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To paraphrase Aretha:
What you want, you know you got it!
Suppliers offering Long Term funding? Cash flow + confidence.
Did you miss Note #4 (and #10) in the 10-Q? Samsung effectively loaned Cytodyn $34m via a "non-standard payment arrangement" not due for more than 12 months - long term on the balance sheet.
Better terms than Fife, I presume.
Was that a typo or a signal - all the other dates above and below leronlimab were 1/1/2021.
Thanks - obviously I'm a beginner on this subject and not medically trained.
In the stroke PR, Kelly is clear about the "macaque model" re leronlimab crossing BBB, citing 70%-75% receptor occupancy in the brain. Is that a trauma situation?
I was musing leronlimab could travel there on the CCR5 receptor of a T-cell, so would only cross in the adverse situations that would let the T-cell cross.
I apologize if the above is nonsense.
OK, morning enthusiasm. I'll quibble on semantics only - I said it's the one and only candidate. True?
Is the argument this simple, then:
(1) coronavirus crosses the BBB and does damage
(2) we know from macaques that leronlimab does as well
(3) no other proposed Covid treatment does (confirm?)
(4) leronlimab is the only possibility for a full cure of Covid
It's sort of like if we get a significant result on the SOFA score - we have not just an MOA, but the primary MOA. Everyone else is looking at secondary impacts.
Wow, so talk about synchronicity. On the other board CT Medic just posted (71054) an older study about inflammation, CCR5 and MS, a classic white matter disease.
"Aberrant T cell migration toward RANTES and MIP-1a in patients with multiple sclerosis: Overexpression of chemokine receptor CCR5"
If there is a connection, look at paths that impact white matter. Huge advancement last 5 years in brain diffusion tensor imaging." A recent study with over 5k images was titled something like "Widespread White Matter Microstructural Abnormalities in Bipolar Disorder."
Basic point is that axons (the long shoots off some neurons) need good insulation (white matter) to communicate at full bandwidth over distance - "saltatory conduction."
I worked for a quantitative equity shop for a while. They had useful models to predict stock moves based on insider buying. However, they were never able to develop a predictive model based on insider selling.
Agree with Ops, likely too many reasons to sell, large among them that they will be getting more shares in the future via stock-based compensation.
We already have 394 patients in a randomized longhaulers study - it's called the "follow-up period" of the CD-12 trial.
At least two endpoints of the new longhaulers trial can be self- or telephonically-assessed: primary Fatigue Severity Score and secondary Mental Fatigue Questionnaire.
Call all the CD-12 enrollees! Create one cohort for each week's enrollees and chart the weekly averages for controls and treated.
At worst, we'll know what to expect from the new trial. At best, if we can get the FDA to formally include these endpoints in follow-up (and the caller is kept blinded, etc.) this large trial may be a strong complement to our smaller, de-novo Phase 2 trial in arguing for early use.
I worked for a while in a quantitative equity shop. They had useful models of how executive stock purchases predicted share price change. However, as hard as they tried, they could never find a formula that made executive stock sales a predictive variable.
In the comments on the WSJ article - however many people read them:
The Longhaulers study will be the fourth leg of data supporting leronlimab's effectiveness in COVID.
As mentioned, the "trial of the sickest " hit full enrollment last week. This Phase 3 registrational trial in severe-to-critical patients has almost no exclusion criteria. Final 28-day mortality data will be collected January 12th.
Excitement is building because the trial's Data Safety Monitoring Board had two chances to weaken the endpoint or require more patients, but chose to continue the trial as begun. No other mortality trial has this distinction.
Previously, a Phase 2 trial in mild-to-moderate patients showed statistically significant reduction in both the UK's "early warning" score and in severe adverse events.
Early in the pandemic, a large "emergency IND" program indicated an apparent roughly 50% reduction in death rate, triggering the randomized trials. The "trial of the sickest" appears sized to confidently detect a reduction of 40% to 50%.
"371 people have enrolled in CD-12, so we're going directly to full-trial results."
Yep, a PR with that statement would have sufficed today. And it would (certainly should!) have been received positively. But I'm happy to hear the comments that add texture to the recruitment dynamics.
Defining the Longhaulers MOA - an essential step to getting a Phase 2 approved ahead of the pack - a huge step and a small step at the same time. Discussion ideal for a science-driven investor base. Few people would review that if written out.
Working the international opportunities - the texture of this conveyed the squishy, but non-zero, nature of these possibilities. No way a PR could have communicated this.
All the rest adds to soup to me - every piece is important to someone - that's the nature of an update. All heading forward, all sounding tasty. No way it fits in a PR.
Yeah, exactly what I expect from a CytoDyn CC, and I'm happy about it.
True - CD12 is "quadruple blind" - including the outcomes assessor. That said, neither death nor oxygen support status endpoints risk assessment subjectivity. Same for SOFA score.
