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Thanks, so that would mean the interim of 50 severe patients has completed and DSMC is doing an interim analysis on that. And till the DSMC corresponds back, Cytodyn is pausing enrollment of both trials. I wish I could see this as nothing but normal procedure but doesn't seem to be at this point. Hope they really intend to get these trials done.
Added at the end, but could not make much of the price action. Only real news will move it now; hopefully something solid tomorrow.
I sent ir@cytodyn.com a general request:
-------------
Hi, please be thorough to the extent possible in discussing our
1. Financial position
2. Brazil trials
Thanks,
---------------
If longs have specific insightful questions, regarding 1 especially, send them.
Misiu I don’t recall this, but did we originally want 14 day as primary and fda in its push-back not only said 2 doses but also made 28 days as primary endpoint?
I also believe him, that's why I quoted him as I remembered. However I need not believe all you say he said or meant, to think I should try answer such claims or the import behind them.
But in this case, I said ok and added your quotes to mine. Fine with that.
Yes, FDA will be blamed by us investors. We wanted 4, they pushed back with 2. Company yielded because it grasped that "FDA is not going anywhere and we need approval through them". Don't fight the bully. Likewise company is totally silent after the letters, that were a public assault on us. Because company knows it lacks leverage and this is not a battle they can win through fight. Nader was always praising the fda. Shareholders certainly need not.
But as far as covid, we are far down the road now. What a relief to be able to say we are not begging the fda on it. Eyes on Brazil. Too bad fda won't let us be and we have to deal with taunts and threats and now do their biddings in hope of forgiveness. But still, Brazil is separate from all this. That's good. Success if somehow it happens there is success, we can work with that and things will follow.
Are you also talking from memory of the same audio clip? If true, then
"We did want 4 doses and FDA "pushed back" saying 2 was enough. He was ~ "never comfortable with that". It is easy to speculate retrospectively what Cytodyn should then have done." But they "felt they were in no position to push back on the FDA" given "that Cytodyn was coming off a clinical hold"."
You talk to him if you wish to know about that hold and all the supposed others and try confirm your other theories as well.
I spoke from memory of that audio tape from last year. What else did he say about 4 doses?
As for Dr. J, I think his endorsement of LL is clear from his letter that Learning53 posted.
In my email to him last year, I asked pointing to this part on 4 doses:
"... I just wanted to let you know that your words in this audio between 0:20 and 0:40 (on FDA pushback on Cytodyn’s dosage proposal, leading to 2 instead of 4 doses in cd12) are being used as a definitive reference by longs for the things said in that clip. You don’t have to confirm to me, but I sure hope you stand by them as the truth... I hope your words in this tape mean what they say and will not back away from them if the powers-that-be challenge them."
He replied "... I appreciate the importance of this issue. I stand by every word I have ever said or written about leronlimab."
On cd10, I am just guessing what they did. Neither FDA nor Cytodyn gave the details.
Cytodyn said the NEWS2 endpoint was met (p<0.05) for Days 3 and 14, so we understand also that it was not met for Day 7 (p>0.05). Cytodyn may be accused of misrepresenting this info in certain communications if they had claimed NEWS2 was fully met without mentioning in some clear manner alongside that "for days 3 and 14 and not day 7"; we have to go back and check the PRs carefully.
FDA just outright says we did not meet any secondary endpoint for cd10, so we have to assume that the NEWS2 endpoint (as a whole for the trial) was agreed upon as being met only if all three days showed success, or some sort of group evaluation showed good p value. It is not to the FDA's advantage in this acrimonious letter to acknowledge any sort of validity to Cytodyn's highlighting the data in positive light. So they went the other route and made it appear that there was nothing whatsoever - which for us investors is misleading in itself. The fact that we had p<0.05 individually for 2 of the days is still good stuff and it cannot be hidden or made to disappear simply because day 7 failed.
I don't recall the DSMC episode precisely but it is confusing as you say. We don't know what they saw at that point or how they thought the trial may succeed from there and the results turned out as they did. We also can't say what effect they saw from the 2 injections since we are mainly referring to the critical subgroup, and the DSMC was seeing the full group. But still they thought in the first check the trial should go ahead without changes. They did suggest a second DSMC check I think (after reaching a certain # of patients) which Cytodyn waved off saying we are already near full enrollment. (?)
