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I agree and I definitely painted with a wide brush there. I think it was one of the FDA transcripts with Bob Temple that influenced me. He waxed on and on about considerations for non-inferiority trials that made my head spin, especially when he started quoting patients numbers of about 1000 for appropriate trials.
I also think that it places a difficult marketing burden on a small biotech when they have to go out and compete with Lilly / Aventis et al based on non-inferiority rather than superiority.
fwiw...
Zhang's comment regarding a poorly designed Telcyta trial was really a funny one, in my view.
Zhang used Hycamtin / Doxil data from patients who have received 1 prior therapy, and compared it to the Telcyta data from patients who had received 3 prior therapies. His conclusion: Telcyta shows similar efficacy to Hycamtin / Doxil.
Problem there is that the comparison is not valid. It disregards the stage of disease that Telcyta's ovarian trial is treating.
After making his case that Telcyta efficacy was no different than Hycamtin / Doxil, Zhang turns around and suggests that Telik should not have designed a superiority trial, but rather a non-inferiority one (this is his trial design flaw argument). Problem is that non-inferiority trials are probably the worst types of trails for a small, unprofitable biotech to get involved in. Made me think that Zhang is either knowingly painting an unreasonable picture for Telik, or that he's very out of touch with the biotech sector.
I have the prudential report if you want to look at it. Drop me an email at poorgradstudent@yahoo.com.
Telk - Anyone here own Telk. Seems to be a good value at these levels?
I own it and have been averaging into it. It is getting a generous valuation, in my opinion. However, the data to date is strong. Investors who average into Telik over the next 12-18 months should be well rewarded.
Wick is a funny / strange guy. However he's smart as hell. The one near term disadvantage for investors is that he has not out-licensed Telcyta. The share price will therefore get hit hard for any delays (and the consequent financing that will be required). The potential benefit for those bearing the risk is complete preservation of North American profits, with the possiblity of a Velcade-like marketing deal. Such a deal would likely assure a competitive royalty for European sales while lessening the $$$ required for post-marketing development activities. For Telik, sharing the costs of furthering Telcyta's clinical development will be a significant gain for shareholders, in my opinion. If Telcyta does get on the market as a monotherapy subsequent to Hycamtin / Doxil, they will still have strong rationale to pursue earlier combination strategies for ovarian and nscl cancers.
you think AGEN's manufacturing issue will also show up on DNDN's doorstep? Admittedly DNDN's process is easier (therefore more easily reproducible), but it is autologous nonetheless.
Before I forget... for that pdf on Genvec's AdPEDF results: They present vision gain / loss in terms of letters, whereas others provide data by lines. I assume the latter is more difficult to achieve. However, is there a standard conversion of letters to lines? 3 letters per line?
Yeah, the enrollment analysis appeared to be his strongest point. But he even makes that analysis moot by saying that the planned telcyta + carbo trial in ovarian cancer will be the basis of approval in 2007. Of all the trials that Telik is running, that one is supposed to have the shortest follow-up time assuming that they stick true to their word and use response rate as the primary endpoint.
His invalid comparisons of clinical data for the ovarian cancer trials were shameful. His analysis of the NSCLC trial, summed up as "risky", is not exactly groundbreaking work for a biotech analyst. I think we all know that each and every pivotal cancer trial out there is risky.
An old copy of the WHO criteria can be obtained at the following link. I believe the guidelines are still valid today:
http://whqlibdoc.who.int/offset/WHO_OFFSET_48.pdf
As for the Telik report, if you IM me with your email address I can send it to you. I've read Zhang's analysis and the problems that he cites. Only one appears valid. The others are laughable.
