The Implications of Cytodyn's Basket Cancer Trial

* Cytodyn May Have a Handle on Metastasis by Blocking the CCR5 Receptor with a Humanized      Monoclonal Antibody

* Cytodyn's Drug Leronlimab Appears to Stop Angiogenesis - It Stops the Growth of a Tumor by Stopping the Growth of the Arteries that Allow It to Grow

* Leronlimab Also Appears to Re-polarize Macrophages from Pro-Inflammatory to Anti-Inflammatory

* Cytodyn Will Conduct a "Basket" Trial of Leronlimab Against 22 Different Types of Cancer

* Additional Bonus - Leronlimab May Prove to be the Best Treatment for Coronavirus - Correcting the Cytokine Storm Which Causes Pneumonia, and It Reduces the Viral Load



On April 15, Cytodyn (CYDY) began a basket trial of its key candidate against 22 different kinds of cancer. Here is a PR video with the announcement of the beginning of that trial.

The CCR5 receptor had been identified as the means HIV uses to enter a cell, and by blocking that receptor with a monoclonal antibody, it appears to halt the progress of the disease. The company has of Monday (April 27) has filed the remaining parts of a BLA (biologic license application) for a combination therapy with standard anti-retroviral therapies, and then later, the company will file a BLA for a monotherapy with leronlimab alone.

Researchers for Cytodyn felt that CCR5 was involved in the spread of cancer, and they tried it against TNBC (triple negative breast cancer) found in a relative of the company’s CEO, Nader Pourhassan, in a compassionate use trial. It appeared to work, with CTC’s (circulating tumor cells) falling to zero. Her condition continued to improve, and now she is officially in remission. They tried it against other women with TNBC, and again, had some luck with it.

They decided to try it out against other cancers. Their announcement states that they will conduct a “Phase 2 clinical trial for the treatment of approximately 22 different solid tumor cancers, including melanoma, brain-glioblastoma, throat, lung, stomach, colon carcinoma, breast, testicular, ovarian, uterine, pancreas, bladder, among other indications.”

The one thing the PR fails to mention is that all of these cancers have a connection to the CCR5 receptor.  So, I was curious and I put all these cancers into the search engine, and here are titles of articles and links that I found for the CCR5 receptor and each cancer to be included in the basket trial:

Melanoma - High expression of CCR5 in melanoma enhances epithelial-mesenchymal transition and metastasis via TGFβ1. (NCBI – National Center for Biotechnology Information)

Brain-Glioblastoma - Cytokine CCL5 and receptor CCR5 axis in glioblastoma multiforme. (NCBI)

Throat – Recent Advances Targeting CCR5 for Cancer and Its Role in Immuno-Oncology (Cancer Research)

Lung - CCR5 is Associated With Immune Cell Infiltration and Prognosis of Lung Cancer(Journal of Thoracic Oncology)

Stomach cancer - Inhibition of the CCL5/CCR5 Axis against the Progression of Gastric Cancer (NCBI)

Colon cancer - CCR5 status and metastatic progression in colorectal cancer (NCBI)

Breast cancer - CCR5 Expression Influences the Progression of Human Breast Cancer in a p53-dependent Manner (NCBI)

Testicular cancer - Study of the HIV-1 receptors CD4, CXCR4, CCR5 and CCR3 in the human and rat testis (Oxford Academic)

Ovarian cancer - Chemokine Receptors in Epithelial Ovarian Cancer (NCBI)

Uterine cancer - Downregulation of CCR5 inhibits the proliferation and invasion of cervical cancer cells and is regulated by microRNA-107 (NCBI)

Pancreatic cancer - CCR5/CCL5 axis interaction promotes migratory and invasiveness of pancreatic cancer cells (Nature)

Bladder cancer - Impact of chemokines CCR5∆32, CXCL12G801A, and CXCR2C1208T on bladder cancer susceptibility in north Indian population.  (NCBI)


Other cancers might include:

Prostate cancer - Discovery of a Novel CCR5 Antagonist as an Effective Therapeutic Agent for Prostate Cancer (Scholars Compass)

Bone cancer - The HIV co-receptor CCR5 regulates osteoclast function (Nature)


Possible other uses of a CCR5 antagonist have turned up for Cytodyn’s leronlimab:

Hypertension: CCR5 as a Treatment Target in Pulmonary Arterial Hypertension
GvH: Chemokine Receptor CCR5 Mediates AlloImmune Responses in Graft-versus-Host Disease. Cytodyn is investigating the possible use of leronlimab in this disease.

Cytokine Storms (Coronavirus) - The cytokine storm of severe influenza and development of immunomodulatory therapy. This article appears to point the way to its use against coronavirus.


The Consequences of a Successful Basket Trial

So, if these cancers are expressing CCR5, which they appear to do in the titles above, then this trial has a good chance of working out. In any event, this study will show what the limitations are of relying on the CCR5 receptor in metastasis and cancer. If this drug is found to solve the metastasis problem for these cancers, it will have gone perhaps 90% of the way to solving the riddle of cancer, a much bigger problem than coronavirus, which social distancing is slowing even before a vaccine is found. Social distancing, obviously, has no effect on cancer.

The news from the company's conference call of April 27 is that in the 12 triple negative breast cancer patients to whom they have given the drug that in 3 to 6 weeks the CTC's dropped to zero.  That is the kind of data that suggests they have figured something out.

