Voyager Therapeutics(VYGR) - 2022 Q4 - Annual Report

Forward-Looking Statements This section outlines the nature and inherent risks of forward-looking statements within the report, covering strategy, operations, and financial projections Content and Caveats of Forward-Looking Statements The report contains forward-looking statements on strategy, operations, and financial position, subject to risks that could cause actual results to differ materially - The report contains forward-looking statements about strategy, future operations, financial position, revenue, costs, prospects, plans, objectives, and market growth[12] - Key areas of forward-looking statements include plans for AAV gene therapy and proprietary antibody development, advancement of TRACER™ discovery platform, identification of product candidates and AAV capsids, strategic collaborations (Neurocrine, Pfizer, Novartis), preclinical development timelines, ability to secure future collaborations, timing of regulatory approvals (INDs), estimates for expenses, revenues, and capital requirements, intellectual property protection, market size estimates, need for additional funding, competitive landscape, impact of government regulations, and cost control initiatives[13] - Readers are cautioned not to place undue reliance on forward-looking statements, as actual results or events could differ materially due to important factors, particularly those detailed in 'Part I, Item 1A - Risk Factors'[15] Risk Factor Summary This section summarizes the principal risks facing the company, including financial challenges, development uncertainties, and operational dependencies Principal Risks Facing the Business This section provides a summary of the principal risks facing the company, including a history of significant losses, the need for additional funding, and challenges in developing novel AAV gene therapies - The company has a history of significant losses and expects to continue incurring losses, potentially never achieving consistent profitability[19] - Additional funding will be required, and failure to secure it on acceptable terms could force delays or termination of product development efforts[19] - Development of AAV gene therapy product candidates is based on proprietary technology and unvalidated treatment approaches, making development duration and cost difficult to predict[19] - Regulatory requirements for gene and cell therapy products are frequently changing, potentially lengthening review processes, requiring study modifications, or increasing development costs[19] - All active product candidates are in preclinical development, facing potential delays or failures in studies, or inability to demonstrate safety and efficacy for regulatory approval[19] - Product candidates or administration processes may cause undesirable side effects, delaying approval or limiting commercial potential[19] - Significant competition exists in a rapidly changing technological environment, with competitors potentially achieving regulatory approval or developing more effective therapies sooner[21] - All revenue to date has been from collaborations (Neurocrine, Pfizer, Novartis, and prior partners); termination of these agreements could harm the business[21] - Gene therapies are complex and difficult to manufacture, with potential manufacturing problems causing development or commercialization delays[21] - Future success depends on retaining key management and R&D teams, and attracting qualified personnel[21] - Gene therapy and vectorized antibody approaches use virus-derived vectors, which may be perceived as unsafe, leading to negative public opinion and increased regulatory scrutiny[21] - Inability to obtain and maintain broad patent protection could allow competitors to develop similar products, adversely affecting commercialization[21] PART I. This part provides a comprehensive overview of the company's business, including its strategy, pipeline, collaborations, competition, manufacturing, intellectual property, and regulatory environment, along with detailed risk factors ITEM 1. Business Voyager Therapeutics is a biotechnology company focused on developing AAV gene therapies and other biological therapies for neurological diseases, leveraging its proprietary TRACER™ capsid discovery platform - Voyager Therapeutics is a biotechnology company focused on AAV gene therapy and neurology, addressing delivery challenges through capsid discovery and neuropharmacology expertise[23] - The proprietary TRACER™ (Tropism Redirection of AAV by Cell Type-Specific Expression of RNA) discovery platform uses directed evolution to identify AAV capsids with enhanced tissue delivery, including across the blood-brain barrier (BBB), aiming for improved efficacy and safety of single-dose gene therapies[24] - Wholly-owned prioritized pipeline programs include SOD1 gene therapy for ALS and an anti-tau antibody for Alzheimer's disease, with IND filings expected in 2024[25] - Collaborative programs with Neurocrine include GBA1 gene therapy for Parkinson's disease and FXN gene therapy for Friedreich's ataxia[25] - The company's strategy includes continuously advancing its AAV gene therapy platform, optimizing pipeline programs with next-generation capsids, partnering to maximize opportunities, retaining commercialization rights for select programs, and expanding its intellectual property portfolio[26][31] - AAV gene therapy is favored for broad applicability, safety (not known to cause human disease), non-integration into the genome (reducing oncogenesis risk), scalability, validated targets in neurological diseases, targeted delivery with TRACER capsids, and potential for durable expression with one-time dosing[32] Company Overview, Mission and Strategy Voyager Therapeutics is a biotechnology company focused on developing gene therapies for neurological diseases, utilizing its proprietary TRACER™ capsid discovery platform to advance life-changing treatments - Voyager Therapeutics is a biotechnology company dedicated to breaking barriers in gene therapy and neurology, focusing on delivery challenges using capsid discovery and neuropharmacology[23] - The company's proprietary TRACER™ (Tropism Redirection of AAV by Cell Type-Specific Expression of RNA) discovery platform facilitates the selection of AAV capsids with enhanced tissue delivery, including across the blood-brain barrier (BBB), for single-dose gene therapies[24] - Current wholly-owned prioritized pipeline programs include SOD1 gene therapy for ALS and an anti-tau antibody for Alzheimer's disease, with IND filings anticipated in 2024[25] - Collaborative programs with Neurocrine include GBA1 gene therapy for Parkinson's disease and FXN gene therapy for Friedreich's ataxia[25] - The company's strategy involves continuous advancement of its AAV gene therapy platform, optimizing gene therapy programs with next-generation AAV capsids, partnering to maximize pipeline opportunities, retaining commercialization rights for select programs, and expanding its intellectual property portfolio[26][31] - AAV gene therapy is considered ideal due to its broad applicability to various cell types (including CNS), safety profile (not known to cause human disease), low integration into the genome (reducing oncogenesis risk), scalability for manufacturing, ability to target validated genetic mutations, enhanced targeted delivery with TRACER capsids, and potential for durable expression from one-time dosing[32] AAV Gene Therapy Platform Voyager's gene therapy platform focuses on identifying suitable diseases, engineering AAV vectors, and optimizing delivery methods, with the TRACER™ capsid discovery platform central to enhanced tissue delivery - The Voyager Gene Therapy Platform involves identifying diseases suitable for AAV gene therapy, engineering and optimizing AAV vectors (capsid, therapeutic gene, promoter), and optimizing delivery methods[34] - Disease selection is based on high unmet medical need, target validation, efficient path to human proof of biology, robust preclinical pharmacology, and strong commercial potential[35] - Vector engineering and optimization involve selecting or engineering AAV capsids (including TRACER capsids), therapeutic genes, and payload control elements for specific programs[36] - The TRACER™ capsid discovery platform facilitates selection of capsids with enhanced BBB-crossing and cell-specific transduction properties in multiple species, including non-human primates, aiming for enhanced gene delivery at lower doses with fewer safety issues[37] - TRACER capsids are being made available to third parties through potential option and license arrangements, with Voyager retaining all associated rights except those specific to the licensee's transgenes or programs[38] Collaboration and License Agreements Overview Voyager has established key collaboration and license agreements with Neurocrine, Pfizer, Novartis, and Touchlight IP Limited, focusing on AAV gene therapies and TRACER capsids - In January 2019, Voyager entered into a collaboration with Neurocrine (2019 Neurocrine Collaboration Agreement) for research, development, and commercialization of AAV gene therapy products, initially covering four programs including the Friedreich's ataxia (FA) Program and two undisclosed discovery programs[39][41] - The VY-AADC Program under the 2019 Neurocrine Collaboration Agreement was terminated in August 2021[41] - On January 8, 2023, Voyager entered into a new collaboration and license agreement with Neurocrine (2023 Neurocrine Collaboration Agreement) for GBA1 gene therapy for Parkinson's disease and three new CNS disease programs, effective February 21, 2023[42] - In October 2021, Voyager entered an option and license agreement with Pfizer, granting options for exclusive licenses to TRACER capsids for AAV gene therapy candidates with specified Pfizer transgenes[43] - In March 2022, Voyager entered an option and license agreement with Novartis, granting options to license TRACER capsids for exclusive use with certain targets[44] - In November 2022, Voyager and Touchlight IP Limited entered a license agreement for historical use of a DNA preparation process and prospective exploitation of TRACER capsids created with it[45] Overview of Our Pipeline Voyager's preclinical pipeline leverages its TRACER discovery platform and proprietary antibodies to develop AAV gene therapies and passive/vectorized payloads for neurological and other diseases - Voyager's pipeline utilizes the TRACER discovery platform, proprietary antibodies, and vectorized antibody platform to develop AAV gene therapies and passive/vectorized payloads[46] - The goal is to address underlying causes or predominant manifestations of specific diseases by significantly increasing or decreasing relevant protein expression in targeted tissues[46] Pipeline Programs (Preclinical Development) | Program (Mechanism) | Ownership | Stage | | :-------------------------------------------------------------------------------- | :------------------------ | :------------ | | ALZHEIMER'S DISEASE: Passive Tau Antibody | Wholly-Owned | IND-Enabling | | FRIEDREICH'S ATAXIA: FXN Gene Therapy (Gene Replacement) | Neurocrine Collaboration | IND-Enabling | | ALS: SOD1 Gene Therapy (Gene Silencing) | Wholly-Owned | IND-Enabling | | PARKINSON'S / OTHERS: GBA1 Gene Therapy (Gene Replacement) | Neurocrine Collaboration | IND-Enabling | | EARLY RESEARCH PROGRAMS: Allele-specific mHTT+MSH3 gene silencing for HD: Tau gene silencing for Alzheimer's; vHER2 antibody for brain mets | Wholly-Owned | Early Research | | UNDISCLOSED DISEASES: Five Gene Therapy Programs | Neurocrine Collaboration | Late Research | | RARE NEUROLOGICAL DISEASE: Gene Therapy | Pfizer License | Late Research | | CNS DISEASES: Two Gene Therapy Programs | Novartis License | Late Research | Anti-Tau Antibody Program for the Treatment of Alzheimer's Disease Voyager is developing proprietary anti-tau antibodies, specifically VY-TAU01, for Alzheimer's disease and other tauopathies, with an IND filing expected in the first half of 2024 - Voyager is developing proprietary anti-tau antibodies to selectively target and reduce the spread of pathological tau for Alzheimer's disease (AD) and other tauopathies[48][49] - The lead candidate, VY-TAU01, targets the C-terminal domain of tau and was selected for its affinity, selectivity, and biophysical characteristics[52] - Preclinical studies in a P301S seeding-propagation tauopathy mouse model demonstrated that the C-terminal targeting anti-tau antibody blocked seeding/propagation and substantially reduced induced tau pathology[50][51] - Process development and manufacturing have begun, with a GLP toxicology study expected to initiate later in 2023, enabling an IND filing in the first half