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The response rate improvement in this trial looks good, and it's great they did a randomized phase II.
But that's a huge drop in the PFS increase when you go from the ITT group (n=110) to the 100 patient group.
Enrollment for a trial offering up-to-date, competitive treatments is not a hurdle.
NSCLC is probably one of the most heated indications with respect to competition, yet all the trials do get filled. I would venture that NSCLC has some of the most extensive data out there for cancer treatments. Prostate is also, unfortunately, an indication with plenty of available patients... in fact, about 1.5x the lung cancer population.
Trials that have trouble enrolling usually are caught by a recent change in treatment paradigm, or the docs and nurses see / feel that things aren't going well and don't funnel patients into the trial.
OSI stated that their analysis of the EGF-R mutant population in the BR21 trial showed that although the population was more apt to see an objective response, they did not do better insofar as overall survival.
So the whole EGF-R mutation thing will require better clarification of context until it is a valid marker to predict survival.
I'm not sure there is a good reason for the benefit in Eastern Asians... yet.
The problem with Folkman is that he thinks every damn drug is an angiogenesis inhibitor.
It's getting kind of tiring.
More Telcyta data:
Telik Reports Positive Interim Results of TELCYTA in Combination With Cisplatin in First-Line Non-Small Cell Lung Cancer
Tuesday May 17, 8:00 am ET
PALO ALTO, Calif., May 17 /PRNewswire-FirstCall/ -- Telik, Inc. (Nasdaq: TELK - News) reported positive interim data from a multicenter Phase 1-2a clinical study evaluating TELCYTA(TM) (TLK286) in combination with cisplatin in the first-line treatment of advanced non-small cell lung cancer (NSCLC) at the annual meeting of the American Society of Clinical Oncology. In the trial, a 36% objective response rate (by RECIST) and an 86% disease stabilization rate were observed in the evaluable patients at the time of the interim analysis.
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At the time of interim analysis, a total of 47 patients were enrolled in the trial. Of these, 22 patients treated at the Phase 2a dose (TELCYTA at 1,000 mg/m2 and cisplatin 75 mg/m2) were evaluable for efficacy. There were eight partial responses and eleven patients with stable disease. Objective responses were observed in subtypes including squamous cell, large cell, BAC and adenocarcinoma, as well as in males and females and current, former and never smokers. Overall the TELCYTA plus cisplatin combination was generally well tolerated, without unanticipated toxicities. Median survival has not yet been reached. Enrollment in the trial is now complete.
"TELCYTA appears to significantly augment the clinical activity of cisplatin without additive toxicity in these patients with advanced non-small cell lung cancer," said Howard A. Burris III, M.D., Director of Drug Development for the Sarah Cannon Cancer Center, and Principal Investigator of the study. "These results warrant additional clinical trials using the combination of TELCYTA and platinum-based drugs."
Complete responses in NSCLC are rare, so hopefully they had an independent board review the scans.
Surprisingly, the overall response rate isn't so hot considering they showed 2 complete responses.
Check out this abstract for an example of a typical response for a more classical type of immunization. You'll note that they did the same T-cell proliferation experiment, with an average of a 45 fold increase following immunization. From other papers that I've read, this is very typical. It appears to me that DNDN's reported index is a little on the low side versus data we have on hand for successful immunization strategies.
J Clin Immunol. 2003 Nov;23(6):528-38. Related Articles, Links
Vaccination with rabies to study the humoral and cellular immune response to a T-cell dependent neoantigen in man.
Brinkman DM, Jol-van der Zijde CM, ten Dam MM, Vossen JM, Osterhaus AD, Kroon FP, van Tol MJ.
Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands. d.m.c.brinkman@lumc.nl
We investigated the humoral (antigen-specific immunoglobulin isotypes, IgG subclasses, and avidity maturation) and cellular (antigen-specific in vitro proliferation) immune response in 18 healthy adult volunteers, following a primary and a single booster vaccination with the T-cell dependent neoantigen rabies administered at a 3-months interval. The IgG antibody titer showed a mean 31-fold increase (range 3-154) 4 weeks after the first vaccination and a memory response was observed after booster vaccination, i.e. high IgG titers, switch from IgM to IgG and IgA and increased antibody avidity. All healthy adults showed a rabies-induced proliferative response with a mean stimulation index of 45 (range 3.5-200) after in vitro stimulation of PBMC obtained at 4 weeks after booster vaccination. The results obtained in this study provide a frame of reference for the interpretation of specific immune responses to the T-cell dependent neoantigen rabies in patients suspected of a primary or secondary immunodeficiency. Humoral and cellular immune responses to the rabies neoantigen provide complementary information on the condition of the immune system of an individual. Five patients diagnosed with a combined immunodeficiency were vaccinated using the same protocol and showed a number of abnormalities, either in the humoral or the cellular immune response to the rabies neoantigen.