One thing I noticed in compiling these links is that other receptors (CCR3, CCR7 and others) may play a role in disease which might be another avenue for Cytodyn or other pharmaceutical company, but certainly CCR5 looks like a big one. If the final results of this trial are positive, then something important and apparently universal will have been discovered about cancer, and that would put leronlimab on the screen for every oncologist in the world. And obviously, someone may be up for a Nobel Prize.

But apparently, their monoclonal antibody may do more than stop metastasis. It may also stop the artery growth that promotes tumor growth known as angiogenesis, and it “re-polarizes” macrophages. Apparently, macrophages are either pro-inflammatory or anti-inflammatory, and leronlimab changes from them from the pro- type to the anti-inflammatory type.  Macrophages are what “eat” microbes and cancer cells, and if they can be directed to properly do their job, then perhaps they can dissolve the primary tumors. If not, perhaps they can be dealt with thru the old standbys – surgery, radiation or chemotherapy.

The value of such a discovery, if it proves out, would be stupendous. The company attempted to put a value on its use in TNBC in a presentation based on the cancer drug trastuzumab that treats breast cancer for HER-2+, and which generates $15 billion sales. Apparently, there are about four times as many triple negative breast cancer patients, so that leronlimab might generate four times as much revenue, or $60 billion. Add to that 22 other cancers (and maybe more), and you are talking hundreds of billions.

But even ignoring these other possibilities, its use in HIV (which may ultimately generate as much as $12 billion), which is pretty much established, together with its use in TNBC, which is looking mighty good, might generate above $70 billion in revenues.

Unfortunately, it may take something big like $60 - $70 billion to move the dial. There are a staggering number of shares. Yahoo says there are 482 million shares. Otcmarkets.com says 490 million, but a posting on a shareholder discussion board says that when you work out all the warrants and options, the share count might be as high as 706 million (here is a pointer, but I don’t know if it will work for you). And I don’t know if that number is definitive. People will make money, but perhaps not as much as they thought they would. A buyout at $7 billion might be a mere $10 per share, though a $70 billion buyout would bring $100 per share.


The Coronavirus Detour That Could Be Great for the Nation

The company apologizes for the slow start of its basket trial, and the late filing of the BLA for HIV to help try and save lives because its drug leronlimab apparently can set right an over-responsive immune system caused by Covid-19. CCR5 seems to have a role in cytokine storms, which are so critical in the respiratory distress caused by coronavirus.

As I approached this article, I viewed the company's work on coronavirus as a detour from what I viewed as the main work on cancer, and I still view it that way, but apparently, from a conference call today it appears that leronlimab (to be known when for sale as Vyrologix) may possibly move up to head of the class as the best candidate for a therapy for corona.  Not only does it correct immune systems gone haywire (and deaths mostly come from immune over-response), but surprisingly, it also reduces the viral load.  Many patients have already been able to go home, including a number that were on respirators.

Many patients die from another underlying condition adversely effected by coronavirus, and it does occur to this writer that one reason that leronlimab may be effective is that it has such wide-ranging effects that it may have a positive effect on a patient's other conditions.

For a discussion of the various therapies under study for on-going cases of coronavirus, please read this piece: Finding the Kink in Covid-19's Armor, Preventing ARDS by Theodore Zucconi.  He believes that the data so far will support "imminent approval of leronlimab."

The company has 40,000 vials on hand, and it takes two vials for each patient dose, so that would be 20,000 patients that could be treated, if only one dose is needed.  The company has two suppliers, and I believe its deal with Samsung Biologics will supply them with all the doses they need.

I do not wish to anticipate the pricing of these doses, but I expect it will be quite expensive, but I think Congress will pay the price of righting the economy, and this will be part of that cost.  It does not obviate the need for a vaccine.  Only with a vaccine will people be truly comfortable, and act as before.  I would ballpark the possible income from this source at $2 billion.  Zucconi believes that an approved therapy could be worth $10 billion in market cap.


The Company is Not Without Competitors

It seems there is competition on every front. Gilead (GILD) and others are hard at work on HIV.

It seems there may be other good therapies for coronavirus. Gilead has remdesivir, which has had mixed reviews.  See Zucconi's article.

Mesoblast (MESO) recently touted Remestemcel-L as a solution for coronavirus, which issued a press release stating that 83% of patients on a ventilator came off the equipment, versus between 9% and 12% in normal circumstances.

Remestemcel-L "is believed to counteract the inflammatory processes implicated in these diseases by down-regulating the production of pro-inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues", which would explain its usefulness against coronavirus.

Mesoblast of Australia has an allogeneic mesenchymal stem cell product candidate which they call remestemcel-L. The company maintains that it is useful in GvH (graft versus host), but this study says they did not meet their primary endpoint.

Triple negative breast cancer is also being researched by Immunomedics (IMMU), which has recently published a paper in the New England Journal of Medicine, in which they described the luck they are having with TNBC.


Last Thoughts

The uses for Cytodyn's leronlimab appear to be every biotech scientist's fantasy, and that gives one pause.  Coronavirus, all manner of cancer; it has been suggested it might be useful against Multiple Sclerosis and NASH (Non-Alcholic SteatoHepatitis).  Can it really be the Swiss army knife of cures?


The trials for HIV have been successful and the first BLA has been filed, if the trials for coronavirus and triple negative breast cancer for which the anecdotal stories and limited data presented so far have been quite positive, then CYDY may be on a path to as much as $70 billion in revenue. If the basket trial works out, the theoretical possibility for which I have demonstrated with the links above to the CCR5 receptor, then doctors will have a nearly universal tool against cancer that might resemble penicillin of years ago and perhaps a path to revenues in the hundreds of billions.