Our lead product candidate, Trans sodium crocetinate (TSC), is being developed to enhance the diffusion of oxygen to tissues with low oxygen levels, also known as hypoxia, a serious complication of many of medicine’s most intractable and difficult-to-treat conditions.
TSC effectively facilitates oxygen movement through the blood plasma, enhancing the rate of oxygen diffusion into hypoxic tissues. The novel mechanism of action improves passive oxygen diffusion from areas of high concentration to areas of low concentration by increasing hydrogen bonding and enhancing the organization of water molecules in blood plasma. This process creates a less dense matrix, reducing resistance to oxygen diffusion across the concentration gradient.
TSC would be the first therapy specifically designed to enhance the oxygen diffusion process, thereby supporting normal, physiologic levels of oxygen diffusion at the uptake and delivery points. In animal models, this diffusion-enhancing mechanism of action has been observed to affect hypoxic tissue preferentially while avoiding excessive oxygen-related tissue toxicity, also known as hyperoxia.
TSC has been observed to be safe and well-tolerated at a variety of doses in over 220 subjects included in clinical studies conducted to date, including those studies that evaluated the effects of TSC in patients with medical conditions often complicated by hypoxia, such as GBM, peripheral artery disease with intermittent claudication, stroke, COVID-19, and interstitial lung disease. We have also obtained valuable new data from our COVID Trial and Oxygenation Trials demonstrating TSC’s safety and effects on oxygenation at higher doses and increased dosing frequencies compared to those previously evaluated.
The TSC Oxygenation Trials: Evaluating the Clinical Effects of TSC
Our Oxygenation Trials, conducted during 2021 and 2022, were a series of three, short-term clinical studies using experimental models to evaluate the clinical effects of TSC on oxygenation. Each of these three studies was designed to look at the effects of TSC on a different component of the oxygenation pathway and fill information gaps related to the effects of TSC on tissue oxygen levels and other direct clinical parameters related to oxygen levels. We believe the results of the Oxygenation Trials provide proof of concept of TSC’s effects on tissue oxygenation, in addition to supplementing our knowledge with new information related to TSC’s pharmacokinetics and pharmacodynamics.
TCOM Trial: TSC’s Effects on Peripheral Tissue Oxygenation
In June 2021, we reported a positive trend among patients who received TSC, when compared to placebo, in peripheral tissue oxygenation measured with the use of a transcutaneous oxygen monitoring (TCOM) device. These results can be seen below in Figure 1 which was created during a supplemental analysis of the TCOM Trial results by subtracting the median response observed in the TCOM Trial’s placebo group from the median response observed in each TSC dosage group at each of the measurement times during the one-hour period following dosing. These data highlight the persistent increase in peripheral tissue oxygenation relative to that observed in the placebo group through the duration of the one-hour measurement period following TSC administration, particularly at the two highest TSC doses tested (2.0 mg/kg and 2.5 mg/kg administered intravenously).
Altitude Trial: TSC’s Effects Under Induced Hypoxic Conditions
In June 2022, we reported that, following exercise under hypoxic (i.e., simulated high altitude) conditions, participants in our Altitude Trial treated with the highest dose of TSC (2.5 mg/kg) demonstrated an effect on physiologic indicators of enhanced oxygenation when compared to placebo, including an increase in plasma pH and a decrease in plasma lactate, both at the end of the exercise period and at 10 minutes post-exercise. We believe these data suggest the 2.5 mg/kg dose of TSC decreased blood acidity (i.e., lactic acid accumulation) and enhanced metabolic recovery at 10 minutes after completion of exercise under the stressful conditions of exercise at simulated high altitude.
ILD-DLCO Trial: TSC’s Effects on Oxygen Transfer Efficiency
In December 2021, we announced dosing of the first patients in our ILD-DLCO Trial, which was designed to evaluate the effects of TSC in certain patients with previously diagnosed ILD using the diffusion of carbon monoxide through the lungs, or DLCO, as a surrogate measure of oxygen transfer efficiency. In August 2022, in order to dedicate more of our human and other resources to our strategic review process and ongoing challenges enrolling patients in clinical trials for respiratory indications due to the COVID-19 pandemic, we made the decision to terminate recruitment and enrollment in the ILD-DLCO Trial and wind the trial down.
