The top pharmaceutical companies are trying every approach they can imagine to find the weakness in COVID-19’s armor. Pharma companies that were arch enemies are working together. Drugs that are approved for other diseases are being tested as treatments. The front runner is Gilead Sciences (GILD) with its lead candidate remdesivir. Gilead expects initial trial results in April. On speculative evidence from a phone call cited by STAT report that remdesivir patients were responding to treatment the stock shot up 9.73%, or $10.5 billion, on hopes of a decent trial report. Soon to join it was Regeneron (REGN) with a rheumatoid arthritis (RA) drug called Kevzara. There are other drugs with some promising results like anti-malaria drug hydroxychloroquine and FujiFilm’s (OTCPK:FUJIY) antiviral generic influenza drug called Avagin (favipiravir). The primary issue is that none of these drugs has finished its controlled trials and none of these drugs prevents Acute Respiratory Distress Syndrome (ARDS), a complication of pneumonia and COVID-19. This is the most critical part of the disease because few recover from it. Data from China indicate that only about 15-20% of patients that go on a respirator recover.
CytoDyn Inc. (OTCQB:CYDY) has a novel way to treat ARDS that could tame the feared COVID-19 infection for serious patients. CYDY trial results are likely to come before heralded GILD presents results, so investors need to be cautious ahead of the announcements. No trials have been completed yet. Many drug companies like Moderna (MRNA) and others are rushing to create a vaccine, but a vaccine is not a cure but a prophylactic, which activates your immune system by producing antibodies for the virus. So, for the first time, we are starting to see hope that something can prevent the COVID-19, but the actual vaccine availability is 12 to 18 months away. Too far away to affect this outbreak and maybe the expected echo surge coming back in the fall. So a therapy for those with serious symptoms is needed as early as possible. There are only a few candidates. CYDY’s drug leronlimab is designed to stop the trafficking of macrophages to the lungs using the same mechanism of action that it uses to stop the trafficking of macrophages in metastatic cancer to the tumor microenvironment (TME). Imbalance in the immune response is ultimately what leads to a cytokine storm in the lungs where a patient's own immune response causes damage to the lung tissue which results in fluid accumulation in the lungs that, when bad enough, results in ARDS.
ARDS is characterized by fluid buildup in the air sacs in the lungs, which prevents a patient from getting enough oxygen in their blood, thereby resulting in hypoxic conditions in the organs that could lead to organ failure and eventually death. ARDS can be caused by a number of things such as pneumonia, aspiration from vomit, inhalation of toxic substances (smoke, chemicals, salt water), septic shock, and trauma. The most common symptoms are labored and rapid breathing, muscle fatigue, low blood pressure, dry hacking cough, fever, headache, mental confusion, and a fast pulse rate. All these symptoms apply to late stage COVID-19 patients.
The only current treatment for ARDS is oxygen therapy combined with a respirator. The respirator is marginally effective in ARDS patients, but in COVID-19 patients it's much worse. The theory behind the respirator is that the pressure forces the fluid levels lower in the air sacks so that the blood is physically closer to capture the oxygen. When the respirator activates and pushes the fluid level in the air sacks closer to the capillaries, more oxygen is likely to bind to the blood cell. The amount of oxygen that binds to a blood cell is a function of the distance to the oxygen source. In the picture below on the right, the fluid level is high and the oxygen is too far from a passing blood cell to oxygenate it well.
In dealing with this outbreak, health officials routinely warn that older males or people with underlying medical conditions are at a greater risk than the young. However, anyone over 80 has a 15% chance of dying from COVID-19 regardless of underlying medical conditions. This mortality rate is based on data that doesn't incorporate cases of the diagnosed. Unfortunately, there is no clear predictability of the seriousness of the disease and death except a general increase with increasing age. Usually, children are more susceptible to viruses, which is not the case with COVID-19. Which is one of a number of attributes of this virus that is not well understood. Others include; being contagious without symptoms, having the infection without symptoms, which make it more dangerous and deadly.
