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Thar' She Blows!
Thanks...the first spotting of the great whale (Chronic Pain)
I agree its a positive (and apparently the market does too!).
It seems to me that Titan just doesn't have the bodies to deal with the issue: not enough of a critical mass to spend significant time on a "rest of the world" marketing deal for probuphine. So we get lip service, but no progress (a consistent theme...).
That's why I'd be thrilled if Braeburn were to buy up ROW rights from Titan even for a one time purchase of $25 million or so (I remember Higgins thought ROW rights were worth $50-$60 million). Sure, we'd lose some royalties in the long run, but I think North America is the best market in the long run and in the short run they could fund parkinsons without the need to dilute shareholders with a secondary offering using the shelf.
I think they are handing off Canada to a licensee more qualified to address that market.
Titan still gets its % of all sales. Financial terms were not disclosed, but I didn't see an upfront license payment mentioned. Titan would receive its royalty % of an upfront payment as well, but perhaps Braeburn opted for a higher royalty % for itself in lieu of an upfront payment.
Yes, we can be thankful at least for that. Resolution, one way or the other, will be good. Well, it will only be good one way actually...
I think that's old information? From Titan's most recent 10-K
"In October 2012, Series B Warrants to purchase 4,627,941 shares of common stock were exercised resulting in gross proceeds of approximately $3,934,000."
Agreed...a definitive bias against small pharma at the FDA. Having Braeburn and Dr. Young behind probuphine should help this time...if it was Titan alone, I think we would have received a CRL already (not on the merits of the NDA, just because the FDA enjoys playing the bully).
Plus...this time a CRL will undoubtedly result in an appeal by Braeburn (similar to VAnda on iloperidone). And a lot of press documenting that appeal, bringing more attention to their questionable decision-making.
Zacks
"We are not sure if two positive advisory committee votes (2013 & 2016) and positive data from three Phase 3 trials will be enough for approval this time around, so we will just have to wait and see until the agency action date."
This is why we are in the 3's. There is only one rational decision for the FDA to make. The question isn't the safety, efficacy or need for probuphine, the question is the rationality of the FDA.
Agreed, there is a lot to look forward to...if probuphine is approved. That "if" is why we are trading at fifty cents a share pre-split. All that is left are retail "investors." No "trader" in his right mind would own the stock now: too many things can go wrong. No hedge funds or institutions are going to gamble money right now. And so with a relatively small investment dollar-wise, a market maker can easily manipulate the stock price and dry up momentum. That's what I think has happened.
I think the FDA knows this will be big if approved, which is why they have been so cautious (even antagonistic). Why wouldn't a doctor prescribe probuphine as a "failsafe" measure, then use SL buprenorhpine to bridge the gap needed to alleviate symptoms of withdrawal. The alternative is to trust an addict. You do the math.
If approved, there will be a lot of catalysts: the fanfare of the Braeburn launch, the DATA 2000 regulations, a sNDA study for chronic pain, a ROW marketing deal. I did the math and assuming they can get to 300 million in sales by year 5 and no growth after that, the present value (discounted at 5% per year) of probuphine royalty and milestone payments over the next ten years is $600 million. That's not including a supplemental pain indication.
Add in ropinrole and the thyroid thing. Add in 20 million shares outstanding, 4 million of which are held by "insiders" and institutions buying up 50-75% of the float leaving very, very few shares left for retail johnny-come-latelys...it's just supply and demand.
And as for a buyout...Braeburn describes itself as a "pill-less" drug company. Hmmm, who fits that profile. For the price of the present value of likely royalty payments, you could get chronic pain, probuphine worldwide rights, parkinson's and oh...what is the net operating loss carryforward...something in the hundreds of millions? So they would also get to keep hundreds of millions of dollars rather than lose it to taxes.
But we are nowhere without approval. And so we wait.
It's about what I'd expect from the business insurance trade publication...if my insurance company is any gauge, any payout whatsoever is bad business.
