CytRx: The BASIC Chemistry

CytRx: The BASIC Chemistry
Oct. 26, 2016 7:54 AM ET179 comments

by: Altum Research
Summary
We discuss recent developments of the company.
We revisit the CytRx approach.
We comment on DK049.
We provide a scientific perspective for new-eyes on the company who may be

considering a value investment in light of the price drop.
This article is meant to explain the general science of CytRx (NASDAQ:CYTR) and why
they will continue to fail. We go over basic chemistry of "pH sensitive linkers" - the
fundamental platform of CytRx. Further, we want to make it clear that although this issue
is popular in academic arenas (you can find lots of publications on pH sensitive linkers),
there's little evidence of it ever making it into commercial use. Since there are many
articles claiming bullish scenarios for CytRx, we are presenting the bearish case here.
We published on CytRx before and we couldn't make a case either long or short. The mice
data was very compelling, the phase II seemed ok, but the fundamental science was not
great and the management team reeked of bad choices. Since that article, this is what has
changed:
1. We are now certain the mice data has very little carry-over to humans.
2. The fundamental science is very bad and we will focus this article on that fact.
3. Management has gone from worrisome, to something we would absolutely avoid.
The pivotal Phase III failed. They make a claim that a large population wasn't included in
the final results - but that doesn't matter, if it worked, it would have worked. It just would
have been a more believable p-value if those others were included. They say they passed
their PFS, but p-value was .048 with a median survival rate that didn't pass... Nothing
about this tells us there might be success hidden in the rough.
So let's outline the simple chemistry of why this stock is going to drag down any
investment.
This is Cytr's drug "Aldoxorubicin," in all its glory. The red arrow indicates the cleavage
site, where an acid-catalyzed hydrolysis should occur. This then gives doxorubicin:
This is all very simple chemistry, hydrolysis being one of the first reactions anyone learns
in organic chemistry reactions. So where is the problem? Let's take a stroll down organic
chemistry 101!
Hydrolysis occurs in a pH-dependent manner. The entire idea behind CytRx's drug (and
many of these 'acid-cleavable pro-drugs') is simple, we'll let CytRx themselves explain:
Aldoxorubicin utilizes a novel acid-sensitive linker that selectively binds to albumin,

shuttling the cytotoxic payload directly into the tumor and potentially sparing the
surrounding tissue. This mechanism leverages the tumor's low pH environment, and
accompanying dependency upon circulating albumin to fuel growth, to enable the
delivery of multifold times the standard dosing of doxorubicin.
The lowering of the pH of tumors is often described as the 'Warburg effect'.

Conversion of glucose to lactic acid in the presence of oxygen is known as aerobic
glycolysis or the 'Warburg effect.'
An excellent review of this can be read about here.
On a surface level, this all makes perfect sense: Have a pro-drug that will be cleaved in
the presence of acid to produce an effective chemotherapy drug - and have it specific to
the tumor microenvironment!
If you're invested in CytRx, this idea is why you are, and you're no fool to believe it could
be possible. But let's go a bit further. We need to answer two questions:
1. What is the pH of the microenvironment (in general).
2. What is the kinetic effect that this would have on aldoxorubicin cleavage (i.e.
how selective would this make it?)
Before we answer (1) we need to understand physiological pH.
The pH of the blood is extremely well curated by the body. Acidosis is the change of pH of
around 0.15-0.25, on a chemistry scale this is exceptionally small.
From that above 'Warburg effect' paper published in Nature, we can see that the pH of a
tumor can approach the low 6.4 range:
This is exceptionally low in a biological context, but really, what is that to chemistry and
kinetics? If we consider that the mean pH of the extracellular space of the tumor is about
6.7, and our normal pH range of blood (where the CytRx drug circulates) is 7.4, we have a
pH of 0.7. That is about 5x more [H+] - that is, there are about 5x more protons - in
the extracellular solution.
This all sounds great, the problem is trying to understand how beneficial that relatively
small (from a chemical perspective) change is for drug delivery.
You can try to search for "pH kinetics hydrazides" (the linker cleavage point is called a
hydrazide), the problem is you will be pressed to find papers or articles that cite a gradient
of kinetics through our range of ~6.4-7.4. The majority of papers compare pH 7.4 to 6.0,
5.0, 4.0. These lower ranges do not exist in our body, in even the most aggressive
tumors! Therefore they are not useful points if we don't include a smaller iterational step
in pH.
To answer question (2) in a very general sense, we can look at the cleavage of some
other drugs in a pH-dependent manner. To be fair, these are different functional groups,
but you will see the general point:
Source - The highlights are added by us to illustrate the range of pH differences that we
are seeing in healthy blood versus the extracellular space of tumors. The bottom axis is
pH, and the left axis is the rate at which degradation (cleavage) occurs.
Again, these are a variety of different drugs which have different functional groups, but the
general idea should be very clear:
The pH difference of healthy blood (7.4) to that of an acidic tumor

microenvironment (>6.4) is not something that is going to dramatically change
the rate of hydrolytic cleavage for doxorubicin!
Further, just because doxorubicin would be cleaved preferentially more so in the acidic
microenvironment, does not mean it will then target the tumor. It will be cleaved in the
extracellular space, and thus has the freedom of motion to stay in the blood circulatory
system - not be uptaken by the tumor!
Is it clear yet that the fundamental principle that CytRx has been promoting for years is
quite weak?
We hope the company would dissolve and give its shareholders something of value.
Unfortunately, we can't see that happening - oh wait! A glimmer of hope! Their pre-clinical
drug!
Surely it has some new science, some new, novel mechanism. Surely after all this failure
with aldoxorubicin, this company is bound to understand they need to do something new...
Oh. Nope. Still albumin-binding linker (red underline), with a hydrazide linker (red arrow).
Is this drug (gemcitabine) even a novel target for this approach?
No. H-gemcitabine was looked at previously and dropped in preclinical phase. The linker
and cleavage point are different, so at least CytRx tried... kind of.
So how do they keep showing pre-clinical and clinical efficacy (albeit never superior)?
Well, it's just because they are, more or less, just injecting slow-release chemotherapy
drugs. The problem is they don't admit this, and act as if they are "targeting" the tumor,
which isn't true. *Unless you are a rat who is growing a tumor ~half the size of your
body - then miraculously the drug shows up in the tumor. Go figure.
To fully appreciate that, one could go to a pet store with large Jawbreaker/Gobstopper
candy in hand, to make a visual comparison.
How it is actually showing beneficial effects is likely quite complicated but will be difficult to
replicate in human clinical trials, unless the tumor is half the size of the subject. Further:
This paper indicates that low doses of gemcitabine is actually beneficial to higher doses,
and has lower toxicity. Here's DK049 data:
Here is the H-gemcitabine data:
h-gemcitabine @ 25 mg/kg 95 umol/kg
Free gemcitabine @ 100 mg/kg 380 umol/kg.
infusion days: 0, 3, 6, and 9
The comparative gemcitabine dose of 240mg/kg is probably just killing the mice, but at
this point, it really doesn't matter.
Management will continue to collect salary as long as they operate; they will continue to
push these skeptical, abandoned drugs (and methodologies) into the clinic and investors
will likely continue to lose money. For all the bullish cases that are out there, here is the
bearish.
While the bulls will focus on the efficacy in trials (the drug does release doxorubicin) and
the lack of cardio AEs, there is little talk about the specificity of the drug. The most
aggressive tumors will accumulate aldoxorubicin/doxorubicin, but the issue is, they would
accumulate doxorubicin alone due to high metabolic consumption. Thus the benefit of
aldoxorubicin is simple extended, dilute release over time - not specificity.
Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any
positions within the next 72 hours.
I wrote this article myself, and it expresses my own opinions. I am not receiving
compensation for it (other than from Seeking Alpha). I have no business relationship with
any company whose stock is mentioned in this article.
Comments (179)
matratra
You may not have position but stock can be shorted for some other interest.
26 Oct 2016, 10:58 AM
Altum Research, Contributor

Authors reply No one has contacted us to write this. We simply wrote it for the sake of what it is.
26 Oct 2016, 11:01 AM
Steven Giardino, Contributor

I finally read this. It's absurd.
A simple question you should be able to answer simply with all the simple chemistry you simply
understand so well:
How did 85% of patients with Kaposi's sarcoma experience a partial response or better (CR) to
aldoxorubicin as a *monotherapy* if the chemistry is all wrong?
Um.
How was the disease control rate (including ORR) nearly double that of investigator's choice in the P3?
Did you see the waterfall plot of the P2b regarding various tumor shrinkage from aldox monotherapy?
Does that just happen?
What were you saying about pH again?
Thanks.
22 Nov 2016, 08:01 AM

Authors reply The points you hit on are all definitely outlining a strong bullish case. Whether the FDA
will pass this on non-inferiority + better safety is a perspective you can strongly argue for a positive
position in the stock.
Here is some basic chemistry that IS worth considering. What may be happening is not a selective
mechanism of aldoxorubicin, but simply extended, systemic release.
Either way, we'll know soon.
You're most graciously welcome.
22 Nov 2016, 01:24 PM
Scientist on Stocks, Contributor

"What may be happening is not a selective mechanism of aldoxorubicin, but simply extended, systemic
release."
Don't you think you are making all this up?
23 Nov 2016, 12:09 AM

Authors reply No.
Based on the comments on your piece in '15. I think we are done here.
23 Nov 2016, 01:49 AM

You are good at evading questions! Yes, I am done here. Good Luck.
23 Nov 2016, 02:56 AM

RussMaGuss
Ouch. My main beef with this company is their shady "management" team. Kriegsman needs to inform investors of
what's what instead of hiding all of this information behind dust and mirrors, it gives me no consolation that he is
still with the company after all we've been through. Get Kriegsman out and watch this stock go back to $1.75-2 in a
day.
26 Oct 2016, 11:05 AM
apdamico
This CEO has to go, he has ZERO credibility in the industry.
Can't wait to see the RS ratio!
26 Oct 2016, 11:20 AM
argon69
I wish we can remove him with my voting power.
26 Oct 2016, 11:33 AM
Tumblebug
Wow, great research and analysis. It sounds a lot like one on those commercials for an herbal remedy found on
the far end of the AM radio dial. "Take xxx to lower / raise your pH level for better ....."
26 Oct 2016, 11:29 AM
argon69
Good explanation. Now here is my question for you. I am not a scientist so please forgive me about dumb
question. I am only looking at facts. Aldox and Dox will travel through blood. Dox has severe side-effect. Aldox
doesn't. So at least we know aldox is not released/accumulated in heart. Will Aldox ever be released to cancer due
to PH issue? If not released at all, we should know different problems by now. BUT it was released to cancer.
Otherwise, we won't get similar mPFS in P3 trial. Thanks.
26 Oct 2016, 11:32 AM

Authors reply We do not have a solid thesis for the absence of cardio effects. Our best guess is that
cardio AE appears due to the relatively high doses of doxo in the blood, whereas Aldoxo is likely just low,
extended release.
From our observation, Aldoxo seems to be analogous to a low-concentration, extended-release form of

doxorubicin. Perhaps if CytRx publicly acknowledged this it would make the science a bit easier to
understand, and perhaps even attract better data.
26 Oct 2016, 12:42 PM
Strong Bio, Contributor

except for the fact they have repeatedly stated that the studies have delivered much higher doses of dox
and e over 500 patients w no cardio tox don't you read anything? are u sure u know what a PhD is? results
to date demonstrate that aldoxorubicin combined with ifosfamide provides significant clinical benefit for
sarcoma patients," said Sant Chawla, M.D., F.R.A.C.P., the trial's principal investigator and Director of the
Sarcoma Oncology Center in Santa Monica, California. "More than one-third of sarcoma patients achieved
a partial response for the target lesion and 61% had prolonged stable disease. Importantly, six patients
with unresectable tumors achieved greater than 50% tumor shrinkage allowing some of them to become
eligible for surgery. Further, we did not see any signs of cardiotoxicity including in patients that received
approximately 10 times the cumulative maximum dose of doxorubicin."
31 Oct 2016, 06:59 AM

Authors reply We're very glad we've gotten you so involved in the comments section. Good luck!
31 Oct 2016, 11:28 AM
wlson
he is destroying your thesis my friend. Aren't u worried you are misleading investor and posting wrongful
comments?
31 Oct 2016, 05:02 PM

Authors reply He is not and has not. He has cherry picked every comment and quote. If you read the
papers he cites, they do say what he says, but again, these papers make it clear that below 6.4 pH is
extreme. "I guess we'll see".
31 Oct 2016, 05:12 PM

@Altum Research
"Aldoxo is likely just low, extended release" - Any reason to believe so?
Oh well, "our BEST GUESS (!!!) is that cardio AE appears due to the relatively high doses of doxo in the
blood"
Any words on why the Aldox P2 results were very good vs. doxo? Temporary malfunctioning of Chemistry?
17 Nov 2016, 02:12 AM

Authors reply P2 is a lot easier to pass than p3. Temporary wiggle room for efficacy
17 Nov 2016, 11:22 AM
CMK.
i am not surprised of your article, here is 1 posts you made in a prior article :
CytRx completes enrollment in mid-stage study of aldoxorubicin in lung cancer!!!

Comments (183) |+ Follow |Send Message
you invested with Kriegsman. Did you expect different?
that comment shows your lack of objectivity and independence !!!
And you also mentioned about how likely a reverse spit is on its way that also gives me
second thoughts of your contribution.
26 Oct 2016, 11:35 AM

Authors reply We stand by that comment.
Why would a reverse split hypothesis give you second thoughts. Look at the PPS and the timeline.
26 Oct 2016, 12:43 PM
runinwind
Great article, and really excited to see some scientific articles here.
I have a general question for the pH dependence of drug. It might not be fair to use the pH-dependent manner of
some other drugs to compare with the acid-cleavable linker. I don't think drug degradation is identical to linker
cleavage. Apparent, none of the four drugs has any designed cleavable linker and the stability reported was only
for the drug decomposition.
One thing that I agree with the author is I don't have too much faith in this company and I don't plan to invest in this
company.
26 Oct 2016, 11:46 AM

Authors reply 1) Degradation is synonymous with cleavage. The first kinetically favorable "degradation"
of aldoxorubicin would be cleavage to release doxorubicin (or do the intra-molecular cyclization reaction
cited above).
2) We specifically state that these are not identical linkers/functional groups and that they are not directly
comparable to aldoxorubicin kinetics. The point is not a direct comparison, but a general idea of how pH
effects SN2 'cleavage' reactions. The window of ~6.5-7.4 is small.
26 Oct 2016, 12:45 PM
System Trader
You admit the examples you chose are unrelated to aldoxorubicin. There are regions on the charts shown
where a .9 change in ph would result is a significant change in cleavage. What is needed is the chart for
aldoxorubicin, not some unrelated compounds.
20 Feb 2017, 03:03 PM

Authors reply Extrapolation from similar compounds is not unwarranted. It's what most of chemistry is
based on.
Good luck with your long.
22 Feb 2017, 12:17 AM
System Trader
Nothing similar about these compounds and you admit it yourself in the text. I have found a number of
cases where there was significantly different performance of therapeutic substance over the relevant pH
range. Here is a case where topotecan is released at 4 times the rate at ph 6 versus pH 7.4, figures D & E
:
http://go.nature.com/2...
Here is a case where docetaxel is released from a conjugate at a significantly greater rate at pH 6.5 than
7.4:
http://bit.ly/2mpYuqF
These are an on point references to actual antineoplastic compounds unlike your irrelevant references to
aspirin etc.
Also your assumption that I am long is wrong. Interested observer at the moment.
23 Feb 2017, 04:00 PM

Authors reply There's a plethora of acid cleavable linker drug chemistry from the late 90s. You can
look. Perhaps you'll find a reason why most of it never made it to the clinic (or maybe you won't).
02 Mar 2017, 08:20 PM
System Trader
Moving the goalposts now that your thesis has been refuted.
05 Mar 2017, 07:56 AM

Authors reply What was the old goal post and what is the new one?
06 Mar 2017, 02:59 AM
System Trader
old goal post: existence of drugs cleavable at pH range applicable to aldoxo
new goal post: whether they made it to the clinic
10 Mar 2017, 10:56 AM

Authors reply Old goal post: thesis on difficulty of making clinical candidates for pH-cleavable drugs
New goal post: same
There is a reason that there was a surge of pH-cleavable drugs developed in academia in the 90s and that
>95% of those never saw a clinical trial.
Hope is not a good investment strategy.
10 Mar 2017, 05:34 PM
System Trader
Neither is falsifying your actual short thesis:
"you will be pressed to find papers or articles that cite a gradient of kinetics through our range of ~6.4-7.4.
The pH difference of healthy blood (7.4) to that of an acidic tumor microenvironment (>6.4) is not
something that is going to dramatically change the rate of hydrolytic cleavage for doxorubicin!"
I will waste no further time in reply.
17 Mar 2017, 09:49 AM

Paclitaxel-albumin conjugate, abraxane, has been approved for metastatic breast cancer, non-small cell lung
cancer, and advanced pancreatic cancer. It is the most clear example of what you state doesn't exist; evidence
that albumin-linkers/conjug... don't work in humans.
J Control Release. 2014 Sep 28;190:331-6. doi: 10.1016/j.jconrel.2014... Epub 2014 Mar 15.
Clin Transl Oncol. 2013 Jan;15(1):26-32. doi: 10.1007/s12094-012-088... Epub 2012 Jul 24.
Dox conjugates and albumin conjugates don't just bind the surface of tumors, they are also taken in these cells
through endocytosis (clathrin coated pits). There they are released inside the tumor cells in the lysosomal
pathways. Incidentally the lysosomal pathway pH is 5.0-5.5. Because doxorubicin binds DNA, thermodynamics
drives it by concentration gradient to DNA binding sites, not back into circulation. That analogy is like saying if you
release pedophiles near a kiddy pool, they will all go back into the parking lot and disburse to the interstates in
their cars and go home.
Mol Pharm. 2015 Jul 6;12(7):2217-28. doi: 10.1021/mp500386y. Epub 2015 Jun 2.
Biomacromolecules. 2016 Jun 13;17(6):2223-32. doi: 10.1021/acs.biomac.6b0... Epub 2016 May 17.
Cytrx has stated evidence that patients who respond to aldoxorubicin have targeted tumor death because they did
tumor resection surgeries in the kaposi's sarcoma and glioblastoma patients that analyzed this fact (and sts now
as well from phase 2b combo study). Now if you choose not to believe these reports or think they are fraudulent
that is your choice.
Hopefully these elementary concepts will help you and the reader in the quest to understand the mechanisms
described, should there actually be a genuine interest.
26 Oct 2016, 11:48 AM
Agamemnus, Contributor
All very interesting. So that's a much bigger difference .. 7.4 to 5.5. Even if the difference was small
though, all it takes is a steep gradient in the pharmacokinetics.
26 Oct 2016, 12:16 PM

Authors reply 1) Abraxane is not a drug-linker conjugate, it is simply albumin-bound paclitaxel.
Mechanism for 'cleavage' is not comparable.
2) You cite the lysosomal pathway, which is not specific to tumors, and DNA, which is not specific to
tumors. These points would not indicate that aldoxo is specific to tumors. The entire thesis is based on the
extracellular pH near active tumors being acidic, not the endocytosis pathways.
3) We're skeptical anything this company publishes - as you may have guessed. Again, you have to
wonder how fast were these tumors growing compared to basal cell division of the body. You will have a
"targeted" effect with any correct dosing scheme of a chemotherapy drug if the relative rates of cell
metabolism are extreme between tumor/basal. The question then becomes - is your drug better than
others?
You are correct, these are relatively elementary concepts in biology.