On doses, I go with what Dr. Lalezari said. We did want 4 doses and FDA "pushed back" saying 2 was enough. He was ~ "never comfortable with that". It is easy to speculate retrospectively what Cytodyn should then have done. cd12 however has given us good info on where we should focus; we have fine-tuned the Brazil trials in a way that investors are comfortable and 'confident' based on the information from cd12 and eINDs.
I see. "Read that its all there" proof. Thanks.
Very interesting what he says on NEWS2, which was checked on days 3, 7, 14.
"outlined" doesn't mean you can spin off whatever you want. Go read it yourself.
"The fact that Cytodyn used "adjusted" p-values violated the FDA Guidelines" - FDA says this in their letter? No. You are spinning again without proof, if your "proof" is FDA letter.
If it is in fact in their guidelines that an 8-k under no circumstance can put up adjusted p-values (noting that it is adjusted by age etc.) and claim SS in that context, then that is material worth considering since it proves Cytodyn violated clear guidelines. If they don't have such rules that prove wrongdoing and simply imagine that in this case Cytodyn should be judged as misleading intentionally, then that would be their interpretation. We need not agree, even if the governing bodies decide against the Company.
NP admitted NEWS2 endpoint claim is false? That's news to me. I wouldn't be surprised if the NEWS2 claim was not exactly correct - won't speculate how badly or closely, but I don't recall him admitting anything about NEWS2 after the letter. Again your present words are not proof. Show at least discussion in forums at that time where people talk about NP having admitted in a CC or elsewhere on record.
Need proof for all that. Your assertions don't make your other inferences true either.
Only thing I agree with is that they did claim NEWS2 as a secondary endpoint that was met.
Ok. that is why I wanted to see if they say things like you can't use the logit or anchova model and must use xxx model. I couldn't find in their guidance the specifications, to the extent I searched. If there are clear rules in place that tell what a Bio company can and cannot put in an 8-k and if Cytodyn can be shown as clearly disobeying such rules, then there is a valid basis to make these charges. Otherwise it will be a judgment game from the top, not necessarily "facts". Cytodyn itself only presented p-values for certain subgroups based on yyy model and adjusted for age etc.; and that was SS in that context. They did not claim endpoints are met otherwise (and I understood "Trial did not meet primary endpoint." from their first PR preceding 8-k, so that guides me properly to understand these further claims contextually.) FDA and SEC can gang up as they want.
Thankfully I have it in email to him, UNFORTUNATELY it no longer works!!
http://ohm20.s3.amazonaws.com/CYDY%2010-20-2020%20--%20Dr.JL.mp3
Maybe some other longs still have it, in twitter etc.
Yes I noted that and so should you and the SEC. No excuses for not noting it and then claiming this and that about misrepresentation. They told you what they were showing in the 8-k, so that is the context of the determination and assertion of SS. It is not an absolute statement on SS, simply because age-adjustment was not part of the trial design - otherwise it could have been. (Likewise for subgroup analyses etc.) So anything said with the footnote of age-adjustment is understood as being contextual and not a straight-out meeting of endpoint. And in the talks they told us good results with "age-adjustment", meaning once again that though we did not meet the trial endpoints as required, still there was promise in the data that suggested possible directions to prove efficacy. As investors betting that LL works, of course we will get hyped and hopeful. For instance, because age-adjusted data shows SS, therefore people thought in the next trial protocol, "we must make sure age-distribution is similar for both the LL and the placebo arms, because cd12 showed positive results when these adjustments are done." And that (I hope) is how we designed the Brazil trial.
Problem is that there is an assumption that by default investors can act blissfully ignorant and hence the company should treat them like grade schoolers. Fact here is they wrote that the p-values are age adjusted and told us about it; they talked on the promise of the data should we correct and focus in such and such manner based on that data. SS was emphasized more in my recollection for time-to-discharge, not as proof that we met the endpoints in cd12 (which we did not) but to tell us therefore that is going to be a main endpoint for the next trial. Note that the primary outcome measure in the Brazil critical trial is "Cumulative proportion of clinical recovery" and all-cause-mortality is now a secondary endpoint only. Of course, we are still very hopeful for mortality results for such patients and the 14-day results is what investors are mainly betting on for this.
