Our Science

Our discovery pipeline leverages model systems and expertise from co-founders Drs. Jianxin Bao and Richard Chole, former faculty at Washington University in St. Louis and Dr. Philip Perez, Assistant Professor, University of Pittsburgh, Department of Otolaryngology. We utilize a broad approach to develop therapies that includes drug repurposing (GW-TT1 and GW-TT2), new chemical entities (GW-TT3), and gene therapies (GW-TT5) to find novel solutions to hearing disorders. This approach takes advantage of the co-founder’s and team’s extensive preclinical and clinical experience in the field and well-established rodent models with quantifiable functional and cellular outcomes (see Information Resources). Our product development for tinnitus is based on a behavioral detection method developed at Gateway, which can detect tinnitus reliably in the same animal, ideal for drug screening.

One major obstacle for small biotech companies is the high cost of drug development. The active pharmaceutical ingredients (APIs) for GW-TT1 and GW-TT2 are currently approved by the FDA for two neurological indications by enteral delivery (e.g., oral routes). Gateway received comments for a Type B Pre-Investigational New Drug (IND) meeting with the U.S. Food and Drug Administration (FDA) for its lead program GW-TT2, a novel intranasally delivered form of the L-type calcium channel blocker, as a tinnitus therapy. The positive response supported the planned CMC, nonclinical and clinical development strategy. The FDA also indicated that the 505(b)(2) NDA approval pathway is an acceptable approach for GW-TT2 drug development.

Importantly, a 505(b)(2) submission enables us to:

• Include data in an NDA filing from FDA’s prior findings of safety and/or efficacy of the approved drug in GW-TT2, saving both time and money.

• Reference nonclinical and/or clinical data from published literature.

• Obtain 3 years of marketing exclusivity with the potential for up to 7 years of exclusivity with an orphan drug designation.

In summary, the 505(b)(2) pathway reduces the cost of preclinical development and significantly de-risks the product through the initial clinical stages.

Gateway Biotechnology established an operant behavioral tinnitus detection platform known as sound-based avoidance detection (SBAD). Our method uses a silent or “No-Go” trial to detect tinnitus behavior and a sound or “Go” trial to monitor possible confounding factors (e.g., motor impairment, loss of motivation, learning/memory deficits).

Mice are trained to cross sides of a shuttle box when sound cues are presented through speakers (Go trial) and to avoid crossing sides when the speakers are off (No-Go trial). Mice receive minor foot shocks (negative reinforcement) if they respond incorrectly to the Go and No-Go trials. After a 10-15 day training period, mice are tested before and after tinnitus induction (e.g., standard traumatic noise exposure procedures to induce noise-induced tinnitus in animals) in which foot shocks are disabled during No-Go trials. A statistically significant reduction in No-Go scores relative to baseline would be classified as tinnitus-associated behavior, as a change in conditioned behavior in silence would indicate phantom sound perception. The SBAD method was validated by our group using two tinnitus induction techniques: noise exposure and salicylate application, we further improved this method and validated in new tinnitus models.

Intranasal (i.n.) drug delivery is well-established as a safe and noninvasive drug route for the central nervous system (CNS) and a reliable alternative to oral and parenteral routes. Our patented nasal formulation is able to deliver hydrophilic drugs in high concentration to the brain and inner ear.

Five main drug transport pathways for i.n. drug delivery include:

1. The olfactory pathway in which the drug passes through the nasal mucosa directly into the brain tissue.

2. The systemic pathway in which the drug is absorbed directly into the systemic circulation across the nasal cavity and then across the blood-brain barrier into the brain.

3. Immunity absorption via the nasopharynx associated lymphoid tissue (NALT).

4. The trigeminal pathway in which the drug is transmitted into the brainstem via axonal transport of the trigeminal nerve.

5. The ventricular pathway in which the drug diffuses along the perineural sheath and is ultimately distributed through cerebrospinal fluid circulation.

Additionally, the drug may also reach the cochlea through the basilar artery as well as the cochlear aqueduct which articulates with the subarachnoid space. The inner ear blood-labyrinth barrier shows selective permeability to lipophilic molecules including GW-TT2.

Overall, i.n. drug delivery offers many advantages over systemic delivery systems such as a fast onset of action, higher efficacy and reduced side effects due to a more targeted delivery to the CNS. Furthermore, i.n. drug delivery would be more convenient for self-administration compared to i.v. delivery methods which would enable precise treatment regimens for our proposed prophylactic and therapeutic applications.

Hearing loss and tinnitus are associated with diverse etiologies and pathologies, which have often not been addressed in previous clinical trials. Here, we focus on specific tinnitus subtypes: those associated with hearing loss and recent-onset tinnitus associated with Sudden Sensorineural Hearing Loss (SSNHL) and Ménière's disease. Because previous clinical studies demonstrated limited efficacy with oral forms of nimodipine for these indications (Sin et al. 2018; Han and Lee 2023), our novel formulation is likely to improve patient experience and drug efficacy.

Pinkl J, Shen T, Cheng J, Hawks J, Bao J. Developing a Calibration Method to Minimize Variability in Auditory Evoked Potentials. J Assoc Res Otolaryngol. 2025 Apr;26(2):111-126.

Perez P, Tsai TH, Hawks J, Barbone HM, Pinkl J, Thirumala P, Bao J. Hearing Loss in the Unoperated Ear After High-Speed Drilling in Otologic and Skull Base Surgery. Otol Neurotol. 2024 Oct 1;45(9):993-997.

Le Prell CG, Clavier OH, Bao J. Noise-induced hearing disorders: Clinical and investigational tools. J Acoust Soc Am. 2023 Jan;153(1):711.

Brutnell TP, Wang X, Bao J. Integrating pharmacogenomics into clinical trials of hearing disorders. J Acoust Soc Am. 2022 Nov;152(5):2828

Bao J, Jegede SL, Hawks JW, Dade B, Guan Q, Middaugh S, Qiu Z, Levina A, Tsai TH. Detecting Cochlear Synaptopathy Through Curvature Quantification of the Auditory Brainstem Response. Front Cell Neurosci. 2022 Mar 9;16:851500.

Harris KC, Bao J. Optimizing non-invasive functional markers for cochlear deafferentation based on electrocochleography and auditory brainstem responses. J Acoust Soc Am. 2022 Apr;151(4):2802.

Bao J, Jegede SL, Hawks JW, Dade B, Guan Q, Middaugh S, Qiu Z, Levina A, Tsai TH. Detecting Cochlear Synaptopathy Through Curvature Quantification of the Auditory Brainstem Response. Front Cell Neurosci. 2022 Mar 9;16:851500.

Bao J, Hungerford M, Luxmore R, Ding D, Qiu Z, Lei D, Yang A, Liang R, Ohlemiller KK. Prophylactic and therapeutic functions of drug combinations against noise-induced hearing loss. Hear Res. 2013 Oct;304:33-40.

Yu Y, Hu B, Bao J, Mulvany J, Bielefeld E, Harrison RT, Neton SA, Thirumala P, Chen Y, Lei D, Qiu Z, Zheng Q, Ren J, Perez-Flores MC, Yamoah EN, Salehi P. Otoprotective Effects of Stephania tetrandra S. Moore Herb Isolate against Acoustic Trauma. J Assoc Res Otolaryngol. 2018 Dec;19(6):653-668.