Novel Treatment for Hermansky-Pudlak Syndrome Pulmonary Fibrosis

National Center For Advancing Translational Sciences

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Abstract

Hermansky-Pudlak syndrome is a rare genetic disorder primarily of lysosome-related organelle biogenesis. There are 10 different types of HPS, depending on which genetic mutation is inherited. Patients with HPS-1, HPS-2 or HPS-4 develop pulmonary fibrosis. In the absence of a Food and Drug Administration (FDA)-approved therapy for HPS-PF, there is an urgent need to identify new therapeutic targets and treatment strategies. It has been shown that the cannabinoid-1 receptor (CB1R) is overactivated in fibrotic lung tissue of mice and humans with HPS. In previous studies, rimonabant, a CB1R antagonist, demonstrated a modest ability to mitigate fibrosis in animal models. However, neuropsychiatric side effects of CB1R inhibition in the central nervous system (CNS) led to rimonabant being withdrawn from all clinical use. Additionally, the activity of inducible nitric oxide synthase (iNOS) is also increased in PF, promoting lung inflammation and progression of fibrosis. Because the pathogenesis of HPS-PF is complex, targeting multiple pathways has been recommended as an approach to improve therapeutic efficacy. To target these independent drivers of PF simultaneously in HPS, the novel drug candidate MRI-1867 was designed as a dual inhibitor of both CB1R and iNOS. To avoid the CNS side effects, MRI-1867 was designed to be restricted to only the peripheral tissues. MRI-1867 is orally bioavailable, and in chronic treatment in animal models of PF it provided increased antifibrotic efficacy compared with targeting either CB1R or iNOS alone. TRND scientists developed a synthetic process for GMP manufacturing of the development compound, S-MRI-1867, including conduct of pre-formulation studies. Studies to evaluate metabolism in vitro, and in vivo metabolite identification and pharmacokinetic analysis in rodents were also completed. MRI-1867 is being developed in parallel for another rare disease indication. The IND-enabling preclinical and Phase I clinical data from those studies are expected to be leveraged to enable the submission of an Investigational New Drug application with the FDA to initiate a pivotal Phase II clinical trial in HPSPF patients.