Might be. They didn't really do a statistical comparison.
Nonetheless, I'm quite sure that CA-125 doesn't correlate with survival. So if you decrease a marker that is not a strong correlate of survival, what do you have?
Surely CTIC has objective tumour response data for the patients in this trial that had measurable disease. My question is why wasn't this presented?
A pessimistic, skeptical attitude is required when dealing with PRs coming from Bianco. He doesn't get the benefit of the doubt
Not until there is a large trial. I say that for 2 reasons:
1) Oncologists, by and large, do not change their treatment strategies based on small trials that are not widely used / accepted by the treatment community.
2) Nobody will be actively promoting this treatment strategy since it is a combination of agents, a couple of which are generics.
However, the results do look strong enough that it would be nice for a cooperative group to undertake a larger trial.
they cheated a little bit... they gave responses as a function of CA-125, a biological marker. Most companies look at tumour responses of measurable disease.
>and I fear sometimes BTM plays to the crowd<
>Plus what I find strange - many of the stocks in the portfolio - they positively no longer like them - but I suppose they can't dump them at current prices (don't want to record the loss - it is a subscription business after all)<
I agree with you and these are points I've previously echoed.
For example, if you peruse their website, Genta is in this year's ASCO issue. Are you kidding me? There is no defendable thesis for covering Genta or Genasense as an interesting company / therapeutic at this stage, let alone a good investment! Yet BTM can't let the coverage drop because that would negatively impact subscriptions. So in effect, they'll have to basically follow the company until they perceive that the retail base has left Genta.
There is inevitably a coverage bias. Investment houses cover stocks that they think they can sell. Biotech Monthly covers stocks that they think have retail followings large enough to aid in their subscriptions. They try to fill that niche generally occupied by stocks that are not well covered by the larger investment houses. That is really the only way to understand their coverage universe.
They have reproducibly shown good synergy in the clinic with the platinum compounds. The presentation on tuesday with telcyta + cisplatin in NSCLC will hopefully show similar synergy, as that trial has been open for an additional 6-8 months longer than today's triplet trial which treated its first patient in august.
Couple of notes from the conference call:
Wick was suggesting that some of the PRs in this trial were pushing 90% or above reduction in tumour size. They may look at 2 doses of Telcyta in the phase II portion of this trial which is currently ongoing.
Their ASSIST-2 phase III trial testing Telcyta vs Iressa has completed enrollment.
Their strategy for presenting the results from the randomized ASSIST-1, 2 and 3 trials will be to put out an announcement of when the last "event" occurs to trigger the analysis, and then present data 12-16 weeks following this event.
For ASSIST-1, they noted that they're not even halfway to the number of events required to trigger the analysis. This is a 440 patient trial in refractory ovarian cancer. It sounds pretty clear to me that they will not have the data for these trials in calendar year 2005.
As disclosure, I do have a position in this stock, so please interpret my comments accordingly.
They announced the initiation of that trial at the end of January.
No you're right. I just posted that to give a little more info about what the actual results were. Wasn't defending them in any way.
Apparently it's 27 evaluable patients. Some may have had only 1 CT scan, however.
These are actually better results than anything that NVGN has previously reported. In fact, I'm somewhat surprised given the crappy previous results. In this setting, however, their 33% response rate is still behind Telik's 54%.
> If the immune system’s efficacy falls even slightly, could it not go from just above the threshold needed to maintain stable disease to just below that threshold? In that case, wouldn’t it be reasonable to think that a booster might help?<
Well, remember that many of the patients, if not all, would be receiving the boosters well after their disease has progressed. So what are we boosting for? A "just in case" scenario where the disease has progressed despite the vaccination, but we're still going to plug along with the vaccination?
Here's a way to clean this possibility up scientifically: measure the immune response to the antigen after 1 year. I'd accept booster shots if DNDN provided robust data regarding the immune response in patients receiving provenge. If patients have developed the immune response, then it should be at the discretion of the doctor. If they haven't developed an immune response, it's hard to justify a booster shot. At that point the initial immunization course was ineffective, so it's hard to understand why a small booster shot in 1 or 2 years would provide an epiphany for the immune system.
>However, this is not a black and white effect, but is rather a shade of gray that perhaps gets grayer over time. Isn't that the point of a booster.<
There is evidence that some vaccinations may "wear off" in tens of years. That may be related somewhat to the dormancy of the immune system against an antigen which it really doesn't see again for years. If you think that the immune system is constantly fighting off something as pervasive as cancer, then you won't need a booster shot as that subpopulation of the immune system is consistently innervated. Otherwise, you get an attenuated response after 10 years or so, but that likely means your cancer went away anyways. It's your call
Not that you're confusing the two, but the more common scenario is for seasonal circumstances such as influenza (as per your earlier post). But these are different than provenge because those are strains that can change over time. Provenge is a single antigen and that will certainly not change over the patient's lifetime.
