About Akouos

Akouos, Inc. operates as a precision genetic medicine company. The company focuses on developing gene therapies with the potential to restore, improve, and preserve high-acuity physiologic hearing for individuals who live with disabling hearing loss worldwide. The company has built a precision genetic medicine platform that incorporates a proprietary vector library consisting of variants of a small virus commonly used in gene therapy, known as adeno-associated virus (AAV) and a novel delivery approach. The company is executing on its core strategic initiatives, which include the advancement of its lead product candidate, AK-OTOF; the expansion of its pipeline to include programs focused on other monogenic conditions, as well as inner ear conditions of complex etiology, such as AK-antiVEGF for vestibular schwannoma; and the development of internal manufacturing capabilities, and ultimately, a commercial infrastructure. The genetic medicines the company is developing have the potential to create a new standard of care for, and to transform the lives of individuals and their families, with disabling hearing loss, by providing a meaningful alternative to the invasive and limited current non-pharmacologic treatments. The company’s delivery approach is designed to allow for safe and effective delivery of product candidates and distribution of product candidates across the full length of the cochlea. The surgical approach is routine in standard otologic practice and the device is designed to deliver product candidates in a fixed volume at a controlled flow rate. The company’s proprietary vector library and delivery approach allow it to utilize AAV-enabled multimodal capabilities, including viral vector delivery to the target cell population where the full-length transgene is split into two vectors, known as a dual vector method. The company’s focused candidate selection criteria allow it to identify promising targets covering a range of inner ear cell types, including sensory hair cells and non-sensory supporting cells, to treat a broad range of inner ear conditions. The company seeks programs that have clinically well-established, objective, and quantifiable endpoints that can be incorporated in translatable nonclinical models during development, which may provide drug development advantages, including the potential for more rapid clinical development. Additionally, given the epidemiology and severity of the conditions the company is initially targeting, available regulatory pathways, such as orphan drug designation and expedited pathways for serious conditions may provide the potential for more rapid regulatory approval. The company’s clinical development plan for AK-OTOF includes measurement of the auditory brainstem response (ABR), an objective, clinically accepted endpoint, which provides both clinical and regulatory advantages. The company has generated promising nonclinical data for its lead product candidate, AK-OTOF, a gene therapy for the treatment of hearing loss due to mutations in the OTOF gene. The OTOF (otoferlin gene) gene encodes otoferlin, a protein that enables the inner hair cells of the cochlea, or the organ in the inner ear responsible for hearing, to release neurotransmitter vesicles in response to stimulation by sound to activate auditory neurons. The auditory neurons then carry electrically encoded acoustic information to the brain, which allows the company to hear. The company aims to restore otoferlin expression through targeted delivery of a proprietary AAVAnc capsid, known as AAVAnc80, containing the OTOF gene to individuals with OTOF-mediated hearing loss. The company has selected AAVAnc80 from the larger AAVAnc (ancestral AAV (adeno-associated virus)) vector library based on its high observed transduction efficiency in inner hair cells. Based on feedback from the U.S. Food and Drug Administration, or FDA, the company is designing its Phase 1/2 trial to include ABR as an efficacy endpoint. This will enable the company to quickly determine a clinical response and potentially result in rapid advancement towards a pivotal trial. There are no pharmacologic therapies approved for the treatment or management of OTOF-mediated hearing loss, or any other form of sensorineural hearing loss. The company’s product candidate has the potential to restore physiologic hearing and provide long-lasting benefits to these individuals and their families. The company is targeting submission of an investigational new drug application (IND) for AK-OTOF for the treatment of OTOF-mediated hearing loss to FDA in the first half of 2022. In addition to pursuing opportunities that require transduction of target cell populations to express intracellular genes of interest, the company identified inner ear conditions that can potentially be treated with secreted proteins. AK-antiVEGF is the company’s product candidate for the treatment of vestibular schwannoma, benign tumors that form in the cells around the vestibulocochlear nerve within the internal auditory canal. An AAVAnc80 vector encoding a secreted anti-VEGF protein, delivered to the inner ear in the same manner as other programs in the company’s pipeline, has the potential to stabilize tumor size and preserve hearing, while potentially avoiding the systemic side effects of high dose intravenous VEGF inhibitor infusion and potentially removing or reducing the need for surgical tumor resection and/or radiation. The company completed a pre-IND meeting with FDA in October 2020. The company plans to submit an IND for AK-antiVEGF in 2022. The company’s diversified portfolio of product and research candidates has been selected to leverage its platform across multiple inner ear conditions, starting with those resulting from mutations in a single gene, or monogenic forms