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Managing Director of Toscana Ventures, engaged in biopharma consulting in the areas of corporate & business development, strategic planning, competitive intelligence and new venture funding, as well as management of a modest family equity portfolio.
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  • The Coup De Grâce To The Feuerstein Thesis On GTx's Enobosarm Phase 2b Data.  87 comments
    Aug 9, 2013 9:33 AM | about stocks: LGND, MRK, TST, GTXI

    The following proves Mr. Feuerstein's assessment of GTx, Inc. (NASDAQ:GTXI) enobosarm Ph2b data, reported by Dobs et al. in Lancet Oncology, is invalid, by examining in detail his faulty math and logic.

    It also provides the Reader with the ACTUAL mean values which Mr. Feuerstein failed to estimate.

    "When you come at the king, you'd best not miss"
    - Omar Little, The Wire.

    Proof of these errors may prove embarrassing to Mr. Feuerstein. But my aim is not to embarrass. Several have shared much of the following with him already, and I repeat here several key parts that have been shared with him in private where the primary request was to make corrections. While he has confirmed receipts of these messages, he has refused to correct even his simplest of his typos. Evidence can now be shown Mr. Feuerstein has been made aware of key flaws with the thesis as early as July 11th, however, instead of undertaking his duty to set the record true, he has engaged in feeble defensive maneuvers to censor exhibits of divergent facts, smear reputations, and now constructed a biased poll that, if anything, is only further evidence of the degree to which his failure to correct the record has damaged the market's opinion on the reputation of GTx as a company and its existing data on enobosarm. In spite of market perceptions, the facts remain Mr. Feuerstein has failed to undertake even the simplest efforts to independently assess the veracity of his short seller source's thesis prior to posting his piece. But this err could have been chalked up to sloppy journalism. What is far more serious now is the mounting evidence that he is attempting to cover up what he knew was an error and when he knew it, thus exhibiting a knowing and reckless disregard for the truth, and callus to the ongoing damage his effort has had to the shareholders of GTx.

    Mr. Feuerstein's tactic is now clear. He seeks to delay. His last hope is to be bailed out by poor Ph3 enobosarm results. However, res ipsa loquitur, such cannot save him.

    "If the stories are controversial, it's all the better, because those are usually the most fun." - Adam Feuerstein

    And so, to Mr. William Inman, Editor in Chief of TheStreet.com (TST), I respectfully ask you to personally investigate the "fun" your Mr. Feuerstein is having at the expense of so many, including your own company's reputation. If you find his story based on error, I request you immediately retract his defamatory effort.

    Backgrounder:

    In the July 10th opinion piece entitled, "The GTx Cancer Muscle-Wasting Drug Studies Will Fail. Here's Why", TheStreet.com journalist Adam Feuerstein (hereinafter "AF") ambushed Memphis-based biopharma GTx, Inc., breathlessly claiming the firm "manipulated" their Ph IIB results with enobosarm (also known as GTx-024 and Ostarine®).1 His claim caused the stock price to crater 25.4% that day alone. From $7.00/sh where it traded just prior the release of his piece, to close the day at $5.20/sh, with most losses occurring in mere seconds of when it post hit the wires. Price action at technical support levels, combined with option transactions in the sessions prior and following, have all the tell tale tracks of a coordinated of a bear raid. And this makes perfect sense as AF admits he got his thesis from one of his "favorite fund managers" who is short, and via Twitter alerted followers of his piece before he posted it.

    With no material news since, the stock has bounce around and drifted still lower, settling two days after AF's August 7th poll of his cherry picked panel of anonymous investment professionals, the price per share hit a new swing low of $4.01. This is 42.7% deduction or $189 Million of GTx's market cap from when AF published his thesis on no other news, or almost 3 times the entire market capitalization of TheStreet.com.

    For those not yet following this Grisham-esque melodrama, enobosarm is a Selective Androgen Receptor Modulator (SARM), a new drug class in late stage clinical development. SARMs are oral, nonsteriodial testosterone mimetics with true anabolic effects on both muscle and bone, but are not substrates for the steroidogenic enzymes that convert testosterone into androgenizing DHT or feminizing estrogen, and furthermore are also thought to have differential nuclear receptor cofactor recruitment leading to enhanced tissue selectivity.2

    SARMs promise to protect muscle in the frail, yet (in exaggerated laymen's terms) not turn Grandma into Grandpa, or Grandpa's prostate into a softball.

    As you've no doubt heard by now, enobosarm is being evaluated in two placebo (PBO) -controlled, randomized, double blind Ph3 studies for the prevention and treatment of muscle wasting (cachexia) associated with advanced non-small cell lung cancer (NSCLC) know as POWER 1&2. Cachexias, and the age-related version of frailty known as sarcopenia, are extremely common, growing in prevalence and substantially unmet medical needs. As such, enobosarm has been awarded Fast Track status by the FDA, and has first to market potential with top line results of expected this (3Q13) quarter.

    The study AF claims "GTx manipulated" is the "Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind randomised controlled phase 2 trial." by Dobs et al., published in the April 2013 issue of the peer-reviewed Lancet Oncology, which reports the successful achievement of the primary endpoint; a quantitative measure of skeletal muscle known as Lean Body Mass by Dual-Energy X-Ray Absorptiometry (LBM by DXA). A close read of AF's piece shows he's not just calling into question the integrity of this small company, but equally all "the authors of the Lancet Oncology paper", thus including lead author Adrian Dobs, M.D. M.P.H., Professor of Medicine and Oncology, Division of Endocrinology and Metabolism and a Vice Chair at The Johns Hopkins University School of Medicine.

    His work is actually a thing of beauty, as it is quite a skillful tour de force of Aristotle's classic fallacies of logic. And since it appeared, we've seen a parade of brave contenders aiming to bring it down. But cataloging errors makes for dreadful reading.

    So, like el toro en el plaza, AF's thesis stands. Bloodied con banderillas. But defiant.

    It's time for a new approach.

    We have watched the lancers harass, and from his reaction have spied the weakness he's long sought to hide. As the bugle sounds, I dedicate this effort to those who have come before, and propose to you, Dear Reader, that with three passes with the cape, and then two hard stabs of logic and math to its very heart, AF's thesis will be proven invalid.

    But whom am I to challenge the Feuericane?

    Fair question. No one really. AF himself predicted all would ignore me. Perhaps he's right. I don't have his hoard of Twitter minions. Nor do I work for a company co-founded by Mr. Jim Cramer of CNBC's Mad Money fame. (Big fan, Mr. Cramer. Please keep fighting for us little guys.) What I have, if it counts for anything anymore, is over a decade working on SARM R&D ... longer than AF has been a blogger covering all biopharma. Too be clear, I've never worked for GTx or any of their vendors. In fact, I'm an odd defender of GTx, as I was their principle competition. At Ligand Pharmaceuticals (NASDAQ:LGND) I was an architect and alliance manager of their 2001-6 SARM R&D collaboration with TAP Pharmaceuticals. Then I was the President of Astrenia Therapeutics, a private stealth-mode spinout co, focused exclusively on the clinical development of next gen SARMs competitive to enobosarm. And now I make my living performing biopharma business and corporate development and new venture consulting, as well as managing my family's equity investments.

    But really, I'm just one "little guy" who sees the Emperor has no clothes.

    Who am I? It really should not matter, as you will see next.

    OK, my stretchy pants are on... time for the show.

    Tandas #1: The Fallacy.

    Recall upfront AF states his source for his bear thesis is the "same fund manager who was most recently short Ziopharm and Celsion in anticipation of negative clinical trial data. He was correct both times." Logicians call this trick the "Fallacy of Genesis"; the inappropriate use of source to defend or refute logic. It's entirely irrelevant.

    Yet for those lazy enough to use this device understand you do have a choice of which source to believe; a Vice Dean of the Johns Hopkins School of Medicine who has no potential for gain either way, or an anonymous short that may already be using options to collar ill got gains.

    Tandas #2: The Misdirection.

    AF's thesis has a challenge from the start. Dobs finds positive results and the study has only one primary endpoint.3 But success doesn't fit his short's preordained narrative.

    No bother. With a bit of misdirection our skilled weaver of words woos your eyes off success, and devotes the vast majority of his missive to discussing minutia of something even Dr. Dobs didn't know was in her study. A co-primary endpoint! Voilà!

    It stretches incredulity beyond the breaking point when a seasoned "columnist" plays fast with the truth and says not once, but twice, that a study with just one primary endpoint actually as two. "Let's take a closer look at the data on the co-primary endpoints of the enobosarm Ph2b study." And elsewhere, "You should see now why GTx chose to analyze the Ph2b co-primary endpoints using mean values."

    You don't need the Dobs article to fact check this one. Check this fact right from the public abstract. Still think AF is correct? Perhaps GTx changed endpoints during the study, you say? Then look at the archive listing on clinicaltrials.gov at the start of dosing:

    Primary outcome

    Measure: To assess the efficacy of GTx-024 on total body lean mass.
    Time Frame: Four Months

    Secondary outcome

    Measure: To assess the effect of GTx-024 on body weight, muscle function and total body fat mass.
    Time Frame: Four Months

    No way around it. AF's mistaken.

    And so he is basing his contrary opinion on results from an under powered yet statistically significant result in an exploratory endpoint, while ignoring the powered and statistically significant primary endpoint result.

    Sure, assessing muscle function via a stair climb test is a co-primary endpoint in the Ph3s, and there it is powered to do so. I've long been on the record to say the enobosarm Ph3 trials are not a sure thing. Still, one of my largest concerns was their ability to get less than the 30% ITT drop out rate, which is a key assumption to reach the sample size required for the target confidence level. I thought they might rather see the 35-40% dropout as seen in Dobs. Luckily for GTx, as reported at ASCO this year, the blinded dropout rate was in fact lower than 30% ITT in each of the two studies.

    Further optimism can be drawn from the design of the new stair climb endpoint in the Ph3s, which is significantly improved over the Phase 2/2b design. Dobs et al. used a 12 step stair climb test, but the Ph3s wisely swapped to an 8 step version. A minor change? Actually, no. By reducing trend count, the Ph3s will be a more pure evaluations of the expected result - increased strength and acceleration. Whereas a test with 50% more trends is relatively more about endurance, momentum, and lung capacity (VO2max) - three parameters SARMs are less likely to impact. As patients fatigue, it obscures strength results. And as one would expect, lung cancer patients - many of whom were smokers - don't have great endurance.

    Tandas #3: The Innuendo.

    Pssst...Did you hear the one about Merck (NYSE:MRK) "abandoning" GTx?

    I could write a dozen pages on this one alone. For the sake of brevity, I'll include a quote from Merck's SARM team, direct from their poster on enobosarm (MK2866) presented at ENDO in June of 2010, several months after the collaboration ended.

    "MK-2866 demonstrated acceptable safety and efficacy for continued development."4

    Merck was always focused outside of cancer cachexia, but in this collaboration the call was not Merck's alone. Corporate terminated the project, rather than be on the hook for the cost of the Ph3s, a victim to R&D rationalization after the Schering-Plough merger. So Merck went back to the well with a weak SARM (MK-0778) in female sarcopenia, and in a recently published Ph2a showed 50mg BID for 6 months failed to provide any functional benefit over PBO, using the non FDA-favored test, the 1-RM BLP.

    However, while not a side by side test, Fig 2 of the Merck ENDO10 poster (below) shows enobosarm 3mg QD has efficacy in this same functional test in that same population at 3 months (n=22), on par with 125mg QD of MK-3984, a prior Merck SARM terminated for tox.

