Treating inflammation and tissue damage in
COVID-19, viral diseases and acute tissue injury

Bessor Pharma is advancing a novel, biomarker-driven, therapeutic approach based on enhancing renalase (RNLS) signaling to prevent and treat the damaging, acute inflammation that often accompanies a range of diseases and conditions, including COVID-19 and other viral diseases, acute kidney injury (AKI) and acute pancreatitis (AP). The company’s lead project is focused on developing a novel RNLS peptide agonist, BP-1002, to treat the potentially fatal hyperimmune response and tissue damage that occurs in many severe COVID-19 patients. The project is a collaboration with Dr. Gary Desir, Chairman of Medicine at Yale, who discovered RNLS. 

BP-1002’s use in COVID-19, which is moving towards an IND, provides a rapid path to improve the treatment of severe COVID-19 patients and demonstrate clinical proof-of-concept for RNLS agonism in the treatment of acute, tissue damaging inflammatory conditions. Although the steroid dexamethasone has been shown to reduce mortality in hospitalized COVID-19 patients receiving oxygen support, there remains an important clinical need for additional therapeutic options for severe COVID-patients.

RNLS is a naturally occurring protein and can function as a survival factor that acts through a membrane receptor (PMCA4b) to initiate a pro-survival, anti-apoptotic signaling cascade (MAPK). The protein also possesses immuno-anti-inflammatory activity, resulting in inhibition of multiple cytokines.

Dr. Desir and colleagues have shown in a large cohort of severe COVID-19 patients that low RNLS levels correlate with mortality and high RNLS levels correlate with survival. The data both supports RNLS agonism as a target and the potential of RNLS as a biomarker for patient selection and monitoring.

Dr. Desir and colleagues have shown similar correlations with RNLS levels and disease severity in patients with acute kidney injury and acute pancreatitis.

Bessor’s lead compound is a novel peptide, BP-1002, that was designed to target the active site on the RNLS receptor. In preclinical studies in a mouse model of COVID-19, BP-1002 improved survival vs. control mice and in another model of severe viral infection, protected RNLS deficient mice from injury. In studies with human blood exposed to COVID-19, BP-1002 inhibited the production of multiple cytokines implicated in hyperimmune responses.

Potential Therapeutic Use in Acute Kidney Injury, Acute Pancreatitis

The team has demonstrated in vivo proof-of-concept in models of AKI and AP with recombinant human RNLS and BP-1002. The AP and AKI projects has been validated through support of three SBIR grants from the National Institute of Diabetes, Digestive and Kidney Diseases and the National Cancer Institute.

AKI is a clinical condition commonly associated with sepsis, surgery, and certain drugs, and which affects up to 20 percent of hospitalized patients. Epidemiologic data indicate the severity of AKI is associated with in-hospital and post-hospital mortality as well as enormous healthcare costs. 

The Bessor-Yale team has demonstrated initial in vivo proof-of-concept in cisplatin-caused AKI. Cisplatin isone of the most widely used chemotherapies. It is a named component in half of the drug cocktails used for cancer. Cisplatin is approved for treating many cancers including bladder, cervical, non-small cell lung, ovarian, testicular cancer, malignant mesothelioma, and squamous cell carcinoma of the head and neck. Kidney toxicity severely limits use of cisplatin, with 25-35% of patients required to reduce dosing or stop otherwise effective therapy. 

In single dose experiments candidate peptides and RNLS prevent and treat cisplatin-induced AKI in mice by reducing renal necrosis, apoptosis, and inflammation, and by blunting 50% of the acute rise in plasma creatinine. Adding RNLS or agonist for 24-72 hours neither diminishes cisplatin effectiveness against cancer cells, nor promotes cancer cell growth.

AP is the most frequent gastrointestinal cause for hospital admission in the US with increasing incidence and is lethal in up to 30 percent of severe cases. AP has multiple causes but inflammation, pain, and cell death are universal hallmarks. Inflammation and edema in the kidney, and particularly the lung as a result of pancreatitis, are major contributors to pancreatitis lethality. There are few effective therapeutic options for AP other than supportive care and none are approved in the US.

The team has demonstrated in vivo proof-of-concept in models of AP with RNLS and BP-1002.

Publications

Bessor’s Collaborators Publish Study on Potential of Renalase as Acute Pancreatitis Treatment showing Renalase reduces cell injury and severity of acute pancreatitis in animal models 01.24.18. Journal of Biological Chemistry. Read the study

Renalase Protects Against Acute Pancreatitis. Pancreas. Nov. 2014, V.43 – Issue 8 – p 1340–1429

Renalase prevents AKI independent of amine oxidase activity. J Am Soc Nephrol. 2014 Jun;25(6):1226-35.

Three-Dimensional Morphology by Multiphoton Microscopy with Clearing in a Model of Cisplatin-Induced CKD. J Am Soc Nephrol. 2016 Apr;27(4):1102-12.

Renalase protects against cisplatin acute kidney injury in mice. The FASEB Journal April 2013 vol. 27 No. 1 Supplement 910.7