February 6, 2023 PAO-02-23-CL-04
Cyrus Arman (CA): CytoDyn was founded in 2002 following a reverse merger from another company called RexRay. CytoDyn was already a publicly traded company at the time listed on the OTCQB in 2012 when the company acquired the rights to a molecule called PRO 140, which was at the time owned by a company called Progenics that had previously acquired it from Protein Design Labs.
Since 2012, CytoDyn has focused on the development of that molecule, which is now called leronlimab. It was originally designed as an HIV treatment, and it acts by binding to the chemokine receptor CCR5, which is present primarily on the surfaces of leukocytes (white blood cells), as well as some other epithelial cells. The CCR5 receptor is one of two critical co-receptors, in addition to CD4, that HIV uses to enter T cells. Blocking the CCR5 receptor completely can prevent HIV from entering T cells and replicating, thus reducing the viral load inside the body.
Around 2016, CytoDyn began investigating the use of leronlimab for the treatment of graft-versus-host-disease (GvHD), a common (20–50%) issue for patients with blood cancers who have received a donor bone marrow transplant. However, that program was eventually terminated owing to downstream effects.
In 2019, as the role of CCR5 in the cancer immune cycle became better understood, CytoDyn started its first oncology clinical program. The company started looking at solid tumors in triple-negative breast cancer and later initiated a basket trial for 22 different solid tumor indications. Data were collected for breast cancers that were not triple-negative, such as hormone receptor–positive breast cancer, as well as for colorectal cancer and prostate cancer. Early clinical signals are driving CytoDyn’s oncology program forward even today.
Shortly afterward, CytoDyn started a clinical program in nonalcoholic steatohepatitis (NASH), which is a fibrotic disease resulting from fat accumulation in the liver. The precursor to NASH is a condition called nonalcoholic fatty liver disease (NAFLD), in which fat accumulates in the liver and accounts for at least 5% of the liver mass. It is thought that as much as 25–30% of the U.S. population has fatty liver disease, many of whom also have diabetes and obesity.
Roughly a quarter of patients with NAFLD will eventually get NASH unless they make changes in their diet and lifestyle. Once patients progress into NASH, inflammation and fibrosis begin to develop, and no drug has yet been approved that actually reverses liver fibrosis. Fibrosis in the liver can lead to a number of downstream complications, including cardiovascular disease. There is also a higher risk of developing cirrhosis of the liver, which is typically irreversible. Patients with cirrhosis have a high likelihood of developing decompensation and ultimately liver failure, as well as an increased risk of hepatocellular carcinoma.
Catching these patients at the stage of early fibrosis and halting, attenuating, or potentially reversing it represents a tremendous unmet medical need. Consequently, much clinical development in the NASH space focuses on halting the progression of early fibrotic development. CytoDyn conducted a three-armed, placebo-controlled clinical trial that enrolled 75–80 patients, and the results were very encouraging. We were able to show that, with a 350-mg dose, both the level of fat in the liver and fibrosis are reduced, as measured through surrogate imaging endpoints that are becoming increasingly more accepted by the medical community.
The NASH and oncology data sets form the basis of our forward-looking strategy for how CytoDyn will continue to pursue the molecule. We are also developing a longer-acting version of leronlimab with our partners at Oregon Health & Science University. It has been tested in animal models, including rhesus monkeys, and has been shown to remain active inside the body for up to 180 days; treated monkeys are highly resistant to HIV infection, even after repeat challenges on a weekly basis for months. These data are really exciting, and there is no reason this long-acting version cannot also be used for the treatment of solid tumors and NASH.
CytoDyn will continue developing both the short- and long-acting versions of leronlimab. The goal is to bundle these two molecules together and find a strategic partner that can help us advance to later-stage clinical development and commercialization.
CA: The biggest indicator and the biggest driver is obesity. We have an obesity pandemic in the United States and Western Europe, and certainly throughout major parts of Asia and the Middle East as well. Alcoholism is the other main cause of fatty liver disease, but that form of fatty liver disease is pretty easy to treat: it generally subsides when patients stop drinking, unless of course fibrosis and cirrhosis have already developed.