I've never trusted ONXX, especially when they initially were reporting the BAY results in kidney cancer based on 25% or more shrinkage. First they had 37 of 89 patients show at least a 25% decrease. Then they kind came clean and said 13 of the 89 had 50% shrinkage by 12 weeks... which was again ambiguous because they never stated if the initial responses were verified by a follow-up scan that the objective response criteria demands. Now they come clean and state that they had 8 patients who experienced partial responses by WHO criteria, but the press release is vague as to whether or not it is 8 out of the 202 advanced kidney cancer patients, or 8 out of the whole 502 enrolled.
It's taking a beating.
As I'm forced to personally justify my large purchase of Genvec shares after the TNFerade hold, I'd thought i'd try to pump... er... provide a couple of references for insight into Genvec's use of PEDF in treating AMD. Today's PR from Genvec was not very informative beyond what Dew already summarized.
A bit about PEDF: PEDF has been shown, in preclinical studies, to have anti-angiogenic properties for the vasculature around the eye, rationalizing its use in slowing excessive neovascularization. Since part of the problem in wet AMD is the abnormal growth and rupture of blood vessels behind the macula, it stands to reason that inhibiting the neovascularization may have its advantages. Additional preclinical studies have suggested that PEDF may lie somewhat downstream of VEGF in its action, as it is able to partially antagonize VEGF-induced vascularization. This may model PEDF and VEGF as physiologically antagonistic proteins that keep each other in check.
I've referenced some papers with their abstracts in case some want to dig deeper into this topic. This is mostly a self-serving post as I already have a position in Genvec. However, even as a trade, I do think purchases in its current range (~1.60) will make a profit by the end of this year as I'm quite certain the clinical hold on TNFerade will be lifted... that's sure to give the share price a bump. They also have a very interesting vaccine platform that may be the long term gem in Genvec's portfolio. Management, however, have left a bit to be desired.
Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13090-5. Epub 2002 Sep 18.
Autologous transplantation of genetically modified iris pigment epithelial cells: a promising concept for the treatment of age-related macular degeneration and other disorders of the eye.
Age-related macular degeneration (ARMD) is the leading cause for visual impairment and blindness in the elder population. Laser photocoagulation, photodynamic therapy and excision of neovascular membranes have met with limited success. Submacular transplantation of autologous iris pigment epithelial (IPE) cells has been proposed to replace the damaged retinal pigment epithelium following surgical removal of the membranes. We tested our hypothesis that the subretinal transplantation of genetically modified autologous IPE cells expressing biological therapeutics might be a promising strategy for the treatment of ARMD and other retinal disorders. Pigment epithelium-derived factor (PEDF) has strong antiangiogenic and neuroprotective activities in the eye. Subretinal transplantation of PEDF expressing IPE cells inhibited pathological choroidal neovascularization in rat models of laser-induced rupture of Bruch's membrane and of oxygen induced ischemic retinopathy. PEDF expressing IPE transplants also increased the survival and preserved rhodopsin expression of photoreceptor cells in the RCS rat, a model of retinal degeneration. These findings suggest a promising concept for the treatment of ARMD and other retinal disorders.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_...
J Cell Physiol. 2001 Aug;188(2):253-63.
Pigment epithelium-derived factor inhibits retinal and choroidal neovascularization.
In this study, we investigated whether overexpression of pigment epithelium-derived factor (PEDF) by gene transfer can inhibit neovascularization by testing its effect in three different models of ocular neovascularization. Intravitreous injection of an adenoviral vector encoding PEDF resulted in expression of PEDF mRNA in the eye measured by RT-PCR and increased immunohistochemical staining for PEDF protein throughout the retina. In mice with laser-induced rupture of Bruch's membrane, choroidal neovascularization was significantly reduced after intravitreous injection of PEDF vector compared to injection of null vector or no injection. Subretinal injection of the PEDF vector resulted in prominent staining for PEDF in retinal pigmented epithelial cells and strong inhibition of choroidal neovascularization. In two models of retinal neovascularization (transgenic mice with increased expression of vascular endothelial growth factor (VEGF) in photoreceptors and mice with oxygen-induced ischemic retinopathy), intravitreous injection of null vector resulted in decreased neovascularization compared to no injection, but intravitreous injection of PEDF vector resulted in further inhibition of neovascularization that was statistically significant. These data suggest that sustained increased intraocular expression of PEDF by gene therapy might provide a promising approach for treatment of ocular neovascularization.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_...