of 2024[52] Friedreich's Ataxia Program: VY-FXN01 (2019 Neurocrine Collaboration) Under the 2019 Neurocrine Collaboration, Voyager is developing VY-FXN01, an AAV gene therapy for Friedreich's ataxia, aiming to restore frataxin protein levels via intravenous injection - Friedreich's ataxia is a debilitating neurodegenerative disease caused by FXN gene mutations, leading to reduced frataxin protein; restoring FXN levels to at least 50% is believed to be a successful therapeutic approach[53][54] - Voyager is developing an AAV gene therapy (VY-FXN01) to deliver a functional FXN gene to sensory pathways via intravenous injection, aiming to improve balance, walking ability, sensation, coordination, and strength[55] - Preclinical studies in non-human primates demonstrated high FXN expression in sensory ganglia and the heart following IV injection, with expression levels in the brain exceeding control human brain tissue[56] - In a genetic mouse model of Friedreich's ataxia, gene therapy candidates durably improved sensory function and rescued the disease phenotype for over 10 months after a single administration[59] - The program, in collaboration with Neurocrine, is identifying a lead candidate, evaluating TRACER capsids for enhanced transduction, and optimizing the promoter for an acceptable therapeutic index, with IND-enabling studies planned[57][59] SOD1 Gene Silencing Program for the Treatment of ALS Voyager is developing a gene silencing therapy for SOD1-mutated ALS, using an intravenously administered AAV gene therapy with a BBB-penetrant TRACER capsid to broadly knock down SOD1 expression - Voyager is developing a gene therapy for SOD1-mutated ALS, a fatal neurodegenerative disease affecting approximately 800 patients in the U.S., using a gene silencing approach[60] - The treatment aims to deliver a vectorized siRNA construct via intravenous AAV gene therapy with a BBB-penetrant, CNS-tropic TRACER capsid to achieve broad CNS knockdown of SOD1[61] - Preclinical data demonstrated robust SOD1 knockdown across the spinal cord and significant improvements in motor performance, body weight, and survival in an SOD1-ALS mouse model[62] - The program is currently selecting a TRACER capsid with BBB-penetration activity in NHP studies for a lead candidate vector[63] GBA1 Gene Replacement Program for the Treatment of Parkinson's Disease (2023 Neurocrine Collaboration) Under the 2023 Neurocrine Collaboration, Voyager is developing a GBA1 gene replacement therapy for Parkinson's disease, aiming to restore Gcase activity via intravenous AAV gene therapy with a BBB-penetrant TRACER capsid - Voyager is developing a GBA1 gene replacement therapy for Parkinson's disease and other GBA1-linked diseases, leveraging a BBB-penetrant, CNS-tropic TRACER capsid[64][66] - Mutations in GBA1 are the most common genetic risk factor for Parkinson's disease, affecting up to 10% of patients and increasing risk by approximately 20-fold[66] - The treatment approach aims to restore Gcase activity via intravenous AAV gene therapy for widespread brain distribution, potentially slowing neurodegeneration[67] - Preclinical data demonstrated CNS target engagement and delivery of therapeutically relevant Gcase levels in a GBA1 loss-of-function mouse model, with sustained expression for over three months[68] - The GBA1 Program, under the 2023 Neurocrine Collaboration, is in preclinical development, identifying a lead candidate vector comprising a TRACER capsid, promoter, and transgene[69] Early Research Programs Voyager's early research includes gene therapy for Huntington's disease and Alzheimer's, and a vectorized antibody for brain metastases from breast cancer - An updated early research initiative for Huntington's disease combines an intravenous TRACER capsid with vectorized siRNAs for specific knockdown of mHTT and MSH3[70] - Another early research initiative investigates a gene therapy targeting intracellular tau for Alzheimer's disease, using an siRNA tau knockdown payload with an intravenously delivered TRACER capsid[71] - A wholly-owned early research program explores a vectorized antibody against HER2 for treating brain metastases from metastatic breast cancer, demonstrating inhibition of proliferation and promotion of antibody-dependent cell cytotoxicity in preclinical data[72] Pfizer Option and License Agreement Voyager's October 2021 agreement with Pfizer granted options for exclusive licenses to TRACER capsids, with Pfizer exercising one option for a rare neurological disease in September 2022, triggering a $10.0 million payment and future milestones - Voyager granted Pfizer options for exclusive licenses to TRACER capsids for AAV gene therapy candidates with specified Pfizer Transgenes for CNS and cardiovascular diseases[73] - Pfizer exercised one option on September 30, 2022, for a capsid for a rare neurological disease, extending the research term to October 1, 2024, during which Voyager may conduct additional research for proprietary capsids[75] - Pfizer is solely responsible for the development and commercialization of the Pfizer Licensed CNS Products, with requirements to use commercially reasonable efforts to obtain regulatory approval and commercialize in the U.S. and at least one Pfizer Major Market Country[77] Pfizer Agreement Financial Terms | Payment Type | Amount | | :------------- | :----- | | Upfront Payment | $30 million | | Option Exercise Payment | $10 million (for rare neurological disease) | | Development, Regulatory, Commercialization Milestones | Up to $115 million (first product) | | Sales Milestones | Up to $175 million (per product) | | Royalties | Mid- to high-single-digit percentages of annual net sales (tiered, escalating) | - The agreement includes exclusivity clauses preventing Voyager from developing or licensing competing products with Pfizer Transgenes and provisions for termination by either party, with specific conditions for license irrevocability and payment reductions upon certain for-cause terminations by Pfizer[80][82][83] Novartis Option and License Agreement Voyager's March 2022 agreement with Novartis granted options to license TRACER capsids, with Novartis exercising options for two targets in March 2023, triggering a $25.0 million payment and future milestones - Voyager granted Novartis options to license TRACER capsids for exclusive use with certain targets to develop AAV gene therapy