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Karin,
Looks like the PM holiday is over. Thanks for the idea, please email me at sdtrond at yahoo and I'll chat with you about it.
Best,
Trond
Argh ... so you give me several links, one of which supposedly tells me that better docs and equipment doesn't lead to better outcomes. It's a ~30 minute presentation and I listened to the first 9 without hearing anything new. If you can give even a range of when to listen, it'd be nice.
Poon is good to listen to, btw - obvious why he's the Man in the Asian world when it comes to lead Dr.
I note you harp quite a bit on the 50% recurrence. I have no issues with that - it is WHEN that recurrence happens at question here.
I'll concur that there's one place where we'll see a lot of early PFS failures - when the second ablation attempt fails those patients will have PFS = 0 and will certainly drive the median lower than it "should" be.
Here's the ultimate problem with having a PFS lower than 12: Based on enrollment, you simply can't fit the necessary numbers into the 219 events known to have occurred around late Sept-2011 and the 380th around 11/9/12. If the 350 placebo patients had a median PFS of 10, we'd have hit 219 much earlier and the 380 MUCH earlier. Unless you want to argue that TDox is having an effect that lends somewhere around a 45-55 month PFS, on those same size tumors that RFA is NOT as effective on?
I'll listen to the other presentations you linked tomorrow, and whatever cc's I can stomach again.... but you haven't convinced me and I probably won't convince you. We're both bullish, so if you're right and it's 7v60, AWESOME.
>>Your quote doesn't mention RFA at all (though it does say target population).
C'mon, he's been saying this for as long as I can remember. He's saying this all on the fly, so every cc is not going to have a nicely packaged quote covering every single definition.
He's talking specifically about the HEAT trial, our patients' population, RFA-only, as closely as they can estimate it. They say 12 months PFS for this population. He even says in six years the numbers do not change.
It's going to be 12 months for placebo. And if its wrong, its going to err on the side of being higher (better quality RFA equipment, clinical sites with top docs, patients in trials tend to do better than overall stats).
My guess is 14v24, with a month to either side probable.
Here's one quick one. It is interesting that you bring up TTP. That was the ph1 endpoint, but PFS as you mention is different. In this quote, he just says "progression" without specifying "local progression" per your post. I'll keep looking.
http://seekingalpha.com/article/1001421-celsion-s-ceo-discusses-q3-2012-results-earnings-call-transcript?part=single
"Our target population, median time to progression is 12 months with median time to death 30 months. Five year survival is in the single digits. I will remind you as I said last call, outcome statistics as we continue to remove them, they have remained constant since we began our research in HCC over six years ago."
That is quite a claim.
I have been on every quarterly call for the last 13 quarters and my understanding has always and absolutely been that they expect 12 months PFS for the HEAT trial's RFA-only arm.
At one point MT even delved into the expectation that patients with tumors > 5cm should have an expected 11 months while those under 5cm would be about 12.
I will have to go back and listen to a few.
Quote:
>>The control arm is way less than 12 months.
Rawnoc, what is your thesis for this? Mgmt has repeatedly said the historical norms they use for this trial would show a 12 month PFS for RFA-only.
Please note Kid's 20 months PFS is for the entire trial. Since we are 1:1, IF the control is 12 months, then TDox arm should be well in excess of 20. It is not exactly algebraic, but you could call it 28 months very imprecisely.
My working estimate is around 13-14 vs. 23-25 months.
Best,
Trond
From the Kid, on ymb:
Bottom line answer is management can break the blind if they want to but it is unlikely they will. Second part is I agree CLSN has an idea of results but not for the reason you state.
More detail: One of the requirements for submitting an NDA is that there be at least one “well-controlled” study. For many studies being well controlled includes being blinded, partially, singly, doubly, triple etc. Most people know this. What they might not know is that in the clinical portion of the NDA submission there is a section where the sponsor needs to defend that the study is in fact well controlled.
Blinding is part of that control. Blinding is not easy to accomplish in the best of circumstances. For example comparing two drugs with different side effect profiles allows for personnel to be fairly well able to know which treatment is being given. In that sense TDOX is not unique.
So to be able to support the well-controlled claim, sponsors routinely set up procedures to ensure the blinding as well as they can, or do things in such a way as to minimize the effect of inadequate blinding. Examples in TDOX would be that shielding vials to hide color of drug, having independent scan review since treating physician will probably be able to guess based on labs and side effects, etc.