26 Oct 2016, 12:36 PM

Authors reply read above comment.
26 Oct 2016, 12:37 PM
System Trader
The article author's attempt to compare cleavage of aldoxorubicin to that of aspirin, methotrexate, etc. is
absurd. He admits: "To be fair, these are different functional groups". Indeed. To be fair, the pH dependent
cleavage of unrelated chemicals is irrelevant.
I am not at all sure CYTR is a winner, but I am sure this article's analysis is invalid.
26 Oct 2016, 12:58 PM

Authors reply We make it very clear these are not direct comparisons. The idea is to look at the pH
window of all these pH-dependent cleavage reactions and realize the difference between ~6.5-7.4 is not
substantial for selectivity.
Title of the article.
26 Oct 2016, 01:10 PM
elmono
Hi Strongbio,
Actually there are articles out there suggesting that the pH is between 4.5-5 inside the lumen.
http://tinyurl.com/zw4...
The pH gradient between blood and such environment is more than enough to devise a linker that is
hardly hydrolyzed in the blood, but is hydrolyzed in the interior of a cell.
In addition the albumin based carrier mechanism takes care of the selectivity between tumor cells and
healthy cells. Is it perfect: no. Does it work: I am inclined to say yes.
Did the company screw up in numerous ways: yes (I can make an easy top ten, don't know where to start).
What does that mean for Cytrx: I am inclined to say there is still a chance of approval in some prespecified
subgroup (the subgroup that did not receive any prior anthracyclines).......... a substantial chance as well
that there isn't a path.
High risk it is....
26 Oct 2016, 05:24 PM

1) mechanism for endocytosis or transcytosis is likely a great model for aldox, thus has many scientific
publications compare the two... Notice I can support my points with publications and facts, as most Ph.D.'s
should know to do. I invite your citations and not just hand-waving, although it is certainly taken as a
friendly gesture.
Journal of Controlled Release vol 190 Sept 2014; 331-6

Mol Cell Therapies 2016 4:3
Int J Nanomedicine 2016; 10: 5327-42
Biotechnol Bioeng 2014 Sep; 111(9): 1699-1716
2) albumin uptake system for abraxane, be it lysosomal or otherwise, provides efficacy for cancer
treatment, in spite of no specificity to tumors or microtubules, likely because cancerous or tumor cells are
in rapid growth and preferentially take up more albumin than a non-dividing cell, Whatever the mechanism
it was thus was approved by FDA after years of testing and trials. If aldox doesn't come unlinked it poses
little harm as dox is not released unless acidic conditions render release. This is one safeguard that
unfortunately abraxane cannot boast. I am not asking you to trust the company with doseage response
curves, I am merely reporting the physicians and scientists work that are doing the studies, some of which
are cited below.
PNAS 2014 Jan; 111(2): E217-26

Invest New Drugs 2015; 33(2): 341-8
Neoplasia 2014 Oct; 16(10): 874-82
So by all means be skeptical of the publications. So let the data speak, but for you to suggest the interim
data didn't pass the SPA implies you don't do much clinical study. To make a long story short we both
know that the interim study diluted out the responder pool of aldoxorubicin treated patients, but why
debate the obvious "elementary" concept in biology when the data will be released this quarter. Thanks for
your discussion. Sorry that you don't trust the company. I hear that a lot during these highly profitable
buyout phases of biotech companies and it gets mundane.
26 Oct 2016, 05:55 PM

Authors reply Every source is correctly cited in the article above. I'm not sure what you're referring to
when you "invite" my citations.
So it looks like your (CytRx's) basis is just the tumors uptake more (albumin) from the blood than other
cells.
That's the basis for all chemotherapy.

I mean I can't bash CytRx for trying this. The amount of academic articles on pH-sensitive chemotherapy
treatments is massive. That is a lot of PhD dissertations through the years.
But in clinical trials, they rarely seem to make it. There are exceptions of course. Maybe your investment
will be one.
We're not betting on it.
26 Oct 2016, 06:29 PM
neonglow
Strong bio: you made the point I was thinking throughout this article: Uptake of the drug into endocytic
pathway is where the pH drop is occurring and allowing the cleavage.
See also my other comment below. Curious to know what your thoughts are.
27 Oct 2016, 02:28 AM

http://tinyurl.com/zwl...
explains how cancer cells or tumors both actively and passively catabolize albumin (and things thereby
attached).
27 Oct 2016, 02:31 PM

http://tinyurl.com/hhg... warburg himself found 6.0 pH was common
29 Oct 2016, 12:29 AM
User 47658440
Why don't you comment on the lack of cardiotoxicity and similar efficacy to dox if you are so unbiased?
26 Oct 2016, 11:55 AM

Authors reply It's a great aspect to the drug!
26 Oct 2016, 12:46 PM
User 14552302
Wow way to pen out an article about a stock that is a failure that failed months ago.
26 Oct 2016, 12:10 PM

Authors reply Apparently to retail investing, a previous failure can sometimes erroneously lead to a
buying opportunity.
Mast Therapeutics.
26 Oct 2016, 12:46 PM
el_paha
On the science part, I feel you are selectively leaving out certain very important facts.
On the "flawed" EMCH-linker in Aldoxorubicin:

- You are substantiating your claim with an irrelevant reference to DOI: 10.1021/bc060117y, since these findings
do not relate to DOXO-EMCH (Aldoxorubicin). Aldox' inventor (Kratz) is well aware of your referenced study.
- How would you account for higher DOXO-concentrations in intratumoral tissue vs pertumoral tissue in 86% of the
patients in the Ph2-Kaposi study?
On DK049:
- You did not address the added moiety preventing deaminase of gemcitabine, and therefor retaining ~90% of the
drug that would otherwise be lost due to cytidine deaminase.
26 Oct 2016, 12:14 PM

Authors reply How is this reference unsubstantiated? It's an obvious comparison. It's an intramolecular
reaction between a hydroxly and a hydrazide.
Higher dox concentrations:

1) How were they measured
2) What's the age of the population
3) How fast were these tumors growing at baseline
4) Was there a comparison to SoC concentrations in tumor/peritumoral tissue in a control arm?
DK049 - Have not researched it. Could be a valid point.
26 Oct 2016, 12:55 PM
el_paha
The referenced studies by DOI: 10.1021/bc060117y were done on different (early) doxorubicin-conjugates
compared to Aldoxorubicin. These were prone to the cyclization-effect.
DOXO-EMCH is its own 6-maleimidocaproyl hydrazone dox-derivative with a specific thiol-binding spacer
molecule (see DOI: 10.1021/jm020276c). And therefor the cyclization effect reported does not have the
same effect on Aldoxrorubicin. It's a different compound, no apples/apples comparison possible.
Plus, you need to take into account that when coupling to albumin, the dox-conjugate can travel places
unreachable (cell-internalization) to free flowing doxorubicin (or -conjugates). Once internalized, the
environment differs from extracelluar.
On Kaposi: best to see the bottom ASCO2016-poster for details: http://tinyurl.com/j38...
On DK049: you also missed the secondary linker (cleaved by cathepsin b), that makes a further selective
application possible.
27 Oct 2016, 09:35 AM

Authors reply If you can actually verify that this reaction has no precedent with AldoxoRubicin, I'd
believe you. But this is very close, since the changes in the molecules are not significantly close to the
cyclization reaction site.
27 Oct 2016, 11:41 AM
el_paha
First, you are of course entitled to your own personal opinion, but because it is you that is trying to make a
point, its your onus.
Why is aldoxorubicin (being a differend compound, with a different linker) prone to cyclization from
referenced DOI 10.1021/bc060117y ?
Please take caution, if you are going to present research of others as substantiation of your thesis, you
lose the right to make subjective interpretations on them. Even if you call it "basic chemistry". Any
reference should be solid.
28 Oct 2016, 03:07 PM
el_paha
In absence of further substantiation on your side, I will underscore mine.
I already stated that:

- The referenced study (DOI: 10.1021/bc060117y) was not done on the Aldox-compound.
- Aldox is a different chemical structure, than the dox-conjugate made/used by Kaneko et al., Padilla De
Jesus et al (aldoxorubicin is not using the hydrazone-carboxylate linker, but instead, a 6-
maleimidocaproyl(hyd...
That in itself is enough to dismiss your claim for aldox being prone to the cyclization-effect, as this is just
not scientifically proven. To assume cyclization is unsubstantiated and your assumption not very scientific.
Not only should one discard the scientific basis of your article, I can also present some facts from clinical
testing to counter your thesis.
First and most simple exibit of the cyclization reaction being absent, is not to ignore the outcome of
NCT01514188, in which Aldox showed superiority in a head-to-head comparison to standalone
doxorubicin in a 1st line STS-study (DOI 10.1001/jamaoncol.2015...
Study was done by PRAHS and superiority was confirmed by a blinded central lab.
If the cyclization from your referenced study (DOI: 10.1021/bc060117y) would have occurred, one would
not only have unable to achieve superiority, but the cyclization product (dihydrooxadiazinone) would
actually have achieved inferior results compared to standalone dox (hence the "poor antitumor activity").
Second exibit:
Confirmation of achieving clean cleavage doxorubicin was demonstrated by skin-biopsy in the Kaposi
study (NCT02029430). I already posted the ASCO2016-poster in a previous post.
Further on DK049:
Per DOI: 10.1021/bc060117y, the cyclization (of the early dox-conjugate by Kaneko et al.) is an
intramolecular nucleophilic attack by the C-14 hydroxyl of doxorubicin on the carbonyl group of the
hydrazone-carboxylate linker.
This reaction is unique to conjugated doxorubicin on one side of the linker and needs actual cleavage of
the hydrazone-carboxylate linker to occur. This reaction (being specific to the Kaneko-conjugate using
hydrazone-carboxylate) is confirmed by DOI: 10.3390/polym6010179.
This dismisses the claim that you make on DK049, since dox is not at all used there.
To conclude: It not the science behind Aldoxorubicin and DK049 that is BASIC, it's your article.
02 Nov 2016, 05:51 AM
wlson
excellent information El paja. Thank you!
02 Nov 2016, 01:03 PM

Authors reply Actually you know what you're correct. The cyclization reaction is different in the two
molecules, given the leaving group in from aldoxorubicin would require an anionic carbon group.
Good find. Good luck!
02 Nov 2016, 08:58 PM
el_paha
What does this insight mean for your article? Any incorrectness (regarding the claim you make on
Aldox/DK049 being prone to cyclization) should be rectified if you value scientific guidelines.
Will you rectify?
03 Nov 2016, 08:34 AM

cyclad
Thank you indeed for a very good research article. You have maintained patience and humor from some
who probably are connected with the company itself. No earnings announcement is already a negative.
Last webcast the CEO sounded as if he were on high dose of sedatives. Law suits being dealt with.
Anyway, this will run a while with some uninformed investors pushing price up. Always a carrot being held.
It takes a long time to die. Thanks again for very good article.
06 Nov 2016, 09:09 AM
Interesting article. Thanks. I hope you might publish a follow-up based on what Strong Bio is saying above -- that
the lysosomal pathway pH is 5-5.5 so the difference is much bigger than compared to just the tumor itself.
26 Oct 2016, 12:18 PM

http://tinyurl.com/hhg...
29 Oct 2016, 11:25 AM
tajd15
If the full data from Phase 3 stays about the same as interim data, we would be looking at similar efficacy and
much better safety. You don't think the FDA offers any sort of approval (such as accelerated approval) based on
the similar efficacy and better safety profile?
26 Oct 2016, 01:03 PM

Authors reply Hazard ratio is .91. If one cardio-AE shows up, that thesis is done, and we're
approaching a population count now that may start to show this.
I'm not sure how equivalency in efficacy will work out since it is designed for superiority (primary endpoint),
given a HR of 0.91.
26 Oct 2016, 01:19 PM
tajd15
Not sure cardio-AE in one patient negates the fact that hundreds of patients have already been treated
using aldoxorubicin without any signs of cardiotoxicity. Would seem irrational for the FDA to ignore that
given doxorubicin has shown serious side effects consistently.
My point is, from a shareholder standpoint, similar efficacy with the much improved safety profile may very
well be enough for approval. I think that needs to be considered to give a fair assessment of this stock
going forward. I am not suggesting bias on your part (I only mention that because other comments have
suggested it), I just believe we may be asking more from Phase 3 results than the FDA will require for
approval.
26 Oct 2016, 04:21 PM

Authors reply Is it that much improved? Do we have the real data from interim? The quote is strange:
"Aldoxorubicin was not associated with clinically significant cardiac, kidney or liver toxicities."
>Clinically significant
Does that mean it was not significantly different than Doxo?
Why don't they comment on whether there were toxicities in the doxo arm?
I see your point, but I'm prone to believe that if the safety were the best aspect (and showed equivalency
to doxo) the company would be structuring it differently as well as reporting on it differently.
26 Oct 2016, 05:02 PM
D-inv
Phase III trial is ongoing, not concluded. Perhaps you have assumed your conclusion?
26 Oct 2016, 01:05 PM

Authors reply "Perhaps you have assumed your conclusion?"
What else would I do with it?
26 Oct 2016, 01:11 PM
D-inv
Reach it on merits rather than assume it and collate argument to support it?
26 Oct 2016, 01:28 PM

Authors reply That's what investing is... Assuming a conclusion.
26 Oct 2016, 01:29 PM
D-inv
Investing is assuming a conclusion? Hog wash! Assuming a conclusion and colating convenient 'facts' in
support of the conclusion after the fact is confirmation bias in action.
26 Oct 2016, 03:57 PM

Authors reply Investing is always an assumption.
First you said to reach my conclusion on merit, and now you are discounting the process of collecting
facts.
You cannot go into the future and collect facts, so how do you suppose I gather them instead?
Facts are facts. You're free to dispute them, or write your own article.
26 Oct 2016, 05:04 PM
D-inv
"You cannot go into the future and collect facts, so how do you suppose I gather them instead?"
Objectively, i.e. - without guidance from a predefined destination.
26 Oct 2016, 07:01 PM

Authors reply So how do you suppose we do things?
26 Oct 2016, 08:34 PM
D-inv
As I read the article, you decided on the destination and looked for facts leading one there. Nothing you've
said since convinces me otherwise.
27 Oct 2016, 02:57 PM
Tumblebug
Is that not what a hypothesis is?
28 Oct 2016, 11:56 AM
Tumblebug
D-inv - please disputes the facts that were presented rather than jumping to a predetermined conclusion
(as you are accusing others). Give us some technicals, some science, rather than conjecture.
28 Oct 2016, 12:00 PM

D-inv
Cytrix's phase III CT of Aldoxorubicin continues is FACT, a fact which contradicts the conclusion as leaped
to by the author that the drug failed. Thus, I dispute the author's conclusion with fact.
You might consider working on improvement in reading comprehension and logic before challenging
further.
28 Oct 2016, 06:52 PM
ChennyBritt
I was long this company this summer and got crushed. I ignored all the warning signs and if it wasn't for a timely
hedge, would've lost a ridiculous amount of money. As a general rule of thumb for us retail investors, stay away
from these microcap biotech companies. While a few of them succeed (CPXX being the biggest example), most of
them are crap and their market caps are low for a reason. You don't think smart money (hedge funds and big
pharma) is always scouring the field for promising technologies? They have access to KOLs all across the world.
They have infinitely more resources than the average retail investor. If they pass on a technology, it's probably
crap. For those of you who are long this stock, you may see some cherry-picked positive p2 results soon. Still,
good luck. I've learned my lesson. Great article btw.
26 Oct 2016, 02:00 PM

