PharmaShots Interview: Diffusion's Dr. Bob Cobuzzi Shares Insights on the Trans Sodium Crocetinate (TSC) to Improve Hypoxia

In an interview with PharmaShots, Dr. Bob Cobuzzi, CEO, President, and Board Member at Diffusion shared his views on the trans sodium crocetinate (TSC) to improve patient outcomes & paradigm of oxygen deprivation treatment

Shots:

Diffusion's TSC directly targets and relieves oxygen-deprivation in affected tissue by enhancing oxygen diffusion & was designed to treat hypoxia include trauma, heart attack, stroke, respiratory diseases (such as COVID-19), and tumor hypoxia
The results from the COVID Trial as reported in May'21 showed that TSC was safe and well-tolerated, patients receiving the highest (1.5 mg/kg) dose of TSC had improved outcomes in the 2EPs and exploratory EPs compared to lower doses of TSC.
The company has designed the oxygenation trials to evaluate the effects of TSC in well-controlled and differentiated clinical models & plans to initiate the Altitude & ILD-DLCO study in Q4'21

Tuba: Discuss the key highlights of Trans-sodium crocetinate (TSC) and how it works in treating the condition of oxygen deprivation.

Dr. Cobuzzi: Diffusion's lead product candidate, trans sodium crocetinate (TSC) has a novel mechanism of action. The compound was designed to treat hypoxia, defined as a non-physiologic level of tissue oxygen, which can lead to and complicate many familiar life-threatening conditions and diseases. These include trauma, heart attack, stroke, respiratory diseases (such as Covid-19), and tumor hypoxia which is a primary factor leading to radiotherapy and chemotherapy treatment resistance as well as increased metastatic potential.

Under normal physiologic conditions, oxygen transfer is highly efficient. However, under stressful conditions such as exercise or illness, the demand for oxygen delivery to the tissue often exceeds the supply. This means the efficiency with which oxygen diffuses from red blood cells to the target (hypoxic) tissue becomes a more important factor.

Multiple methods of treating hypoxia by augmenting oxygen delivery have been developed and are commonly used in modern medicine. These include mechanical methods to administer pure oxygen, improving cardiac output with medications and mechanical pumps, blood transfusions to supplement the supply of red blood cells, and the use of hormones to stimulate the production of red blood cells. All of these interventions can increase mass oxygen delivery in the body, but none of these interventions improve diffusion at the uptake or delivery points.

TSC works by enhancing hydrogen bonding among water molecules in blood plasma, creating a more organized matrix that facilitates the passive diffusion of small molecules like oxygen (O2) and carbon monoxide (CO2) from areas of high concentration to areas of lower concentration. This mechanism of action improves the diffusion component of oxygen delivery through the blood in a manner that is independent of cardiac output, hemoglobin content, or oxygen saturation of the hemoglobin. Further, this passive diffusion process avoids over-oxygenating the body, where too much oxygen can itself cause tissue damage.

Tuba: What drove Diffusion Pharma to develop such oxygen deprivation treatment therapy?

Dr. Cobuzzi: TSC was designed and developed by Dr. John Gainer, who was a professor of Chemical Engineering at the University of Virginia. Dr. Gainer was focused on identifying oxygen diffusion-enhancing compounds to improve the treatment of hemorrhagic shock low blood flow resulting in inadequate oxygen availability to tissue. This work was done under a grant from the Office of Naval Research (ONR) and initially focused on a naturally occurring carotenoid called crocetin, derived from the spice saffron. Crocetin itself was not ideal, so Dr. Gainer and his lab worked to identify pharmacologically acceptable forms of crocetin, and in the process developed the synthetic analogue, TSC.

In 2001, Diffusion Pharmaceuticals was formed. With the ONR grant money and private funding, the company set up a lab and worked with external collaborators to evaluate the use of TSC in the treatment of hemorrhagic shock and other hypoxic conditions, such as stroke and cancer.

Tuba: What were the challenges Diffusion Pharma faced while developing TSC?

Dr. Cobuzzi: TSC development is still ongoing today. We are conducting what we have termed our Oxygenation Trials to determine the dose-response relationship between TSC and oxygenation in normal healthy volunteers and patients.

