The Making Of A Platform Drug

Let me give thanks to u/Expensive-Tea-4007 for not just the title of this post, but also for the upshot and substance of it.

Greetings to All of You. Welcome All of You here. We study and this is what we come up with.

Enough has happened recently here at CytoDyn to allow us to draw to some conclusions. The news last week is a prelude to what comes on Tuesday. We don't know exactly what is to be discussed, but we can make some "educated guesses" or hypotheses, can we not? Yes, I know, they are still guesses and that of course is the point of this. Reasoned conjecture is what you find here.

Thankfully the FDA Has Lifted the second Clinical Hold on 2/29/24. Subsequently, the next day, a 424B3 - 03/01/2024 was filed with the SEC.

Take note of some of the wording of that 424B3:

"On February 27, 2024, CytoDyn Inc. (the “Company”) received confirmation from the U.S. Food and Drug Administration (the “FDA”) that its clinical hold on leronlimab has been lifted. The Company now intends to pursue its plan for the further development of leronlimab as a therapy that provides clinical benefit by modulating chronic inflammation. The Company believes its proposed inflammation study will allow the Company to further establish leronlimab’s mechanism of action in a cost-effective manner."

How was this point phrased in the Press Release of 2/29?

"VANCOUVER, Washington, Feb. 29, 2024 (GLOBE NEWSWIRE) -- CytoDyn Inc. (OTCQB: CYDY) ("CytoDyn" or the "Company"), a biotechnology company developing leronlimab, a CCR5 antagonist with the potential for multiple therapeutic indications, announced today that the FDA has lifted the clinical hold on leronlimab. The Company is now free to proceed with its proposed HIV clinical trial exploring leronlimab and its effects on chronic inflammation.

CytoDyn's CEO, Dr. Jacob Lalezari, stated, "We are excited that the clinical hold on leronlimab has been lifted by the FDA. CytoDyn is grateful for the FDA's guidance on our protocol and we are excited to open a new chapter in the development of leronlimab as a therapy that provides clinical benefit by modulating chronic inflammation.""

They are Similar. I see "modulating chronic inflammation" in both accounts. But what happened to the "HIV" inclusion? Remember? It used to say, "...who are living with HIV". Now, there is no mention of "HIV". Hmmm.

Looking back 2 months to the 12/14/23 Webcast, how did Dr. Jacob Lalezari originally introduce the coming trial?:

"00:03:45, Dr. Jacob Lalezari:

I'm also excited to announce that CytoDyn submitted a new phase two protocol to the FDA to evaluate the effects of 24 weeks of leronlimab on chronic immune activation and inflammation in cisgender men and transgender women living with HIV. This protocol was submitted in early November alongside the company's response to the partial clinical hold. Chronic immune activation and inflammation cause strokes, heart attacks, and other vascular events and remain the leading cause of death in people living with HIV. The FDA letter of November 30th, in addition to lifting the partial clinical hold, also provided extremely helpful guidance on CytoDyn's proposed immune activation protocol in order to help optimize our chances of success while taking aim at this complicated therapeutic challenge and critical unmet need.

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What happened that caused CytoDyn to remove "HIV"? Did the FDA feedback have anything to do with why "HIV" was removed?

00:04:45, Dr. Jacob Lalezari:

Now, to be clear, CytoDyn was again placed on a new clinical hold for the immune activation study while we incorporate FDA feedback and prepare a revised protocol. I want to stress that this new clinical hold is often a normal part of the FDA review process on newly submitted protocols. The hold does not raise any new regulatory or safety concerns and it will be removed after we respond to FDA's guidance concerning our protocol design, primary and secondary endpoints, and stopping rule. We're reviewing the FDA guidance now with our key consultants and expect to submit our revised protocol in January.

00:05:40, Dr. Jacob Lalezari:

So, just to summarize and be clear, the partial clinical hold over the last 22 months has been removed and all past issues have been completely addressed. We expect the new hold to be lifted after we incorporate FDA's recent suggestions and submit our revised immune activation protocol in January. After that resubmission, the FDA will have 30 days to respond to comments. I know that the simultaneous removal of one hold and the imposition of a new hold can seem confusing. But I want to assure everyone today that this is all very good news for CytoDyn, and we are excited to be turning the page and moving forward."

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Let's take a look at how the coming trial was presented in the Investor Meeting from Late November?

First: why the move towards attenuation of immune activation and inflammation. There were "provocative" signals.