Authors reply And that is why we write. The public doesn't have access to a lot of that knowledge
produced by massive funds, nor is the general investor able to truly evaluate biotech on a deep level.
So we try to bridge that gap.
26 Oct 2016, 03:03 PM
Plus, the CEO refused to use moisturizer. Big red flag...
26 Oct 2016, 03:12 PM
tomale
Great write up. Hope and options are alli have left on this one. What are your thoughts on the clinical hold patient?
I believe he had acidosis, and it must have cleaved quickly...
26 Oct 2016, 03:09 PM
elmono
I am not the greatest fan of Cyrtx right now, for various reasons. However the biggest point that seems to
be overlooked/hardly touched upon in the whole analysis, is the albumin based carrier system for drug
delivery itself, and its benefits. The biggest advantage being that albumin allows for selective delivery of
drugs to tumor tissue (and inflamed tissue). This benefit goes beyond the benefit of choosing the right
linker technology to further fine tune the release mechanism of doxorubicin. I do however admit that I do
not know the exact pharmokinetics of the release mechanism. It may well be that it is indeed a slow
release mechanism, the point however being that much more of it is targeted to tumors than to healthy
tissue due to the albumin..........which means that less of it is released in healthy tissue than in tumor
tissue, slow or not.........
To put it all in a bit of a perspective, I found a nice write up, that is very informative to all interested in the
merits......
http://tinyurl.com/jbh...
Cheers.
26 Oct 2016, 05:07 PM

Authors reply Thanks for the article.
Apparently as outlined in the article there are (were) only two (one?) other companies pursuing covalently-
linked albumin drugs.
Both seem to be discontinued.
Conjuchem no update since 2011, AccessPharmaceuticals 2006.
26 Oct 2016, 05:20 PM
elmono
Apparently, although the author may have worked from outdated info (stating that aldoxo is in PI seems a
bit outdated at least).....
Surely not a lot of companies pursuing the same route as Cytrx, although quiet a bit seem to leverage the
benefits of albumin as carrier system...........
26 Oct 2016, 06:00 PM
wlson
Thank you for the link to the Article, really impressive.
26 Oct 2016, 06:35 PM
D-inv
thanks for trying, but the link provided takes me to a MicroSoft online store. Not interested in anything
there.
26 Oct 2016, 07:18 PM
offsitehelp
The link worked for me. Interesting, if not a little eye-glazing. Good info all the way around in this thread.
Holding shares but not buying any more.
26 Oct 2016, 08:19 PM

Its a common topic but you have to have about 4 semesters of biology before it gets discussed ad nosium
27 Oct 2016, 02:33 PM
Bigdaddio45
Good article but I would point out, while not a biochemist, I am a chemist and once worked for a company that
specialized in themoset acid catalyzed reactions. You'd be surprised at how tight a pH range you can cleave a
blocker. In regards to this specific molecule, I couldn't guess but I'm sure the company knows exactly what pH it
will cleave and this can be adjusted based on the chemistry. Giving a range of hydrazide derivatives and saying
this is similar because it is also a hydrazide is like saying all carbohydrates are the same. It just isn't so. No
position in the stock, just doing a little reading on some stuff that showed up on my screen.
26 Oct 2016, 09:11 PM
seekingmark
So you spend 10 hours plus on a negative article for no reason @ all .....Something smells fishy here ....
27 Oct 2016, 12:03 AM

Authors reply Are you in a room with fish?
27 Oct 2016, 12:41 AM
Scrying Biotech, Contributor

Altum Research:
This article is well worth the read if only for the citation from 2006. Investors would have appreciated your work
more had it been published weeks before the phase-3 readout.
Nice work though.
Michael
27 Oct 2016, 01:31 AM
neonglow
Altum: thanks for your article. You present an interesting take on this, with some good points. But as commented
above, I don't think this is all dependent on blood pH and Warburg effect.
Questions for you and others here:
1. The albumin targets to the tumors, I think, but the mechanism isn't clear to me. Maybe just due to accumulation
of serum due to vascularization or mdscs? Anybody clear on this?
2. My sense is it's unlikely doxo is more efficacious at similar dosing, but less toxicity seems plausible. In this case,
drug dosing could be higher or treatment longer and thus ultimately more efficacious overall. Can anyone
comment on whether the company did an escalation dosing and how that plays int this phase 3?
Thanks
27 Oct 2016, 02:37 AM

best article on the subject that I can find to date
27 Oct 2016, 02:32 PM
apdamico
Thanks for your contrarian view, it actually boosted the stock price.
27 Oct 2016, 11:09 AM

Authors reply Not the chart I'm looking at. And we don't really care what the price is.
27 Oct 2016, 11:42 AM
apdamico
Same chart I'm looking at since your article and the price is up.
Sure you don't care about price lol. BTW, that's me making you buy at higher prices. I won't allow it to go
back down to $.45.
27 Oct 2016, 12:25 PM

Authors reply Ok.
27 Oct 2016, 12:46 PM
apdamico
I thought you'd like that comment!
Fact of the matter is most of these small Bio Tech firms are nothing more than research scams. The only
one's getting rich are the board members each year. Some companies do happen to stumble onto some
ground breaking treatments, but most simply keep kicking the can down the road for as long as possible.
In this company's case, they've been around long enough to construct Kriegsman's vacation retreat in
Freiberg, Germany.
27 Oct 2016, 01:38 PM
wlson
What i don't quite seem to understand is why there are two doctors, one being a neurologist and the other
a biotech specialist, with over 30 million dollars combined in shares in this stock. Do you grasp the Idea?
two very knowledgeable people in this for more than 4 years for a total of 30 million?
think about it...
27 Oct 2016, 04:20 PM
apdamico
I have and hence my comment. It's much longer than 4-years. I know I was in the stock when I used to live
in HI and that was 2002.
Board members latch on to a couple researchers and they are the ones making all the money and milking
the system.
Once the election is over and the new year starts, if Bio Tech stocks go up, so will this stock.
28 Oct 2016, 01:25 PM
japasiamerica
Shiela Olson wrote an interesting piece on CYTRx for Investopedia:
What the ESMO presentation showed

Heres where the data gets more interesting. Of the 36 patients who were evaluated, 13 had a partial response to
aldoxorubicin (39%) and 22 had stable disease (61%). Only one patient in the study showed progression.
More importantly, however, the study revealed that no dose-limiting toxicities were reported, either in the cohort
receiving the 170 mg/m2 dose or the higher 250 mg/m2 dose. In addition, 17% of the patients tumors shrunk by
50% or more, in some cases making them suitable for surgical resection. Another 56% saw their tumors shrink by
20%.
Overall, the findings indicate that 96% of patients treated with aldoxorubicin saw no no progression of their disease
during the trial period.
Read more: What CytRx Latest Trial Results Really Mean (CYTR) | Investopedia http://tinyurl.com/gle...
27 Oct 2016, 11:11 AM

several conditions in nature result in an extracellular pH lower than 6.4. osteoclast pH is an example creating a
microenvironment of 5.0 to 5.5. tumors often are measured with acid indicators such as bcecf or non methyl ester
derivatives and are frequently shown to have microenvironment and environments between 6.0 and 6.5. bear in
mind your paper skewed the range to 6.4 and higher. although there is going to be some variability in acidity based
upon a multitude of effects, it is accepted that 6.0 to 6.5 is the rule of thumb for tumors. see ref:
http://tinyurl.com/jcw.... it doesn't sound like a lot but a ph of 7 is 10 x less acidic than 6.0. So by this logarithmic
scale 6.0 is 4x more acidic than 6.4. So I'm not sure there is much about this paper that holds water, especially
given that the cyclo reaction derivative would be displaced once protons are available to create the dox reactive
species. still the data between sts subtypes could lend support for your thesis if more acidic subtypes respond
more robustly
27 Oct 2016, 10:22 PM

Authors reply Your reference cites this paper for the 6.0-6.5 range
http://tinyurl.com/jqk...
I'll let you look at the pHs they test.
28 Oct 2016, 10:52 AM

Cancer research 2012; 72:2746-56. "Here we report that lowering the microenvironmental pH to values
that characterize tumor masses (6-6.5) was sufficient to establish an aneroid state..."
28 Oct 2016, 11:10 AM

anergic
28 Oct 2016, 11:11 AM

common knowledge in biology but u r a chemist so u r excused it's an extinct field unless aldox is
approved in which case it's revived
28 Oct 2016, 01:50 PM

In addition, excessive CO2 release caused by altered glycolysis leads to increased tumor expression of carbonic
anhydrase IX (CA-IX), thus contributing to further acidification of the extracellular tumor environment (8, 9).
Hypoxia also activates the hypoxia-inducible factor (HIF) pathway, which in turn upregulates glucose transporters
and CA-IX and leads to additional exacerbation of tumor acidosis (8). As a result, the extracellular pH can drop to
values of 6.0 or less and is on average 0.2 to 1.0 units lower than that of normal tissues (10, 11).
28 Oct 2016, 11:14 AM

Nat Med. 1997 Feb;3(2):177-82.
28 Oct 2016, 11:18 AM

However, in diseased tissues such as the tumor microenvironment a local pH range from 5.5 to 7.0 is not
uncommon (Vaupel et al., 1989; Gatenby and Gillies, 2004). Moreover, intracellular pH of tumor cells is slightly
alkaline in comparison to the extracellular space, which has been demonstrated to facilitate cell proliferation and
tumor growth (Tannock and Rotin, 1989; Vaupel et al., 1989; Griffiths, 1991; Griffiths et al., 2001; Webb et al.,
2011).
28 Oct 2016, 11:39 AM

wike-hooley et al. microelectronics range range of pH in both human and rodent malignant cells 5.8 to 7.0
30 Oct 2016, 10:56 AM
R2G2
Seems like everyone is missing the forest through the trees. Is not the ultimate goal to replace Dox with Aldox
based on how much more patients can take during chemo along with being less toxic and harmful. Who cares
about all the "basic chemistry of pH sensitive linkers".
02 Nov 2016, 01:07 PM

elmono
Actually the P3 STS study's primary objective is to show superiority to SOC.
If this is not conceived, question is what will be required by the FDA to achieve approval on another basis,
if feasible. Lot's of other articles about this....
This article is clearly written with a focus on the moa of aldoxo and (indirectly) whether the moa makes it
likely that it can achieve superiority over dox, and not so much with a focus on better tolerability and less
severe AE.
02 Nov 2016, 01:27 PM
tajd15
Agreed, though I wonder if superior efficacy was required because of the Special Protocol Assessment? I
don't see FDA turning down a drug with similar efficacy and better safety that would replace a drug as
common as doxorubicin.
02 Nov 2016, 03:52 PM
elmono
The spa is pretty much a blueprint for approval, if you follow the agreed protocol, and the primary
endpoints are met, and there are no unexpected safety concerns.
If these primary endpoints are not met, or if the protocol is not followed, all bets are off.
This pretty much means that you would have to plead your case in front of the FDA based on the data
available. This can go either way, as I don't think the FDA has a good track record for predictable
decisions.
The risk for investors of this scenario (pleading your case on for instance an improved safety profile), is
that we do simply not know the safety data right now. Aldoxo is not only being compared to doxo but also
to other SOC, and there is no way of being sure about the outcome of this comparison. What we do know
is that in the P3 there is a prolonged dosing of aldoxo as compared to the P2. We also know that in the P3
aldoxo may be provided to patients that were treated before with doxo. There is very limited data on the
treatment effect of doxo followed by aldoxo. What appears to be an established fact is that the risk of
cardio myopathy increases with cumulative dosing of doxo. What we don't know is the effect of prolonged
dosing of aldoxo on top of prior doxo treatment.
In my opinion there is still a lot of uncertainty on what the data will reveal. If data reveal that there is no
path to approval, I have said this before, the sp will easily drop to the low teens, as it may be assumed that
Hercules will then recall the loan.
If there is a narrow path for approval, of course the sp will rise, although cytrx will need additional funding
for further developing its clinical programs and for commercialization. As Hercules will probably not recall
its loan then, in my opinion, the company has bought itself time to negotiate a licensing deal.
There is also a (slim) chance that the primary endpoints will be met. When that happens (a small small
chance in my opinion) the sky is the limit.....
02 Nov 2016, 05:09 PM

superior efficacy achieved, as previously described
05 Dec 2016, 05:34 PM
wlson
Hello based on what the FDA GUIDELINES SAY:
And If There is No Significant PFS Difference?
If PFS is statistically significant ("SS"), aldoxorubicin would very likely get full approval, aka 'regular approval'
("RA"), for 2nd line STS - and possibly even if not - but if it is not SS and if they cannot get RA, there is a good
chance that aldoxorubicin would be granted accelerated approval ("AA") instead.
Where there is an unmet medical need, FDA exercises greater flexibility of judgment. EMA also has expedited
programs to meet these needs. But what determines whether or not there is an unmet medical need?
FDA defines unmet medical need as "a condition whose treatment or diagnosis is not addressed adequately by
available therapy." Priority medicines for Europe focuses on conditions for which some treatments exist, but the
delivery mechanism, or formulation may be inappropriate for the target patient group and conditions for which no
effective treatment is available.
Both of these definitions fit the current treatment landscape for 2nd line STS. Let's focus on FDA's.
A condition whose treatment or diagnosis is not addressed adequately by available therapy. An unmet medical
need includes an immediate need for a defined population (i.e., to treat a serious condition with no or limited
treatment)...
So what's "available therapy?" Available therapy is a viable treatment approved for the indication in question.
There could be some argument over whether or not 2nd line STS even has "available therapy" as defined by FDA.
If not, then:
1. Where There Is No Available Therapy
If there is no available therapy for a serious condition, there is clearly an unmet medical need.
That could be the end of the story as to whether or not 2nd line unresectable STS presents an unmet medical
need (it's obviously a "serious condition"). The only approvals specific to STS are for 1st line (doxorubicin) and 3rd
line (eribulin and trabectedin). There is no recognized, FDA approved 2nd line therapy. Just a lot of off label use.
But let's continue on with the FDA guidance to find out how they define an unmet medical need when there is
available therapy. I will put in brackets whether or not the mention could possibly apply to aldoxorubicin for 2nd line
STS, and consider "available therapy" to mean any of the five in investigator's choice:
2. Where There Is Available Therapy
When available therapy [investigator's choice] exists for a condition, a new treatment [aldoxorubicin] generally
would be considered to address an unmet medical need if the treatment [aldox]:
Has an effect on a serious outcome of the condition that is not known to be influenced by available therapy (e.g.,
progressive disability or disease progression when the available therapy has shown an effect on symptoms, but
has not shown an effect on progressive disability or disease progression)
[No]
Has an improved effect on a serious outcome(s) of the condition compared with available therapy (e.g.,
superiority of the new drug to available therapy when either used alone or in combination with available therapy
(i.e., as demonstrated in an add-on study) )
[Yes, via ORR, and possibly via PFS, but only if the difference becomes significant]
Has an effect on a serious outcome of the condition in patients who are unable to tolerate or failed to respond to
available therapy
[Yes. Double the ORR in anthracycline fails vs control]
Can be used effectively with other critical agents that cannot be combined with available therapy
[Possibly, but not tested]
Provides efficacy comparable to those of available therapy, while (1) avoiding serious toxicity that occurs with
available therapy, (2) avoiding less serious toxicity that is common and causes discontinuation of treatment of a
serious condition, or (3) reducing the potential for harmful drug interactions
[Yes. No cardio toxicity, despite the compound being an athracycline. And much better safety profile than
gemcitabine+doxetaxel]
Provides safety and efficacy comparable to those of available therapy but has a documented benefit, such as
improved compliance, that is expected to lead to an improvement in serious outcomes
[Possibly, we will have to see how many discontinuations due to unacceptable toxicity in control vs aldox group]
Addresses an emerging or anticipated public health need, such as a drug shortage
[Possibly, as there have been multiple dox and Doxil shortages]
We SHOULD BE GETTNG THE AA!
Steven is in fact correct!
all the longs shall be rewarded as long as management gets us there!