I was bothered that in page 21,23, they give p-values and refer to the data being SS based on logit or Ancova models but only refer us to the Table elsewhere. In the table there is mention of age adjustment. I thought that can give reason for people to say they misrepresented in page 21 for people who don't go and check the table. But then I went back to look at the initial summary pg 7-8 and in page 8 itself they had put the Note that the data was analyzed with age and other adjustments. So in the first instance of mentioning p-values, they are open about how it should be understood, and the reader has to go to page 21 already having read page 8, so that is not a valid charge of misrepresentation. For further clarifications, go to the CC or ask them to clarify; that's our job as investors.
All this should be separated from the EUA hope that investors had based on such data. Because EUA hope is not the same as belief that we had passed the regular trial process; it is a different category unto itself where people are hoping or expecting a more lenient judgment for the sake of expediency. That is more a black-box. Don't blame the company or demand the CEO should not show enthusiasm for the current data for the possibilities it shows just because shareholders think for themselves that the FDA ought to grant EUA for the present results. They are different things happening. If there was nothing to be enthused about the cd12 and CEO should act like a robot, we won't want to go to the Brazil trials to prove more definitely that LL works. The positives from that trial are positives, even if not perfect; you can't negate their worth by simply saying generally that there will be negatives if you look at it in some other way. We are looking at it in this way and feeling good about our chances next when we design the trial in our way. We will take care of age-distribution, we will have 4 doses, we will focus on specific type of patients, etc. cd12 data has shown promise if such is done and given us the guidance. Investors may still think that already in a pandemic situation the FDA should consider it our way or at least support us rather than act aloof or against. That is a different matter; company's representation of data contextually to bring out potential positive possibilities to investors is forward-looking only and should be understood in the right sense.
I meant Cytodyn's chances in Covid are not a done deal. That's all. We await the Brazil results or the Company to tell us otherwise. Till then no done deal. Not waiting on the FDA at all, only they got it in their heads to screw us, it seems.
Yeah, I saw some links for their guidance. Too general; can't pinpoint specific things that can easily imply that Cytodyn did wrong to claim ss in their 8-k - like "You can't use Logit model when computing SS", or "You must use such and such model to find p-value" etc.
No done deal. Your inferences are not self evident to anyone. What adjustment to p-value? Perhaps they rounded down from 0.0552 to 0.05? Otherwise no one knows what you mean. FDA says a bunch of things, let them prove what they want; as if that will disprove Leronlimab. Like I said, shareholders are interested with the critical subgroup info and the potential of LL in this regard. If FDA cares, they can talk more about that and less about what we ourselves are not talking about.
If you have a link to their Stat guidance and methods document, you can send that.
Take the 4 doses that FDA denied and ANVISA approved. ANVISA did not do this just because all of a sudden, safety was proven in cd12 by the standards of clinical trials (does FDA agree that safety is established?). Rather it is acknowledgment that cd12 data suggests the possibility that 4 doses can be particularly relevant and that unlike FDA, ANVISA did not think it necessary or proper to reduce 4 to 2 when the Cytodyn team asked for it pointing out our past data including cd12. cd12 had something to do with ANVISA thinking 4 doses should be allowed. Of course it is not an endorsement of the drug; it is an endorsement of the phase 3 trial protocol that it is consistent with the data and evidence coming out of past trials - in this case that we are justified in seeking to test critical and oxygen requiring severe patients with four doses of our drug.
What do you mean "manipulation of statistics"? They are not barred from giving you an analysis and interpretation of data that they think is significant to explain the overall results. If they think age may have mattered, then they are making that point - are they the first company to do an age-adjusted assessment of the data? Who said this is necessarily improper to put in an 8-k on trial results?
Definitely, cd10 NEWS data involved misrepresentation of some kind since the company said it was a secondary endpoint that succeeded but never countered the FDA letter that said no secondary endpoint was met. They may not have wanted to show opposition to FDA but it left a bad taste. I give you that. But that does not transfer over to cd12 and its critical subgroup. You can distrust them for that cd10 statement, but it is not a proof here and I don't club it all together.
And with cd12, I do see the words "statistically significant" in the 8-k for three things: mortality benefit for LL+commonSOC over common SOC (p=0.0319), mortality benefit for LL+Dex over Dexamethasone (p=0.0552), and the Time to Discharge for Critical patients (p=0.005). This is on pages 19, 21, 23. SS is not given for the Dex result here but is tagged in page 7 for the same.
The first two are determined based on the Logit model whereas the Discharge analysis is based on Rank-ANCOVA model. Let's assume Cytodyn was honest about it this far.
Its interesting how the FDA addresses SS in their letter.