Our Hypoxic Solid Tumor Program
In July 2022, we announced alignment with the FDA on the design of an open-label, dose-escalation, Phase 2 safety and efficacy study of TSC administered with standard of care to newly diagnosed GBM patients, designated “Study 200-208.” The design of this trial has been reviewed and cleared to proceed by the FDA’s Office of Oncologic Diseases. Key elements of the Study 200-208 trial design the following:
- Innovative incorporation of PET scans and hypoxia-specific radiotracers to evaluate the oxygenating enhancing effects of TSC on tumor hypoxia;
- PET scan data readouts from the first phase of the trial are expected to be available within one year of the first patient being dosed, multiple years earlier than the survival data readout in most clinical trials involving hypoxic solid tumor patients; and
- Building upon the knowledge obtained in our COVID and Oxygenation Trials, patients in Study 200-208 would receive TSC at a significantly increased dose (up to 2.5 mg/kg v. 0.25 mg/kg) and frequency (five days/week v. 3 days/week) as compared to our prior GBM trials, representing an increase in weekly TSC exposure of nearly 1,700% at the highest potential dose.
The design of Study 200-208 is complete, but in connection with our ongoing strategic review process and pending its conclusion, we have paused significant portions of our TSC development activities, including initiation of Study 200-208.
Expanded Access Policy
Diffusion is a biopharmaceutical company developing novel therapies that may enhance the body’s ability to deliver oxygen to areas where it is needed most. As a part of the drug development process, human clinical trials are conducted to show that investigational products are safe and effective. The data from these trials are designed to be used to support marketing applications submitted to the U.S. Food and Drug Administration (FDA) and other regulatory authorities.
Under FDA regulations, expanded access to investigational new drugs may be made available to certain patients outside of the clinical trial setting. A manufacturer developing drugs for serious or life-threatening diseases or conditions that has advanced to a certain stage of development must make its policy on evaluating and responding to requests for such “expanded access” publicly and readily available. More information on the U.S. FDA’s expanded Access process can be found here.
Diffusion believes the best way to access its investigational products is through one of its clinical trials. At this time, Diffusion does not offer expanded access, and participation in clinical trials is the only way to gain access to investigational therapies in development by Diffusion.
Clinical Trials: For more information on Diffusion clinical trials that may be recruiting, search “Diffusion” at www.clinicaltrials.gov.
Contact Information: A treating physician may request additional information about Diffusion’s clinical trials or its expanded access policy via email at the following address: email@example.com. You should expect a response within 5 business days.
The posting of this policy by Diffusion Pharmaceuticals Inc. shall not serve as a guarantee of access to any specific investigational drug by any individual patient. Diffusion may revise this expanded access policy at any time. This posting will be updated should there be any policy change.
Prior Clinical and Preclinical Experience
TSC has been evaluated in a variety of preclinical and clinical studies. The data obtained through certain preclinical studies provides support for TSC’s ability to improve oxygenation, while prior clinical trial data suggest that TSC is safe and well-tolerated at the doses tested. This includes administration of TSC to more than 200 human subjects and patients.
A maximum tolerated dose was identified in the initial clinical study of TSC conducted in normal healthy volunteers, and subsequent clinical studies have been conducted with lower doses.
In the initial Phase 1a study, 30 normal healthy volunteers received a single IV dose of TSC (NCT04808622). TSC was very well tolerated, and the maximum tolerated dose was identified to be 2.5 mg/kg. There were no clinically significant changes in safety lab parameters, vital signs, or electrocardiogram (ECG) findings, and there were no serious adverse events (SAEs), deaths, or withdrawals due to AEs.
TSC may be able to benefit cancer patients by enhancing oxygenation in hypoxic cancer tissue, making the cells more susceptible to the therapeutic effects of standard-of-care radiation therapy and chemotherapy. In particular, glioblastoma multiforme (GBM) is an especially deadly form of brain cancer for which TSC has received an Orphan Drug Designation from the FDA.
In an open-label, historically controlled, Phase 2 clinical trial, 59 patients with newly diagnosed GBM received TSC combined with standard of care treatment for GBM (NCT01465347). TSC demonstrated a favorable safety and tolerability profile. A post hoc subgroup analysis of inoperable patients suggested a higher proportion of TSC-treated patients survived at two years compared to those in the historical control group. Based on this subgroup analysis and guidance from the FDA, we initiated the TSC GBM Trial in a newly diagnosed, inoperable GBM patient population in December 2017. This trial was designed to enroll 236 patients in total, with 118 in the treatment arm and 118 in the control arm.
The GBM Trial began with an FDA-mandated, open-label, dose-escalation safety run-in that included a total of 19 patients in the FDA-specified 42-month exposure period. At a meeting in the third quarter of 2019, the data safety monitoring board for the trial concluded that no adverse safety signal was present and unanimously recommended the trial continue as planned, with TSC to be used in combination with temozolomide, an anti-cancer chemotherapy drug, during the adjuvant treatment chemotherapy period. However, it was determined at the time that there was a lack of adequate resources to fully support the randomized portion of the TSC GBM Trial, so commencement of enrollment in the randomization portion of the TSC GBM Trial was suspended. Further consideration of how to continue the development of TSC as a treatment for GBM — including any restart of the TSC GBM Trial — will take place following completion of the TSC Oxygenation Trials.