    (click to enlarge)
    SOURCE: Marcantonio, et al. ENDO 2010.

    Three passes of the cape.

    Three redirects made.

    And not one fatal blow to AF's thesis. Yet.

    The Main Event. El Tercio de Muerte:

    "This is where it gets interesting..."-AF

    Feuerstein's Thesis on GTx's Enobosarm Phase 2b Data is Invalid.

    Here's Why.

    Even AF admits his ESTIMATES of mean stair climb power (SCP) at baseline (BL), a value not reported in Lancet Oncology, is a logically necessary condition on which rests the entire foundation of his simplistic linear-structured bear thesis.

    1. But for his equation to deduce mean SCP at BL, our bear has no estimates of mean SCP at BL.
    2. But for his estimates of mean SCP at BL, and more so a material difference between which favors the active arm, our bear has no rational basis from which to make his claim of an imbalance SCP BL in Dobs.
    3. But for his claim of an imbalanced SCP BL, our bear has no rational basis from which to make his claim that the positive results reported by Dobs et al. should be rejected in favor of his own null hypothesis that the study is flawed by a false positive/type I error.
    4. But for his claim of a false positive, our bear has no rational basis from which to make his (shrill and otherwise utterly unsupported5) claim that "enobosarm is basically a placebo".
    5. But for his claim that "enobosarm is basically a placebo" our bear has no rational basis from which to make his leap to his conclusion and predict the null hypothesis will be the outcome of the pending Phase III results.

    Therefore, logic dictates that IF;

    A. AF's equation used to ESTIMATE his means SCP at BL can be shown to be erroneous, or

    B. the ACTUAL mean SCP at BL of the relevant arms can be shown not to have a statistically significant differences,

    Then, AF's bear thesis must be rejected for the finding of logical invalidity. This work will accomplish both. In doing so, by attacking its foundation, his Jenga-like thesis will collapse.

    Stab #1, La Estocada:

    A. Challenges to AF's Estimate.

    In my first read of AF's piece, the most glaring of his many misstatements was his estimate of 46w for the mean baseline power for the PBO-e group. In a blink, I knew something was a miss.

    AF's Estimate of 46w mean is suspect.

    46w is very light, very low, very slow or all three.

    To those familiar with the test, 46w is a notably low result by itself - and even more so as a mean. Consider the power equation:

    SCP = (9.8[m/s2]× stair height[m] × weight[kg])/ stairclimb time(s).

    For sake of argument, if one assumes typical 12 step stair height is about 2.4 m, as well as a "rule of thumb" weight of approx 70 kg., this yields about 1650 joules. For this set up, a power of 46 watts equates to about 36 sec task time ... about 3 sec per step. Now go to a flight of stairs and walk this slow. Yes, these are sick cancer cachexia patients, but even so this rate is considerable slower than one would expect for the mean.

    AF's est. 46w is incongruent with other data in Dobs.

    Digging deeper, one would think in a treatise attempting to prove a baseline imbalance, the author making such a heretical claim would provide his readers the data of the actual demographics and clinical characteristics at baseline. But oddly, AF doesn't. So I will.

    (click to enlarge)

    Source: Table 1. Dobs et al., Lancet Oncology

    If he did, it would be all too easy to see more red flags with his 46 w mean estimate, as it is incongruent with the range of raw values at baseline reported by Dobs. See Table 1 (above), specifically second column, down to the stair climb power grouping to Stairs 1-12 (watts). The median baseline is reported as 150.2w and in the brackets, the range of raw values reported as 72.8 to 442.3 w. Ask yourself; is it reasonable to have an estimate of an average (mean) for a dataset, that is lower than the lowest value in that dataset?6 AF's estimates, though not yet proven in error, must be seen as highly suspect.

    In the absence of the actual means, to reject the AF estimate requires one to either, a) confirm the invalidity of his equation, or b) confirm a material arithmetic error with at least one of his two BL estimates.

    1. The equation AF used to arrive at 46w is erroneous.

    Unfortunately, AF did not provide his equations in his piece. In it, he only said "these numbers can be calculated using the data available in the Lancet Oncology paper" and more generally "I don't want to get too bogged down into mathematical concepts".

    As I'm one of those types who is often willing to get "bogged down into mathematical concepts" on July 11th I began requesting AF make his equations public. At first he ignored my requests, so I and several others kept at it. Remember what I said about watching the lancer harass? One of the most effective of the lancers, and the real hero of this story is Twitter user @biopeon. He first appeared in our Corrida the day after AF dropped his piece and was the first to report the mean discrepancy to AF.

    On July 11th, @biopeon tweeted:

    "$gtxi AF "calculated" the placebo group's MEAN BL as 46 watts. Uh.. the study states range is 72.8 w - 442 watts. 46w = #MATHFAIL"

    After about a half dozen such tweets, AF's eventually totted out a weak defense;

    On July 12th, @adamfeuerstein replied to @biopeon:

    "Can someone please double check this math: 2.21/.048 = 46 @biopeon calculator appears to be broken. Thanks."

    Seconds later Patrick Crutcher, Cheif Research Analyst at Chimera Research Group (who is working on his Ph.D. in Statistics at UCLA and otherwise is someone to watch, even if he harbors Feuerstein fanboy tendencies) confirmed the obvious. "@biopeon that's right" Yep. 2.21/0.048 = 46.

    After which @adamfeuerstein arrogantly tweeted:

    "@biopeon You can go away now. You have no legit rebuttal, just WAH WAH WAH!"

    And a bit later:

    "@biopeon For placebo patients: mean change in stair climb power 2.21 divided by 4.8% mean improvement equals mean baseline of 46. $GTXI"

    ...however before @biopeon could reply, AF blocked @biopeon from responding to AF on Twitter and censoring from that point on to any other of AF's tweets.

    Obviously, @biopeon was not questioning the AF's division. Just the veracity of the result and the algebra behind it.

    But with these tweets, AF let slip his equation.

    AF's est. of mean SCP at BL for PBO= 2.21/0.048 = 46w

    To get his estimate for the PBO - efficacy group, AF took 2.21 [the mean of the absolute changes in power (Table 3, shown below)] and divided that 4.8% [the mean of the percent changes for each patient from BL (reported in the text7on pg. 340)].

    (click to enlarge)
    Source: Table 3. Dobs et al., Lancet Oncology

    If one glances quickly, AF's simple equation is seductive. He thinks he's dividing an absolute mean increase from baseline by the percentage that equates to that absolute increase over its baseline. And if that was that case, it would yield him the baseline.

    While he thinks this is but ninth grade algebra, he fails to realize he's comparing apple and oranges. What his equation is actually doing is taking the mean of absolute change from baseline for the population, divided by the mean of percentage changes for each individual (not the percent change of the mean for the population). Anonymous Twitter user @biolong has written an elegant hypothetical example8 using AF's equation, which shows why the algebra behind it does not compute.

    In general, AF's original failure is in reading comprehension and arrogance not to both check his work with the authors. But it gets worse for AF. To make his baseline imbalance case, his thesis requires an accurate estimate for BOTH mean of the PBO-e group and the 3mg-e group. We've already shown he uses a faulty equation to get his means, so with this result alone, his thesis must be considered suspect. But let's now examine his estimate for the 3mg-e group.

    2. AF has an arithmetic error in one of his BL estimates (3mg).

    With his above Tweet, AF disclosed the (now discredited) equation he used to estimate of the PBO-e mean for SCP at BL. And while he has now refused to confirm it is the same equation he used for the 3mg-e group, I can find no logic that would suggest he used a different equation, just different values for its variables.9

    If so, it would be:

    AF's est. of mean SCP for 3mg at BL = 16.81 / 21.7%,
    again from Table 3 and the Dobs text, and if so...

    ...the math yields 77.4 watts! Not the AF's 80watts.
    And yet both are wrong, given the equation is wrong.

    The above proves both AF's equation for stair climb power at baseline, as well as his estimates suggesting his imbalance are erroneous. And thus his thesis can now be declared invalid.

    Without accurate estimates of each base line mean, he can not make his claim that they are different and thus imbalanced. Without accurate estimates of each base line mean, he can not make his claim that there is a skew. Without claims of baseline imbalance or skew he can not claim a type 1 error. Without claims of a type 1 error, he can not claim the statistically significant results are in fact a false positive. And finally, without his false positive claim, he has no rational basis from which to make any predictions on the Ph3s.

    quod erat demonstrandum

    Oh, but it gets better still!

    Stab #2, El Descabello:

    B. The ACTUAL Means for SCP at BL.

    Even with the AF's logic and math now bleeding out before your eyes, in the absence of the actual means from Dobs it was still theoretically possible there was a mean imbalance. Yet any statistician worth his "piled higher and deeper" should care less of the mean descriptives any way, given the reported balanced median is actually the appropriate measure of the central tendency of absolute power improvement given the non normal distribution of values. Such values are typically not normally (Gaussian) distributed (two tailed bell curve), but more Poisson (one tail to the right). For this same reason, the appropriate measure of statistical significance is the exact paired Wilcoxon - the method used by Dobs.

    This is where I thought our tale would end (mercifully). At least until the Ph3 results were released.

    But then, in a post which briefly appeared in the comment section under AF's original article - but was later mysteriously deleted - @biopeon posted what he claimed were the ACTUAL means for SCP at BL from the company and suggested AF call to confirm for himself. While that post was removed, days later @biopeon essentially repeated the same in the comment section of a different article which openly questions AF's ethics in this matter. An article which AF has also tried to get this third party to remove.

    But July 23rd, unable to stop himself, our social media addicted adamfeuerstein replied:

    "@Biopeon I see my recent favorite Internet troll stalker has found his way to this web site. Biopeon has a hard time accepting the truth so he spreads his own lies around the interwebs. He's ignored everywhere. Have a nice day!"

    Now I'm not one to trust the comments of some anonymous Tweeter, short or long. But I'm also not one to ignore the promise of data that could double check my work and tell me once and for all if my proof on the invalidity of AF's thesis is right or wrong.

    And so I did as @biopeon suggested. I called GTx. And I called Dr. Dobs too.

    I few minutes later I got a return call from GTx's Marc Hanover, Pres. & COO with Mayzie Johnston, Pharm.D., VP, Medical Affairs. Dr. Johnston patiently answered my all my questions and confirmed Dobs Table 1 above is correct. She then confirmed as I'd already concluded that one could not accurately estimate the means using the results in Dobs, but she was happy to give the actual means to me and stated the authors have long given them to all who've asked. She also stated GTx has no record that AF ever called to fact check his story.

    So here are the ACTUALS from GTx:

    Means for Stair Climb Power at BL in Efficacy Subgroups.

    PBO: 166.2 watts (not AF's 46 w)
    1mg: 136.9 watts
    3mg: 151.4 watts
    (not AF's 80 w)

    No statistical difference noted between the means for SCP at BL between efficacy subgroup, except between the 1mg and the PBO group (p=0.029).

    GTx confirmed values from the Phase 2b study
    Source: Personal Communication.

    This effort has now shown, using both methods described, that AF's thesis is invalid and his mean estimates are utterly erroneous. Thus @biopeon is correct. Still don't believe? Call GTx or Dr. Dobs for yourself.

    And yet - look at that - there is a statistically significant baseline imbalance at the mean, between the PBO and the 1mg! The PBO has a "head start" over the 1mg. Opps. This is the exact opposite of what AF's flawed "head start" thesis requires to have merit. Of course, it's only with the 1mg dose, which the Ph1 showed to be an inferior dosage10, and is not relevant to the Ph3's.