candidates[84] - Novartis received a non-exclusive research license to evaluate TRACER capsids for three Initial Novartis Targets during the Novartis Research Term, with the option to assess up to two Additional Novartis Targets[85] - Upon exercise of a Novartis License Option, Voyager grants Novartis a target-exclusive, worldwide license, with Novartis responsible for development and commercialization of Novartis Licensed Products[86][90] - Effective March 1, 2023, Novartis exercised options for two undisclosed Initial Novartis Targets, triggering a $25.0 million option exercise payment to Voyager and eligibility for potential development, regulatory, and commercial milestone payments, plus mid-to-high single-digit tiered royalties[87][92] - Novartis retains the right to expand the agreement to include options for up to two Additional Novartis Targets for a fee of $18.0 million per target, with further milestone and royalty potential[87][92] - The agreement includes exclusivity clauses and termination provisions, with the licenses becoming irrevocable and perpetual with reduced payments upon certain for-cause terminations by Novartis[94][96][97][98] Neurocrine Collaborations Voyager has two collaboration agreements with Neurocrine, covering the FA Program, GBA1 Program, and several discovery programs, with Neurocrine funding early-stage R&D and Voyager retaining co-development options - The 2019 Neurocrine Collaboration Agreement covers the FA Program and two 2019 Discovery Programs, with Voyager having operational responsibility prior to specified 'Transition Events' and Neurocrine funding costs[99][102][105] - Voyager has a 2019 Co-Co Option for the FA Program, allowing co-development and co-commercialization in the U.S. with a 60/40 cost- and profit-sharing arrangement (Neurocrine/Voyager)[105][106] 2019 Neurocrine Collaboration Financial Terms | Payment Type | Amount | | :------------- | :----- | | Upfront Payment | $115.0 million | | Equity Purchase | $50.0 million (4,179,728 shares) | | Development Milestones (FA Program) | Up to $195.0 million | | Development Milestones (Each 2019 Discovery Program) | Up to $130.0 million | | Commercial Milestones (Each 2019 Collaboration Product) | Up to $275.0 million (aggregate cap $1.1 billion) | | Royalties (FA Program, US) | Low-teens to high-teens | | Royalties (FA Program, ex-US) | High-single digits to mid-teens | | Royalties (Each 2019 Discovery Program, US) | High-single digits to mid-teens | | Royalties (Each 2019 Discovery Program, ex-US) | Mid-single digits to low-teens | - The 2023 Neurocrine Collaboration Agreement, effective February 21, 2023, covers the GBA1 Program and three 2023 Discovery Programs, with Voyager responsible for identifying capsids, producing candidates, and non-clinical activities, funded by Neurocrine[119][120][121] - Voyager has a 2023 Co-Co Option for the GBA1 Program, allowing co-development and co-commercialization in the U.S. with a 50/50 cost- and profit-sharing arrangement, subject to repayment of Neurocrine's prior development costs from Voyager's profit share[122][124] 2023 Neurocrine Collaboration Financial Terms | Payment Type | Amount | | :------------- | :----- | | Upfront Payment | ~$136.0 million | | Equity Purchase | ~$39.0 million (4,395,588 shares) | | Development Milestones (GBA1 Program) | Up to $985.0 million | | Development Milestones (Each 2023 Discovery Program) | Up to $175.0 million | | Commercial Milestones (GBA1 Program, up to two products) | Up to $950.0 million (per product) | | Commercial Milestones (Each 2023 Discovery Program, one product) | Up to $275.0 million (per product) | | Royalties (GBA1 Program, US) | Low double-digits to twenty | | Royalties (GBA1 Program, ex-US) | High single-digits to mid-teens | | Royalties (Each 2023 Discovery Program, US) | High single-digits to mid-teens | | Royalties (Each 2023 Discovery Program, ex-US) | Mid-single digits to low double-digits | - The 2023 Neurocrine Amended and Restated Investor Agreement includes standstill, lock-up restrictions, and a voting agreement for Neurocrine's shares, and appointed Jude Onyia, Ph.D., CSO of Neurocrine, to Voyager's board of directors[139][140][141] License Agreement with Touchlight IP Limited In November 2022, Voyager entered a license agreement with Touchlight IP Limited, authorizing historical use of a DNA preparation process and prospective exploitation of TRACER capsids, involving a $5.0 million technology access fee and future milestones/royalties - Voyager and Touchlight IP Limited entered a license agreement in November 2022 to authorize historical use of a DNA preparation process and prospective exploitation of TRACER capsids created with it[144] - A one-time, non-refundable technology access fee of $5.0 million was paid to Touchlight in Q4 2022[145] - Future milestone payments and low single-digit royalties are payable to Touchlight if Voyager or its collaborators/licensees utilize these TRACER capsids in therapeutic products or in connection with licensing to third parties (excluding Voyager's own therapeutic programs)[146] Competition The biopharmaceutical industry is highly competitive, with Voyager facing numerous larger, better-funded companies and academic institutions developing AAV gene therapies and other treatments - The biopharmaceutical industry is characterized by intense and dynamic competition from larger, better-funded pharmaceutical, specialty pharmaceutical, and biotechnology companies, as well as academic and research institutions[147] - Voyager's TRACER discovery platform and preclinical programs face competition from companies developing AAV capsids (e.g., 4D Molecular Therapeutics, Dyno Therapeutics)[153] - Specific program competition includes: GBA1 mutations (Prevail Therapeutics, Pfizer, Biogen), tauopathies (Roche Genentech, Eli Lilly, Biogen), monogenic ALS (Biogen, Novartis Gene Therapies), and Friedreich's ataxia (LEXEO Therapeutics, PTC, Pfizer, Novartis Gene Therapies)[153] - Competitors often have substantially greater financial, technical, and human resources, potentially leading to faster approvals, more effective products, or stronger market positions, which could harm Voyager's business[149][152] Manufacturing Gene therapy manufacturing is technically complex, and Voyager relies on third-party contract manufacturers for program materials, maintaining internal oversight