The statistics in the JAMA report showed that some of the primary underlying medical conditions were hypertension (19.4%), diabetes (10.9%), nervous system dysfunction (3.5%), chronic lung disease (2.5%), chronic kidney disease (1%), endocrine disease (1%), and tumors (.5%). Blood panels were taken to search for a prognostic test but the results were inconclusive. Although the researchers didn’t consider the notion that people with underlying disease have high galectin-3 expression, it’s worth mentioning that COVID-19 patients in the future should be screened for the biomarker galectin-3. High galectin-3 expression is associated with hypertension, diabetes, lung disease, kidney disease, and cancer and galectin-3 itself is implicated in the disease progression of each of these diseases. Based on the overwhelming evidence, galectin-3 expression is a prognosticator of heart failure and might be a prognosticator of outcomes and could be used in the future to characterize the risk levels of COVID-19 patients. It is possible that big and small test kit makers like Roche Holding (OTCQX:RHHBY), Thermo Fisher Scientific (TMO), Becton, Dickinson (BDX), Predictive Technology (OTC:PRED) and Todos Medical (OTCQB:TOMDF) might want to add a galectin-3 companion diagnostic to not only tell if the patient is positive, but also quantify the stage of the disease. High galectin-3 staining appears to be an excellent prognosticator in lung cancer, but Merck (MRK) appears to be ignoring these groundbreaking results from the International Journal of Molecular Sciences in favor of treating people with Keytruda that are unlikely to respond.
The Lancet study uncovered some very sobering statistics with respect to prognosis for COVID-19 patients with ARDS. The median time from the onset of illness to discharge was 22 days with a range between 18-25 days. The median time to death was 18.5 days with a range of 15-22 days. If the disease progressed to the point where mechanical ventilators were needed, the survival rate was only 3%. In fact, 31 of 32 patients that required mechanical ventilators died. An even more radical treatment is extra-corporeal membrane oxygenation (ECMO) which is what laymen call a heart lung machine. On that treatment all died. The incidence of ARDS was 31%, but it was also accompanied by sepsis and respiratory failure. The survival rate after contracting ARDS was only ~15%. By all measures, an 85% mortality rate for those that contract ARDS is something to be extremely concerned about.
The key to preventing ARDS is maintaining a homeostatic balance in the immune system between the innate and adaptive immune response. The best way to understand how this works is to examine what an ideal response looks like. When a virus first invades, pro-inflammatory cytokines, like interferon alpha (INF-A) and interferon beta (INF-B), alert the innate immune system. These cytokines first attract neutrophils and then natural killer (NK) cells. Working together, the innate immune system does a pretty good job of knocking down the viral load. In the background, macrophages are being recruited to the infection site in order to ramp up the adaptive immune response which consists of B-Cells and CD8+ T-Cells.
The pictorial above illustrates the delicate balance needed to keep homeostasis and how the viral load, or virus titer, reacts to the immune response. It also shows the transition from the innate immune system to the adaptive immune systems and the cells involved in the clearance of infected cells and the neutralization or destruction of the virus.
There are instances when the immune system is slow to respond. Addressed earlier in the article, these are patients with high galectin-3 expression which may result in people with underlying medical conditions. The patients have a tendency to not react quickly enough to the initial exposure and then overcompensate later by creating a hyper inflammatory environment known as a cytokine storm.
In COVID-19, the cytokine storm is directly related to the progression of ARDS in patients. The cytokine storm is a result of an imbalance between the innate and adaptive immune systems. A journal article by Karen Oslund detailed that “dysregulation occurs at the level of the epithelial cell response and/or the leukocytes that are residing in or are recruited to the site of infection.” In preparation for a viral attack, the body prepositions neutrophils (leukocytes) in the lungs using adhesion molecules such as galectin-1 and galectin-3 which also promote chemotaxis of the immune modulating cells. Initially galectin-3, a pro-inflammatory response, enables the trafficking of neutrophils to the site of injury. Then cytokines take over the regulation of the immune response. According to Dr. David Baror, a member on Ampio Pharmaceuticals (AMPE) scientific advisory board, “the development of ARDS during viral infection to a dysregulated immune response is characterized by alveolar macrophage/neutrophil hyper-activity, elevated levels of inflammatory cytokines and chemokines (ie. TNF-A, IL-6, IL-12, CXCL10), and increased vascular leakage."
