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Exactly. If AA, they by 24E. If not, 5 years.
1. Why did CM not talk about OR and thresholds BEFORE December 22, in any of his numerous conference presentations? Is non-transparency the fundamental aspect of company's policies and business model?
2. Why did CM not address many of the obvious mistakes (as per the whole world, around him) in the December, 22 data release? Because he cannot?
3. Why did he never disclose delta-RSBQ for the Avatar study -- even if he, mysteriously, decide to switch to RSBQ-AUC endpoint?
4. Why does it take the company months/years to disclose full results?
These are the Qs that should have been asked.
My estimates come from SRPT’s filings after FDA’s OK. And, typically, the timeline of FDA meetings set-ups etc. it takes 30-60 days (or more) for FDA to even put you on their calendar.
NDA preparation takes months for even a big company — AVXL is only 40 employees. And they take MONTHS to analyze trivial data.
Anyway, you are welcome to think it will be merely weeks to file NDA.
Nope. At least 6-12 months after data release. It will take 2-6 months to talk to FDA (if at all), and 3-6 months to prepare an NDA.
Yes, shorting without the uptick rule can have serious problems.
But, a stock market where shorting is not allowed --- can be easily rigged and fundamentally unfair. If you don't see it, then too bad. Why do you think SEC or most modern stock markets allow for shorting to begin with? Companies/Economy certainly doesn't benefit from shorting.
I rarely ever short --- certainly not in the last 15 years. But, I take great solace in the fact that shorting is allowed. I wouldn't be comfortable investing/trading in a stock market where shorting weren't allowed.
CEO has his shortcomings --- doesn't necessarily doom the company. At least, not yet. I'm sure hoping he'll be replaced, or perhaps, will get his act together soon enough. A company is much more than the CEO. In fact, the drug/products of a company has much more intrinsic value than a CEO.
No, the stock at $9.4 for crappy results is the sign of stock manipulation (pumping by the pumpers).
Yes to both questions (but I never disclosed the number of shares I have, but I haven’t decreased my position at all — my number of shares is the max I have had).. You can see the last 15 mins of the AdCom, wherein they give their reasoning for the vote. FDA looks at that seriously.
Being allowed to short is EXACTLY the reason what makes the stock market a FAIR GAME. Else, it can be easily “rigged”.
Things take time, yes, but it’s prudent to recognize the obvious too.
CM hid/lied the truth in December 22, when he claimed that the trial met all primary endpoints with statistical significance.
The WHOLE WORLD (except for a handful of blindfolded, mostly here on this board) saw it —- stock is at $9 (that’s the proof that whole world saw it).
CM himself confirmed it in many ways:
1. Complete silence for 5-6 months, not answering any of the obvious discrepancies and critiques on the data.
2. Deciding to go AA, rather than full.
Being consciously blindfolded is still better than not realizing that one is being blind to the obvious.
Investment (holding vs selling) is a somewhat independent decision. In spite of the above, I decided to hold for multiple reasons: (1) $9-10 seemed low point, (2) Short-term, it showed strength at various points, (3) The long term windfall can still happen — from Rett and otherwise. (4) IMO, even with a failed P2b/P3, the company is worth acquiring for $15-20.
Few days ago, I was very tempted to buy AVXL more. But — yesterday and today, I bought (quite) a bit more SRPT instead. Much more confidence there.
Avxl does have a very interesting set-up (good and pivotal need to come) —- but can’t be too trusting in CM delivering. I hope with the new hire — CM/company is a changed man.
Great to know. For many years, I have had a very concentrated position (in SRPT), and sometimes I have wondered if it’s a good idea to go against popular wisdom. So the below helps (I actually read this in some article too — by a hedge fund manager).
Of course, I’m hoping AVXL to explode and be a more significant part of my portfolio. It has potential—-just want the CEO to be more TRANSPARENT (and he is not; guaranteed).
Anavex has decided to pursue the AA path based on a biomarker.
It is silly to be confident about approval without having seen the biomarker data.
Please be welcome/free to think so. IMO, your imagination/understanding of how FDA approves drugs is misplaced.
