Co-founded in 2001 in Virginia (USA) by David Kalergis and Professor John L. Gainer, this company wishes to develop a technology of compounds improving the diffusion of oxygen with its flagship drug called "trans sodium crocetinate", better known under the name TSC. Since TSC has an impact on the rate at which oxygen moves through our blood plasma through the diffusion process, this biotechnology company recently started clinical trials on the use of TSC in the treatment of COVID-19. Thus, these trials focus on solutions to help patients who may have suffered from respiratory distress related to oxygen deficiency.

In order to discuss this innovation within our BlastingTalks project, which consists of focusing on the challenges companies face in the changing digital world and during this period of unprecedented health crisis, the floor was given to Diffusion Pharmaceuticals CEO Robert Cobuzzi, Jr., and Chief Medical Officer Christopher Galloway.

Diffusion Pharmaceuticals is a biopharmaceutical company developing novel therapies which enhance the body’s ability to deliver oxygen to the areas where it is needed most. You are currently developing a new kind of treatment, trans sodium crocetinate (TSC), which targets treatments for hypoxia. What is hypoxia and can you tell us more about your technology?

Diffusion is developing a molecule called trans sodium crocetinate, TSC, to enhance the movement of oxygen to areas of the body where it is needed most.

Oxygen is essential for life. When we do not have enough oxygen in a tissue (such as muscle), that is called hypoxia. Under hypoxic conditions, cells cannot make energy to perform their functions. So, hypoxia can lead to tissue death and organ failure, which occurs in many life-threatening conditions, including stroke, heart attack, and respiratory diseases, such as COVID-19.

When everything is normal, we take-in oxygen with each breath, and breathe out carbon dioxide. With each breath, oxygen moves through the lungs and diffuses into the bloodstream where it attaches to hemoglobin molecules contained within the red blood cells. The oxygen-carrying red blood cells move through the circulatory system, and release their oxygen payloads in the tissues where needed.

To reach the red blood cells or tissues, oxygen moves through blood plasma, the liquid part of blood, by a passive process called diffusion. There is no energy expended, the oxygen simply moves down what is called a concentration gradient, from areas of high concentration to areas of low concentration in an effort to establish equilibrium. TSC works by enhancing this diffusion of oxygen down the concentration gradient. It does this by changing the way the water molecules in the blood plasma interact, or hydrogen bond, resulting in reduced plasma density. This improves diffusion of oxygen to cells and tissues that have low oxygen levels, which can happen in conditions such as stroke, where there is a reduced amount of blood and oxygen available to the tissue downstream from the clot or broken blood vessel.

The intent is that TSC will help improve the availability (by enhancing diffusion) of the oxygen from the blood that does get to the tissue.

Why did you choose to focus your technology and work around oxygen deprivation in the first place?

Diffusion was founded in 2001 based on the research of Dr. John Gainer who was a professor of chemical engineering at the University of Virginia. Dr. Gainer initially developed TSC to treat trauma-induced hemorrhage working under a grant from the Office of Naval Research. Hemorrhage, or profuse blood loss due to broken blood vessel, can result in hypoxia, tissue damage and even death. Since inception, the company has worked to extend the initial research on TSC, developing the compound as a treatment for conditions where hypoxia, or low tissue oxygen levels, plays a significant role.

I see you are working on several therapeutic areas including COVID-19, how can your treatment help in the fight against complications from COVID-19?

As most people now know, COVID-19 is caused by the SARS-CoV-2 strain of Coronavirus. This virus typically affects the respiratory system, although gastrointestinal, neurological and other symptoms, including severe blood clotting are frequently reported. Patients with severe COVID-19 often develop low blood oxygen levels, known as hypoxemia, and require supplemental oxygen therapy to avoid developing tissue hypoxia which can lead to tissue damage, organ failure and even death. TSC has been developed with the objective of enhancing oxygen diffusion to areas of the body where it is needed most.