Much of the focus with respect to the cytokine storm has been on Interleukin-6 (IL-6) biomarker, but it is not the magic bullet. Interleukin-6 (IL-6) is responsible for modulating the macrophages and T-Cells. Other cytokines, like Tumor Necrosis Factor Alpha (TNF-A), which control activation of the CD-8+ T-Cells, and lInterleukin-2 and (IL-1Beta) Interferon Gamma (IFN-gamma), start the cycle of activation of macrophages and natural killer cells from both the innate and adaptive immune systems.
There are two components to a cytokine storm, the immune cells and the cytokines. So within the immune modulatory approach, there are different approaches to therapy. Some therapies are looking to lower the cytokine production, others seek to stop the trafficking of suppressor cells, and one does both. The primary focus of COVID-19 treatments has been tocilizumab, known as Actemra, which is manufactured by Genentech, a subsidiary of Roche Holding. A phase 3 trial of Actemra was given the green light by the FDA in March. Actemra is designed to block the IL-6 chemokine from signaling the cell.
However, this drug is not a panacea because it has a boxed warning label of serious infections including pneumonia, myocardial infarctions, serious hepatic events, gastrointestinal perforations, and risk of cancer.
More importantly, the answer to a viable treatment is not just targeting one cytokine. CytoDyn uses a different approach. Its lead candidate leronlimab stops the trafficking of immune cells, specifically the CD4+ suppressor cells. A cytokine signaling firework show could be going off in the lungs, but if the suppressor cells can't get there because they are blocked by the CCR5 inhibitor from traveling, they are incapable of bringing additional macrophages to the infection site to perpetuate the cycle of inflammation. Instead the Natural Killer cells are left alone to eradicate the viral infection without suppression. In the past 2 weeks, CytoDyn has started a phase 2 trial in mild to moderate COVID-19 patients and a pivotal phase 3 study in severe or critical COVID-19 patients.
Other treatments like Ampio Pharmaceuticals’ Ampion are designed to “interfere with the transcription and subsequent production of inflammatory cytokines …. While increasing the production of beneficial prostaglandins.” The scientific rationale was extremely well elucidated in its short white paper. Ampion is expected to use an inhaler to directly deliver the drug into the lungs. Ampion calms the inflammation by lowering the cell's production of chemokines that attract the suppressor cells and assist in the healing process via the helpful prostaglandins.
Galectin-3 is also responsible for viral budding. The increase in budding activity eventually results in viral cell explosion and the release of the virus along with the Galectin-3 in the blood. Although the company, Galectin Therapeutics (GALT) has been quiet on COVID-19, it's important to note that its galectin-3 inhibitor in theory can treat the elevated galectin-3 serum concentrations that lead to poor responses and T-Cell anergy in viral infections. Galectin-3 is also responsible for suppressing “immune surveillance mediated by Natural Killer (NK) cells.” There are very few galectin inhibitors but this represents one of the most promising approaches for future research.
Athersys (ATHX) has the most advanced ARDS therapy in clinical trials, with its regenerative medicine product, MultiStem, being the first-ever therapeutic to show significant signs of efficacy in ARDS (small patient population, so therefore statistically insignificant, although clinically significant) in a phase 2 study. As a result, the FDA awarded MultiStem the only fast track designation for ARDS. Also, BARDA has recently designated MultiStem “highly relevant” in treatment of COVID-19, as its phase 2 trial was able to about “half” the mortality rate of severely ill ARDS patients. Athersys’ MultiStem is currently in a pivotal trial in Japan, run by its partner Healios, with top line results expected this year. MultiStem is also an immunomodulatory treatment that also facilitates healing, as the cells home to the distressed site and work through multiple mechanisms of action over a period of time -producing anti-inflammatory cytokines, transferring mRNA and mitochondria to distressed cells, being phagocytized by the host’s immune system, etc. These multiple mechanisms of action allow the immune system to remain effective yet controlled, without interfering with healing mechanisms. COVID-19 induced ARDS seems to have different mortality outcomes than regular pneumonia-induced ARDS, and so the company is initiating an ~400 patient trial for MultiStem treatment in COVID-19 induced ARDS.