    What's more, Dr. Johnston confirmed that these means, combined with the absolute mean improvement value reported in Dobs Table 3, one could calculate the final mean SCP results. By my math:

    Means for Stair Climb Power at Final in Efficacy Subgroups.

    PBO: 168.41 watts (166.2w + 2.21w) 1.3%
    1mg: 151.16 watts (136.9w + 14.26w) 10.4%
    3mg: 168.21 watts (151.4w + 16.81w) 11.1%

    As I see it, it's unlikely there is any statistically significant difference at the final means. To which I say, who cares. Again, mean improvement of the population does not tell this story, even if there is a material difference. To me the mean of the percentage improvements for individuals is more interesting, and already reported in Dobs as 18.0% with 1mg and 21.7% with 3mg and just 4.8% with PBO. And again, this was an exploratory endpoint in a widely varied mixed population, using the inferior 12SSC test and not powered to confidence to show significant results. And yet it did.

    One might ask why Dr. Dobs did not report means at BL. Or the modes, for that matter. When I asked, she stated that given the distribution of the values, the median is the most appropriate descriptor.

    Given the wide range of the raw values at both baseline and final, a strong case can be made that ALL measure of central tendency (mean, median, mode, or any of the 10 or so others) are woefully inadequate to tell the story. The real possibility of responders and non-responders in each arm introduce the plausibility of a bimodal distribution. Yet, even without an outlier analysis, the actual results in Dobs proved to be significant using the appropriately applied exact paired Wilcoxon method. This works as the Wilcoxon doesn't depend on any measure of central tendency. It draws its conclusion on the actual raw results. Which is why it is used here, and why the FDA requested the Responder Analysis method for the Ph3s.

    As for Dr. Dobs, though AF's accusations were an obvious annoyance, she seemed to take it all in stride and quipped something to the effect, "This poor fellow must not have any experience with statistics or clinical trials."

    Quite insightful as she hadn't even seen AF's bio.

    In Conclusion, the above proves that AF's opinion piece is based on blatant errors and faulty logic. While he is entitled to his opinion, he is not entitled to his own facts or math. Therefore, its existence, without even the smallest correction, is ongoing damage to the reputation of GTx and enobosarm, but also that of AF's employer, TheStreet.com.

    Caution: I am long on GTXI as I believe the probability of ultimate FDA approval with enobosarm is now far better than the equity market currently believes. To me, this has all the making of a worthy speculative market dislocation situation. But success in POWER 1&2 is by no means a sure thing. AF's opinion, even if his thesis could not be more worthless if he rather based it on a coin flip, still could come to pass. For the most part, I believe the stock analysts who cover GTx have a far better grasp of the issues surrounding the enobosarm trials. Several have since reiterated their recommendations and bullish predictions of the Ph3 studies following AF's piece. I'll just add that while AF thought he saw a PBO effect that he felt was too weak (thus the type I error), to my eyes and that of cachexia experts I spoke with when this data was first presented at the 2009 ENDO meeting, Dobs reports a PBO effect that is surprisingly strong. Better than many other studies in cancer cachexia that often show 1 to 2% loss of LBM per month. In Dobs, LBM did not materially change, and average power actually increased though not significantly, which is not in keeping with many other studies. As such, part of my bet is based on my expectation of reversion to the mean for a lower PBO response rate.

    Thank you for reading. All comments welcome.

    -----

    El Paseíllo. (Further reading and acknowledgements.)

    Banderillero #1 was clearly Wedbush's analyst David Nierengarten who on July 11th was the first analyst to come to GTx's defense in a short note11, reiterating his pre-data GTXI $9.00 price target, and the first analyst to publicly state that AF's assertions were "unfounded". While not addressing the math or logic errors, his most effective blow was to lay bare that AF had little grasp of the Ph3 design on which he was opining. After Nierengarten's work, the price of GTXI recovered somewhat. At least until AF replied in his July 12th "Mailbag" declaring Nierengarten's defense "weak" and "not persuasive" (yet failing to discuss even one of Nierengarten's points). Instead AF devoted the rest of his retort to impugning the FDA requested Responder Analysis statistical method, calling it "one of the tricks companies use to rig the analysis of a clinical trial", though admitting its use was news to him, despite it being public for several months.

    By the way, anyone with experience with the responder analysis method already knows how ridiculous it is for AF to lambaste it as he does. It is the FDA - not the sponsors - who are encouraging use of this method. And yet, specifically in cachexia, it does hold promise to generate the composite endpoint the agency seeks to show both muscle well as a functional benefit, linked to clinically validated cutoffs of effect. But more to the point, industry has actually made an extensive effort to resist use of Responder Analysis. As evidence, I point to the official PhRM position paper which aims to stem the tide of FDA requests to use it more. PhRM is cool on the method, in part, as it requires taking a statistical hit to get similar levels of confidence for an endpoint, requiring larger more expensive clinical trials.

    Banderillero #2 is a newcomer to the ring. Dr. H. S. Choi, a practicing physician and, like me, writing his first article for Seeking Alpha. While his instablog was not widely picked up as at the time he laid out some of the qualitative reasons for rejecting AF's baseline imbalance theory. If reading his piece, I suggest one starts with the comment section first, as he corrects a small but key error (he swapped median to mean) which requires him to withdrawal his point #6, and while the text of his #7 is impacted by the error, this effort shows he is factually correct. Dr. Choi, I look forward to your next article.

    Banderillero #3 is a tough one to award to one person, so it goes to the rest, as in the last few days there has been a rush of articles on this topic. Cora Schlesinger's piece is a great read, particularly as she makes mention of Kenneth Fearon's review which accompanied Dobs paper in the Lancet Oncology. For those who do not know, Dr. Fearon is considered by those in the frailty field to be the principle thought leader on cancer cachexia world-wide. For example, Dr. Fearon is the lead author of the 2011 definition and classification cancer cachexia consensus effort. And in my opinion there is no better expert to give a review of the Dobs work than the guy who has spent much of his career trying to untangle the Gordian knot that is the optimal way to treat cancer cachexia. Here, I'll also mention Jefferies analyst Biren Amin July 17th brief note where he reiterates his $8 pre-data price target, as well as fine effort by Natty Greene's July 26th article focused on a Merck collaboration rehash and various predictions of the Ph3s results. I've also already mentioned the note of @biolong, and the July 20th and 21st articles by Kevin McKenzie, which raise questions on AF's ethics. (Not my thing. I'm more about laying bare the facts and allow each to judge for them self. I merely note others are looking into this.)

    But to me, top honors goes to @biopeon, which is actual an very apropos handle for our Corrida analogy. For it is a special peon called the Puntillero (not the Matador) who skillfully employs a small dagger to administer the coup de grâce.

    So, while AF has correctly suggested the following element is not central to his now invalidated thesis, I close by giving the honor to @biopeon, and quote him as he fillets the last of AF's math errors:

    "Adam claims: "The median improvement in stair climb power for placebo patients: 7.5 percent. The median improvement in stair climb power for 3mg enobosarm patients: 8.3 percent." Again-- these numbers are completely faulty.

    To arrive at this faulty improvement percentage Adam divided the avg. median change data in Table 3, by the RAW baseline data in Table 1. For example: 12.84/154.5=8.3%. In a vacuum, this simple calculation makes sense. But if you have any knowledge of statistics for a clinical trial, then it's naive at best.

    Adam's problem is that his data from Table 3 (avg. median) can't be directly computed with the RAW data from Table 1. In the data from Table 3-- the average (median) percentage change is observed among individuals. Then each individual's percentage change from that subject's baseline is computed, then within an arm, the average (median) of these individual percentage changes are computed.

    This average (median) change cannot be divided by the average baseline (raw wattage) of the entire group (in Table 1) to ascertain a raw wattage improvement that corresponds to this percentage change.

    Adam is not a mathematician/statistician and he should not be masquerading as such."

    ¡Ole!

    It remains a mystery why AF appended this little side adventure at the end of this thesis. Dobs already reports the relevant metric for improvements in this secondary endpoint. While AF again commits a similar error of algebra, it doesn't fit the structure of his logic, other than perhaps being disembodied anecdotal (yet erroneous) support. Again, measures of central tendency are not the goal with the Ph3s.

    =====

    1 To quote; "Remember above when I said GTx manipulated the phase IIb data using mean values (instead of medians) to make enobosarm look more effective than it really is?"

    2 Expert Opinion on Drug Discovery, February 2013, Vol. 8, No. 2 : Pages 191-218

    3 "The evaluable efficacy population included 100 participants (placebo, n=34; enobosarm 1 mg, n=32; enobosarm 3 mg, n=34). Compared with baseline, significant increases in total lean body mass by day 113 or end of study were noted in both enobosarm groups (enobosarm 1 mg median 1·5 kg, range -2·1 to 12·6, p=0·0012; enodosarm 3 mg 1·0 kg, -4·8 to 11·5, p=0·046). Change in total lean body mass within the placebo group (median 0·02 kg, range -5·8 to 6·7) was not significant (p=0·88)

    4 ENDO 2010: "A 12-week Pharmacokinetic and Pharmacodynamic Study of MK-3984 and MK-2866 in Postmenopausal Subjects", by Marcantonio, et al. Available on request.

    5 It is obvious that AF has not reviewed the other GTx studies with enobosarm. Or even the YouTube videos and blog reports of body builder taking black market Ostarine. While not the most potent compared to some banned steroids, it is certainly no placebo.

    6 The footnote reports "not all patients had a baseline value", which make sense as the group is defined by the primary endpoint. So it is a reasonable hypothesis that null baselines might be the reason for AF's low mean. Backtesting for worst case (1 at 442.3, rest at min val of 72.8 or 0 for n=36) shows need zero for half (n=18 with a null BL) to obtain his estimate. However, such a distribution can still be rejected as it fails to comply with the reported 150.2 w median w/ or w/o the null values. Missing values is not the issue.

    7 "Absolute changes in stair climb power represented a mean of 18.0% (SD 31.1) improvement compared with baseline for enobosarm 1mg and 21.7% (SD 65.7) for enobosarm 3mg (vs placebo, 4.8% [SD 23.2])".

    8 http://i.imgur.com/8h4sC8s.jpg; Note however Dobs does not support his statement "it is true the placebo arm in the IIb trail was sicker than the enobosarm arm". If there is interest I can add more on this later.

    9 I have made multiple requests to AF to describe how he obtained his 80w est and to make his 3mg equation public. In Twitter, he has replied with his usual, but ignored the question. On July 22nd, he then blocked me on Twitter, thereafter preventing me from repeating my questions. I followed up with an email to the address he provided just the week prior. To my surprise, he replied, confirming receipt, but his only comment was to accuse me of stalking him and demand that I no longer try to contact him.

    10 GTx Enobosarm ASCO 2007 http://i.imgur.com/MHkpoqn.jpg

    11 More detail on the Wedbush note posted on my Twitter homepage @JJSchaible

    Disclosure: I am long GTXI, LGND. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company whose stock is mentioned in this article.

    Additional disclosure: Note LGND may make an interesting, lower risk way to play the enobosarm event, given their next gen SARM LGD-4033 has shown promise in a phase 2a test.

    Themes: long-ideas Stocks: LGND, MRK, TST, GTXI
Back To JJSchaible's Instablog HomePage »

Instablogs are blogs which are instantly set up and networked within the Seeking Alpha community. Instablog posts are not selected, edited or screened by Seeking Alpha editors, in contrast to contributors' articles.