It's hard to imagine how knowing the aggregate results on the first 293 could bias reporting on the later patients, which are still blinded to the assessor.
I would hope the FDA would see that and allow unblinding of the data on 293 once all 390 are enrolled.
Typo in a financing doc? Yep, I remember in the 1990s United Airlines was in trouble and did a big bailout financing. Confidence was further decreased when people noticed the header on each page was "UNTIED AIRLINES."
Jay - I read that phrase as hgen saying their power is below 90% for the 75% readout.
Humanigen and implications for CD-12: The nice phrasing of the Lenzi study is that enrollment is specified by recoveries, not enrollees.
The bad news is how much the trial was extended. The review was at 201 recoveries, they thought 257 would be enough to have the desired 90% power at a 1.29 hazard ratio. The DSMC said, nope, that needs over 400 recoveries. Ouch.
With this data, Humanigen can back-calculate the hazard ratio on the first 201 recoveries - it's 1.37.
NP knows what mortality differential we targeted and what power we wanted when we calculated the N of 390. He also knows total deaths at interim. He knows the power at 390 is no lower than what he originally requested. Hence, he can calculate the minimum death differential at the interim readout.
I guess that's why he didn't feel the need to pay a penalty to unblind the data.
Bad DSMC news for Regeneron that RGN-COV2 can't be used on high-flow oxygen patients in the hospital.
Their non-hospitalized trial (effectively p-2 report on an integrated P-1-2-3 trial) was significant in, get this, reducing % people who had a follow-up doctor visit.
The main medical press reaction was that you had to treat 27 people to prevent one from advancing that one step - big yawn.
That calcs to saving one or two lives per thousand people injected. Maybe 5 times that for the sickest end of the spectrum in that study.
This says they can't continue up the illness chain much further to get a clinically meaningful response without generating safety signals.
Right, Regeneron is an infusion. Yet the title of the study says "ambulatory patients." Guess they brought them in once.
Regeneron: Great news for some patients, very small societal impact.
The clinical outcome - at least one subsequent visit to an MD - was reduced from 6.5% to 2.8% - that is, 37 people out of 1,000 treated won't have that next visit.
Great for them, but, in the big picture, that probably means 1 or 2 fewer deaths per 1,000 treated.
Even projecting use in only their sickest cohort, it's hard to WAG a savings of 5-10 lives per 1,000 treated. How many doses are available?
The "trial of the sickest" (CD-12) will show vastly higher lives saved per (very limited) available dose.
"Clinical Infectious Diseases" has an "impact factor" of 9.1 - very solid, though not on the the scale of JAMA or Nature (40ish) or NEJM/Lancet (higher).
Any healthcare professional will be comfortable citing it or passing on a cite.
Please read articles before posting links.
The article said the aerosols produced by intubation/ extubation were smaller than expected as compared to the average cough.
Discussion was about whether extra-super-safety-protocols were required during those procedures.
It said nothing about whether aerosols, in the general public environment, were a big or small risk.
Grip - it's a body of work: 84 m/m + 195 s/c + 61 EIND = 340 COVID pats already, plus
(1) Safety - we have >1k pats w/ safety data - others have proven worse record or are newbies lacking data, and
(2) Efficacy: square root rule - if you have half the effect, you need four times the trial size to detect it.
All longs here believe in a minimum 50% reduction in mortality in S/C and 50% reduction in progression of m/m to s/c (data: m/m NEWS2 80% LL improved vs. 50% control)
So, considering the RCTs together, compared to a drug targeting half that, in terms of stat power for proving efficacy, we already have data matching a 1,000 person trial.
Of course, each trial was/will be on its own statistically significant on its relevant endpoint. The body of work will be "big enough" and have unmatched consistency.
Doesn't the UK have some multi-arm, adaptive RCT taking advantage of a common control group and evolving drugs in and out?
Thanks, I'll have to listen to pitch as deck just says due to rapid enrollment - matching RDV's metric is at least a reason for changing primary.
Hey, (all) MaBs to the rescue. As Patterson noted, we will need more than one therapeutic drug.
Getting ready to enter HGEN, own CYDY and RELTF - likely a trifecta in some order.
Two questions on statements made about yesterday's call before I invest: (1) the comment that an interim analysis causes a 28 day delay makes no sense - CYDY is still recruiting - is there a better answer?, and (2) was the endpoint changed, as some have asserted?
I'd appreciate a link but value any response.
Rockleo - Fully appreciated.
This Aviptadil PR, saying the DSMC softened their endpoint, came out July 16th. They said the next DSMC was in 4 weeks - shouldn't we have heard something?
Jaylimab - conceivable (not likely) to change endpoints. The 7-point ordinal scale is the secondary measure in this study that others are using that has better resolution.
In the other direction, we could have significance in both the primary endpoint and the SOFA (organ failure, clotting driven) secondary measure. That would conclusively support the Patterson's MOA.
