The endostatin Phase I results looked no better than OK. Good safety and reasonable PK, and a few responses. Looks like they haven't hit the higher dose levels yet, so maybe there is still room for improvement (and of course the drug would likely do better in less sick patients). No mention of any dose-response curve though, which may mean higher doses won't help. There's also a mouse model abstract which suggests you can use a 10x smaller daily dose if you give it via continuous infusion instead of bolus.
Hard to know how the market will react - right now it's slightly up in premarket compared to yesterday's close. People may be waiting to see if there is any update when the presentations are actually made later this week. I'm probably not going to play this one either way.
Bottom line though is that it doesn't seem like the spectacular mice results are being replicated in humans. Maybe they still haven't got the structure quite right? I came across the following abstract (not at this conference) which raises this issue:
Authors
Hohenester E, Sasaki T, Mann K, Timpl R.
Author e-mail Address
e.hohenester@ic.ac.uk
Title
Variable zinc coordination in endostatin
Source
Journal of Molecular Biology. 297(1):1-6, 2000 Mar 17.
Abbreviated Source
J. Mol. Biol. 297(1):1-6, 2000 Mar 17.
Copyright Publisher
ACADEMIC PRESS LTD, 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND. URL: apnet.com
ISSN
0022-2836
Author Keywords
Angiogenesis, Tumour growth, Collagen, Metal binding, Mutagenesis.
KeyWords Plus® by ISI®
Angiogenesis inhibitor endostatin, Molscript, Binding, Program.
Abstract
Endostatin is a proteolytic fragment of collagen XVIII that potently inhibits angiogenesis and tumour growth. Human endostatin contains a zinc ion, bound near the N terminus, which was not observed in the original structure of mouse endostatin at pH 5. Controversial data exist on the role of this zinc ion in the anti-tumour activity. We report two new crystal structures of mouse endostatin at pH 8.5 with bound zinc. One crystal form shows a metal ion coordination similar to that in human endostatin (His132, His134, His142, Asp207), but the conformation of the N-terminal segment is different. In the other crystal form, Asp136 replaces His132 as a zinc ligand. Site-directed mutagenesis of zinc-binding residues demonstrates that both coordination geometries occur in solution. The large degree of structural heterogeneity of the zinc-binding site has implications for endostatin function. We conclude that zinc is likely to play a structural rather than a critical functional role in endostatin. (C) 2000 Academic Press. [References: 23]
Peter |
