The stroke market is ripe for the taking. Existing treatments are limited, and the unmet medical need is great. In contrast to breakthroughs in many diseases over the past two decades, stroke treatment, especially from drugs, has had minimal improvement for the past 23 years. Large biopharmaceutical companies such as Biogen (BIIB) are building whole drug development portfolios for stroke, while other companies like SanBio (OTC:SNBIF) are researching more creative ways to treat stroke, such as via regeneration months after the stroke. Readers who read my recent Athersys (ATHX) article may have familiarized themselves with some stroke pathophysiology, including cell necrosis and the hyperinflammatory reaction that primarily damages the penumbra. This underscores the value of an immune modulating therapy in the hours or days after stroke, as well as the preservative (anti-necrotic) and trophic mechanisms.
However, the fundamental root cause of ischemic injury and the hyperinflammatory after effect is hypoxia, a condition that Bioxytran may be able to treat in a very timely manner. Bioxytran Inc. (OTCPK:BIXT) has a novel drug for stroke patients that can restore the supply of oxygen to the brain though clots. This drug, BXT-25, also has the potential to treat many other ischemic injuries such as ARDS and sepsis.
Stroke is a leading cause of death in the U.S.; there are approximately 800,000 strokes and 140,000 deaths per year. This accounted for about 1 in 20 deaths between 2000 and 2015. Worldwide, it is the second-largest cause of death. In addition to being the leading cause of disability in the U.S., stroke costs America $34 billion annually in terms of healthcare services, medications and lost productivity. Needless to say, stroke is costly economically.
Some stroke statisticians believe that the cost is underestimated, with annual costs for elderly caregiving alone standing at over $18 billion. The total annual economic cost of stroke may surpass $240 billion by 2030.
There is currently a large unmet medical need for safe and efficacious therapy, as current treatments are either time-dependent, limited to certain clot types, or both.
Types of Stroke and Current Immediate Post-Stroke Treatments
Stroke is characterized as ischemic (where the issue is a lack of blood supply to a part of the brain), hemorrhagic (blood vessel rupture), or TIA (transient ischemic attack - temporary lack of blood supply).
In the 87% of strokes that are ischemic, a treatment called tPA (tissue plasminogen activator), a clot-breaking agent, is used. Sometimes, a mechanical operation (a thrombectomy) is performed, as well. The problem with tPA is that it has a very limited treatment window, and many people just don’t go to the hospital right away (because they don’t realize they had a stroke). Various studies have shown an absolute maximum treatment window of 4.5 hours. In a recent study, the maximum treatment window was cited at 3 hours, but only ~25% of stroke patients arrived within that time period, and the ideal “door-to-needle” time of less than one hour was only between 11% and 20%. In this study, tPA was administered in 3% of patients in Georgia and 8.5% of patients in Massachusetts. According to the Journal of the American Medical Association (JAMA), the average onset-to-treatment (OTT) time is ~2.5 hours for patients receiving tPA within 4.5 hours of stroke onset.
Thrombectomy has a less limited treatment window (6-24 hours), but it is restricted to specific types of clots and is therefore only used in about 9% of patients.
Dire Stroke Outcomes
Despite tPA or thrombectomy therapy, stroke patients will still sustain an injury due to the quick onset of neuronal ischemia and the subsequent inflammation that damages the surrounding penumbra, where neurons have metabolic activity but significantly decreased electrical activity. For most patients, there is no promise of recovery; whatever cognitive functioning a patient may regain at 90 days post stroke is considered final.
Time Sensitivity of the Ischemic Brain
When the supply of blood or oxygen is cut off to the brain for a period of time, brain cells die. Studies have shown that the average ischemic stroke consumes almost 2 million neurons every minute until blood flow is restored. This translates into 14 billion synapses lost and 7.5 miles of myelinated fibers lost every minute, and accelerated aging of the brain by 3.1 weeks. In a typical stroke scenario, 30 minutes is spent getting to the hospital, which results in brain aging of 1.8 years, and then the additional 2 hours to get imaging results in another 7.2 years of aging. This brings the total aging of the brain to 9 years in the average stroke case. The initial injury, as outlined in my article covering Athersys, is exacerbated by secondary inflammation damage triggered by the initial injury. Thus, minimizing initial injury may help reduce secondary injury via a decrease in damage-associated molecular patterns (DAMPs) and reduced chemokines, etc. [1,2].
Since no treatment exists to get oxygen to the affected parts of the brain, the emphasis had been on awareness and quickly routing patients to stroke treatment centers. As stated before, it is estimated that patients who are able to receive tPA spend 2.5 hours from the onset of stroke until they can get tPA treatment to remove the blockage and restore oxygen supply to the brain. BXT-25, the company’s lead drug, candidate serves as an oxygen bridge for the stroke victim until they can get treatment. This company is addressing a huge unmet medical need that could eliminate a large portion of restorative care and rehabilitation needed after a stroke.
