A randomized, double-blind, placebo-controlled study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of CTO1681 (GP1681) in healthy adult participants Free

CytoAgents is developing CTO1681 as an orally available immunomodulatory agent capable of reducing the exaggerated inflammatory response frequently associated with hypercytokinemia.

Cytokine release syndrome (CRS) is a systemic inflammatory response that can be triggered by overactivation of the immune system, in particular T cells. This immune response can be serious and has been a side effect associated with viral infections such as COVID-19 and influenza. Recently CRS has been seen as a serious comorbidity that can occur when treating certain cancers with immune-mediated therapies like CAR T-cell therapy and bispecific T-cell engagers. In these cases, the CRS is due to the uncontrolled release of proinflammatory cytokines which can cause a serious systemic response leading to a range of symptoms like fever, hypotension, hypoxia and even death. The current standard-of-care treatment for CRS is tocilizumab and/or corticosteroids. However, these treatments fail to prevent these toxicities and can lead to additional comorbidities. Therefore, there is a need for alternative therapies to prevent and treat CAR T-cell therapy related toxicities to help lessen the incidence of hospital admission, length of hospital stay and reduce mortality.

Using in vitro and in vivo models of systemic inflammation, our group demonstrated that the PGE2 and PGI2 agonist CTO1681 downregulates the production of over 20 cytokines directly involved in CRS, ameliorates end-organ responses associated with excessive cytokine production. We hypothesized that CTO1681 may mitigate CRS in patients receiving CAR T-cell and bispecific T-cell engagers therapies and offer an oral therapy to provide a safer and more efficacious treatment compared to the current IV therapies.

This was a double-blinded, randomized (3:1), placebo-controlled, multiple ascending dose study of CTO1681 compared with placebo in healthy volunteers (ACTRN12620000834954). Participants were sequentially enrolled into 3 Cohorts and received TID administration of investigational products at doses of 15 μg/day and 30 μg/day for 7 days and in the last cohort received 45 μg/day CTO1681 for 3 days then 60 μg/day for 4 days. All participants were confined to the CRU for 7 days. After discharge, a safety follow-up visit was conducted.

The objectives of this study were to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of repeat oral doses of CTO1681.

A total of 24 healthy adult participants were enrolled. Blood and urine samples were collected for assessment of clinical laboratory and PK/PD parameters, PCR for viral load determination, physical examination, cardiac monitoring and adverse event collection.

The PK parameters for CTO1681 show that the oral formulation investigated displayed a short half-life that appeared to be approximately dose proportional over the dose range studied. CTO1681-associated cytokine suppression was not expected when circulating cytokine levels are at normal serum levels and not associated with the elevated expression as would be seen in disease states associated with inflammatory sequelae. Results showed that there was no evidence of complete or substantive cytokine suppression across study cohorts.

Treatment emergent AEs were generally mild and transient. There were no AEs that were attributed to fluctuations in cytokine levels in any participant across cohorts. There were no deaths, no AEs that were life threatening, and no SAEs.

There was no evidence of positive viral reactivation during study. Latent viruses (EBV, HSV, VZV, and CMV) were not detected in any participant, and there were no reports of skin lesions that might be indicative of viral reactivation.

The PK, PD, and safety data presented in this clinical study report supports further clinical development of CTO1681.