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  • Karyopharm Therapeutics: Will It Be An EPIX Fail? [View article]
    I agree with the author on the importance of proper due diligence. In that vein, an another quote from the article in which the author found his response rate:

    “Intermittent courses of dexamethasone (NYSE:DEX) were administered to 112 consecutive, previously untreated patients with multiple myeloma”

    Unfortunately for the author the test subjects in Karyopharm Selinexor plus Low Dex group were previously treated:
    100 % steroids
    100 % alkylators
    100 % IMIDs
    100 % protoase inhibitors
    87 % Velcada (bortezomid)
    87 % carfilzomib
    87 % ASCT (high-dose chemotherapy and stem cell transplantation)
    and so on…

    Word relapse comes to mind, doesn’t it? Well, according to this study published in The New England Journal of Medicine:
    Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma
    link: http://bit.ly/1tzTLAr

    DEX has only 18 % overall response rate including 1% complete response rate when dealing with relapsed myeloma. This translates to 1 or 2 overall responses and zero complete responses for 8 patients.

    Does the above guarantee that Selinexor is going to be a success? No, but at least the science side odds for that seem to be better than the ones the author is advertising.
    Jul 23, 2014. 10:07 AM | Likes Like |Link to Comment
  • Expecting Continued Increase In Capstone's Share Price [View article]
    Here is a news bit about Wrightspeed selling a hybrid using Capstone turbines.
    http://bit.ly/1h1y8m5
    Jun 3, 2014. 05:26 PM | 2 Likes Like |Link to Comment
  • Bill Gates Invested In KiOR And Nobody Cares [View article]
    I am interested to know where did you get 400 M usd number for Columbus II? What I have seen is around 225 M usd. Please explain! That 225 M usd comes from here: a reference to an article in a professional ( a term SeekingAlpha editors seem to abhor) webzine published just a day before your article

    http://bit.ly/1bWhvaD
    Nov 21, 2013. 09:47 PM | Likes Like |Link to Comment
  • GOP Hearings On Climate Change May Threaten Entire Green Economy [View article]
    Robert,
    As a person well versed in statistics you should know that one point does not trend make. This august ice coverage seems to be only a return to long term trend line, and has happened before. .
    Sep 9, 2013. 06:20 AM | Likes Like |Link to Comment
  • FDA's Rejection Of Aveo's Tivozanib Defies Logic [View article]
    I agree. Aveo should be fighting like made. Apparently they are not. Why? At the very least Aveo should have published MSKCC risk group stratified survival results to make the evaluation of crossover effect possible. They have not. Why? A conspiracy theorist would say that Aveo has somehow been cowed by Pazdur & Co. If so, go to congress. I bet there are some republican congressmen (one from California comes to mind) that are more than willing to take on Obama's FDA. On the other hand - maybe there is more than crossover to deal with - bad science elsewhere in the study. I don't see how, but as they say in commercials, I am not a doctor...

    Third possibility. Compared to colon/rectal cancer kidney cancer is a small market. If Aveo has any reason to believe that tivozanib is doing well in it's current colon cancer trial, they may have a back door entry to kidney cancer treatment via approval for colon cancer. In any case, there is more money to be made in colon cancer than in kidney cancer. It does not make sense to endanger a good change there by poking already miffed FDA with lesser things.
    Aug 17, 2013. 09:39 AM | 1 Like Like |Link to Comment
  • FDA's Rejection Of Aveo's Tivozanib Defies Logic [View article]
    I agree that survival is better end point than PFS. Death is seldom a matter of opinion. What I like to see is survival per prognostic groups - a very hard measure to manipulate and a more useful than OVERALL survival. As to crossovers and subsequent treatments - I doubt if there has ever been perfectly balanced kidney cancer trial. Sorafenib, the first approved drug, had crossover on it's trial. Sunitinib, the second approved, had a small crossover and plethora of subsequent treatments in control arm etc... Because these trials were against placebo or marginally effective drugs, the crossover did not become a problem. Axitinib, the only other drug to go against active comparator, did not have crossover and it eked out just parity with sorafenib on survival. The comparison between axitinib vs sorafenib from AXIS trial makes interesting reading: sorafenib beats axitinib in MSKCC intermediate group, axitinib beats sorafenib in other MSKCC groups, sunitinib plus sorafenib beats sunitinib plus axitinib, cytokines plus axitinib beats cytokines plus sorafenib, bevacizumab plus sorafenib beats bevacizumab plus axitinib, temsirolimus plus axitinib beats temsirolimus plus sorafenib. All, of course, statistically not significant, except sorafenib beating axitinib out in MSKCC intermediate group. So, in the end, FDA may have made one more misstatement in tivozanib ODAC meeting, they have approved a drug with demonstrated survival inferiority to control - axitinib - the other drug tested against active comparator.