Anatomy of a Thrombus
Some may believe that a blood clot is an impermeable barrier; however, it is actually quite porous. Clots that form in the brain’s blood vessels don’t happen overnight either. They are a result of atherosclerosis, which is a build-up of fats and cholesterol on the artery walls. The build-up on the vessel wall constricts the vessel’s cross-section, allowing blood cells to bunch up, which eventually results in fibrin production. Fibrin production is caused by clotting factors and fibrinogen, which is normally dissolved in blood plasma. Through a cascade of interactions [3,4], fibrinogen generates thrombin, which converts fibrinogen in the blood plasma into long strands of fibrin that emanate from the clumped cells, designed to trap even more blood cells.
BXT-25: An Elegant Drug Design
Rather than dissolving or breaking up the clot, Bioxytran simply intends to use an oxygen delivery vehicle that is small enough to pass through the clot. Clots act like fishnets, spanning the blood vessel cross-section so anything tiny will pass right through them, but larger items will be caught. BXT-25 is a small drug molecule that is 1/5000th the size of a blood cell and has the ability to easily pass through the clot within the blood plasma.
BXT-25 is a hemoglobin-based polymer that is simply a combination of heme, derived from hemoglobin, and a copolymer designed to stabilize it in the blood system. Heme had been used for years commercially as a meat flavoring, including in the Impossible Burger’s meatless patties. Heme, however, if injected directly into the bloodstream, would be filtered out by the liver.
The ingenious idea conceived by the inventor and CEO of the company, David Platt, was to stabilize the heme and prevent it from being filtered out immediately. He managed to do this with carbohydrate chemistry that mimics natural carbohydrates on blood cells. New blood, created in the bone marrow, has a surface sugar signature that is recognized by the liver. As the blood cell ages, the sugar breaks down to the point where the liver decommissions the cell and filters it out. BXT-25 is comprised of molecules of heme, which are the oxygen carriers of human blood cells, bonded to a copolymer stabilizer that mimics the sugars found on the blood cells. The polymer is made from the galactoarabinan family of sugar chains and is therefore not metabolized. The most important difference between BXT-25 and blood is that BXT-25 is about 0.02% the size of a red blood cell, and can pass right through a clot and even the blood-brain barrier.
BXT-25 is specific to O2, as opposed to, say, nitrous oxide (NO). It doesn’t depend on blood to work - it works independently of blood. It is also a neutral sugar in terms of pH - it isn’t alkaline or acidic. The sugar keeps the structure of the heme, and the drug is stable in solution for three years at 250°C.
Oxygen Level Control
One might question whether the oxygen delivered via BXT-25 would be transported specifically to the ischemic portion of the brain after stroke and result in over-oxygenation, which has undesirable side effects. However, this is not likely a problem, because BXT-25 is modeled after the body’s natural control systems, using the same heme as in blood itself, and the company has a means of measuring overall oxygen levels. Many don’t realize that the laws of physics and partial pressure chemistry are responsible for preventing over-oxygenation. This phenomenon of natural regulation of oxygen and carbon dioxide levels and their associated transfer in and out of the body is called the Bohr-Haldane effect.
The Bohr-Haldane effect describes the competitive affinities of CO2 and H+ versus O2 for hemoglobin. The body’s natural concentration differences of these molecules affect the local affinity for hemoglobin, allowing the hemoglobin to transport oxygen to tissues and also transport carbon dioxide out of tissues. Thus, when oxygenated hemoglobin enters a low-oxygen environment, the low partial pressure of oxygen forces the oxygen to dissociate from the hemoglobin, thus oxygenating the area. Then, the hemoglobin will pick up CO2 and H+, transporting it out of the area.
The beautiful thing is that the same principle is true for BXT-25. Since BXT-25 should have a very similar dissociation curve as it uses the same heme from hemoglobin, it can be administered safely to patients and it will properly oxygenate the tissue without over-oxygenating. Furthermore, Bioxytran has access to an FDA-approved device to accurately measure tissue oxygenation so that it can tailor the amount of BXT-25 administered and monitor the tissue metabolism.
Method of Use: First Responders
Once developed and approved, BXT-25 is envisioned to be administered intravenously by first responders to provide oxygen to the brain while they transport the stroke patient via ambulance to a stroke center for further evaluation. The drug could also be administered at the E.R. This is not meant as a long-term solution, but rather as a stop-gap measure to prevent or greatly attenuate the cell death in the brain while the patient is awaiting imaging results, which determines the course of treatment for an ischemic or hemorrhagic stroke.
However, if the patient cannot get a clot removed, it is a possibility that BXT-25 could be used to oxygenate the patient’s brain over a longer period to minimize damage.
