Q32 Bio Inc.(QTTB) - 2021 Q4 - Annual Report

PART I Item 1. Business Homology Medicines is a clinical-stage genetic medicines company using its AAVHSC platform for gene therapy and nuclease-free gene editing in rare diseases - Homology Medicines is a clinical-stage genetic medicines company focused on rare genetic diseases, utilizing a proprietary platform with human hematopoietic stem cell derived adeno-associated virus vectors (AAVHSCs) for both gene therapy and nuclease-free gene editing[18] - The company's clinical programs include HMI-102 (gene therapy for adult PKU), HMI-103 (gene editing for PKU), and HMI-203 (gene therapy for Hunter syndrome). Earlier-stage candidates include HMI-104 (GTx-mAb platform for PNH) and HMI-202 (gene therapy for MLD)[18][20][25][27][30][31] - Homology Medicines closed a transaction with Oxford Biomedica plc to establish Oxford Biomedica Solutions LLC, a manufacturing company. Homology contributed its manufacturing team, facility, and IP, receiving a $130 million upfront payment and a 20% ownership stake in the new company[32][126][128] - The company's HR-driven gene editing approach aims to replace entire diseased genes with functional copies by harnessing homologous recombination, avoiding exogenous nucleases and reducing the risk of unwanted modifications[19][36][38] Overview Homology Medicines is a clinical-stage genetic medicines company leveraging its AAVHSC platform for gene therapy, nuclease-free gene editing, and GTx-mAb in rare genetic diseases - The company's platform uses human hematopoietic stem cell derived adeno-associated virus vectors (AAVHSCs) for gene therapy, nuclease-free gene editing, and GTx-mAb to deliver single-administration genetic medicines[18] - AAVHSCs enable precise targeting of tissues including liver, CNS, PNS, bone marrow, cardiac and skeletal muscle, and the eye[18] - The product-development strategy involves parallel development of gene therapy and gene editing, leveraging gene therapy experience to advance gene editing[18] Clinical-Stage Product Candidates Homology Medicines has three clinical-stage product candidates: HMI-102 (gene therapy for adult PKU) in Phase 2, HMI-103 (gene editing for PKU) in Phase 1, and HMI-203 (gene therapy for Hunter syndrome) in Phase 1 HMI-102: Investigational Gene Therapy for the Treatment of Adult Patients with PKU HMI-103: Gene Editing Candidate for the Treatment of Patients with PKU HMI-203: Investigational Gene Therapy for the Treatment of Adult Patients with MPS II (Hunter Syndrome) - HMI-102, a gene therapy for adult PKU, is in Phase 2 of the pheNIX clinical trial and has received Fast Track Designation from the FDA[20] - HMI-102 pheNIX trial was placed on clinical hold in February 2022 due to elevated LFTs, with the company planning to propose a new, more targeted immunosuppressive regimen[23][24] - HMI-103, a gene editing candidate for classical PKU, initiated a Phase 1 trial (pheEDIT) in October 2021 and received Fast Track Designation[25] - HMI-203, a gene therapy for Hunter syndrome, initiated a Phase 1 trial (juMPStart) in October 2021[27] Earlier-Stage Product Candidates Homology Medicines is advancing HMI-104, a GTx-mAb platform candidate for Paroxysmal Nocturnal Hemoglobinuria (PNH), and optimizing HMI-202, a gene therapy candidate for Metachromatic Leukodystrophy (MLD) - HMI-104, a GTx-mAb platform candidate, was named in August 2021 for the treatment of PNH, leveraging AAVHSCs to express and secrete antibodies from the liver[30] - IND-enabling studies for HMI-202, a gene therapy for MLD, have been completed, showing sustained reduction of sulfatides in brain regions in preclinical models, with the company optimizing the vector for a better therapeutic profile[31] Manufacturing Homology Medicines completed a transaction with Oxford Biomedica plc to form Oxford Biomedica Solutions LLC, a new AAV vector manufacturing company, receiving $130 million upfront and a 20% ownership stake - Homology Medicines contributed its manufacturing team (125 experts), facility, equipment, and IP to Oxford Biomedica Solutions LLC[32] - Homology received a $130.0 million upfront payment and holds a 20% ownership stake in Oxford Biomedica Solutions LLC, with Oxford Biomedica plc owning 80%[32] - The agreement establishes Homology as a preferred client, aiming to reduce manufacturing costs and ensure dedicated capacity for its product candidates[32] Management Team and Cash Raised Homology Medicines' management team has a strong track record in rare disease therapeutics, having raised approximately $721 million in net proceeds since inception, and holds a robust intellectual property portfolio - The management team has a successful track record in discovering, developing, and commercializing rare disease therapeutics[33] - Homology Medicines has raised approximately $721 million in aggregate net proceeds since its inception in 2015[34] - Key funding sources include an IPO, follow-on public offerings, 'at-the-market' sales, equity investments (Novartis, Pfizer), and a $130 million upfront cash payment from the Oxford agreement[34] - The company possesses a robust intellectual property portfolio, including issued composition of matter patents in the U.S. for its 15 AAVHSCs[33] Our Opportunity in Genetic Medicines Homology Medicines focuses on monogenic diseases, aiming to correct genetic abnormalities through gene therapy or nuclease-free gene editing to replace entire diseased genes - The company targets monogenic diseases by adding a functional