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>> VRTX-The impressive efficacy of VX-950 isn't in question. It's been out there for awhile now about how well the drug clears the HCV viral load. The remaining question mark for VX-950 is safety, specifically the monkey toxicity studies, which have yet to be conducted. <<
I agree with you that the safety issue is a remaining question mark , and VRTX is hardly home free at this point. However , unless I missed something presented previously , this is the first I've seen of viral load measurements beyond 28 days. Thw rapid viral load reduction by VX-950 ( 2 days , 14 days , 28 days , whatever ) is old news. That kind of viral load reduction , that early , is an encouraging signal of possibly impressive SVR rates , but it is no guarantee. Negative HCV RNA at 12 weeks post-VX-950 is no guarantee either , but it's getting a whole lot closer to being one , IMO.
I've seen figures that have shown that > 80% of patients ( on pegifn + riba) that are HCV-RNA negative at 12 weeks go on to achieve SVR. This was in mixed genotype , naive patients , I believe. If the 8-patient study results holds up in larger trials , and achieve SVR results in this range ( after only 14 days of VX-950!) , it will be big news. Thus I consider the recent 12-week data to be very important , and real news , not a re-hash.
There will be opinions on both sides of this, on this board and elsewhere, for the next week or so , I'm sure.
Re: VRTX
>>>The VX-950 results are very impressive indeed, but this has been known since January (#msg-9177786). I don’t see anything in today’s PR, specifically, that changes the competitive landscape.<<<
Dew,
This data was new:
"Researchers reported for the first time today that 8 of 8 patients who received VX-950 and peg-IFN in combination for 14 days have no detectable virus in their blood at the end of 12 additional weeks of peg-IFN+RBV dosing"
Although it was only 8 patients , I think this is very important if it holds up in larger trials. A 12-week EVR ( i.e at least a 2 log drop ) is highly predictive of SVR when using pegifn plus riba (~ 65-75%). I would expect a 12-week complete viral response to result in even higher SVR rates.
I think VRTX is moving to the front of the pack on hep c. A few weeks of treatment including VX-950 followed by a few months more of pegifn + riba that results in SVR rates of 80 or 90 % in gen 1 patients would capture the naive markets in the U.S and Europe, IMO. They're not there yet , of course , but I think this data will make a splash , and it may explain some of IDIX' recent weakness.
IDIX : You're probably right, Dew. I'm just trying to make sense of the recent swoon , which seems way overdone. I just get the feeling someone has heard something we haven't. Maybe it's just the market doing its thing.
Re : IDIX
My WAG is that IDIX will announce a fairly significant delay in the NM-283 program as a result of the recent high-dose problems and that word has leaked to somebody(s) with deep pockets.
RE: BIOM
From the PR :
"Our enthusiasm around Stimuvax® continues," said Alex McPherson, MD, PhD, President and CEO of Biomira. "These data from the Phase 2b trial are encouraging and have been reviewed by an independent statistician, who confirms our findings."
Since there were no p-values given , what exactly did the independent statistician confirm , that they correctly calculated the median survival ?? They're paying the guy, so why not ask him if the results are significant?
re: subgroups
Your post raises another question I have about subgroup analysis. Let's say a company is running a registration trial for a cancer drug , and has an SPA defined for several biomarkers. The company would like to get approval for the entire population , rather than subgroups , naturally. Now , assume that the endpoints are met for the entire group , which would seem to negate the need for subgroup analysis. Does the FDA grant full approval ? If so , what if one of the biomarkers measured showed that the responders could be reliably determined using that biomarker , thus avoiding unnecessary treatment of nonresponders? Since the overall endpoints were met , is that data never examined ?
Re: Off-topic quiz
States with the highest wife / husband ratio ?