Such procedures could also include having separate personnel responsible for safety monitoring and efficacy monitoring. Putting such procedures in place and documenting them is an integral part of the NDA process. Having an experienced DMC responsible for helping ensure the trial is scientifically valid allows a company to anticipate potential problems in blinding. The alopecia and white counts are clear potential problems for blinding. A prudent company would set up SOPs to avoid these issues.
All that said, if a sponsor wants to break the code they can circumvent their SOPs and break the code. I suggest it would be easier to just look at the randomization list and get all the pt assignments rather than guess based on labs and AEs.
So I believe but don’t know that CLSN has procedures in place to address this. And I believe they would be foolish to jeopardize the trial to get knowledge of who is getting what.
But I do believe management has a good sense of the results for the same 2 reasons that I have that sense. First simple arithmetic using publically available enrollment data and times when event milestones were reached gives an overall PFS median of at least 20 months. This is far above published control rates and while not conclusive is highly encouraging.
Second the DMC recommendation at the interim to add additional look based on results at or better than the boundary. Note the potential impact on the conduct of the trial should be covered in the above mentioned well-controlled justification.
Re: Japan:
See http://investor.celsion.com/releasedetail.cfm?ReleaseID=549437
"The Company further announced that the DMC has maintained its recommendation to continue withholding enrollment of additional patients in Japan pending certain guidance from the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. The recommendation follows a review of safety data from 18 Japanese patients enrolled in the study, when compared to patient data from the rest of the Phase III trial. As a part of its commitment to Japan's PMDA, the DMC independently assesses patients randomized at Japanese sites. As previously noted, overall toxicities for patients in the HEAT study are consistent with doxorubicin's labeled safety profile. Doxorubicin, the active therapeutic in ThermoDox®, is a widely used chemotherapeutic with a well known safety profile and approved globally for use, including Japan, in many cancer indications. "
Please note the second to last sentence, "As previously noted, overall toxicities for patients in the HEAT study are consistent with doxorubicin's labeled safety profile."
The best guess here is simply the standard of care differences are too great for valid comparisons. RFA in Japan evidently comprises a much longer stay in the hospital that it does elsewhere, with much closer monitoring. Thus, we'd have a huge collection of headaches, fatigue, nausea, etc listed as AEs compared to other countries. They were very careful to say the overall AEs were comparable to known dox, though.
No one has actually tackled the second part of the question and it's legitimate to answer because it certainly sounds bad.
Longs probably know all this, but newbies might not.
The issue is that only the 11/28/11 review (the interim look) was an official peek for safety, futility, and success. And that look has an extremely high bar for success. In layperson terms, it'd be like trying to judge if a coin were fair by flipping it only 50 times - if it comes up heads 20 times, can you "guarantee" that it is fair? How about 22? 25?
The remaining dates he listed (and he missed several, before the interim look!) were simply reviews for safety. He's also stupid, for a bear, neglecting to point out the one "almost" bad thing resulting from these safety reviews, which was the DMC decision in late 2010 to halt enrollment in Japan.
There was absolutely NO possibility of halting those other reviews for success. When he says "no benefit" it is a total mischaracterization. I kind of doubt the "Dr." part of Tony.
I'm just Pollyanna this morning, huh?
'... It depends whether CLSN gets bought out immediately or raises money and continues to be an independent company. With few quarters of revenue of TDOX, CLSN can easily be a 200 dollar stock by end of 2014.'
Doubtful, IMO. With FDA approval probable in 1Q14, Europe in 2/3Q14, and China 4Q(ish)14, and the inevitable ramp, we won't have 'a few quarters of revenue" until mid-to-late 2015.
And that will be HCC-only, which is not a large indication in US/Eur. We need ABLATE data (2Q14 or so?) to expand to MLC, and I do not recall ABLATE was registrational. But with good data you'll see a lot more off-label usage.
I can see $50+ by the end of '14, a LOT would have to go fantastically right to get to triple digits. All IMO.
Trond
Careful with the optimism there.
Double blinding also means that patient data is shielded. They may suspect (okay, know) on a doctor/patient level that the patient had TDox and not placebo, and the dashboard would show data relating to AEs like that, BUT ...
the data would also be masked so that nobody can arrive at if a particular patient who had a particular AE has yet evented.
And trial site docs would NOT risk their reputation (and future trial $$$) by telling mgmt how individual patients are doing.
Is it possible? Of course. Is it probable? No.
All IMO.
Trond
This was a Very Good article, written for the layperson but nothing *wrong* either. (heehee, except the MLC indication)
Agree with you here! Have to assume approval based on meeting primary endpoints.