I choose my words carefully. See below what I said. There is no legal (as in, there is no law by Congress) and neither is there any FORMAL guidance (meaning, there is no written guidance document from FDA). Feel free to correct me if you find either, based on your DD. Instructions to specific companies is neither.
Specifically, when BMRN filed for AA of its Prosensa's DMD drug in 2016 --- it was asked exactly that question during a CC, i.e, how do you expect an AA when you don't have any confirmatory trials started? The CEO/CMO of BMRN answered after some pause -- that FDA doesn't have any such requirement. BMRN's drug was finally rejected but for clinical efficacy and safety reasons (though, yes, lack of confirmatory studies may have played a role too).
Part of the reason for lack of such requirement is that only the FDA review can truly determine the right design for such a confirmatory trial.
There is no requirement (legal or even formal guidance). It’s just an implicit preference.
How can you imagine FDA giving an approval based on post-hoc subgroup analysis? NEVER (esp from just one trial). Impossible.
You managed $1B together? Wow! Would love to get to know you more, and understand your thinking/strategies -- off the board.
I have watched the Sarepta's AdComs completely --- because, of course, I have a lot/everything riding on them ... and I believe listening to everything -- helps. E.g., I have now 99.99% confidence that FDA will approve SRP-9001. In fact, I even exchanged an email with the FDA (top person of authority) sharing my insight into one of the sticking points in the AdCom; got a prompt response -- that he appreciated my input/perspective.
I'm hoping/wishing that AVXL becomes my 2nd Sarepta! :)
Yes, I'm not 100% sure of my assertion either. Does a patient have a right to find out whether he got the placebo or not -- before the trial ends? I mean it must be part of the patient's consent -- that the trial needs to be blinded till it ends. But perhaps -- a patient has a legal right to find out ... once he/she decides to drop out. I don't know.
Yes. That’s the prediction. Times may have changed.
I personally think the ethics question in Sarepta’s was not warranted:
Context:
AA may happen on 5/29; P3 completes in 4 months (9/23). So the risk in question is placebo patients dropping out to get commercial access and just putting the P3 completion at risk.
My reason: Placebo patients won’t know whether they got the drug or placebo (blinded trial). So, they can’t possibly get commercial access (only one dose allowed in a lifetime).
Anyway, in the AdCom: Sarepta said that commercial access will take 4 months to get. While being in the trial, the placebos will get doses earlier than that — so no incentive for anyone to dropout. Also the number of theoretical patients were like 20-30.
Ok. I won’t argue anymore then. I had replied earlier only as a courtesy. No worries.
Big difference between 'intermediate' and 'full' clinical end points.
e.g., In oncology, intermediate endpoint could be 'tumor size' and the full endpoint would be survival time.
To corroborate the intuition that SRPT’s AdCom result will boost the entire biotech market on Monday:
CAPR’s CEO Linda M on Thursday said that “Sarepta’s AdCom meeting will have an impact on the entire biotech industry”…
Seems like a strong statement to make … but I agree and get a feeling that Sarepta’s gene therapy result is a pretty significant or pivotal to the biotech industry and/or FDA’s thinking. It’s likely as big as Adu’s approval process. Big implications—partly because gene therapy is the hottest and greatest innovation right now in health care IMO.
AVXL could get a serious boost on Monday. Likely $10-11 at least, if not $12 plus!
Clinical data needs to be supportive—so is not ignored at all. But the key data which will drive the AA decision will be the biomarker data.
This came out 6pm ET yesterday — about 21 hours ago. I watched the whole AdCom live.
Yes, I have 80-90% in SRPT; bought mostly in single digits. Am not selling any yet.
It should give a boost to biotech sector and likely to AVXL too (AA route).
No -- AVXL/FDA has to ultimately pick ONE pathway to AA. Either, a surrogate marker or an INTERMEDIATE clinical endpoint. We have no intermediate endpoint to consider. So, only surrogate marker is in play here.
With that knowledge/background, I'm surprised that you continue to insist that the confirmatory trial would be "precision medicine (PM)" trial --- i.e., it will show clinical benefit on only a selected subgroup (based on some biomarker) of patients. That can't be true.
If AVXL gets A A ---- presumably not based on any subgroup analysis within P2b/P3 --- then, the confirmatory trial will have to have almost the same inclusion/exclusion criteria as the P2b/P3. Else, it won't be confirming the basis of AA approval.