Re: subgroup analysis
>>> If K independent tests are conducted, one way to ensure that the overall chances of a false positive result are no greater than 5 percent (0.05) is for each test to use a criterion of (1–0.95)1/K, or about 0.05÷K, to assess statistical significance. <<<
Thanks for that, PGS. I've always wondered if there was some rule of thumb to interpret subgroup significance in trials and published research , and the one above is simple enough even for me !
It's common to see publications of data where 30 or 40 different measures are examined and a few are labelled "p<.05" , even though it's clear that some of those would be expected due to chance alone.
Re : Goostree
"Apropos to funny names: Goostree stands out for the simple reason that geese do not go in trees. Never, ever."
Sorry , Dew , I couldn't resist:
http://tinyurl.com/zmljs
Jazz / nuere,
This is a good board - you guys have a lot of info right at hand , it seems. Now all I have to do is find the time to sit down and digest a bunch of it.
Jazz , your last link didn't work but I'll try typing the URL and see if I can get it - I usually mess something up when I do that though. I did look at the Blood article on HIV that you referenced and nuere's post was along the lines of what I was interested in. It strikes me that the anti-PS antibody response is probably more the rule than the exception in cases where PS is expressed 'inappropiately'. This probably bodes well for the safety of Tarvacin and maybe efficacy also. It might be that Tarvacin will benefit most those indications ( or particular patients ) where there is little or no normal anti-PS response , but not necessarily. I can also see how it might function better than the host polyclonal response by virtue of factors like concentration , specificity , affinity , isotype and such.
I'll try to get more up to speed on PPHM before I bug you all with more questions. Thanks again.
Re: GoFish, Animal to Human Transition
Thanks for the links. It seems like there is reasonable justification to think that safety won't be a major problem, though you never really know until a sufficient number of human subjects have been followed for a while. Even if there are some SEs , it wouldn't prevent Tarvacin from being used in cancer or antiviral applications where current treatments are ineffective or have their own bad sides , like ifn and riba.
I'm still curious why we don't develop our own anti-PS repertoire as part of antiviral immunity or tumor surveillance immunity. It may relate to the way the PS is displayed on the cells. My understanding is that the known lipid antigens ( e.g. mycobacterial ) are presented by the CD1 family of molecules , which are analogous to MHC 1 and MHC 2 for peptide antigen presentation. It could be that the PS molecules rarely present themselves in a way that would generate an immune response ( with the obvious exception of the anti-phospholipid syndromes ) in which case Tarvacin would indeed be providing an 'upgrade' to immunity.
If you know offhand of any papers that explore this issue , Tarvacin-related or not , I'd appreciate any links. Do you know if PPHM has looked for CD1-bound PS in any of their studies ?
Thanks again , and good luck. It's a little early for me to think about investing just now , but I'm going to follow PPHM and will be eager to see the upcoming data.
Re: Tarvacin Safety – what we know
Thanks to all for the replies. Lots of good info to review.
It seems like steps were taken during the development process (i.e. screening of MAB candidates ) to minimize the possibility of adverse reactions. The safety data in primates is encouraging too , hopefully it will be reproduced in human studies.
Post from the Biotech Values board.
I posted this query to Preciouslife1 who suggested I repost it here. My apologies if this has been repeatedly addressed here , as I've just started looking into PPHM and haven't read this board much yet :
Re: Some concerns about Tarvacin
I'm just beginning to look at PPHM and admit to being intrigued already , but a couple of obvious questions arise that you may be able to shed some light on:
1) Side effect issues: I have to think that the probability of side effects is pretty high for an anti-PS antibody , given the ubiquitous nature of PS in the body. In a quick search I found these two citations suggesting possible AE's :
Phosphatidylserine IgG and beta-2-glycoprotein I IgA antibodies may be a risk factor for ischaemic stroke.
http://tinyurl.com/buln6
Behcet's disease is associated with increased concentrations of antibodies against phosphatidylserine and ribosomal phosphoproteins.
http://tinyurl.com/8vsz6
I only picked these out of the first page of a PubMed search , so I'm pretty sure there are others in a similar vein. As a treatment for late-stage cancer the presence of side effects like these may be acceptable but it would certainly cause concern for other indications. If Tarvacin is cleared pretty quickly it may not be an issue but if the treatment is continued for a length of time it may.