"00:19:34 Dr. Jay Lalezari:

You all are familiar with the literature, CCR5 is popping up everywhere. Stellate cells in the liver are CCR5 positive, and they lay down the fibrosis in the liver. We've all lived through the COVID story with Bruce, and elevated RANTES levels in the ICU patients, and the role of CCR5 in the tumor microenvironment, and this is all much more complicated than simply blocking viral entry. So, what is the next step for CytoDyn to take? When I look at the COVID study, I personally believe, and all the caveats apply, I believe, I think, that it worked in the ICU population, and that it was consistent with what Bruce had shown with elevated RANTES levels. Obviously, we had some patients on ECMO who had dramatic responses, and what I take away from that COVID experience was that the decreased mortality, 78%, and then 82% at day 14, tapering off after the drug was withdrawn, and unfairly, I think, for the day 28 endpoint, that the signal there was very provocative, and that the number needed to treat in the ICU population was less than five.

The signal was great and needs to be published.

But as the FDA has made clear, it's a provocative signal without a significant P-value, and that will never be adjudicated as either right or wrong until somebody repeats that study in an ICU population. That will never be CytoDyn, among other reasons. It's become very difficult logistically to do inpatient COVID studies. But my hope there is simply that we get the CD12 data published, and that someone else, like NIH, can then review peer-reviewed data and make a decision as to whether that signal needs to be followed up and adjudicated or not. But in many ways, I think it's out of our hands, out of CytoDyn’s hands, and kind of up to God.

Something might be happening, something with significant clinical impact. This is the reason for the move.

00:21:56 Dr. Jay Lalezari:

With the NASH study, I think you see kind of the opposite, where there is a significant p-value, but it's unclear whether the signal itself is of clinical significance, in that the change on the radiology was just in the orders of milliseconds or a percent reduction in fat. But there was a statistically significant p-value at 350. When I first thought about the study, I was put off by the fact that 350 was significant, but 700 wasn't. Having reviewed the top-line summary now, I understand that the changes in markers were in the same direction with 350 and 700. It's not like 350 worked and 700 didn't work. They were both moving the markers in the same direction, and I think it's a small study. And in fact, what I take away from it is that it's amazing that anything moved at all after 12 weeks of treatment. We do six or seven NASH studies treating patients for a year, and more often than not, we see nothing happening. So I'm encouraged, again, like COVID, it's a signal, it is unproven, it needs to be absolutely confirmed in larger studies, and that's true of both COVID and NASH, and certainly everything that's been claimed about cancer. But what we're seeing here is two provocative signals in that telling us that in the realm of leronlimab activity in the biology of CCR5, something might be happening, and something with significant clinical impact. So what is the next study that CytoDyn can do to come off clinical hold and generate data that's not ambiguous, that tests this hypothesis around its activity in affecting signaling through CCR5?

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Dr. Jay Circling Back to "HIV", but with a twist.

00:24:03 Dr. Jay Lalezari:

And the consensus with the HIV consultants has been that we look, go circle back to HIV, but instead of looking at leronlimab as an antiviral, we are looking now at leronlimab as a modulator of immune activation. Is that a relevant endpoint? It is, because immune activation inflammation is the primary driver of mortality in HIV patients. Strokes, heart attacks, liver, kidney. It is unfortunately a much more difficult endpoint to assess than simply following an HIV viral load, but it is kind of in the wheelhouse of what we're believing leronlimab is capable of. So, the proposed next study is to look at leronlimab in HIV positive ambulatory subjects. We know it's safe in that group. In individuals who demonstrate elevations of immune activation markers. So known evidence of immune activation inflammation. And then we're tentatively looking at both doses 350 and 700mg and looking at a nested placebo arm so that at the end of 24 weeks of treatment, we can at least get a real measurement of whether leronlimab has moved the needle there or not.

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The FDA requires some kind of proof to allow the move towards immune modulation and inflammation attenuation.

00:25:36 Dr. Jay Lalezari:

I think that's a study that the FDA is going to have a hard time not wanting to see done. There is currently no therapy for immune activation in HIV. Half the patients we're going to enroll are going to be transgender women who have elevated activation markers because of the hormonal therapy they're taking. And in fact, what I had mentioned earlier was that the FDA, having received the protocol, has asked if they can cross-reference the IND file for NASH, which is exactly the right question to be asking is “what other evidence do we have that leronlimab is mediating inflammation and immune activation?”. So that we are waiting to hear. I believe the clock is ticking and that we're expecting to hear one way or another from the FDA in the next two weeks. And from there, it's either we're off clinical hold and we're raising the money and we're launching this study, or we're dealing with whatever else is being sent our way. And I think I will just stop there and happily answer any questions. Thank you all for listening."

