rpwg, actually, I think the first NDA for a small molecule drug will face the most difficult time. The FDA will have to develop their standards of performance and later apps should be able to take advantage of the already blazed trail.
O-15 is still our best hope, however I believe that those little elves over in California are also working on other surprise goodies.
That's how I realized how old I had gottrn. I could no longer jump over the brooks, I used to pee over. also when I figured out that IBS is a pain in the ass. Maybe a little BAD humor will mellow you guys a bit.
I think that we should be worried about small molecules because ONXX is competing with companies like HGSI, and MLNM, for capital from big pharma. The fact that it will take a long time and has some possible regulatory obstacles to overcome (as you state) makes it worse for ONXX. The money is flowing to organizations like HGSI and MLNM because the perception is that they offer the greatest potential for the most gain. Until that perception changes money will continue to flow their way and little will be left over for ONXX. What ONXX has taken in so far is chump change.
I just keep praying for very strong clinical results, the sooner the better.
rpwg, I agree, we are natural allies which is why a shift in perspective has thrown me off.
I don't have a problem with negative truths, but will argue till the point is proven, double ditto for negative opinions.
I'm not too worried about the genome data, nor small molecules. Genome will take years to assess. The interrelationships of non-adjacent genes is such a huge problem that there is no computer large enough to study the iterations/
And if we think the FDA has problems with modified virus therapies, small molcules that interfere with cellular 'operations' will give them total fits. That includes our own RAS therapy.
This is all in my own opinion. I am learning.
Here's a few tidbits.
PEG is commonly used to hide immunogenic proteins from the immune system. There several other competing methods including glycosylation and albumin.
From the 1998 10-K:
Initial research and clinical development of ONYX-015 in the p53 program was
focused on direct intratumoral dosing of the virus. The next step was to
introduce the virus regionally, as has been done in the ovarian cancer Phase I
trial, by delivering the virus into the peritoneal cavity via indwelling
catheter, and in the Phase I/II trial involving colorectal cancer that has
metastasized to the liver, via infusion into the hepatic artery. In order to
meet the needs of a wider spectrum of cancer patients and to treat metastatic
cancers, the virus would need to be delivered systemically. Research is underway
to attempt to formulate or modify the virus for systemic delivery. Onyx has
collaborated with a third party, which has proprietary technology for coating
adenovirus with polyethylene glycol ("PEG"), a process called PEGylation.
Preclinical studies have shown that ONYX-015 can be PEGylated and maintain
infectivity. PEGylation of the virus may increase the circulating lifetime of
the virus in the bloodstream by reducing the clearing efficiency of the liver
with consequential increased uptake of the virus by tumors. If PEGylation is not
successful, other modifications to the virus to improve targeting to specific
tumor types or reduce inherent immunogenicity of the virus may be required.
Since fewer virus particles are likely to reach the target tumor cells, a number
of enhancements to the virus may be desirable. One area of research focuses on
engineering changes to the viral genome to enhance potency by increasing
replication or cell lysis efficiencies.<<
From the 1999 10-K:
>>We have also identified a PCT patent application, PCT/US98/04080, that
claims pegylated adenovirus. Pegylation is one of many methods we are exploring
to modify our viruses for systemic delivery. Calydon, Inc. filed this
application with a priority date of March 3, 1997. Corresponding patent
applications are also pending in the United States. There can be no assurance
that these patent applications, should they issue, will not restrict our freedom
to operate in the area of pegylated adenovirus.<<
From the 2000 10-K:
Not a thing about PEG.
Rod, Onyx has been working on methods of defeating the immune response for some time. The polymer coating apparently is one of the more promising techniques. Until it actually gets into trials, it is hard to say.
PS It also brings up an interesting factoid, before human trials are begun, initial 'live' testing is done on animal subjects. Sadly, the results do not always follow to humans. But it has also been suggested that numerous drugs that have been tried and found ineffective on animals, may well work on humans. However, under current proceedures, we are unlikely to ever find out.
Anyone care to comment on the following? I do not know how effective this is at making the virus stealth to the immune system, or if there is a half-life to the cloaking process. Comments welcomed.
In June 1997, PolyMASC and Onyx entered into a collaborative agreement for PolyMASC to develop a PEGylated version of Onyx's ONYX-015 cancer therapeutic in development, and in April 1999, PolyMASC and Onyx signed a non-exclusive license for PEGylated versions of replicating adenoviruses. Under the terms of the agreement, Onyx has the right to develop PEGylated replicating adenoviruses, and PolyMASC will supply the activated PEG species required to manufacture the PEGylated virus. The goal is to assist ONYX-015 in treating not only primary tumors but also sites of metastases. http://www.megabios.com/Collaborations/Corporate_Collaborations/corporate_collab
PEGylation is an established technology that involves the attachment of the polymer polyethyleneglycol ("PEG")to therapeutics to alter their pharmacokinetics (distribution in the body, metabolism and excretion). The alteration of the pharmacokinetics of biologics due to PEGylation can lead to improved dosing intervals and may also have beneficial
effects on safety and efficacy. PEGylation also masks biologics from the immune system. Both recognition by antibodies (antigenicity) and stimulation of immune responses immunogenicity) are reduced.
AZ and micro,
Why don't both of you stop the pissing contest. You are both obviously well informed ONXX investors. I have followed and been grateful for the analyses/info that both of you have provided in the past (on this board and in the club) . I hope that both of you continue.
As you know I have been accumulating ONXX since 1996. I am concerned at this point about all the things that micro has been talking about. AZ, you have acknowledged most of his points at one time or another, and done your best to refute them. IMO, it is clear that you tend to look on the bright side. I am holding onto my position in the hope that you are right.
However, like microcapfun, I have posted a number of negative thoughts dealing mostly with the manufacturing issues. There are reasons other than short bashing for a person to post a negative opinion. Some of us may hope that management actually takes a look at this board once and a while and considers some of the more reasonable posts. I have been involved with pharmaceutical start-ups, and seen the good, the bad, and the ugly. Many good products have been lost because of inability to manufacture the scale-up batches on time and within a budget.
With the heavy bias in the mainstream pharma/biotech industry toward small molecule targets resulting from the illucidation of the human genome, the data will have to be extremely strong, and the market very large for PFE to remain involved very much longer with something so wild and revolutionary as a live therapeutic virus. As all long term followers know, the raf kinase inhibitor collaboration with Bayer is more mainstream and may ultimately be more valuable than the virus. The question is can the company survive to bring anything to market.
Long and Hopeful,
I know it is convenient to suggest that there are only two possible positions, cheerleading and critical truth, right? I assume that is what you wish to convey. Well, I'm not buying.
I did notice that you ignored my remark:
"No, this is not the same as an 'open' i/v injection, but has that even been tried? I don't know that it has."
Do you know of any trial, test, experiment where O-15 was tried systemically? If you do, please reference it, otherwise how does anyone know its performance or non-performance in this application?
I have no need to discredit anyone or anything that is factually based. And I am willing to admit error when I make one. If those attributes are cheerleading, hooray for me.
Simply put, don't expect to make negative remarks unchallanged. If they are true, you need not be concerned, otherwise, you get the same treatment that you so deftly dished out last year.