To: Miljenko Zuanic who wrote (250 ) 2/23/1999 11:55:00 AM From: Steven Rachbach Read Replies (1) | Respond to
Miljenko,
Thank you so much for posting a reply. It would be great for this board if you could continue adding your expertise as an R&D Chemist. As a clinician (I am a board certified Family Physician who now practices Urgent Care Medicine), I have a different perspective than you in regard to development of medicines. Physicians usually just want to know if a drug works and what to use it for. We typically give very off-the-cuff and simplistic explanations of the "science" behind the effect.
With this in mind I'd like to try and answer some of your questions in your post. My information comes from reading HGSI press releases, the Director of Investor Relations at HGSI and press reports pertaining to HGSI:
1. "What is VEGF-1 and..VEGF-2" -- From what I can gather, VEGF-1 is Genentech's product that stimulates blood vessel formation. Genentech just reported the negative Phase II trial using IV VEGF-1 of the protein. It is my understanding that Dr. Symes got approval from the FDA to administer the gene VEGF-1 (which expresses the VEGF-1 protein) by cardiac injection.
2. What you say about the other forms of VEGF being "different only in protein extension with additional ac..." makes sense to me. HGSI states that VEGF-2 not only stimulates blood vessels, but it stimulates lymphatic vessel formation as well. Perhaps the protein extension on HGSI's VEGF-2 produces the effect on the lymphatic vessels. By the way, I am not sophisticated enough to know what "ac" and "EC" means.
3. About the VEGF-1 Genentech protein trial: I don't much about the results except that the press reported that "preliminary review of the data" was "disappointing" and the trial "failed."
4. The gene versus the protein: I think only time will tell which is more efficacious and has less side effects. I wouldn't be surprised if in some cases genes would work better and in some instances the protein would be more effective. Conceptually, the effects of genes could outlast the effects of the protein if the gene becomes well integrated into the cell and cranks out protein until the gene degrades. I don't know if that will be clinically important. I am sure there must be studies where the gene and then its expressed protein were injected into some tissue and the concentration of the protein measured over a period of time -- I am just too lazy to try to find that information.
5. Route of administration of VEGFs for CAD: It seems to me that the IV route makes no sense whether you're injecting the protein or the gene. With a negative Phase II trial, I agree with your conclusion that the dose was too low. However, I believe a higher dose may have too many side effects. Since it is given IV, a high dose may stimulate blood vessel formation at multiple sites. This may lead to complications. For example, patients with diabetes can have a sight-threatening condition caused by the production of new blood vessels on the retina -- this is called "neovascularization." A high dose of IV VEGF could cause problems at many sites. Much better, it seems to me, is to inject the drug directly into the site where you want the blood vessels to go -- such as around a blocked artery in the heart or leg. More local gain, less systemic pain.
Thank you again for your post.
Regards,
Steve Rachbach
