K-1032

K-1032 is a novel prodrug intended for the treatment of chronic inflammatory skin diseases, such as Acne Vulgaris. K-1032 is the L-valine-ester derivative of CBD. Acne is a chronic inflammatory disease of the sebaceous-pilosebaceous unit and is the most common skin disease, affecting 45 million people in the USA; nearly 80 percent of adolescents present with acne. Progressive acne is closely linked to activation of inflammation. CBD, is known for its immunosuppressive and anti-inflammatory properties, which has been demonstrated in rodent models of arthritis via transdermal application. More importantly, in vitro studies reveal that CBD directly suppresses hyperactivation of the pilosebaceous unit.

K-1032 was selected as a relevant prodrug since substantial evidence has been provided to support the assertion that the biotransformation of drugs, including CBD, occurs in human skin, and that this biotransformation may impair efficacy. Esterases have particularly high activity in the epidermis and hair follicles. These intracellular esterases are important for metabolism and/or pro-drug activation. Nonspecific esterase activity has been demonstrated in human skin. Our assumption is that K-1032 will be captured in the skin, due to the valine moiety, and rapidly cleaved by esterases to yield the active CBD. We have developed a number of formulations for K-1032 to be administered topically.

In vivo efficacy studies in a rodent model of acne have been used to determine suitable dosing and exposure time. We intend to undertake detailed ADME/PK analysis of K-1032 in pigs, as well as non-clinical safety assessment of K-1032 in rats and dogs that will include safety pharmacology and toxicologic IND-enabling studies.

Despite the existence of numberous topically products and systemic drugs that have being applied to treat acne, all possess significant side effects or are limited in efficacy. Therefore, there remains an unmet need for an effective, safe, and well-tolerated treatment for Acne Vulgaris.

K-1012

K-1012 is a novel prodrug invented by Kalytera Therapeutics, intended for the treatment of Adult Respiratory Distress Syndrome (ARDS). Designed as a bi-phosphate derivative of cannabidiol (CBD), K-1012 will be administrated intratracheally via a novel formulation expected to increase the bioavailability of CBD, known for its immunosuppressive and anti-inflammatory properties.

Direct exposure to the lungs is a prerequisite in ARDS therapy, thus we have developed an aerosolized formulation. In contrast to its payload CBD, K-1012 is soluble in aqueous solution, allowing the development of an isotonic solution for an aerosolized formulation. Due to the fixed negative charge of the phosphate groups at physiological pH, K-1012 is predicted to be entrapped in the lung lumen until undergoing cleavage by various intraluminal phosphatases. Given the increased levels of lung alkaline phosphatase (ALP) in the bronchoalveolar fluid as a result of pulmonary damage, we predict ALP will liberate bioactive CBD in ARDS disease models. Progressive ARDS is closely linked to activation of inflammation. The benefits of CBD are expected to be augmented via regional targeting of K-1012 to the lung by means of the phosphate additions.

In vivo efficacy studies in rodent models of E. coli LPS induced ARDS have been utilized to determine appropriate dosing and exposure time. We expect to carry out detailed ADME/PK analysis in rats as well as a non-clinical safety assessment of K-1012 in rats and dogs that will include safety pharmacology and toxicologic IND-enabling studies.

To date, no effective therapy exists for ARDS, thus there remains an urgent need for a new first-line therapeutic to improve the survival of patients suffering from ARDS. The development of K-1012 will provide the first pharmacological treatment for patients with ARDS.

K-1022

K-1022 is a novel prodrug invented by Kalytera Therapeutics, intended for the treatment of Ulcerative Colitis (UC), a chronic condition characterized by inflammation of the colonic mucosa extending from the rectum proximally to varying portions of the large intestine. The increase in pro-inflammatory factors promotes inflammation and facilitates damage to intestinal tissues. Understanding the pathophysiology of colitis has provided us an opportunity to identify new targets for this disease. The active parent compound of K-1022, CBD, is known for its immunosuppressive and anti-inflammatory properties.

