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yup. Tocilizumab is making a showing but it is bound to fall short of leronlimab.
Egad. I missed the "non" in "non-randomized". Although low, their p-values are garbage without a good sample.
Still waiting for a good sample for tocilizumab. And it looks like we won't have one until September for lenzilumab. But any day now for leronlimab.
spiritof76, the paper you cited claims the exact opposite of your summary. tocilizumab showed highly significant results for reducing mortality and need for ventilation--far beyond what remdesivir did (but paling in comparison with what leronlimab will do because of its more holistic MOA).
totally agree...CYDY management checks in here all the time to get the scoop, the best information they have about leronlimab MOA, clinical trials, uplisting, etc. Without us, they wouldn't have a clue what was happening in the company.
Not pretty indeed...if one of my students turned in report like that, I'd give them a D+: too many deceptions, irrelevancies, and just plain bad writing.
"What bomb can he drop?" The answer is crystal clear to all investors who've been paying attention even a little: results from clinical trials (any day now) and uplisting (within ~2 weeks).
All the rest of your doubt-casting and deceptions ("data...bad") are pathetic drivel.
Interesting that you would say that "the data on that [tocilizumab study] is bad"...short of actual leronlimab clinical trial results, this is about the most superb and reassuring data I could hope for at this point.
https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30173-9/fulltext
Promising results for tocilizumab via blocking IL-6:
IL-6 is one of the primary chemicals causing inflammation in serious covid-19 cases. Tocilizumab is an IL-6 blocker that has shown promising results in preliminary studies in China and France. This new study shows reduction in mortality from 20% to 7% (p < 0.0001) in critically ill covid-19 patients and hazard ratio for mechanical ventilation was 0.61 (p = 0.02), meaning that tocilizumab patients had a significantly reduced risk of requiring a ventilator. Side effects? Significantly greater incidence of new infections (13%) vs. control group (4%) [p < 0.0001].
What about leronlimab?
I've been looking at tocilizumab as a benchmark for leronlimab, with the idea that leronlimab should do at least as well as tocilizumab against covid-19....IL-6 levels are immediately and dramatically reduced (see Patterson et al 2020 preprint) but also there is reduction of other proinflammatories (esp. CRP), rejuvenation CD8+, and reduction in plasma viral load. Also, the CCR5-RANTES signaling pathway is cut off, which should have a much more profound effect than IL-6 blocking in isolation. That a simple IL-6 blocker has shown such promising results is GREAT NEWS for leronlimab. In addition, tocilizumab has a reputation for leading to secondary infections, which (unfortunately) was borne out in the trials, as tocilizumab was associated with increased incidence of other infections. No such effect has been observed in ~1000 patients (including ~800 HIV patients) treated with leronlimab. In fact, leronlimab may even boost immune response by restoring CD8+.
Time to take advantage of the dip and load up.
NAIAD is running trials with remdesivir + baricitinib
What?! you don't think incellDx can provide thousands of instant RANTES tests at very low cost every day?
Dr. Patterson is suggesting using RANTES as a diagnostic
There was. CYDY has put the ball in their court with trial design, NP dpesn't know the Mexico bureaucracy and cannot give an update on how long it will take for them to begin moving forward. Once they do, it should progress very fast.
no. FDA wants success. Pipsqueaks like CYDY have to prove themselves, but when they do, "Welcome to the club!"
I would expect the unresolved ECMO cases to skew toward survival because the fatal cases tend to progress surprisingly quickly once ARDS sets in.
There's another study from WVU that shows ballpark similar survival numbers in 32 patients (5/15 survive, 17 unresolved) but again with a large number of unresolved cases and a mishmash of treatments.
I don't think we can say what the expected survival rate is for ECMO patients in general because we don't have anything approaching a good sample, but the anecdotes indicate that survival rates may be pretty good. [Keep in mind these >1400 patients are all ECMO + remdesivir or HCQ or tocilizumab or other treatment.]
good sized data base of ECMO patients (~1400) shows 55% survival among the roughly 50% of the cases that had been resolved (discharged or fatal = 50%, unresolved = 50%)
https://www.elso.org/COVID19.aspx
just a couple closing comments...
I guess I should have put quotes around my, "why would there be so
many chemicals involved in such a non-serious infection?" which was my impression of the authors' argument after I read the paper, and not my thoughts.
At the end you write:
Sorry if I offended, ohm20. It's not that I don't think you know what you are talking about, it's that I don't know what you are talking about, and I am not inclined to just accept expert opinion without question. So I ask questions, and I'm completely willing to listen and change my mind on anything but never without questions.
The reason I am interested in this particular question is because my working hypothesis is that, for the most part, the immune system knows what it is doing. Sometimes, it makes mistakes, like the SARS-CoV2-induced cytokine storm that kills and debilitates in covid-19. And that ordinary inflammation in response to infection is not merely an artifact of chemotaxis but also serves a purpose in isolating the infection, stimulating the immune response locally, and in processing the carnage from the fight against the pathogen.
