AuraquellTM Technology

Research from Dr. Josef Miller’s laboratory in the Kresge Hearing Research Institute at the University of Michigan has demonstrated that the combination of active agents in AuraquellTM provides significant therapeutic efficacy above that demonstrated with the antioxidants or magnesium alone, with treatment administered for the first time only 1 hour prior to noise exposure.  In this guinea pig study, baseline threshold sensitivity was determined binaurally (in both ears) using the auditory brainstem response (ABR) at 4, 8 and 16 kHz.  The animals were then treated with saline (as a control), or magnesium (Mg), or a combination of vitamins A, C and E (ACE), or a combination of ACE and Mg (ACEMg).  One hour later, the animals were exposed to loud sound (120 dB sound pressure level (SPL) octave-band noise centered at 4 kHz) for five hours, which results in significant permanent hearing loss.  Post-noise treatment was administered immediately after noise exposure and daily treaments contined until day 5 post-noise.  Ten days post-noise, auditory sensitivity was re-measured using ABR.  As shown in Figure 4, there is no statistically reliable improvement in NIHL using the ACE antioxidants or the Mg vasodilator alone.  However, there is a substantial and dramatic improvement with the combination of antioxidants and vasodilator (ACEMg) (data shown here are averaged across the three test frequencies).  The improvement in post-noise hearing thresholds is statistically reliable (p’s < 0.001) for comparisons between the ACEMg group and all other groups. It is important to note that the changes are measured in decibels (dB), which  is log scale, thus a reduction in threshold shift from 45 dB to 10 dB represents >1000 fold improvement in hearing sensitivity. The reduction in NIHL was achieved by prevention of sensory cell death in the organ of Corti.  The combination of ACEMg significantly reduced hair cell loss, as measured using precise measurements from histological samples, that occurs after loud noise.

Additional research from Dr. Miller’s laboratory (Yamashita, D., Jiang, H.-Y., Le Prell, C. G., Schacht, J. and Miller, J. M. (2005). "Post-exposure treatment attenuates noise-induced hearing loss," Neuroscience 134, 633-642) provides compelling evidence that treatment initiated up to three days after noise exposure reduces NIHL.  Although these results were obtained with a different antioxidant combination (not suitable for long term human use), they detail a window of opportunity for rescue from noise trauma.  Based on the significant protection afforded by pre-treatment with the AuraquellTM ingredients, it is likely that the combination will be effective post-noise exposure.

OtoMedicine, Inc. has an exclusive option from the University of Michigan for worldwide license to the patent application claiming the combination of agents in AuraquellTM.  The unique combination of compounds in AuraquellTM places it outside of the sphere of existing antioxidant patents, providing freedom to operate for development of the product.

Technology Development

Technologies underlying the creation and subsequent growth and marketing objectives  of OtoMedicine are based upon more than 25 years of NIH (>$10 MM) funded research on the mechanisms of hearing loss, along with foundation and industrial gifts (>$2 MM) to support translational studies in the laboratories of Dr Miller and his colleagues (for list of references, see Appendix 10).  This basic research has focused on defining the key biochemical events that lead to cell death in the inner ear, identification of molecules that can block these events, factors that can induce repair and regrowth of tissues in the inner ear, and drug delivery systems to selectively treat the inner ear.  Based on the latest understanding of several mechanisms of NIHL, OtoMedicine will become the first company to offer an FDA-approved treatment to prevent this hearing impairment.

In addition to prevention of NIHL, there are other potential markets for this technology.  The role of free radicals in drug-induced hearing loss and age-related hearing loss is increasingly well-established, and evidence for free radical based mechanisms underlying the ototoxic effects of drugs and age suggests AuraquellTM will be effective in preventing these forms of hearing loss. Testing AuraquellTM in a mouse model of age-related hearing loss is the aim of a Phase I SBIR, which has been awarded to OtoMedicine.  While some 30% of all hearing loss is a consequence of noise exposure, age alone results in hearing loss in one-third of those who reach 60 years of age, and one-half of the population aged 85 or older.

In extending the basic research of antioxidant agents to prevent hearing loss, Dr. Miller’s laboratory has shown that local application of thiourea (an antioxidant) can prevent hearing loss without inhibiting the efficacy of the anti-cancer agent, cisplatin, to destroy cancer cells.  Cisplatin is a powerful anticancer agent, particularly used in children, with the unfortunate side effect of causing profound hearing loss.  OtoMedicine holds the option to an exclusive license for this technology from the University of Michigan.

Other research in Dr. Miller’s laboratory has shown that growth factors and immunosuppressants prevent NIHL.  These agents operate independently and, in combination with AuraquellTM, may demonstrate enhanced efficacy.  Unlike AuraquellTM, though, these other agents may have side effects when delivered systemically.  OtoMedicine holds the option to an exclusive license of a drug delivery system (assigned to the University of Michigan by Dr. Miller) which will control unwanted systemic side effects and permit selective and local treatment of the inner ear tissues.  Development of these agents as second generation products will occur at a slower pace because of the greater regulatory requirements as compared to AuraquellTM.

Parallel studies of agents that prevent the degeneration of the auditory nerve and stimulate a regrowth of the nerve have shown that both growth hormones and antioxidants may prevent degeneration of the nerve following sensory cell loss, and that growth hormones can actually induce a regrowth of damaged auditory nerves.  These strategies to pharmaceutically tissue engineer the auditory nerve can enhance the benefits of cochlear implants for the deaf.  Furthermore, ongoing studies in Dr. Miller’s laboratories on the use of stem cells to repair the inner ear hold promise for novel technologies that can underlie the future growth and development of OtoMedicine, allowing the company to achieve its mission of eliminating hearing loss in the 21st century.