NP found the subgroup where LL showed merit. That is all. If you think that criteria that define that subgroup are inadequate or defective, then make the case for that by pointing out the details; otherwise it is well and good that he found it, designed the next trial based on it, and ANVISA approved that trial based on their own assessment of cd12 and Cytodyn's explanations. The fact ANVISA approved it as we wanted is a big statement for many of us regarding their assessment of cd12 data, though not for you based on your ideas on how/why phase 3 gets approved.
The words you use, "manipulate" and "misrepresent" of the clinical subgroup, where is the proof? If you are simply going to quote the FDA letter like it is scripture or God, then I cannot say much about it further rationally. Others think the FDA is misrepresenting what Nader said. I saw what Cytodyn said of cd12 data and its critical subgroup, and I have written about it as well to the extent I understood the data and the mathematics. I don't see any misrepresentation or manipulation there. The numbers are what they are; and they are positive. No one said, positive enough for full approval by the regular process, though investors hoped for EUA in a pandemic, based on lesser data or through other assessments. It is not illegal to hope this or to ask the FDA whether the data merits an EUA - I don't recall if Nader said after cd12 that we are going to even ask for EUA. All I heard was emphasis on the promising critical subgroup data, but it was clear to me that it was not SS and we had more work to do.
Here is what my first assessment of the cd12 PR of Cytodyn was:
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=162372983
Note 1 and 4, which is the essential practical summary of cd12.
In a random selection of 62 critical covid patients, our drug outperformed the placebo at Day 14 by a factor of 82%. That is fact.
That data is useful to inform us for a future trial. That is the significance. That even if we cannot consider it as sufficient evidence for concluding efficacy (based on the anyhow inconclusive methods of chance) in the larger population, still we cannot deny that this data aligns congruently to the thesis that LL works for these patients. The data is suggesting the possibility of success and not the possibility of failure, and hence we are able to design the new trial based on it.
And we are presently doing that trial (hopefully). We will see what the results will bring. Proving in covid can have implications beyond covid since the MOA gets confirmed and that can find use elsewhere.
Covid results were good for the critical subgroup but formally speaking we cannot determine efficacy on that basis due to the small sample size. However that trial informed us how we should refine the patient requirements, the endpoints and that we must have 4 doses. We convinced ANVISA on the new design and they approved. Unfortunately we got a bit unlucky since by the time we finally got approved by ANVISA, the situation in that country had drastically improved and our enrollment came to a standstill. So our chances to prove in that indication before funding issues became too urgent were gone and now things are moving slow (we think). Of course, longs are still hoping those trials can be completed and we will know the results soon. CoV chapter for LL is not closed unless and until Brazil verdict is out.
(To add generally: I am also concerned regarding the patients we will get at this time, since I thought we were best positioned to prove the worth of LL (and separate from other medicines) against the cytokine-storm scenarios of the Delta variant. The trial protocols in Brazil seemed specially designed for this purpose. Now we are dealing with a less-aggressive variant and the patients who become critical may do so more because of the mix of comorbidities (than primarily the viral cytokine aggression) for which LL may not be as effective. Hopefully we get a suitable patient pool.)
I agree that things are not clear about the cancer (and NASH) data.
HIV for what I understand is still open ground for us to make a mark. The first question is whether LL can secure approval based on the completed trial, vindicating its 81% efficacy, and enter the market. That is a leap from where we are right now and that is what longs are betting on happening. Things you predict are for much after; a lot of things can turn our way by then.
Thanks for the explanation. Essentially the indication has space for multiple medicine options which don't all overlap exactly; so Leronlimab with its safety profile and 81% efficacy will have its niche in spite of the approved and other drugs. If anything there is scope for partnership to attack the disease in multiple ways. We just need to prove ourselves at this point against the existing SOC (and complete BLA etc.), then we should be in good standing.
But how do you answer this statement of Hygro:
someone's buying today again. low volume overall but price running up
Basically the claim is that we have lost the competitive edge in both HIV and NASH, hence essentially can't bring LL to the market based on our present results in them. That leaves us with Covid hope and Cancer; and even in cancer, the previous trial as I recall did not show us as sufficiently superior to the current SOC.
Longs need to respond to and counter these assertions if you believe otherwise, that our drug still has a good chance of getting approval for these indications.