DATA 2000 BUPRENORPHINE PRESCRIPTION LIMITS
Apparently on January 7th the Department of Health & Human Services has provided to the White House its proposed changes to the buprenorphine prescription rules. http://www.reginfo.gov/public/do/eoDetails?rrid=125851
As best as I can tell, the time line is the rule will be published in April 2016 with the public comment period ending in June 2016. http://www.reginfo.gov/public/do/eAgendaViewRule?pubId=201510&RIN=0930-AA22
Interesting excerpt: "This rule is needed to improve the national response to the rise in prescribed opioid misuse and heroin use and related morbidity and mortality by proposing an approach to increasing access to buprenorphine treatment while protecting against diversion."
If they stick to their statutory authorization (a big if...), the FDA is supposed to consider the public need for the drug when doing its cost-benefit analysis on approval.
Need has been demonstrated in that probuphine is much less likely to be abused or diverted than current forms of orally administered buprenorphine.
And as has been pointed out countless times on this board, need has been demonstrated by the fact that, despite the availability of orally administered buprenorphine over the past decade, the epidemic of addiction to opioids continues to grow: much worse now than it was in 2013 when the first CRL was issued. The currently marketed solutions are not reversing that epidemic, and health care providers need every weapon in their arsenal to fight addiction.
I limited my search to psychopharmalogical advisory committee approvals, and I didn't find one approved by the Ad Comm the first time that had a second Ad Comm...but there isn't a database or anything so I may have missed one.
This is probably worth what you’re paying for it, but over the weekend I looked at how drugs reviewed by the Psychopharmacologic Advisory Committee did following their Ad Com’s in recent years. Specifically, I looked at Ad Comm votes where at least 50% of the members voted yes, but it was not unanimous (similar to the vote for probuphine).
From what I can tell:
For Astra Zeneca’s Seroquel XR for major depressive disorder, the Ad Comm voted 4-4 and the FDA approved.
For Alexza Pharma’s Adsuave for schizophrenia, the Ad Comm voted 9-8 YES, but the FDA issued a CRL. The FDA later approved the drug on resubmission without an Ad Comm.
For Eli Lilly’s Zyprexia for bipolar disorder, the Ad Comm voted 11-4 to approve, and the FDA then approved.
For Eli Lilly’s Zyprexia for schizophrenia, the Ad Comm voted 10-4 to approve, and the FDA then approved.
For Titan’s 2013 probuphine NDA, the FDA voted 10-4 to approve, and issued a CRL.
For Lunbeck’s Rexulti for schizophrenia, the Ad Comm voted 8-2 to approve, and the FDA issued a CRL. Rexulti was approved last year on resubmission without an Ad Comm.
Thus, probuphine is the only one not eventually approved. On the whole, I think this bodes well, but who knows when the FDA is involved.
Nice call
Looks like another fun day. If my math is correct, it was worth more per share the day after the CRL in 2013.
Brutal.
We don't really know the cap until we see how well it sells, but if approved (fingers crossed) I doubt we ever get to see...Braeburn is smart enough to eat this thing up. Assume Braeburn forecasts $2.0 billion in sales over 10 years...by purchasing TTNP for $250 million they would be avoiding around $400 million in royalty payments and $165 million in milestone payments and have chronic pain all to themselves with ropinrole (right in their CNS wheelhouse) to boot. Plus, they own 10% so their costs are even less...
Well, you’re entitled to disagree with how they treated the missing urine tests. Braeburn took the position that with a clinically stable population, it was unreasonable to automatically impute a missing test as positive for illicit opioid use, and instead assumed missing values would be similar to non-missing values. To be conservative, the imposed a “20% penalty” penalty on any missing value in the probuphine arm which they did not apply to the SL buprenorphine arm. The FDA didn’t like that apparently (or perhaps didn’t like it showed they should have approved the drug the first time around), and so had them do all sorts of sensitivity analyses to show less robust efficacy. It worked, kind of, because when you assume missing to be positive, efficacy drops, but probuphine still remained non-inferior.
