Financial Performance - The company has incurred significant losses since inception and anticipates continued losses for the foreseeable future, which may affect the market value of its common stock[8]. - The company raised approximately $721 million in net proceeds since inception, including a $130 million upfront cash payment from the agreement with Oxford Biomedica[23]. - The company reduced its workforce by 86% to significantly lower ongoing operating costs while evaluating strategic alternatives[10]. Strategic Partnerships and Mergers - An Agreement and Plan of Merger was entered into with Q32 Bio Inc., with Q32 having an aggregate equity value of $195 million and the company's equity value expected to be approximately $80 million[11][12]. - Q32 is expected to complete a Concurrent Financing with gross proceeds of $42 million prior to the Merger[13]. - OXB (US) LLC was established in 2022 to support scalable AAV manufacturing, achieving high-quality titers of E15 vg/L and over 90% fully intact vector[77]. Clinical Trials and Product Development - The company has withdrawn all clinical trial applications for its investigational gene therapy candidates, including HMI-102 and HMI-203, and terminated all related clinical studies[17]. - Clinical data from the pheEDIT trial indicated that HMI-103 was generally well-tolerated, with participant 1 achieving a reduction in plasma phenylalanine levels below the treatment guideline threshold[17]. - The company is exploring strategic alternatives for its product candidates, including potential sales of HMI-103 and HMI-204[17]. - The pheEDIT Phase 1 clinical trial for HMI-103 was inactivated in September 2023, with clinical data showing that HMI-103 was well-tolerated in all three participants, with no serious adverse events reported[59]. - The company has completed IND-enabling studies for HMI-202, a gene therapy for MLD, and announced HMI-204, an optimized one-time gene therapy candidate that showed significant expression of human ARSA in multiple brain regions[18]. Regulatory Environment - The regulatory approval processes for the company's product candidates are lengthy and inherently unpredictable, which may impact future commercialization efforts[8]. - The company must comply with Good Manufacturing Practices (GMP) and conduct stability studies to ensure product quality over its shelf life[94]. - The FDA review process for biologics includes submission of a Biologics License Application (BLA) that must demonstrate safety, purity, and potency[95]. - The company is required to navigate extensive regulatory processes for product approval, which demand significant time and financial resources[90]. Gene Therapy and Gene Editing Technologies - The company focuses on gene therapy and gene editing approaches to address monogenic diseases, aiming for functional gene integration through HR[24]. - The proprietary AAVHSC platform enables nuclease-free gene editing and gene therapy with improved safety profiles and therapeutic efficiencies[29]. - AAVHSCs demonstrate high gene integration efficiencies, achieving therapeutic ranges significantly higher than traditional nuclease-based methods[29]. - The company’s gene editing approach aims to achieve functional gene integration into the patient's genome, potentially addressing the majority of monogenic diseases[24]. Market and Competitive Landscape - The company has paused development of its product candidates, facing competition from major pharmaceutical and biotechnology firms[80]. - Coverage and reimbursement decisions by third-party payors are increasingly restrictive, impacting sales of medical products[108]. - Legislative proposals in the U.S. aim to contain healthcare costs, which may affect the pricing and profitability of pharmaceutical products[111]. Intellectual Property - The company relies on a combination of patents and trade secrets to protect its intellectual property, with a focus on maintaining a competitive advantage[82]. - The patent term for most applications is 20 years, with potential extensions available under the Hatch-Waxman Act[83]. - The company holds 13 granted patents in the U.S. related to novel AAV capsids, expected to expire in 2031, with possible extensions of up to five years[85]. Employee Relations - The company emphasizes the importance of maintaining good relationships with employees, as none are represented by a labor union[136]. - As of December 31, 2023, the company had 7 full-time employees, including one with an M.D. or Ph.D. degree[136].