J Cell Physiol. 2001 Dec;189(3):323-33.
Novel mechanism for age-related macular degeneration: an equilibrium shift between the angiogenesis factors VEGF and PEDF.
We investigated gene expression profiles of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) in differentiated and non-differentiated retinal pigment epithelial (RPE) cells during oxidative stress. Human RPE cells were grown in culture on laminin-coated flasks to obtain differentiated features. Cells cultured on plastic were used as non-differentiated controls. After confluence, hydrogen peroxide (H2O2) was added for 48 h, then, total RNA was extracted and used for RT-PCR and Northern blot analysis. Medium conditioned by RPE was used for ELISA, Western blotting, and in vitro angiogenesis assay. As a result, differentiated RPE cells expressed significantly higher levels of VEGF protein, as compared to their non-differentiated counterparts. The expression pattern remained consistent even after cellular exposure to H2O2. Conversely, while elevated levels of PEDF transcript and protein were seen in differentiated RPE cells, compared to non-differentiated cells, a marked decrease at both PEDF mRNA and protein levels was seen after treatment with H2O2. Moreover, this decrease in PEDF expression was dosage dependent. In in vitro angiogenesis assay, conditioned medium from differentiated human RPE cells after exposure to H2O2 showed a dramatic increase in tubular formation and migratory activity of microvascular endothelial cells. These data suggest that, in physiological conditions, a critical balance between PEDF and VEGF exists, and PEDF may counteract the angiogenic potential of VEGF. Under oxidative stress, PEDF decreases disrupting this balance. This equilibrium shift may be significant in promoting a pathological condition of RPE cells and contributing to choroidal neovascularization in age-related macular degeneration.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_...
Suppression of corneal neovascularization by PEDF release from human amniotic membranes.
PURPOSE: Human amniotic membrane (HAM) transplantation is commonly used in corneal surface reconstruction and is known to inhibit neovascularization of this tissue. The purpose of the present study is to reveal the molecular basis underlying antiangiogenic activity of HAM. METHODS: The effects of HAM protein on proliferation of vascular endothelial cells and corneal epithelial cells were determined by quantifying viable cells using the MTT assay. The presence of pigment epithelium-derived factor (PEDF) in HAM was demonstrated at the protein level by Western blot analysis and immunohistochemistry using a monoclonal antibody specific to human PEDF. The PEDF concentration was measured by a specific ELISA. The expression of PEDF in HAM was confirmed at the RNA level by RT-PCR and DNA sequencing. RESULTS: Soluble proteins from HAM inhibited proliferation of human umbilical vein endothelial cells and bovine retinal capillary endothelial cells (BRCECs) while promoting proliferation of bovine cornea epithelial cells. Moreover, the HAM-induced inhibition of BRCECs was neutralized by a specific anti-PEDF antibody. PEDF protein was identified with an abundance of 103.84 +/- 33.21 ng/mg of soluble proteins, which is comparable to that in the retina, a PEDF-rich tissue. PEDF expression was predominantly localized in the basement membrane of HAM. RT-PCR using specific PEDF primers amplified a single product from HAM RNA. The PCR product has a sequence identical with that of human PEDF. CONCLUSION: HAM specifically inhibits endothelial cell growth and thus suppresses neovascularization in the cornea. PEDF in HAM has a major role in eliciting this antiangiogenic activity.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_...
Biochem Biophys Res Commun. 2003 Apr 11;303(3):962-7.
Related Articles, Links
Vascular endothelial growth factor upregulates pigment epithelium-derived factor expression via VEGFR-1 in human retinal pigment epithelial cells.
