Novel Small Molecule for the Prevention of Hemorrhagic Cystitis

About This Grant

PROJECT SUMMARY/ABSTRACT CMTx Biotech is an emerging drug development company working to commercialize novel, host-directed, small molecule drug candidates invented at partnering academic research institutions for the treatment of diseases with high unmet medical needs, including orphan indications and conditions for which there are limited treatment options. Hemorrhagic cystitis (HC) is a severe inflammatory condition of the lower urinary tract (LUT) that leads to hematuria, blood clots in urine, dysuria, fever, inability to urinate, and loss of bladder control. HC is most common in patients treated with ifosfamide and high-dose cyclophosphamide (CYP) in the setting of bone and soft tissue sarcoma and hematopoietic cell transplantation, or as a late toxicity of pelvic radiation therapy (RT) when the bladder is within the radiation treatment field. HC occurs in up to 70% of patients exposed to high doses of CYP or ifosfamide chemotherapy, and in 5-10% of patients who undergo pelvic irradiation to treat malignancy. Current management strategies and therapies include supportive measures, intravesical astringents or the drug sodium 2-mercaptoethane sulfonate (mesna). Mesna is associated with a number of adverse effects. Importantly, findings from a number of studies including a retrospective study of 718 patients receiving CYP with or without mesna do not support the use of mesna as a preventative measure against HC in patients receiving CYP and suggest that mesna may actually be harmful in such patients. Thus, there remains a critical unmet need for safe and effective therapeutics for the treatment of HC. The product of this STTR will be a novel, orally administered small molecule, 8-aminoguanine (8-AG), for the treatment of patients with HC. We anticipate the 8-AG will be a safe and effective treatment for HC patients by reducing bladder inflammation and bleeding, promoting healing of the bladder lining, and relieving symptoms including bladder pain, as well as urinary frequency, urgency and dysuria. The Specific Aims of this STTR are (a) to conduct oral 8-AG dose optimization to identify a dose that preserves efficacy (e.g., improve LUT function, reduce nocifensive behavior) in a rat model of CYP induced HC and (b) to determine the potential genotoxicity of 8-AG by the bacterial reverse mutation test, commonly known as the Ames test. We anticipate that 8-AG will significantly improve LUT structure and function in a rat model of CYP-induced HC. Our long-term goal is to secure FDA approval for 8-AG as a safe and effective treatment of HC patients. Successful completion of these studies will allow CMTx Biotech to (a) prepare and submit a pre-IND meeting request and briefing document, (b) scale-up cGMP production of 8-AG, (c) develop and manufacture an orally-administered formulation of 8-AG, (d) conduct IND-enabling, non-clinical toxicology studies, (e) design a Phase I clinical trial, and (f) submit an Investigational New Drug (IND) application focused on this indication. As technical and regulatory milestones are achieved, we will work to forge a strategic partnership with an established pharmaceutical company in the form of a license, co-development agreement, or acquisition.