I think the side effect profile for patients with their prostates may be different than for those that are post-prostatectomy. Albeit side effects for most of these vaccine attempts have been mild, I still think that it would need to be monitored especially if provenge breaks down the "self" tolerance a little bit. I wasn't questioning the efficacy as much.
As for the booster shot issue, the dendritic or antigen presenting cells that are reintroduced into the patient will create two populations of T lymphocytes, Th1 and Th2. Th2 cells will stimulate B-lymphocytes which are the antibody producing lineage (also the lineage used to make monoclonal antibodies). B-lymphocytes will remain as part of immune system's "memory". Future response against the antigen is now built into the immune system.
I don't follow the story too closely, so it was my supposition that most, if not all, of the 9901 and 9902A patients to date were those that had had their prostate's removed. Therefore, the earlier post from the yahoo board suggesting widespread usage in patients with or without their prostates sounded a bit like hype at this stage.
As for the booster shots, I'm naive in that I don't see why the "science" behind a vaccine would require one.
>However, I think it’s reasonable to presume that some patients might benefit from a booster on a less frequent schedule.<
We'll see what they do. It is counter-intuitive that a single antigen vaccine would legitimately require booster shots on a continuous schedule.
Of course, it helps the balance sheet when you can retreat. That isn't so counter-intuitive
I presume that DNDN's trials have focused on patients with and without their prostate. But a more curious question is why do the patients need yearly shots of an effective vaccine?
Not a surprise that the researcher has his bias.
I only posted because it appeared that the quotes, by mentioning culture media, were addressing the purification of monoclonal antibodies which are a special case. Under current production methods, the hybridomas that synthesize the monoclonals secrete them into the culture medium. For any other protein, the cells that produce the protein will maintain them intracellularly, so you'll have to crack the cells open to purify the protein. That's when things get messy and goat's milk finds its advantage.
I don't have experience with plants, so I can't compare plants to goat's milk.
>"These factors are slowing the interest in transgenic animals as a production alternative (...) as protein purification is generally easier from serum-protein free cell cuture media than from milk" (...) "the benefic of trangenics is in cost-of-goods, the ability to scale up by breeding animals instead of building bioreactors (...)<
This is a comment that applies almost specifically to monoclonal antibodies. For any other protein, milk has the starting advantage.
I'm just pulling your chain on the SPA bit.
I was initially skeptical because I feared that the company would try to severely lowball the enrollment on the dg031 trial based on their confidence in enriching the patients population through markers. Based on the enrollment number mentioned in the CC, that concern has been alleviated for me.
But Stefansson is great to hear on CC. I particularly like the annoyed sigh that he delivers after each analyst delivers his/her question.
From my perspective, the point of any discussion board is to identify all the possibilities.
Individual investors will decide which is likely and which isn't, and invest accordingly.
>In your two possible explanations, you overlook the prime concern of a small company; keep interest of investors alive.<
That suggests cynicism worthy of me.
For those interested in DeCode, the quarterly conference call is worth listening to as they provide some guidance for their clinical trials. They also expect to have an SPA for their phase III using DG031 in heart attack. Some here seem to think that's a big deal.
>1. The “208”protocol specified that manner in which interim data would be made available to the sponsoring company (GENR) and it specified that the Evizon arms were to be bundled<
Certainly possible. But if the company designed the protocol for the interim analysis (they presumably did with some consultation), then it was a bad mistake or an oversight on their part to create a scenario where they themselves received bundled data. The bundled data isn't very useful, and it would be shocking to know that the company tied its own hands in such a manner.
The other side of this argument is that if you believe the management is bright, then they would have ensured that they receive as much data as possible from an interim analysis. That scenario would suggest that they have the data broken down by dose levels as well.
(They already have data segregated by treatment, so I don't think revealing the results by dose level undermines the masking of the trial in any way.)
>2. GENR did not want to reveal the unbundled data because the data are not great. If this is the case, the company is effectively using the bundling as a smokescreen to hide the data for the individual doses.<
One other possibility here is that the results by dose levels may have revealed something unpleasant or confounding. For example, if your best results are at 20 mg and you see poor results at 10 and 40 mg, that almost suggests that the 20 mg results are a fluke as well. How else, biologically, can you explain that an intermediate dose had an effect while half the dose and double the dose were entirely ineffective?
>I think the problem with BTM is that other people pay for this service.<
Clients of institutions like Lehman pay for the service through their account fees.
>Moreover, the company will be in deep doo-doo legally if it turns out they fibbed about the quality of these data.<
I'm not suggesting that DNDN has fibbed in any way. However, they've only described the interim 9902A results as "similar", so I'm not sure anyone could pin them down on it even if they are being coy with the wording.