We previously demonstrated that differentiated retinal pigment epithelial (RPE) cells express high levels of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF), and a critical balance between VEGF and PEDF is important to prevent the development of choroidal neovascularization. We report here that VEGF secreted by RPE cells upregulates PEDF expression via VEGFR-1 in an autocrine manner. PEDF mRNA and protein expression was downregulated by neutralizing antibody against VEGF in differentiated human RPE cells. VEGFR-1 neutralization decreased PEDF mRNA and protein expression whereas anti-VEGFR-2 antibody had no effect. Addition of placenta growth factor (PlGF) restored PEDF expression in the presence of anti-VEGF antibody. These results demonstrate a regulatory interaction between angiogenesis stimulators and inhibitors to maintain homeostasis in normal human retina.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_...
Stan Hazen at the Cleveland Clinic has really been one of the researchers on the forefront of this field. His work on myeloperoxidase hasn't escaped dcgn's attention.
Decode is a special case in that they really cherry pick their trial participants. Their strength of being able to use the Icelandic population as a database may also become a weakness when they're forced to pursue their large clinical trials in North America with a more heterogenous population.
I shorted dcgn this morning and just covered. The PR was really not as significant as the price pop made it out to be... the drug works as an inhibitor, as designed. The heavy lifting has yet to come.
I don't consider the Retaane trial to be a failure in the clinical sense. We have no idea whether or not the patients who respond to Retaane versus Visudyne are overlapping populations, or entirely exclusive populations. We just do not design clinical trials to test this scenario... and I wonder if we're therefore throwing away drugs with utility.
I will agree that this is a failure for the stock.
I really like the way Needham is stacking their biotech research group with MDs - guys who actually understand the science.
They'd need Ph.D.s for that, not M.D.s
Really.
>My first question was whether excess VEGF was a cause of asthma or an effect of it. The scientists in your article seem convinced it’s a cause. <
haven't looked at the paper yet, but when they use the terms "transgenic mice", that means that they've mostly likely inserted a VEGF gene with a promoter sequence that targets overproduction of VEGF in the lungs. Therefore, the VEGF in this case would be the cause since it is VEGF overexpression that perturbs the system.
Promoter sequences in front of genes act to define when and where the gene product is expressed.
OT: There are secret service all over campus today. Couldn't even go to the gym to play basketball... i guess neither Cheney nor Edwards were interested in a game of pick-up
Re: Tarceva filing...
Since the FDA's Pilot 1 Program is relatively new (at least to me!), I'm not fully versed in its regulations and guidelines. However, as a I understand it, it guarantees priority review since the FDA is committed to review every part of the NDA within 6 months of receipt. If they had not received priority review, then the review time would have extended past the guidelines of Pilot 1.
My assumption is that the designation of priority review for these Pilot 1 drugs is a mere formality. But I could most certainly be wrong...
hey rkrw...
can i borrow a couple of bucks now?
Interesting NEJM Question / Commentary that was brought to my attention by Biowatch.
Two independent groups cite observations in glioblastoma and NSCLC that patients responsive to Iressa tend to have cytoplasmic expression of EGF-R. It would be interesting if cytoplasmic expression becomes a validated biological finding in these tumours... it would have some consequences in the battle between small molecules and antibodies aimed at EGF-R.
Ken Walsh from our department also moved out to St. Elizabeth's Hospital about a decade ago, and he's been an important pioneer in some of the research looking at growth factors in restoring blood flow, as well as dissecting some of the important molecular pathways in the heart. I think he had a hand in an earlier trial looking at VEGF to restore blood flow, similar to the one you pulled from Corautus.
>Then why doesn’t the phrasing say, “without any risk of incorporation”? “Without any requirement of incorporation” sounds like they are stopping short of asserting that there is no incorporation.<
Because it is theoretically possible for the plasmid to incorporate into the genome. Circular plasmids (as i believe this one most likely is) do not incorporate well at all. When linearized, such plasmids are more likely to incorporate.