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So, the FDA provided the course.

"In terms of having a solid understanding of what it will take to come off hold this time, again I think the FDA's comments were really deeply thought out as to how CytoDyn could move forward in immune activation. I think it's worth noting that no one has succeeded in immune activation. Of course no one's been going at it with a drug quite like leronlimab, but I think FDA considered this indication and the challenges ahead and gave us some really good advice about how to move forward. So, you know, I think I have a solid understanding that we're actually finally engaged in a collaborative relationship with FDA and that they are helping us do everything possible to move past this latest clinical hold. And I don't think it's going to be a huge challenge; I think pretty much everything the FDA asked for have made a lot of sense to me and would be fairly easy to implement in our revised protocol. "

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So, I presented all that to show what was said at the conception and what is being said most recently, to understand how things have slightly changed, but in a BIG way. I guess it is clear that "HIV" has essentially been removed from being included in the indication criteria of the coming trial. Now, the trial indication includes patients requiring the "Modulation of Chronic Inflammation" in general. Now, that inclusion criteria are vastly wider than if it were to only include HIV patients that require the modulation of chronic inflammation. It now seems to have become much wider and broader. It no longer seems to be limited by the inclusion criteria of chronically ill HIV patients who are also severely inflamed. No, now it appears that the new clinical trial protocol could be for anybody with severe and chronic inflammation.

I believe this might be discussed in the upcoming webcast on Tuesday 3/5/24.

In addition to the above, in this cool post by u/Pro140_LVMN, I put forth the notion that in consideration of the removal of "HIV" as part of the inclusion criteria of the indication, a possible consequence of that removal might have nullified the Regnum Corp. Agreement/Contract they had with CYDY, because that agreement was based on leronlimab being distributed for HIV. Recently, it appears as if Regnum is no longer trading and I was considering that could have happened because the HIV inclusion criteria might have been removed from this indication. The day the share price went to $0.0001 was on 2/16/24 and that may be the day CytoDyn removed HIV from its pipeline. Thank you so much u/psasoffice; you are all over this post. His recommendation to all is for patience; it will happen, but realize and take it to heart, that we just came out of the oven. If I were to choose a song that u/psasoffice would sing to you, it would be not to look back and it is the same song which I would sing to him; yes, Don't Stop my friend. Our u/Upwithstock helps me out here to understand that it may not have been Mitch Cohen that influenced the change in the indication, but rather it was through the acceptance of the FDA that the inclusion criteria were developed, and things might have simply naturally unfolded to our benefit.

The important thing to grasp here is that the inclusion criteria of the indication for this coming clinical trial has changed for the better. For the much much better. The clinical trial indication is no longer limited by the requirement to include only HIV patients; rather, it may have changed to something far huger and more massive. The Making of a Platform Drug. It could have changed in accordance with the making of something truly massive. But can one trial really be conducted to prove leronlimab as an Attenuator of Inflammation in every inflammatory condition? I think it can, but in general terms. First off, let's remember, this is a Phase II trial, so it shall be designed in such a way as to learn from. How does leronlimab do what it does? By what means can the effects of the anti-inflammatory drug leronlimab be quantified and measured? What are the pertinent biomarkers to obtain to prove leronlimab does what it does?

Going on the premise that leronlimab is a very versatile drug which can be used in a myriad of inflammatory processes, it makes so much sense to make full use of the collaboration/partnership agreement CytoDyn has with Albert Einstein College of Medicine and Montefiore Medical Center in New York. Why stop at GBM? These types of studies are relatively short and quickly resulted. We just need to know the best CCR5 dependent processes to go after. That is to partner with. Now, considering the arrangement CytoDyn has with Montefiore, could it be that CytoDyn needed to drop the MD Anderson trial in CRC on account of the agreement CytoDyn now holds with Montefiore? Maybe the real reason CytoDyn dropped it is that it knew the PD-1 blockade was superfluous and not necessary, that leronlimab could do it by itself, without the PD-1 blockers help. Maybe Dr. Lalezari knew that the path to success would be to pursue the path of Attenuation of Inflammation and Immune Activation, from what I laid out above.

So, let's go back over a year ago and start off with the first Sign. That was the R & D Update 12/7/22.

Cyrus stated:

"1:31: 40: So, in terms of what potential timelines can look like, I think it's really important to highlight that from a value-creation standpoint, and I've mentioned this before, we truly do need to generate a large robust and what I call unequivocal data set that will leave no questions left on the table, right? And that a strategic partner would find attractive and attractive enough to do a real value-accretive deal with the company. 