03 Nov 2016, 10:40 AM
wlson
I only needed to write "yes" once for there to be an unmet medical need in 2nd line STS, and for aldox to have the
potential to meet that need as a new treatment option.
So what? So, that means aldox is a candidate for accelerated approval. Even without having to show clear
superiority over available therapy. FDA guidance continues:
In some disease settings, a drug that is not shown to provide a direct efficacy or safety advantage over available
therapy may nonetheless provide an advantage that would be of sufficient public health benefit to qualify as
meeting an unmet medical need.
For example, in a condition for which there are approved therapies that have a modest response rate or significant
heterogeneity in response, a drug with a novel mechanism of action (but comparable safety and effectiveness)
could have the potential to provide an advantage over available therapy in some patients. In such a case, the
novel mechanism of action should have a well-understood relationship to the disease pathophysiology.
In addition, there should be a reasonable basis for concluding that a significant number of patients may respond
differently to the new drug compared with available therapy. Thus, mechanistic diversity, even without a
documented efficacy or safety advantage, could be advantageous in disease settings in which drugs become less
effective or ineffective over time.
For example, infectious disease drugs or targeted cancer therapies with novel mechanisms of action, although
appearing to have efficacy similar to available therapy across the disease population, could benefit patients who
no longer respond to available therapy. Accordingly, FDA intends to consider a range of potential advantages over
available therapy beyond those shown in head-to-head comparisons.
03 Nov 2016, 10:42 AM

Authors reply good research
03 Nov 2016, 04:45 PM
elmono
http://bit.ly/2eGEsVk
The above is a good example of AA, allbeit in 1st line STS. I wonder whether Aldoxo meets any of these
criteria.................
Cytrx management to blame for not having persisted in having a trial design wherein aldoxo is exclusively
compared against doxo. This would have greatly enhanced the probability of a successful outcome, and it
would have meant for the trial design to simply exclude pts with prior anthracycline use from participation.
Such cleaner design would have meant less worries about:
- drug resistance (doxo followed by aldoxo)

- accumulated dosing of anthracyclines leading to potentially higher risk for AE
I am afraid that the current trial will generate a very messy picture. Of course subgroup analysis can be
done to clean up the picture, but will the se subgroups provide enough statistical power to warrant
approval for a more limited indication..........th... the question.
All in my opinion of course.
04 Nov 2016, 09:12 AM

The reason for not using doxo alone have been discussed by CytRx as:
- FDA encouraged (=forced) them to do so ...
17 Nov 2016, 03:28 AM
elmono
I know and it is a ridiculous excuse. Moments like these define the company. Separate the boys from the
men. How is it that other companies are allowed to test their compounds against doxo alone and cytrx
would not be allowed to test aldoxo against doxo, in strong contrast to the p2. Doesn't make sense now,
does it?
17 Nov 2016, 04:41 AM
tajd15
If the FDA required it, not sure what Cytrx is going to do about that other than comply.
For all we know, the FDA plans to pass it just based on safety alone (assuming efficacy is at least similar)
and thus wanted to see it against more than just doxo.
17 Nov 2016, 11:34 AM
elmono
I am not sure if it required to follow FDA guidance. You may just not get the spa. However what is a spa
worth if the FDA guidance is a recipe for failure?
And I am not sure the FDA is ready to pass this just on safety at all. Remember there is a dox combo just
approved that is far better than dox alone.
"Patients in this trial who received Lartruvo with doxorubicin had a statistically significant improvement in
overall survival: the median survival was 26.5 months compared to 14.7 months for patients who received
doxorubicin alone. Patients who received Lartruvo with doxorubicin had a median progression-free survival
of 8.2 months compared to 4.4 months for patients who received doxorubicin alone. Tumor shrinkage was
18.2 percent for patients who received Lartruvo with doxorubicin and 7.5 percent for those who received
doxorubicin alone."
I assume the FDA would consider all treatment options available (including the latest approved combo)
when making a decision on allowing an additional drug that is not based on the spa agreed primary
endpoints.
Even when allowed in the market, if given the choice between this combo and aldoxo, I am not so sure
what patients would prefer. Such combo may easily outperform aldoxo as well on mPFS or OS. Hence
even assuming a somewhat improved safety profile for aldoxo that would be a tough choice to make.
And as far as providing aldoxo to pts that received doxo in 1st line, I am not sure if they can even get that
label, as it would mean competing with other 2nd line options available. That subgroup analysis may not
be so favourable I am afraid.
23 Nov 2016, 10:22 AM
tomale
I think the company pushed for standard of care, so the FDA said beat everything else. And the company
was wrong.
23 Nov 2016, 11:31 AM
corbitt
Bottom line is the company in the last couple of years has settled one lawsuit and is involved in a 2nd. Both are for
misleading investors, which I was one. This company has enough cash for two more qtrs at best. They have
nowhere to turn to for additional cash and no significant breaking news due in that time period. Filing for
bankruptcy is inevitable.
03 Nov 2016, 07:42 PM
seekingmark
I thought they had $75 million in cash ....
04 Nov 2016, 09:00 PM
Jim in SoCal
Per the last corporate presentation, they do.
05 Nov 2016, 02:32 PM

tomale
Has the company defined what statistical superiority is? Is it >1 month compared to "placebos"? Or just p value
less than .05?
23 Nov 2016, 11:58 AM
Anthony Cataldo, Contributor

Nice news this AM. AJ
29 Nov 2016, 08:11 AM

Authors reply When you delete 17% of your treatment population to gain statistical significance, I guess
it can be spun as good.
29 Nov 2016, 10:04 AM

You know, I have actually seen top line academic journals publish articles like this, where the footnote
explains the "fraud," when faculty authors are pals with the editor and need the publication for tenure and
promotion. Saw one, years ago, where they extracted far more than 17%. Wish I could recall. Accounting
Review article. Anyway, that's life on Wall Street. Stay well and preserve capital. AJ
29 Nov 2016, 10:09 AM
They did not remove 17% of the treatment population... They removed some of the other diseases in the
trial to achieve a highly statistically significant result (p < .007) with n=246, versus n=433 in the entire
population. There must be something in the other diseases that makes the treatment unworkable.
29 Nov 2016, 04:19 PM
agent frog
The hazard ratio for the entire study was .81. Your comment shows a bias.
29 Nov 2016, 06:03 PM
agent frog
Unworkable no. Just not as good.
29 Nov 2016, 06:04 PM
"Unworkable as a better option".
29 Nov 2016, 06:06 PM

Aldox is certain to get approval now.
29 Nov 2016, 05:48 PM
wlson
hey steven
lm really glad you are finally are right and unprofessional people like this author cant bash your work
anymore. you where right all along and now its proven. l want to thank you for your work. ln all this mess
you kept me believing. when do you think the SP will bounce back?
Cheers!
29 Nov 2016, 07:04 PM
Crazy price action, isn't it?
29 Nov 2016, 07:14 PM

Authors reply HR of 0.81 and removing a large population to gain significance. Not things the FDA
likes.
Maybe approval after another P3. Hope you didn't buy in pre-market.
29 Nov 2016, 07:58 PM
agent frog
Altum - You couch your comment as if the HR of .81 is part part of a population removal. It needs to be
repeated once again as I posted before that .81 was the total trial and not a subset of the trial. The subset
rightly featured in the press release was an HR of .62. The HR of .81 for the total trial is statistically
significant.
29 Nov 2016, 10:46 PM
tio1234
Why do you think the stock remained essentially flat despite this apparently excellent news?
30 Nov 2016, 02:02 AM

Hey wlson,
Well, I feel like I'm half right lol. But the end result is essentially the same. I'm writing an article now, but
what the market is overlooking imo is that lipo and leio were pre-specified subgroups, and are major
subtypes of sarcoma. They represent somewhere around 60% of all patients. Two recent approvals were
in lipo only (eribulin) and lipo an leio (trabectedin). And the funny thing is, the subgroups were much
smaller than in the aldox P3, and trab even FAILED its primary endpoint in that subtype (overall survival),
but made it in its secondary ep (PFS). It was approved on secondary. And rather than tested against an
array of chemos, it was only pitted against dacarbazine, which is relatively weak.
Aldox is clearly superior. FDA will also like that the overall North American pop was stat sig. I've seen that
cause problems for drugs getting approval the other way around, where the overall pop was stat sig, but
the EU was not. EMA didn't like that.
Where there is no SOC there is great flexibility and eagerness to approve on FDA's part. See my prior
approval examples in my last article.
Cheers
ps I think we'll get a run up into Q1 as funds realize the import of these data, and then a nice pop on pre-
NDA information (FDA giving positive feedback on filing NDA). That's Q1, maybe March-ish.
I bought a bunch more on the pullback yesterday. Will be sitting tight on those for a while. Maybe unload a
few after pre-NDA meeting. Buyout also possible here, but not before a solid run-up imo. What's really
valuable about aldox is the off-label use. It can get staggering. Doxorubicin is used everywhere.
30 Nov 2016, 08:08 AM
elmono
"Where there is no SOC there is great flexibility and eagerness to approve on FDA's part."
Lartruvo is now SOC and superior to all other treatments so far.

Forget the discussion about 1st or 2nd line:
- it is indicated for use when no prior anthracyclines have been provided. This can be 1st or further line
therapy.
- if given choice between Lartruvo combo and Aldoxo, guess what will be the choice?
- Aldoxo has most potential if doxo was 1st treatment (as it would than not have to compete with Lartruvo
in 2nd line), however:
- is there a subgroup analysis specified in the spa related to this pts population? and if so: are the results
in this group favorable to warrant an approval?
That is the question
30 Nov 2016, 10:39 AM
A mischaracterization. It was up 50% and is now down 8% from initial levels
30 Nov 2016, 01:03 PM
tio1234
Steve, thanks for your very helpful articles. I'm totally confused as to why CYTR has been doing so badly
today despite the very good news yesterday. Any thoughts?
30 Nov 2016, 03:11 PM
D-inv
Adam Feuerstein sour grapes article (http://tinyurl.com/z2h...) plus tax loss selling?
30 Nov 2016, 03:54 PM
A number of companies have had very good news come out with the stock price later imploding.
Who knows why. Retail has been sheared constantly this year by moneyed HFTs.
It doesn't help in this particular case that the management isn't trustworthy.
30 Nov 2016, 06:38 PM

Elmono, Lartruvo is an adjuvant given with dox. And it's for first-line. Aldox is vying for refractory (2nd and
more advanced lines). There is NO SOC for this indication.
There is no "Lartruvo vs Aldox" decision that will have to be made, except for those docs who may decide
to use aldox+lartruvo as an off-label option instead of dox+lartruvo. That might happen more often than
you think. But the Lartruvo accelerated approval does not get in the way of aldox's forthcoming approval in
the least.
Apples an oranges my friend.
01 Dec 2016, 07:30 AM

tio1234
Basically the market doesn't understand the import of pre-specified analyses, nor the flexibility and
eagerness to approve that FDA exhibits where there is no SOC.
Look at topotecan for 2nd line SCLC. There was no SOC at the time it was tested against the most
commonly used triplet chemo regimen, which was at that time being prescribed off-label. How did it do? It
proved equal in efficacy, and much better in safety. Was it a non-inferiority trial? NO! It wasn't. It was a
superiority trial. What did FDA do? Grant topotecan full approval. I repeat, it FAILED the study. Why did
FDA do that? Because there was no SOC. Think of it like an empty slot. FDA is eager to fill empty slots.
For 2nd line STS, there is an empty slot.
Then look at Eribulin. That was approved for liposarcoma only. How? Because the study had analysis of
lipo and leiomysarcoma as pre-specified. That means in study design, alpha was allocated to the analysis
of these, and their randomization was stratified. In that study, only about 100 patients were of that subtype.
But they did well on Eribulin. FDA then granted full approval to eribulin for that subtype and who have
failed an anthracycline.
So that's what the market doesn't get. They think this is just another post hoc data-dredged analysis put in
a PR to soften the blow of the bad news. It's NOT.
I'm loading the boat :)
GL
01 Dec 2016, 07:50 AM
elmono
LARTRUVO is a platelet-derived growth factor receptor alpha
(PDGFR-) blocking antibody indicated, in combination with
doxorubicin, for the treatment of adult patients with soft tissue sarcoma (STS) with a histologic subtype for
which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment
with radiotherapy or surgery. (1)
Do you see 'exclusively usable as first line' in the above approval package? I don't.
Furthermore Lartruvo is approved under AA as a combo with doxo. For argument sake, if what you say
were to be true, and it would be only officially allowed 1st line (e.g. before any other chemotherapy), then
surely any off-label use in 2nd line will also be the combination of Lartruvo + dox only. The combination
Aldoxo + lartruvo has never been tested in any indication, which makes it a no-go area 'as such'.
Such combination would thus proof to be a formidable competitor to aldoxo alone (if the latter ever makes
it to the market), which is good for pts, but no good for Cytrx.
Of course the easy and cheap, although of little merit, argument is to say: 'apples and oranges', where
there is, in any comparison, always a difference to be found.
01 Dec 2016, 09:22 AM

elmono
Good luck with loading the boat. Better hope Hercules doesn't pull out ;-)
01 Dec 2016, 09:24 AM
buy_low28
Steve I would like to hear your thoughts in response to this comment
03 Dec 2016, 12:20 PM
buy_low28
There are many drugs on the market that aren't necessarily better than its predecessors. It's hard to see a
situation where you can have another effective option to treat cancer not be approved.
03 Dec 2016, 12:59 PM
buy_low28
It looks like the loan should be extended by 6 months of interest-only payments and the next 15 mil is to
be paid if they begin a clinical trial on another new drug candidate by 12/31/16
03 Dec 2016, 04:21 PM
Rociletinib? Ended up potentially better than Tagrisso once data was more fleshed out, but Clovis had to
can the program since it couldn't afford the regular approval process. The short-sighted advisory
committee KILLED PEOPLE by not recommending accelerated approval.
04 Dec 2016, 08:25 PM
Simon/bags -- why are you repeating AF's trash? The subpopulation had a p value of less than .007. You don't run
another trial with this p-value.
30 Nov 2016, 04:36 AM
elmono
I am sceptical the FDA will grant approval based on the subgroup analysis, unless it was part of the pre-
agreed spa.
Furthermore the voices around a possible AA based on an improved safety profile are silent now. I guess
that didn't work out....
My suspicion, awaiting confirmation, is that in the 'selected' indications, patients were less pretreated with
an anthracycline, than in the other subtypes. That means that these patients would either have received
(predominantly) doxo, or alternatively aldoxo.
In such subgroup, as I said before, aldoxo stands a better chance, as the patients that have become
resistant to prior doxo treatment (and would thus not respons as well to aldoxo), have been filtered out.
I didn't listen to the cc yet, so this is the hypothesis.
30 Nov 2016, 04:54 AM
The SPA does not bind the company to not doing a regular accelerated approval request. Further, it will be
a different FDA in 2017.
30 Nov 2016, 06:03 AM
Oh and yes the analysis was pre-specified; not sure if that was part of SPA but I assume it probably was.
30 Nov 2016, 06:10 AM
elmono
It doesn't bind it. however deviating from the spa significantly decreases chances of success in my
opinion.
I am not sure if a different FDA makes any difference ;-)
30 Nov 2016, 06:43 AM
elmono
The North American subgroup appears pre-specified. I am not sure if the subtypes analysis was
prespecified, and whether it was agreed per spa that meeting primary endpoints in these subtypes would
mean approval based on a limited label (e.g. only for these subtypes).
30 Nov 2016, 06:47 AM
"Pre-specified analyses were based on sarcoma histopathology and geography."
30 Nov 2016, 07:49 AM
elmono
You are right. Now let's hope they had the wisdom to agree per spa that if the primary endpoints would be
met for these prespecified subtypes, that they would be granted an approval (on a more limited label). If
they were only able to confirm that...........I would jump right back in ;-)
30 Nov 2016, 09:57 AM

Elmono,
"The voices around AA are silent" referring to mine? If so, yeah of COURSE, because FULL approval is
now obvious ;)
Stop being so damn bitter. Only hurtin yourself.
30 Nov 2016, 10:29 AM
elmono
Haha you are a funny man. Not bitter at all. Just realistic.......unlike others :-)
Full approval, do not make me laugh so much, it hurts...
30 Nov 2016, 12:56 PM

Authors reply There is no way for full approval with this data. Subgroup analysis might get approved,
maybe, but the FDA is not friendly to this.
Likely will require another P3, I expect a CRL.
AF's points are worthy of consideration - if they weren't, don't you think it the shares would be doing quite
well given "success"?
A buyout is not going to happen here.
What was the one death in aldoxo arm?
30 Nov 2016, 03:11 PM

Subgroup analysis might get approved? First of all, very weird wording sir. Secondly, that IS full approval.
If it gets approved for lipo/leio, that represents over 60% of all STS. Then you also have the MASSIVE off-
label stuff where aldox can replace doxorubicin. Do you know how often dox is prescribed??????
Pre-specified means alpha was allocated. Look at the Eribulin approval closer. And there is no SOC for
2nd line STS. That's a big deal.
These are the granular details the market doesn't get. And I'm going to try to capitalize on that.
01 Dec 2016, 07:54 AM
elmono
There is Regular Approval and there is Accelerated Approval as recognized terms by the FDA. The term
"full approval" does not have a strictly defined meaning, however in the context of this discussion it is kind
of clear, isn't it?
To me it is clear that the trial results do not warrant a broad label that covers all STS subtypes. In that
aspect the trial hopelessly failed (in my opinion that is).
However there may be basis for a more limited label, based on the recent news release.................. all
depends on the quality of the data behind the data, if you see what I mean. So let's wait and see :-)
01 Dec 2016, 09:41 AM
"AF's points are worthy of consideration"
What points? Did he make a point? I didn't see any.
01 Dec 2016, 02:53 PM
tajd15
Truthfully, Altum Research, I have given you the benefit of the doubt as an objective bystanders, but it has become
continuously difficult to see you as such.
Can you expand upon your reasoning for stating there is no way for full approval with this data and the FDA not
being friendly to approving subgroups?
As for AF's points... I honestly thought he should be embarrassed that the article has his name at the bottom of it.
30 Nov 2016, 04:35 PM
AF beyond embarrassment at this point... has been for years. CLVS at $36.
01 Dec 2016, 02:53 PM