and process R&D capabilities - Gene therapy manufacturing is technically complex, requiring substantial expertise and capital investment, with potential production difficulties causing delays[155] - Voyager has a proprietary manufacturing platform for scalable AAV production, using HEK 293 cells for preclinical research and baculovirus/Sf9 AAV production system for clinical development[155] - Both manufacturing processes have been successfully transferred to contract manufacturing organizations (CMOs), with the baculovirus/Sf9 process used for cGMP-compliant clinical materials[155] - The company relies on third parties for manufacturing program materials, with no current plans to build its own clinical or commercial scale manufacturing capabilities, but maintains personnel for oversight[156] Intellectual Property Voyager protects its proprietary technology, inventions, and know-how through patents, trade secrets, and in-licensing, aiming for an industry-leading intellectual property portfolio - Voyager protects its proprietary technology, inventions, and know-how through patents, trade secrets, and in-licensing, aiming for an industry-leading intellectual property portfolio[157][158][161] - The company owns at least 54 issued patents and 390 pending patent applications, and co-owns at least 10 issued patents and 43 pending applications in the U.S. and foreign jurisdictions[159] - The patent portfolio covers AAV constructs for Parkinson's (AADC), Huntington's (HTT), ALS (SOD1, C9orf72), Friedreich's ataxia (frataxin), GBA1 gene therapy, vectorized antibodies, tauopathies, vectorized anti-HER2, regulatable expression, and delivery systems (cannula, V-TAG®)[162][163][164][165][166][167][168][169][170][171][172][173] - TRACER discovery platform and identified capsid variants are protected by two pending patent families (10 applications) and four pending patent families (34 applications), respectively, with expected expiration dates in the 2039-2043 range[174] - Voyager has licensed patent rights and technology from third parties, including the University of Massachusetts (RNAi constructs, AAV capsids), Ablexis, LLC (AAV capsids), and California Institute of Technology (AAV capsids), and the University of Pennsylvania (microRNA detargeting)[181][182][183][184][185][187][188] - Trademark registrations include VOYAGER THERAPEUTICS, V-TAG, and TRACER for pharmaceutical R&D, gene therapy preparations, and platform technologies[189][190] - Trade secrets are protected through confidentiality agreements with employees, consultants, and partners, along with physical and electronic security measures[191] Government Regulation The company's operations are extensively regulated by governmental authorities in the U.S. and other countries, covering all stages from research and development to commercialization, with evolving requirements impacting product development and market access - The research, development, testing, manufacture, and commercialization of biological products are extensively regulated by governmental authorities in the U.S. (FDA, CBER, OTAT) and other countries[192][194][214] - The U.S. biological product development process includes preclinical studies (GLP), IND/IRB processes, human clinical trials (Phase 1, 2, 3, 4) conducted under GCP, cGMP manufacturing, BLA submission and review, and post-approval requirements (e.g., REMS, post-approval studies)[195][196][197][198][199][200][201][203][204][205][206][207][208][209][210][211][212][218][219][220][221][222][224][225][226][227][228][229][230][231] - Gene therapy products are subject to specific FDA guidance, including recommendations for long-term follow-up (up to five years for AAV vectors) for potential adverse events[215] - Expedited review programs (Fast Track, Breakthrough Therapy, Priority Review, Accelerated Approval, Regenerative Advanced Therapy) are available but do not guarantee faster development or approval[233][238] - Orphan Drug Designation provides market exclusivity (7 years in U.S., 10 years in EU) for rare diseases, but its scope and 'sameness' criteria are subject to regulatory interpretation and potential challenges[236][237][239][240][241][242] - The Biologics Price Competition and Innovation Act (BPCIA) established an abbreviated pathway for biosimilars, granting reference biologics 12 years of data exclusivity[243][244] - The company is subject to federal and state healthcare laws (Anti-Kickback Statute, False Claims Act, HIPAA, Physician Payments Sunshine Act) and healthcare reform measures (ACA, IRA) that aim to control costs and impact pricing and reimbursement, potentially leading to reduced demand or pricing pressures[246][247][248][249][250][251][252][253][254][255][256][257][258][259][260] - Operations outside the U.S. are subject to foreign regulatory requirements, including clinical trial applications (e.g., EU CTR), marketing approvals, price controls, and compliance with laws like the U.S. Foreign Corrupt Practices Act (FCPA)[264][265][266][246][498][499][500][501][502][503][504] Corporate Information and Employees Voyager Therapeutics, incorporated in Delaware in June 2013, maintains its principal offices in Cambridge, Massachusetts, and employed 125 full-time employees as of December 31, 2022, with 94 in research and development - Voyager Therapeutics was incorporated in Delaware in June 2013, with principal executive offices in Cambridge, Massachusetts, and laboratory space in Lexington, MA[267] - As of December 31, 2022, the company employed 125 full-time employees in the U.S., including 94 in research and development positions[268] - The company's human capital objectives include identifying, recruiting, retaining, incentivizing, and integrating employees, primarily through equity incentive plans[269] ITEM 1A. Risk Factors This section details significant risks that could materially and adversely affect Voyager Therapeutics' business, financial condition, results of operations, and future growth prospects - Investment in Voyager's securities involves significant risks and uncertainties, which are detailed to inform evaluation of the business[271] - The risks are categorized into several areas: financial position and capital needs, development and regulatory approval of product candidates, reliance on third parties, manufacturing, business operations, commercialization, intellectual property, and ownership