2) If anti-PS antibodies are so active against so many pathologies I would think the human immune system would have evolved this capability as a regular feature of its response to tumors or pathogens. Is it a normal immune reaction that gets shut down inappropriately during disease , or does the body avoid this approach for reasons suggested above , i.e. collateral damage ?
TIA for any thoughts you may have on this , and good luck with PPHM. I hope it's effective in upcoming trials since it really would be a new weapon in the arsenal against cancer and other bad actors.
Re: Some concerns about Tarvacin
I'm just beginning to look at PPHM and admit to being intrigued already , but a couple of obvious questions arise that you may be able to shed some light on:
1) Side effect issues: I have to think that the probability of side effects is pretty high for an anti-PS antibody , given the ubiquitous nature of PS in the body. In a quick search I found these two citations suggesting possible AE's :
Phosphatidylserine IgG and beta-2-glycoprotein I IgA antibodies may be a risk factor for ischaemic stroke.
http://tinyurl.com/buln6
Behcet's disease is associated with increased concentrations of antibodies against phosphatidylserine and ribosomal phosphoproteins.
http://tinyurl.com/8vsz6
I only picked these out of the first page of a PubMed search , so I'm pretty sure there are others in a similar vein. As a treatment for late-stage cancer the presence of side effects like these may be acceptable but it would certainly cause concern for other indications. If Tarvacin is cleared pretty quickly it may not be an issue but if the treatment is continued for a length of time it may.
2) If anti-PS antibodies are so active against so many pathologies I would think the human immune system would have evolved this capability as a regular feature of its response to tumors or pathogens. Is it a normal immune reaction that gets shut down inappropriately during disease , or does the body avoid this approach for reasons suggested above , i.e. collateral damage ?
TIA for any thoughts you may have on this , and good luck with PPHM. I hope it's effective in upcoming trials since it really would be a new weapon in the arsenal against cancer and other bad actors.
Bioinformatics ideas , anyone ?
This might not fall under the Biotech Values heading in a strict sense but it's an important related field.
Given the crushing amount of data generated in genomic , proteomic and other -omic studies it strikes me that some companies that might do very well going forward are those that sell systems that make sense of all the data via various data processing techniques.
Any ideas on this , or is it too early ( or too late ! ) to pick the winners ?
TIA
Re: NEOL quiz
I'll let others take a stab at the NEOL quiz since I bombed on my first try , but I have another question for the statistics buffs :
Lets say an early stage dose-ranging trial shows a benefit for a treatment that results in p values for the different dosing arms (compared to the control arm ) of 0.25 , 0.20 , 0.15. Now , if you assume that a p value of 0.05 will be necessary for approval down the road , those results might not seem so hot. However , I would think that the probability that the benefit demonstrated was due to chance in all three arms would be the product of the individual probabilities , or .25 X .20 X .15 = .0075. Thus the dose ranging study would appear to virtually guarantee that a stat sig benefit can be demonstrated in a sufficiently powered registration trial , assuming no other confounding variables.
What am I missing here ? ( And I know I'm missing something :~))
Re : NEOL quiz
My guess is that a p value of .005 at the interim look is equivalent to the p value subtracted from the final analysis ( .002 ) because less information is available at interim time points. The closer to the end of the trial one takes an interim look , the more the p value penalty approaches the 'real' value.
GNVC : TNFerade publication in Cancer Gene Therapy
Free full-text review :
http://tinyurl.com/db64r
Ionizing radiation: a genetic switch for cancer therapy
J J Mezhir, K D Smith, M C Posner, N Senzer, B Yamini, D W Kufe and R R Weichselbaum
Cancer Gene Ther 13: 1-6; advance online publication, August 5, 2005; doi:10.1038/sj.cgt.7700879
Re : Generic biotech drugs
I'm confused about the term 'biosimilar'. If the protein has the same amino acid sequence with no other modifications , and is folded properly , etc., it would seem to me it would be 'bio-identical'. ( assuming absence of contaminants )
If it's not bio-identical , how could they justify not doing new trials ?