of hearing loss, such as OTOF-mediated hearing loss, and building toward clinical development of genetic medicines for the most common forms of hearing loss, such as age-related and noise-induced hearing loss. In addition to its AK-OTOF and AK-antiVEGF programs, the company’s pipeline product and research candidates address a range of inner ear cells and leverage different modalities. These programs include AK-CLRN1 for Usher Type 3A, an autosomal recessive condition characterized by progressive loss of both hearing and vision, and a program targeting gap junction protein beta 2 gene, or GJB2, for a common form of monogenic hearing loss. In 2020, the company completed the development of internal infrastructure, including the acquisition and installation of equipment, as well as successful completion of commissioning runs, necessary to manufacture vectors for good laboratory practices, or GLP, toxicology studies. The company is establishing current good manufacturing practice, or cGMP, capabilities that will enable the manufacture of gene therapy vectors to support activities through Phase 1/2 clinical trials for its product candidates. The company has also partnered with third-party manufacturers for production of IND-enabling nonclinical and cGMP material for its product candidates. The company has made, and will continue to make, significant investments to further optimize its manufacturing capabilities to produce high-quality AAV vectors. Programs AK-OTOF Using the company’s precision genetic medicine platform, it is developing the company’s lead product candidate, AK-OTOF, a gene therapy intended for the treatment of individuals with OTOF-mediated hearing loss. AK-OTOF is designed to treat the underlying cause of OTOF-mediated hearing loss through the delivery of a transgene using a dual vector technology that results in expression of normal, functional otoferlin protein in the affected cells, namely inner hair cells, in the cochlea. AK-OTOF has the potential to meaningfully improve overall hearing function in individuals with OTOF-mediated hearing loss. The company is targeting an IND submission, for AK-OTOF for the treatment of OTOF-mediated hearing loss, to FDA in the first half of 2022. AK-OTOF is designed to treat individuals with OTOF-mediated hearing loss by delivering the normal OTOF gene in order to produce normal, functional otoferlin in affected inner hair cells. The presumed mechanism of action for AK-OTOF is the recovery of otoferlin protein function resulting in an increased signal from the affected inner hair cells to the auditory cortex in the brain. AK-OTOF uses AAVAnc80 as a delivery vehicle for the normal human OTOF gene. Because the length of the OTOF complementary DNA, or cDNA, exceeds the packaging capacity of an individual AAV vector, the company is using a dual vector approach. In the case of AK-OTOF, one AAVAnc80 vector carries the 5’ fragment of the OTOF gene, and the other AAVAnc80 vector carries the 3’ fragment of the OTOF gene. The company conducted an initial dose range finding study in Otof knock-out mice to determine the biologically active dose range of AK-OTOF. Based on input received in the company’s September 2019 pre-IND meeting with FDA, the company completed a GLP toxicology study in cynomolgus monkeys using AK-OTOF. The company intends to initiate a proposed Phase 1/2 clinical trial for AK-OTOF for the treatment of individuals with OTOF-mediated hearing loss, subject to FDA acceptance of an IND. This trial will be conducted in two parts. The first part will be an adaptive dose escalation phase to assess the safety, tolerability, and bioactivity of escalating doses of AK-OTOF administered to trial participants through a single unilateral intracochlear injection. The second part will be a cohort expansion phase to assess both continued safety, as well as effectiveness. The company expects eligibility with respect to age for this Phase 1/2 clinical trial to be based on both published data and data from its natural history studies. Additionally, based on its pre-IND meeting with FDA in September 2019, the company anticipates that its Phase 1/2 clinical trial may enroll children as young as one year old in the expansion phase. Outcome assessments will include objective and clinically relevant ABR (auditory brainstem response) testing and age-appropriate behavioral audiometry. Based on the company’s discussions with representatives of FDA's Center for Biologics Evaluation and Research, or CBER, and Center for Devices and Radiological Health, or CDRH, in the company’s pre-IND meeting, it intends to file the delivery device along with the investigational product in an IND application as a combination product. Prior to seeking a marketing application for AK-OTOF, or for another of the company’s product candidates, with CBER, but following demonstration that the probable benefits of delivery of therapeutic agents to the cochlea outweigh the potential risks, the company may pursue the de novo pathway for its delivery device with the CDRH. While technically a combination product given anticipated cross-labeling of the biologic to the company’s specific delivery device, it may choose to submit separate applications for the constituent parts of a combination product. In 2021, AK-OTOF was granted orphan drug designations by the FDA and the European Commission, and rare pediatric disease designation by the FDA. These designations could accelerate the company’s development of AK-OTOF. Product Candidate for Secreted Protein: AK-antiVEGF In addition to pursuing opportunities that require transduction of target cell populations to express intracellular genes of interest, the company has identified inner ear conditions that can potentially be treated with secreted proteins. To address these