of common stock[271] - Additional risks not currently known or deemed less significant may also impair business operations[271] Risks Related to Our Financial Position and Need for Capital Voyager has a history of significant operating losses and an accumulated deficit of $393.5 million, requiring substantial additional funding to advance its pipeline and achieve profitability - Voyager has a history of significant operating losses, with net losses of $46.4 million in 2022 and $71.2 million in 2021, and an accumulated deficit of $393.5 million as of December 31, 2022[272] - The company anticipates continued significant expenses and operating losses for the foreseeable future, as all product candidates are in early stages of development[272][274] - Expenses are expected to increase substantially with preclinical and clinical development, investment in gene therapy platforms (TRACER™), strategic collaborations (Neurocrine), manufacturing, regulatory approvals, intellectual property, and public company operations[275][278] - The company will need to raise substantial additional funding, which may not be available on acceptable terms, potentially forcing delays or termination of product development[284][289] - As of December 31, 2022, cash, cash equivalents, and marketable securities were $118.8 million, expected to fund operations into 2025 with anticipated collaboration payments[285] - Raising additional capital through equity or equity-linked securities may dilute stockholders' ownership interests and could include liquidation preferences or restrictive covenants if debt financing is used[290] - The early preclinical stage of development makes it difficult to evaluate business success and future viability, with significant fluctuations in financial condition and operating results expected[294][296] Risks Related to the Development and Regulatory Approval of Our Product Candidates Developing and obtaining regulatory approval for Voyager's novel AAV gene therapy product candidates is a difficult, expensive, and uncertain process, with all active candidates currently in preclinical development and subject to evolving regulatory requirements - AAV gene therapies are a relatively new technology, making it difficult to predict the effectiveness, safety, and regulatory approval timeline or cost for product candidates[297][298][299][302] - Regulatory requirements for gene and cell therapy products frequently change, potentially lengthening the review process, requiring additional studies, or increasing development costs[303][305][306][308][309] - All active product candidates are in preclinical development, and the company may face substantial delays or difficulties in commencing, enrolling, or completing studies, or fail to demonstrate safety and efficacy[315][316][318][319][320][321][322][323][324][325][326][327][328][329] - Product candidates or their administration may cause undesirable side effects (e.g., immunologic reactions, insertional oncogenesis), which could delay or prevent regulatory approval or limit commercial potential[330][334][335][336][337] - Orphan drug designation or exclusivity may not be obtained, or competitors could obtain exclusivity for similar products, limiting market opportunities[338][339][340][342][343][344][345][346][348] - Breakthrough therapy, regenerative medicine advanced therapy, fast track, or priority review designations do not guarantee faster development, regulatory review, or marketing approval[349][350][351][352][354][355][356] - The marketing approval process is expensive, time-consuming, and uncertain; failure or delays in obtaining approvals would materially impair revenue generation[357][358][359][360][361][362] - Even after regulatory approval, products remain subject to ongoing regulatory oversight, including manufacturing, labeling, advertising, and post-market studies, with non-compliance leading to sanctions[363][364][365][367][368][369] - Conducting clinical trials outside the United States introduces risks, including non-acceptance of data by the FDA, differing regulatory requirements, and political/economic instability[313][314][315][374][375][376][377][379] - Approved biologics may face competition from biosimilars through abbreviated regulatory pathways, potentially impacting business due to increased competition and pricing pressure[380][381] Risks Related to Third Parties Voyager's revenue is entirely dependent on collaborations, and the termination or unsatisfactory performance of these agreements or third-party service providers could significantly harm the business - All of Voyager's revenue to date has been derived from collaborations with Neurocrine, Pfizer, Novartis, and prior partners; termination of these agreements would harm the business[382][383] - The termination of the VY-AADC Program by Neurocrine in 2021 resulted in loss of reimbursement and future milestone/royalty eligibility for that program[384][386] - Pfizer's partial exercise of its option means Voyager is no longer eligible for payments related to the cardiovascular disease target[387] - Novartis's partial exercise of its option means Voyager is no longer eligible for payments related to one Initial Novartis Target[388] - Collaborators may not successfully obtain approvals, commercialize products, or may halt/slow development, potentially taking actions adverse to Voyager's interests[389][393][395] - Voyager relies on third parties (CROs, clinical trial sites, vendors) to conduct preclinical studies and clinical trials; unsatisfactory performance by these parties could harm the business[401][402][403][404][405] - Failure of third-party service providers to comply with GLPs or GCPs could render preclinical or clinical data unreliable, requiring additional studies and delaying regulatory approval[402][403][404] Risks Related to Manufacturing Manufacturing gene therapy products is complex and difficult, with reliance on third-party contract manufacturers posing risks of delays, supply disruptions, and non-compliance with cGMP requirements - Gene therapies are novel, complex, and difficult to manufacture, requiring substantial expertise and capital investment, with potential production difficulties causing delays[406] - Voyager relies on third-party contract manufacturers for program materials, and any failure to adhere to cGMP requirements could lead to sanctions, delays, or