I will caution that CMC can really muck up the process though. Don't know if you are familiar with Discovery Labs - they have a really good product - surfaxin - that the FDA seemingly just didn't trust on the manufacturing side for about 3 straight years.
And yes, price should precede approval.
My "too early" was really directed towards using PE or sales estimates prior to HEAT data. Once we know what we are dealing with, it is MUCH easier to construct models.
Best,
Trond
yes, LTG, it certainly will be discussed, and often...
IMO, it will be ad nauseam.
There will be hundreds of posts that disagree violently on whether we should assign a PE multiplier of 20 or 25. Or maybe a xSales of 5? Maybe 7?
But IMO for a biotech that has one candidate for approval, with segmented geographical availability, and EXTREMELY lumpy sales for years out, and LOTS of costs coming up... trying to nail down a SP target by using a single multiple is just wasting lots of bandwidth.
IMO, by the way, means "in my opinion" and that is ALL this post is... my opinion.
Pricing, BTW, has only ever been addressed by MT by saying it's too early to speak of pricing. Bios will hardly ever talk pricing before the drug is actually approved. We can only talk ranges, and even that is probably going to be strongly influenced by the HEAT data. 12v16 will be much different that 13v30, for example.
umiak,
Good point, multiples will be important to consider for valuation.
Too early, IMO to use anything like this, though. We don't even know pricing and that will be a year out still, assuming approval.
Analyst estimates will be all over the place depending on how conservative they are. US/Eu will be assumed first, and I doubt that most will be brave enough to include China earlier than 2015. HCC only will also make it tough to show impressive numbers right off.
And of course there will be discounts for time, for approval risk, and for execution risk.
IMO, we see $16-22 after data, unless extremely impressive, where we could spike higher. One of my main worries was macro and that seems to be okay at this point *grin*.
Happy New Year to all.
Best,
Trond
Looping sez,
"... you're affiliated to SA, trashing Celsion stock somehow regardless. If you feel that unsecure about this paricular stock let it go and come back to the board crying after data release in a couple of weeks."
My reply:
Bwhahahahahahaha. If you think my almost relentlessly and publicly bullish stance on Celsion for the Last. Three. Years can be taken as "trashing" then I simply don't understand your reading skill level.
Between several social media methods, the last 13 quarterly conference calls, innumerable conversations with MT or JC that I've posted publicly, a barrage of bearish articles I've commented on, and the inordinate amount of time I've spent following this stock and sharing info... if you find ANYTHING I've posted that trashes this stock then please enlighten me.
I absolutely recommend caution in one's investing:
- taking basis off the table
- not to indulge in options when timing is not precisely known
- to at least consider the role of (bad) luck in biotech trials
- to do one's own DD in some measure
- to realize brute force models come up with more optimistic scenarios than the Kaplan-Meier curves the actual HEAT analysis will use
I've been calling (for months) for somewhere around 14-15 months placebo PFS vs. 24-25 months TDox. I consider that bullish since the SPA wants 12v16. I am SO not unsecure about data release in anywhere from 4 to 40 days that I sleep quite well at night, even having some clients' money invested here. Again, please feel free to call this, "trashing Celsion stock."
Hmmph. Diatribe off.
Disclosure:
WRT "affiliated to SA" - absolutely false. I am registered at the site in order to comment on posts; I have never written an article there or been compensated in any way by them.
Disclaimer:
This is presented for educational and informational purposes only, and should not be construed as personalized legal, tax, investment, or financial advice. My own resources, risk tolerance, and personal situation have been taken into consideration for any trades mentioned and should not be used as a basis for someone else's trades. Stocks may lose value and this is not recommendation to buy or sell this particular issue.
GLTA (except shorts)
Trond
My reply on YMB, regarding the processing of data and what happens afterwards.
My opinion only on the timelines provided, and intended as a primer for people who may not know the details of the FDA decision process:
---
They have several steps to go through on a bureaucratic level.
First of all, the Jan data we're expecting is simply what is called "top line data".
That is, they have to tediously going through EVERY patients' records of EVERY single dr visit and scan. Keep in mind this is in ~11 different countries, 100+ sites, from up to 4 years of data in some cases. Then they double check each of these to make sure they entered the info correctly. This is important because once they signal they are ready to calculate ANY unblinded data, the data is locked, even if they find incorrect data later - and the FDA will not accept any corrected data (called post-hoc analysis). And people complain because it takes weeks-to-months for this process!
Once they are satisfied the data is correct, they unblind the data - letting them see what arms the patients are in. Then it literally takes only minutes to calculate the PFS comparison.