Comments (87)
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  • Blair O'Neill
    , contributor
    Comments (125) | Send Message
     
    You should get this submitted as an article.
    9 Aug 2013, 11:20 AM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Tried. SA refused. Said it was "too personal".
    9 Aug 2013, 12:34 PM Reply Like
  • Blair O'Neill
    , contributor
    Comments (125) | Send Message
     
    Ah that makes sense I guess.
    9 Aug 2013, 02:01 PM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Does it? This is a response to an attack, and I've taken great pains to not make it ad hominem.

     

    But he's choosen to make this issue about himself now by refusing to make corrections.

     

    Seems someone has even refused my attempt to link this page to the comment section of his original paper.
    9 Aug 2013, 02:25 PM Reply Like
  • Cora Schlesinger
    , contributor
    Comments (666) | Send Message
     
    Great article, expected nothing less. Talk about moving the needle! About face on Yahoo's board. Do you know the kid's series "Diary of a Wimpy Kid?"
    9 Aug 2013, 07:11 PM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Thx. I think the needle has only started to move the right way. So far the read count is still VERY low. Much more to come. Daily technical buy if confirmed today. Next week, GTXI will be on a weekly technical buy if.

     

    Sorry, not familiar with DoaWK. More a fan of Green Eggs and Ham.

     

    As in...

     

    "Will you retract with a fox? Will you retract in a box?"
    "Will you retract standing in a pail? Will you retract once put in...."
    9 Aug 2013, 10:44 PM Reply Like
  • Cora Schlesinger
    , contributor
    Comments (666) | Send Message
     
    lol, one of the greatest books in the English literature. Maybe some regulatory agency is going to come to visit and seize his hard drive before he puts the final touches on his retraction.
    9 Aug 2013, 10:58 PM Reply Like
  • Rick Berger
    , contributor
    Comments (1246) | Send Message
     
    Great job! Looks like retail investors took notice today. I completely understand your wrath against AF. A purposely erroneous article on his part is financially damaging to investors. And while SA must intervene to protect it's own interests, AF's motivation appears transparent.
    He's in a good position to short the stock, then get a great entry price.

     

    The fact the SEC allows this to continue earmarks the level of manipulation in the market place.
    10 Aug 2013, 12:36 AM Reply Like
  • Deep.Blue
    , contributor
    Comments (131) | Send Message
     
    C'mon Feuerstein where is your comment? You are always so quick and witty.
    10 Aug 2013, 01:51 PM Reply Like
  • Intrinsic Value Asset Manag...
    , contributor
    Comments (195) | Send Message
     
    JJ, If you had just submitted the article without making it about AF, they probably would have accepted it.

     

    Then, once the article was accepted, you could use it as evidence against the lies by AF, in your blog.

     

    Please consider rewriting your article so it just states the facts, and does NOT mention AF.

     

    Simply state that there is some confusion about the facts.

     

    List the conclusions from AF one by one, and respond in your article without attacking AF.
    10 Aug 2013, 02:54 PM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Thank you for the suggestion of writing an AF-free version. That was actually my first thought too.

     

    But then I realized such an article would read. "Dobs 2b data is as reported". Not exactly news worthy, is it? And several have already written such notes, with no effect.

     

    As such, "it is time for a different approach".

     

    No, AF injected himself in this story by his errors, and now more so by repeatedly refusing to correct to the facts. Little new material information has been issued since, so clearly it is his work that was the vast cause of the massive slide in the stock price. As such, he is a necessary element of this story. And if he corrects / retracts, I can see no reason why it would not return with speed to the $7/sh mark...and perhaps more given insiders now control 70% of the float, but the SI is now far above were it was prior.

     

    I understand others are now writing more politically correct articles that intend to reference my effort (thank you!). And of course each can help by follow me here and on Twitter at @JJSchaible and by retweet the above link over and over until we get a response from TheStreet.com. If each sends it to two people, and they send it to two people.

     

    We live in a Twitter world now. Twitter has given AF his voice. It can just as easily be used to silence it. I feel no need to water down anything I've said here - especially just so that it would pass the review of some editor who has no familiarity of the case and declines it with a form letter.

     

    .
    10 Aug 2013, 05:25 PM Reply Like
  • Intrinsic Value Asset Manag...
    , contributor
    Comments (195) | Send Message
     
    JJ, >>>"he has engaged in feeble defensive maneuvers to censor exhibits of divergent facts, smear reputations, and now constructed a biased poll "<<<

     

    He did the same towards Vical (VICL)

     

    The SEC/DOJ should investigate and prosecute this corrupt liar.

     

    Please feel free to contact me... I am not afraid of AF.
    10 Aug 2013, 02:54 PM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    vical actually failed but his analysis is probably as convoluted as ever in hindsight for any of his short pieces
    13 Aug 2013, 05:42 AM Reply Like
  • biopeon
    , contributor
    Comments (28) | Send Message
     
    Masterful rebuttal, JJ. Elegant, informative, and entertaining as well. For all GTXI investors (myself included), AF's flawed math is by no means a guarantee of a successful trial, but you should at least realize the BS that AF is spewing. Arm yourselves with the most accurate info, take a stand, and X your fingers. That's what I'm doing. Bring on the data!
    10 Aug 2013, 02:54 PM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Ah, @biopeon....our should I say, our Puntillero?

     

    Thank you. Means a lot coming from you, who ever you are. Again, much of the honor here for the early and persistent AF harassing goes to you.
    10 Aug 2013, 05:35 PM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Look who I just caught peeking at my Linkedin profile:

     

    Adam Feuerstein 1st
    Senior Columnist, TheStreet

     

    Location Winchester, Massachusetts
    Industry Online MediaShared connections
    9 shared connections
    Date 1 day ago

     

    Adam, all comments are welcome. Even apologies.
    10 Aug 2013, 10:58 PM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    your obviously a threat to the feuerstein with your well thought out analysis now he has your on his radar i suppose
    13 Aug 2013, 05:43 AM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Thank you. If AF has me on his radar, he now has all sorts of ways to contact me. Yet he still has not. BTW, I've also emailed the above to the company, which also has yet to reply.
    13 Aug 2013, 10:29 AM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    he wont contact you he will just treat you like bipeon and delete your posts in the future for his articles
    13 Aug 2013, 12:44 PM Reply Like
  • Cora Schlesinger
    , contributor
    Comments (666) | Send Message
     
    Not just lol, rofl
    11 Aug 2013, 02:59 PM Reply Like
  • Cora Schlesinger
    , contributor
    Comments (666) | Send Message
     
    Submitted my new article, you're a star.
    11 Aug 2013, 07:03 PM Reply Like
  • Cora Schlesinger
    , contributor
    Comments (666) | Send Message
     
    And it's now published!
    11 Aug 2013, 10:11 PM Reply Like
  • Rick Berger
    , contributor
    Comments (1246) | Send Message
     
    Welcome to - **WAR OF THE WORDS **
    A new internet sequel to the masterful sci-fi classic.
    This colorful drama features Adam the "F" as the editorial villain.
    JJ and Cora defend a promising new drug with potential to help millions of people across the globe, but the sadistic A.F has other ideas.
    Stay tuned!!!
    11 Aug 2013, 11:20 PM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » The only thing fictional in this epic is AF's math skills.
    12 Aug 2013, 02:24 AM Reply Like
  • cvdeaner
    , contributor
    Comments (10) | Send Message
     
    I just about choked to death laughing because of this comment...
    12 Aug 2013, 11:05 AM Reply Like
  • Rick Berger
    , contributor
    Comments (1246) | Send Message
     
    Well, you're in the right place. I almost choked on an apple some years back. It too came while having a laugh attack. I can't divulge the brand of apples, but the initials A.F. played a ''central role'':(
    13 Aug 2013, 12:30 AM Reply Like
  • biopeon
    , contributor
    Comments (28) | Send Message
     
    No offense to Cora, but I think it's ridiculous that this article is only on an "instablog." There is more practical, factual, insightful info in JJ's article than any of the recent GTX articles. Seeking Alpha is doing itself a dubious disservice by not making this an official "published" selection. That is all.
    12 Aug 2013, 03:05 AM Reply Like
  • Cora Schlesinger
    , contributor
    Comments (666) | Send Message
     
    No offense was meant. IBs don't show up on the Stock Focus list, and can be hard to locate if you aren't aware it's there.
    12 Aug 2013, 11:12 AM Reply Like
  • MikeMikm
    , contributor
    Comments (62) | Send Message
     
    Wow. Bravo for a well documented and balanced article. I believe AF should be speaking with his legal defense team sometime soon. It would be nice for Jim Cramer to make a comment on AF's article.

     

    How classy for both Dr. Dobs and Gtxi not comment on the article. It reminds me of growing up with the bully vs the athlete scenario. Everyone knew who was the better person.
    12 Aug 2013, 04:28 AM Reply Like
  • anomaly1
    , contributor
    Comments (932) | Send Message
     
    interesting info... when is the next catalyst event(s) for GTXI?
    12 Aug 2013, 03:14 PM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Thank you.

     

    The next catalyst is the biggie... ph3 data top line.

     

    GTx guidance so far is sometime in 3Q13. Could be a bit after...but also could be tomorrow!

     

    Of course, one might also now include a retraction by TheStreet.com as a catalyst. While I don't think they have the guts to offer one prior to the data readout, such could also come any day. If that was to occur, we might see a return to $7 on a retraction alone - where the price was on July 10th when AF dropped his piece.
    12 Aug 2013, 04:36 PM Reply Like
  • Jon Jegglie
    , contributor
    Comments (40) | Send Message
     
    Have not made it all the way through the Lancet piece. Does it specify why 1mg seems to be better than 3mg? Furthermore, I don't recall seeing a rationalle for ph3 focus on NSCLC. Indications in the ph2 data? Higher response? More gain from baseline??
    12 Aug 2013, 05:02 PM Reply Like
  • Cora Schlesinger
    , contributor
    Comments (666) | Send Message
     
    For P2, there were 5 cancer types, multiple chemo regimens for each cancer, enobo was started almost any time during the cycle-- 1st line, second line, begin cycle, middle of cycle--sloppy, a lot of variation there. P3: one cancer, 2 chemo regimens, enobo starts Day 1 of chemo. Much cleaner studies, far fewer variables. NSCLC was chosen b/c, altho colon ca had more lean muscle increase, lung ca group had greater increase in power. If it works w/ this group, it will work w/ any group. Think P3 will also stratify out which pts do better on drug. Speculate poss a difference b/t stages 3&4, or tumor burden.
    12 Aug 2013, 06:39 PM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Hi Jon,

     

    Great Qs. Thanks. I’m growing tired of this $GTXI story being about AF, when it should be about the Ph2 data and the Ph3 design.

     

    As Cora mentions, Dobs states "We noted a greater increase in lean body mass in patients with colorectal cancer whereas we recorded the greatest increases in stair climb power in patients with NSCLC." But to me the n was so small I'd not make too much of the subgroups.

     

    For me the choice was always obvious. In fact I've always been perplexed why they did a mixed cacx Ph2B in the first place. NSCLC has higher incidence of cachexia and is more prevalent as a tumor type...thus is one of the few relatively more attractive tumor types to conduct cacx trials. It also has a male skew for which androgen use is in general of less a concern. And advanced NSCLC has fairly standarized Tx but still a high death rate, so a better shot than most ca to obtain the holy grail... mOS (even as this is just a secondary endpoint and not powered for such in the ph3). Over colon ca, NSCLC also has less nutritional disturbance and less surgical contraindications to the SC test.