1:32:14: And so, we've gone through and knocked out what the potential timelines are across each of the different areas that we presented on today. And we're -- as I mentioned before, NASH & Oncology are our priorities. However, because this is all going to be funding dependent, we're going to focus on NASH initially and work with co-development partners to the extent that we can to develop in oncology. "

"1:32: 44: So, what do we expect in 2023? So, our largest priority is the removal of the clinical hold in HIV. This is essentially a gating step for us to be able to get back to normal operations as a company and do what biotech companies do*, which is advanced therapeutics and try to bring them to market.*

1:33:10: Following the lift of the clinical hold, we expect financing to fund operations and to achieve this value inflection point that I've just alluded to. We intend on initiating a new NASH trial. We would like to commit to an investment in and advance longer-acting CCR5 molecules, as this is potentially the future of at least certainly HIV therapy*, as Dr. Sacha presented.* 

1:33:35: We continue to contribute in medical meetings and peer-reviewed publications. Again, the CD02 trial data is in process for that right now*. We're going to continue to reshape our team and our capabilities in order to meet our goals. And at some point following the achievement of earlier metrics listed on the slide, we're starting a corporate rebranding as well."*

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How does all that compare and contrast with what Dr. Jacob Lalezari says now?

"00:28:02 Marta:

All right, so let's start with questions from the audience now. What is the trade-off between chasing bigger markets like Nash and Cancer versus faster potential past revenue in a smaller market like HIV?

Dr. Jacob Lalezari:

Well, I'll just start by saying there is no treatment for immune activation in HIV, so it's actually considered a very large market. All patients with HIV are having to deal with some level of immune activation and inflammation, which is the driver of their increased mortality. I think that NASH and cancer are very appealing markets, but way beyond the can of CytoDyn at this stage to really make inroads in on their own. They're going to have to partner*. And* I think it will be a lot easier to partner when leronlimab has a proven role in reducing immune activation, the inflammation, proven role in affecting the biology of CCR5.**"

If it is a very large market in patients that have HIV, how much larger is it when the inclusion criteria is not restricted by mandating only patients with HIV?

Dr. Lalezari indicates here that this coming trial is necessary to facilitate partnerships.

Here Dr. Lalezari is showing that the market is huge:

"Marta:

Great, thank you. What are your estimates of the size of the market out there that CytoDyn can go after?

00:49:00 Dr. Jay Lalezari:

I haven't done a market analysis, but the HIV population is aging. When I started as a young man with Pro140, the average age in clinical studies is around 38 years old. Twenty years later, it's still the same, you know, it's 20 years later. And those older individuals with HIV who have had the virus now for several decades, their risk is cardiovascular inflammation, immune activation. So even though I can't give you a number, I know that it's significant. And that's something that we probably need to be prepared to answer the next time we do one of these calls."

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So, my commentary. We now know that the child delivered on 2/29/24 was represented both by 1) the lift of the second hold in conjunction with 2) the FDA's acceptance of the protocol for the new clinical trial. Extrapolating, the child, composed of 2 parts, becomes the embodiment of the clinical trial which has now been officially accepted by the US FDA, because the drug is safe and because the protocol is deemed as necessary by the FDA. Despite all of CytoDyn's bloody labor pains in delivering that child, it was born healthy. Therefore, the part in the R & D Update where they were aiming for the lift of the hold has been fulfilled. We got it under our hat now. That has been achieved.

Now we have a situation taking place currently where, as I've said before, CytoDyn's enemies did not want this to happen. Yet it did happen. Retaliation did not take long. Out of nowhere, we see a competitor in chronic inflammation. I mean really? A Coincidence? Yeah, right. Where did that come from? Of all that might, it was Abbvie? What? Are they really going to try to beat us at our own game? They wish they had the weapon we have. They may have the $$, but they don't have what it takes. I'm not worried though. I see everything going down in fire except leronlimab in this broad indication of chronic inflammation. What is really weird though, is that Abvvie has a license agreement with CytoDyn and wouldn't you think they would want to bring their own drug to market? No, they choose to offer OSE Immunotherapeutics to receive an upfront payment of $48 million and will be eligible to receive up to an additional $665 million in milestone payments instead of working with CytoDyn to advance an FDA deemed safe drug which they already have a license agreement with. If they had chosen leronlimab, it would have placed them light years ahead especially because of the agreement with CytoDyn already in place. Abbvie just trying to apply more pressure to CytoDyn to get things done? Could be. Trying to heat things up and light a fire under our ass? Possibly.