Authors reply Aga, if that were the case, the market would ignore his articles.
Tajd, for full approval CytRx would have had to have passed the original phase 3. Passing the secondary
readout with a subgroup is not 'full' approval. That is obvious. That would still be a worthy investment, if
that were a likely scenario. I do not believe it is.
I don't have anything to gain or lose in this except credibility. We have made (I believe) a case that
aldoxorubicin is simply slow-release doxorubicin, hence it shows efficacy, but we still have significant side
effects. An HR of .81 in the total pop clearly indicates that there are off-target effects and the drug is not
simply *only* accumulating in the tumors.
I don't like this company and to be honest I would put little trust in any results they put out unless it is
absolutely clear that the drug works. An "almost" significant finding is obviously not going to sway me, and
looking at a subgroup (even if prespecified), without any mention for reasoning or rational behind it, makes
me question how they came up with the pre-specification.
This company is not transparent, and given their dire situation and stock price, they most likely would be if
in fact they had great data.
02 Dec 2016, 12:20 AM
agent frog
There is another name for what you call prespecified subgroups. They are called " primary endpoints". As
for the reasoning or rational for the "primary endpoints" you could ask someone who has one of the 2
primary cancer types or you could ask the FDA why they wanted them. Seems obvious to me. You are
correct when you say that this is an opportunity for you to gain or lose credibility.
02 Dec 2016, 05:48 AM
Again, CLVS at $36.50... got shorted into submission by AF and JC (another paid basher) $12 earlier this
year. $12!
The market is starting to ignore his articles. He penned an AERI article and the stock went up. His short
buddies got bullied by multiple long hedge funds into submission on that one.
I would like to understand why it worked better in those subgroups as well, and I would like to see the SPA
to see if they really will get approval based on subgroups in a guaranteed fashion. I don't trust the
company, but the subgroup results are not in question at this point.
One thing that isn't really a question for me is that AF consistently writes trashy articles, devoid of content
or analysis... so again, beyond embarrassment.
02 Dec 2016, 10:33 AM

Authors reply Aga: what's the last bearish article you read that you thought was informative?
02 Dec 2016, 06:00 PM

The problem is that bearish points of view are very easy to describe, because you only need one problem.
Thus, there aren't many legitimate articles on it (no offense). There isn't much meat that is needed. And
those who do write such articles typically just write *much more* than perhaps needed -- no offense again.
Edit: For the record, I did think your article did bring up an interesting potential problem and point of
discussion, but it wouldn't convince me to short, for example.
An example of a succinct bearish point of view:

http://seekingalpha.co...
Ta-da!
02 Dec 2016, 06:03 PM

Authors reply That's quite there opposite, bullish points of view are the easiest to create because every
company will supply you with them. Bearish stories are always harder by nature.
03 Dec 2016, 03:12 PM
seekingmark
Looks like the author is wrong ....CYTR followed and did just as the FDA ask then too ....
02 Dec 2016, 10:22 AM
longJohnp7
The one death was the result of an oncologist who pleaded with Cytrx for compassionate use but mistakingly
misdiagnosed his OWN patient for acidosis.
19 Feb 2017, 11:08 PM
Comments (179)
matratra
You may not have position but stock can be shorted for some other interest.
26 Oct 2016, 10:58 AM

Authors reply No one has contacted us to write this. We simply wrote it for the sake of what it is.
26 Oct 2016, 11:01 AM

I finally read this. It's absurd.
A simple question you should be able to answer simply with all the simple chemistry you simply
understand so well:
How did 85% of patients with Kaposi's sarcoma experience a partial response or better (CR) to
aldoxorubicin as a *monotherapy* if the chemistry is all wrong?
Um.
How was the disease control rate (including ORR) nearly double that of investigator's choice in the P3?
Did you see the waterfall plot of the P2b regarding various tumor shrinkage from aldox monotherapy?
Does that just happen?
What were you saying about pH again?
Thanks.
22 Nov 2016, 08:01 AM

Authors reply The points you hit on are all definitely outlining a strong bullish case. Whether the FDA
will pass this on non-inferiority + better safety is a perspective you can strongly argue for a positive
position in the stock.
Here is some basic chemistry that IS worth considering. What may be happening is not a selective
mechanism of aldoxorubicin, but simply extended, systemic release.
Either way, we'll know soon.
You're most graciously welcome.
22 Nov 2016, 01:24 PM

"What may be happening is not a selective mechanism of aldoxorubicin, but simply extended, systemic
release."
Don't you think you are making all this up?
23 Nov 2016, 12:09 AM

Authors reply No.
Based on the comments on your piece in '15. I think we are done here.
23 Nov 2016, 01:49 AM

You are good at evading questions! Yes, I am done here. Good Luck.
23 Nov 2016, 02:56 AM
RussMaGuss
Ouch. My main beef with this company is their shady "management" team. Kriegsman needs to inform investors of
what's what instead of hiding all of this information behind dust and mirrors, it gives me no consolation that he is
still with the company after all we've been through. Get Kriegsman out and watch this stock go back to $1.75-2 in a
day.
26 Oct 2016, 11:05 AM
apdamico
This CEO has to go, he has ZERO credibility in the industry.
Can't wait to see the RS ratio!
26 Oct 2016, 11:20 AM
argon69
I wish we can remove him with my voting power.
26 Oct 2016, 11:33 AM
Tumblebug
Wow, great research and analysis. It sounds a lot like one on those commercials for an herbal remedy found on
the far end of the AM radio dial. "Take xxx to lower / raise your pH level for better ....."
26 Oct 2016, 11:29 AM
argon69
Good explanation. Now here is my question for you. I am not a scientist so please forgive me about dumb
question. I am only looking at facts. Aldox and Dox will travel through blood. Dox has severe side-effect. Aldox
doesn't. So at least we know aldox is not released/accumulated in heart. Will Aldox ever be released to cancer due
to PH issue? If not released at all, we should know different problems by now. BUT it was released to cancer.
Otherwise, we won't get similar mPFS in P3 trial. Thanks.
26 Oct 2016, 11:32 AM

Authors reply We do not have a solid thesis for the absence of cardio effects. Our best guess is that
cardio AE appears due to the relatively high doses of doxo in the blood, whereas Aldoxo is likely just low,
extended release.
From our observation, Aldoxo seems to be analogous to a low-concentration, extended-release form of

doxorubicin. Perhaps if CytRx publicly acknowledged this it would make the science a bit easier to
understand, and perhaps even attract better data.
26 Oct 2016, 12:42 PM

except for the fact they have repeatedly stated that the studies have delivered much higher doses of dox
and e over 500 patients w no cardio tox don't you read anything? are u sure u know what a PhD is? results
to date demonstrate that aldoxorubicin combined with ifosfamide provides significant clinical benefit for
sarcoma patients," said Sant Chawla, M.D., F.R.A.C.P., the trial's principal investigator and Director of the
Sarcoma Oncology Center in Santa Monica, California. "More than one-third of sarcoma patients achieved
a partial response for the target lesion and 61% had prolonged stable disease. Importantly, six patients
with unresectable tumors achieved greater than 50% tumor shrinkage allowing some of them to become
eligible for surgery. Further, we did not see any signs of cardiotoxicity including in patients that received
approximately 10 times the cumulative maximum dose of doxorubicin."
31 Oct 2016, 06:59 AM

Authors reply We're very glad we've gotten you so involved in the comments section. Good luck!
31 Oct 2016, 11:28 AM
wlson
he is destroying your thesis my friend. Aren't u worried you are misleading investor and posting wrongful
comments?
31 Oct 2016, 05:02 PM

Authors reply He is not and has not. He has cherry picked every comment and quote. If you read the
papers he cites, they do say what he says, but again, these papers make it clear that below 6.4 pH is
extreme. "I guess we'll see".
31 Oct 2016, 05:12 PM

@Altum Research
"Aldoxo is likely just low, extended release" - Any reason to believe so?
Oh well, "our BEST GUESS (!!!) is that cardio AE appears due to the relatively high doses of doxo in the
blood"
Any words on why the Aldox P2 results were very good vs. doxo? Temporary malfunctioning of Chemistry?
17 Nov 2016, 02:12 AM

Authors reply P2 is a lot easier to pass than p3. Temporary wiggle room for efficacy
17 Nov 2016, 11:22 AM
CMK.
i am not surprised of your article, here is 1 posts you made in a prior article :
CytRx completes enrollment in mid-stage study of aldoxorubicin in lung cancer!!!

Comments (183) |+ Follow |Send Message
you invested with Kriegsman. Did you expect different?
that comment shows your lack of objectivity and independence !!!
And you also mentioned about how likely a reverse spit is on its way that also gives me
second thoughts of your contribution.
26 Oct 2016, 11:35 AM

Authors reply We stand by that comment.
Why would a reverse split hypothesis give you second thoughts. Look at the PPS and the timeline.
26 Oct 2016, 12:43 PM
runinwind
Great article, and really excited to see some scientific articles here.
I have a general question for the pH dependence of drug. It might not be fair to use the pH-dependent manner of
some other drugs to compare with the acid-cleavable linker. I don't think drug degradation is identical to linker
cleavage. Apparent, none of the four drugs has any designed cleavable linker and the stability reported was only
for the drug decomposition.
One thing that I agree with the author is I don't have too much faith in this company and I don't plan to invest in this
company.
26 Oct 2016, 11:46 AM

Authors reply 1) Degradation is synonymous with cleavage. The first kinetically favorable "degradation"
of aldoxorubicin would be cleavage to release doxorubicin (or do the intra-molecular cyclization reaction
cited above).
2) We specifically state that these are not identical linkers/functional groups and that they are not directly
comparable to aldoxorubicin kinetics. The point is not a direct comparison, but a general idea of how pH
effects SN2 'cleavage' reactions. The window of ~6.5-7.4 is small.
26 Oct 2016, 12:45 PM
System Trader
You admit the examples you chose are unrelated to aldoxorubicin. There are regions on the charts shown
where a .9 change in ph would result is a significant change in cleavage. What is needed is the chart for
aldoxorubicin, not some unrelated compounds.
20 Feb 2017, 03:03 PM

Authors reply Extrapolation from similar compounds is not unwarranted. It's what most of chemistry is
based on.
Good luck with your long.
22 Feb 2017, 12:17 AM
System Trader
Nothing similar about these compounds and you admit it yourself in the text. I have found a number of
cases where there was significantly different performance of therapeutic substance over the relevant pH
range. Here is a case where topotecan is released at 4 times the rate at ph 6 versus pH 7.4, figures D & E
:
http://go.nature.com/2...
Here is a case where docetaxel is released from a conjugate at a significantly greater rate at pH 6.5 than
7.4:
http://bit.ly/2mpYuqF
These are an on point references to actual antineoplastic compounds unlike your irrelevant references to
aspirin etc.
Also your assumption that I am long is wrong. Interested observer at the moment.
23 Feb 2017, 04:00 PM

Authors reply There's a plethora of acid cleavable linker drug chemistry from the late 90s. You can
look. Perhaps you'll find a reason why most of it never made it to the clinic (or maybe you won't).
02 Mar 2017, 08:20 PM
System Trader
Moving the goalposts now that your thesis has been refuted.
05 Mar 2017, 07:56 AM

Authors reply What was the old goal post and what is the new one?
06 Mar 2017, 02:59 AM
System Trader
old goal post: existence of drugs cleavable at pH range applicable to aldoxo
new goal post: whether they made it to the clinic
10 Mar 2017, 10:56 AM

Authors reply Old goal post: thesis on difficulty of making clinical candidates for pH-cleavable drugs
New goal post: same
There is a reason that there was a surge of pH-cleavable drugs developed in academia in the 90s and that
>95% of those never saw a clinical trial.
Hope is not a good investment strategy.
10 Mar 2017, 05:34 PM
System Trader
Neither is falsifying your actual short thesis:
"you will be pressed to find papers or articles that cite a gradient of kinetics through our range of ~6.4-7.4.
The pH difference of healthy blood (7.4) to that of an acidic tumor microenvironment (>6.4) is not
something that is going to dramatically change the rate of hydrolytic cleavage for doxorubicin!"
I will waste no further time in reply.
17 Mar 2017, 09:49 AM

Paclitaxel-albumin conjugate, abraxane, has been approved for metastatic breast cancer, non-small cell lung
cancer, and advanced pancreatic cancer. It is the most clear example of what you state doesn't exist; evidence
that albumin-linkers/conjug... don't work in humans.
J Control Release. 2014 Sep 28;190:331-6. doi: 10.1016/j.jconrel.2014... Epub 2014 Mar 15.
Clin Transl Oncol. 2013 Jan;15(1):26-32. doi: 10.1007/s12094-012-088... Epub 2012 Jul 24.
Dox conjugates and albumin conjugates don't just bind the surface of tumors, they are also taken in these cells
through endocytosis (clathrin coated pits). There they are released inside the tumor cells in the lysosomal
pathways. Incidentally the lysosomal pathway pH is 5.0-5.5. Because doxorubicin binds DNA, thermodynamics
drives it by concentration gradient to DNA binding sites, not back into circulation. That analogy is like saying if you
release pedophiles near a kiddy pool, they will all go back into the parking lot and disburse to the interstates in
their cars and go home.
Mol Pharm. 2015 Jul 6;12(7):2217-28. doi: 10.1021/mp500386y. Epub 2015 Jun 2.
Biomacromolecules. 2016 Jun 13;17(6):2223-32. doi: 10.1021/acs.biomac.6b0... Epub 2016 May 17.
Cytrx has stated evidence that patients who respond to aldoxorubicin have targeted tumor death because they did
tumor resection surgeries in the kaposi's sarcoma and glioblastoma patients that analyzed this fact (and sts now
as well from phase 2b combo study). Now if you choose not to believe these reports or think they are fraudulent
that is your choice.
Hopefully these elementary concepts will help you and the reader in the quest to understand the mechanisms
described, should there actually be a genuine interest.
26 Oct 2016, 11:48 AM
All very interesting. So that's a much bigger difference .. 7.4 to 5.5. Even if the difference was small
though, all it takes is a steep gradient in the pharmacokinetics.
26 Oct 2016, 12:16 PM

Authors reply 1) Abraxane is not a drug-linker conjugate, it is simply albumin-bound paclitaxel.
Mechanism for 'cleavage' is not comparable.
2) You cite the lysosomal pathway, which is not specific to tumors, and DNA, which is not specific to
tumors. These points would not indicate that aldoxo is specific to tumors. The entire thesis is based on the
extracellular pH near active tumors being acidic, not the endocytosis pathways.
3) We're skeptical anything this company publishes - as you may have guessed. Again, you have to
wonder how fast were these tumors growing compared to basal cell division of the body. You will have a
"targeted" effect with any correct dosing scheme of a chemotherapy drug if the relative rates of cell
metabolism are extreme between tumor/basal. The question then becomes - is your drug better than
others?
You are correct, these are relatively elementary concepts in biology.
26 Oct 2016, 12:36 PM

Authors reply read above comment.
26 Oct 2016, 12:37 PM
System Trader
The article author's attempt to compare cleavage of aldoxorubicin to that of aspirin, methotrexate, etc. is
absurd. He admits: "To be fair, these are different functional groups". Indeed. To be fair, the pH dependent
cleavage of unrelated chemicals is irrelevant.
I am not at all sure CYTR is a winner, but I am sure this article's analysis is invalid.
26 Oct 2016, 12:58 PM

Authors reply We make it very clear these are not direct comparisons. The idea is to look at the pH
window of all these pH-dependent cleavage reactions and realize the difference between ~6.5-7.4 is not
substantial for selectivity.
Title of the article.
26 Oct 2016, 01:10 PM
elmono
Hi Strongbio,
Actually there are articles out there suggesting that the pH is between 4.5-5 inside the lumen.
http://tinyurl.com/zw4...
The pH gradient between blood and such environment is more than enough to devise a linker that is
hardly hydrolyzed in the blood, but is hydrolyzed in the interior of a cell.
In addition the albumin based carrier mechanism takes care of the selectivity between tumor cells and
healthy cells. Is it perfect: no. Does it work: I am inclined to say yes.
Did the company screw up in numerous ways: yes (I can make an easy top ten, don't know where to start).
What does that mean for Cytrx: I am inclined to say there is still a chance of approval in some prespecified
subgroup (the subgroup that did not receive any prior anthracyclines).......... a substantial chance as well
that there isn't a path.
High risk it is....
26 Oct 2016, 05:24 PM

1) mechanism for endocytosis or transcytosis is likely a great model for aldox, thus has many scientific
publications compare the two... Notice I can support my points with publications and facts, as most Ph.D.'s
should know to do. I invite your citations and not just hand-waving, although it is certainly taken as a
friendly gesture.
Journal of Controlled Release vol 190 Sept 2014; 331-6

Mol Cell Therapies 2016 4:3
Int J Nanomedicine 2016; 10: 5327-42
Biotechnol Bioeng 2014 Sep; 111(9): 1699-1716
2) albumin uptake system for abraxane, be it lysosomal or otherwise, provides efficacy for cancer
treatment, in spite of no specificity to tumors or microtubules, likely because cancerous or tumor cells are
in rapid growth and preferentially take up more albumin than a non-dividing cell, Whatever the mechanism
it was thus was approved by FDA after years of testing and trials. If aldox doesn't come unlinked it poses
little harm as dox is not released unless acidic conditions render release. This is one safeguard that
unfortunately abraxane cannot boast. I am not asking you to trust the company with doseage response
curves, I am merely reporting the physicians and scientists work that are doing the studies, some of which
are cited below.
PNAS 2014 Jan; 111(2): E217-26