Vascular Disease Experience
Conditions such as peripheral artery disease (PAD) and stroke result from narrowing or occlusions of blood vessels that limit blood flow and oxygen delivery to tissue and can result in significant morbidity and mortality. TSC may benefit patients who suffer from impaired oxygen delivery due to pathologic vascular conditions by improving the availability of oxygen to tissues beyond the point of the obstructed blood flow.
A Phase 2a, double-blind, placebo-controlled, single, ascending dose (0.25 to 2 mg/kg IV) safety, PK, and efficacy study was conducted in 48 symptomatic PAD patients with intermittent claudication. Patients were randomized to receive placebo or 1 of 8 dosing levels of TSC ranging from 0.25 mg/kg to 2.0 mg/kg given IV once daily for 5 days. The primary endpoint in the study was the effect of TSC on the change in peak walking time (PWT) from baseline to Day 5. PWT was evaluated via standardized treadmill protocol. The investigators reported TSC was safe and well-tolerated at all doses tested, and that positive changes in PWT were noted with TSC doses above 1.00 mg/kg after both the 1st and 5th dosing days. Due to the chronic nature of PAD, future evaluation of the potential benefits of TSC in this condition and other conditions treated as an outpatient will await the further formulation work ongoing with TSC.
A randomized Phase 2 trial to evaluate TSC in the treatment of acute ischemic or hemorrhagic stroke began enrollment in October 2019 (NCT03763929). This trial was designed to enroll 160 total patients, evenly split between the TSC treatment arm and the control arm, with all patients to receive TSC or placebo treatment, as applicable, while in the ambulance to ensure treatment as soon as possible after the onset of clinical symptoms. We voluntarily terminated the TSC Stroke Study in the second half of 2020, prioritizing resources for shorter duration studies, including the TSC COVID Trial. Further consideration of if, when, and/or how to continue the development of TSC as a treatment for stroke will take place following completion of the TSC Oxygenation Trials.
Respiratory Disease Experience
TSC’s oxygen-enhancing mechanism could potentially provide benefits to patients with low oxygen levels at risk of developing Acute Respiratory Distress Syndrome (ARDS) and multiple organ failure, such as patients with COVID-19.
On September 10, 2020, we announced dosing of the first 2 patients in our TSC COVID Trial evaluating TSC in hospitalized COVID-19 patients at the NIID in Bucharest, Romania. The primary endpoint of the TSC COVID Trial was to evaluate the safety and tolerability of TSC administered every 6 hours for at least 5 and up to 15 days, a more frequent dosing regimen than had been used in our previous clinical studies. Secondary endpoints included pharmacokinetic measurement of TSC levels after dosing, relative improvements in blood oxygen levels, and certain other clinical parameters related to COVID-19. On February 9, 2021, we completed dosing of the twenty-fourth and final patient in the TSC COVID Trial. No dose-limiting toxicities or SAEs were observed among any patients in the study, including those who received the highest dose of 1.5 mg/kg every 6 hours.
In May 2021, we announced final results of our COVID Trial, which included the secondary and exploratory endpoints including time to improvement in World Health Organization ordinal scale by day 7 and through day 29, time on oxygen supplementation, and hospital length of stay. Although the study was not designed or powered to evaluate efficacy, the study’s external safety monitoring committee observed that patients receiving the 1.5 mg/kg dose had improved outcomes in these secondary and exploratory endpoints compared to those receiving lower doses.
Further consideration of if, when and/or how to further develop TSC as a treatment for COVID-19 — including any commencement of enrollment in the previously announced Phase 2b portion of the TSC COVID Trial — will take place following completion of the TSC Oxygenation Trials.
TSC has been evaluated in a variety of preclinical models intended to mimic relevant human conditions known to be complicated by hypoxia. In these studies, a number of positive effects have been observed, including: enhancing oxygenation of hypoxic rat brain tumors without hyperoxygenation of normal tissue; improving survival in a rat brain tumor model when added to radiotherapy ± chemotherapy; enhancing tissue oxygenation without hyperoxygenation of normal tissue and reducing infarct size in a rat ischemic stroke model; demonstrating a functional benefit in a rabbit ischemic stroke model, ± tPA at 1-hour post-clot infection and + tPA at 3 hours post-clot infection; and enhancing arterial PaO2 levels in a rat model of ARDS.