Yeah, you can't tell me that they don't confederate with each other. How much more should we expect? Watch how the shorts meet every long dollar with two of their own short dollars. They offer up their cheap short shares to the longs who are happy to pick them up for less. Yes, this lowers the share price, but that is why the shorts do what they do. In order to lower the share price and boy do they have the funds to do it all day long, until of course, the Institutional Investors come in who begin buying not a million or two million shares daily, but rather 10 million, 20 million or even 50 million shares daily. Even then, the shorts might be able to offer these Big Buyers and Venture Capitalists a few cheaper shares, but they won't be able to do it day after day. Not at a volume of over 25M shares daily. Eventually, these long and strong Big Money buyers sink the shorts and that day is not too far off. Now with the hold lifted and the drug declared as safe, CytoDyn needs something to attract the Big Money Institutional Investors, such as the venture capitalists.

Bring on the peer reviewed and published articles which Dr. Lalezari has discussed. Bring on the results of the GBM study at Albert Einstein. Bring on the newborn clinical trial; let's get her up to speed, first teaching her how to crawl. Sure, she will stumble, but before you know it, she'll be walking and talking. You will see her fall every now and again, but in a blink, she will be running, jumping, dancing, doing the twist and never be looking back. The day the shorts are eliminated is in the distance, but as the trial gets underway and as stated above, CytoDyn makes strong headway into the dollars and exits permanently from the share price in terms of cents. The battle continues to rage on, but over appropriate time, the share price climbs an upward trajectory.

When the "AbbVie and OSE Immunotherapeutics Partnership" fizzles out, that also pushes us higher. Any competitor who fails, pushes us higher. Big Pharma tries to gain a handle on chronic inflammation, but it can't. It loses its grip. It's worried and scared. So, it plays its cards. They were seriously caught off guard with the FDA acceptance of CytoDyn's new protocol in the Modulation of Chronic Inflammation. They knew they had to do something right this minute to combat this or else they would lose their momentum.

Can you see that they are oh so willing to combat us? Therefore, we can expect more of the same. We can expect more of the same shorting tactics, until the Big Money comes in. That money comes in with the Peer Reviewed Published articles and with the Definitive Results from the clinical trial and from the strategic partnering studies performed at Albert Einstein.

Studies in GBM and who know what else lead to partnerships. In every promising indication in which a study takes place at Montefiore, so shall that door be opened up to partner behind. Partnerships become deathblows to the shorts. Another death blow to the shorts is the uncovering of the status of CytoDyn's long lasting leronlimab and of the progress they have made along the way. The revelation of the intentions which CytoDyn has for the long-lasting drug hits the shorts below and between the knees.

At this point, with the hold lifted, patients can feel very comfortable taking leronlimab as it has been deemed utterly safe by the FDA. At this point, shareholders who have once sold out of the stock can begin to feel more comfortable returning back to owning the stock as the FDA has given CytoDyn its blessing to go out into the world. Yes, the enemies remain and continue in their opposition, but the truth wins in the end every time. That truth results in an outcome of the Phase II trial which allows a subsequent transition to a Phase III trial. That truth results in the making of partnerships along the way in various inflammatory indications which will already have been previously studied in the labs of our hospital partner and determined by our AI partner to be partnership worthy indications.

Leronlimab won't be compromised, and neither does CytoDyn compromise itself or its assets. The trial commences and delivers the expected and calculated result. In fact, the outcome of the trial is already known even prior to its actual initiation because the calculated result was derived at according to our own AI calculations. CytoDyn's AI partner is yet to be revealed and the means by which the results of the trial are achieved, and the trial outcomes have already been calculated and are being tweaked as we draw closer and closer. Even as the trial proceeds, the calculations continue, and tweaking might be required, but the end result is refined and perfected as the data comes in.

Folks, it is now only a matter of time. The hard part is over. We are at the point now where we don't know when or how long, but we do know that it shall happen. I understand, it has been a long time already, but we got through the hard part. The rest should be a back-and-forth upward grind letting the world know what we know which is exactly what Dr. Lalezari intends on doing and not just Lalezari, but the whole company. There is no division at CytoDyn, rather, it is unified. All at CytoDyn are united in the task at hand and united within the cross hairs of the FDA that they do not deviate from this accepted protocol, and their determination and resolution cannot be swayed. This is CytoDyn's strength. We are on track because our mindset is right, so I just wanted to give you that.

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