Your assertion, if true, that leronlimab would be helpful in fighting a common cold (but is too expensive) would rock that whole immunological world view of mine (namely that the immune system knows what it's doing most of the time). If all inflammation indicates immune system malfunction and we have a chemical that helps control inflammation by hamstringing CCR5 and thereby helping resolve the disease, it raises the question of why would our ignorant immune system create such a stupid feature as CCR5 that helps cause inflammation? My null hypothesis is that it is an critically important feature of the immune system and should not be disabled except in extreme circumstances unless we are sure that we clearly understand the consequences. Some of the extreme circumstances are 1) HIV, which is a deadly virus that gains entry into cells via CCR5, 2) mTBC and certain other cancers whose proliferation is promoted by CCR5, and 3) cytokine storm at the moment when a haywire immune response becomes a greater threat than the virus itself. Temporarily disabling a key feature of the immune system is a serious intervention and should not be taken lightly.
You linked to a 2008 PR from P&G that gives a brief summary of a paper they had just published in American Journal of Respiratory and Critical Care Medicine (Proud et al 2008). I looked up the paper. They list a bunch of chemicals that they noted were upregulated in rhinovirus infection. RANTES (CCL5) and IL-6 were not mentioned. Dr. Patterson's paper did not show much change in other indicators (besides CCR5 occupancy and viremia), so it's not obvious that leronlimab would help with the inflammation. Also, they do not demonstrate that the inflammation in a cold (sore throat, runny nose) is the result of immune system overreaction; they hypothesize that it is overreaction because they were impressed by how many chemicals were involved: why would there be so many chemicals involved in such a non-serious infection? Not very convincing to me...perhaps the impressive constellation of chemicals keeps the infection in check, making sure it "non-serious".
The EIND stories are over. We are waiting for more interesting data that are coming very soon. Yes, Dr. Patterson is the best for talking about the science, but that is not what is needed now, and he will be exactly where he should be Thursday afternoon--working his tail off in the lab.
Dr Patterson is a crucial part of the whole enterprise, but let him use his talents where they are most needed, which is doing science, not PR work.
Dr. Patterson's absence is easy to explain: he's a scientist, not a PR guy and not a CYDY business plan guy. It's always nice to hear from him, sure, but at this point he has nothing to say. Status of the paper? "In review." Status of the trials? "In progress." He won't give details on the paper until it is accepted and won't give any more info on the trials until the data are unblinded. There's no need for him to give tutorials at this point...the trial enrollment is wrapping up in a matter of days, and there's no point in him making an appearance when there will be so much to talk about in the coming weeks. I'd rather have him in the lab working on research than making a bunch of press appearances.
Actually, he does have some control over the timing of the review process. Inevitably, he will be asked at least once (more likely twice or even three times) to make revisions. The first round for this paper will a good deal of work. You'd think that the quicker the revisions are done, the quicker the review process will be, but it's not quite so simple. If the revisions are rushed or not adequate, the paper will go out for review a second time, which adds a lot of time to the publication schedule. If the revisions are good, then the editor is happy, and they can begin work on the final draft. Taking a little more care with the revisions might cost some extra time now, but it pays off in the long run (hopefully turning it into a short run).
Yep. Covid-19, AIDS, mTBC, some other cancers, NASH, gvhd, maybe MS, who knows.
Yep. It took me awhile to understand that too, that leronlimab should be able to prevent progression from mild/moderate to severe (but not prophylactic in the sense of preventing infection in the first place). I was always thinking in terms of "calm the cytokine storm!" and treatment of severe cases, but "stop the cytokine storm before it takes root!" is where the real action and greatest benefit might be.
Thanks, LifeLongLearner. I'm not a doctor, but I do have a PhD and ask a lot of questions.
Right. The role of leronlimab in covid-19 is to take a hammer to an abnormal immune response that would turns normal, mild cases into severe cases. It wouldn't be expected to do much in mild/moderate cases other than prevent their progression and allow the immune system to purge the virus safely in its own time...radically different from something like a common cold.
ohm20, I'm not a doctor (obviously), but I find this all very interesting. Your comments sound vague and hand-wavy to me; maybe that's because I don't have a clue about medicine, and maybe it's because they really are vague and hand-wavy. That's fine. The questions are not important for most people or most investors, but I really like to know what's going on.
Thanks, ohm20, but it's a little too high level for me. I see that in critical covid-19 cases the CD8+ increases relative to CD4. True, but how does that come about and why would we expect a similar effect in a cold? Why would we expect that to have any effect (quantitative, clinically significant effect) on the cold virus?
leronlimab works by occupying the CCR5 receptor on macrophages and T cells. That seems to strongly affect the pro-inflammatory IL-6 levels in critical covid-19 cases. Also CD8+ seems to increase (but no mention of the status of the cells w.r.t. T cell exhaustion) and, presumably as a result, reduction in plasma viral load. It is hard to see other significant effects in the blood panels, except increased lymphocytes. But these effects may be important in managing the cytokine storm that is so damaging in critical covid-19 cases.