As the drop-out rate was very similar (6 of 87 for probuphine and 5 of 89 for SL buprenorphine) between the two patient arms, perhaps they didn’t think it merited highlighting in a press release. The same can be said of the need for rescue meds.
Luckily, you have a chance to get out now with a portion of your investment if you so choose. I think the data justifies approval (as have two Advisory Committees), but I also sense a lingering animosity on the part of the FDA staff. I mean, there is not one, single positive thing to say about probuphine? It's not anything Braeburn or Titan has done that worries me...it's ego of the FDA reviewers.
We shall see...
A thought...
Stepping back from the microcosm of the daily share price fluctuations to view the big picture, has anyone noticed that the Department of Health and Human Services hasn't come out with the revision to the DATA 2000 buprenorphine prescription limits yet?
I thought it was a little weird when Braeburn issued a press release on it back in September. To me, you don't issue a press release like this unless you are trying to butter someone up. https://braeburnpharmaceuticals.com/braeburn-pharmaceuticals-commends-hhs-secretary-burwell-for-initiative-to-expand-access-to-medication-assisted-treatment-for-opioid-addiction/
Is it possible HHS is waiting for a decision on probuphine before issuing the guidelines...i.e., they are planning on exempting probuphine from the prescription limitations?
Hmmm.
It's laughable. The time to sell on the news is over, so this must be manipulation. Pretty transparent, but admittedly frustrating...and they count on frustration to shake loose shares.
BioTuesdays
Nice to see another positive article that doesn't just reiterate the concerns raised by the CDER staff.
http://biotuesdays.com/2016/01/13/fda-committee-votes-to-approve-titans-probuphine/
Definitely, I’ll take it.
Remember this time yesterday, when they were about to vote on question #8. If someone would have guaranteed a 12-5 yes vote and 15% gain the next day, you would have been happy.
I’m not smart enough to figure today out. Selling on the news? Maybe. Naked shorting? Okay, sure.
My net net is we are up today, and still alive to fight another day. Two approvals by Advisory Committees by a 70% margin on a drug for an indication recognized as an epidemic by the POTUS and HHS.
I understand Braeburn went quiet before the advisory committee so as to not give the FDA any ammunition against it. Now is the time to reverse course, get the message out, and amp up the pressure on the FDA decision makers.
For Titan, it needs to start thinking real deal analysts coverage post-approval. Which means having a story about how much an implant will cost, how much Braeburn is spending on marketing and training and getting off their @#$ on ropinrole.
Well, if you're right, here's hoping for a surprise early FDA approval that will squeeze the MMs.
I'm 4/4 so far on my predictions ...I'm buying a Power Ball ticket while my luck's still running.
Thanks, I appreciate your feeling for us long termers. But considering how things could have gone yesterday, I am happy we aren't at 30 cents right now. There will be time enough for gains later...the message needs to slowly get out.
With average biotechs on Nasdaq having 60-70% institutional ownership, and Titan having less than 1% institutional ownership, the buys are coming. Its not a matter of if but when, and the "when" won't happen until FDA approval. Until then, in the words of Shakespeare, its all "sound and fury, signifying nothing."
I second that thank you!
Thanks to all that reported!
I get what they are saying, but I just don't buy that line of reasoning. The extra medication is needed to suppress the symptoms of opioid withdrawal, not to block the effects of other illicit opioids. That to me is not a "rescue." The primary purpose for probuphine is to prevent further use of illicit opioids, not to make the patient absolutely 100% comfortable.
Preposterous is the right word for it. The FDA has coined the term "rescue" meds. What is the nature of the "rescue" taking place. Is it related to efficacy, i.e., preventing a user from getting high? No. Efficacy remains exactly the same whether or not rescue medication is used.The "rescue" is from symptoms of discomfort felt by less than one in five of trial participants from withdrawal from opiates. In other words, about 17% of people that use probuphine may need more juice in order not to feel so jumpy.