Re : gofishmarko - SCLN
If the new CEO is correct, SVR is the primary endpoint. The talk of two primary endpoints may be just hot air.
Terry,
Since I've been the source of most of the hot air on this I guess I need to document my sources.
All of the PRs and SEC filings that discuss the trials in detail specify the two endpoints for each. Also here's a paste from the Walter Reed site protocol : (Sorry , no link. This is from a pdf I have but it's on the web , somewhere.)
Report Date: 8 January 2003 Work Unit # 02-92009
DETAIL SUMMARY SHEET
TITLE: A Multicenter Double-Blinded Study in Non-Cirrhotic Patients With Chronic Hepatitis C Who
Are Non-Responders to Prior Interferon Alfa or Interferon Alfa + Peginterferon Alfa-2a With Peginterferon
Alfa-2a + Placebo
PRINCIPAL INVESTIGATOR: Sjogren, Maria H. COL MC
DEPARTMENT: Clinical Investigation STATUS: O
SERVICE: INITIAL APPROVAL DATE: 26 March 2002
STUDY OBJECTIVE
The purpose of this study is to determine the safety and effectiveness of treatment with Thymosin alpha-1
in combination with Pegylated interferon alpha-2a in adult patients with chronic hepatitis C already treated
with and not responding to interferon monotherapy or interferon plus ribavirin combination therapy.
The primary efficacy endpoints are:
1) Proportion of patients who are HCV RNA negative from month 12 to month 18 (sustained
virological response)
2) Proportion of patients demonstrating an improvement in liver histology as measured by 2-point
improvement of Knodell scores post-treatment with no worsening in fibrosis score.
The secondary efficacy endpoints are:
1) Proportion of patients with normal ALT at month 12 (end of treatment biochemical response)
2) Proportion of patients with normal ALT at month 18 (sustained biochemical response)
3) Proportion of patients who are HCV RNA negative at the end of treatment (end of treatment
virological response)
Scln -drbio45 , etc.
"What made the stock run to 8 between july and august. I know sigma tau was buying but they only paid up to about 4.50"
There was a bogus report circulating in June about a tender offer from a Portuguese co. that may have contributed to the rise , then Biotech Monthly covered SCLN in an issue and had an exclusive interview with the new CEO around that time , I believe. I suspect that most of that runup was retail and momo buyers.
Thanks to Dew for his answer to my question about the complicated endpoints / p value issue surrounding the SCLN HCV trials. I think his advice is good , but think that this case presents some special problems in interpretation of results , unless they are compelling ( good or bad ).
For example , a close miss on the histology endpoint in the first trial ( non-cirrhotics ) , combined with a good SVR result might well portend a double positive in the second trial ( early cirrhotics ). I don't know how the FDA would consider that dataset as to granting full approval , but I suppose there is the additional possibility of approval restricted to cirrhotics. The separation of the two groups in separate trials implies a built-in stratification of results , to me at least. ( comments on this are welcome )
I'm fairly confident that both trials will show stat sig SVRs , but am less certain about the histology improvement reaching significance , though Zadaxin plus ifn has shown improvements over ifn alone in the studies that mention histological data.
New treatment for depression...
(should be very cost-effective ,too)
Interaction With Dolphins May Be Beneficial in Mild to Moderate Depression
Dec. 1, 2005 — Compared with exposure to water in the natural setting, interaction with dolphins is beneficial for the treatment of mild to moderate depression, according to the results of a randomized trial reported in the Nov. 26 issue of the British Medical Journal.