Is there a similar problem with rampant IL-6 levels and CD8+ cell exhaustion in common cold? I'm dubious. I'm also dubious that using a powerful immunosuppressant in a normal, mild infection is wise. Normal, acute inflammation is a natural immune system response in fighting off viral infections.
Wouldn't it be kind of dodgy to bust in with a hammer to give your immune system an attitude adjustment in its fight against a cold? Not for me, thanks. Leronlimab is a serious drug for treating seriously misbehaving immune systems.
So, tell me, what is the mechanism by which it reduces viremia in severe covid-19 cases and how that might work in a common cold?
Pro-140 doesn't interact with the coronavirus, and common cold doesn't invoke cytokine storm. No role for pro-140 in common cold.
2/3 to 1/3 translates to a big win for leronlimab (as long as the enrollment is closer to 120 than 50).
The widely-cited 88% figure (doi:10.1001/jama.2020.6775) is misleading and probably off by a substantial amount. In particular, the figure is based on 1151 severe/critical patients, of whom 252 died, 38 were discharged, and 831 remained in the hospital at the end of the study. The 88% is 252/(38 + 252), which ignores the 72% of patients whose cases were unresolved. The problem is that mortality tends to be fairly quick after hospitalization, so unresolved cases in studies like this tend to skew toward survival. In any case, the sample that the 88% figure is based on is a convenience sample with a 72% non-response rate that very likely introduces a large bias.
A later study at Emory (Auld et al 2020) that followed critically ill patients for longer found the mortality rate for was 67/217 = 30.9% vs. 131/217 = 60.4% discharged and 19/217 = 8.8% unresolved.
Another paper (Savel et al 2020) discuss further the widespread media-driven misperceptions of the mortality rate for severe/critical patients and give several further references to look at.
I'm betting we see 40% mortality for severe/critical in the control group. If we then have less than about 25% in the leronlimab group then, we are looking good!
I did a power analysis based on trial size and mortality rate for the control group, asking what size treatment effect would give a p-value of 0.05 with probability 0.8. If mortality rate is 0.4 for the control, we'd need leronlimab to have a mortality rate of 0.2 to get power of 0.8 with 51 patients. With full enrollment, leronlimab would only need to have a mortality rate of 0.345 to be reasonably sure of showing statistical significance.
Here's the full table:
n p_ctrl p_leron
51 0.2 0.023
60 0.2 0.03
75 0.2 0.049
120 0.2 0.099
240 0.2 0.143
390 0.2 0.156
51 0.4 0.19
60 0.4 0.227
75 0.4 0.265
120 0.4 0.298
240 0.4 0.329
390 0.4 0.345
51 0.6 0.426
60 0.6 0.443
75 0.6 0.462
120 0.6 0.494
240 0.6 0.527
390 0.6 0.544
51 0.8 0.643
60 0.8 0.658
75 0.8 0.676
120 0.8 0.707
240 0.8 0.737
390 0.8 0.752
without any supporting evidence, "snake oil" is generic OTC FUD, totally unrelated to CYDY. A lot like elementary school name-calling has no meaning
tradero, yes, the road to approval is a long one. CYDY has been on that road with leronlimab for about a decade, funded by dilution, dilution, dilution until very recently. But at this point, the long pre-revenue road is almost at an end, with approval for covid-19 and HIV close. The CEO has said that further dilution is not likely, but one more dilution of about 5% or so is possible. 5% is nothing at this point because on the upside we're talking 100-200% in the near term and 1000% or so in the not-too-distant future. On the downside, it could still crash to zero if nothing at all works out. In that case, the 5% won't mean much either. But, really, it is far, far past the promising results in the petri dish or animal models; we're done with clinical trials for HIV combo therapy and have submitted the package for approval, and we're nearing the end of clinicals for covid-19.
and the interest rate for borrowing has plummeted from >140% to around 40% the past couple days, while the number of shares borrowed has skyrocketed this week. Even still they haven't been able to make much downward movement compared to a month or two ago.
They'll almost surely use a one-sided test. The two alternatives are either leronlimab is better or it doesn't get approved.
buy at 0.3. sell at 3.46. buy at 2.53. sell at 3.24. buy at 2.68. sell at 3.20. buy at 2.82. The shorts make the dips very easy to read. That streak may be coming to a close now with so many catalysts coming on line, so I'm going more into strict holding mode now, especially since the engineered dips have been so weak lately.
I got 1000%...and then used the proceeds to load up. Looking forward to the next 1000%
How would saving Samantha Mottet be bad news if she had been NP's neighbor? That one is confusing to me.
1. no more eIND, presumably because 75 is already an unusually large number and FDA wants to see trial data instead...too much distraction for a small company
2. CYDY is stopping the mild/medium trial on June 15. enrollment is now at 58, should be close to 75 at that point.
others?
requirement for uplisting
yup. pretty clear there's no science in the heads of some conspiracy-headed newbies here.