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.
In June 2021, the Company reported a positive trend in oxygenation from its Phase 1b TCOM Trial evaluating TSC using transcutaneous oxygen monitoring (TCOM). The TCOM Trial was designed to evaluate the effect of TSC versus placebo on peripheral tissue oxygenation in normal healthy volunteers. Topline results based upon analyses of primary endpoint data indicated, as compared to placebo, a positive dose-response trend in TCOM readings after TSC administration that persisted through the measurement period with no evidence of hyperoxygenation. TSC was safe and well-tolerated at all doses tested.
This trial will be a double-blind, randomized, placebo-controlled study which will evaluate the effects of TSC on maximal oxygen consumption, or VO2, and partial pressure of blood oxygen, or PaO2, in normal healthy volunteers subjected to incremental levels of physical exertion while exposed to hypoxic and hypobaric conditions through simulated altitude. The study is designed to evaluate the effect of TSC versus placebo on maximal oxygen consumption and partial pressure of blood oxygen. Diffusion anticipates initiating and completing the Altitude Trial in the fourth quarter of 2021, with topline results available within one to two months of study completion.
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.
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.
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.