Drug Name: vatalanib
World Status: Phase III Clinical Trial
Pharma Status: Active
Synonyms: CGP-79787
CGP-79787D
PTK-787
PTK/ZK
VEGF-TK1
ZK-222584
Originator: Novartis (Switzerland) [Phase III Clinical Trial]
Licensee: Bayer (Germany) [Phase III Clinical Trial]
New Entity: Yes
Latest Upd: Updated On By Latest Change
20070119 JB Filing plans updated
ACTIVITY DATA
Therapy: Code Description
K6Z Anticancer, other
S1Z Ophthalmological
Rte of Admin: Code Description
A-PO Alimentary, po
Pharmacology: Code -- Description
KI-GFEN2-AN -- Endothelial growth factor receptor-2 kinase inhibitor
KI-GFPL-AN -- Platelet-derived growth factor receptor kinase inhibitor
KI-TY-KT-AN -- C-kit inhibitor
KI-GFEN1-AN -- Endothelial growth factor receptor-1 kinase inhibitor
KI-GFEN3-AN -- Endothelial growth factor receptor-3 kinase inhibitor
ANGG-AN -- Angiogenesis inhibitor
Therapy Pharmacology
Linking: Code Code1 Code2 Code3 Status
K6Z KI-GFEN2-AN KI-GFPL-AN KI-TY-KT-AN Phase III Clinical Trial
S1Z KI-GFEN2-AN ANGG-AN Phase II Clinical Trial
Indication: Description -- Status
Cancer, colorectal -- Phase III Clinical Trial
Cancer, renal -- Phase II Clinical Trial
Cancer, brain -- Phase II Clinical Trial
Cancer, breast -- Phase II Clinical Trial
Cancer, ovarian -- Phase II Clinical Trial
Cancer, pancreatic -- Phase II Clinical Trial
Cancer, prostate -- Phase II Clinical Trial
Cancer, lung, non-small cell -- Phase II Clinical Trial
Macular degeneration -- Phase II Clinical Trial
Target Data Codes:
3791: KDR
3791: FLK1
3791: VEGFR2
3791: VEGF receptor-2 tyrosine kinase
3791: VEGFR-2 tyrosine kinase
3791: vascular endothelial growth factor receptor 2
3791: CD309
5156: PDGFRA
5156: CD140a
5156: PDGFR2
5156: PDGFR kinase, bcr fusion-linked
5156: PDGFR/bcr fusion, PDGFR component
5156: PDGF receptor kinase, bcr fusion-linked
5156: platelet-derived growth factor receptor tyrosine
kinase, bcr fusion-linked
5156: PDGFR alpha
5156: PDGF receptor alpha
5156: MGC74795
5156: Rhe-PDGFRA
3815: KIT
3815: SCFR
3815: CD117
3815: SCF receptor
3815: stem cell factor receptor
3815: kit oncogene
3815: mast cell growth factor receptor
3815: c-kit receptor tyrosine kinase
3815: c-kit oncogene
3815: c-kit kinase
2321: FLT1
2321: FLT
2321: VEGFR1
2321: vascular endothelial growth factor receptor 1
2321: VEGF receptor-1 tyrosine kinase
2321: VEGFR-1 tyrosine kinase
2321: vascular permeability factor receptor 1
2324: FLT4
2324: PCL
2324: VEGFR3
2324: vascular endothelial growth factor receptor 3
2324: VEGF receptor-3 tyrosine kinase
2324: VEGFR-3 tyrosine kinase
2324: FLT41
Target Families:
3791: Enzyme > Kinase;
3791: Receptor;
5156: Enzyme > Kinase;
5156: Receptor;
3815: Enzyme > Kinase;
3815: Receptor;
2321: Enzyme > EC number > 2.7.10.1;
2321: Enzyme > Kinase;
2321: Receptor;
2324: Enzyme > EC number > 2.7.10.1;
2324: Enzyme > Kinase;
2324: Receptor.