Invest New Drugs 2015; 33(2): 341-8
Neoplasia 2014 Oct; 16(10): 874-82
So by all means be skeptical of the publications. So let the data speak, but for you to suggest the interim
data didn't pass the SPA implies you don't do much clinical study. To make a long story short we both
know that the interim study diluted out the responder pool of aldoxorubicin treated patients, but why
debate the obvious "elementary" concept in biology when the data will be released this quarter. Thanks for
your discussion. Sorry that you don't trust the company. I hear that a lot during these highly profitable
buyout phases of biotech companies and it gets mundane.
26 Oct 2016, 05:55 PM

Authors reply Every source is correctly cited in the article above. I'm not sure what you're referring to
when you "invite" my citations.
So it looks like your (CytRx's) basis is just the tumors uptake more (albumin) from the blood than other
cells.
That's the basis for all chemotherapy.
I mean I can't bash CytRx for trying this. The amount of academic articles on pH-sensitive chemotherapy
treatments is massive. That is a lot of PhD dissertations through the years.
But in clinical trials, they rarely seem to make it. There are exceptions of course. Maybe your investment
will be one.
We're not betting on it.
26 Oct 2016, 06:29 PM
neonglow
Strong bio: you made the point I was thinking throughout this article: Uptake of the drug into endocytic
pathway is where the pH drop is occurring and allowing the cleavage.
See also my other comment below. Curious to know what your thoughts are.
27 Oct 2016, 02:28 AM

explains how cancer cells or tumors both actively and passively catabolize albumin (and things thereby
attached).
27 Oct 2016, 02:31 PM

http://tinyurl.com/hhg... warburg himself found 6.0 pH was common
29 Oct 2016, 12:29 AM
User 47658440
Why don't you comment on the lack of cardiotoxicity and similar efficacy to dox if you are so unbiased?
26 Oct 2016, 11:55 AM

Authors reply It's a great aspect to the drug!
26 Oct 2016, 12:46 PM
User 14552302
Wow way to pen out an article about a stock that is a failure that failed months ago.
26 Oct 2016, 12:10 PM

Authors reply Apparently to retail investing, a previous failure can sometimes erroneously lead to a
buying opportunity.
Mast Therapeutics.
26 Oct 2016, 12:46 PM
el_paha
On the science part, I feel you are selectively leaving out certain very important facts.
On the "flawed" EMCH-linker in Aldoxorubicin:

- You are substantiating your claim with an irrelevant reference to DOI: 10.1021/bc060117y, since these findings
do not relate to DOXO-EMCH (Aldoxorubicin). Aldox' inventor (Kratz) is well aware of your referenced study.
- How would you account for higher DOXO-concentrations in intratumoral tissue vs pertumoral tissue in 86% of the
patients in the Ph2-Kaposi study?
On DK049:
- You did not address the added moiety preventing deaminase of gemcitabine, and therefor retaining ~90% of the
drug that would otherwise be lost due to cytidine deaminase.
26 Oct 2016, 12:14 PM

Authors reply How is this reference unsubstantiated? It's an obvious comparison. It's an intramolecular
reaction between a hydroxly and a hydrazide.
Higher dox concentrations:

1) How were they measured
2) What's the age of the population
3) How fast were these tumors growing at baseline
4) Was there a comparison to SoC concentrations in tumor/peritumoral tissue in a control arm?
DK049 - Have not researched it. Could be a valid point.

26 Oct 2016, 12:55 PM
el_paha
The referenced studies by DOI: 10.1021/bc060117y were done on different (early) doxorubicin-conjugates
compared to Aldoxorubicin. These were prone to the cyclization-effect.
DOXO-EMCH is its own 6-maleimidocaproyl hydrazone dox-derivative with a specific thiol-binding spacer
molecule (see DOI: 10.1021/jm020276c). And therefor the cyclization effect reported does not have the
same effect on Aldoxrorubicin. It's a different compound, no apples/apples comparison possible.
Plus, you need to take into account that when coupling to albumin, the dox-conjugate can travel places
unreachable (cell-internalization) to free flowing doxorubicin (or -conjugates). Once internalized, the
environment differs from extracelluar.
On Kaposi: best to see the bottom ASCO2016-poster for details: http://tinyurl.com/j38...
On DK049: you also missed the secondary linker (cleaved by cathepsin b), that makes a further selective
application possible.
27 Oct 2016, 09:35 AM

Authors reply If you can actually verify that this reaction has no precedent with AldoxoRubicin, I'd
believe you. But this is very close, since the changes in the molecules are not significantly close to the
cyclization reaction site.
27 Oct 2016, 11:41 AM
el_paha
First, you are of course entitled to your own personal opinion, but because it is you that is trying to make a
point, its your onus.
Why is aldoxorubicin (being a differend compound, with a different linker) prone to cyclization from
referenced DOI 10.1021/bc060117y ?
Please take caution, if you are going to present research of others as substantiation of your thesis, you
lose the right to make subjective interpretations on them. Even if you call it "basic chemistry". Any
reference should be solid.
28 Oct 2016, 03:07 PM
el_paha
In absence of further substantiation on your side, I will underscore mine.
I already stated that:

- The referenced study (DOI: 10.1021/bc060117y) was not done on the Aldox-compound.
- Aldox is a different chemical structure, than the dox-conjugate made/used by Kaneko et al., Padilla De
Jesus et al (aldoxorubicin is not using the hydrazone-carboxylate linker, but instead, a 6-
maleimidocaproyl(hyd...
That in itself is enough to dismiss your claim for aldox being prone to the cyclization-effect, as this is just
not scientifically proven. To assume cyclization is unsubstantiated and your assumption not very scientific.
Not only should one discard the scientific basis of your article, I can also present some facts from clinical
testing to counter your thesis.
First and most simple exibit of the cyclization reaction being absent, is not to ignore the outcome of
NCT01514188, in which Aldox showed superiority in a head-to-head comparison to standalone
doxorubicin in a 1st line STS-study (DOI 10.1001/jamaoncol.2015...
Study was done by PRAHS and superiority was confirmed by a blinded central lab.
If the cyclization from your referenced study (DOI: 10.1021/bc060117y) would have occurred, one would
not only have unable to achieve superiority, but the cyclization product (dihydrooxadiazinone) would
actually have achieved inferior results compared to standalone dox (hence the "poor antitumor activity").
Second exibit:
Confirmation of achieving clean cleavage doxorubicin was demonstrated by skin-biopsy in the Kaposi
study (NCT02029430). I already posted the ASCO2016-poster in a previous post.
Further on DK049:
Per DOI: 10.1021/bc060117y, the cyclization (of the early dox-conjugate by Kaneko et al.) is an
intramolecular nucleophilic attack by the C-14 hydroxyl of doxorubicin on the carbonyl group of the
hydrazone-carboxylate linker.
This reaction is unique to conjugated doxorubicin on one side of the linker and needs actual cleavage of
the hydrazone-carboxylate linker to occur. This reaction (being specific to the Kaneko-conjugate using
hydrazone-carboxylate) is confirmed by DOI: 10.3390/polym6010179.
This dismisses the claim that you make on DK049, since dox is not at all used there.
To conclude: It not the science behind Aldoxorubicin and DK049 that is BASIC, it's your article.
02 Nov 2016, 05:51 AM
wlson
excellent information El paja. Thank you!
02 Nov 2016, 01:03 PM

Authors reply Actually you know what you're correct. The cyclization reaction is different in the two
molecules, given the leaving group in from aldoxorubicin would require an anionic carbon group.
Good find. Good luck!

02 Nov 2016, 08:58 PM
el_paha
What does this insight mean for your article? Any incorrectness (regarding the claim you make on
Aldox/DK049 being prone to cyclization) should be rectified if you value scientific guidelines.
Will you rectify?
03 Nov 2016, 08:34 AM
cyclad
Thank you indeed for a very good research article. You have maintained patience and humor from some
who probably are connected with the company itself. No earnings announcement is already a negative.
Last webcast the CEO sounded as if he were on high dose of sedatives. Law suits being dealt with.
Anyway, this will run a while with some uninformed investors pushing price up. Always a carrot being held.
It takes a long time to die. Thanks again for very good article.
06 Nov 2016, 09:09 AM
Interesting article. Thanks. I hope you might publish a follow-up based on what Strong Bio is saying above -- that
the lysosomal pathway pH is 5-5.5 so the difference is much bigger than compared to just the tumor itself.
26 Oct 2016, 12:18 PM

http://tinyurl.com/hhg...
29 Oct 2016, 11:25 AM
tajd15
If the full data from Phase 3 stays about the same as interim data, we would be looking at similar efficacy and
much better safety. You don't think the FDA offers any sort of approval (such as accelerated approval) based on
the similar efficacy and better safety profile?
26 Oct 2016, 01:03 PM

Authors reply Hazard ratio is .91. If one cardio-AE shows up, that thesis is done, and we're
approaching a population count now that may start to show this.
I'm not sure how equivalency in efficacy will work out since it is designed for superiority (primary endpoint),
given a HR of 0.91.
26 Oct 2016, 01:19 PM
tajd15
Not sure cardio-AE in one patient negates the fact that hundreds of patients have already been treated
using aldoxorubicin without any signs of cardiotoxicity. Would seem irrational for the FDA to ignore that
given doxorubicin has shown serious side effects consistently.
My point is, from a shareholder standpoint, similar efficacy with the much improved safety profile may very
well be enough for approval. I think that needs to be considered to give a fair assessment of this stock
going forward. I am not suggesting bias on your part (I only mention that because other comments have
suggested it), I just believe we may be asking more from Phase 3 results than the FDA will require for
approval.
26 Oct 2016, 04:21 PM

Authors reply Is it that much improved? Do we have the real data from interim? The quote is strange:
"Aldoxorubicin was not associated with clinically significant cardiac, kidney or liver toxicities."
>Clinically significant
Does that mean it was not significantly different than Doxo?
Why don't they comment on whether there were toxicities in the doxo arm?
I see your point, but I'm prone to believe that if the safety were the best aspect (and showed equivalency
to doxo) the company would be structuring it differently as well as reporting on it differently.
26 Oct 2016, 05:02 PM
D-inv
Phase III trial is ongoing, not concluded. Perhaps you have assumed your conclusion?
26 Oct 2016, 01:05 PM

Authors reply "Perhaps you have assumed your conclusion?"
What else would I do with it?
26 Oct 2016, 01:11 PM
D-inv
Reach it on merits rather than assume it and collate argument to support it?
26 Oct 2016, 01:28 PM

Authors reply That's what investing is... Assuming a conclusion.
26 Oct 2016, 01:29 PM
D-inv
Investing is assuming a conclusion? Hog wash! Assuming a conclusion and colating convenient 'facts' in
support of the conclusion after the fact is confirmation bias in action.
26 Oct 2016, 03:57 PM

Authors reply Investing is always an assumption.
First you said to reach my conclusion on merit, and now you are discounting the process of collecting
facts.
You cannot go into the future and collect facts, so how do you suppose I gather them instead?
Facts are facts. You're free to dispute them, or write your own article.
26 Oct 2016, 05:04 PM
D-inv
"You cannot go into the future and collect facts, so how do you suppose I gather them instead?"
Objectively, i.e. - without guidance from a predefined destination.
26 Oct 2016, 07:01 PM

Authors reply So how do you suppose we do things?
26 Oct 2016, 08:34 PM
D-inv
As I read the article, you decided on the destination and looked for facts leading one there. Nothing you've
said since convinces me otherwise.
27 Oct 2016, 02:57 PM
Tumblebug
Is that not what a hypothesis is?
28 Oct 2016, 11:56 AM
Tumblebug
D-inv - please disputes the facts that were presented rather than jumping to a predetermined conclusion
(as you are accusing others). Give us some technicals, some science, rather than conjecture.
28 Oct 2016, 12:00 PM
D-inv
Cytrix's phase III CT of Aldoxorubicin continues is FACT, a fact which contradicts the conclusion as leaped
to by the author that the drug failed. Thus, I dispute the author's conclusion with fact.
You might consider working on improvement in reading comprehension and logic before challenging
further.
28 Oct 2016, 06:52 PM
ChennyBritt
I was long this company this summer and got crushed. I ignored all the warning signs and if it wasn't for a timely
hedge, would've lost a ridiculous amount of money. As a general rule of thumb for us retail investors, stay away
from these microcap biotech companies. While a few of them succeed (CPXX being the biggest example), most of
them are crap and their market caps are low for a reason. You don't think smart money (hedge funds and big
pharma) is always scouring the field for promising technologies? They have access to KOLs all across the world.
They have infinitely more resources than the average retail investor. If they pass on a technology, it's probably
crap. For those of you who are long this stock, you may see some cherry-picked positive p2 results soon. Still,
good luck. I've learned my lesson. Great article btw.
26 Oct 2016, 02:00 PM

Authors reply And that is why we write. The public doesn't have access to a lot of that knowledge
produced by massive funds, nor is the general investor able to truly evaluate biotech on a deep level.
So we try to bridge that gap.
26 Oct 2016, 03:03 PM
Plus, the CEO refused to use moisturizer. Big red flag...
26 Oct 2016, 03:12 PM

tomale
Great write up. Hope and options are alli have left on this one. What are your thoughts on the clinical hold patient?
I believe he had acidosis, and it must have cleaved quickly...
26 Oct 2016, 03:09 PM
elmono
I am not the greatest fan of Cyrtx right now, for various reasons. However the biggest point that seems to
be overlooked/hardly touched upon in the whole analysis, is the albumin based carrier system for drug
delivery itself, and its benefits. The biggest advantage being that albumin allows for selective delivery of
drugs to tumor tissue (and inflamed tissue). This benefit goes beyond the benefit of choosing the right
linker technology to further fine tune the release mechanism of doxorubicin. I do however admit that I do
not know the exact pharmokinetics of the release mechanism. It may well be that it is indeed a slow
release mechanism, the point however being that much more of it is targeted to tumors than to healthy
tissue due to the albumin..........which means that less of it is released in healthy tissue than in tumor
tissue, slow or not.........
To put it all in a bit of a perspective, I found a nice write up, that is very informative to all interested in the
merits......
http://tinyurl.com/jbh...
Cheers.
26 Oct 2016, 05:07 PM

Authors reply Thanks for the article.
Apparently as outlined in the article there are (were) only two (one?) other companies pursuing covalently-
linked albumin drugs.
Both seem to be discontinued.
Conjuchem no update since 2011, AccessPharmaceuticals 2006.
26 Oct 2016, 05:20 PM
elmono
Apparently, although the author may have worked from outdated info (stating that aldoxo is in PI seems a
bit outdated at least).....
Surely not a lot of companies pursuing the same route as Cytrx, although quiet a bit seem to leverage the
benefits of albumin as carrier system...........
26 Oct 2016, 06:00 PM

wlson
Thank you for the link to the Article, really impressive.
26 Oct 2016, 06:35 PM
D-inv
thanks for trying, but the link provided takes me to a MicroSoft online store. Not interested in anything
there.
26 Oct 2016, 07:18 PM
offsitehelp
The link worked for me. Interesting, if not a little eye-glazing. Good info all the way around in this thread.
Holding shares but not buying any more.
26 Oct 2016, 08:19 PM

Its a common topic but you have to have about 4 semesters of biology before it gets discussed ad nosium
27 Oct 2016, 02:33 PM
Bigdaddio45
Good article but I would point out, while not a biochemist, I am a chemist and once worked for a company that
specialized in themoset acid catalyzed reactions. You'd be surprised at how tight a pH range you can cleave a
blocker. In regards to this specific molecule, I couldn't guess but I'm sure the company knows exactly what pH it
will cleave and this can be adjusted based on the chemistry. Giving a range of hydrazide derivatives and saying
this is similar because it is also a hydrazide is like saying all carbohydrates are the same. It just isn't so. No
position in the stock, just doing a little reading on some stuff that showed up on my screen.
26 Oct 2016, 09:11 PM
seekingmark
So you spend 10 hours plus on a negative article for no reason @ all .....Something smells fishy here ....
27 Oct 2016, 12:03 AM

Authors reply Are you in a room with fish?
27 Oct 2016, 12:41 AM

Scrying Biotech, Contributor
Altum Research:
This article is well worth the read if only for the citation from 2006. Investors would have appreciated your work
more had it been published weeks before the phase-3 readout.
Nice work though.
Michael
27 Oct 2016, 01:31 AM
neonglow
Altum: thanks for your article. You present an interesting take on this, with some good points. But as commented
above, I don't think this is all dependent on blood pH and Warburg effect.
Questions for you and others here:
1. The albumin targets to the tumors, I think, but the mechanism isn't clear to me. Maybe just due to accumulation
of serum due to vascularization or mdscs? Anybody clear on this?
2. My sense is it's unlikely doxo is more efficacious at similar dosing, but less toxicity seems plausible. In this case,
drug dosing could be higher or treatment longer and thus ultimately more efficacious overall. Can anyone
comment on whether the company did an escalation dosing and how that plays int this phase 3?
Thanks
27 Oct 2016, 02:37 AM

best article on the subject that I can find to date
27 Oct 2016, 02:32 PM
apdamico
Thanks for your contrarian view, it actually boosted the stock price.
27 Oct 2016, 11:09 AM

Authors reply Not the chart I'm looking at. And we don't really care what the price is.
27 Oct 2016, 11:42 AM

apdamico
Same chart I'm looking at since your article and the price is up.
Sure you don't care about price lol. BTW, that's me making you buy at higher prices. I won't allow it to go
back down to $.45.
27 Oct 2016, 12:25 PM