     

    As for 1mg over 3mg, the Dobs data in the Ph2b does not support your claim that the 1mg is "better than" the 3mg. While the absolute LBM by DXA was slightly higher in the 1mg than the 3mg (1.5 vs 1.3 at mean: 1.5 vs 1 at median) no significant difference was reported between. On a mITT basis, the p between 1mg and PBO was not significant 0.066 at a=0.05 (one of several of AF's typos)) but between WAS for the 3mg over PBO (p=0.041). But more importantly, both active arms ARE significant over their baselines using the exact Wilcoxon (0.0012 and 0.046) while the PBO was not (0.88).

     

    While I think GTx could have done better proving the upper limit of the dose range (I can only wager a why 3mg was the highest does tried in the Ph1s) I'm satisfied with the Ph2a data the shows the 3mg is an effective does to build muscle in normal elderly adults (P<0.001) vs PBO. See Fig 1 of J Cachexia Sarcopenia Muscle (2011) 2:153–161, specifically on pg 156, which anyone access for free at http://tinyurl.com/l7n...

     

    As for if 3mg is an effective does in NSCLC cachexia? We shall see!

     

    Any other questions?
    12 Aug 2013, 08:37 PM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    would the severity of the patients lung cancer have any bearing on the stair climb power test (as one aspect of physical exertion is the supply of oxygen which could be affected by restrictions in oxygenation secondary to lung cancer)? If so, would the test be confounded by the severity of lung cancer between the groups?
    13 Aug 2013, 05:34 AM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    also a few on the y boards are saying they should have presented topline data by this point with data lock in may...why could this be
    13 Aug 2013, 05:46 AM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Hi Peter,

     

    Great q's. Theoretically yes and yes. It is theoretically possible that the results were due to the PBO-e group being "sicker". But that it not what the Dobs data teaches.

     

    VO2max is certainly a function in power generation... on the endurance side. Plays less a role in overt strength and little at the start of a task, but at some point in a task endurance gates strength. This is one of the reason the 8SSCt is being used in the Ph3 over the 12SSCt of Dobs.

     

    But overall pts in Dobs the severity of tumor burden is fairly balanced (see Table 1 above). AF has tried to mix apples and oranges here as well... using the stage balance from the safety groupings to suggest the PBO-e group was sicker. It's just not what Dobs shows.

     

    Table 5 is a good way to get the 30K foot level. It shows change in ECOG status compared to baseline. In the PBO-e group, only 6 (15.8%) worsened which 8 (22.9%) worsened, while in both 5 pts "improved". Hard to make an argument that the PBO group was "sicker".

     

    But let's drill deeper into just NSCLC, even as the law of small numbers starts to creep in.. ECOG status was not broken out here, but we have other data we can look at. Recall that as Dr. Choi rebuttal calls out, advanced cancer is defined as stage III &IV tumor burden. But still, given the different death rates, one would still want balance between the stages. In the NSCLC efficacy groups, there was 10 and 13 pts in the PBO and 3mg respectively. Of theses, 6 and 5 had stage IV tumor burden, respectively. So what AF is attempting is to get you to believe the PBO-e was sicker than the 3mg-e given just 1 more NSCLC stage IV pt.

     

    Now given the 1 yr mOS of stage IV NSCLC is like 18%, you would expect in a 4 month trial (and for here, let's assume a linear death rate) to have only about 56% left alive at the end. Or about 3 in each NSCLC group. But the dealt rates in Dobs were much lower in each, as the inclusion criteria required all pts had to have a >6 mo expected survival. So these stage IV pts in Dobs were the healthiest of the sIV out there. More like stage III based on survival and K performance.

     

    As for when the data is coming I have no special insight and still going by what GTx told us in their last filing: sometime in 3Q13. I fall into the "late in the qtr" camp - perhaps even after labor day. This is a small company trying to get it right. Not some big pharma co with everything pre programmed and zillions of foot soldiers watching each pt. There is a lot to do here to check and clean and lock the data and to run the stats.

     

    Did I answer your questions or do I need to take it the next level of detail?
    13 Aug 2013, 10:24 AM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    i do not have high hopes for mOS its sort of the gravy on the top

     

    given the climb power improvements for the mixed cancer pii trial for individuals from baseline..."the mean of the percentage improvements for individuals is more interesting, and already reported in Dobs as 18.0% with 1mg and 21.7% with 3mg and just 4.8% with PBO" and the improvement in stair step time for both 1mg and 3mg that seem dose dependent then it seems the drug does work

     

    also considering that it should not matter what the cause is cancer or duchennes dystrophy or other wasting it should work the same way in a predicable fashion since its just an androgen receptor antagonist right?

     

    did the 10 and 13 patients in the nsclc arm respond with the same frequency as the other cancers in the last trial?

     

    also the pii trial had only about 60 patients evaluable for efficacy in the enobosarm arms is that enough power to be comfortably forward looking in expecting the same efficacy in the piii trials?
    13 Aug 2013, 12:54 PM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    also noticed the data for leg press and the enobosarm being competitive with the merck sarm without toxicity that is remarkable
    13 Aug 2013, 01:22 PM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Great qs. Yep mOS would be gravy. To be clear, it is being looked at on a noninferiority basis for safety.

     

    Q1: Actually I would argue the cause of the myopenia does matter.

     

    DMD, for example, might be one where one where hAR stimulation might not do much good. The loss of muscle function in DMD is due to mutated dystrophin, a key protein in a complex that strengthens and protects muscle cells as they work. hAR stimulation will not correct the gene causing this mutation. And building more mutated muscle might actually be counter productive. But this is debatable and very much pt specific. Also with DMD the pop is mostly pre teen boys. Not really the group to be hitting with large doses of an anabolic - even if it is a SARM with less andronizing affect than a steroid. Some types of muscle weakness are due to loss of innervation. Now it is true that the existence of new muscle does stimulate new innervation. But if function is lost due to nerve issues (parkinson’s) much of the loss of muscle is actually due to deconditioning or in some muscles over conditioned due to hyperstimulation.

     

    But look at the other end of life. Elderly man and post meno women. Massive growing chronic markets. After age 40, all start losing large amounts of muscle, often due to suppressed levels of androgens. The result is a steady progression of frailty. Force bed rest is also a major cause of muscle loss called deconditioning, which is quite rampant in today’s PC &TV obsessed world. We build less muscle in our youth so have less to lose as we age. Grandma falls and breaks her hip...not because her bone is weak (the brittle bone is a co-incidence). The causation of her fall that leads to her trauma is most likely loss of muscle function. SARMs promise to do for muscle what SERM and bis Rx have done for the treatment of osteoporosis.

     

    (BTW, SARMs are also very effective on building bone. Unlike SERMs, they are actually anabolic on bone. The only approved anabolic bone Rx today in the US is inj PTH. Oral SARMs could be developed to treat and protect bone, but that is an even longer clin/reg path in an area of considerably less unmet medical need.)

     

    Changing subjects.... We need to be careful on terms. There were 2 phase 2 trials. For clarity, it is on Dobs that I base the rest of this reply.

     

    Q2: Dobs does not report much quantitative results by ca types, but does report “We noted a greater increase in lean body mass in patients with colorectal cancer whereas we recorded the greatest increases in stair climb power in patients with NSCLC.”

     

    Q3: While the SCP did show stat sig on the Wilcoxon, the SCT was not powered to a prospective level of confidence...in part as it was one of the first studies to ever look at SCP in cacx. Thus there was little effect value on which to prospectively base the sample size approximation analysis for the Ph3 trials. The SCP was an exploratory endpoint in Dobs. It provided further evidence of effect, and with that effect helped determine the approx sample size required for the ph3. If Dobs was the only study showing SCP effect, and enobosarm was the only anabolic, I'd be more concerned.
    13 Aug 2013, 01:58 PM Reply Like
  • Cora Schlesinger
    , contributor
    Comments (666) | Send Message
     
    Are we going to have to start calling you Mr. Encycplopedia? lol
    13 Aug 2013, 09:45 PM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    strength is a part of the stair step test, but certainly not the whole story. If you look at the paper you will find data that directly tests strength alone (NS), strength + CV status (NS) and strength + CV status + balance coordination ( the only positive finding).

     

    Is 'strength' is the attribute that caused the significant difference in stair step, why is it not also detected with the other two tests?
    14 Aug 2013, 09:25 AM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Aha! .... peterthepanzer = NTTG on the Y!MB? Howdy, "son".

     

    I'll repeat part of my reply.

     

    "We disagree with your implication that hand grip strength is a pure way to measure relevant strength here. Lot of divergent force vectors in the grip. My experience is that hand grip strength does not change much as rarely does one reach max grip strength in activities of daily living...and as such, they don't get a load to support the SARMs development of muscles. Even steroid users still need to go to the gym. Maybe would work if you require pts to practice a few grips - say 10x each day each hand. But otherwise, I'm just not a fan of grip, even as I think Dobs reports they used one of the better ways to measure it

     

    Gait speed also is not much of a test of strength or CV status and has a sig coordination component. And lots of momentum. It is another test of an activity that few reach capacity in activities of daily living. Most have a considerable reserve in leg muscles to maintain their “normal” gait speed...until they reach a point of major muscle loss. Then it goes fast. So perhaps a better test for treatment of those already showing a cachexia caused gait speed deficit. If you want gait speed, do it a wind tunnel, so use have a force on vector to resist.

     

    But the quads? quads get loaded all the time. Just standing, they are engaged as one maintains balance and resists the pull of gravity. Leg weakness is one of the first areas sarcopenia starts to be seen. Difficulty standing from a seated position.

     

    If you are concerned by the SC test (like the purists from Merck) I guess you prefer the 1RM of the bilateral leg press? Even as the FDA is cool on overt strength tests as a reg tract endpoint? But even so, you should take comfort in Fig 2 of Marcantonio, et al. ENDO 2010, which showed enobosarm produced a 20lb increase in sarcopenic woman after 3 mo.
    14 Aug 2013, 02:00 PM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    its actually not me i just reposted to stimulate debate im actually ieteriinto on the y board
    15 Aug 2013, 09:56 AM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    did you say 20 lbs or 2lbs are 3 mos thats a humongous increase

     

    is the leg press data seperate from the sarcopenic women or are they one in the same?
    15 Aug 2013, 01:32 PM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Got it. The copy/paste confused me. perethepanzer =ieteriinto makes much more sense.

     

    Yep. Humongous.

     

    Ave. 20+lbs strength gain in 84 days as measured by 1RM for BLP was in sarcopenic women (mean 57 yo) on 3mg enobosarm..

     

    Follow me on twitter @JJSchaible so I can direct message you to provide you with the Merck ENDO10 poster. (That goes for anyone out there. Anyone - bull or bear $GTXI - owes it to themself to see this poster from Merck.)
    15 Aug 2013, 04:48 PM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    the stair climb power for nsclc makes perfect sense considering the nutrition neccessary to build decent muscle tone; this should be a reality in this trial

     

    the broad applications of enobosarm could end up making acadia's drug for parkinsons psychosis look like a small potatoes market

     

    280m cap this could be worth 10x more easily with just a few cancers used off label and with other diseases like diabetes kidney disease and this is worth 10-30x upside easily
    13 Aug 2013, 02:05 PM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » > 280m cap this could be worth 10x more easily with just a few cancers used off label and with other diseases like diabetes kidney disease and this is worth 10-30x upside easily.

     

    No doubt. Sarcopenia alone is huge. Old formualtions of T (topical gel) are all the rage for men with Abbott and Lilly blanketing the airwaves. Sale still growing and over $1b. Now what if that was a pill, with less SE and less contact risk to love ones? And what if it also works in women?

     

    I truely beleive if the Ph3 work, $GTXI will rocket.