Unfortunately, in some ways NAFLD and NASH are understudied because the etiology is complex, but these are ultimately metabolic diseases related to dysregulation of metabolism. Physicians are usually more interested in treating diabetes first if patients have both NASH and diabetes, as it is the more acute issue. In the case of NAFLD or early-stage NASH where there is no diabetes, there is an issue around diagnosis. Since there is no treatment for early-stage fibrosis, there is a reticence to perform a liver biopsy, FibroScan® testing, or advanced imaging — all of which can be expensive — to diagnose these patients.
That is changing a bit because I think in the next year or so we’ll see at least one approval in NASH. There is some exciting work by companies like Madrigal Pharmaceuticals and Akero Therapeutics. Akero just received breakthrough designation for their agent, which they acquired from Amgen several years ago.
The NASH space has historically seen a lot of failure, but these new developments are going to show the investor base and the larger biopharma developers that NAFLD/NASH is not an intractable disease — there are at least one or two molecular pathways that can work. It will also show that there is a more clear regulatory path with the U.S. FDA, which is equally important, because for a long time there was a lack of clarity about what the agency wanted to see from some of these studies in terms of which surrogates were the right ones. The regulators were waiting for drug developers to bring unequivocal data sets that show strong correlation between surrogate endpoints and actual outcomes, in particular biopsies that actually show reversal of fibrosis.
Biopsy remains the gold standard for fibrosis diagnosis and staging. Unfortunately, obtaining a liver is highly invasive and uncomfortable for the patient and can lead to other complications like infection. Getting a biopsy is not something taken lightly, particularly for obese patients with no symptoms related to fibrosis.
In addition, liver biopsies are a poor gold standard as far as gold standards go, because the results are dependent on where the liver is sampled. Fibrosis is not uniform throughout the liver in its earliest or even middle stages of development, so sampling location is important. Furthermore, the baseline and on-treatment biopsies must be taken from nearly the exact same area to get any real information about the effectiveness of the treatment.
Furthermore, a pathologist evaluates the sample and makes a judgment about the amount of collagen, fibrosis, and scarring present. Inter-reader errors have become a real issue. On a positive note, there is technology coming out that leverages artificial intelligence and automation to make the classification, which will hopefully increase consistency, but that technology is still early in development.
Given that the gold standard that the FDA has wanted to see is fraught with issues, it is encouraging that the agency is willing to start looking at a surrogate endpoint that correlates with biopsy. It means there is a path forward, not only with the FDA but to truly treat the disease.
CA: While that has yet to be definitively determined, I believe so, because our imaging data shows that leronlimab may actually attenuate and reverse fibrosis. The question then becomes whether it matters how the fibrosis developed. Was it due to alcoholism or obesity, or perhaps because the patient has HIV? Indeed, it turns out that patients who are living with HIV have a much higher propensity for fatty liver disease and subsequently NASH as a result.
Patients with HIV are susceptible to other infections, including hepatitis C, which is known to cause liver disease and liver damage. In addition, patients who have been living with HIV for many years and received earlier-generation antiretroviral therapy often suffer from metabolic dysregulation that causes accumulation of fat in the liver as a side effect of these medications.
Given this information, CytoDyn may be looking at a subpopulation of patients in our next NASH trial who have HIV and NASH. Since our molecule was originally developed as an HIV treatment, and we’ve shown that leronlimab suppresses viral load in the body, we think we are in a unique position to treat HIV plus NASH. Further down the road, the question of whether it matters how fibrosis developed will be one that CytoDyn will address.
CA: The CCR5 receptor is a G protein–coupled receptor (GPCR) that is very large (352 amino acids) relative to other receptor types that sit on the surfaces of cells. Typically, GPCRs are very hard to fully block with anything smaller than a very large peptide; generally, an antibody or larger protein is needed to fully bind CCR5. Leronlimab is a monoclonal antibody that binds to the N-terminus of the extracellular part of the receptor, as well as to the second extracellular loop of the GPCR.
The other CCR5 inhibitors in development only bind one part of the receptor. Only one CCR5 inhibitor — a small molecule that binds to one site — has been approved to date. These small molecules seem to bind deep down inside one of the pockets of the receptor. We are learning that where you bind CCR5 really matters. Binding it to prevent HIV from entering is better achieved with an antibody. Attenuation of downstream signaling — either as an agonist or an antagonist — is also dependent on the binding site. As a competitive inhibitor versus an allosteric inhibitor, leronlimab attenuates downstream signaling differently than small molecules.