So that is topline data. A yes/no on PFS 33% improvement powered at 80%. Company will get a "little" more color on stats, but probably not much. They'll get some data on stratifications - like tumor size 3-5cm vs. 5-7cm and RFA procedure types.
Your question is what happens then. They start going through the data with a fine tooth comb, teasing out all sorts of comparisons; gender, age, tumor size broken out more finely, and 180 other ways I can't even guess at. The FDA will want all sorts of combinations and it takes lots of person-hours to simply wade through these and actually digest the results.
Once they have a degree of comfort with the data, they can ask for a pre-NDA meeting (don't recall the official name for it). They'll get more clarity from the FDA on exactly what comparisons they should be looking at, for example. THAT MEETING CAN TAKE TWO MONTHS TO SCHEDULE. And that is AFTER they have waded thru the data.
I expect if we get data in Jan, we will file the NDA in July.
We do have FastTrack status which allows us to file a "rolling NDA". The NDA has several modules and the rolling part means we can file some of them early. We probably already have the preclinical and manufacturing (CMC) modules ready to file. But here's the thing: although we can file some of it early, NONE of it is reviewed until we have finished all of it and they have accepted the filing.
I expect the acceptance to come in August-ish. If accepted then because of Accelerated Approval we will be issued a PDUFA Date six months after the filing date. I thus expect a PDUFA date in January 2014.
They can approve or issue a CRL earlier, but I expect them to take approximately the whole time. I've seen every argument that the FDA "wants" this treatment but put no stock in it - bureaucracy reigns supreme. I'd love to be disappointed and again admit it could happen but MY OPINION ONLY is that we get approval sometime in Jan14.
I am relatively certain the overall process is as I describe but if anyone can fill in more details or correct any of it I would appreciate it.
Best,
Trond Hildahl
umsugarplum, no disrespect was intended. I agree with you.
But we have an awful lot of newbies who are reading these boards and I've seen way too many times where a general post, by someone who knows the story, gets picked up and repeated with each-time-exagerated prowess... that's all I'm trying to provide.
Trond
I was away from IHUB for several months but I'm quite confident Sia is as respected here as anywhere. He is THE person to follow for trial and data issues.
His reply to this "Biotech Sage" is spot on and should be screamed from the rooftops. Its worth re-reading several times; I learned or was reminded of something a couple times already.
I am personally certain that "BS" is simply a rather large short trying to escape his/her position.
But a reminder: nothing in biotech is absolutely certain and while I'm long, I've already taken basis+ out. Things go wrong and even though a long shot, data can simply be screwed up without it being a conspiracy. Look at PPHM (Peregrin) from a couple months ago as an example - their data was simply copied down wrong between arms and the company lost 75% of its value while they go back and try to figure out the correct data. IMO never bet the farm (just most of the cows).
You said
>>Doxorubicin is prescribed for treating several types of cancer, including certain types of leukemia, breast cancer, Hodgkin's disease, and lung cancer. While doxorubicin can kill both healthy and cancerous cells, it has a greater effect on the cancer cells because they multiply more rapidly. Some off-label doxorubicin uses can include treating other types of cancer that the medication has not been approved to treat.
Leukemia for one is out, for now. Keep in mind we have to also have a way to heat the TDox where it is present in order to release it. Solid tumors are where we will position ourselves for quite a while.
Also, though, dox is not the only chemo we can encapsulate. I am hoping to hear more of carboplatin, e.g., following good HEAT data.
You asked
>>When is the news expected.
This is more of a musings post and I have no claim to any better understanding than anyone else.
The company has stated "Data in January." We have absolutely no other knowledge except that. Most people are worried about January 18th because that is Jan opex. Others are worried simply because they want to be out before data release.
IMO in the second case one should consider selling or hedging soon. We have had one heck of a runup (although obviously a lot of peope have recently bought in the 7s and 8s and so are not up by very much) and while we could certainly go the low double digits, we could also simply bounce around for 2-4 weeks between $7 and $8.50. If you're only in it for a trade, and have to ask advice on a message board, then take your profit and run.
If you are worried about opex, then it is more critical, because it's 100% loss if you are wrong on timing. My general advice is always, "It takes longer than you think."
More musings:
They announced they had "projected" 380 events on Monday 11/12/12.
They get blinded #s of events so could project it pretty closely, it is assumed that they only announced after they were pretty certain it had occurred, with a cushion of a few more. (the risk there is that upon review, some of what were assumed to be progression really weren't and so they'd have to wait until they legitimately hit 380).
Ten weeks from that date is Monday 1/21/13. That is one trading day AFTER Jan opex.