PART I—FINANCIAL INFORMATION [Item 1. Financial Statements](index=5&type=section&id=Item%201.%20Financial%20Statements.) The company's financial statements reflect a strategic halt in operations, resulting in significant net losses and going concern doubts | Indicator | As of Sep 30, 2023 (in thousands) | As of Dec 31, 2022 (in thousands) | | :--- | :--- | :--- | | Cash and cash equivalents | $29,111 | $33,986 | | Short-term investments | $74,187 | $141,040 | | **Total current assets** | **$106,635** | **$181,015** | | **Total assets** | **$140,063** | **$228,470** | | Total liabilities | $51,852 | $50,492 | | **Total stockholders' equity** | **$88,211** | **$177,978** | | Accumulated deficit | ($525,979) | ($429,137) | | Indicator (in thousands) | Three Months Ended Sep 30, 2023 | Three Months Ended Sep 30, 2022 | Nine Months Ended Sep 30, 2023 | Nine Months Ended Sep 30, 2022 | | :--- | :--- | :--- | :--- | :--- | | Collaboration revenue | $0 | $802 | $1,156 | $2,406 | | Research and development | $17,519 | $25,854 | $60,489 | $71,202 | | General and administrative | $6,842 | $7,810 | $23,355 | $29,991 | | Restructuring and other charges | $6,640 | $0 | $6,640 | $0 | | **Loss from operations** | **($31,001)** | **($32,862)** | **($89,328)** | **($98,787)** | | Gain on sale of business | $0 | $0 | $0 | $131,249 | | **Net income (loss)** | **($32,954)** | **($33,726)** | **($96,842)** | **$29,290** | | **Net income (loss) per share-diluted** | **($0.57)** | **($0.59)** | **($1.68)** | **$0.51** | - In July 2023, the company initiated a review of strategic options, stopped further development of its programs, and reduced its workforce by **86%** to significantly cut operating costs[23](index=23&type=chunk) - Management has concluded there is **substantial doubt** regarding the company's ability to continue as a going concern for more than twelve months from the financial statement issuance date[30](index=30&type=chunk) - A restructuring charge of **$6.9 million** for severance and related costs was recorded in Q3 2023 in connection with the 86% workforce reduction[84](index=84&type=chunk) - Effective October 1, 2023, the company was released from its primary lease obligations, which is expected to result in a gain of **$8.8 million**[132](index=132&type=chunk) [Item 2. Management's Discussion and Analysis of Financial Condition and Results of Operations](index=30&type=section&id=Item%202.%20Management's%20Discussion%20and%20Analysis%20of%20Financial%20Condition%20and%20Results%20of%20Operations) Management discusses its strategic pivot, program halts, and workforce reduction, which significantly lowered operating expenses - In July 2023, the Board approved a plan to explore strategic options, including mergers or asset sales, and consequently stopped all program development and reduced its workforce by **86%**[137](index=137&type=chunk) | Expense Category (in thousands) | Three Months Ended Sep 30, 2023 | Three Months Ended Sep 30, 2022 | Change | | :--- | :--- | :--- | :--- | | Research and development | $17,519 | $25,854 | ($8,335) | | General and administrative | $6,842 | $7,810 | ($968) | | Restructuring and other charges | $6,640 | $0 | $6,640 | - The **$8.3 million decrease** in Q3 2023 R&D expenses compared to Q3 2022 was primarily due to the decision to stop program development and the workforce reduction[167](index=167&type=chunk) - As of September 30, 2023, the company had **$103.3 million** in cash, cash equivalents, and short-term investments, but management has concluded there is **substantial doubt** about its ability to continue as a going concern[151](index=151&type=chunk)[199](index=199&type=chunk) [Item 3. Quantitative and Qualitative Disclosures About Market Risk](index=42&type=section&id=Item%203.%20Quantitative%20and%20Qualitative%20Disclosures%20About%20Market%20Risk) The company's primary market risk is interest rate sensitivity on its cash and investments, with inflation deemed immaterial - The company's main market risk is interest rate sensitivity on its **$103.3 million** of cash and investments; a hypothetical 10% change in interest rates is not expected to have a material effect[206](index=206&type=chunk) - As of September 30, 2023, the company does not believe inflation has had a material effect on its business, financial condition, or results of operations[207](index=207&type=chunk) [Item 4. Controls and Procedures](index=43&type=section&id=Item%204.%20Controls%20and%20Procedures) Management concluded that disclosure controls and procedures were effective, with no material changes to internal controls - Based on an evaluation as of the end of the period, the CEO and CFO concluded that the company's disclosure controls and procedures were **effective**[210](index=210&type=chunk) - No changes in internal control over financial reporting occurred during the three months ended September 30, 2023, that have materially affected, or are reasonably likely to materially affect, internal controls[211](index=211&type=chunk) PART II. OTHER INFORMATION [Item 1. Legal Proceedings](index=44&type=section&id=Item%201.