Authors reply Ok.
27 Oct 2016, 12:46 PM
apdamico
I thought you'd like that comment!
Fact of the matter is most of these small Bio Tech firms are nothing more than research scams. The only
one's getting rich are the board members each year. Some companies do happen to stumble onto some
ground breaking treatments, but most simply keep kicking the can down the road for as long as possible.
In this company's case, they've been around long enough to construct Kriegsman's vacation retreat in
Freiberg, Germany.
27 Oct 2016, 01:38 PM
wlson
What i don't quite seem to understand is why there are two doctors, one being a neurologist and the other
a biotech specialist, with over 30 million dollars combined in shares in this stock. Do you grasp the Idea?
two very knowledgeable people in this for more than 4 years for a total of 30 million?
think about it...
27 Oct 2016, 04:20 PM
apdamico
I have and hence my comment. It's much longer than 4-years. I know I was in the stock when I used to live
in HI and that was 2002.
Board members latch on to a couple researchers and they are the ones making all the money and milking
the system.
Once the election is over and the new year starts, if Bio Tech stocks go up, so will this stock.
28 Oct 2016, 01:25 PM

japasiamerica
Shiela Olson wrote an interesting piece on CYTRx for Investopedia:
What the ESMO presentation showed

Heres where the data gets more interesting. Of the 36 patients who were evaluated, 13 had a partial response to
aldoxorubicin (39%) and 22 had stable disease (61%). Only one patient in the study showed progression.
More importantly, however, the study revealed that no dose-limiting toxicities were reported, either in the cohort
receiving the 170 mg/m2 dose or the higher 250 mg/m2 dose. In addition, 17% of the patients tumors shrunk by
50% or more, in some cases making them suitable for surgical resection. Another 56% saw their tumors shrink by
20%.
Overall, the findings indicate that 96% of patients treated with aldoxorubicin saw no no progression of their disease
during the trial period.
Read more: What CytRx Latest Trial Results Really Mean (CYTR) | Investopedia http://tinyurl.com/gle...
27 Oct 2016, 11:11 AM

several conditions in nature result in an extracellular pH lower than 6.4. osteoclast pH is an example creating a
microenvironment of 5.0 to 5.5. tumors often are measured with acid indicators such as bcecf or non methyl ester
derivatives and are frequently shown to have microenvironment and environments between 6.0 and 6.5. bear in
mind your paper skewed the range to 6.4 and higher. although there is going to be some variability in acidity based
upon a multitude of effects, it is accepted that 6.0 to 6.5 is the rule of thumb for tumors. see ref:
http://tinyurl.com/jcw.... it doesn't sound like a lot but a ph of 7 is 10 x less acidic than 6.0. So by this logarithmic
scale 6.0 is 4x more acidic than 6.4. So I'm not sure there is much about this paper that holds water, especially
given that the cyclo reaction derivative would be displaced once protons are available to create the dox reactive
species. still the data between sts subtypes could lend support for your thesis if more acidic subtypes respond
more robustly
27 Oct 2016, 10:22 PM

Authors reply Your reference cites this paper for the 6.0-6.5 range
http://tinyurl.com/jqk...
I'll let you look at the pHs they test.
28 Oct 2016, 10:52 AM

Cancer research 2012; 72:2746-56. "Here we report that lowering the microenvironmental pH to values
that characterize tumor masses (6-6.5) was sufficient to establish an aneroid state..."
28 Oct 2016, 11:10 AM

anergic
28 Oct 2016, 11:11 AM

common knowledge in biology but u r a chemist so u r excused it's an extinct field unless aldox is
approved in which case it's revived
28 Oct 2016, 01:50 PM

In addition, excessive CO2 release caused by altered glycolysis leads to increased tumor expression of carbonic
anhydrase IX (CA-IX), thus contributing to further acidification of the extracellular tumor environment (8, 9).
Hypoxia also activates the hypoxia-inducible factor (HIF) pathway, which in turn upregulates glucose transporters
and CA-IX and leads to additional exacerbation of tumor acidosis (8). As a result, the extracellular pH can drop to
values of 6.0 or less and is on average 0.2 to 1.0 units lower than that of normal tissues (10, 11).
28 Oct 2016, 11:14 AM

Nat Med. 1997 Feb;3(2):177-82.
28 Oct 2016, 11:18 AM

However, in diseased tissues such as the tumor microenvironment a local pH range from 5.5 to 7.0 is not
uncommon (Vaupel et al., 1989; Gatenby and Gillies, 2004). Moreover, intracellular pH of tumor cells is slightly
alkaline in comparison to the extracellular space, which has been demonstrated to facilitate cell proliferation and
tumor growth (Tannock and Rotin, 1989; Vaupel et al., 1989; Griffiths, 1991; Griffiths et al., 2001; Webb et al.,
2011).
28 Oct 2016, 11:39 AM

wike-hooley et al. microelectronics range range of pH in both human and rodent malignant cells 5.8 to 7.0
30 Oct 2016, 10:56 AM

R2G2
Seems like everyone is missing the forest through the trees. Is not the ultimate goal to replace Dox with Aldox
based on how much more patients can take during chemo along with being less toxic and harmful. Who cares
about all the "basic chemistry of pH sensitive linkers".
02 Nov 2016, 01:07 PM
elmono
Actually the P3 STS study's primary objective is to show superiority to SOC.
If this is not conceived, question is what will be required by the FDA to achieve approval on another basis,
if feasible. Lot's of other articles about this....
This article is clearly written with a focus on the moa of aldoxo and (indirectly) whether the moa makes it
likely that it can achieve superiority over dox, and not so much with a focus on better tolerability and less
severe AE.
02 Nov 2016, 01:27 PM
tajd15
Agreed, though I wonder if superior efficacy was required because of the Special Protocol Assessment? I
don't see FDA turning down a drug with similar efficacy and better safety that would replace a drug as
common as doxorubicin.
02 Nov 2016, 03:52 PM
elmono
The spa is pretty much a blueprint for approval, if you follow the agreed protocol, and the primary
endpoints are met, and there are no unexpected safety concerns.
If these primary endpoints are not met, or if the protocol is not followed, all bets are off.
This pretty much means that you would have to plead your case in front of the FDA based on the data
available. This can go either way, as I don't think the FDA has a good track record for predictable
decisions.
The risk for investors of this scenario (pleading your case on for instance an improved safety profile), is
that we do simply not know the safety data right now. Aldoxo is not only being compared to doxo but also
to other SOC, and there is no way of being sure about the outcome of this comparison. What we do know
is that in the P3 there is a prolonged dosing of aldoxo as compared to the P2. We also know that in the P3
aldoxo may be provided to patients that were treated before with doxo. There is very limited data on the
treatment effect of doxo followed by aldoxo. What appears to be an established fact is that the risk of
cardio myopathy increases with cumulative dosing of doxo. What we don't know is the effect of prolonged
dosing of aldoxo on top of prior doxo treatment.
In my opinion there is still a lot of uncertainty on what the data will reveal. If data reveal that there is no
path to approval, I have said this before, the sp will easily drop to the low teens, as it may be assumed that
Hercules will then recall the loan.
If there is a narrow path for approval, of course the sp will rise, although cytrx will need additional funding
for further developing its clinical programs and for commercialization. As Hercules will probably not recall
its loan then, in my opinion, the company has bought itself time to negotiate a licensing deal.
There is also a (slim) chance that the primary endpoints will be met. When that happens (a small small
chance in my opinion) the sky is the limit.....
02 Nov 2016, 05:09 PM

superior efficacy achieved, as previously described
05 Dec 2016, 05:34 PM
wlson
Hello based on what the FDA GUIDELINES SAY:
And If There is No Significant PFS Difference?
If PFS is statistically significant ("SS"), aldoxorubicin would very likely get full approval, aka 'regular approval'
("RA"), for 2nd line STS - and possibly even if not - but if it is not SS and if they cannot get RA, there is a good
chance that aldoxorubicin would be granted accelerated approval ("AA") instead.
Where there is an unmet medical need, FDA exercises greater flexibility of judgment. EMA also has expedited
programs to meet these needs. But what determines whether or not there is an unmet medical need?
FDA defines unmet medical need as "a condition whose treatment or diagnosis is not addressed adequately by
available therapy." Priority medicines for Europe focuses on conditions for which some treatments exist, but the
delivery mechanism, or formulation may be inappropriate for the target patient group and conditions for which no
effective treatment is available.
Both of these definitions fit the current treatment landscape for 2nd line STS. Let's focus on FDA's.
A condition whose treatment or diagnosis is not addressed adequately by available therapy. An unmet medical
need includes an immediate need for a defined population (i.e., to treat a serious condition with no or limited
treatment)...
So what's "available therapy?" Available therapy is a viable treatment approved for the indication in question.
There could be some argument over whether or not 2nd line STS even has "available therapy" as defined by FDA.
If not, then:
1. Where There Is No Available Therapy

If there is no available therapy for a serious condition, there is clearly an unmet medical need.
That could be the end of the story as to whether or not 2nd line unresectable STS presents an unmet medical
need (it's obviously a "serious condition"). The only approvals specific to STS are for 1st line (doxorubicin) and 3rd
line (eribulin and trabectedin). There is no recognized, FDA approved 2nd line therapy. Just a lot of off label use.
But let's continue on with the FDA guidance to find out how they define an unmet medical need when there is
available therapy. I will put in brackets whether or not the mention could possibly apply to aldoxorubicin for 2nd line
STS, and consider "available therapy" to mean any of the five in investigator's choice:
2. Where There Is Available Therapy
When available therapy [investigator's choice] exists for a condition, a new treatment [aldoxorubicin] generally
would be considered to address an unmet medical need if the treatment [aldox]:
Has an effect on a serious outcome of the condition that is not known to be influenced by available therapy (e.g.,
progressive disability or disease progression when the available therapy has shown an effect on symptoms, but
has not shown an effect on progressive disability or disease progression)
[No]
Has an improved effect on a serious outcome(s) of the condition compared with available therapy (e.g.,
superiority of the new drug to available therapy when either used alone or in combination with available therapy
(i.e., as demonstrated in an add-on study) )
[Yes, via ORR, and possibly via PFS, but only if the difference becomes significant]
Has an effect on a serious outcome of the condition in patients who are unable to tolerate or failed to respond to
available therapy
[Yes. Double the ORR in anthracycline fails vs control]
Can be used effectively with other critical agents that cannot be combined with available therapy
[Possibly, but not tested]
Provides efficacy comparable to those of available therapy, while (1) avoiding serious toxicity that occurs with
available therapy, (2) avoiding less serious toxicity that is common and causes discontinuation of treatment of a
serious condition, or (3) reducing the potential for harmful drug interactions
[Yes. No cardio toxicity, despite the compound being an athracycline. And much better safety profile than
gemcitabine+doxetaxel]
Provides safety and efficacy comparable to those of available therapy but has a documented benefit, such as
improved compliance, that is expected to lead to an improvement in serious outcomes
[Possibly, we will have to see how many discontinuations due to unacceptable toxicity in control vs aldox group]
Addresses an emerging or anticipated public health need, such as a drug shortage

[Possibly, as there have been multiple dox and Doxil shortages]
We SHOULD BE GETTNG THE AA!
Steven is in fact correct!
all the longs shall be rewarded as long as management gets us there!
03 Nov 2016, 10:40 AM
wlson
I only needed to write "yes" once for there to be an unmet medical need in 2nd line STS, and for aldox to have the
potential to meet that need as a new treatment option.
So what? So, that means aldox is a candidate for accelerated approval. Even without having to show clear
superiority over available therapy. FDA guidance continues:
In some disease settings, a drug that is not shown to provide a direct efficacy or safety advantage over available
therapy may nonetheless provide an advantage that would be of sufficient public health benefit to qualify as
meeting an unmet medical need.
For example, in a condition for which there are approved therapies that have a modest response rate or significant
heterogeneity in response, a drug with a novel mechanism of action (but comparable safety and effectiveness)
could have the potential to provide an advantage over available therapy in some patients. In such a case, the
novel mechanism of action should have a well-understood relationship to the disease pathophysiology.
In addition, there should be a reasonable basis for concluding that a significant number of patients may respond
differently to the new drug compared with available therapy. Thus, mechanistic diversity, even without a
documented efficacy or safety advantage, could be advantageous in disease settings in which drugs become less
effective or ineffective over time.
For example, infectious disease drugs or targeted cancer therapies with novel mechanisms of action, although
appearing to have efficacy similar to available therapy across the disease population, could benefit patients who
no longer respond to available therapy. Accordingly, FDA intends to consider a range of potential advantages over
available therapy beyond those shown in head-to-head comparisons.
03 Nov 2016, 10:42 AM

Authors reply good research
03 Nov 2016, 04:45 PM
elmono
http://bit.ly/2eGEsVk
The above is a good example of AA, allbeit in 1st line STS. I wonder whether Aldoxo meets any of these
criteria.................
Cytrx management to blame for not having persisted in having a trial design wherein aldoxo is exclusively
compared against doxo. This would have greatly enhanced the probability of a successful outcome, and it
would have meant for the trial design to simply exclude pts with prior anthracycline use from participation.
Such cleaner design would have meant less worries about:
- drug resistance (doxo followed by aldoxo)

- accumulated dosing of anthracyclines leading to potentially higher risk for AE
I am afraid that the current trial will generate a very messy picture. Of course subgroup analysis can be
done to clean up the picture, but will the se subgroups provide enough statistical power to warrant
approval for a more limited indication..........th... the question.
All in my opinion of course.
04 Nov 2016, 09:12 AM

The reason for not using doxo alone have been discussed by CytRx as:
- FDA encouraged (=forced) them to do so ...
17 Nov 2016, 03:28 AM
elmono
I know and it is a ridiculous excuse. Moments like these define the company. Separate the boys from the
men. How is it that other companies are allowed to test their compounds against doxo alone and cytrx
would not be allowed to test aldoxo against doxo, in strong contrast to the p2. Doesn't make sense now,
does it?
17 Nov 2016, 04:41 AM
tajd15
If the FDA required it, not sure what Cytrx is going to do about that other than comply.
For all we know, the FDA plans to pass it just based on safety alone (assuming efficacy is at least similar)
and thus wanted to see it against more than just doxo.
17 Nov 2016, 11:34 AM
elmono
I am not sure if it required to follow FDA guidance. You may just not get the spa. However what is a spa
worth if the FDA guidance is a recipe for failure?
And I am not sure the FDA is ready to pass this just on safety at all. Remember there is a dox combo just
approved that is far better than dox alone.
"Patients in this trial who received Lartruvo with doxorubicin had a statistically significant improvement in
overall survival: the median survival was 26.5 months compared to 14.7 months for patients who received
doxorubicin alone. Patients who received Lartruvo with doxorubicin had a median progression-free survival
of 8.2 months compared to 4.4 months for patients who received doxorubicin alone. Tumor shrinkage was
18.2 percent for patients who received Lartruvo with doxorubicin and 7.5 percent for those who received
doxorubicin alone."
I assume the FDA would consider all treatment options available (including the latest approved combo)
when making a decision on allowing an additional drug that is not based on the spa agreed primary
endpoints.
Even when allowed in the market, if given the choice between this combo and aldoxo, I am not so sure
what patients would prefer. Such combo may easily outperform aldoxo as well on mPFS or OS. Hence
even assuming a somewhat improved safety profile for aldoxo that would be a tough choice to make.
And as far as providing aldoxo to pts that received doxo in 1st line, I am not sure if they can even get that
label, as it would mean competing with other 2nd line options available. That subgroup analysis may not
be so favourable I am afraid.
23 Nov 2016, 10:22 AM
tomale
I think the company pushed for standard of care, so the FDA said beat everything else. And the company
was wrong.
23 Nov 2016, 11:31 AM
corbitt
Bottom line is the company in the last couple of years has settled one lawsuit and is involved in a 2nd. Both are for
misleading investors, which I was one. This company has enough cash for two more qtrs at best. They have
nowhere to turn to for additional cash and no significant breaking news due in that time period. Filing for
bankruptcy is inevitable.
03 Nov 2016, 07:42 PM
seekingmark
I thought they had $75 million in cash ....
04 Nov 2016, 09:00 PM

Jim in SoCal
Per the last corporate presentation, they do.
05 Nov 2016, 02:32 PM
tomale
Has the company defined what statistical superiority is? Is it >1 month compared to "placebos"? Or just p value
less than .05?
23 Nov 2016, 11:58 AM

Nice news this AM. AJ
29 Nov 2016, 08:11 AM

Authors reply When you delete 17% of your treatment population to gain statistical significance, I guess
it can be spun as good.
29 Nov 2016, 10:04 AM

You know, I have actually seen top line academic journals publish articles like this, where the footnote
explains the "fraud," when faculty authors are pals with the editor and need the publication for tenure and
promotion. Saw one, years ago, where they extracted far more than 17%. Wish I could recall. Accounting
Review article. Anyway, that's life on Wall Street. Stay well and preserve capital. AJ
29 Nov 2016, 10:09 AM
They did not remove 17% of the treatment population... They removed some of the other diseases in the
trial to achieve a highly statistically significant result (p < .007) with n=246, versus n=433 in the entire
population. There must be something in the other diseases that makes the treatment unworkable.
29 Nov 2016, 04:19 PM
agent frog
The hazard ratio for the entire study was .81. Your comment shows a bias.
29 Nov 2016, 06:03 PM

agent frog
Unworkable no. Just not as good.
29 Nov 2016, 06:04 PM
"Unworkable as a better option".
29 Nov 2016, 06:06 PM

Aldox is certain to get approval now.
29 Nov 2016, 05:48 PM
wlson
hey steven
lm really glad you are finally are right and unprofessional people like this author cant bash your work
anymore. you where right all along and now its proven. l want to thank you for your work. ln all this mess
you kept me believing. when do you think the SP will bounce back?
Cheers!
29 Nov 2016, 07:04 PM
Crazy price action, isn't it?
29 Nov 2016, 07:14 PM

Authors reply HR of 0.81 and removing a large population to gain significance. Not things the FDA
likes.
Maybe approval after another P3. Hope you didn't buy in pre-market.
29 Nov 2016, 07:58 PM
agent frog
Altum - You couch your comment as if the HR of .81 is part part of a population removal. It needs to be
repeated once again as I posted before that .81 was the total trial and not a subset of the trial. The subset
rightly featured in the press release was an HR of .62. The HR of .81 for the total trial is statistically
significant.
29 Nov 2016, 10:46 PM
tio1234
Why do you think the stock remained essentially flat despite this apparently excellent news?
30 Nov 2016, 02:02 AM

Hey wlson,
Well, I feel like I'm half right lol. But the end result is essentially the same. I'm writing an article now, but
what the market is overlooking imo is that lipo and leio were pre-specified subgroups, and are major
subtypes of sarcoma. They represent somewhere around 60% of all patients. Two recent approvals were
in lipo only (eribulin) and lipo an leio (trabectedin). And the funny thing is, the subgroups were much
smaller than in the aldox P3, and trab even FAILED its primary endpoint in that subtype (overall survival),
but made it in its secondary ep (PFS). It was approved on secondary. And rather than tested against an
array of chemos, it was only pitted against dacarbazine, which is relatively weak.
Aldox is clearly superior. FDA will also like that the overall North American pop was stat sig. I've seen that
cause problems for drugs getting approval the other way around, where the overall pop was stat sig, but
the EU was not. EMA didn't like that.
Where there is no SOC there is great flexibility and eagerness to approve on FDA's part. See my prior
approval examples in my last article.
Cheers
ps I think we'll get a run up into Q1 as funds realize the import of these data, and then a nice pop on pre-
NDA information (FDA giving positive feedback on filing NDA). That's Q1, maybe March-ish.
I bought a bunch more on the pullback yesterday. Will be sitting tight on those for a while. Maybe unload a
few after pre-NDA meeting. Buyout also possible here, but not before a solid run-up imo. What's really
valuable about aldox is the off-label use. It can get staggering. Doxorubicin is used everywhere.
30 Nov 2016, 08:08 AM
elmono
"Where there is no SOC there is great flexibility and eagerness to approve on FDA's part."
Lartruvo is now SOC and superior to all other treatments so far.