They say "without requirement" simply because there is no integration requirement for the plasmid to start vegf production. On the other hand, it is very, very difficult for them to determine if there has been incorporation, so in the absence of data, they can't say that there is no incorporation. So you're left with writing something that is technically correct, but not overly informative.
As for how devastating the impact... well, a biowatch said, the majority of the genome has vast spaces full of nothing (at least that's what we think). So if it incorporates in these areas, then the effect should be nil. If it incorporated into an essential gene, that cardiomyocyte would likely turn nonfunctional. Won't help their attempt at demonstrating efficacy, but it won't kill anybody either.
The bigger problem in this approach is that the VEGF has to bind to its receptors on the cell surface. So the VEGF produced inside the cell with this approach has to properly cycle to the exterior of the cell, and then find its receptor. I think this raises the bar a bit on trying to demonstrate efficacy.
Re: VEGF for heart disease:
>The part I don’t get is “…without a requirement of incorporation…” in the paragraph below.<
My bet is that they included such language to calm fears regarding the random insertion of the plasmid into the genome. Such a random insertion could be very problematic, as you may imagine.
These types of plasmids can work in a stand-alone manner because they will have a promoter in front of the gene of interest. That will allow the gene of interest (VEGF-2 in this case) to be expressed. Absent a promoter, the gene of interest would not be expressed because the coding sequence of the gene, by itself, can not recruit the transcriptional machinery.
s that an indictment of the quality of research at BU?
No. I usually take papers at face value, provided the controls are there and the interpretation is solid. I do not doubt that the researchers found what they found. It's just that this has been seen over and over in the lab, and while it has validity in a preclinical setting, it really hasn't shown promising results in the clinic.
It is more and indictment of CNVX and their dd during in-licensing.
Didn't i already bitch about something that cnvx previously in-licensed? I must be in a bad mood!
I just read/scanned the paper.
These guys must be desperate for product candidates or are unaware that Genasense already failed for melanoma.
My bet is that the T-oligo gets chewed up in the bloodstream (a la genasense) before it even attempts to enter cells... which it really can't because it is a standard charged oligo.
Man, i gotta stop working on cardiovascular stuff and start working on cancer. Lots of opportunities to make easy research dollars from desperate oncology companies.
sigh... back to grant writing for me...
I'll take a stab...
For smooth muscle cells that line vessels, charged compounds (as I understand macugen to be underneath its PEG clothing) can and do cause them to contract. Smooth muscles can maintain stress almost indefinitely (which may relate to the clot issue mentioned). However, innervating smooth muscles to maintain stress will cause them to hypertrophy (get larger) as well as proliferate. I'd bet that at the higher dose, they're getting proliferation of smooth muscle cells that is counter-productive to their desired physiological. The hypertrophy and proliferation of smooth muscle cells is also likely to be a primary contributing factor to any fibrosis that may take place, if we believe a certain biotech ceo.
Nitromed:
Granted, the only thing innovative about BiDil is its marketing plan. But I fail to see why you think it won’t sell.
Well, you have an NO donor that is the primary one used in the clinic (isosorbide dinitrate) coupled with a drug, hydralazine, that is typically third in line behind an ACE inhibitor and an Angiotensin II antagonist (provided the patients do not tolerate the latter two very well). Practically, by the time patients get to hydralazine, they already have an active prescription for the NO donor, meaning that they'll just get an additional prescription for hydralazine. The three cardiologists that I have spoken to (all active in practice at the hospital here) said that there is no practical advantage, from a health care standpoint, to having these two drugs combined. They were, however, interested in the outcome of the trial (all were familiar with the recent news, actually), and intended to take advantage of the study results (once released) in treating their patients.
My gut feeling from talking to them is that they will not change their prescription habits, especially since they can prescribe these drugs individually and gain the clinical benefit. It will be a difficult marketing effort for Nitromed, in my opinion. I may be all wet on this one, but what else is new?