We believe this mechanism of action lends itself well to addressing the needs of patients with low oxygen levels due to COVID-19 as well as many other severe respiratory conditions. So, a study was started in September 2020 at the National Institute of Infectious Diseases in Bucharest, Romania to evaluate the effects of TSC in hospitalized COVID-19 patients who have low blood oxygen levels.

Before this study, TSC had only been dosed a maximum of one time per day in previous clinical studies. Since patients with severe COVID-19 can have persistently low oxygen levels, this study was designed to evaluate the safety, tolerability and the pharmacokinetics (the study of the effects of the body on the drug, including the duration of the time the drug remains in the body after administration) of TSC administered every 6 hours for up to 15 days.

To monitor patient safety, an external Safety Monitoring Committee (SMC) was put in place to review the data after each group of three patients receives at least 5 days of TSC. The study is ongoing at the time of this writing, and we expect enrollment by the end of first quarter 2021.

How and when did Diffusion realize that TSC can be used as a therapy for COVID patients?

When the COVID-19 pandemic began in early 2020, Diffusion was in the early stages of conducting a clinical study to evaluate TSC in acute stroke patients. The design of the stroke trial required TSC be administered on the ambulance to ensure patients received TSC as soon as possible after the onset of symptoms. Unfortunately, the study had to be stopped, because the ambulance crews were too busy with COVID-19 patients to focus on conducting a clinical study.

Given TSC’s oxygen enhancing mechanism, and the low oxygen levels being reported in COVID-19 patients, the company decided to pivot and begin the study I described above that is being conducted in Romania in hospitalized COVID-19 who have low blood oxygen levels.

What are your thoughts as a doctor, scientist and biotech executive, about the recent “race for a vaccine”? How novel is the speed and progress of what we are witnessing?

The “race for a vaccine” has been amazing to witness. The pandemic has created a unique situation that has brought together an array of incredibly talented and dedicated clinicians and scientists from across the biopharmaceutical industry and the regulatory bodies that oversee the industry, including the US FDA, all focused on solving this existential problem.

The focus and investment has enabled the typical development timelines to be shortened considerably. Drug research and development is typically kept secret to protect the intellectual property needed to support the return on investment required to support such speculative work. This secrecy remains for the unique vaccine technology developed by each company in the race. However, in this case, product development was facilitated by the fact that the SARS-CoV-2 virus was identified and characterized by an incredibly efficient and focused open-source global research collaboration. Once acceptable lab data was obtained, the various interested parties facilitated access to patients and healthy participants for vaccine clinical trials.

The speed with which patients and volunteers can be recruited into clinical trials is typically rate limiting in terms of both time and money for biopharmaceutical companies, so this appeared to be an enormous assistance for the vaccine development process. Several companies have reportedly taken advantage of government funding to accelerate investment in product manufacturing, which also has shortened timelines. Finally, in the US, the government and Operation Warp Speed have moved production of vaccines to the front of the queue at several high profile third-party manufacturing facilities.

Each of these elements has enabled the SARS-CoV-2 vaccine development process to surpass expectations in terms of both time and quality.

The question is whether these efficiencies can be translated to future drug development efforts? As noted previously in this article, Diffusion had to stop a clinical study in acute stroke patients and pivot to COVID-19 because it was not possible to enroll the stroke trial during the pandemic. We were not alone; many other companies reported challenges with clinical trial enrollment during the pandemic. There also have been many reports of companies having difficulty obtaining drug supply for both development stage and marketed products due to the prioritization of the vaccine. So, while the race for the vaccine has been an incredible success, demonstrating the ability of multiple interested parties to come together to expedite development, it should be recognized that it has occurred at a cost to other drug development programs.

I believe prioritizing the vaccine was the right thing to do, but the impact on other programs should not be lost, because I do not believe it is possible to expect all future vaccine or therapeutic development to occur with the same efficiency brought on by the unique and unfortunate circumstances of the COVID-19 pandemic.

Today, almost two million deaths have been attributed to COVID-19 around the world. This new year, many countries have already begun their vaccine campaign. Your technology is not a vaccine, but a therapy - can you explain the difference and how will your therapy help fight complications from the virus?

