Demonstrating the feasibility of CCG-257081 as a preventive therapy to inhibit bleomycin-induced lung fibrosis in mice

ABSTRACT Front-line therapy for patients diagnosed with Hodgkin’s lymphoma or germ cell cancers includes the drug bleomycin, a highly effective agent with a debilitating side effect. About 10-12% of bleomycin-treated patients develop pneumonitis with progression to pulmonary fibrosis during therapy as a direct result of bleomycin. An estimated 10-20% of these cases are fatal. The current standard approach to this problem involves elimination of bleomycin from the chemotherapy regimen and long-term treatment with corticosteroids, which have no effect on fibrosis. This makes bleomycin-induced lung fibrosis a significant treatment-limiting side effect that impedes the ability of patients to complete therapy. The team behind FibrosIX LLC has developed a novel compound, CCG-257081, that has shown efficacy in preventing bleomycin-induced fibrosis in several mouse models. The molecular target of this compound was recently found to be a nuclear protein regulator of NFkB, a crucial mediator of inflammation. Our data suggest the target is also a regulator of the pro-fibrotic myocardin-related transcription factor (MRTF)/serum response factor (SRF) gene transcription pathway. The MRTF/SRF gene transcription pathway is a critical step in the fibroblast-to-myofibroblast transition that occurs in fibrosis development. This unique dual mechanism means that our compound can inhibit both inflammatory (NFkB) and pro-fibrotic (MRTF) effects of bleomycin toxicity. The goal of this Phase I SBIR is to test the hypothesis that targeting this dual mechanism with CCG-257081 can prevent lung fibrosis in mouse models that mimic bleomycin chemotherapy. We will test the ability of CCG-257081 at multiple doses to prevent lung fibrosis in mice given repeated, systemic injections of bleomycin. Fibrosis in the lungs will be measured by collagen content assessed through both histopathological and biochemical assays. Our results will be validated by an independent contractor and compared to standard therapy with prednisolone and a potential anti-fibrotic competitor, pirfenidone. Blood and peripheral tissues will also be examined for preliminary measures of toxicity. Upon successful achievement of milestones in Phase I, we will submit an application for a Phase II SBIR to conduct IND-enabling studies of CCG-257081. Our ultimate goal is to incorporate CCG-257081 as a standard component of all bleomycin-containing chemotherapy regimens to allow oncologists to treat patients with the full course of bleomycin treatment, resulting in reduced mortality and improved patient outcomes. With over 8,000 new cases of Hodgkin’s lymphoma and over 9,000 new cases of germ cell cancers that are treated with bleomycin each year, this creates a total addressable market of about 17,000 patients per year who could benefit from CCG- 257081.PROJECT NARRATIVE In this Phase I SBIR, FibrosIX LLC plans to develop a therapeutic to prevent the treatment-limiting side effect of bleomycin-induced pneumonitis and lung fibrosis in cancer patients undergoing chemotherapy. This therapeutic would allow patients to continue full bleomycin therapy, thus improving their probability of achieving remission, resulting in reduced mortality and improved patient outcomes.