     

    PPS reallly starting to move = here at $4.33 again. After a day of pushing $GTXI down to buy options, the equity is again getting the start of a run. Got to love OPEX week on thin float stocks.
    14 Aug 2013, 12:55 PM Reply Like
  • crismih19
    , contributor
    Comments (21) | Send Message
     
    a quick back-of-the-envelope calc (at work, so I don't have links for the stats):
    US figures
    28% of cancer patients will develop cachexia.
    1,660,290 new cancer cases expected in 2013
    Therefore 464,881 patients
    Management estimates $1,500 to $3,000 per month cost => 18,000 to 36,000 a year

     

    Management estimated $750 market in the US, back calc shows they expect 41,667 patients (I think they used 1,500 cost per month) => only about 8.96% of above 464,881 patients, which is a low estimate

     

    if 20% of 464,881 patients => 1.6B to 3.3B peak sales per year => $26 -$53 SP => 6 - 13 x upside in cachexia ONLY! (COGs, misc cost, and discount not included)

     

    With Enobosarm success in this P3, it will open the gate to multiple indications. Potential is ridiculous!

     

    PS - Thank you for this awesome article and your determination to report the facts, not AF-style fiction
    14 Aug 2013, 03:25 PM Reply Like
  • Deep.Blue
    , contributor
    Comments (131) | Send Message
     
    According to Natl Cancer Institute, up to 1/3 of cancer patients die from cachexia...
    17 Aug 2013, 06:22 PM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » UR too kind.

     

    I did get more "in your face", as AF often does, even though such is not my normal demeanor. But as a tactic, there is no debate that it draws attention.

     

    Yep, potential is ridiculous. When I was leading the Astrenia team, we were not even focused on SARMs for cacx as a lead indication, and more towards the pet indications of $MRK and others, willing to let $GTXI own that space.

     

    I'd be interested in your source for your 29% cacx incidence. When doing MR, one needs to take care of what that definition of cachexia is used by the source. The definition has been quite dynamic. When I talk about cacx, I now use the Fearon 2011 definition and staging, but not all are on board: http://1.usa.gov/13AMfaK
    14 Aug 2013, 04:19 PM Reply Like
  • crismih19
    , contributor
    Comments (21) | Send Message
     
    I can't find the link for the 29% figure, so please disregard until I can back it up.

     

    But per Tackling the Conundrum of Cachexia in Cancer, "nearly one-third of cancer deaths can be attributed to ... cachexia" http://1.usa.gov/14fZEF3
    15 Aug 2013, 10:36 AM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    the fact that a 3mg dose is competitive with 125mg for leg press does suggests a very high level of specificity for the androgen receptor

     

    since two successful trials for both healthy elderly and random cancer populations then this is highly pointed toward a good trial result with a low bar for statistical significance, also can now include the leg press data from an earlier trial which is good so three trials

     

    ;The last patients completed these clinical trials during May 2013. Vital status (survival) of patients participating in the studies will continue to be periodically monitored in accordance with the clinical trial protocols. The Company anticipates providing the topline results for both studies later this quarter which will include the coprimary endpoints, safety assessments, and an update on survival;

     

    so the company said on July 19 they were doing follow up for survival and safety data which is interesting...so maybe they are sitting on good data and waiting to blow everyone out of the water with both endpoints, because why would they sit on bad data if vical is a good example they usually release bad data right away like with allovectin missing both endpoints on Aug 12 it must be somewhat illegal to sit on bad data for a long time i would think
    15 Aug 2013, 10:02 AM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Don't mean to muddy the pond. And as fair warning, I'm about to go full geeek again.

     

    But one can not conclude "a very high level of specificity for the androgen receptor" from the "fact that a 3mg dose (of enobosarm) is competitive with 125mg (an old Merck SARM) for leg press". SPECIFITY is typically measured ACROSS an array of nuclear receptors. (Say AR vs ERa vs ERb vs GR vx RAR, etc.)

     

    Another term of art one often hears is SELECTIVITY which serves as a descriptor of relative tissue level response (say comparing a range of doesages of your SARM for anabolic effects on muscle to say the androgenic effect on skin, often against a comparator androgen - often T).

     

    Other data suggests that enobosarm has decent specificity and selectivity.

     

    I think you might rather mean EFFICACY. And even here, if one depends on that data alone, all one can really say is that 3mg of enobosarm resulted in a comparable results in that study.

     

    There is a lot of ADME that goes on after one ingests a pill, before it results in so many mols hitting the ligand binding domain. As such when comparing SARMs the gold standard for research is actually ACTIVITY, measure in vitro. There is a number of ways now that such can be done, but the classic way is using the co-transfection assay to measure receptor based activity.

     

    But don't worry ... with the correction of term, your point is still valid.
    17 Aug 2013, 08:07 PM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » To update, above I wrote:

     

    "anonymous Twitter user @biolong has written an elegant hypothetical example using AF's equation, which shows why the algebra behind (AF's estimates for SCP at baseline) does not compute."

     

    Well @biolong is anonymous no more. He's Blair O'Neill, and he's written a new article on $GTXI on Seeking Alpha and goes into more detail on his hypothetical example comparing results using the equation AF thought he was using to the one he was actually using.

     

    While I took a linear algebra approach to backtest and prove invalidity, his example is easier for most to follow and can be found here: http://seekingalpha.co...
    16 Aug 2013, 04:03 AM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    nttg said on the board:

     

    ;LOL...relevant strength now, you are starting to catch on to the data trap. Strength and relevant strength are two different terms, studied in two separate ways. GTx has done 3 different tests that measure various dimensions of strength, the purest measure is NS. However, luckily for GTx, the test related to their PIII co-primary end point turns out to be significant in a PII report.... its a 'miracle'....now everyone wants to know if lightning strikes twice. 2/3 of the available PII data says no;

     

    is he right or completely wrong here
    16 Aug 2013, 10:36 AM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    After 12 weeks of treatment, both MK-3984 and MK-2866 significantly increased LBM from baseline. A mean
    difference of LBM from baseline versus placebo was observed as 1.54 kg (p-value < 0.001) for both 3 mg of MK-2866
    and 50 mg of MK-3984, and 1.74 kg (p-value < 0.001) for 125 mg of MK-3984.

     

    i would expect the weight gain to be easier in cancer patients considering how the colon patients responded in the first trial with more lean mass suggestive that more wasting equates to more response to SARM drug, also considering sarcopenic women then you can say that these two facts are very suggestive of more wasting is more response is this right
    16 Aug 2013, 09:32 PM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » The math of "New to the game"(Y! MB) is as bad as AF's short source. Perhaps they are one in the same?

     

    My guess - given some verbatim quotes - NTTG's none other than Patrick Crutcher of Chimera. If not, he’s cribbing Patrick’s notes.

     

    He says "2/3 of the available PII data says no". Referring to the functional exploratory endpoints of Dob. But Dobs wasn't "2/3" no. It only has one primary endpoint, thus was 1 for 1 yes. It is a fool errand to complain that two of the three exploratory endpoints did not reach a level of sat sig, when none of these tests were powered to show such. He's also conveniently forgetting that Dobs is not the only PhII study. And the Ph2a was also 2 for 2 yes (LBM & SCP)(sarcopenic pts).

     

    I've already had this debate with Patrick in private, but he's locked in to a position given public comments he's already made ... comments I see as woefully inaccurate, naïve and biased. Patrick thinks it was silly for GTx to do functional tests in Dobs as exploratory endpoints. My reply is how else could they do them? To design a prospective trial, one requires an "effect value" to calc the sample size to obtain a pre-specified level of confidence. But Dobs was the first exposure of enobosarm to cacx pts. And also as Dobs reports in her paper, this was one of the first times the SC test was ever used in cacx pts.

     

    Also, there is yet another efficacy study one might wish to consider. MRK's ENDO2010 poster in sarcopenic old ladies (MK2866=enobosarm). While not powered to confidence as this was an exploratory study as well, it showed LBM gains (by both MRI & DXA) as well as a "purer" test of strength, the 1RM BLP, where enobosarm added 20+lbs of strength to little old ladies. (Poster is available from the company or I'll send it to any who request one from me via Twitter @JJSchaible)

     

    So to conclude on NTTG... we're far beyond "lighting" striking once and hoping for a second. By my count on 3mg on LBM by DXA, it's like 8 for 8 strikes and no misses. By SCP, it is 2 for 2. And by 1RM BLP, it is 1 for 1. (Yes, the grip and 6m walk did not meet stat sig levels. But they are not endpts in the Ph3. Also on the yahoo board I also go into more detail on why some feel the grip and 6m walk are less optimal tests of relevant strength.)

     

    For your second comment, when looking at the 1.54 kg gain, the first thing to keep focused on is this is not wt gain. It is LEAN MUSCLE MASS gain. Big diff. And I tend to think of it in number of streaks. 1.54 kg is about seven of those 8oz steaks.

     

    That's a lot of meat to add to the ave little old lady.

     

    But to me it is unclear if it will be easier or harder to maintain LBM in cachexia pts than in little old ladies. One factor should help is NSCLC is a male skewed cancer...and men tend to be relatively more responsive to short courses of androgen treatment.
    17 Aug 2013, 05:32 AM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    true so if the trial has more men and men tend to gain more muscle than women then the bar is set fairly low here considering all the previous data

     

    did the company say that they would do several months follow up after locking up the data for the primary endpoint, as in did they mention this a long time ago since the four months quiet period seems very odd you think they would be trumpeting their glaring success if they nailed their endpoint or at least i would if i was in their shoes

     

    can you give me a link for the rat model you mentioned before
    17 Aug 2013, 09:26 PM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    do you think they know the primary endpoint data at this point is it fully analyzed its been over three months now

     

    also why did they not also do a piii trial for sarcopenia considering how potent enobo is in that population

     

    would the lung patients data for stair climb be better because they also got a benefit in parabronchial smooth muscle (PBSM) cells or diaphragm muscles, otherwise what explanation can be given as to the inferred benefit in the stair climb over all the other cancers
    18 Aug 2013, 05:24 PM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Inital reaction to the data: AF got lucky. That's all.

     

    Math and fact errors on the Ph2B data don't suddenly become correct just because he guessed right on the outcome of the Ph3.
    19 Aug 2013, 10:37 AM Reply Like
  • Deep.Blue
    , contributor
    Comments (131) | Send Message
     
    Jake

     

    You did a great job on analyzing gtx. AF does nothing but write vomit regardless of the stock and relies solely on the fact that this stuff is hard and failure is part of the game. Tus his blind squirrel hit rate will obviously be a bit higher....
    19 Aug 2013, 10:34 PM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    Initial exploratory quantitative (continuous variable) analysis demonstrated that enobosarm had a consistent effect on LBM relative to placebo in both studies at all assessment times (p values were 0.0003 and 0.0227 at Day 84 for POWER1 and POWER2, respectively). Corresponding analyses for SCP were inconsistent between trials (p values were 0.0336 and 0.7923, respectively). Missing data were well balanced between the arms in both trials for both endpoints.

     

    “While we are disappointed that both studies did not meet the pre-specified responder analyses, we are encouraged by the unambiguous effect of enobosarm on muscle and we are confident that it will translate to clinical benefit and potentially increase survival in patients with non-small cell lung cancer,” said Mitchell Steiner, M.D., CEO of GTx. “We look forward to sharing our clinical data from these and previous trials with FDA and European authorities to discuss the path forward. I would like to personally thank all the employees at GTx for their tremendous effort in conducting two high quality Phase 3 clinical studies and the principal investigators and their staff at over 80 clinical sites in 8 countries for their help recruiting and managing these studies. Most of all, I want to thank the patients with non-small cell lung cancer who participated in the POWER1 and POWER2 clinical trials in order to make it possible for future patients to potentially have access to important therapies.”

