eiF2B Activators to Treat Noise-Induced Hearing Loss

ABSTRACT Noise induced hearing loss (NIHL) is one of the most common types of acquired hearing loss in the US. Often stemming from occupations with elevated noise environments like construction sites, manufacturing plants, law enforcement agencies, armed forces, and aviation, NIHL emerges as a significant public health concern. Furthermore, recreational activities involving amplified music, firearms, and motorized vehicles also contribute to this auditory impairment. Indeed, an estimated 10-15% of Americans aged 20 to 69 exhibit varying degrees of hearing deterioration linked to high noise. Currently NIHL has no approved therapeutical treatments. A recent legal suit between 3M and the military was just settled today for $5.5 billion over military earplugs underscores this important linkage. Jacaranda Bioscience offers a distinctive solution that stands out not only due to the absence of existing treatments but also because our drug treatment runs through a cellular pathway (the Unfolded Protein Response or UPR) that has remained unexplored in this context. Our passionate commitment at Jacaranda Bioscience Inc. (JBI) is to lead the development of an innovative and effective therapy, thereby addressing NIHL in an unprecedented manner. Within this Phase II proposal, JBI will advance a highly effective small molecule therapeutic into preclinical development (JBI-015) as well as two backup compounds (JBI-016 and 028) with great therapeutic potential. The objective of Phase II is therefore to optimize these compounds, in preparation for an investigational new drug application. Our approach involves a rigorous process of medicinal chemistry, encompassing in-depth studies of Absorption, Distribution, Metabolism, and Excretion (ADME), Pharmacokinetics (PK), and formulation development. Additionally, we will conduct rigorous assessment of in vivo efficacy including their effects on cell viability, cell death, and cell toxicity. Importantly we will establish an oral formulation that will make future JBI compounds readily usable in the clinical marketplace. Upon the end of our grant period, our objective is to collect a robust dataset substantiating the rationale for initiating an Investigational New Drug (IND) application. This will pave the way ultimately for the progression into a human Phase 1 clinical trial, a significant stride towards realizing the potential of our therapeutic approach.