PHARMACOKINETICS
Model (Dose)--Parameter--Values--Unit
Human--MTD--750--mg
CHEMICAL DATA
Origin: Code Description
CH-SY Chemical, synthetic
CAS Reg. No: 212141-54-3
Rot. Bonds: 4
Mol. Formula: C20H15CLN4
Hydrogen Bond Donors: 1 Hydrogen Bond Acceptors: 4
Mol. Weight: 346.82 AlogP: 4.46
Chemical Name:
N-(4-Chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine
STRUCTURE
COUNTRY DATA
Status: (Active)
France Phase II Clinical Trial/Licensing
Availability Unknown
Germany Phase III Clinical Trial/Licensing
Availability Unknown
Switzerland Phase III Clinical Trial/Licensing
Availability Unknown
World Phase III Clinical Trial
MAJOR EVENTS
Event Date A/E Event--Details
20060119 Est New Indication--Macular degeneration
20050124 Est New Therapeutic Activity--Ophthalmological
20031119 Est Pharmacology Identified--VEGFR-1 and -3 kinase
inhibitors KI-GFEN1- and KI-GFEN3-
20030123 Est Change in Status--Phase III Clinical Trial
20021121 Est New Indication--Cancer, renal and cancer, brain
20010621 Est New Indication--Cancer, colorectal
20010601 Act Names Granted--ZK-222584
20010515 Est Change in Status--Phase I/II Clinical Trial
20000803 Act New Chemical Structure--New
20000705 Act New Product in Pharmaprojects
RATING: Novelty: 6 (Leading Compound)
Development Speed: 4 (Faster than Average)
Market Size: 3 (US$ 2001-5000 million)
Total Rating: 13 (Total Rating)
TEXT:
Vatalanib (ZK-222584; PTK-787) is an oral VEGF KDR receptor tyrosine kinase inhibitor, under co-development by Novartis and Bayer Schering Pharma (Bayer) (Schering AG before the acquisition) as an angiogenesis inhibitor for the treatment of solid tumours and age-related macular degeneration (AMD) (Ann Reps, Novartis, 2001 & 2005). It is a competitive inhibitor of the ATP binding site of the VEGF receptor (7th Meet Soc Neuro-Oncol (San Diego), 2002). It also inhibits all other VEGF receptors, the PDGF receptor and c-Kit, whose overexpression may stimulate the growth of some tumour types.
Marketing
Registration filings for colorectal cancer and AMD are expected in 2007 and 2010, respectively (Ann Rep, Novartis, 2006). EU and US registration filing plans are under review following CONFIRM-1 and - 2 trial results (Company presentation, Novartis, 20 Sep 2005). Novartis will lead Asian and N American promotion and Schering AG will lead promotion in Africa, Australia, Europe and Latin America, with both companies co-promoting in Japan, for all oncology indications. Novartis has exclusive rights for ophthalmic indications (Press release, Novartis, 25 Jan 2005).
Clinical
Phase III
In the multinational CONFIRM-1 trial in 1168 previously-untreated metastatic colorectal cancer patients given vatalanib + oxaliplatin (qv), 5-FU and leucovorin (FOLFOX-4), patients on vatalanib + FOLFOX had a 17% reduction in risk of disease progression cf FOLFOX alone, when assessed by patients' physicians. However, central review assessment showed a 12% reduction in risk of disease progression, which was not significant. The trial has been extended, and overall survival endpoint analysis was expected in the 2nd half of 2006 (Scrip Daily Online, 4 Apr 2003, S00795906; Press release, Novartis, 13 May 2005). Preliminary results from the Phase III CONFIRM-2 trial, assessing the 2nd-line use of vatalanib + FOLFOX-4 in 830 metastatic colorectal cancer patients with disease progression following 1st-line treatment with irinotecan hydrochloride (qv) showed that vatalanib only increased progression- free survival to 7.7mth, cf 7.6mth with placebo. There was a greater effect in patients with high lactate dehydrogenase levels. Final overall survival data was expected in 2006 (Scrip Daily Online, 4 Apr 2003, S00795906 & 28 Jul 2005, S00890590; Press release, Novartis, 28 Jul 2005).