     

    “Muscle wasting in patients with non-small cell lung cancer is devastating and unfortunately it affects hundreds of thousands of patients worldwide,” said Jeffrey Crawford, M.D., Chief, Division of Medical Oncology at Duke University School of Medicine, and principal investigator for the POWER1 and POWER2 trials. “While some of the pre-specified primary endpoints were not met, I am encouraged by the substantial and consistent effect of enobosarm on muscle in these patients with lung cancer receiving chemotherapy.”

     

    “Data from the POWER trials provide compelling evidence that enobosarm maintains or increases muscle,” said Carla Prado, Ph.D., Assistant Professor, Nutrition, Food and Exercise Sciences at Florida State University. “Loss of muscle, independent of weight loss, is a common and often occult feature of cancer, and is acknowledged as a remarkable and powerful prognostic indicator of shorter survival.”

     

    For your second comment, when looking at the 1.54 kg gain, the first thing to keep focused on is this is not wt gain. It is LEAN MUSCLE MASS gain. Big diff. And I tend to think of it in number of streaks. 1.54 kg is about seven of those 8oz steaks

     

    ...therefore the price action here makes no sense to me based on the press release even though the endpoints were not perfectly met the increase in LBM was positive

     

    was LBM not the main thing observed in pii especially in colon cancer patients
    19 Aug 2013, 02:05 PM Reply Like
  • biopeon
    , contributor
    Comments (28) | Send Message
     
    Clearly the data could have been better. I suspect the varied health status of the patients played a bigger than expected role. The p values of the stair climb power are all over the place.

     

    Still, I found lots of positives in the data. Basically, the trial confirms that very sick lung cancer patients on chemo can take Enobosarm, do no exercise, and still gain significant amounts of lean muscle!

     

    Uh... that sounds like a huge deal to me! Imagine if you gave this drug to healthier patients. Heck, do you think normal men and women who just want to gain muscle would like to pop a muscle building pill that has no side effects??? People pay a lot of money for losing fat... so... yeah, they also pay a lot of money for gaining muscle. And you can do it WITHOUT exercise. That's the American way, lol. I'm adding.
    19 Aug 2013, 04:55 PM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    bipeon where did you find the actual data for the power trial all i found on their site was a press release stating the general data outcomes

     

    also i suspect that they might have added at least 1-1.5 lbs in lean muscle mass on average which is half the phase ii 3mg response of 3.4 lbs in lean mass considering the statement Initial exploratory quantitative (continuous variable) analysis demonstrated that enobosarm had a consistent effect on LBM relative to placebo in both studies at all assessment times

     

    i feel they should have been pickier in picking their stage 4 patients for early stage because rapid tumor growth will cause accelerative wasting and fight the benefit of enobosarm...this means the bar was higher than with the sarcopenic elderly patients who were healthy in the pii trial

     

    it all comes down to how lenient the fda is on a gain in lean mass while having no statistical increase in observed strength from stair climb
    19 Aug 2013, 09:34 PM Reply Like
  • Cora Schlesinger
    , contributor
    Comments (666) | Send Message
     
    JJ and others:
    I feel sick at my stomach with the POWER trials results, and need to apologize to my readers. I will be more formal with a specific article tomorrow. The retro-spectoscope is out, and looking outside of the box. I realize that the lack of SCT improvement could have been expected. To go geek, as you say:

     

    Patients with smoking-related lung disease, any benign chronic lung disease (CLD), and virtually all cancer patients, develop what is known as "anemia of chronic disease" (ACD). It means the body is no longer able to to make new red blood cells (RBC) from iron (Fe) stores. Fe levels in RBCs are measured in a lab test called hemoglobin (Hgb). Anemias are loosely graded as mild, moderate or severe, determined by Hgb levels. Hgb ferries oxygen (O2) around the body in the blood stream, with normal O2 saturation (levels) of 95- 100%. Patients can have decreased O2 sat, i.e., less than 95%, due to underlying CLD. The lower the number, the weaker they are.

     

    The above can be determined in CLD patients with 2 easy-to perform tests, pulmonary function tests (PFTs), a breathing test; and pulse oximetry, measuring O2 sat. If the focus had been CLD, instead of cancer, these would have been performed and noted. For benign lung diseases and most cancers, drugs Procrit, Epogen and Aranesp are routinely used to raise Hgb levels in ACD, giving each heartbeat more Hgb to oxygenate, improving hypoxemia. Blood transfusions are used for severe anemia, and the ability for phys improvement, unlikely. Benign CLD patients benefit from continuous supplemental O2 and phys therapy to improve muscle function, w/ patient compliance a sine qua non.

     

    In P2 there are no records of anemia being corrected, altho it probably was going on in some patients. Patients were de-conditioned, with muscular atrophy, the same as in age-related sarcopenia. What I saw in P2 that didn't register, and does now, is that anemias, not further specified, were listed as 4- 17%, highly unlikely in this population. Frequency should be similar to cacx itself. So, I missed it, but everyone else did as well, no excuse.

     

    My recommendation were based on information I had at the time, that is, yesterday. Taking all efficacy patients in the P2, the p values for improvement in LBM, SC time and SCP were highly statistically significant. The P2 mortality rate of 9 (of 159) was 6% in all cancers, whereas the P3 mortality rate is 280 (of 650), or 43% at 5 mo. Given the nature of NSCLC, this is not too surprising. Survivability will be assessed and actionable after 450 deaths.

     

    I apologize much to my readers. Although not a consolation, I do eat my own cooking, and have probably lost a lot more $$ than most longs. Option traders are probably sitting on the side, thankful they did not commit to long. Congratulations.

     

    Again, sorry to my long readers. Nothing else I could say will make things better. I will be coming out with a more complete article tomorrow.
    Cory
    19 Aug 2013, 10:49 PM Reply Like
  • Rick Berger
    , contributor
    Comments (1246) | Send Message
     
    Cory, manning up after taking a hit is admirable. JJ can take a page from UR your character, as he made this a personal war with AF.
    Adam called it right, so he must be given credit. Why he was right or wrong, or why he's so disliked among the biotech community is not the point. The fact the stock tanked upon his piece only proves he's got a track record that is heavily considered, and will continue to carry much weight.

     

    Personally, I can't stand his arrogance. But my not making an admittance of his latest call only makes me less of what I am.
    As for your own take on the GTXI data, good investors weigh the pros AND the cons. Think of it this way: Good horse owners don't apologize to the betting public: They simply get ready for the next big race.

     

    Rick
    20 Aug 2013, 04:43 AM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Good Morning Rick.

     

    Like Cora, I have deep sympathy for any who lost wealth by investing in GTXI, especially those who based part of their decision to buy or hold on any evidence I presented. And like Cora's, our portfolio took a considerable hit.

     

    But unlike others, I took great pains to focus on the Ph2B results. I never made recommendations that anyone buy any stock. I only reported what I was doing with my investments in GTXI. Likewise, my call that $LGND would turn out to be a lower risk way to play enobosarm turn out to be true.

     

    Even in the face of the Ph3 result (reaching significance for a 20+% RR in 1 of 4 endpoints for the US responder SAP, as well as the EMEA continuous variable result reaching significance in 3 of 4), I stand by every word I said above. Based on what I knew then, I would make the same bet again, though I might have structured it slightly differently.

     

    All AF's math and many of his facts from his July 10th piece remain as wrong now as they were the day he first reported them. The Ph3 data has not changed that fact that the company confirmed the mean of SCP for the PBO-e group at BL was 166.2 watts (not AF's 46 w). Nor the fact that 16.81 / 21.7 equals 77.456. Not 80.

     

    As for AF, I do not have any animus towards him. Never did. I never called for him to be fired. Never suggested he gained financially from this saga. Only asked that TheStreet.com investigate the merit of my rebuttal and make corrections. I have no evidence that they ever did.

     

    If there was ever a "personal war", it was unilaterally declared by AF against the authors of the Ph2b article and the management of GTXI. I just voluntarily rose to their defense given his article was based on such obvious errors.

     

    But yes, such is "arranging deck chairs" now. To the victor go the spoils. C’est la vie.

     

    In conclusion, AF never addressed the merits of this rebuttal. But I can now report that he did finally reply. After 10 days of silence, but seconds after the Ph3 results were announced, AF finally came out of hiding to gloat. He unblocked me from his @adamfeuerstein Twitter feed just long enough to tweet; "Hey Jake go F%^& yourself". (The "%^&" edits are mine.)

     

    Apparently, it’s good to be the King.
    20 Aug 2013, 11:13 AM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    jj it seems like its not completely failed they nailed some of their data based on the conference call

     

    they achieved the ema endpoint for continous variable is this not remarkable
    20 Aug 2013, 02:24 PM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » The GTX cc quote re the EMEA is "...for Europe we believe that all the pre specified endpoints for Europe are primarily met."

     

    I must take some issue with Dr. Steiner here. As I understand it, the pre specified endpoints for Europe were 2 ph3 on SCP evaluated by continuous variable. They got 1 of 2. So where will he go to get the 2nd? I suspect he will attempt to use Dr Dobs SCP data for such. Except that SCP was an exploratory endpoint in Dobs not prospectively powered for such. And I'm uncertain if they have met that bar even using a post hoc continuous variable SAP.
    20 Aug 2013, 03:19 PM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    jj i think your reading into this too much...the p value was very good at day 147 with continuous variable and one study might suffice considering a lenient stance by the agency

     

    so it really all depends on the stance taken by the fda ema on an oncology indication that has no known treatment available

     

    survival signal is excellent as well 20% hazard ratio...could be the cherry on the top of this data in my opinion

     

    on a side note you might not be qualified to take an issue with dr steiner on anything considering he probably has a masters in this science

     

    i say 70% chance of approval from one of the agencies im betting on the fda first since they have fast track there
    20 Aug 2013, 03:33 PM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » I'm not debating the limited data as so far disclosed, so let's hope for patient’s sake you’re right.

     

    It’s just that I tend to be a skeptic on the degrees of freedom regulatory agencies grant sponsors for post hoc changes to statistical analysis plans. Not saying it is never done. Just that it is a high bar. But luckily, survival is the one topic that will almost always permit a sponsor to have that discussion.

     

    As for Dr. Steiner, he does have a fine scientific pedigree. But more relevant, I also recognize he has the privilege and benefit of specific confidential discussions on enobosarm with both the FDA and EMA.

     

    I still remain an ardent support of the central dogma of cachexia treatment. That "Muscle Matters" and that LBM is an important predictor of survival. Yet it remains to be proven that the contrapositve is valid. That the hypothesis of increasing/maintaining LBM will likewise increase survival is valid. Yet such is the very hope for treating cachexia, and why I remain hopeful of the development of LBM as a surrogate endpoint for survival.

     

    I also remain positive on the future for SARMs more broadly, even as I suspect if GTx had selected a different setting (such as those Merck sought – without anemia) they might now be sitting on a more robust dataset at least for the EMA. But such “Monday Morning QB” service little purpose for enobosarm and GTx.