Gilead's drug remdesivir is in pole position as a broad spectrum non-specific antiretroviral, but this approach is flawed. Dr. Bruce Patterson explained in the Superstock video that “this is not a viral disease at a certain point. ...it’s the immunological abnormalities that are causing the morbidity and mortality.” The current focus of COVID-19 treatment is to get people out of the hospital quickly so the healthcare system doesn’t get overwhelmed. GILD’s remdesivir requires 5 or 10 days of intravenous therapy. This is not “quick” and nowhere near the speed demonstrated in leronlimab’s compassionate use trials. The ultimate goal is to save people’s lives. Remdesivir seems to be somewhat effective in the early stage to control the viral load, but seems to have little impact in later stages. The reason the antiviral approach is flawed is that people can die with little to no viral load in their system. What kills people is the cytokine storm. There is a great analogy to cancer. A well-cited article said “metastasis is responsible for about 90% of cancer deaths.” To be effective in cancer treatment, you have to control the spread of the disease, not only the primary source of the disease. The spread of the disease in COVID-19 is clearly the cytokine storm not the viral load. Reducing the viral load may not help in reducing the mortality rate.
The recent success of remdesivir in the STAT report was overstated. Beyond the ethical implications of an uncontrolled release of the data and complete disregard for clinical trial protocol, a look at Gilead’s numbers is not that impressive. The investigator, Kathleen Mullane, the University of Chicago infectious disease specialist, said “most of our patients have already been discharged, which is great. We’ve only had two patients perish.” The report stated 113 had severe disease and “most” had been discharged. “Most” is not a scientific number to get excited about yet the market cap of Gilead increased over $10 billion on the news.
There is no data to figure out what the mortality rate would have been if there was a placebo arm. Assuming the best-case scenario, the mortality rate in moderate COVID-19 would be as low as 1.7%. The trial size in moderate COVID-19 increased from 400 to 1600. The severe COVID-19 study increased from 2400 to 6000. Both trials are uncontrolled and don't have a placebo arm and by Mullane's own admission “it's always hard for comparison.” What she did observe was “fever curves falling,” but that is not a requirement of the trial. She also noticed that many are “leaving after six days.” When you have a 10-day treatment regimen it's hard to interpret these findings when a person leaves in 6 days. It's just anecdotal evidence at this point that demonstrates the assumption in their trial design was not very good. Increases in trial sizes are typically used to increase the power of the study. The lack of a control group might have been a big tactical error in the trial design. The first 400 patient results are going to be locked soon, but GILD is going to have extra scrutiny due to the data leak.
Safety is still a real issue with antiretrovirals. During the Ebola outbreak, where remdesivir was first used, the drug was declared ineffective. Researchers at the University of North Carolina and Vandebilt found it to be “safe but ineffective.” Safe is a relative term when dealing with a hemorrhagic disease like Ebola. Results from the Ebola study showed that 25% of patients receiving it had severe side effects that included multiple-organ dysfunction syndrome, septic shock, acute kidney injury and low blood pressure. In addition, 23% had evidence of liver damage in lab tests. According to Prof. Simon Maxwell from the University of Edinburgh, citing data from a small uncontrolled study published in the New England Journal of Medicine, patients had adverse events of 60%. Within this group 23% had serious events which included multiple organ failure, septic shock, acute kidney injury, and hypotension. The side effect profile seems consistent regardless of disease. When dealing with patients that are critical, serious side effects may be tolerated but they must be considered when treating less severe patients. So all of the trial data, efficacy and side effects, must be understood before treating patients with COVID-19.