Congrats on the stock price appreciation, however. After all, the market *is* about making money
Nitromed:
There is some silliness being written in the media regarding the nitric oxide effect, so let's clear that up first.
Nitric oxide is released from the endothelial cells that line arteries. It diffuses to the smooth muscle lining the arteries and activates the soluble pool of guanylate cyclase, an enzyme that generates the intracellular messenger cGMP (cyclic GMP) through the catabolism of GTP. cGMP activates another protein, cGMP-dependent protein kinase (also called Protein kinase G) to increase the activity of myosin phosphatase, an intracellular enzyme that acts to antagonize the contractility of smooth muscle. Therefore, administration of nitric oxide through a nitric oxide donor starts the cascade to relax the smooth muscle lining arteries, decreasing peripheral resistance and lowering blood flow.
The concept that blacks have insufficient nitric oxide is a nonsense comment that i would expect from any analyst working at a securities firm
The second point I'd like to make is how terribly difficult it is to design a clear, unequivocal study in the cardiovascular setting. Patient stratification and the balance between groups with respect to New York Heart Association (NYHA) class settings and additional drug usage (beta blockers) makes it very tricky. I've been in countless cardiology meetings where the docs just blast trial design and are loathe to change their prescription preferences based on what they perceive to be trials with deficient designs.
Therefore, the only real recourse for companies is to have their product actually included in the treatment recommendations put out by the larger collaborative groups or not-for-profit organizations such as the American Heart Association. With Bidil, it does not introduce a novel treatment concept, but rather fortifies the concept that amelioration of hypertension is a clinically relevant endpoint in a population known to be at higher risk for hypertension. For me, this study is more a population study than the study of a new treatment modality. For this reason, I have serious reservations as to whether or not Bidil will actually sell in the marketplace. My bet is that it won't.
No position, short or long.
Cancervax's new drug seems like a hodge-podge cancer vaccine attempt to me... a cross between BIOM's single antigen approach and AGEN's tumour-derived hsp vaccine.
And as is obligatory for vaccine's, their initial phase I/IIs trial were successful, with the old "those who developed an immune response did better than those who didn't" story.
Wonder if history will repeat itself with this drug?
OT: A couple of years ago, two friends and I walked to the Cleveland Clinic to sign up for an Aventis study looking at differential display for people before and after smoking pot.
When we went there, the nurse informed us that the study enrollment closed about 30 minutes after they put up the signs asking for volunteers
I'm still looking for other studies... will let you know if I find any with openings!
Avastin failed in 3rd line MBC.
Is it unreasonable to believe that Avastin will pass the muster in 1st line MBC?
If we assume that MBC will behave as CRC, then I guess you could make that assumption. However, they are clearly different indications and I do not see any scientific evidence to suggest that the above train of thought is necessarily applicable. It appears to be the "we'll get better results in less sick patients" theory. Tarceva/Iressa negated that theory, suggesting that there is an underlying change in the biology of disease as patients progress through the various stages of treatment.
Anyways... hope your pipeline flourishes! That's all that counts.
Not to belabour the point, but if we start to consider additional trials as part of the pipeline, then i can name many companies that have large pipelines
For example, master named avastin in metastatic breast cancer as one of the pipeline events. Avastin has already failed in one metastatic breast cancer setting, so it becomes hard to consider another avastin breast cancer trial in another setting as part of a promising pipeline.
I don't doubt the financial impact that label expansion can have for the company. It's a personal semantics thing, but i just don't consider these label expansions as the pipeline. I'm putting my foot down on this one...
I never really considered follow-on trials of a marketed drug to be under the "pipeline" umbrella.
Guess it's just me.
is there a specific expertise that insbrooklad had?
It appears that the ARQL phase I is a simple dose ascending trial in cohorts of 3 patients. The claim to date is that they have not yet run into the MTD; once they do, it is my impression that they will focus on one cancer and run another small trial to look for an objective response or two.