(Assuming I understand these trials correctly):
The original trial evaluated for 48 weeks. Cytodyn has found that patients are doing well much beyond, so this trial is making a statement regarding safety after 200 weeks for those who passed the 48 week mark. That is a 4 x time extension. For us it may seem like "Old stuff" because the old trial is ongoing (as recruits join at different times) but if you believe LL has something good to do for these patients surviving this long, then proving for 200 weeks is essentially regarded a New trial's result over the result for 48 weeks. At least that is the intended impression we want to make with the FDA.
But I don't understand how they will use 56 patient data so that the end result informs about 200 week safety over the set of all patients who survived the 48 weeks. (For example, they can't start this extension trial so late that most of their selected 56 patients had already survived to week 120 and avoid those who died by its start date). They should have some acceptable selection process that is in place.
They have effectively broken the silence through this communication. That is the news. You can talk down the implications and try monger fear; but the message for the optimist is that they have the wherewithal and confidence to plan ahead and announce their intentions to the world. If they are in desperate straits looking hopelessly at bankruptcy, they might as well keep silent and look to wind down, and not make themselves subject to further scrutiny (and future lawsuits and FDA reprimands) by initiating what can be accused as another round of false hope to investors. This is not a PR either; it is just a matter-of-fact information at a public website. You think they have no money, and they are uploading a plan for a trial just because they can conjure it in their heads or to trick investors. The company is in a different position now and cannot afford to be so impulsive. Perhaps the thesis of some longs that there is some partnership or other funding getting set is happening in the background, and hence they can plan a future trial focused on other HIV indications.
It is not just what it is or is not, but also the fact that Cytodyn has very recently posted plans for a future trial even while everyone was pondering the meaning behind their silence. I may have missed the forums talking about it but it seems something significant as indication that the Company is not asleep but thinking forward - whether you believe or not.
I can't find the cd12 completed trial listed in clinicaltrials.gov. I tried key words cytodyn and Leronlimab. The phase 2 trials are showing up but not cd12 phase 3. An mTNBC trial is no longer available. Check for other possible changes.
Edit: it is likely this one: https://www.clinicaltrials.gov/ct2/show/NCT04347239?term=leronlimab&draw=2&rank=7 (Active Not recruiting) listed as Phase 2? But says 2b/3 later; got confused by the Active, not recruiting and Phase 2 mention initially.
Perhaps it is a mutual agreement to gather new data to make up for whatever Amarex lost.
NEW trial posting March 9, 2022
https://www.clinicaltrials.gov/ct2/show/NCT05271370?term=cytodyn&draw=2&rank=2
Was this noted before?
Is this FDA approved trial? Site says "Listing a study does not mean it has been evaluated by the U.S. Federal Government." but I am thinking Cytodyn at this point will go through the process properly so FDA is not miffed.
Strange price bahavior the past three days. Not high volume; but price going up with intent. Buyers thinking this has value above 40 cents, or shorts are covering anticipating the possibility of good news in the short-term; long-turned-sellers seem to have exhausted at this point.
I think Nader said these things last year. In the Jan 4 update at clinicaltrials.gov, there is no such change mentioned. So we have to assume that they did not formally make such changes to the enrollment size. (The website says "Information provided by (Responsible Party): Hospital Israelita Albert Einstein")
Of course Cytodyn may still do an interim and get the data; we don't know where the trials are in this process, whether the interim is finished and they are keeping silent about that as well, or it is yet to be done, or whether they decided to do the interim later with more patients or skip it altogether.
This site says Cost in Brazil is 75-80% of US cost.
https://www.complianceonline.com/clinical-trials-in-brazil-trends-and-experiences-10649-prdad
This site says avg cost in US phase 3 trial is 19 million, although not clear how it depends on number of patients enrolled.
https://www.nature.com/articles/nrd.2018.198
So we can expect ~16 million or more for each trial in Brazil.
I wonder if we are still enrolling both trials or whether things have been modified since Jan 4. Not able to get further info; tried asking Scott and also the Brazil contacts for the trials. No response.
Can anyone give an educated estimate of how much $$$ it will take to enroll and complete our Brazil trials? (I assume it is a lot cheaper to do trials in Brazil than US.)
Not necessarily Musk but that's not a bad idea, that someone was interested to fund the Brazil or other trials but wanted Nader out and absolute silence till solid results out. Just a hopeful possibility, if such agreement and transaction can be done legally behind the scenes (?).
I see, that’s the criteria for getting phase 3 trial approved. “That’s it. That’s all.” Glad you agree Leronlimab is safe.