There is nothing magical about ten weeks except that in interim timing they had said 8-10 weeks and it was closer to 12-13 weeks (and every one of those days after 10 weeks had passed was agony).
Last time I spoke to Jeff Church I asked if final data scrub would be "easier" because they had already gone through so much data for the first 219 events from the interim review. (IOW they only had to look at another 180 or so) As expected he said they'd be re-reviewing ALL the data. This is because once they lock the database and commit to unblinding the arms, they cannot change anything, even if wrong. The FDA can only look at the locked data, anything else is considered post-hoc analysis.
MT has said several times he wants the data to be ACTIONABLE. IE, correct in all respects.
OTOH, it's been mentioned that it is convenient for the DMC (all geographically proximate) to meet in very early Jan.
And there's a conference (don't recall which one) in mid Jan that would be logical and great to present late-breaking data at, if available. Some very smart people are banking on that combo to mean data will occur by then.
My bottom line: Only options I hold right now are Feb13 or later. I've already sold personally the shares I need to in order to derisk. I have no need to guess when in January we get data. If I had to, though, I would NOT put myself in a position where I had to be right, before Jan opex. IMHO it will be later Jan (but I'd love to be wrong!)
GLTA
Trond Hildahl
*** This is presented for educational and informational purposes only, and should not be construed as personalized legal, tax, investment, or financial advice. My own resources, risk tolerance, and personal situation have been taken into consideration for any trades mentioned and should not be used as a basis for someone else's trades.
*** Stocks may lose value and this is not recommendation to buy or sell this particular issue.
NDG you are quite right. I apologize to all about that comment.
I'm not a trader and am just not concerned about daily fluctuations but that doesn't mean it's not important to those doing shorter term trading as their bread-and-butter.
Happy weekend, all.
I have to say it still astonishes me about all the posts about daily price movement.
We will not get HEAT data until January. We may get some PR about the HIFU trial enrolling or DIGNITY/ABLATE blah-blah (I doubt this, BTW, mgmt has the IMO nice habit of NOT releasing "fluff" PRs), but nothing else really matters for us right now until we find out about HEAT.
We're at year end, with the additional impact of tax selling due to fiscal-cliff tax-increase-worries, and we've had a recent run-up, with a barrage of negative articles (barrage, hah - more like 3?). A combo like that naturally means the momo players start moving out as soon as their charts tell them it's going down. With a recent rise, it brought out extra short sellers, who naturally short biotechs on the verge of results - historically it's a good play. And nervous nellies who bought in late will be selling early.
Most longs who know the story pretty much exhausted their dry powder already. For example, my last "large" buy was pretty much a year ago when we were in the $2s. If I had more, I'd already have bought in the $3s, or $4s, or $5s, or $6s... good grief, people chattering about going from $8 to $7?
Sorry for the venting post. If you're worried, sell. If you're a trader, make your choice on your TA.
If you're an investor, take this time of "worry" and make your decisions about when and what prices you truly will sell at, and set your limits. Much better to do this when you are realistically worried, and not when SP starts acting bullish again and you get swept away.
Last note, I am personally agnostic wrt Jan13 options. I see no impressive arguments that we will get data before the Jan13 opex. We certainly *could* but nothing with certainty. Last time I spoke to Jeff Church I asked if the final data scrub would take less time because they'd already done 209 at the interim scrub. His answer was that they'd redo it all. One because obviously some of those patients continued to accrue data (dr visits/scans, etc) and two because this data is the most important of this company's life. Getting it right is more important than doing it quickly. Ten weeks from the 380 PR is exactly one trading day AFTER Jan opex.
GLTA
Trond Hildahl
>>I assume the phase 3 is over and the analysis process has been happening for the last weeks, which could be 'leaked'?!
Impossible. Yes the ph3 met the 380 events necessary for unblinding, but that process will take us into January before they become unblinded. There is nothing to be leaked, yet, just individual patients' data that cannot be traced to a particular arm.
Biomanbaba, thanks for the note. I have not looked here before, but looks interesting after a cursory glance.
My first impression is that we're too early for both drugs and cash; it appears even after the early Dec financing that they only have about 4 more months operating income before they have to go back to the well again. Is that correct?
CALAA01 looks interesting. I put no stock in the weight loss there, way too early (and I'm rooting for ARNA in that space).
Overall I've put it on my watchlist but if you know of anything that makes it more of a priority, let me know.
Thanks again (and no offense to this board's regulars).
Trond
Ph1 vs. ph3 comparison.
Huge props to roseny1, YMB poster.