The company is small, and over the years it faced the most common challenge for early-stage biopharmaceutical companies: Obtaining adequate funding. A large amount of preclinical data has been generated by the Company, and early-stage clinical studies have been conducted evaluating the use of TSC in enhancing the standard of care treatment in peripheral artery disease, glioblastoma multiforme (GBM; an aggressive form of brain cancer that is often hypoxic, leading to treatment resistance), acute stroke and more recently in hospitalized patients with COVID-19. Across the clinical studies TSC was observed to be safe and well-tolerated, and there were signals of efficacy in all of the completed clinical studies.

The COVID-19 study was also quite challenging treating hospitalized patients during a pandemic for something other than the primary cause of their condition. Given the complexity of the study, operational challenges associated with enrolling patients internationally, and other factors, we made a strategic decision to end the study after the original 24 patients were enrolled and treated, and focused on the clinical development plan originally announced in November 2020. This was focused on optimizing the clinical dose and dosing frequency for TSC, including evaluating higher doses, to evaluate TSC in well-controlled and differentiated clinical models designed to establish proof of concept for improvement in oxygenation that we believe will position TSC as a platform therapeutic for hypoxia-related conditions.

Tuba: How does TSC work in COVID hospitalized patients?

Dr. Cobuzzi: In May 2021, we announced the final results of our COVID Trial, which was initiated in 2020 based upon the potential of TSC to improve low tissue oxygen levels in patients with COVID-19. The study's primary objective was to evaluate the safety and tolerability of TSC administered on a more frequent dosing regimen than we had previously tested in a clinical trial setting. The study tested doses of TSC ranging from 0.25 mg/kg to 1.5 mg/kg administered intravenously every six hours.

We are pleased with the results of the study.

TSC was found to be safe and well-tolerated when administered on a more frequent dosing regimen than previously tested in a clinical trial setting. Further, the study included secondary and exploratory endpoints to evaluate the efficacy, including time to improvement in World Health Organization (WHO) ordinal scale by day 7 and through day 29, time on oxygen supplementation, and hospital length of stay. Although this study was not specifically designed or powered to evaluate the efficacy, the study's external safety monitoring committee observed that patients receiving the highest (1.5 mg/kg) dose of TSC had improved outcomes in the secondary and exploratory endpoints compared to those receiving lower doses of TSC. The clinical effects observed in patients afflicted with a complicated respiratory condition like COVID-19 provide further evidence of the therapeutic effects of TSC in indications complicated by hypoxia.

Tuba: Can we discuss more about the interim results from the P-Ib study assessing TSC in hospitalized COVID patients?

Dr. Cobuzzi: As noted, we are quite happy with the results of the Phase 1b COVID Trial.

This study was originally designed as a lead-in trial intended to obtain safety and dosing information to guide a larger, Phase 2b study. However, given the complexities encountered during the Phase 1b lead-in study and other factors, including the emphasis on the development and release of vaccines and a large number of antiviral therapy trials ongoing in the US and Europe, we turned our focus and resources to the execution of Oxygenation Trials announced in November 2020.

Tuba: Can we know more about the other three clinical studies such as trial design, results (if any)?

Dr. Cobuzzi: In November 2020, we were a very new management team at Diffusion.

So, we took the opportunity to conduct a thorough analysis of all available data to map our go-forward development strategy. The available data at that point supported TSC's potential to enhance the standard of care for many hypoxia-related indications but did not yet provide direct evidence of TSC's ability to enhance oxygenation in humans.

To address this gap, we announced plans to conduct a trilogy of short-term, clinical studies we collectively refer to as the Oxygenation Trials. These studies utilize three different experimental clinical models of oxygenation.

The first of the Oxygenation Trials used transcutaneous oxygen monitoring (TCOM) technology to measure the direct effects of TSC on peripheral tissue oxygenation in healthy normal volunteers. Topline results from the TCOM Trial were reported in June 2021 and indicated increasing peripheral tissue oxygenation following TSC administration that persisted through the one-hour measurement period, particularly at the two highest doses tested (2.0 mg/kg and 2.5 mg/kg). Furthermore, TSC was safe and well-tolerated at all doses tested with no serious adverse events or dose-limiting toxicities. Additionally, there was no evidence of hyperoxygenation.