The plot above shows that a typical stroke victim in Israel, even if possibly eligible for tPA or mechanical thrombectomy, may not even arrive at the ER in time to determine whether they do not have a hemorrhagic stroke so that they can get treatment. Many patients are simply too late. As the graph shows, stroke onset to CT time is, on average, 3.7 hours, which is almost past the time possible to be administered tPA. BXT-25 could be administered as soon as the victim is known to have a stroke so that they can have oxygenation much sooner, while they wait for their CT scan and subsequent therapeutic decisions. So, this could be in the ambulance or in the ER.
Chances For Clinical Success
Previous studies have found that even normobaric oxygen therapy within 12 hours can help preserve the aerobic pathway so that the infarct core and penumbra sizes are minimized, as shown by a statistically significant difference in mRS score at discharge after therapy compared to control. How much more effective will permeable, stable heme (BIX-25) be in treating stroke, as it can be administered within the “golden hour” - the critical time for the brain - and physically transport oxygen directly to the injury?
The main takeaway is that BXT-25 is a very simple root-cause solution to stroke. With previous studies of inferior administration of oxygen showing benefit in patients along with the carbohydrate composition of BXT-25, the anticipated chances of success for this drug may be greater than average for other preclinical compounds.
Oxygenation Measurement and Approval Process
The company plans to submit an Investigational New Drug Application (IND) to the Food and Drug Administration (FDA) after completing its master drug file. Preclinical results have shown that the drug is safe and non-toxic. The key to approval rests in Bioxytran’s exclusive license to use the MDXViewer to measure tissue oxygenation. It’s anticipated that tissue oxygenation levels using the Tissue Metabolic Score (TMS) will be measured before the injection and then after. It takes ~3 minutes for BXT-25 to take effect. The TMS is a real-time vital sign of tissue health. By proving that tissue oxygenation increased, the drug can be approved on that basis alone without making any claim regarding the benefit to stroke patients. That can come in time. When making efficacy claims about benefits to the stroke patients, it’s difficult to quantify which treatment - the BXT-25 or the tPA - ultimately accounted for the benefit. A large, costly trial with multiple arms that uses a subjective impairment study would be the only path forward without the FDA-approved MDXViewer.
- Mitochondrial NADH redox state via surface fluorometry/reflectometry
- Tissue blood flow (TBF, AKA microcirculatory blood flow) via laser Doppler flowmetry
- Blood oxygenation (tissue oxyhemoglobin - HbO2) via spectroscopy
- Tissue blood volume (TBV) via reflectometry
These parameters are then combined with systemic hemodynamic parameters, cardiovascular and respiratory, including heart rate, systemic blood pressure, respiratory rate, systemic hemoglobin saturation and body core temperature. The result is an entire body score, which is important to monitor whenever there is a hypoxic or critical pathologic state in the body. Essentially, in events including but not limited to perinatal hypoxemia, sepsis, hemorrhagic shock, cardiovascular surgery, heart attack or trauma, the body enters into a body emergency metabolic state (BEMS), where the sympathetic nervous system is activated, adrenaline kicks in and blood flow will be redistributed within the body from all other tissue to the brain, heart and adrenal glands. Thus, the less vital organs will have an energy imbalance and their local mitochondrial production of ATP will be affected. This process is summarized in the graphic below:
Stoke is an enormous market, but there are other low-hanging fruit for Bioxytran, such as Acute Respiratory Distress Syndrome (ARDS), which is, in simple terms, lung edema without heart failure. When in an Intensive Care Unit (ICU), many patients develop ARDS, which consists of fluid that leaks into the lungs and eventually develops into a mucus-like substance that forms on and in the lungs’ air sacs (also known as the alveoli). This makes breathing extremely difficult or even impossible; blood cannot move in close enough proximity to the surface of the alveoli to pick up the oxygen. A small molecule like BXT-25 can go through a much smaller capillary and possibly damaged microvasculature and get closer to the alveoli to bind to oxygen. When the lungs lose their ability to exchange oxygen and carbon dioxide, the body doesn’t get enough oxygen, and eventually, this leads to organ failure and death. The MDXViewer, which measures the tissue oxygenation vital sign, can predict organ shutdown. BXT-25 can provide that lifeline of oxygen to the organs, allowing the body time to recover.
There are 200,000 cases of ARDS each year in the U.S. and multiples of that worldwide. The mortality rate of ARDS is about 40%, based on an international study of 3022 patients with disease severity which ranges from mild (35%) to severe (46%). The average cost of an ARDS episode in the U.S. was recently calculated to be ~$117,000 per hospitalization, based on a study published by the European Respiratory Journal. This study showed that if patients survived, they had a 53.2% chance of a relapse, costing an additional $82,749. Critical care medicine costs are estimated at $108 billionannually in the U.S., and ARDS prevalence, although estimates vary, is suggested to be about 10.4% of ICU admissions across 50 countries. ARDS, therefore, represents up to a $28 billion market in the U.S., based on annual initial treatment and subsequent relapse costs. If BXT-25 could lower the mortality by even a couple of percent, it could be a blockbuster based on ARDS alone.