As for the copyright thing, my angle is more ethical. So I don't think passing out the info from a Lehman report is anything different than passing out a BTM report. They both note that no part of the document can be reproduced in any matter.
I think pixantrone was the only worthwhile drug in CTIC's pipeline. I felt that if an investor was interested in pix, the only worthwhile time to buy was after stellar results came out. CTIC does have an imminent cash crunch, so that has to factor into any purchase.
I think part of the reason that ctic may be holding up a little is because the company was a little more transparent in the safety of Xyotax in the recent press release. For stellar 3, they never revealed the prevalance of neutropenia, so I was skeptical of Xyotax's claimed safety superiority. With the latest PRs, the data provided would reasonably suggest that Xyotax does have a reduced side effect profile versus the comparator drugs. I suspect that a fraction of the investors believe a drug with comparable efficacy and better safety has a role in the market. There are a couple of angles that CTIC can play *if* they get the drug to market. However, I don't believe that the company or the management has the savvy to pull it off.
What if the actual 30 month results leaked? Could they really be that much more different than the upcoming 36 month analysis?
As an aside, I find the vigilance of BTM subscribers to respect the service's copyright quite admirable. Hopefully they're equally vigilant on all such copyright matters that pertain to analyst reports.
CYTK:
Their kinesin spindle protein program doesn't appear to be anything uber-special in my opinion. It's another cancer play targeting the microtubule system. I think they've had some stable diseases but I'm not aware of an objective response yet.
Their cardiovascular program targeting myosin is going to flop, in my opinion. They're trying to activate myosin to increase the heart's force generation during heart failure. Problem is that this method has been tried before using beta receptor agonists; the patients fare poorly. Conversely, beta receptor blockers were found to be effective. CYTK appears headed to repeat that mistake.
Actually, moskowitz didn't forget cancer, heart disease et al because he's claimed to be curing all that as well. With one noteable and bizarre exception: he usually makes a point of mentioning that their drug can work well against all cancers but prostate cancer.
What is his drug you ask?
The ACE inhibitors regularly used for hypertension. He claims they are the cure to the worlds ailments... except prostate cancer.
I've followed this one occassionally because it is both funny and sad. Funny with respect to the claims, sad that the nation allows this type of scam to exist.
funny thing is that our cardio staff doesn't really use angiomax, so i'm a little curious about where angiomax is making its headway.
Integrilin will remain a solid revenue producer, but it will certainly not enjoy robust or even moderate growth in the absence of new data.
With earnings coming out this week, prudence suggests waiting for those numbers prior to deciding on a position. Some street estimates are predicting a decline in q/q velcade sales and i can't figure out if this is a game by the street or a legitimate concern.
fwiw, i think their developmental research has improved somewhat over the last 12-18 months. However, they're still paying for the excessive r&d spending in prior years.
thanks
free drug is a bit of a push since patients receive free drug if on an nci or a company sponsored trial.
I need to look into the costs for access to data.
Really?
I'd be interested to know the specifics of this support if you could elaborate.
I've long been of the mind that for-profit companies that benefit from public funds (NIH) should refund a percentage of their profits to the sector that supports them. So something like a 1% tariff on Avastin sales that goes back to the NIH, or better yet, medicare / medicaid.
Of course, then I realized that the companies would simply raise their prices by the cut asked for by the government.
You know me... I'm always skeptical when companies do not release the results of formal analyses. I like to make up my own mind after seeing the data rather than being coached.
If Dr. Gold considered it worthwhile enough to tell investors and doctors that 9902A was tracking similar to 9901, then it should be worthwhile enough to give investors and doctors the data. Plus, as a bit of a purist, I think it goes against the concept of scientific meetings to present some data while holding back other data.
Well, for scientific conferences, data are presented "as is". I think attendees realize that research is a dynamic and ongoing process. DNDN would have done well to present the data in a national forum, imo.
Also, I think the concept of tainting sensitive FDA discussions by presenting data is bunk. I talked to an FDA staffer a few years ago who came here to discuss clinical trials and drug development. She said that the FDA does not, in any way, discourage companies from presenting their clinical trial data in whole or in part at whatever forum they choose. What is discouraged are claims of efficacy and safety of a drug prior to FDA approval.
for example, the following is ok:
Our company's drug X showed median survival of 10 months versus competitor Y's median survival of 7 months. The following adverse events were reported...
Not ok:
Our drug showed efficacy because median survival was 10 months versus 5 months for placebo. The results also show that our drug is safe.
at first i thought that there might be some disagreement between the PI and the company as to what could and could not be presented.
If dndn does not want the 9902a interim data to be presented, then i can see why the PI would have no interest in making a presentation at ASCO where she couldn't really discuss any data.
> The negative progression data from 9902A would probably muddy the waters<
Data are data.
Hopefully management isn't being shaken by the perception on Wall street.