Yes, with CM's remarks in the last ER CC (i.e., AA possibility with new positive biomarker data), the AVXL's story is completely NEW now (i.e., the CTAD data fumbles are semi-irrelevant now).
The only negative with the current status I find is --- why the 5-6 month delay in releasing the biomarker day. That's the main thing I don't like.
Nevertheless, I'm strongly considering increasing my position ---- the set up is just too tempting (CEO says positive news to be shared soon, news can be very pivotal, and stock is still slow to react). Till the biomarker is shared (can't predict the reaction to that) --- the stock can't possibly go anywhere but UP.
Yes, I had closely followed the previous saga of Sarepta's Eteplersen AA. That AdCom video was even more lucid and elaborate --- but doesn't exist on the internet anymore.
I don't understand your Q.
AA is based on surrogate marker (it can be based on an intermediacy clinical endpoint too -- but lets ignore that, since it doesn't apply here).
That means for AA:
(i) the evidence needs to show drug's impact ON SURROGATE MARKER (not necessarily on clinical endpoints -- such as Cog, ADL, etc).
(ii) And, the surrogate marker needs to be valid.
So, yes -- if AVXL goes AA-route, the biomarker results ARE MUCH MORE IMPORTANT and CENTRAL to the approval -- then the endpoint results shown till date.
You misunderstand. For avxl, the process is.
1. What is the surrogate marker? Let’s say it’s X (from CM’s comment it seems like it may be amyloid-beta).
2. P2b/P3 MUST show that the drug had a positive impact on X (wrt placebo) with p < 0.05. Perhaps, higher impact for higher dose.
3. X must be a valid surrogate marker (Ie, it should be reasonably likely to predict clinical benefit).
(a) If X is amyloid-beta, then it has already been accepted as a surrogate marker by FDA —- and there is nothing to do here.
(b) If X is something else, then it’s very tricky — AVXl will have to make a case that X is reasonably likely to predict clinical benefit.
Summary:
1. X better be Amyloid-Beta/Tau.
2. P2b/P3 must show impact on X
3. Rest of the endpoints (Cog, ADL, CBR, etc — ORs or not) only play a supportive role. But if there are very negative results for these endpoints, then a flag would be raised and a valid explanation would be required. But minor issues such as p not being less than 0.05 may not derail acceptance.
So much silly discussion on P3 vs P4 etc.
This is how AA works per FDA.
(Bunch of trials, irrespective of names) ——> AA ——> Confirmatory trial (name P3 or P4 doesn’t matter) ——> Full Approval.
Yes, during the AA application process, FDA likes the confirmatory trial to be already designed and running.
SRPT’s AdCom link:
https://m.youtube.com/live/k33d4h-CpGU
It’s best to listen to the initial FDA’s presentation, where they clearly explain their expectations and requirements for AA.
Very relevant to avxl (Ie this is not off-topic).
People who still don’t understand much about AA — should listen to todays AdCom of Sarepta’s AA application.
AA requires a confirmation trial.
FDA strongly prefers the confirmation trial to be already started when the AA application comes.
Well, FDA doesn't factor in costs/price into approval process. That's all I mean.
AFTER approval, the costs/price will have implications on insurance reimbursement, Medicare, revenue, etc etc. Of course.
Regulators never ever care about the price — Ie, the drug approval process is completely oblivious to the cost/price considerations.
No. AA can be granted irrespective of the timing of confirmation trial. SRPT’s first drug (Exondys) got the AA in 2016 and the confirmation trial only started in mid-2020 with readout in 2026 (?). There were trials running during AA approval process, but FDA asked for a newly designed confirmation trial.
From a site: US data show that, of 23 accelerated approvals granted in 2010-20 to non-oncology drugs, only four had converted to full approvals through clinical confirmation as at the end of 2020, taking an average of 3.5 years to do so.
However, FDA does like to see the promise of completion of the confirmation trial — in ongoing case of SRPT’s gene therapy AA (AdCom panel on Friday and decision on 5/29), the confirmation trial is fully enrolled and finishing in a few months. I think FDA likes that.
To submit (if at all): I'd say 6-9 months.
The review will take 6-9 months.