CA: Different protein engineering solutions have been employed over the years to create longer-acting mAbs. For instance, there is a published molecular biology tool that leads to replacement of two amino acids of the antibody, thus turning a short-acting molecule into a long-acting one.
CytoDyn used this same approach, but also made additional changes to increase the stability of the molecule and confer other biophysical properties that cannot be outlined. The end result is that the half-life of the molecule has been extended. Importantly, this performance was achieved without changing anything about where or how the molecule binds to the CCR5 GPCR.
CA: We absolutely believe it has value in other indications. The reason why we’re starting in HIV is twofold: first, our academic collaborators are infectious disease specialists; so they can run those trials very readily and very easily. And two, there is a real demand in the HIV space for longer-acting injectables.
We recently presented preclinical data for this longer-acting version, and the feedback from the larger biopharmaceutical players in the space is that this type of solution is exactly what they’ve been looking for — a long-acting antiviral medication. In addition, from the perspective of preclinical development, there are good animal models for HIV, but there really aren’t any in the NASH space.
We also expect that cancer patients would appreciate a once-every-three-months dosing frequency. The optimum dosing frequency for fighting cancer has yet to be determined. There is always a benefit to being able to switch treatment regimens quickly, so a very-long-acting version might not be the best in the oncology setting.
CA: I think there are probably two drivers. One is your cost of goods, which is not trivial, particularly if you’re talking about treating a mass market disease like NASH. Dosing once a week with an antibody gets expensive from a manufacturing standpoint.
The convenience for the patient is also a consideration, particularly from a persistence and compliance standpoint. Again, we are talking about a disease that can be silent in the sense that symptoms may be minimal until all a sudden things get really bad. We hope that, by offering something that’s less of a burden for patients, at least from a compliance standpoint, they will be more likely to stay on therapy. Perhaps moving from injections once every week or once every two weeks to injections once every three or six months would increase patient compliance.
CA: Steps have been taken to revitalize the leadership of the company. The board has been made fully independent, with board members separate from the company and its day-to-day operations. The organization has also been right-sized, with certain unnecessary leadership positioned eliminated. A couple of new people with specific expertise will be hired to backfill those roles.
Our primary focus at the moment is lifting the partial clinical hold placed on CytoDyn’s HIV trials. The hold initially resulted from the failure of the CRO (contract research organization) hired to manage the trials; they unfortunately failed to deliver on many things they were contracted to do. Then three cardiac events occurred within a few weeks of on another—two in a COVID-19 trial in Brazil and one in an HIV trial. The former occurred in high-risk patients, for which cardiovascular events are one of the sequelae of the disease. Certain illicit chemicals found in the HIV patient are thought to have been the cause of the cardiovascular event seen there.
The FDA requested that CytoDyn address five discreet items. Three have been submitted to the agency, and the other two should be submitted shortly. The FDA will then have 30 days to review the information and will hopefully lift the hold.
Once that is taken care of, we plan to go out and raise financing to fund operations. Once the financing has been stabilized, we will bring people onboard with relevant biotech experience and expertise that can support our development goals, which include starting a NASH trial and continuing to invest in and advance our long-acting CCR5 molecule. A corporate rebranding campaign will also be implemented to put some of these issues in the past while creating a new face for the company.
CA: I’ve seen a lot of molecules over the last 15 years. I’ve also seen a lot of different clinical programs in which the same molecule is being used in different programs. To me, leronlimab has all the hallmarks of a winner.
I continually tell the team that we are really fortunate. It’s a gift that we have this molecule in our hands and that we can develop it, because we have something that we really believe works. The molecule is fantastic. There is a path here to value generation and to helping patients with this molecule. The future is exciting. We look forward to coming together with a strategic partner that can help CytoDyn get this molecule over the finish line.
Cyrus Arman is a life sciences and biotechnology executive whose experience and depth of knowledge spans numerous therapeutic areas while guiding corporate development initiatives, licensing agreements, financial investments, and strategic alliances for numerous companies. Prior to CytoDyn, he served in leadership positions with several biotechnology companies, including Amgen, Neuvogen, and Nimble Therapeutics. Cyrus received his Ph.D. in neuroscience and M.S. degree in biomedical engineering from the University of Southern California, and his M.B.A from the UCLA Anderson School of Management.
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