gene, replacing a diseased gene, or expressing an antibody[35] - Gene therapy (gene transfer) is used for slowly or non-dividing cells, while gene editing (gene integration) is for rapidly dividing cells[35] - Homology's HR-driven gene editing aims for functional gene integration, potentially addressing the majority of monogenic diseases by replacing entire diseased genes, unlike nuclease-based gene knockout which only addresses a minority[36] DNA Repair Pathways Human cells use homologous recombination (HR) for precise DNA repair and non-homologous end joining (NHEJ) for rapid, error-prone repair, with Homology Medicines focusing on HR for nuclease-free gene integration - Human cells utilize homologous recombination (HR) for precise DNA repair and non-homologous end joining (NHEJ) for rapid, but error-prone, DNA repair[37][42] - Nuclease-based gene editing primarily uses the NHEJ pathway, which can lead to unwanted mutations, whereas Homology's platform focuses on the HR pathway for precise nuclease-free gene integration[37][38] Our Approach Homology Medicines' platform utilizes novel AAVHSCs for both gene therapy and nuclease-free gene editing, leveraging homologous recombination for precise gene integration with high efficiency and broad tissue targeting Modality (in vivo) Figure 1. Our Genetic Medicines Platform. Figure 2. How our AAVHSCs are designed to enable each therapeutic modality. - The company's strategy is to develop both gene therapy and gene editing modalities in parallel, selecting the best fit for each disease based on biology, AAVHSC biodistribution, and cell division rates[39] - The platform uses novel AAVHSCs packaged with either a gene therapy construct (functional gene, no integration) or a gene editing construct (homology arms for HR-driven gene integration)[41] - Key advantages include nuclease-free HR-mediated gene editing with high integration efficiency, ability to introduce entire genes, high precision with lack of off-target modifications, ability to target multiple tissues (liver, CNS, PNS, muscle, bone marrow, eye, heart), in vivo single-component delivery, and low frequency of pre-existing neutralizing antibodies[43][44] Our Pipeline Strategy Homology Medicines' pipeline strategy focuses on monogenic diseases with significant unmet medical needs, validated regulatory pathways, and commercial opportunities, leveraging AAVHSC tropism for targeted gene therapy and editing - The pipeline targets monogenic diseases with known genetic abnormalities, significant unmet medical needs, validated regulatory pathways, and commercial opportunities[45] - Initial focus areas include intracellular, inborn errors of metabolism and other genetic conditions, with AAVHSCs showing high tropism for liver, CNS, peripheral tissues, bone marrow, and eye[45][46] - Gene therapy is deployed for slow- or non-dividing cells (e.g., adult liver, CNS), while gene editing is used for rapidly dividing cells (e.g., hematopoietic CD34+ cells, pediatric liver cells) for permanent correction[46] Our Product Pipeline Homology Medicines' product pipeline includes clinical-stage gene therapies for adult PKU (HMI-102) and Hunter syndrome (HMI-203), and a gene editing candidate for pediatric PKU (HMI-103) Homology Medicines Product Pipeline Status | Modality | Indication | Research | Preclinical | Phase 1 | Phase 2 | Phase 3 | | :-------------- | :------------------------------- | :------------ | :------------ | :------------------ | :------------------------------------ | :------ | | Gene Therapy | Adult Phenylketonuria (PKU) | | | | HMI-102 - Ph 2 Dose Expansion Phase* | | | | MPS II (Hunter syndrome) | | | HMI-203 - Ph 1 Trial| | | | | Metachromatic Leukodystrophy (MLD) | HMI-202 - Vector Optimization | | | | | | GTx-mAb Platform| Paroxysmal Nocturnal Hemoglobinuria (PNH) | HMI-104 | | | | | | Gene Editing (Nuclease-Free) | Pediatric PKU | | | HMI-103 - Ph 1 Trial in Adults | | | | | Human Stem Cells | X | | | | | | | Eye | X | | | | | *pheNIX clinical trial is on clinical hold Our Strategy Homology Medicines aims to deliver single-administration curative therapies for rare genetic diseases using gene therapy and nuclease-free gene editing, advancing its pipeline and platform while expanding its IP portfolio - The company's core strategy is to transform rare genetic disease treatment with single-administration curative therapies via gene therapy or HR-driven gene integration[49] - Key strategic components include advancing clinical programs (HMI-102, HMI-103, HMI-203), expanding the pipeline in existing and new therapeutic areas (liver, CNS, PNS, eye, hematopoietic system), strengthening the AAVHSC and HR gene editing platform through R&D and collaborations, leveraging integrated manufacturing capabilities, and expanding the intellectual property portfolio[49][50][52] - The pheNIX gene therapy trial for HMI-102 is on clinical hold due to elevated LFTs, with plans to propose a new immunosuppressive regimen[49] Our Genetic Medicines Platform Homology Medicines' genetic medicines platform, built on novel AAVHSCs, enables nuclease-free gene editing and gene therapy for precise, HR-mediated DNA correction with high efficiency and broad tissue distribution - The platform uses novel AAVHSCs for nuclease-free gene editing (gene integration) and gene therapy, allowing modality selection based on disease biology and cell division rates[51] - AAVHSCs are engineered to contain long, single-stranded DNA corrective sequences for precise HR-mediated gene