interruptions in supply[407][410] - Biological products are inherently difficult to manufacture, requiring specialized equipment, facilities, and raw materials from limited suppliers, posing risks of shortages, contamination, or technical issues[411][417][418] - Delays in obtaining regulatory approval for manufacturing processes and facilities, or disruptions in these processes, could delay commercialization efforts[412] - Failure to comply with ongoing regulatory requirements (cGMP) could result in production suspension or costly remedial measures[413][415] - Inability to obtain access to or protect intellectual property related to manufacturing could lead to changes, delays, or inability to manufacture products[419][420] Risks Related to Our Business Operations Voyager's future success depends on identifying new product candidates, retaining key personnel, managing growth, mitigating misconduct risks, and navigating evolving healthcare legislation impacting pricing and reimbursement - Voyager may not be successful in identifying or discovering additional product candidates and could fail to capitalize on greater commercial opportunities due to limited resources[421][422][423] - Future success is highly dependent on retaining key management and R&D teams, and attracting qualified personnel in a competitive biotechnology industry[424][425][427] - Inability to manage expected growth in operational scale and complexity could negatively impact performance, requiring expansion of managerial, operational, and financial systems[428] - The company is exposed to risks of misconduct by employees, principal investigators, consultants, and commercial partners, including non-compliance with regulatory standards and insider trading, which could lead to sanctions or reputational harm[429] - Current and future legislation (e.g., ACA, IRA) and executive actions may increase the difficulty and cost of obtaining marketing approval, restrict post-approval activities, and affect product pricing and reimbursement, particularly in Medicare Part B and D[430][431][432][433][434][435][436][437][438][439][440][441][442][443][445][446][447][448][449] - The company is subject to stringent privacy and information security laws (HIPAA, CCPA, CPRA, GDPR) globally, with non-compliance potentially leading to significant fines, penalties, litigation, and reputational damage[456][457][458][459][460][461][462][463][464][465] Risks Related to the Commercialization of Our Product Candidates The commercial success of Voyager's product candidates is uncertain, depending on patient populations, market acceptance, adequate insurance coverage, and reimbursement, while facing risks from public opinion and international commercialization challenges - The affected populations for product candidates may be smaller than projected, impacting addressable markets due to factors like diagnosis criteria, medical community acceptance, patient access, pricing, and reimbursement[472][473] - Inability to establish sales, medical affairs, and marketing capabilities or enter into agreements with third parties would prevent generation of product revenue[474][478] - The cost of gene therapy products is expected to be substantial, making adequate insurance coverage and reimbursement by government and private payors essential for market acceptance[480] - Obtaining coverage and reimbursement is a time-consuming and costly process, with no uniform policy among third-party payors, and approved reimbursement amounts may be inadequate[482][483][484][485][487][488][489][490] - Ethical, social, and legal concerns about gene therapy, including negative public opinion or unforeseen adverse events, could result in additional regulations or damage public perception, adversely affecting business and regulatory approvals[494][495][496][497] - Commercializing products outside the U.S. (e.g., UK, EU) involves additional risks such as differing regulatory requirements, reduced intellectual property protection, economic instability, foreign currency fluctuations, and compliance with diverse international laws (e.g., FCPA)[498][499][500][501][502][503][504] Risks Related to Our Intellectual Property Voyager's ability to develop and commercialize product candidates relies heavily on licensed patent rights and proprietary technology, which may not provide exclusive rights or be effectively maintained, facing risks from litigation and trade secret protection challenges - Voyager's rights to develop and commercialize product candidates are subject to licenses from third parties, which may not provide exclusive rights, require grant-backs, or involve payment obligations (e.g., Touchlight License Agreement)[505] - Licensors may not diligently prosecute, maintain, or enforce licensed patents, potentially reducing or eliminating Voyager's rights[506] - Disagreements over contract interpretation in license agreements could narrow rights, terminate access, or increase financial obligations[508][509] - Failure to comply with license obligations or bankruptcy could lead to license termination, loss of development/marketing rights, or unfavorable terms[510] - U.S. government funding for some licensed technology may result in 'march-in rights' for the government, potentially harming Voyager's competitive position[511] - Obtaining and maintaining broad patent protection is expensive, time-consuming, and uncertain, with pending applications not guaranteed to issue as patents or effectively prevent competition[512][513][514][516] - Issued patents can be found invalid or unenforceable if challenged in court or administrative bodies, potentially leading to loss of exclusivity or narrowed claims[517][519] - Inability to obtain necessary rights to product candidates through acquisitions or in-licenses, especially for co-owned intellectual property, could significantly harm the business[521][522][523][524] - Compliance with procedural, document submission, and fee payment requirements for patents is critical; non-compliance can lead to abandonment or lapse of patent rights[525][526] - Protecting intellectual property globally is challenging due to varying laws and enforcement, potentially allowing competitors to use technologies in countries without patent protection[527][528][529][530] - Third parties may initiate legal proceedings alleging infringement of their intellectual property rights, leading to