opportunities, the company intends to use an AAVAnc vector to transduce a range of cell types and enable these cells to secrete a protein with the potential to restore, improve, or preserve hearing and/or other functions of inner ear. The secreted protein can be one that is normally expressed in the ear, as in the case of a gene transfer approach for a monogenic indication, or it can be an exogenous therapeutic protein, as in the case of a vector-mediated therapeutic protein expression approach for an inner ear condition of complex etiology. The company’s preclinical AK-antiVEGF program is focused on vestibular schwannoma, an inner ear condition of complex etiology. The company completed nonclinical studies involving direct intracochlear administration of AAVAnc80 encoding anti-VEGF protein to wild-type mice to assess tolerability, and to determine secreted levels of anti-VEGF protein in the cerebrospinal fluid. The company completed a pre-IND meeting with FDA in October 2020. The company conducted IND-enabling studies in 2021 and is targeting an IND submission, for AK-antiVEGF for the treatment of vestibular schwannoma, to FDA in 2022. Additional Pipeline Programs Hair Cell Targets In addition to AK-OTOF, the company is developing its pipeline to focus on other monogenic gene mutations of hair cells. AK-CLRN1: The company’s AK-CLRN1 program is initially focused on the auditory manifestations of Usher syndrome 3A, or USH3A, an autosomal recessive condition characterized by progressive loss of both hearing and vision, with post-lingual onset typically in the first decade of life. The company is developing an AAVAnc80 vector encoding a functional version of the CLRN1 gene and has generated nonclinical data in collaboration with Case Western Reserve University, demonstrating restoration of hearing in an animal model that recapitulates the auditory pathophysiology observed in humans. In addition to USH3A, other hereditary deaf-blind conditions could be treated with AAVAnc80-based gene therapies. In 2020, the company identified a product candidate for the AK-CLRN1 program. The next key milestone will be a pre-IND meeting with FDA. Autosomal Dominant Hearing Loss: The company is developing AAVAnc80 vectors encoding RNA interference sequences intended to knock down toxic gain-of-function and dominant negative mutations responsible for autosomal dominant hearing loss and the company is collecting nonclinical data on several potential targets. In February 2022, the company presented nonclinical data that showed, with both microRNA and CRISPR/Cas9 constructs, a reduction of protein expression for the target autosomal dominant hearing loss gene. The data showed no measurable decrease in the protein product of a codon-modified add-back target gene, suggesting that the microRNA and CRISPR/Cas9 constructs are selective for the intended endogenous sequence. The company continues to consider targets for autosomal dominant nonsyndromic hearing loss. Supporting Cell Targets The company is also leveraging its precision genetic medicine platform to address hearing loss related to genes needed for supporting cell function. GJB2: The company is conducting nonclinical studies in collaboration with researchers at University of Michigan and has observed that AAVAnc-mediated delivery of GJB2 (gap junction protein beta 2 gene) to supporting cells partially restored hearing in neonatal mouse models representing the spectrum of hearing loss observed in humans with GJB2-mediated hearing loss. In 2021, the company generated nonclinical data that describe multiple potential product candidate options. In February 2022, the company presented nonclinical data that demonstrated that a combination of AAVAnc80 and a supporting cell selective promoter can drive widespread GJB2 expression in supporting cells, while limiting expression in, and loss of, hair cells in mature cochleae in wild-type mice. The company continues to evaluate the most promising product candidate options in mice and non-human primates. Regeneration: The company is collaborating with the Bionics Institute to test the ability of AAVAnc to transduce supporting cells that could transdifferentiate into mature, functional hair cells. The company’s studies in non-human primates have suggested that the AAVAnc80 vector can transduce several supporting cell sub-types that could transdifferentiate into functional hair cells. The company is in the process of evaluating several development candidate leads to identify those with the potential to regenerate mature, functional hair cells in multiple animal models. AAVAnc gene therapy has the potential to restore hearing in individuals with a wide range of environmental hearing loss by regenerating hair cells from neighboring supporting cells. The company has identified multiple factors that, when delivered in combination, result in new hair cell formation in neonate mice, and the company plans to continue preclinical development work in 2022. Other Discovery Programs The company is evaluating additional hearing or deaf-blind conditions, and the company intends to continue to identify areas with high unmet need where its precision genetic medicine platform could potentially restore, improve, and preserve hearing. Intellectual Property As of December 31, 2021, the company owned nine U.S. pending non provisional patent application, 83 foreign pending patent applications, seven pending Patent Cooperation Treaty (PCT) applications, and seven pending U.S. provisional patent applications. The company had licenses to 30 granted U.S. and foreign patents and 50 pending U.S. and foreign patent applications covering its key programs and its pipeline. AK-OTOF The patent portfolio for the company’s AK-OTOF program is based upon its owned and in-licensed patent portfolio, which