integration, capable of accommodating up to 85% of human genes[55] - The single-component AAV system simplifies manufacturing and delivery, and the naturally occurring AAVHSCs are modified to be non-replicating to minimize potential safety issues[51][53] Homologous Recombination—A Powerful Basis for Gene Editing Homology Medicines' gene editing technology leverages homologous recombination (HR) for precise, nuclease-free gene integration using AAVHSCs to deliver specific DNA corrective sequences, reducing off-target risks Figure 3. Schematic of homologous recombination. - The technology induces endogenous HR using AAVHSCs to insert replacement or corrective genes into cells with mutations[55] - AAVHSCs are engineered with long, specific single-stranded DNA corrective sequences (up to 4.7 kilobases) to target precise genomic locations, reducing off-target integration risk[55] - This HR-based approach avoids exogenous nucleases, simplifying the process and reducing risks associated with non-HR-based repair mechanisms[54][55] Our Proprietary AAVHSCs Homology Medicines' proprietary family of 15 AAVHSCs offers a versatile platform for efficient, precise, nuclease-free gene editing and gene therapy with broad tissue targeting and low pre-existing neutralizing antibodies Single AAVHSC Platform for Both Gene Therapy and Gene Editing Modalities Ability to Perform In Vivo Nuclease-free Gene Editing Mediated by HR Figure 4. In vivo gene editing proof-of-concept at the murine F8 locus. Figure 5. In vivo gene editing proof-of-concept at the murine F8 locus. Ability to Introduce Entire Gene into the Genome Mediated via HR High Precision and Lack of Unwanted Off-target or On-target DNA Modifications Ability to Target Multiple Tissues Figure 6. Our family of AAVHSCs has demonstrated the ability to target a wide variety of tissues. In Vivo Administration with a Single Component Delivery System Figure 7. Our nuclease-free AAVHSC single component gene editing construct vs. nuclease-based multiple component gene editing construct for gene editing applications. Ability to Target a Broad Range of Patients Given Low Frequency of Pre-Existing Neutralizing Antibodies - The platform utilizes a family of 15 proprietary AAVHSCs, isolated from human stem cells, for both gene therapy and gene editing modalities[57][58] - Preclinical studies demonstrated in vivo nuclease-free gene editing with AAVHSC15, achieving up to 2.8% allele editing in murine liver models, leading to high and sustained luciferase expression for over 470 days[59][60][63] - The HR-based gene editing ensures high precision with no detected de novo mutations or viral ITR sequences at the integration site, and 99.967% of insertions at the targeted site in human AAVS1 locus[67][68][102] - AAVHSCs can target multiple tissues including neurons (crossing blood-brain/nerve barriers), retinal cells, skeletal muscle, cardiomyocytes, and liver, with a single intravenous administration[69][70] - The single-component delivery system for gene editing simplifies manufacturing and delivery compared to nuclease-based approaches requiring multiple vectors[69][74] - Approximately 80% of individuals lack pre-existing neutralizing antibodies to AAVHSCs, suggesting a broad patient population can be targeted[71] Our Product Candidates Homology Medicines is developing HMI-102 and HMI-103 for PKU, HMI-203 for Hunter syndrome, HMI-202 for MLD, and HMI-104 for PNH, with clinical and preclinical data supporting their therapeutic potential HMI-102 for Treatment of PKU in Adult Patients and HMI-103 for Treatment of PKU in Pediatric Patients PKU Disease Overview Current Treatments Our Gene Therapy and Gene Editing Approaches to PKU HMI-102: Our Gene Therapy Approach for PKU Preclinical Studies with HMI-102 Optimized HMI-103: Our Gene Editing Approach for PKU Additional Product Opportunities CNS Diseases HMI-203: Our Gene Therapy Approach for Hunter Syndrome HMI-202: Our Gene Therapy Approach for MLD HMI-104: Our Gene Therapy Approach for PNH Other CNS Diseases Other Liver Diseases and Therapeutics Hemoglobinopathies Ophthalmological Diseases - HMI-102 (gene therapy) and HMI-103 (gene editing) are lead product candidates for Phenylketonuria (PKU), both having received Fast Track Designation from the FDA[73][74] - HMI-102's pheNIX trial showed marked Phe reductions in Cohorts 2 and 3, with some patients achieving target Phe levels, even with diet liberalization, however, the trial is on clinical hold due to elevated LFTs[89][90][93][95] - Preclinical studies for HMI-102 in PAH-deficient mice demonstrated rapid and sustained reductions in serum Phe and increased Tyr levels for 48 weeks, and normalized brain Phe and serotonin metabolite levels[96][97][98] - HMI-103 preclinical data showed durable PAH gene integration (6% integration rate in humanized liver model) and marked serum Phe reduction in PKU murine models, supporting its potential for long-term benefit in pediatric patients[100][102][103][104] - HMI-203 (gene therapy) for Hunter syndrome is in a Phase 1 trial (juMPStart), with preclinical data showing robust biodistribution, hI2S enzyme expression, significant reductions in GAGs in multiple tissues and CSF, and amelioration of skeletal deformities[106][107][109] - HMI-202 (gene therapy) for MLD has completed IND-enabling studies, demonstrating blood-brain/nerve barrier crossing, broad CNS/PNS tissue tropism, increased ARSA enzyme activity, and reduction of LAMP-1 and sulfatide accumulation in murine models[111][113][115] - HMI-104 (GTx-mAb platform) for PNH showed preclinical proof-of-concept with single I.V. administration leading to sustained, therapeutic levels of anti-C5 antibodies expressed from the liver[116][120] Manufacturing Homology Medicines has established a scalable, commercial manufacturing platform for gene therapy and gene editing, which was transferred to Oxford Biomedica Solutions LLC, securing Homology as a preferred client Oxford Biomedica Solutions Transaction - Homology has a commercial manufacturing platform for gene therapy and gene editing, scalable from preclinical to GMP, using HEK293 transfection in serum-free suspension bioreactors and chromatography-based purification[124][125] - The Oxford Biomedica Solutions Transaction, closed March 10, 2022, transferred Homology's manufacturing assets and team to a new AAV vector manufacturing company, with Homology retaining a 20% ownership and preferred client status[126][128] - This transaction aims to reduce Homology's manufacturing costs and maintain dedicated capacity for its product candidates[126] Competition Homology Medicines operates in a highly competitive biotechnology and pharmaceutical industry, facing numerous companies with greater resources developing gene therapy and gene editing products - The biotechnology and pharmaceutical industries are characterized by rapid technological change, intense competition, and a strong emphasis on intellectual property[131] - Homology's PKU treatments may compete with therapies from American Gene Technologies, BioMarin, Generation Bio, Moderna, Nestlé Health Science, PTC Therapeutics, Jnana Therapeutics, and Synlogic, though Homology believes only gene therapy/editing can restore the normal Phe biochemical pathway[133] - Hunter syndrome treatment may compete with IZCARGO®, Avrobio, Denali Therapeutics, REGENXBIO, and ERTs from Takeda/GC Pharma. MLD treatment may compete with Libmeldy (Orchard Therapeutics), Takeda, and Passage Bio[135][136] - Many competitors have significantly greater financial resources and expertise in R&D, manufacturing, clinical trials, and marketing[137] Intellectual Property Homology Medicines protects its intellectual property through patents, trade secrets, and confidentiality agreements, holding exclusive or co-exclusive licenses under 18 U.S. issued patents and 52 pending applications - Homology protects its IP through patents, trade secrets, and confidentiality agreements, with success dependent on securing and maintaining patent protection[139] - As of December 31, 2021, the company had exclusive or co-exclusive licenses under 18 U.S. issued patents, 9 foreign patents, and 52 pending patent applications[140] - U.S. patents generally have a 20-year term from filing, with potential for up to five years of patent term extension under the Hatch-Waxman Act for FDA-approved drugs[141][143][144] - Key licensed portfolios include AAV capsids and genome editing from City of Hope (U.S. patents expiring 2031 and 2035) and AAV capsids for CNS diseases from Caltech (U.S. patents expiring 2034)[147][148][149][150] Strategic Collaborations Novartis terminated its collaboration with Homology Medicines in August 2021, returning ophthalmic rights, while the company maintains license agreements with Caltech and City of Hope for AAV-related patents - Novartis terminated its collaboration and license agreement with Homology in August 2021, returning worldwide exclusive rights for the ophthalmic target to Homology[152] - Homology has a co-exclusive license agreement with Caltech for AAV-related patents for human therapeutic applications, involving up to $7.2 million in milestone payments and low single-digit royalties on net sales[153][154] - An exclusive license agreement with City of Hope for AAV vector-related patents and know-how includes annual fees, up to $3.2 million in potential milestone fees, and low single-digit royalties[156][158] - In August 2021, City of Hope converted Homology's exclusive license in non-mammalian therapeutic fields to non-exclusive due to unmet partnering milestones, but this does not affect current therapeutic product candidates[160] Government Regulation and Product Approval The development and commercialization of Homology Medicines' genetic medicine products are subject to extensive and complex regulations by governmental authorities in the U.S. and internationally FDA Approval Process U.S. Biological Products Development Process U.S. Review and Approval Processes Orphan Drug Designation Rare Pediatric Disease Priority Review Voucher Program Expedited Development and Review Programs Post-Approval Requirements Biosimilars and Exclusivity Other Healthcare Laws and Compliance Requirements Coverage and Reimbursement Healthcare Reform Data Privacy and Security Laws Additional Regulation Government Regulation Outside of the United States Non-clinical Studies and Clinical Trials Marketing Authorization Data and Marketing Exclusivity Orphan Medicinal Products Pediatric Development Post-Approval Requirements - Genetic medicine products are extensively regulated by the FDA in the U.S. and comparable authorities internationally, covering research, development, testing, manufacturing, labeling, marketing, and post-approval monitoring[161][162] - The U.S. biological product development process includes preclinical testing (GLP), IND submission, IRB approval, multi-phase human clinical trials (GCP), BLA submission, FDA advisory committee review, and GMP compliance inspections[165][166][168][169][170][172] - Expedited