    Tivozanib is the only drug to go against active comparator in a trial allowing crossover. A bad design or overtly ethical trial? FDA did not like the apparent survival trend and Aveo's presentation was not enough to dispel doubts. The sad thing is that Aveo could have done better job than they did with their presentation - I think the data is there. It just needs to be presented in correct (and factual) way.
    Aug 17, 2013. 08:48 AM | 1 Like Like |Link to Comment
  • FDA's Rejection Of Aveo's Tivozanib Defies Logic [View article]
    MSKCC risk groups in temsirolimus arm: Favorable 19 %, Intermediate 69 % and Poor 12 %. About THE same in the sorafenib arm. What seems to have doomed temsirolimus in this trial was the heavy presence of the Intermediate group (sorafenib's strong group). I do think that temsirolimus is a good and necessary drug (it performs well also in non-clear cell carcinoma). I am using it only to show how looking just at overall survival can be very misleading, even dangerous when some nitwit doctor draws wrong conclusion based on OS number alone.
    Aug 16, 2013. 03:21 PM | 1 Like Like |Link to Comment
  • FDA's Rejection Of Aveo's Tivozanib Defies Logic [View article]
    True, OS trended the sorafenib way. The question is why? There were no other drugs in sequence with sorafenib except tivozanib. Now, if tivozanib would be ineffective or toxic you would see no change or a dip in sorafenib survival curve after the crossover begun. Well, it does the opposite, indicating reduced hazard. If you bother to calculate cumulative hazard function out of KM curves you see this even more clearly. Tivozanib alone - near constant hazard. Sorafenib plus tivozanib - reducing hazard over time.
    BTW: FDA has tried to get drug companies to go against sorafenib or sunitinib since those two were approved. Most of the time drug companies have smartly declined. Glaxo went so far as to move pazopanib trial completely out of US and launched the trial against placebo in Europe. Only axitinib and tivozanib have gone against active comparator and at the time of data cutoff for it's approval submission axitinib's hazard ratio over sorafenib was 1.01. Hardly favorable.

    source:
    http://1.usa.gov/16ttyvl
    Aug 16, 2013. 03:08 PM | 1 Like Like |Link to Comment
  • FDA's Rejection Of Aveo's Tivozanib Defies Logic [View article]
    No, I am not suggesting any cross trial comparisons. I am referring to well known kidney cancer risk (prognosis) factors alone: MSKCC risk groups. Check what those groups were in temsirolimus trial: 75.8 % Poor prognostic group, 24.2 % Intermediate prognostic group. Survival performance vs interferon: 13.0 months (temsirolimus) vs. 17.7 months (interferon) in Intermediate group (yes interferon beat out temsirolimus, and badly) and 10.2 months (temsirolimus) vs. 6.0 months (interferon) in Poor group. Overall performance 10.9 months (temsirolimus) vs. 7.3 months (interferon) due to favorable IN-TRIAL risk group distribution. And: the patient population was treatment naive and there was no crossover. I leave you to calculate what the overall performance would have been if the patient risk group ratio had been similar to tivozanib trial's, i.e. with intermediate group about 60 %. The same holds for Axitinib trial where sorafenib did outperform axitinib in MSKCC Intermediate group, but axitinib eked out overall survival tie because Intermediate group was only about 30 % of overall population .
    What I am advocating is a MORE SCIENTIFIC APPROACH on survival analysis than just stupidly eyeballing overall survival numbers, which, as I have stated, can be grossly misleading. I recommend the use stratification by MSKCC risk ( and/or similar) groups.
    sources:
    http://bit.ly/16sWBz2
    http://1.usa.gov/16sWBix
    http://bit.ly/16sWBz5~/media/Files/slides/2...
    Aug 16, 2013. 12:21 PM | 1 Like Like |Link to Comment
  • FDA's Rejection Of Aveo's Tivozanib Defies Logic [View article]
    There were no other options after sorafenib and tivozanib were exhausted.

    One comment on Chris Rees article: In my opinion Chris is too much of a gentleman to really point out the obvious. What was the remark on the page 7 of FDA's briefing book doing there: "Note that a substantial number of patients had a MSKCC favorable prognosis" when the numbers are about average for all kidney cancer trials i.e. definitely not substantially different (even the original sorafenib trial had higher percentage ~ 52 %). Were they put there in preparation of something - like the switch of numbers in the slides? If so - what would you call this deed?
    Aug 16, 2013. 10:29 AM | 1 Like Like |Link to Comment
  • Tivozanib, Aveo And FDA; Did A Good Drug Get Mugged? [View instapost]
    Thanks for your comments. I do agree that the outcome of stratified analysis is not guaranteed victory for tivozanib. However, MSKCC Poor group in this trial is so small (17 patients in tivozanib group and 10 in sorafenib group) that results for it are meaningless.

