Indication Drug Name Patients in U.S. U.S. Market
Prevention of Acute GvHD CBD 10,000 $200M
Treatment of Acute GvHD CBD 5,000 $400M
Severe Traumatic Brain Injury CBD 56,000 $2B

Graft versus Host Disease (“GvHD”)

A hematopoietic stem cell transplantation (“HCT”) is a procedure whereby the stem cells of the bone marrow or peripheral blood of a healthy donor are transplanted into a new host after chemotherapy or radiation. This is a lifesaving procedure for many diseases of the blood and bone marrow including leukemia, Hodgkin and Non-Hodgkin lymphoma, multiple myeloma, sickle cell anemia, and thalassemia. There were over 8,000 HCT procedures in the U.S. in 2014 and the use of HCT is expected to continue to increase at a rate of 7% per year. Whereas HCT procedures can be lifesaving, they pose many dangerous side effects, including infection and GvHD.

GvHD is a multisystem disorder that occurs when the transplanted cells from a donor (“the graft”) recognize the transplant recipient (“the host”) as foreign. This interaction initiates an immune reaction that causes disease in the transplant recipient. This reaction can occur within days after the transplant (acute GvHD) or months to years after HCT (chronic GvHD).

GvHD can be mild, moderate, severe, and even life threatening. Patients with acute GvHD may suffer from rashes and blistering of the skin, nausea, vomiting, abdominal cramps accompanied by diarrhea, and jaundice. Generally, acute reactions are more severe and life threatening.

GvHD is a major cause of morbidity and mortality following HCT. Researchers estimate that even with intensive prophylaxis with immunosuppressive treatments, 30-50% of patients transplanted from fully matched sibling donors and 50-70% of patients transplanted from unrelated donors will develop some level of GvHD.

The first step in prevention of GvHD is the selection of donor cells that closely match the genetics of the immune system of the transplant recipient, ideally a sibling donor. From there, the patient relies on drugs that have been developed to prevent or treat GvHD. Medicinal prevention of acute GvHD is dependent on immunosuppression of the donor cells, either pharmacologically or through T cell depletion. Common drugs include methotrexate, cyclosporine tacrolimus, sirolimus, mycophenolate mofetil and ATG. Preventive measures and clinical practices vary by institution.

Treatment of GvHD involves pharmacologic suppression of the graft’s immune cell activation and reestablishment of donor-host immune-tolerance. Most patients are prescribed corticosteroids, which directly suppress the donor’s immune cell attack on host tissue, but also raise the risk of infection and cancer relapse. As with prevention, the optimal drug strategy for GvHD is not well defined. Only 30-50% of patients with moderate to severe GvHD respond to corticosteroids, putting many at risk for fatal outcomes. Better treatment options are needed to improve the mortality and morbidity outcomes for transplant recipients.

In 2015, Professor Moshe Yeshurun, Senior Scientific Consultant of Kalytera, published the results of a Phase IIa clinical trial evaluating the safety and efficacy of CBD in the prevention of acute GvHD. 48 Patients undergoing matched unrelated donor transplantation received oral CBD a week before and 30 days after HCT. The incidence of acute Grade II-IV GvHD was 12%, as compared to a rate of 48% in 102 consecutive patients evaluated before at the same unit at Beilison Hospital in Petach Tikvah, Israel. Based on the promising results of that study, a subsequent Phase IIa clinical study was undertaken to evaluate the efficacy of prolonged administration of CBD following HCT. In that study, which enrolled 12 patients, participants were provided daily doses of CBD seven days prior to transplantation and for 100 days following the procedure. With a median follow-up of 8.5 months following transplantation, 85% of patients did not develop significant (Grades II-IV) acute GvHD, despite the fact that the majority of the patients (10) received stem cells from unrelated donors, including five patients who received stem cells from non-fully matched donors. Only 15% of patients developed Grade II-IV GvHD, versus the predicted incidence of 60-70% in the scientific literature, potentially representing a more than four-fold reduction. In a further Phase IIa study, Professor Yeshurun established that treatment of Grade III-IV steroid-refractory acute GvHD with oral CBD resulted in a complete response in 7 of 10 patients and a very good partial response in 2 of 10 patients. These findings contrast with the immediate historical experience in Dr. Yeshurun’s unit at Beilinson Hospital since 2006, wherein 32 consecutive patients presenting with Grade III-IV acute GvHD had a mortality of 33% for Grade III patients and 100% of Grade IV patients.

Kalytera intends to carry out additional studies in GvHD to strengthen the initial findings of Dr. Yeshurun and to advance towards regulatory approval and market authorization. These clinical studies may support U.S. Food and Drug Administration (“FDA”) Breakthrough Therapy and Fast Track Designations, which could accelerate the regulatory approval process.

Severe Traumatic Brain Injury (“TBI”)

TBI is a highly complex multi-factorial disorder, involving 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. Ultimately, the inflammation within the brain is reflected by an increase intracranial pressure (ICP) that impedes vascular perfusion of the brain paranchyma and may in extreme cases result in downward movement of the brain through the foramen magnum, leading to tentorial herniation and brain death.

CBD is known for its neuroprotective role and is therefore expected to control TBI-associated neuroinflammation, attenuate blood-brain barrier (BBB) damage, and consequently reduce the formation of post-traumatic brain edema. CBD is known to block the release of HMGB1, a nuclear protein released into surrounding tissue and cerebral spinal fluid during acute TBI. HMGB1 is a powerful inducer of pro-inflammatory gene expression, leading to secretion within the brain of TNF-alpha, IL-1beta, IL-6, and IL-8. IL-6 in turn induces astrocytic expression of membranous aquaporin, a protein responsible for the uptake of fluid into astrocytes, resulting in brain edema and increased ICP. It is expected that therapeutic administration of CBD will block HMGB1 release and thereby attenuate elevations in ICP. We predict that this neuroprotective and anti-inflammatory compound will result potent resuscitation of TBI and improve functional outcome. In support of this hypothesis, Kalytera has obtained pre-clinical data demonstrating that resuscitation with CBD following TBI reduces morphological evidence of neurotrauma and improves functional outcome. Based on these compelling findings, Kalytera is evaluating the potential use of CBD as a therapy for acute TBI.