includes patents and patent applications directed generally to compositions of matter, pharmaceutical compositions, and methods of delivering and using the same to treat hearing loss resulting from OTOF mutations. The in-licensed patents and patent applications are subject to license agreements with the Massachusetts Eye and Ear Infirmary and The Schepens Eye Research Institute, Inc., which the company refers to collectively as MEE, and Lonza Houston, Inc., or Lonza. As of December 31, 2021, the company owned or in-licensed eight U.S. patents, 19 foreign patents, and 66 pending U.S., PCT, and foreign patent applications covering the company’s product candidate AK-OTOF, including methods of treatment of hearing loss resulting from OTOF mutations. Any U.S. or ex-U.S. patents that may issue from pending applications that the company controls, if any, for its hearing program, including the company’s lead product candidate AK-OTOF, are projected to have a statutory expiration date in between 2034 and 2041, excluding any additional term for patent term adjustments or patent term extensions, if applicable. AK-antiVEGF The patent portfolio for the company’s AK-antiVEGF program is based upon its owned and in-licensed patent portfolio, which includes patents and patent applications directed generally to compositions of matter, pharmaceutical compositions, and methods of delivering and using the same to treat vestibular schwannoma. The in-licensed patents and patent applications are subject to license agreements with MEE and Lonza. As of December 31, 2021, the company owned or in-licensed seven U.S. patents, 13 foreign patents, and 57 pending U.S., PCT, and foreign patent applications covering the company’s vestibular schwannoma product candidate, including methods of the treatment of vestibular schwannoma. Any U.S. or ex-U.S. patents that may issue from pending applications that the company controls, if any, for its hearing program, including the company’s product candidate for vestibular schwannoma, are projected to have a statutory expiration date in between 2034 and 2041, excluding any additional term for patent term adjustments or patent term extensions, if applicable. Trademark Protection As of December 31, 2021, the company held 13 U.S. trademark applications, 104 foreign trademark applications, and 43 foreign trademark registrations for the marks ‘Akouos’, the Akouos logo, ‘Resonate’, the Resonate by Akouos logo, ‘The Sing Registry’, and the Sing logo in connection with the company’s biological products and related services. Licensed Intellectual Property Massachusetts Eye and Ear License In October 2017, the company entered into a License Agreement with MEE, or the MEE License, under which the company received an exclusive, non-transferable, sublicensable, worldwide, royalty-bearing license to certain patent rights and know-how, including rights related to AAVAnc-, including AAVAnc80, to research, develop, make, have made, manufacture, use, sell, offer to sell, import, export, market, promote, distribute, register and otherwise commercially exploit licensed products in the treatment, diagnosis, prevention, and palliation of any and all balance disorders or diseases pertaining to the inner ear and/or any and all hearing diseases or disorders, in each case, with a total prevalence in the United States of less than 3,000 patients; and an exclusive, non-transferable, sublicensable, worldwide, royalty bearing license under MEE’s rights, title and interest in certain patents co-owned by MEE and Children’s Medical Center Corporation, or BCH, to research, develop, make, have made, manufacture, use, sell, offer to sell, import, export, market, promote, distribute, register and otherwise commercially exploit licensed products in the treatment, diagnosis, prevention, and palliation of any and all balance disorders or diseases pertaining to the inner ear and/or any and all hearing diseases or disorders, including but not limited to, those with a total prevalence in the United States of less than 3,000 patients. Lonza Houston, Inc. Sublicense In October 2017, the company entered into a Sublicense Agreement with Lonza, or the Lonza Sublicense, as amended on December 11, 2018, under which the company received an exclusive, nontransferable, sublicensable, worldwide, royalty-bearing sublicense to certain MEE patent rights and knowhow related to AAV ancestral technology, including AAVAnc80, to research, develop, make, have made, manufacture, use, sell, offer to sell, import, export, market, promote, distribute, register and otherwise commercially exploit licensed products for the treatment, diagnosis, prevention, and palliation of any and all balance disorders or diseases pertaining to the inner ear and/or any and all hearing diseases or disorders, but excluding all such disorders or diseases with a total prevalence in the United States of less than 3,000 patients. The company is obligated to use commercially reasonable efforts to develop and commercialize the Lonza sublicensed products, including filing an IND or Investigational Medicinal Product Dossier in any country in the European Union or an equivalent application in any country within 18 months of the completion of GLP toxicology studies for a licensed product. Government Regulation In the United States, the company’s product candidates are regulated as biological products, or biologics, under the Public Health Service Act, or PHSA; and the Federal Food, Drug and Cosmetic Act, or FDCA and its implementing regulations and guidance. Research and Development The company’s research and development expenses were $64.6 million for the year ended December 31, 2021. History Akouos, Inc. was founded in 2016. The company was incorporated under the laws of the Commonwealth of Massachusetts in 2016.