From YMB, MUCH better than I could describe it. IMO one of the most important posts of the year.
http://finance.yahoo.com/mbview/threadview/;_ylt=Aq5CzNDlvMYRvBHnG5q7MATeAohG;_ylu=X3oDMTFqcDkwNG1uBG1pdANNZXNzYWdlIEJvYXJkcyB3aWRnZXQEcG9zAzUwBHNlYwNNZWRpYU1zZ0JvYXJkcw--;_ylg=X3oDMTFlamZvM2ZlBGludGwDdXMEbGFuZwNlbi11cwRwc3RhaWQDBHBzdGNhdAMEcHQDc2VjdGlvbnM-;_ylv=3?&bn=690bb330-e5e7-33e0-b867-fafc4d32ec82&tid=1355984089144-5cb337cd-2842-4ce9-a6f4-4c70852192db&tls=la%2Cd%2C23
The CEO in the 3Q webcast described the majority of P1 patients as "salvage" patients, who had had numerous prior chemo treatments. This very sick majority defined the low P1 medians. To understand how prior treatments effect things look at the Yin study (on Bio blog). This study's first-treatment cohort is considered by the CLSN CMO to be the best comparison with the P3 control. In Yin the first-treated had a time to median DR (distant recurrence) of 21 months, whereas the prior treated had a median time of just 6.7 months. Big difference!
Now PFSs equal first DRs in patients plus first LRs (local recurrences) in patients (but only 1 LR or 1 DR per patient). In the CLSN P1 (which measured TTF, time to treatment failure, which is fairly close to PFS) less then 5% of the treatment failures came from LRs. This is very low, for example in Yin first-treated and prior-treated patients both had about 22% LRs. What this less-then-5% LRs with T-dox means is that at least 45% of P1 median treatment failures came from DRs. Now since the dose response was statistically significant and the highest dose more than doubled lowest dose in TTF, this means that T-dox WAS effective against both LRs and DRs.
The YIN study first-treated cohort also predicts that the P3 control will be under 11 months to median PFS. This is because it was at a DR rate of 47% at 11 months (it then took 21 months to get to 50%) and to get PFS median LRs must still be added which will take this cohort to a median PFS time at something less than 11 months. Thus the P1 predicts P3 success as does the Yin study.
You are welcome, and I appreciate the comments.
I do have one correction to the article, having written this too quickly off just my recollection about the Yakult partnership.
The reduction applies ONLY to the approval milestone payment of $18M. Basically Yakult paid $2M more upfront, maybe another $2M later, and then would avoid paying an extra $7.2M, which is the 40% of the $18M approval milestone.
Royalties are not affected. Details are in Note 13 of the 1Q11 10Q.
-Trond
Sorry to tease but yes, I'm pimping for hits, lol....
Anyway, I do have friends who are in ONTY and I really feel for them. I know the feeling quite well, was in Elan for both the PML and ICAD drops, and DNDN on their first CRL.
That prompted me to write this, wrt CLSN:
http://trondsworld24.blogspot.com/2012/12/celsion-and-oncothyreon.html
No-dough seems to answered the six month question thoroughly.
I'm too wrapped up in the story, not sure where this six month thing even came from. Mgmt has insisted from the trial construction that expected PFS for the placebo arm is 11-12 months. And as recently as the last CC they affirmed 12 months from the literature.
The problem is that liver cancer is very varied. Lots of things interact, size & # of tumors, Child-Pugh, even how close the tumor is to major veins. There are quite a few trials but almost none are apples to apples.
I brought this up in a conversation with MT a year or so ago and he agreed - that HEAT is pretty much going to be THE definitive trial going forward for RFA comparisons. We were among the largest ever HCC trials w/ 600 and now that its expanded to 700 it might be THE largest. With arms 1:1 that is 350 RFA patients, stratified by tumor size and ablation type.
KEY take-away: all other trials vs RFA will have to surpass Themodox's performance if good!
More precisely to the original point, Karin had it right that HEAT is RFA-alone vs. RFA+TDox. RFA works, and is "curative" for smaller tumors that are amenable to RFA (20-35%ish of the HCC indication). But local progression frequently occurs because of micromets that left behind in the ablative fringe. TDox should help immensely in keeping local reoccurance from happening. That leaves progression elsewhere in the liver or outside the liver as the main things to worry about, and they WILL happen. Just not as timely.
I'm a bull, but eyes open - the distant mets issue is real. But size of trial, size of ph1, and similar "problems" are red herrings.
Been awhile since I posted here. Lol... think it was sub $3 last time.
I left a couple comments on the Seeking Alpha bear piece, this is the first of them.