So, the logical solution appears to be to give them more juice in the form of a supplemental buprenorphine oral tablet or film. Coupled with the implant, you can alleve whatever symptoms of discomfort are being felt, and have 100% confidence that the patient cannot get high.
I cannot believe the need for rescue medications will be the cause of a CRL, but that's worth what you paid for it.
It's hard not to really despise the FDA...
Thank you...that was a great analysis. I hadn't gone into the Braeburn materials in detail, but you point out that they have an answered the FDA's arguments. Thanks again!
Yes, that passage is negative, but most of us expected the briefing document to be full of negatives. The FDA sees it as their role to unearth every possible problem for the advisory committee; it is certainly thorough but in my opinion creates more confusion than clarity.
I'd be interested to hear your thoughts. Mine are as follows:
1. The protocol specified analysis demonstrated non-inferiority. To me, case closed. The protocol was designed in conjunction with the FDA after all.
2. The protocol treated inconclusive urine testing as being "inconclusive." The FDA postulates that if the inconclusive testing were instead automatically assumed to be positive for illicit drug use, the trial results would not be anywhere near as good. But that would mean an ex post factor redesign of the protocol which, in my opinion, would be ridiculous, and I think they will get push back on the panel for that argument. I am sure Dr. Frank Young is ready for that one.
3. The FDA states that "one would expect" a clearer demonstration of superiority. That may be true, but the standard of review is non-inferiority, not superiority. Braeburn is well aware of that, and will hammer it in their presentation.
None of that means the FDA will approve probuphine. But their criticism, at least in this section of the briefing, appears based on "what ifs" and conjecture that have nothing to do with the standard of review they are charged with administering.
Adverse Events
So at page 97 of Braeburn's presentation, they note that in the sublingual buprenorphine arm of the study (not the probuphine arm), there was an adverse event when the 2yr old daughter of a study participant found her parent's buprenorphine pills and ingested them, necessitating a hospital visit, etc.
Funny...the FDA forgot to mention that.
I don't think its a reason to vote against probuphine. 15 participants on probuphine (17% of the group) needed rescue medication (one 4mg and the rest 2mg), and 13 in the control group needed it, so it's about the same proportionately. The probuphine users that needed rescue medication returned about half of the number of pills as the control group, so perhaps they needed more of a "rescue."
I like Question #9
The FDA thought a higher dosage of probuphine should be tested. Braeburn and Titan instead opted to test the same dosage on a more stable patient population, which was the smart play because they had the safety/efficacy data already on you never know what will happen when you change dosages.
Question 9 doesn't appear to be a sine qua non for approval: i.e., they are not saying "what other dosages should be tested for approval." Instead, it seems to me they are opening the door/asking for Phase IV studies at a higher dosage to make probuphine a possible "frontline" therapy for those who have only recently stopped illicit drug use. In other words, they want more testing to expand probupine's market.
Obviously I haven't had time to review the entire submission, but my initial impression is the FDA Notes are orders of magnitude better than those in 2013.
Can't speak for the content, but the Braeburn presentation looks pretty awesome and much better than Titan's in 2013.
You need to give your comment some context, or you just magically appeared here to add confusion. The cited reference is a summary of the FDA's conclusion in 2013...not on the resubmitted NDA.
Jeesh. Anyone got a Magic Eight Ball, because I'm scratching my head here.
It's Titan, which seems to have been cursed by the Greek Gods, so here's my expectation.
1. The FDA briefing materials will be negative. It's what they do.
2. The stock will go down further when the briefing materials are released.
3. Probuphine will get a positive vote in the Ad Comm. It got a 10-4 vote last time, and now they have even better results coming from the Phase III designed in cooperation with the FDA in response to the CRL.
4. The stock will bounce after the vote, but not as much as we would like.
5. The FDA will take its time (until February 27th) in making its decision. As we all know, the FDA is not bound by the Ad Comm vote. But, to my knowledge, the FDA has never failed to approve a drug after two positive Ad Comm votes.