K-1052 is a novel prodrug invented by Kalytera Therapeutics, intended for the treatment of Sepsis-induced Acute Renal Failure (ARF) and Traumatic Brain Injury (TBI). Designed as an iNOS inhibitor derivative of cannabidiol (CBD), K-1052 is being developed to improve the long-term outcome of ARF and TBI patients.
ARF is a syndrome characterized by rapid loss of kidney function, specifically the glomerular filtration rate, measured by increases in serum creatinine and limited or lack of urine output. ARF is a common complication of acute illness, affecting more than 35% of critically ill patients. Despite advances in treatment and prevention, ARF continues to be associated with high rates of mortality and morbidity, particularly for patients admitted to the intensive care unit (ICU), where mortality rates can exceed 50%. Various types of injury lead to ARF. Common to all these injuries is an inflammatory response due to the kidney insult.
TBI is a highly complex multi-factorial disorder, which involves primary and secondary injury cascades that underlie delayed neuronal dysfunction and death. Following head injury, TBI is a consequence of neuroinflammation caused by an increase in reactive oxygen species (ROS) production and a concomitant increase in levels of inflammatory cytokines.
The active parent compound of K-1052, CBD, is known for its immunosuppressive and anti-inflammatory properties. Thus, we anticipate K-1052 to suppress the inflammation present in ARF and TBI patients and improve long-term outcome.
K-1052 consists of two pharmacologically active components, that are coupled together into a single prodrug molecule. The first one, CBD, is known for its anti-inflammatory properties. The second component, (S)-2-amino-(1-iminoethylamino)-5-thioheptanoic acid, is a specific inducible Nitric Oxide Synthase (iNOS) inhibitor that has been tested in phase III human clinical trials for other indications.
K-1052 was selected as a relevant prodrug for acute resuscitation of TBI because iNOS-produced nitric oxide (NO) was shown to mediate blood-brain barrier (BBB) damage, and consequently drive the formation of post-traumatic brain edema. iNOS-derived NO, formed during the earliest stages of severe TBI, combines with superoxide anion in the renal epithelium to form peroxynitrite, a highly toxic oxidizing species. Peroxynitrite in turn triggers DNA single strand breakage, which induces activiation of poly(ADP-ribose) polymerase, a key cell necrosis-inducing enzyme. Pharmacologic inhibition of iNOS, interrupts this injury cascasde and thereby preserves renal epithelial viability and renal function. We anticipate that a combination of CBD and a potent iNOS inhibitor, joined together in a single prodrug form, will yield powerful therapy for diseases where inflammation and iNOS-derived NO play prominent roles. Our novel formulation will be administered intravenously (IV) to hospitalized patients, in order to avoid first-pass metabolism of CBD and to improve the pharmacokinetic (PK) profile.
In vivo efficacy studies in rodent models of renal ischemia, induced by sepsis or reperfusion injury, and in TBI models, induced by closed head trauma, have been utilized to determine suitable dosing and exposure time. Additionally, we intend to undertake detailed pharmacokinetic studies in rats in order to design clinical PBPK/PD-based human models to inform the design of clinical PK studies. Non-clinical safety assessment of K-1052 will include safety pharmacology and toxicology studies. These investigations will include separate studies that permit full toxicokinetic (TK) characterization of K-1052. The toxicology of K-1052 will be evaluated in rats and dogs, two pharmacologically-relevant species, given IV, the intended route of administration in humans.
The standard of care for the treatment of ARF is renal replacement therapy, which is supportive but not curative. To date, there is no drug treatment for ARF. Thus, an urgent need remains to develop an effective treatment for ARF. As well, there is no efficacious therapeutic or intervention utilized by physicians in daily clinical practice for severe TBI patients. Hence the urgent requirement for an effective therapy for both conditions. The development of K-1052 intended to provide the first pharmacological treatment for patients suffering from ARF or TBI.