     

    Fair enough?
    20 Aug 2013, 05:09 PM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    i think you might have overanalyzed this from the beginning syngergizing every piece of data to say lightning was striking 8 times out of 8 for the studies...the wrong patient population could throw all your efficacy out the window in an oncology setting
    (the fda might be lenient considering this fact as well)

     

    if the survival signal is robust and holds up then there is no way the fda will require a post approval study this endpoint is attractive enough

     

    what they should have done was run a piii for aging sarcopenia and this trial at the same time so you have one potential hit or two

     

    i think they could still run a trial and if i was mr hyde i would give them the funding to run a trial for early stage 4 crc and sarcopenia both piii and nail both of them probably for lean muscle mass and then change the strength text to DEXA and.or leg press instead of the confounding stair climb test which didnt actually corelate to survival benefit in the power trials which makes it seem pointless

     

    so the ema and fda will evaluate the drug data seperately and hopefully one of them sees some promise usually the europeans are very liberal about certain kinds of drugs this could be that one

     

    its outrageous that some oncology drugs only have a modest or hairline benefit to OS or PFS yet proceed to get quick approval ie avastin...this drug shows consistently across many pii trials which is not a fluke imo,
    also the market cap is now 90m this seems like a cheap valuation for a company that could proceed to run future trials and succeed
    20 Aug 2013, 06:12 PM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » As for me, a picture is worth a thousand words....

     

    (WARNING: LINK CONTAINS EXTREMELY GRAPHIC PHOTOS).

     

    http://huff.to/14Ya823
    20 Aug 2013, 11:35 AM Reply Like
  • Rick Berger
    , contributor
    Comments (1246) | Send Message
     
    I'm surprised A.F. didn't send you that photo/link, JJ.
    I spoke of character earlier. Adam doesn't know the meaning of the word. I detest him and have openly accused him of stock manipulation. And I'll continue to do so.

     

    I'm a baseball fan and as such I detest everything AROD (of the NY Yankees) stands for. Did AF really get "lucky"?
    How much of AROD's production is steroid driven?
    My point is, I do respect what they know and the abilities they have.
    They're both gifted, but just as shallow, IMO.

     

    I also respect the amount of knowledge both you and "petethepanzer"
    have exhibited in your elongated discussion. It's one of the finest back-and-forths I have ever seen. It's not been clouded with emotion, just pertinent perceived facts. Kudos to you both for the time and effort involved.

     

    The conclusion I came to was that it was probably gonna be a very close call.
    I don't have much trust in the FDA as it tends to play GOD with micro-cappers. And AF uses this bias to his advantage. But that's a subject better suited for a rainy day.

     

    What I'd like to know is your opinion on the potential success for Capesaris.
    21 Aug 2013, 01:03 AM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Today TheStreet.com's Greg Greenberg lauded AF in his Aug 23rd installment of his weekly "The 5 Dumbest Things on Wall Street" series.

     

    I have submitted a comment, which has not been accepted. (Not a surprise, as TheStreet.com also refused to append a materially similar comment to AF's August 19th blog on the same topic.)

     

    My comment to Mr. Greenberg is as follows:

     

    "Yes, it's true GTx's Ph3 POWER 1&2 studies, only reached 1 of 4 primary endpoints for the higher bar for the FDA, and only achieved 3 of 4 endpoints for Europe. But the POWER 1 study actually supports the positive findings of their Ph2A and Ph2B studies. And there may be sound science based reasons POWER 2 study was a whiff, having to do with a plausible adverse effect from concomitant usage of androgens + nucleoside analogs, which I suspect the company will now explore.

     

    Yet to say AF's July 10th piece GTx was "thorough and sourced fine"? Oh contraire!

     

    AF never once checked his story with any primary source. Not the company. Not the authors of the paper he slammed. He just wrote up a short thesis of his "favorite fund manager". If that is what you call well “sourced” then it is at least far off the fair and balanced mark.

     

    As for “thorough”, you're wrong there too. AF’s article on the Ph2B study is based on his faulty equations. Even as the Ph3 results did not reach, such does not suddenly make AF’s math errors and faulty logic of his review of the Ph2b study correct. No, his math remains wrong to this day as I "spelled out in painstaking detail" here: http://bit.ly/178IifI. I still stand behind every word.

     

    While AF was right about the direction of the stock price, he got luckily on the results of the Ph3 data, for it certainly was not the result of his invalid thesis. By the way, the Phase 3 results also statistically disprove his alternative hypothesis that the GTx's drug "is basically a placebo".

     

    Don’t believe that AF’s math on the Ph2B is wrong? Then have him disclose how he got 80 watts for his estimate of mean stair climb power of the 3mg at baseline. He won’t. The actual mean was 151 watts."
    23 Aug 2013, 11:20 AM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    3 of 4 endpoints for europe will be enough especially if they show the survival signal as real but i would think that it is

     

    the study was powered for 450 deaths to eval OS, 280 so far. Using 280, 43% of patients have died overall, and as you say, 63% of powered OS...so unless the next third of patients kills of this effect then you have your EMEA approval

     

    http://bit.ly/179XnO6

     

    Body mass index (BMI) distribution was 17% obese, 35% overweight, 36% normal weight, and 12% underweight. Patients in all BMI categories varied widely in weight loss, muscle index, and muscle attenuation. Thresholds defining associations between these three variables and survival were determined using optimal stratification. High weight loss, low muscle index, and low muscle attenuation were independently prognostic of survival. A survival model containing conventional covariates (cancer diagnosis, stage, age, performance status) gave a c statistic of 0.73 (95% CI, 0.67 to 0.79), whereas a model ignoring conventional variables and including only BMI, weight loss, muscle index, and muscle attenuation gave a c statistic of 0.92 (95% CI, 0.88 to 0.95; P < .001). Patients who possessed all three of these poor prognostic variables survived 8.4 months (95% CI, 6.5 to 10.3), regardless of whether they presented as obese, overweight, normal weight, or underweight, in contrast to patients who had none of these features, who survived 28.4 months (95% CI, 24.2 to 32.6; P < .001).
    23 Aug 2013, 06:35 PM Reply Like
  • Rick Berger
    , contributor
    Comments (1246) | Send Message
     
    Ahhhhh me, Capesaris gets no luv.
    Clinging to Enobosarm and the feud w/The Street reminds me of how the film MURPHY'S WAR concluded.
    26 Aug 2013, 05:00 AM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    rick its still worth fighting the good fight if you can you should try
    26 Aug 2013, 02:30 PM Reply Like
  • Rick Berger
    , contributor
    Comments (1246) | Send Message
     
    That's also what "Murphy" thought, Pete.
    He ended up fighting his OWN war, as the real one was over.

     

    I think at this point it makes more sense to focus on Capesaris'
    chances for success than it does to be tied to a sinking Enobosarm.
    28 Aug 2013, 01:34 AM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    rick im not clinging onto enobo my investment there is dead money...im just saying based on all the previous data and adding 3.5 lbs in lean mass to sarcopenic older women so i could infer that 1-3 lbs was added in these very sick patients and this gave them a very low p value for both power trials by continous variable where you dont give zeros based on someone dying that makes no sense like in responder analysis

     

    also survival signal was shown as 20% the same as in the pii so i feel like this proves that there was a decent number of responders

     

    also unmet clinical need especially oncology is very positive
    29 Aug 2013, 12:47 AM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Murphy's War. Great movie. Poor analogy.

     

    Poor analogy, as neither TheStreet.com nor GTx have surrendered on the war that is enobosarm.

     

    While the results of the Ph3 were no success for GTx, they still are not a total defeat for the drug, though admittedly it was a painful loss in the near term for owners of GTx's equity. More than likely additional studies will be required for the US. And studies take funding which GTx currently does not have in the bank. So the fall in the stock is not unexpected given the mixed results.

     

    No, I propose a better movie analogy might be Battle Los Angeles. Complacent in our own prowess, a sneak attack by unknown forces inflect major damage. But through faith and skill of a rag-tag band of survivors, they seek, find, and use new insight to overcome the enemy and win the war even when all hope appears lost.

     

    For the sake of both cachexia patients and investors in GTx, let's just hope that unlike Battle Los Angeles, the story of enobosarm turns out not to be fiction.
    30 Aug 2013, 04:46 PM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    "...we are encouraged by the unambiguous effect of enobosarm on muscle and we are confident that it will translate to clinical benefit and potentially increase survival in patients with non-small cell lung cancer," said Mitchell Steiner

     

    unambiguous effect sounds like the drug works jj just to a lesser degree of intensity than in healthier patients
    30 Aug 2013, 06:10 PM Reply Like
  • Rick Berger
    , contributor
    Comments (1246) | Send Message
     
    " Murphy's War. Great movie. Poor analogy'.

     

    @JJ

     

    That depends on the realistic future of Enobosarm. If you honestly think GTX will continue this expensive pursuit, given the uncertainty of how future data will be acknowledged, then you'll be proven right.

     

    I believe GTX will soon focus all their efforts in Capesaris.
    And I think you'll find that any battle trying to revive the dead will end in the futility of MURPHY'S WAR.

     

    We'll know in time.
    3 Sep 2013, 01:40 AM Reply Like
  • JJSchaible
    , contributor
    Comments (110) | Send Message
     
    Author’s reply » Hi Rick,

     

    Strategically, any biopharma company is fool to put all their cash and future "eggs" in one drug development "basket". So I don't see it as likely at all that will do as you believe and "soon focus all their efforts in Capesaris."

     

    At a minimum, the PhII on enobosarm in met breast CA (9 mg/day) which is now recruiting, will advance. And I do believe the company still sees a bright future for enobosarm in cachexia. The drug works, but I believe they need to do a better job to define the optimal dosage (just 3mg QD?) and suitable background chemo regimes.
    4 Sep 2013, 12:36 PM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    so JJ just so i understand do you think the power trials failed and will not have a good chance of approval

     

    is a miss on stair climb the sword of Damocles or is it just a large root that trips you for a moment then you recover and continue your run
    4 Sep 2013, 09:54 PM Reply Like
  • petethepanzer
    , contributor
    Comments (1072) | Send Message
     
    DAY 84

     

    LBM1 LBM2 SCP1 SCP2

     

    p value RA 0.036 0.113 0.315 0.289
    p value CV 0.00003 0.0227 0.0336 0.792

     

    DAY 147 - only this day for RA, no zeroes counted

     

    LBM1 LBM2

     

    p value RA 0.026 0.013 X 0.68
    p value CV 0.0001 0.0036 X 0.67

     

    survival benefit 20% HR seen in each trial with n= 70, since 280 events

     

    ...therefore permitted a look at pii with 20 and 30% survival HR and some literature with strong signals showing muscle correlates survival infer the reversal with 3 small n lightning strikes 3 times

     

    Body mass index (BMI) distribution was 17% obese, 35% overweight, 36% normal weight, and 12% underweight. Patients in all BMI categories varied widely in weight loss, muscle index, and muscle attenuation. Thresholds defining associations between these three variables and survival were determined using optimal stratification. High weight loss, low muscle index, and low muscle attenuation were independently prognostic of survival. A survival model containing conventional covariates (cancer diagnosis, stage, age, performance status) gave a c statistic of 0.73 (95% CI, 0.67 to 0.79), whereas a model ignoring conventional variables and including only BMI, weight loss, muscle index, and muscle attenuation gave a c statistic of 0.92 (95% CI, 0.88 to 0.95; P < .001). Patients who possessed all three of these poor prognostic variables survived 8.4 months (95% CI, 6.5 to 10.3), regardless of whether they presented as obese, overweight, normal weight, or underweight, in contrast to patients who had none of these features, who survived 28.4 months (95% CI, 24.2 to 32.6; P < .001)...n=1473 patients

     

    if one agency overlooks stair climb in favor of survival then there is still a possibility of approval here
    3 Sep 2013, 03:11 AM Reply Like
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