"Disrupting the affiliation with nature and thus losing the biophilic equilibrium means to alter and damage our psychophysical health," write Christian Antonioli, MD, and Michael A. Reveley, MD, from the University of Leicester Medical School and Leicester General Hospital in the United Kingdom. "Numerous researchers have presented evidence showing the therapeutic value of nature and animals for sick and disabled people.... We chose the bottlenose dolphin, Tursiops truncatus, for the animal-facilitated therapy and mild to moderate depression as the illness to be treated."
This single-blind study took place in Honduras, with recruitment of outpatients in the United States and Honduras, using announcements on the Internet, radio, newspapers, and at hospitals.
Of the 30 patients randomized to the 2 treatment groups, 2 dropped out of the treatment group after the first week and 3 in the control group withdrew their consent after they had been randomized. For those who completed the study, the mean severity of depressive symptoms was more reduced in the treatment group than in the control group (Hamilton rating scale for depression, P = .002; Beck depression inventory, P = .006).
Modified intent-to-treat and last observation carried forward methods of analysis resulted in highly significant mean differences for the Hamilton and Beck scores between the 2 groups (P = .007 and P = .012, respectively).
"The therapy was effective in alleviating symptoms of depression after two weeks of treatment," the authors write. "Animal-facilitated therapy with dolphins is an effective treatment for mild to moderate depression, which is based on a holistic approach, through interaction with animals in nature.... The echo location system, the aesthetic value, and the emotions raised by the interaction with dolphins may explain the mammals' healing properties."
There were no adverse effects noted, but the authors mention the potential for accidental injuries, and they point out that water phobia and inability to swim represent limitations of the treatment.
http://www.medscape.com/viewarticle/518204?src=nldne
A question on p values I posed to Dew in a private email , and he suggested I post here :
Dew , seeking some guidance ...
I'm a new reader of Biotech Values and I'm already sorry I missed it for so long. I'm hoping you'll share your thoughts with me on an issue regarding SCLN , one of my holdings.
As you know , their P3 Hep C trials are nearing an end. I've been convinced that if they achieve a p value less than .05 for SVR that chances for approval of Zadaxin would be good. After reading some recent posts of yours though , I'm not so sure. There are two separate trials , one in non-cirrhotics , the other in early cirrhotics. Both trials have two primary endpoints , SVR and histological improvement. Results from the two trials will form the basis for an NDA , hopefully.
Looking at both trials , there are four primary endpoint data. I'm assuming that if all four show p < .05 , that would be considered a success , barring safety or side effect issues , etc. The question in my mind is what if one or more endpoints are not met at .05 , what would be the requirements for the other data points? I'm trying to get a feel for how to evaluate the first trial results , due in 2 weeks , as they relate to chances for approval.
Any input you can provide on this would be greatly appreciated. I'm not looking for your opinion on SCLN or Zadaxin , though you can feel free to provide that as well if you like. I may share your thoughts with the Yahoo SCLN board , unless you'd prefer that I don't.
TIA , and keep up the good work on Biotech Values . It's a big help to me , and I'm sure many others as well
Do the patients get a Boost?
I haven't looked at the study you mentioned , but my understanding of the Ontak approach is that it's a rather blunt instrument. Ontak targets CD25 , and not all CD25+ cells are regulatory cells ( e.g. actvated T and B cells ) and not all regulatory cells are CD25+.
It seems to me that what's needed is a method to overcome tumor-specific suppression and that the Ontak method throws out a lot of babies with the bathwater. Myeloablation by means of chemo- or radiotherapy removes suppressor cells as well , but nobody is getting excited about that.
That said , I hope it works.
NHL page -links to personal experiences
This page has a load of links that you may find valuable , including some to patients relating their own stories. I hope you find some that will provide encouragement to your daughter.
Good luck to both of you.
http://tinyurl.com/docjl
BTW , my first post to a great board and I'm sorry it has to be on something like this , but I think this thread proves that the value of this board extends beyond biotech investing.