Phase II
It is in a Phase II trial for AMD (Company presentation, Novartis, 19 Jan 2006; Ann Rep, Novartis, 2006). In a Phase II trial (GOAL) in France and Germany as a 2nd-line monotherapy, 54 patients with stage IIIb/IV nsclc were given vatalanib 1250mg po once-daily. The dose was generally well tolerated. The most frequent adverse events (AE) were vomiting, nausea and dizziness, with the most frequent grade 3 AEs being dyspnoea, hypertension and thrombosis. After 12wk, there was 1PR, 17SDs, 9 unknown and 27PDs. 29SDs were recorded at wk 4. 19 patients had SD >12wk, and 5 patients had SD >28wk. A further cohort of 55 patients is being enrolled for trials with vatalanib po bid (42nd ASCO (Atlanta), 2006, Abs 7195). Broad Phase I/II trials are ongoing to identify further indications for development, including breast, haematological, ovarian, pancreatic and prostate cancers, and glioblastoma (Press release, Novartis, 20 Jan 2005). In Phase I/II trials in 360 advanced cancer patients, PRs and SDs were obtained in colorectal cancer, renal cell carcinoma (RCC) and glioblastoma multiforme patients over 15mth. The optimal dose was 1250mg once-daily (Company Web Pages, Novartis, 31 Oct 2001 & 21 Nov 2002).
Phase I
It is in Phase I trials for the treatment of solid tumours (Company presentation, Novartis, 20 Sep 2005). In an open-label Phase I trial in 49 patients with metastatic RCC, vatalanib 300-1500mg once- daily was well tolerated. 19% of patients had PR and a further 60% had SD. Median time to progression and median overall survival were 5.3 and 21mth, respectively. Vatalanib 1200mg/day caused a significant change in tumour blood flow in an additional 30 patients, which correlated with disease progression (3rd Targ Anticancer Ther (Amsterdam), 2005, Abs 0.302). In a dose-escalation Phase I study of 23 heavily-pretreated cancer patients, the MTD was 750mg bid. Adverse events were dose-related. Promising tumour regression was observed in heavily-pretreated patients with liver metastases from colorectal cancer (14th EORTC-NCI-AACR Symp Molec Targ Cancer Ther (Frankfurt), 2002, Abs 244). It is in a Phase I trial in patients with recurrent glioblastoma multiforme, in combination with temozolomide (qv), to determine the MTD, DLTs and antitumour efficacy. In a preliminary analysis of 11 patients, vatalanib + temozolomide 500 or 1000mg was well tolerated, and there was 0 and 1 (transient grade 3 transaminase elevation) DLTs, respectively. There was a decrease in tumour permeability after administration (7th Meet Soc Neuro-Oncol (San Diego), 2002). In a Phase 1b open-label dose-escalation trial, evaluating MTD and DLT, 42 patients with epithelial ovarian cancer were given vatalanib 250- 1250mg on days 3 to 21 of each chemotherapy cycle, paclitaxel (qv) 175mg/m2 iv over 3hr followed by carboplatin (qv) on day 1. Initial results showed 62% of patients achieved CR/PR, 14% had SD, 7% had PD and 17% unknown. No DLTs were reported. The most frequent grade 3/4 toxicities were neutropenia, leukopenia and hypertension. Vatalanib did not aggravate chemotherapy-related side effects, had no impact on carboplatin exposure and decreased paclitaxel exposure by an average of 18% in the 2nd cycle cf the 1st cycle. Further combination trials are under consideration (42nd ASCO (Atlanta), 2006, Abs 5075).
Preclinical
A back-up compound (AAL-993; qv) is under evaluation (BIO 2004 (San Francisco)). In rats, vatalanib po inhibited tumour vascularization and growth, particularly in prostate carcinomas. In mice, 50mg/kg po once-daily significantly inhibited tumour growth, and 3/7 mice had no macroscopically visible tumours at sacrifice (Scrip Daily Online, 21 Jun 2000, S00669492; 91st AACR (San Francisco), 2000, Abs 299). In nude mice with human squamous cell carcinoma, 50mg/kg po reduced tumour growth rate (11th Eur Cancer Conf (Lisbon), 2001, Abs 528). In a mouse growth factor model, vatalanib 12.5-50mg/kg/ day po dose-dependently inhibited VEGF- and PDGF-induced angiogenesis, and in nude mice transfected with human epithelial carcinoma A431 it inhibited cancer cell growth (89th AACR (New Orleans), 1998, Abs 655). Updated by JB on 19/1/2006.
Revised: 20070406
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