programs like Fast Track, Breakthrough Therapy, and RMAT (U.S.) or PRIME (EU) can facilitate development and review but do not alter approval standards or guarantee faster approval[188][189][190][191][193] - Orphan Drug Designation provides incentives and 7-10 years of market exclusivity, while the Rare Pediatric Disease Priority Review Voucher program offers a transferable voucher for subsequent priority review, subject to specific deadlines[183][184][185][235] - Post-approval, products are subject to ongoing GMP compliance, adverse event reporting, and strict regulation of marketing and promotion, with penalties for non-compliance including withdrawal of approval[194][197][198] - The EU regulatory landscape is evolving with the Clinical Trials Regulation (CTR) harmonizing clinical trial assessment and the Pharmaceutical Strategy for Europe initiative potentially revising legislative instruments[216][217][219][223][224][225][226][227][228][230][231][232][233][234][235][236][237][238][239][240][241][242][243][244] Employees As of December 31, 2021, Homology Medicines had 224 full-time employees, with 197 in R&D, which decreased to 104 employees (75 in R&D) after the Oxford agreement in March 2022 - As of December 31, 2021, Homology Medicines had 224 full-time employees, with 197 in research and development[246] - Following the Oxford agreement on March 10, 2022, the company's employee count decreased to 104 full-time employees, with 75 in research and development, due to the transition of 125 manufacturing employees to Oxford Biomedica Solutions LLC[246] Corporate Information Homology Medicines, Inc. was incorporated in Delaware in March 2015, with its principal executive offices located in Bedford, MA - Homology Medicines, Inc. was incorporated in Delaware in March 2015[247] - The principal executive offices are located at One Patriots Park, Bedford, MA 01730[247] Available Information Homology Medicines files its annual, quarterly, and current reports, proxy statements, and other information electronically with the SEC, which are publicly available on the SEC's website and the company's investor relations website - The company files annual reports (Form 10-K), quarterly reports (Form 10-Q), current reports (Form 8-K), and other information with the SEC[248] - These filings are available on the SEC's website (http://www.sec.gov) and the company's investor relations website (www.homologymedicines.com)[248](index=248&type=chunk) Item 1A. Risk Factors Homology Medicines faces significant financial, clinical, regulatory, and operational risks, including HMI-102's clinical hold and novel gene editing uncertainties Risks Related to Our Financial Position and Need for Additional Capital Risks Related to Discovery, Development, Clinical Testing, Manufacturing and Regulatory Approval Risks Related to Healthcare Laws and Other Legal Compliance Matters Risks Related to Commercialization Risks Related to Our Dependence on Third Parties Risks Related to Our Intellectual Property Risks Related to Employee Matters and Managing Growth and Other Risks Related to Our Business Risks Related to Our Common Stock General Risk Factors - The company has incurred significant losses since inception ($95.8 million in 2021, $128.7 million in 2020) and anticipates continued losses, requiring additional capital to fund operations into the second half of 2024[251][252][255][256] - Success is heavily dependent on HMI-102, which is currently on clinical hold due to elevated liver function tests (LFTs), posing a significant risk to business if regulatory approval or commercialization is not achieved[264] - The novel genetic medicines platform and gene editing technology make development time and cost difficult to predict, with no gene editing products yet approved in the U.S. or Europe[274][275] - Clinical trials are expensive, time-consuming, and unpredictable, with potential for delays or termination due to regulatory feedback, patient enrollment issues, or adverse events[284][285][287] - Adverse public perception of genetic medicine, particularly gene editing, could negatively impact regulatory approval or demand for products[294][295][296][297] - The company relies on third-party manufacturers (including Oxford Biomedica Solutions LLC) and CROs, increasing risks related to supply, quality, regulatory compliance, and potential delays[319][320][325][412][413][414][415][418][419][420][421] - Intellectual property protection is crucial but uncertain, with risks of patent challenges, infringement claims, and the inability to obtain or maintain broad patent coverage[435][436][437][438][439][441][442][443][444][445][446][447][448][449][450][451][452][453][454][455][456][457][458][459][460][461][462][463][464][465][466][467][468][469][470][471][472][473] - The COVID-19 pandemic has caused and could continue to cause delays in clinical trials, disruptions in supply chains, and increased cybersecurity risks[474][475][476][477][478] Item 1B. Unresolved Staff Comments The company reported no unresolved staff comments from the SEC - There are no unresolved staff comments[502] Item 2. Properties The company occupies 26,850 sq ft of office and R&D lab space in Bedford, MA, under a sublease expiring in 2024 - The company occupies approximately 26,850 square feet of office and R&D laboratory space in Bedford, Massachusetts[503] - This space is held under a sublease agreement with OXB Solutions, which expires in 2024[503] - Management believes current facilities are sufficient