Vaccines are intended to provide immunity and prevent a disease from occurring in the recipient. In the case of COVID-19, multiple different vaccines have been developed to target the immune system to the SARS-CoV-2 virus. Some of these vaccines have been reported to be more than 90% effective in clinical trials. This means we should start seeing a reduced spread in new infections as vaccinations expand. In the meantime, a high rate of infections continues to be reported, and new variants of the virus also have been reported for which the effectiveness of the vaccines has not yet been determined. So, effective therapeutics are still required to combat the COVID crisis.

In contrast to the preventative benefits of a vaccine, a therapy is intended to improve the condition of someone already infected with the virus. Therapeutics are designed for a wide variety of purposes. Some therapies are designed to kill the virus, while others, including TSC, are intended to provide other benefits. As discussed above, TSC is intended to improve the availability of oxygen. This mechanism of action is agnostic to the causal pathology and therefore has the potential to be of value across a wide variety of indications where low tissue oxygen levels lead to poor clinical outcomes; such as patients with severe COVID-19 symptoms including difficulty breathing and/or low blood oxygen levels. This would be the potential adjunctive benefit in treating COVID-19 patients with TSC, to enhance the diffusion of oxygen to hypoxic patients with difficulty breathing and/or who have low blood oxygen levels.

We have been living for 10 months in an unprecedented crisis causing healthcare to be placed at the top of the concerns of many governments around the world. What longstanding changes do you think will take place in the world of healthcare due to this crisis?

The availability and affordability of healthcare is an ongoing, global issue due to the economic challenges it presents. The stark reality is that new therapeutics, vaccines, devices and diagnostics are expensive to discover, develop and commercialize. Success rates for development of such products remains low, yet the height of the expectations bar continues to climb with regard to the expectations for safety, efficacy and affordability. The speed with which the first COVID vaccines have been developed will continue to fuel expectations regarding the speed and success of drug development. As noted, this may not be as readily duplicated across the spectrum of drug development as many people hope. The silver lining for me, amidst this tragedy, is that it has renewed focus on the importance of scientific research, and the need for new treatments. In this case the spotlight has been placed on the need for new vaccines and therapeutics to combat infectious diseases. This has been an under-appreciated area for many years now, because the economic incentive that typically drives industrial scale R&D has been absent. Economic realities will remain gating issues, but I believe there is now an understanding that we have not yet solved all the potential health issues with the existing armamentarium of vaccines, therapeutics, devices and diagnostics. Genetic mutations and other natural forces continue to drive biological changes and the need for new tools to combat public health issues.

What are some other therapeutic indications that Diffusion will explore in 2021? How much of a therapeutic need is there for these indications across the population?

For 2021, Diffusion will continue to focus on the development of TSC. Given the breadth of indications where low oxygen levels present a significant therapeutic challenge, there are more potential uses for TSC than a small company like Diffusion can pursue at one time. I and several other members of the management team joined the company in the latter part of 2020, and we devoted the fourth quarter to evaluating the development plans and opportunities for TSC. Over the years, the company has obtained safety and tolerability data from more than 150 participants in completed clinical trials. So, the first step for 2021 is to definitively demonstrate the effects of TSC in at least two well-established clinical models of oxygenation without the confounding/complicating variables that exist in COVID-19 patients. These studies will provide the dose-response data we need to efficiently pursue development of this exciting drug candidate consistent with applicable regulatory requirements. The next step will be to evaluate the broader clinical effects of TSC in indications where improved oxygenation remains an unmet clinical need. My colleagues and I are working through that analysis now and will complete that work in time to take the data from the oxygenation studies and launch a definitive development program aimed at regulatory approval of TSC. Although COVID-19 challenges are significant, our belief is that this issue is acute and will be addressed successfully by the vaccines now being rolled out. There are many other medical challenges that remain where low oxygen levels present a significant therapeutic challenge, so we want to focus on where the unmet need and probability of clinical and regulatory success are greatest.
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