Forget the discussion about 1st or 2nd line:
- it is indicated for use when no prior anthracyclines have been provided. This can be 1st or further line
therapy.
- if given choice between Lartruvo combo and Aldoxo, guess what will be the choice?
- Aldoxo has most potential if doxo was 1st treatment (as it would than not have to compete with Lartruvo
in 2nd line), however:
- is there a subgroup analysis specified in the spa related to this pts population? and if so: are the results
in this group favorable to warrant an approval?
That is the question
30 Nov 2016, 10:39 AM
A mischaracterization. It was up 50% and is now down 8% from initial levels
30 Nov 2016, 01:03 PM
tio1234
Steve, thanks for your very helpful articles. I'm totally confused as to why CYTR has been doing so badly
today despite the very good news yesterday. Any thoughts?
30 Nov 2016, 03:11 PM
D-inv
Adam Feuerstein sour grapes article (http://tinyurl.com/z2h...) plus tax loss selling?
30 Nov 2016, 03:54 PM
A number of companies have had very good news come out with the stock price later imploding.
Who knows why. Retail has been sheared constantly this year by moneyed HFTs.
It doesn't help in this particular case that the management isn't trustworthy.
30 Nov 2016, 06:38 PM

Elmono, Lartruvo is an adjuvant given with dox. And it's for first-line. Aldox is vying for refractory (2nd and
more advanced lines). There is NO SOC for this indication.
There is no "Lartruvo vs Aldox" decision that will have to be made, except for those docs who may decide
to use aldox+lartruvo as an off-label option instead of dox+lartruvo. That might happen more often than
you think. But the Lartruvo accelerated approval does not get in the way of aldox's forthcoming approval in
the least.
Apples an oranges my friend.
01 Dec 2016, 07:30 AM

tio1234
Basically the market doesn't understand the import of pre-specified analyses, nor the flexibility and
eagerness to approve that FDA exhibits where there is no SOC.
Look at topotecan for 2nd line SCLC. There was no SOC at the time it was tested against the most
commonly used triplet chemo regimen, which was at that time being prescribed off-label. How did it do? It
proved equal in efficacy, and much better in safety. Was it a non-inferiority trial? NO! It wasn't. It was a
superiority trial. What did FDA do? Grant topotecan full approval. I repeat, it FAILED the study. Why did
FDA do that? Because there was no SOC. Think of it like an empty slot. FDA is eager to fill empty slots.
For 2nd line STS, there is an empty slot.
Then look at Eribulin. That was approved for liposarcoma only. How? Because the study had analysis of
lipo and leiomysarcoma as pre-specified. That means in study design, alpha was allocated to the analysis
of these, and their randomization was stratified. In that study, only about 100 patients were of that subtype.
But they did well on Eribulin. FDA then granted full approval to eribulin for that subtype and who have
failed an anthracycline.
So that's what the market doesn't get. They think this is just another post hoc data-dredged analysis put in
a PR to soften the blow of the bad news. It's NOT.
I'm loading the boat :)
GL
01 Dec 2016, 07:50 AM
elmono
LARTRUVO is a platelet-derived growth factor receptor alpha
(PDGFR-) blocking antibody indicated, in combination with
doxorubicin, for the treatment of adult patients with soft tissue sarcoma (STS) with a histologic subtype for
which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment
with radiotherapy or surgery. (1)
Do you see 'exclusively usable as first line' in the above approval package? I don't.
Furthermore Lartruvo is approved under AA as a combo with doxo. For argument sake, if what you say
were to be true, and it would be only officially allowed 1st line (e.g. before any other chemotherapy), then
surely any off-label use in 2nd line will also be the combination of Lartruvo + dox only. The combination
Aldoxo + lartruvo has never been tested in any indication, which makes it a no-go area 'as such'.
Such combination would thus proof to be a formidable competitor to aldoxo alone (if the latter ever makes
it to the market), which is good for pts, but no good for Cytrx.
Of course the easy and cheap, although of little merit, argument is to say: 'apples and oranges', where
there is, in any comparison, always a difference to be found.
01 Dec 2016, 09:22 AM
elmono
Good luck with loading the boat. Better hope Hercules doesn't pull out ;-)
01 Dec 2016, 09:24 AM
buy_low28
Steve I would like to hear your thoughts in response to this comment
03 Dec 2016, 12:20 PM
buy_low28
There are many drugs on the market that aren't necessarily better than its predecessors. It's hard to see a
situation where you can have another effective option to treat cancer not be approved.
03 Dec 2016, 12:59 PM
buy_low28
It looks like the loan should be extended by 6 months of interest-only payments and the next 15 mil is to
be paid if they begin a clinical trial on another new drug candidate by 12/31/16
03 Dec 2016, 04:21 PM
Rociletinib? Ended up potentially better than Tagrisso once data was more fleshed out, but Clovis had to
can the program since it couldn't afford the regular approval process. The short-sighted advisory
committee KILLED PEOPLE by not recommending accelerated approval.
04 Dec 2016, 08:25 PM
Simon/bags -- why are you repeating AF's trash? The subpopulation had a p value of less than .007. You don't run
another trial with this p-value.
30 Nov 2016, 04:36 AM

elmono
I am sceptical the FDA will grant approval based on the subgroup analysis, unless it was part of the pre-
agreed spa.
Furthermore the voices around a possible AA based on an improved safety profile are silent now. I guess
that didn't work out....
My suspicion, awaiting confirmation, is that in the 'selected' indications, patients were less pretreated with
an anthracycline, than in the other subtypes. That means that these patients would either have received
(predominantly) doxo, or alternatively aldoxo.
In such subgroup, as I said before, aldoxo stands a better chance, as the patients that have become
resistant to prior doxo treatment (and would thus not respons as well to aldoxo), have been filtered out.
I didn't listen to the cc yet, so this is the hypothesis.
30 Nov 2016, 04:54 AM
The SPA does not bind the company to not doing a regular accelerated approval request. Further, it will be
a different FDA in 2017.
30 Nov 2016, 06:03 AM
Oh and yes the analysis was pre-specified; not sure if that was part of SPA but I assume it probably was.
30 Nov 2016, 06:10 AM
elmono
It doesn't bind it. however deviating from the spa significantly decreases chances of success in my
opinion.
I am not sure if a different FDA makes any difference ;-)
30 Nov 2016, 06:43 AM
elmono
The North American subgroup appears pre-specified. I am not sure if the subtypes analysis was
prespecified, and whether it was agreed per spa that meeting primary endpoints in these subtypes would
mean approval based on a limited label (e.g. only for these subtypes).
30 Nov 2016, 06:47 AM
"Pre-specified analyses were based on sarcoma histopathology and geography."
30 Nov 2016, 07:49 AM
elmono
You are right. Now let's hope they had the wisdom to agree per spa that if the primary endpoints would be
met for these prespecified subtypes, that they would be granted an approval (on a more limited label). If
they were only able to confirm that...........I would jump right back in ;-)
30 Nov 2016, 09:57 AM

Elmono,
"The voices around AA are silent" referring to mine? If so, yeah of COURSE, because FULL approval is
now obvious ;)
Stop being so damn bitter. Only hurtin yourself.
30 Nov 2016, 10:29 AM
elmono
Haha you are a funny man. Not bitter at all. Just realistic.......unlike others :-)
Full approval, do not make me laugh so much, it hurts...
30 Nov 2016, 12:56 PM

Authors reply There is no way for full approval with this data. Subgroup analysis might get approved,
maybe, but the FDA is not friendly to this.
Likely will require another P3, I expect a CRL.
AF's points are worthy of consideration - if they weren't, don't you think it the shares would be doing quite
well given "success"?
A buyout is not going to happen here.
30 Nov 2016, 03:11 PM

Subgroup analysis might get approved? First of all, very weird wording sir. Secondly, that IS full approval.
If it gets approved for lipo/leio, that represents over 60% of all STS. Then you also have the MASSIVE off-
label stuff where aldox can replace doxorubicin. Do you know how often dox is prescribed??????
Pre-specified means alpha was allocated. Look at the Eribulin approval closer. And there is no SOC for
2nd line STS. That's a big deal.
These are the granular details the market doesn't get. And I'm going to try to capitalize on that.
01 Dec 2016, 07:54 AM
elmono
There is Regular Approval and there is Accelerated Approval as recognized terms by the FDA. The term
"full approval" does not have a strictly defined meaning, however in the context of this discussion it is kind
of clear, isn't it?
To me it is clear that the trial results do not warrant a broad label that covers all STS subtypes. In that
aspect the trial hopelessly failed (in my opinion that is).
However there may be basis for a more limited label, based on the recent news release.................. all
depends on the quality of the data behind the data, if you see what I mean. So let's wait and see :-)
01 Dec 2016, 09:41 AM
"AF's points are worthy of consideration"
What points? Did he make a point? I didn't see any.
01 Dec 2016, 02:53 PM
tajd15
Truthfully, Altum Research, I have given you the benefit of the doubt as an objective bystanders, but it has become
continuously difficult to see you as such.
Can you expand upon your reasoning for stating there is no way for full approval with this data and the FDA not
being friendly to approving subgroups?
As for AF's points... I honestly thought he should be embarrassed that the article has his name at the bottom of it.
30 Nov 2016, 04:35 PM
AF beyond embarrassment at this point... has been for years. CLVS at $36.
01 Dec 2016, 02:53 PM

Authors reply Aga, if that were the case, the market would ignore his articles.
Tajd, for full approval CytRx would have had to have passed the original phase 3. Passing the secondary
readout with a subgroup is not 'full' approval. That is obvious. That would still be a worthy investment, if
that were a likely scenario. I do not believe it is.
I don't have anything to gain or lose in this except credibility. We have made (I believe) a case that
aldoxorubicin is simply slow-release doxorubicin, hence it shows efficacy, but we still have significant side
effects. An HR of .81 in the total pop clearly indicates that there are off-target effects and the drug is not
simply *only* accumulating in the tumors.
I don't like this company and to be honest I would put little trust in any results they put out unless it is
absolutely clear that the drug works. An "almost" significant finding is obviously not going to sway me, and
looking at a subgroup (even if prespecified), without any mention for reasoning or rational behind it, makes
me question how they came up with the pre-specification.
This company is not transparent, and given their dire situation and stock price, they most likely would be if
in fact they had great data.
02 Dec 2016, 12:20 AM
agent frog
There is another name for what you call prespecified subgroups. They are called " primary endpoints". As
for the reasoning or rational for the "primary endpoints" you could ask someone who has one of the 2
primary cancer types or you could ask the FDA why they wanted them. Seems obvious to me. You are
correct when you say that this is an opportunity for you to gain or lose credibility.
02 Dec 2016, 05:48 AM
Again, CLVS at $36.50... got shorted into submission by AF and JC (another paid basher) $12 earlier this
year. $12!
The market is starting to ignore his articles. He penned an AERI article and the stock went up. His short
buddies got bullied by multiple long hedge funds into submission on that one.
I would like to understand why it worked better in those subgroups as well, and I would like to see the SPA
to see if they really will get approval based on subgroups in a guaranteed fashion. I don't trust the
company, but the subgroup results are not in question at this point.
One thing that isn't really a question for me is that AF consistently writes trashy articles, devoid of content
or analysis... so again, beyond embarrassment.
02 Dec 2016, 10:33 AM

Authors reply Aga: what's the last bearish article you read that you thought was informative?
02 Dec 2016, 06:00 PM
The problem is that bearish points of view are very easy to describe, because you only need one problem.
Thus, there aren't many legitimate articles on it (no offense). There isn't much meat that is needed. And
those who do write such articles typically just write *much more* than perhaps needed -- no offense again.
Edit: For the record, I did think your article did bring up an interesting potential problem and point of
discussion, but it wouldn't convince me to short, for example.
An example of a succinct bearish point of view:

http://seekingalpha.co...
Ta-da!
02 Dec 2016, 06:03 PM

Authors reply That's quite there opposite, bullish points of view are the easiest to create because every
company will supply you with them. Bearish stories are always harder by nature.
03 Dec 2016, 03:12 PM
seekingmark
Looks like the author is wrong ....CYTR followed and did just as the FDA ask then too ....
02 Dec 2016, 10:22 AM
longJohnp7
The one death was the result of an oncologist who pleaded with Cytrx for compassionate use but mistakingly
misdiagnosed his OWN patient for acidosis.
19 Feb 2017, 11:08 PM

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Oct. 26, 2016 7:54 AM ET179 comments

We discuss recent developments of the company.

We revisit the CytRx approach.

We provide a scientific perspective for new-eyes on the company who may be

3. Management has gone from worrisome, to something we would absolutely avoid.

Aldoxorubicin utilizes a novel acid-sensitive linker that selectively binds to albumin,

The lowering of the pH of tumors is often described as the 'Warburg effect'.

An excellent review of this can be read about here.

1. What is the pH of the microenvironment (in general).

Before we answer (1) we need to understand physiological pH.

The pH difference of healthy blood (7.4) to that of an acidic tumor

Is this drug (gemcitabine) even a novel target for this approach?

h-gemcitabine @ 25 mg/kg 95 umol/kg

Free gemcitabine @ 100 mg/kg 380 umol/kg.

infusion days: 0, 3, 6, and 9

26 Oct 2016, 10:58 AM

Altum Research, Contributor

26 Oct 2016, 11:01 AM

Steven Giardino, Contributor

Does that just happen?

What were you saying about pH again?

22 Nov 2016, 08:01 AM

Altum Research, Contributor

Either way, we'll know soon.

You're most graciously welcome.

22 Nov 2016, 01:24 PM

Scientist on Stocks, Contributor

Don't you think you are making all this up?

23 Nov 2016, 12:09 AM

Altum Research, Contributor

23 Nov 2016, 01:49 AM

Scientist on Stocks, Contributor

23 Nov 2016, 02:56 AM

26 Oct 2016, 11:05 AM

Can't wait to see the RS ratio!

26 Oct 2016, 11:20 AM

26 Oct 2016, 11:33 AM

26 Oct 2016, 11:29 AM

26 Oct 2016, 11:32 AM

Altum Research, Contributor

From our observation, Aldoxo seems to be analogous to a low-concentration, extended-release form of

Strong Bio, Contributor

31 Oct 2016, 06:59 AM

Altum Research, Contributor

31 Oct 2016, 11:28 AM

31 Oct 2016, 05:02 PM

Altum Research, Contributor

31 Oct 2016, 05:12 PM

Scientist on Stocks, Contributor

Altum Research, Contributor

17 Nov 2016, 11:22 AM

Altum Research, Contributor

that comment shows your lack of objectivity and independence !!!

26 Oct 2016, 11:35 AM

Altum Research, Contributor

26 Oct 2016, 12:43 PM

26 Oct 2016, 11:46 AM

Altum Research, Contributor

26 Oct 2016, 12:45 PM

20 Feb 2017, 03:03 PM

Altum Research, Contributor

Good luck with your long.