Hydroxychloroquine is also considered an antiretroviral that was pushed by the President's administration. There are many studies being conducted, but one study reported by CNN found no benefit and actually a higher death rate in COVID-19 patients taking it. This was not a peer-reviewed journal, but a retrospective study of 368 veterans that found 97 patients who took it had a 27.8% death rate versus the 158 who didn’t take it and had a 11.4% death rate. The data was relevant enough to cause a panel of experts to convene, warning of the potentially harmful effects of combining hydroxychloroquine and azithromycin. Last month Trump tweeted the drugs “taken together, have a real chance to be one of the biggest game-changers in the history of medicine.” Unfortunately, this was ill-advised. It does emphasize that doctors, patients and investors must be data and results driven in their decision making.
Patients can be divided into different stages of disease. The mild patients come into the hospital with a cough and fever they can’t shake. The moderate patients usually need oxygen support and the severe patients are likely to need a ventilator. The critical cases are experiencing renal failure, liver abnormalities, and their expected lifespan is measured in hours to days. The first 11 patients that were treated with CytoDyn’s leronlimab were all critical patients treated in New York City at the world renowned Montefiore Medical Center. In the coming weeks, a journal article will present the detailed results. In a Proactive Investors Video update, the company indicated all the patients were treated and eventually discharged from the hospital. All patients experienced similar results with respect to their bloodwork. Within three days there was a significant lowering of the cytokine storm with a massive reduction in IL-6 and by day seven, the ratio of CD4/CD8 cells was normalized. In the first 11 compassionate use patients, 8 out of 11 survived at least 7 days. Until the official report is issued it is unclear what happened to the remaining 3 patients. In this initial group a total of 4 were extubated from the ventilator within 3 days. More than 30 patients have had compassionate use.
The investor update on Superstock Live detailed more anecdotal results from a patient enrolled in a clinical trial run by Dr. Otto Yang, a professor of medicine at UCLA’s David Geffen School of Medicine. He went on camera to talk about Samantha Mottet who was functionally cured in 5 days using leronlimab after she failed two prior therapies, most likely hydroxychloroquine and remdesivir. In her case she was using less oxygen within 24 hours of injection, was extubated on day 3 and then by day 5 didn’t need any supplemental oxygen. She is now in the comfort of her home recovering. As of April 17, 11 patients were dosed at UCLA; 3 were critical and 8 were severe. Out of the 3 critical patients 2 were off the ventilator in 3 days and the 3rd is recovering and using less oxygen. Of the severe patients 6 have improved and 2 were just too early for an update. Of the 6 that improved, 4 have already been discharged. Results like this are highly supportive of the imminent approval of leronlimab.
With vaccines still a year or so away, an effective treatment for those in distress could mean the difference between life and death. The ideal treatment for the COVID-19 pandemic will get patients of all severity stages out of the hospital. Mortality increases as the number of cases grows and the large number of patients stresses the medical system. The ideal treatment gets people off ventilators and oxygen and back home.
Current compassionate use results suggest that leronlimab gets people off ventilators and back to their homes with one treatment in about a week. This is a valid treatment if not the ideal solution to the COVID-19 pandemic. The market cap of CYDY is $1.3 billion and as the recent STAT report effect on GILD showed investors, an effective treatment could be worth $10 billion. For CYDY investors, greater news coverage of just the existing and pending results could yield a sizable return. Despite better anecdotal evidence than GILD, few are talking about CYDY in the mainstream media, but the tide is shifting. The company has been on local FOX, ABC, CBS, NBC. It has also been on national FOX, FOX Business, Cheddar, Yahoo Finance, New York Post, The Wall Street Journal, and Newsweek. So this company is one to watch and possibly one Tweet away from an upside re-evaluation. Later in the year the companies developing vaccines, including those outside the US, should be evaluated for an investment opportunity.
This article was written by
Disclosure: I am/we are long CYDY, AMPE, GALT. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.
Additional disclosure: I plan to add to CYDY and GALT