and additional space will be available as needed[503] Item 3. Legal Proceedings Management believes no pending legal claims would materially adversely affect the company's operations or financial condition - Management believes there are no current legal claims or actions that could materially adversely affect the company's results of operations or financial condition[504] Item 4. Mine Safety Disclosures This item is not applicable to Homology Medicines, Inc - Not Applicable[505] PART II Item 5. Market for Registrant's Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities Common stock trades on Nasdaq under 'FIXX' since 2018, with 57.4 million shares outstanding and no cash dividends paid - Common stock has traded on The Nasdaq Global Select Market under 'FIXX' since March 28, 2018[508] - As of March 11, 2022, there were 57,385,285 shares of common stock outstanding with 17 holders of record[509] - The company has never declared or paid cash dividends and plans to retain future earnings for business development[510] 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 The company, a clinical-stage genetic medicines firm, reported a reduced net loss in 2021, with liquidity expected to fund operations into H2 2024 Overview Homology Medicines is a clinical-stage genetic medicines company focused on rare genetic diseases, leveraging its AAVHSC platform for gene therapy, nuclease-free gene editing, and GTx-mAb modalities - Homology Medicines is a clinical-stage genetic medicines company focused on rare genetic diseases, using AAVHSCs for gene therapy, nuclease-free gene editing, and GTx-mAb[520] - The platform allows precise targeting of diverse tissues, including liver, CNS, PNS, bone marrow, cardiac and skeletal muscle, and the eye[520] - The company's HR-driven gene editing approach aims for efficient gene integration without unwanted on- and off-target modifications, avoiding exogenous nucleases[521] Clinical-Stage Product Candidates Homology Medicines' clinical pipeline includes HMI-102 (gene therapy for adult PKU) in Phase 2, HMI-103 (gene editing for PKU) in Phase 1, and HMI-203 (gene therapy for Hunter syndrome) in Phase 1 HMI-102: Investigational Gene Therapy for the Treatment of Adult Patients with PKU HMI-103: Gene Editing Candidate for the Treatment of Patients with PKU HMI-203: Investigational Gene Therapy for the Treatment of Adult Patients with MPS II (Hunter Syndrome) - HMI-102, a gene therapy for adult PKU, is in Phase 2 of the pheNIX clinical trial and has received Fast Track Designation[522] - The pheNIX trial for HMI-102 was placed on clinical hold in February 2022 due to elevated LFTs, with plans to propose a new, more targeted immunosuppressive regimen[525] - HMI-103, a gene editing candidate for classical PKU, initiated a Phase 1 trial (pheEDIT) in October 2021 and received Fast Track Designation[526] - HMI-203, an investigational gene therapy for Hunter syndrome, initiated a Phase 1 trial (juMPStart) in October 2021[528] Earlier-Stage Product Candidates Homology Medicines is developing HMI-104, a GTx-mAb platform candidate for PNH, and optimizing HMI-202, a gene therapy candidate for MLD, after completing IND-enabling studies - HMI-104, a GTx-mAb platform candidate for PNH, was named in August 2021, leveraging AAVHSCs to deliver one-time in vivo gene therapy for antibody expression from the liver[531] - Preclinical data for HMI-104 showed high efficiency of AAVHSC vector delivery to the liver and sustained antibody expression consistent with C5 antibody therapeutics[532] - IND-enabling studies for HMI-202, a gene therapy for MLD, have been completed, demonstrating that a single I.V. administration crossed blood-brain and blood-nerve barriers and led to sustained reduction of sulfatides in brain regions[533] Oxford Biomedica Solutions Transaction Homology Medicines completed a transaction with Oxford Biomedica to establish Oxford Biomedica Solutions LLC, an AAV vector manufacturing company, receiving $130 million upfront and a 20% equity stake - On March 10, 2022, Homology closed a transaction with Oxford Biomedica to form Oxford Biomedica Solutions LLC, a new AAV vector manufacturing company[534] - Homology assigned and transferred its manufacturing assets and team to OXB Solutions in exchange for 175,000 common equity units[535] - Homology sold 130,000 units to Oxford for $130.0 million cash, and Oxford contributed $50.0 million to OXB Solutions for an additional 50,000 units. Post-closing, Oxford owns 80% and Homology owns 20% of OXB Solutions[536] - Homology is a preferred client of OXB Solutions, aiming to reduce costs and maintain dedicated manufacturing capacity[534] Corporate Headquarters Lease In November 2021, Homology Medicines amended its corporate headquarters lease in Bedford, Massachusetts, expanding space and extending the term to June 2030, with the lease now assigned to OXB Solutions - In November 2021, the company amended its corporate headquarters lease, increasing space by approximately 23,011 square feet and extending the lease expiration date to June 2030[539][540] - Annual base rent for the existing premises is approximately $4.7 million (starting March 2027), and for the expansion premises, it is approximately $1.4 million per year, both increasing by 3% annually[540] - The lease for the corporate headquarters has been assigned to OXB Solutions, with Homology subleasing a portion of lab and office space back[540] License Agreements Novartis terminated its collaboration with Homology