The concept of checkpoint therapy is interesting. Nonetheless, I can see a very real possibility of arq501 falling flat on its face... sometimes drugs that have no toxicity also have no efficacy
My exposure is limited, and it helps to know that arql is perceived to be one of the better chem outfits. It should help their liquidity situation while they pursue their oncology program.
Trendy???!!!
Here I thought I was actually thinking and objectively deciding... apparently I'm simply following fads! I should become a biotech analyst!
TLRK (soon to disappear) and AMEV (disappeared) were scientifically interesting (read: in my portfolio). TLRK was way more interesting to me than AMEV; the latter being more of a "brute force" approach to drug optimization.
I'd love to own some Cor, but it would make me think that I knew something about neurology. Other than knowing what an ion channel's current - voltage relationship looks like, my neurology knowledge is nil.
I have a position in mlnm that has had me nervous for ~18 months. Also own a small position in nbix from a looooooong time ago. I've basically stopped following them.
Re: Ariad and similar, early stage cancer compounds...
This is a late reply. However as a matter of strategy, I often will start small positions in companies that have scientifically interesting compounds in phase I. I've done so with Ariad, as well as ARQL. I find that the biotechs developing such compounds are often cheap, and since it is practically impossible to know how a drug will do in phase I... it's worth the small gamble.
But they have to be "scientifically" interesting. Don't ask me exactly what that means
I believe Randy is correct in his references. That is the same line of reasoning that I've previously dug up. Carbo does appear to be a little milder than cisplatin insofar as safety.
Also, don't dismiss the fact that Carbo is BMY's and so is Taxol... helps to have *both* your drugs in the front line chemo doublet
OT: Rstor
I was happy with the latest round of Genvec data. Especially by the finding that they're showing a dose-dependence with respect to PFS and, to a lesser degree, with overall survival.
But I'm a Genvec investor, so accept the bias within.
As for Dendreon, I do not have a position. I've been trying to stay away from stocks that base future success on observations from previous subsets. I realize that Dendreon was very close in their ITT analysis, but I'd still rather wait. I feel the same for ALTH. I believe there is merit to both drugs, but I'd like that merit to be demonstrated prospectively.
I can't provide any reassurance, but I admit that I'm surprised you're letting a sector shake-down rattle your nerves a bit!
Buck up!!!!
Further OT: For those who always claim that stocks go down when they buy them, could you look into buying a little AMGN? I need that sucker to dive before the TLRK acquisition officially closes... thanks in advance
Many Imclone investors are holding out hope that Erbitux is magical amongst the EGF-R inhibitors and will succeed where Iressa and Tarceva failed: 1st line NSCLC.
However, the activity of Erbitux in the refractory NSCLC setting is not an improvement over Iressa or Tarceva. Erbitux showed a 6% ORR. I'm skeptical that it will fare any different in the first line, unless IMCL/BMY/Merck KgAa adopt a novel treatment schedule.
>That won’t work unless the drugs are given to only the patients with the mutant EGFR. However, patients without the mutation do show some benefit from taking these drugs, so some of them will opt for treatment.<
Well, I was speaking to the argument around many parts (press / message boards) that testing for the mutation will decrease Iressa / Tarceva income. If a situation arises that it is only given to those with the mutation, then i think price will increase. If, as you suggest and i believe, that the drug will still be given to those without the EGF-R mutation, then i believe that the early forecasts of reduced usage are premature. Interestingly, if the degree of overexpression of EGF-R is a prognostic indicator, Tarceva may have an advantage over Iressa due to its higher affinity for the target... therefore greater chance to saturate the available targets.