Financial and Strategic Analysis
The company has 85 million shares issued and outstanding, but insiders own 77%, making this a very closely held company. The trading volume is low, which makes for large volatility on high-volume days. The true float of the company resembles about 100K shares given the currently very thin trading volume. The published float is 8 million, which represents approximately 10% of the outstanding. Bioxytran is in compliance with OTC Markets and listed as a Pink Sheets current filer. Given the market cap and filing status, it has met all the requirements for an uplisting to OTCQB. The company has $118,000 cash on hand since the Q1 ended March 31, 2019. To date, the only financing has been through two convertible notes that have not yet been converted.
Bioxytran recently added to its management team Juan Carlos Lopez-Talavera, who has licensing experience with Big Pharma drugmaker Bristol-Myers Squibb (BMY). Notably, the company already has one key licensing agreement with MDX Life Sciences. This license gives Bioxytran exclusive developmental use of the MDXViewer for commercial development of MDX technology to develop new protocols that measure the tissue metabolic state of the brain (in conjunction with the BXT-25 research). What is particularly significant about this license is that tissue oxygenation and the TMS vital sign have been shown to improve patient outcomes in emergency medicine. In other words, if Bioxytran can show improvement in cellular health measured by the MDXViewer, this should correlate directly with improved clinical outcomes. This correlation, as well as improved methods and outcomes, gives the company the ability to negotiate a licensing deal with medical device producers to start the manufacturing of the next-generation MDXViewer, which is needed in almost all operating rooms in hospitals throughout the nation. Thus, Bioxytran could have a stable source of income in the next year or so through the rollout of the new and improved MDXViewer.
Management is key in any investment, and the old saying “Bet on the jockey and not the horse” applies here. David Platt, one of very few expert carbohydrate chemists worldwide, has a history of successful startups. He drove SafeScience Inc. from $5 million to a $500 million market cap. He subsequently co-founded Pro-Pharmaceuticals, which eventually changed its name to Galectin Therapeutics (GALT). In this company, he had a key role, along with Anatole Klyosov, in developing the galectin inhibitor, Davanat. This had a ~$500 million market cap at its peak; previous articles I have written on NASH and Galectin in cancer therapeutics outline my case that GALT is massively undervalued.
Platt is very skilled with cost control and running cost-efficient trials, which optimizes returns for investors. His goal is to get the drug to market efficiently and to avoid as many regulatory hurdles as possible while meeting their stringent guidelines. In addition, Dr. Talavera has key Big Pharma relationships that will benefit the company.
On the financial front, raising money under the S-1 registration statement would show a huge market validation of the oxygenation technology. Bioxytran is poised for an uplisting to OTCQB, and the next medical milestone is the drug master file which will allow the company to complete their animal studies and IND for stroke. The company is clearly building a team of seasoned veterans to tackle the upcoming drug development pipeline. Bioxytran’s pipeline clearly shows that tissue oxygenation has many uses, and it has the exclusive rights to measure tissue oxygenation and treat it in various indications.
The amount of oxygenation of ischemic tissue in a stroke patient treated with BXT-25 and the correlation of that amount of oxygenation to clinical outcomes is not quite certain - there are a lot of questions to be answered. With respect to the treatment, how much does the therapy actually oxygenate the ischemic tissue? Can a patient who is not eligible for tPA get BXT-25 for a longer period of time to mitigate damage? Regardless, lack of oxygen is a root cause of ischemic injury, and investors in companies such as Athersys or Biogen, which are developing drugs for stroke treatment, should consider Bioxytran as a hedge or simply an addition to their investment portfolios in case BXT-25 is a large success. After all, BXT-25, if successful, will have applications far beyond golden-hour stroke therapy.
Will BXT-25 be used to oxygenate patients who cannot get tPA or a clot removed mechanically? Will it be used before tPA to improve outcome? Or, will it be used to extend the timeline at which someone can receive tPA or mechanical thrombectomy? The exact clinical path that BXT-25 will take is not known at this time, but the very significant claim Bioxytran will make is in regard to what extent BXT-25 oxygenates tissue. I expect Bioxytran to establish collaborations with other firms to advance BXT-25 in the clinic, validating the huge potential of BXT-25.
Bioxytran is not listed on the NYSE or Nasdaq and has a very low amount of cash. There will be dilution. It is also a preclinical biotech company at this point, putting it in one of the riskiest investment categories. Clinical trials may fail and the company may run out of money.
Disclosure: I am/we are long BIXT, GALT, ATHX. 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.