--
OK, time for a structured criticism of this article.
You have three main points, 1) Limited clinical experience with ThermoDox, 2) Phase 1 data fail to demonstrate a clear dose-response, and 3) RFA+ThermoDox responses are consistent with RFA alone.
For point #1, I cede the point that the ph1 was small, and as you say the HCC patient count was minute.
However, it was also on the basis of this trial, as well as animal studies that we are not privy to, that the FDA agreed to an SPA. While many SPA-granted trials fail, it is at least recognition that the trial data was meaningful.
Further, the NIH has designated HEAT a Priority Trial, again while meaningless for approval purposes, this is only one of 8 or so HCC trials granted this distinction out of the 400+ HCC trials currently underway.
Finally, you point out that only 1 patient in ph1 had HCC and tumor size > 3cm treated at 50mg. I admit this is an absurdly small size to bet a ph3 global trial. Fortunately, we also have the MLC patients which also showed a dose-response. We have ph1 data in recurrent chest-wall cancer which showed a 45% “clinically meaningful” response rate. We have buy in from Philips Healthcare which partnered to design a ph2 trial for palliation of painful bone-metastases. We have the company’s willingness to use precious dollars to begin the ph2 ABLATE trial prior to HEAT results, and begin enrollment in the ph2 section of the RCW DIGNITY study. Japanese partner Yakult agreed to pay an additional upfront payment in early 2011 in order to garner future lower royalty rates. Why on earth would they pay more than they had to now, if their best medical people thought it might fail, based on one such ph1 patient?
For point #2, you claim the ph1 data does not demonstrate a dose-response. However the study abstract concluded the dose-response was statistically significant – I am not quite sure how you manage to word your way around that.
The abstract also notes the median tumor was 3.7cm. So pairing that with the decision to enroll patients up to 7cm, which was driven by key opinion leaders, I want to point out 2 issues of why TDox+RFA should work in the real world (please see page 15 from the presentation poster available from http://bit.ly/UFI2P4: a) The cyctotoxic effect of dox is enhanced by heat. b) Dox reduces the ablation threshold temperature.
So we are releasing dox by heating the TDox IN the tumor tissue. I do not believe you are arguing that does not occur? Dox is more effective and the abalative zone increases because dox is present. It is not a very large jump to predict that larger tumors are naturally a better target.
And lastly, please see http://1.usa.gov/T5b8sS, where it states, “RFA/LTLD can treat Child-Pugh class A-B patients with tumors up to 7 cm, a substantial increase in curable patients.” Kindly note the word, “curable.”
Finally, for point #3, you argue RFA alone is as effective as RFA+TDox.
I love this! In your article, you specifically (sentence 3 under the section bolded, “Phase 1 data fail to demonstrate a clear dose response”) say, “The data clearly suggests that only HCC patients derive a benefit from ThermoDox therapy, while other liver metastases do not.” Regardless of other liver metastases, HEAT is HCC-only and you’ve here admitted these patients derive a benefit! Your own words kind of blows up your main thesis, hmmm?
Now, in the Wang et al study you cite, the most important statement is, “The ablative volume decrease was significantly greater for the RFA alone group than for the combination group (26.1 vs. 12.1%, p = 0.018).”
Really think about what this says. The combo group lost 14% less than RFA-only, a stat-sig result! In essence, you are arguing then the combination group DECREASED the effectiveness of RFA. Since you already ceded the point that HCC patients derive a benefit from Thermodox, this study is obviously totally inappropriate for comparison purposes. Another comment already notes that pegylated liposomal doxorubicin is not really comparable to Thermodix anyways…
Let me summarize your article back to you.
The ph1 trial was very small.
Fortunately the company had lots of preclinical data and an entirely understood MOA and already-approved drug to reassure the FDA that a jump to an SPA-granted ph3 was justified.
Fortunately the ph1 data was statistically significant in dose response, even though it was tiny! Trials that aren’t really comparable don’t show much correlation.
The only thing I agree with you on, really, is that you should not invest more on either the short or long side than you can afford to lose. I hope you’ve followed that on your short here.
Trond Hildahl
Ticker changes - we don't have an "Ultrasonic Generator Technology."
But we do have a pretty good pipeline, although young, and results coming up for a ph2b trial in type 2 diabetes - HUGE market. It'll take years, not months .... but mgmt has indicated once they have good-to-great results with LX4211, they'll partner it out. A Big Pharma will have the cash and resources to pilot it through a ph3 and an NDA. Short term, we have LX4211 results in about 2 more weeks, and if good we should see another 10-20% move. Percentage wise not too much, because we've had a pretty good runup already, from the $1.55 area. I'd love to be wrong on the low end though!