Medicines in August 2021, returning ophthalmic rights and recognizing $30.8 million in deferred revenue, while City of Hope converted a non-mammalian license to non-exclusive - Novartis terminated its collaboration and license agreement with Homology, effective August 26, 2021, leading to the recognition of approximately $30.8 million in deferred revenue in 2021[541][548] - Upon termination, Homology regained worldwide exclusive rights to the ophthalmic target[541] - City of Hope converted Homology's exclusive license in non-mammalian therapeutic fields to non-exclusive in September 2021 due to unmet partnering milestones, but this does not affect current therapeutic product candidates[542] Management Team and Financial Overview Homology Medicines' management team has a strong track record, supported by a robust IP portfolio, and has raised approximately $721 million in net proceeds since 2015, with existing capital expected to fund operations into H2 2024 - The management team has a successful track record in discovering, developing, and commercializing rare disease therapeutics[543] - The company holds a robust intellectual property portfolio, including 18 U.S. issued patents, 9 foreign patents, and 52 pending applications, with specific patents for AAVHSCs and gene editing[543] - Since inception in 2015, Homology has raised approximately $721 million in aggregate net proceeds from various offerings and investments, including a $130 million upfront payment from Oxford and a $60 million equity investment from Pfizer[544] Net Losses and Accumulated Deficit | Metric | 2021 (in millions) | 2020 (in millions) | | :--------------------- | :----------------- | :----------------- | | Net Loss | $(95.8) | $(128.7) | | Accumulated Deficit | $(424.1) | $(328.4) | - Existing cash and cash equivalents, along with the $130.0 million from Oxford, are expected to fund operating expenses and capital expenditures into the second half of 2024[552] Impact of the COVID-19 Pandemic The COVID-19 pandemic has caused delays in Homology Medicines' clinical trials and supply chains, with its full impact on business and financial condition remaining uncertain - The company implemented a hybrid remote/in-office work policy and modified lab schedules to ensure business continuity and employee safety[556] - COVID-19 has caused delays in enrolling the Phase 1/2 pheNIX clinical trial and could lead to additional disruptions in other trials and preclinical studies[557][558][559] - The pandemic's impact on business, revenues, and financial condition is highly uncertain and depends on its duration, new variants, travel restrictions, and global economic effects[560] Components of Our Results of Operations Homology Medicines' operations primarily involve collaboration revenue, R&D expenses (expected to increase), and G&A expenses (also expected to increase), with no product sales revenue and accumulated NOLs subject to a full valuation allowance Revenue Operating Expenses Research and Development Expenses General and Administrative Expenses Interest Income Income Taxes - The company has not generated product sales revenue and does not expect to in the foreseeable future[561] - R&D expenses are expected to increase due to advancing clinical trials (HMI-102, HMI-103, HMI-203), preclinical activities (HMI-202, HMI-104), pipeline expansion, and increased costs with CMOs, partially offset by the Oxford transaction[564] - G&A expenses are expected to increase due to higher personnel headcount, public company operating costs, and professional fees[569] - Interest income decreased in 2021 due to lower invested balances and yields[570] - As of December 31, 2021, the company had federal and state NOL carryforwards of $367.2 million and $369.0 million, respectively, and R&D tax credit carryforwards of $43.2 million and $10.8 million, respectively, all subject to a full valuation allowance[571] Critical Accounting Policies and Use of Estimates Homology Medicines' financial statements rely on critical accounting policies and estimates for revenue recognition and accrued R&D expenses, and the company has elected the extended transition period for new accounting standards Revenue Recognition Accrued Research and Development Expenses Emerging Growth Company Status Recent Accounting Pronouncements - Critical accounting policies include revenue recognition (ASC Topic 606, five-step model, cost-to-cost method for collaboration revenue) and accrued research and development expenses (estimating services from CROs and CMOs)[574][575][578][579] - The company has elected the extended transition period for complying with new or revised accounting standards as an 'emerging growth company' under the JOBS Act[581] - ASU 2016-13 (Financial Instruments - Credit Losses) is effective for the company starting January 1, 2023, and its impact is currently being evaluated[582] Results of Operations Homology Medicines reported a net loss of $95.8 million in 2021, a significant improvement from $128.7 million in 2020, driven by increased collaboration revenue and decreased R&D expenses Comparison of Years Ended December 31, 2021 and 2020 Collaboration Revenue Research and Development Expenses General and Administrative Expenses Interest Income Net Loss Consolidated Statements of Operations Summary (in thousands) | Metric | 2021 | 2020 | Change | | :------------------------ | :---------- | :---------- | :---------- | | Collaboration revenue | $33,971 | $2,702 | $31,269 |\n| Research and development | $93,085 | $100,392 | $(7,307) |\n| General and administrative| $36,835 | $32,573 | $4,262 |\n| Total operating expenses | $129,920 | $132,965 | $(3,045) |\n| Loss from operations | $(95,949) | $(130,263) | $34,314 |\n| Interest income | $185 | $1,569 | $(1,384) |\n| Net loss | $(95,764) | $(128,694) | $32,930 | - Collaboration revenue increased significantly to $34.0 million in 2021 from $2.7 million in 2020, primarily due to the recognition of deferred revenue upon the termination of the Novartis collaboration agreement[585] - Research and development expenses decreased by $7.3 million in 2021, mainly due to lower direct expenses for HMI-102 (slow enrollment, lower manufacturing costs) and other development-stage programs (completion of IND-enabling studies for HMI-202), partially offset by increased expenses for HMI-103, HMI-203, and employee-related costs[586] - General and administrative expenses increased by $4.2 million in 2021, driven by higher stock-based compensation, market research, legal costs, professional fees, recruiting fees, licensed software, and insurance costs[588] - Interest income decreased by $1.4 million in 2021 due to lower invested balances and significantly lower yields[589] Liquidity and Capital Resources Homology Medicines has incurred significant operating losses and requires additional capital, with $155.9 million in cash and investments as of December 31, 2021, and the Oxford transaction expected to fund operations into H2 2024 Equity Offerings and ATM Program Oxford Biomedica Solutions Transaction Strategic Collaborations and Investments Cash Flows Cash Flows for the year ended December 31, 2021 Cash Flows for the year ended December 31, 2020 Funding Requirements Contractual Obligations - The company has incurred significant operating losses and requires additional capital for preclinical and clinical development[591] - Cash, cash equivalents, and short-term investments were $155.9 million as of December 31, 2021[599] - The $130.0 million upfront payment from the Oxford Biomedica Solutions transaction (March 2022) is expected to fund operations into the second half of 2024[592][608] - In 2021, the company raised $49.7 million net from a follow-on public offering and $1.5 million net from 'at-the-market' offerings[594][595] Cash Flow Summary (in thousands) | Cash Flow Activity | 2021 | 2020 | | :----------------------------- | :---------- | :---------- | | Net cash used in operating activities | $(109,751) | $(94,332) | | Net cash provided by (used in) investing activities | $(50,788) | $204,896 | | Net cash provided by financing activities | $52,169 | $53,093 | - Contractual obligations for operating leases significantly decreased from $48.2 million to approximately $3.8 million through 2024 due to the assignment of the facility lease to OXB Solutions and a sublease arrangement[613] Item 7A. Quantitative and Qualitative Disclosures About Market Risk The company's primary market risk is interest rate sensitivity on its $155.9 million cash and investments, with no material impact from a 10% rate change - The company's primary market risk exposure is interest rate sensitivity on its cash, cash equivalents, and short-term investments[615] Interest-Earning Assets | Metric | December 31, 2021 (in millions) | | :----------------------------------- | :------------------------------ | | Cash, cash equivalents, and short-term investments | $155.9 | | Percentage of total assets | 73.6% | - A 10% change in interest rates would not materially affect the fair value of the investment portfolio as of December 31, 2021[615] - The company had no debt outstanding as of December 31, 2021 and 2020[615] Item 8. Financial Statements and Supplementary Data Financial statements and supplementary data are appended to the report and indexed in Item 15 of Part IV - Financial statements and supplementary data are appended to the report and indexed in Item 15 of Part IV[616] Item 9. Changes in and Disagreements with Accountants on Accounting and Financial Disclosure The company reported no changes or disagreements with accountants on accounting and financial disclosure - There were no changes in or disagreements with accountants on accounting and financial disclosure[617] Item 9A. Controls and Procedures Management concluded disclosure controls and internal control over financial reporting were effective as of December 31, 2021 - Disclosure controls and procedures were effective at the reasonable assurance level as of December 31, 2021[619] - Management concluded that internal control over financial reporting was effective as of December 31, 2021[620] - As an 'emerging growth company,' the company is exempt from the auditor attestation report on internal control over financial reporting[621] - No material changes in internal control over financial reporting occurred during the quarter ended December 31, 2021[621] Item 9B. Other Information No other information required to be disclosed in this item - None[622] Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections This item is not applicable to Homology Medicines, Inc - Not applicable[623] PART III Item 10. Directors, Executive Officers and Corporate Governance This section details executive officers, directors, corporate governance, Section 16(a) compliance, and director independence Directors and Executive Officers Delinquent Section 16(a) Reports Code of Ethics Audit Committee and Audit Committee Financial Expert Family Relationships Executive Officers and Directors | Name | Age | Position |