Silicon Investor (SI) -- The First Internet Community

STOCKTALK

We've detected that you're using an ad content blocking browser plug-in or feature. Ads provide a critical source of revenue to the continued operation of Silicon Investor. We ask that you disable ad blocking while on Silicon Investor in the best interests of our community. If you are not using an ad blocker but are still receiving this message, make sure your browser's tracking protection is set to the 'standard' level.

Biotech / Medical : Pharmos (PARS) -- Ignore unavailable to you. Want to Upgrade?

To: NeuroInvestment who wrote (1369)	12/21/2004 11:59:37 AM
From: Clarksterh	Respond to of 1386

Thanks neuro - Upon further thought, I came up with a broader list of possible failure modes and lessons learned. I thought I'd share them to get feedback. Note that like most people I have an ability to lie to myself and one of my mechanisms to control that is being very analytic about penalties - and the amount of money I invest is a function of my expected probability of success. But take the exact numbers with a grain of salt. Lessons learned from the Dex TBI trial. I may update this in the future if Pharmos publishes meaningful data (given that Pharmos wants to use Dex for CABG it is in their self interest to determine what went wrong, but it is not necessarily in their interest to publish it.). First lesson: 1) If the insiders are selling extensively. Discount from 25% to 75%. Exacerbating factors: a. They are essentially selling all of the shares they are allowed to sell b. They started selling after getting extensive data (even blinded data – especially if the company clearly has good parametric models). Don’t assume you are smarter than the insiders. Remaining lessons: For right now I somewhat arbitrarily divide up the possible failures into ICP failure and no ICP failure for the simple reason that if there is no ICP failure there are fewer lessons to be learned since it is clear that the whole model for TBI is wrong which is more TBI specific than broadly applicable. 1) How many factors has the company changed between Ph II and Ph III. This is a judgement call, but discount between 5 and 10% per changed parameter. (in the case of Dex they clearly changed CT entry critieria, mGCS and they might have used a different manufacturing technique to produce Dex) 2) How much ability/pressure do the participating doctors have to cheat on the entrance criteria (e.g. in Dex there was probably substantial pressure on the participating doc’s to enroll people after the 6 hour window – they have been talking to the family for 2 or 3 hours trying to convince them, but the family agrees only as things get worse, and the phase II data says that is 2 or 3 hours outside the 6 hour window. Were I Pharmos I’d audit extensively - it should be easy to find ambulance records indicating when the injury occurred and it should be easy to find when randomization occurred since it was centrally controlled.). Exacerbating factors: a. Very multicenter trial. This tendency to cheat is probably much easier to control in a trial with only a few centers that are easily audited. Also the doctors are substantially less likely to think ‘if I cheat it won’t hurt the trial’ if they are treating ¼ of the total patients. b. Are the admitting doctors doctors whose primary job does not entail much trial work – doctors who work primarily on trials are likely to be better used to the pressures and resisting them. Comments? Clark

To: NeuroInvestment who wrote (1369)	12/21/2004 5:16:22 PM
From: Biomaven	Read Replies (1) \| Respond to of 1386

Harry, I wonder if timing of dosing might not be very critical? I don't know if this article might have any relevance: Dynamic changes in N-methyl-D-aspartate receptors after closed head injury in mice: Implications for treatment of neurological and cognitive deficits. Biegon A, Fry PA, Paden CM, Alexandrovich A, Tsenter J, Shohami E. Department of Functional Imaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. biegon@bnl.gov Traumatic brain injury is a leading cause of mortality and morbidity among young people. For the last couple of decades, it was believed that excess stimulation of brain receptors for the excitatory neurotransmitter glutamate was a major cause of delayed neuronal death after head injury, and several major clinical trials in severely head injured patients used blockers of the glutamate N-methyl-D-aspartate (NMDA) receptor. All of these trials failed to show efficacy. Using a mouse model of traumatic brain injury and quantitative autoradiography of the activity-dependent NMDA receptor antagonist MK801, we show that hyperactivation of glutamate NMDA receptors after injury is short-lived (<1 h) and is followed by a profound and long-lasting (> or =7 days) loss of function. Furthermore, stimulation of NMDA receptors by NMDA 24 and 48 h postinjury produced a significant attenuation of neurological deficits (blocked by coadministration of MK801) and restored cognitive performance 14 days postinjury. These results provide the underlying mechanism for the well known but heretofore unexplained short therapeutic window of glutamate antagonists after brain injury and support a pharmacological intervention with a relatively long (> or =24 h) time window easily attainable for treatment of human accidental head injury. Free full text available at: pnas.org Fortunately I had no position here - mostly I reflexively avoid trials in indications that have proven historically difficult (TBI, sepsis, diabetic ulcers, etc.). Peter