substantial costs, distraction of personnel, and potential liability (e.g., injunctions, damages, licensing fees)[533][534][535][536][537] - Claims asserting wrongful use or disclosure of trade secrets by employees or consultants, or ownership of Voyager's intellectual property, could result in litigation, loss of rights, or personnel[538][539][540] - Changes in U.S. patent law (e.g., Leahy-Smith Act, court decisions on patenting genes) could diminish patent value and impact the ability to protect products[541][542][543][544][545][546][547] - Failure to obtain patent term extension and regulatory exclusivity for product candidates could shorten the period of exclusive market rights, increasing competition[548][549][550][551][552] - Maintaining control over proprietary know-how and trade secrets is challenging, with risks of discovery by competitors or misappropriation by former employees or collaborators[555][556][557][558] Risks Related to Ownership of Our Common Stock The market price of Voyager's common stock is volatile and can fluctuate substantially, influenced by various factors, and the company does not anticipate paying cash dividends - Sales of a substantial number of common stock shares by existing stockholders or the eligibility of shares under stock incentive plans could cause the stock price to fall[559][560][561][562] - The price of common stock is volatile, influenced by factors such as clinical trial results, regulatory actions, competition, collaborations, intellectual property disputes, personnel changes, financial results, and general market conditions[563][564][565][566] - If operating results fall below expectations, the stock price could decline substantially, and past volatility has led to class-action litigation, which could incur significant costs[566][567] - Management has broad discretion in applying available funds, and ineffective use could negatively affect operating results and stock price[568] - As a 'smaller reporting company,' Voyager utilizes reduced disclosure requirements, which may make its common stock less attractive to some investors and potentially increase stock price volatility[569][570][572] - Provisions in the company's amended and restated certificate of incorporation and bylaws, along with Delaware law, could make an acquisition more difficult and prevent stockholders from replacing current management[575][576][578] - The designated Court of Chancery of the State of Delaware as the sole forum for certain actions may limit stockholders' ability to choose a favorable judicial forum[579][580] - The company does not anticipate paying cash dividends in the foreseeable future, making capital appreciation the sole source of gain for stockholders[581] General Risk Factors Voyager faces general risks including the potential inability to utilize its net operating loss carryforwards due to ownership changes and vulnerability of its computer systems to cyber-attacks - Voyager may not be able to utilize a significant portion of its federal and state net operating loss (NOL) carryforwards ($175.1 million and $166.5 million, respectively, as of December 31, 2022) due to expiration or annual limitations under Section 382 of the Code following ownership changes[582] - Internal computer systems and those of collaborators/contractors are vulnerable to cyber-attacks, viruses, unauthorized access, and other security breaches, which could materially disrupt product development programs, lead to loss of trade secrets, or incur substantial remediation costs[583][584] ITEM 1B. Unresolved Staff Comments This item states that there are no unresolved staff comments from the SEC ITEM 2. Properties Voyager's corporate headquarters are in Cambridge, Massachusetts, with additional laboratory space in Lexington, Massachusetts, under leases expiring in 2026 and 2031, respectively - Corporate headquarters are in Cambridge, Massachusetts, with additional laboratory space in Lexington, Massachusetts[586] - The company leases approximately 26,148 square feet in Cambridge (lease expires 2026) and 32,142 square feet in Lexington (lease expires 2031)[267][586] ITEM 3. Legal Proceedings As of December 31, 2022, Voyager Therapeutics was not a party to any material pending legal or governmental proceedings, nor were any directors or senior management involved in such proceedings - As of December 31, 2022, Voyager Therapeutics was not a party to any material pending legal proceedings[587] - No material governmental proceedings are pending or contemplated against the company[587] - No director, senior management member, or affiliate is a party adverse to the company or has a material adverse interest in any material proceedings[587] ITEM 4. Mine Safety Disclosures This item is not applicable to Voyager Therapeutics PART II. This part covers market information for the company's common equity, management's discussion and analysis of financial condition, market risk disclosures, financial statements, and internal controls ITEM 5. Market for Registrant's Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities Voyager Therapeutics' common stock has traded on the Nasdaq Global Select Market under "VYGR" since November 2015, with approximately 12 holders of record as of March 2023, and the company does not anticipate paying cash dividends - Voyager's common stock has traded on the Nasdaq Global Select Market under "VYGR" since November 11, 2015[590] - As of March 1, 2023, there were approximately 12 holders of record of the common stock[591] - The company has not paid cash dividends since inception and does not anticipate paying them in the foreseeable future[592] - In 2022, the company granted unregistered restricted stock unit awards for 163,000 shares and stock options to purchase 114,000 shares as inducement awards to new employees[594][595] ITEM 6. [Reserved] This item is reserved and contains no information ITEM 7. Management's Discussion and Analysis of Financial Condition and Results of Operations This section provides an overview of Voyager Therapeutics' financial condition and results of operations, highlighting its focus on gene therapy, history of net losses, and reliance on collaboration revenue for funding future growth - Voyager Therapeutics is a biotechnology company focused on AAV gene therapy for neurological diseases, leveraging its TRACER™ capsid discovery platform[597][598](index=598&ty