Organ failure is a rarer event I think, so more difficult to detect, but given BP's statements about zero clotting, it's possible we could have zero events on this score. That drops the variance!
Yep, reduced overall mortality decreases statistical power. Those power calcs were on this board long ago - have to revisit.
The trial has been modified twice to offset the trend. First, the age limit (prev <65) was removed. Then they changed language regarding intubation at admission.
Every effort to keep this the "trial of the sickest."
Positive on this? If so, will we just get stop/continue signal like last safety meeting or do we get detail? Will it be as fast as last DSMC readout?
Indeed - if the SOFA (organ failure) secondary endpoint, including coagulation issues, is improved, that would uniquely confirm the RANTES hypothesis.
Outstanding, but Forbes disclaimer: "Opinions expressed by Forbes Contributors are their own."
No joke - 2000 patients a big trial, but still only gets 3.16 time the resolution of a 200 person trial. Could mean any combo off: (1) they are targeting a 15% reduction, vs our 50% or so, and/or (2) their population is healthier - expecting fewer events per patient. Actually, I should read the endpoints before sending this ....
Based on the call, here is a re-written press release focusing on the leronlimab body of work:
Leronlimab in COVID: Program Builds with Actionable Phase 2 Results in Mild/Moderate Patients; Severe/Critical Phase 2b/3 Trial Nears Interim Analysis Enrollment
CytoDyn today filed outcome data with the FDA regarding an 84-patient multi-center Phase 2 randomized controlled trial in mild-to-moderate COVID-19 patients.
The company believes the results justify early approval, and has requested that from the FDA. If not, it believes it will be granted a Phase 3 trial with minor changes informed by the current results. Either outcome is a significant success from a mid-sized trial in a population where most patients recover from symptoms by day 14.
Results highlights are as follows:
** The primary endpoint, an index of the severity of four symptoms at day 14, improved by a clinically important, but not statistically significant amount versus controls. Among the sicker cohort, the day 3 change reached significance, reflecting earlier symptom resolution.
** The “National Early Warning Score 2,” or NEWS2, showed a statistically significant improvement at 3, 7 and 14 days. P-values were .02, .03 and .02. At day 14, 50% of those treated improved on this score, versus only 20% for controls. NEWS2 is an index of 7 objective parameters that is currently in use for hospital patient triage. It was recently shown to have high sensitivity and specificity to progression to severe disease.
** There were 64% fewer severe adverse events ("SAEs”) (p<.04) in the treatment group, While SAEs are typically considered a drug safety issue, in the COVID-19 environment they largely reflect disease progression and as such could be a valid efficacy endpoint. There were no drug-related SAEs in the leronlimab group.
There are currently 175 patients enrolled in a Phase 2B/3 multi-center randomized controlled trial of severe-to-critical COVID-19 patients.
** At 195 patients, the company will perform a previously-specified interim analysis of the data. Because of leronlimab’s superior safety record, this is the “trial of the sickest,” as it includes patients that would be excluded from other trials. The primary end-point is mortality at 28 days.
** The company believes the patient population of this trial will resemble that of its third set of COVID-19 data: its early, highly successful 60 patient emergency IND program. In the largest subset of that group - 31 patients at UCLA - under 15% of severe patients and 30% of critical patients died. After that EIND program, UCLA became a treatment site for both of the above trials.
This is how restricted stock award vesting works at any compliant company. They only give the recipient a fraction of the shares, while selling the rest - enough to cover withholding on the gain recognized - on the same day as the vesting. E*Trade handles the mechanics at one company I know.
The company passes on the proceeds to the IRS/State tax. None (OK, a fractional share amount) goes to NP. It's not like NP had any choice.
As JustDF noted, the acquisition price is zero - standard for restricted stock vesting - so the entire price is short-term taxable gain. And the governments require their money ASAP.
That's diligence that could be done - I'm out for the night.
I've seen people on this board use numbers from 36% to 79%, with little clarity on the mix of S vs. C.
We don't know the ratio of severe to critical in the trial. At 50/50, though, it would prorate to "only" 22.5% lost.
I think a lot of people are mentally thinking we want to cut deaths in half. Will the placebo group (at 50/50) lose 45%?
I'm trying to remember the stats - I'm pretty sure 45% vs 22% at 100 patients or higher was significant - anybody remember or want to check?
Here's the precise reality of the UCLA EIND experience - not quite as rosy as painted.
At 7:46 in the June 2nd presentation, NP shows a slide of the results of 31 patients at UCLA:
11 critical: 4 extubated and discharged, 4 stable, 3 deceased
20 severe: 15 discharged, 1 improved, still hospitalized, 1 too early, 3 deceased.
Hopefully, the trial-enrolled patients are healthier, or were treated more knowledgeably than the earlier ones. But our trial has few exclusions - it's truly the "trial of the sickest."
We have to be mentally prepared to see a lot of deaths in both arms of the severe/critical trial.