Designed as a bi-sulfate derivative of cannabidiol (CBD) with a novel formulation, K-1022 will be administered orally to maximize the anti-inflammatory effect of CBD. The rationale for constructing a sulfate-derivatized prodrug of CBD (K-1022) lies in the augmented delivery to the colon, where K-1022 will be converted to the active compound via the activity of colon-specific microbial sulfatases. In contrast to CBD, the disulfated derivative is water soluble, enhancing the probability of developing a successful oral formulation of K-1022. Given the safety profile and anti-inflammatory properties of CBD, it is expected that K-1022 may serve as a potent and tolerated treatment for UC.

In vivo efficacy studies have been used to determine suitable dosing and exposure time. We are currently performing detailed ADME/PK analysis in rats, as well as non-clinical safety assessment of K-1022 in rats and dogs that will include safety pharmacology and toxicology studies, to complete IND-enabling studies.

K-1022, by virtue of the remarkable safety profile of CBD is intended to occupy a position as a first-line therapeutic for UC. Currently there is a population of patients with UC that do not respond to first-line therapy and therefore require corticosteroids and anti-TNF biologics. It is anticipated that K-1022 may find a place across the full spectrum of UC patients including those with refractory disease, given that its mechanism of action diverges entirely from the existing armamentarium of therapeutics.

K-1052

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.

Bone Fracture Healing (KAL436/9)

Therapeutic goal and molecular design Kalytera is investigating two compounds to assess their potential ability to improve bone fracture healing, including cannabidiol (“CBD”), a natural non-psychoactive cannabis constituent, and KAL436/9, a synthetic derivative of CBD that has been structurally modified to enhance solubility in water to improve potency.

Current pharmacology studies Kalytera is collaborating with Dr. Yankel Gabet, the Director of the Bone Research Laboratory at Tel Aviv University. In 2015 Dr. Gabet published a study showing that cannabidiol (“CBD”) increased collagen cross-linking and stabilization in rat femurs, increasing the maximal load and work-to-failure, but not the stiffness.

Unmet need Approximately one-third of all tibial and femoral shaft fractures have delayed rates of healing or non-healing. Patients with delayed union or non-union can expect poorer outcomes, including increased pain, loss of function, loss of quality of life, and delay in return to work. There are currently limited treatment options available for improving the rate of bone healing and bone fracture repair. Bone morphogenetic proteins (“BMPs”) and anabolic agents, including Teriparatide (“TPD”), are costly and may lack desired efficacy; improved therapeutic options are desired.

Osteoporosis (KAL671)

Therapeutic goal and molecular design KAL671 is a unique synthetic fatty acid amide and an endocannabinoid-like molecule that may restore bone in persons suffering from osteoporosis. Kalytera has obtained an exclusive license to KAL671 from Yissum Research Development Company, Hebrew University’s technology transfer arm.

Current pharmacology studies Studies in mice have shown that KAL671 increases bone volume density with a favorable side effect profile. Researchers used a mouse ovariectomy (“OVX”) model where mice ovaries were surgically removed at six weeks of age; the OVX model mimics osteoporosis in women post-menopause, when sex hormone levels are significantly altered. OVX mice were treated with daily doses of KAL671 and a control group of OVX mice were administered a solvent. The mice’s skeletons were analyzed for physical variations at weeks 1, 6, and 12; serum markers were tracked to identify bone remodeling patterns. Compared to controls, mice treated with KAL671 (0.5 mg/kg/day) recovered more than half of the OVX-attributed bone loss. No serious side effects observed as a result of KAL671 administration.

Unmet need Osteoporosis, the most common bone disease, is a chronic condition characterized by a weakening of the bone and an increased risk of fracture. Osteoporosis typically does not manifest until late in life, when bone loss begins due to bone breakdown and decreased levels of bone formation. Loss of bone mass leads to the development of structural abnormalities that make the skeleton more fragile. According to the National Osteoporosis Foundation (“NOF”), osteoporosis affects approximately 10.2 million adults in the U.S. alone. The NOF estimates that an additional 43.4 million U.S. adults may have low bone mass. Globally, one in five men and one in three women aged 50+ will experience osteoporotic fractures.