The second Oxygenation Trial has been named the Altitude Trial. We expect to initiate this study soon, in the fourth quarter of this year. It is designed to measure the effects of TSC on maximal oxygen consumption and partial pressure of blood oxygen in healthy normal volunteers exercising under conditions that simulate altitude and induce hypoxia.

The last of the planned Oxygenation Trials is what we call the ILD-DLCO Trial. We expect to initiate the ILD-DLCO study late in the fourth quarter of this year. This study is designed to measure the effects of TSC on the diffusion of carbon monoxide through the lungs (DLCO) as a surrogate measure of oxygen transfer efficiency, or uptake, from the alveoli of the lungs through the plasma and onto hemoglobin within red blood cells, in patients previously diagnosed with interstitial lung disease (ILD).

We believe the data we have obtained and expect to obtain from the Oxygenation Trials are very important, as we had relatively limited information on the dose-response relationship between TSC and oxygenation in either normal healthy volunteers or patients. Through the completion of our COVID-19 study last Spring, all of Diffusion's completed clinical studies had been conducted in patients with complex conditions, such as peripheral artery disease and GBM. While we had preclinical data that showed there was a direct effect of TSC on oxygenation in multiple models, we did not have the equivalent human data. Since we believe TSC has the potential to be a platform therapeutic for a host of hypoxia-related conditions, we designed the Oxygenation Trials to specifically evaluate the effects of TSC in well-controlled and differentiated clinical models, each looking at a different aspect of oxygenation. The pharmacodynamic data from the Oxygenation Trials will guide the design of future studies and we believed this enhanced understanding will increase the probability of achieving successful study outcomes.

Tuba: What are more indications Diffusion Pharma is assessing and planning to assess/ test for TSC?

Dr. Cobuzzi: We are optimistic about the platform therapeutic potential of TSC. As noted, the Company previously has initiated studies in several different conditions where hypoxia is a complicating factor, including peripheral artery disease, cancer (GBM brain cancer), acute stroke, and COVID-19.

We believe the remaining Oxygenation Trials will provide important additional data related to TSC dose and oxygenation as well as the mechanism of action. This includes data on the dose-response effects of TSC on peripheral oxygenation (TCOM Trial), oxygen availability and consumption under induced-hypoxic conditions (Altitude Trial), and the uptake of oxygen through the lungs (ILD-DLCO Trial). This information will supplement our selection of the initial TSC indication and dosing to be studied as we pursue a path to regulatory approval.

While we get the remaining two Oxygenation Trials running, we are analyzing available data and discussing the next steps with our expert advisors so we can move quickly as we seek to pursue the most efficient path to approval with the highest probability of technical and regulatory success. We believe we owe that to both patients and shareholders.

Tuba: Discuss more about Diffusion's pipeline?

Dr. Cobuzzi: In addition to TSC, we have a second product candidate called DFN-529. This is a novel, allosteric inhibitor of the P13K/Akt/ mTOR (dual TORC1/TORC2) pathway, which is involved in the control of cell-cycle signaling and directly related to cellular proliferation and cancer. DFN 529 is in early-stage development. Two Phase 1 clinical trials were previously completed evaluating DFN-529 in age-related macular degeneration, and the FDA has granted Orphan Designation for DFN 529 in GBM for which preclinical studies have been conducted.

As discussed above, we believe TSC has the potential to be a platform therapeutic, or a pipeline in a product, that would be useful in many different indications.

We would like to explore all of these if possible, but time and money are the biggest limiting factors in any drug development program. Diffusion is a small company with limited resources, so TSC will remain the primary focus of our resources for the near future.

Source: Spinal Cord

About Author: Dr. Bob Cobuzzi is the CEO, President, and Board Member of Diffusion. He has over 25 years of cross-functional leadership experience in the pharmaceutical and biotechnology industries across the areas of Corporate Development, Research & Development, and Operations. Dr. Cobuzzi holds an AB in Biochemistry and Art History from Colby College & Ph.D. in Molecular and Cellular Biochemistry from Loyola University Chicago. He was a post-doctoral fellow in the Department of Experimental Therapeutics at the Roswell Park Cancer Institute in Buffalo, N.Y.