    As to my inconsistency claim: I chose to use Fisher exact test because the outcome numbers were so low as to render Z-test, Chi-square or any other test based on assumption of normalcy unreliable. And, my interpretation still is: you can not claim inconsistency against previous trials (as FDA does) if the previous trials are themselves inconsistent.The correct claim (which FDA did not state) would have been: These trial are all inconsistent with each other. But that would not have helped FDA's cause.

    Oh, I almost forgot. Plain stratification would very likely give similar results to the presented overall survival curve. I think Aveo did do this step, and stopped. But what they did not realize was that by stratification they could demonstrate the effect of crossover. Stratify also crossover only group and you get results for groups with different percentages of tivozanib as secondary treatment - all the rest being equal. I have never seen the last step done (there has not been need for it) - so maybe they just did not get it.
    Aug 16, 2013. 10:07 AM | Likes Like |Link to Comment
  • FDA's Rejection Of Aveo's Tivozanib Defies Logic [View article]
    Facts:
    Aveo's study may have been the most biases study in the history of kidney cancer trials: against tivozanib (strange, I know, but true)
    Also true: at least two out of the six approved drug would have failed in the same settings (temsirolimus and axitinib). Failure count is likely to be higher, but missing (not reported) data.
    Also true: the respected oncologists on the ODAC seemed not know FDA recommended dosing for sorafenib or the fact that administering temsirolimus to any other than MSKCC Poor prognostic patients (clear minority) comes alarmingly close to euthanasia.
    Also fact: The number one kidney cancer drug in U.S., sunitinib, is maybe the least tolerated whereas tivozanib has more benign toxicity profile and about the same efficacy.
    Also fact: Overall survival is about as useful measure of efficacy as rusty nail in the head. It can be manipulated (a la temsirolimus trial) to give impressive results.
    Aug 16, 2013. 09:07 AM | 3 Likes Like |Link to Comment
  • FDA's Rejection Of Aveo's Tivozanib Defies Logic [View article]
    The claim that sorafenib is a weaker drug than sunitinib is only partially true. Sorafenib seems to have stronger performance in MSKCC intermediate group than any other TKI. A fact that people testing temsirolimus against sorafenib found out in a very bad way: temsirolimus (an approved drug, and the only one with FDA sanctified survival benefit) was beaten by 16.6 to 12.3 months with HR 1.31 - all survival numbers worse than tivozanib's. Is FDA going to ban temsirolimus? Not likely. Also, there is mounting evidence that sorafenib is a superior 'front runner' i.e. sorafenib provides significant boost in performance by the folllow-up drug (TKI) if administered as a first drug in sequential treatment. For instance, sorafenib followed by sunitinib results in significantly longer survival than sequence sunitinib followed by sorafenib. It is only the denseness and arrogance of U.S. doctors that have prevented the wider application of sorafenib as a first line kidney cancer drug.

    What the above has to do with tivozanib? About 65 % of patient population in tivozanib trial belonged to MSKCC Intermediate group (bad choice of population?) and the only drug administered after sorafenib (disease progression) was tivozanib, which happens to be TKI.

    Aveo might have a way to prove tivozanib's efficacy even with the current trial data and without resorting to cross trial comparisons. I have notified Dr. William Slichenmyer about this approach - no answer, so far. I wonder if I got past the secretary.
    Aug 15, 2013. 11:53 AM | 4 Likes Like |Link to Comment
  • Yongye International: A Victim of Bad Logic and Misleading Math [View article]
    Dear BuyersStrikeWP,
    what YONG reports is not the point of my article. What I am saying is that Mr. Roe's method does not work. Not on truthful numbers, not on false numbers. The whole article is about a method, not about any particular set of numbers.
    Jun 24, 2011. 12:36 AM | Likes Like |Link to Comment
  • Yongye International: A Victim of Bad Logic and Misleading Math [View article]
    Did I tout about how great a company Yongye is? I am truly sorry if that is what you got out of my writing. I thought that I was just pointing out some mathematical impossibilities. And I would have done that if the subject of Mr. Roe's article would have been Apple Inc, which I do consider to be a great company.
    Jun 24, 2011. 12:36 AM | Likes Like |Link to Comment
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