Best regards,
Trond
Ok, I understand your point that PR does not specifically say the DMC said "take another look." I think they would not approach FDA w/ amendment proposal unless they had "something" from them, though.
On cash, why so hard? "Dire need", etc. That is wording for cash under 3-6 months - we have under a year yes, but it's more like 8-11 months. And I think even the possibility of a license deal will keep us in the $2s and eventually the $3s.
-Trond
Been posting on YMB and IV, but here are my thoughts as of now:
http://trondsworld24.blogspot.com/2011/11/celsion-safely-past-interim-look.html
Bottom line - there is NO reason the DMC advised asking to amend SPA unless the data said it was a good idea. That is the real "tell" from the interim.
-Trond
Some thoughts, now that I've digested today...
Posted on the yahoo board...
Cash burn almost $7M - said will decrease slightly. But w/ ABLATE started it won't go down too much. With $21.4M in cash, we have three full quarters - end of Q2 2012. THIS MEANS WE HAVE LESS THAN ONE YEAR. I'd expect a cash raise if the last-second interim runup+presentations get us to $4+. We'll scream and holler, especially if we get a successful interim, but if its a continue and we sink to $2.50 then we'll be glad we did. Probably a $15-18M raise, to be sure we get through end of Q4 - whatever shares that works out to be at the price we're at.
700 enrollment target is really great news, after thinking about it. And he said China is "quickly approaching" 200, which probably means they've enrolled at least 30 odd patients (from the 40-50 they needed). Since 7/29, that's a bit more than 3 months... so almost 10 a month? We'll be there by the end of the year.
I'm curious where the other 50-60 patients are coming from? Spread from a bunch of sites or targeted in Asian countries? If we can get 10/month from all countries we could be fully enrolled by eoQ2... HOPE its quicker, but we all know how enrollment has gone for us. Seeing that in black & while (or, pixels...) makes me think 4q12 is not a shoe in for the final 380, but the extra enrollees definitely will help!
Problem is, if median is what we want, then extra "new enrollees" might "drag down" the Tdox arm at final. Any thoughts here? In other words, using a small N, if we had 12,16,20,24,28,32,40,44,44 - then the median is 28. But with a flood of new enrollees, we see the 12s, 16s, and 20s repeat .. so you have 12,12,16,16,20,20,24,28,32,40,44,44. That drags the median down to 20. Ouch -- any thoughts, summer, kid?
Got it straight in my mind that 190 did NOT occur as I assumed - by 8/14. Probably closer to 9/12-9/16? 11/25 then becomes 10 weeks. Would they REALLY be off too much in the 8-10 weeks, when they are at least six weeks into that period?
Placebo median remains the absolute key. If the company is right about 12 months, then its locked... the variance from that is the sole thing that determines our fate vis-a-vis the interim. I ask the board again - what would cause this to be higher than anticipated?
Regards,
Trond
I was speaking of Jan options still being okay exactly because we still have the interim results to look forward to. I do have some Jan's, and I'm only in them because I'm half expecting an interim success. Risk/reward-wise, there's nothing like them right now.
Investor/Gambler ... you are right, but any option is a gamble. I've *always* said shares here are better than options.
Nevertheless, they are a tool to increase leverage. $0.40 of Jan5s, if the share price is $20, is $15 intrinsically, or 37x your basis. Buying at $3 gets you less than 7x. With a little mad money, I'll take those odds.
I also don't necessarily agree that on a continue, we're sentenced to $2.75 or less all the way through Jan. Yes, we'd probably dip somewhat... but China is almost finished enrolling and they are going to go to 700 enrollment. With that, I can see getting to the 380 by eo12 - and w/ a continue funds will start positioning for that. They're hitting the road hard coming up, and getting past this interim takes nearly ALL the "real" risk out of a position.
Only a couple more weeks until we find out! TG!
-Trond
I wouldn't say Jan options are toast. Looks like 12/9/11 now the latest date.
8-10 weeks, and 190 occurred in Q3. 10 weeks from 9/30 is 12/9.
Only new of note from the 8K is that cash burn higher than projected and that 190 events were confirmed "in the 3rd quarter".
I woul not expect ANY HEAT news tomorrow - they will punt on it if they have not heard from DMC. And I think they have not heard because that would easily take up its own conference call.
Expect to hear a lot about ABLATE, and questions and expenses/cash.
-Trond
... so you're saying you have a chance with Lindsey Lohan?