>Iressa had two phase-3 trials: one in the second line and one in the third line. Tarceva had one trial with mixed second/third line. For all practical purposes, the two drugs were tested in the same setting.<
I should have indicated that I was confining my comments to Iressa's approved setting. Iressa's label indicates approval based on 216 patients split roughly evenly between 250 mg and 500 mg per day doses. More relevant for this discussion, the entry criteria underlying these data were "failure of both platinum-based and docetaxel chemotherapies". Therefore, these patients had gone through the carbo/taxol and then taxotere regimens, meaning that the minimum amount of prior treatments were 2. As you indicated, I believe that the Tarceva trial would accept those who had only failed one regimen.
If the EGF-R mutation is an inherited one, it can be easily tested for, at any time, using some DNA extracted from the blood. If it is a mutation that is gained following birth, then an actual biopsy sample from the tumour is needed. Assuming that material is available, the test can be done at any time.
Second, I do not think that this test will have a huge impact on the income derived from the EGF-R inhibitors. If the test is validated and used, then the companies like AZN and OSIP will be able to offer a more tailored therapy with a heavily increased chance of therapeutic benefit. This will likely prompt the companies to increase the cost of their drugs in a manner analogous to Genzyme's enzyme therapies.
Furthermore, selecting a patient population that is very likely to benefit also means that you're focusing on a population that will take the drug for a longer average duration. Coupled with a price increase, the companies involved will do their best to make the economics work.
As for the FDA delaying Tarceva because they already offer Iressa... anything is possible, but I doubt it would fly. If I'm not mistaken, the patient populations that Iressa and Tarceva were tested on were not identical. Iressa patients had failed 2 previous regimens whereas, Tarceva's had failed at least 1. Furthermore, such an action by the FDA would really be a large blow to many of us biotech investors... especially if we can no longer count on life extension as a fundamental step towards FDA approval.
John Jackson (CEO), Sol Barer (COO) and Robert Hugin (CFO) are kind of a three-headed monster for the company. They're all active in CCs as they were in the last one, which is where I think that quote is from.
Perhaps it is best to wait for the actual data.
If the baseline survival in the Tarceva trial was 4-5 months as you recite, then for the trial to take this long to accrue the necessary events (estimate late jan/early feb from CCs), you'd be looking at a hazard ratio of 0.5 or less. In any case, I believe it is relatively clear that the trial did not conform to the 4.5 month vs. 6 month structure.
As for the value of such a drug.... it all depends on the quality of life. At this terminal stage of cancer, my opinion is that the best thing that can happen to patients is that they stay out of bed longer. Once they hit the bed, it's game over. So if Tarceva gives them an extra month or so before they hit the bed... then, well, you decide what that is worth to you. No one is forced to take and pay for Tarceva. If this was a straight chemo regimen, then i'd say that the clinical relevance would be of very limited value. But it's not.
However, this was a well designed and, apparently, a well executed trial. Perhaps it is more and indictment on where we at with the "war on cancer", rather than OSIP/DNA/Roche trying to milk patients for $15-25K for another month of life.
Couple of points on adenovirus dosing...
Historically, virus and phage are quantitated based on their ability to infect. In the classical work with bacteriophage lambda, the concentration of the phage was quantified based on its ability to infect and lyse bacteria, thereby causing "plaques" or seemingly empty spots in a lawn of grown bacteria. This is generally why people refer to viral titres as plaque-forming units (PFU). Furthermore, in stark contrast to the mass-oriented measurements for normal drug administration ( x mg dose), PFU measurements are really related to the number of *molecules* of individual virus present in the sample... that's why we get to rather large numbers (to the 8th-12th powers) when discussing amounts. People often work with viral titres that vary sequentially by 10 fold differences in magnitude... so a 3000 fold difference between lowest and highest dose is really ~3 dose increments. Considered in that fashion, it is not unlike the number of dose increments that occur for traditional small molecule drugs in phase I studies.
In reading through some of dew's referenced posts, i noted one correction to an earlier suggestion: the adenovirus used by GenVec is replication defective.
At this point, hard to determine if GenVec has even a fledgling AMD program since they did not provide any data. Sigh...