%20Legal%20Proceedings) The company is defending a securities class action lawsuit related to its HMI-102 clinical trial disclosures - The company is defending a putative class action lawsuit filed in March 2022 related to disclosures for its HMI-102 clinical trial; a motion to dismiss the case is currently pending[213](index=213&type=chunk) [Item 1A. Risk Factors](index=44&type=section&id=Item%201A.%20Risk%20Factors) Key risks include a history of losses, going concern doubts, strategic uncertainty, and consequences of workforce reduction - The company has a history of significant operating losses, with an accumulated deficit of approximately **$526.0 million** as of September 30, 2023, and anticipates continued losses[216](index=216&type=chunk) - Management has concluded there is **substantial doubt** regarding the company's ability to continue as a going concern for more than twelve months[231](index=231&type=chunk) - The ongoing evaluation of strategic alternatives is costly and complex, with **no assurance** that any transaction will be completed or have a positive impact[218](index=218&type=chunk)[222](index=222&type=chunk) - The recent **86% reduction in force** may lead to unintended consequences such as loss of institutional knowledge and decreased morale[481](index=481&type=chunk)[483](index=483&type=chunk) - The company's novel gene editing and AAVHSC platforms are unproven in late-stage trials, and the regulatory landscape for such therapies is **uncertain and continues to change**[250](index=250&type=chunk)[251](index=251&type=chunk)[253](index=253&type=chunk) [Item 2. Unregistered Sales of Equity Securities, Use of Proceeds, and Issuer Purchases of Equity Securities](index=93&type=section&id=Item%202.%20Unregistered%20Sales%20of%20Equity%20Securities,%20Use%20of%20Proceeds,%20and%20Issuer%20Purchases%20of%20Equity%20Securities) This section is not applicable for the reporting period [Item 5. Other Information](index=93&type=section&id=Item%205.%20Other%20Information) The company reports no other material information and notes its status as a smaller reporting company - The company is a **smaller reporting company** and is not required to provide information otherwise required under Item 408(a) of Regulation S-K[527](index=527&type=chunk) [Item 6. Exhibits](index=95&type=section&id=Item%206.%20Exhibits) This section lists all exhibits filed with the Form 10-Q, including corporate governance documents and certifications

UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, D.C. 20549 FORM 10-Q (Mark One) ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the quarterly period ended June 30, 2023 OR ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from ___________________ to ___________________ Commission File Number: 001-38433 Homology Medicines, Inc. (Exact Name of Registrant as Specified in its Charter) De ...

Financial Performance - Net loss for Q1 2023 was $28,844,000, compared to a net income of $92,105,000 in Q1 2022, reflecting a significant change in financial performance[13]. - Loss from operations for Q1 2023 was $27,511,000, compared to a loss of $37,618,000 in Q1 2022, indicating an improvement of about 27%[13]. - For the three months ended March 31, 2023, the company reported a net loss of $28.8 million compared to a net income of $92.1 million for the same period in 2022[20]. - The company incurred a loss from operations of $28.8 million during the three months ended March 31, 2023, and has an accumulated deficit of $458.0 million as of the same date[26]. - The accumulated deficit increased to $457,981,000 as of March 31, 2023, from $429,137,000 at the end of 2022[11]. Revenue and Expenses - Collaboration revenue for the three months ended March 31, 2023, was $802,000, consistent with the same period in 2022[13]. - Total operating expenses decreased to $28,313,000 in Q1 2023 from $38,420,000 in Q1 2022, representing a reduction of approximately 26%[13]. - Research and development expenses for Q1 2023 were $19,988,000, down from $24,273,000 in Q1 2022, a decrease of approximately 18%[13]. - General and administrative expenses also decreased to $8,325,000 in Q1 2023 from $14,147,000 in Q1 2022, a reduction of about 41%[13]. - The company did not generate any revenue from product sales and does not expect to do so in the foreseeable future[26]. Cash Flow and Liquidity - Cash and cash equivalents decreased to $39.5 million as of March 31, 2023, down from $248.4 million at the end of the same period in 2022[36]. - The company recorded a net cash used in operating activities of $26.1 million for the three months ended March 31, 2023, compared to $30.7 million for the same period in 2022[20]. - The company provided $31.4 million in net cash from investing activities during the three months ended March 31, 2023, compared to $168.3 million in the same period in 2022[20]. - As of March 31, 2023, the company believes its cash and cash equivalents will enable it to continue operations for at least one year[27]. - The company expects to incur additional operating losses and negative operating cash flows for the foreseeable future[26]. Stockholders' Equity and Investments - Total stockholders' equity decreased to $151,899,000 as of March 31, 2023, down from $177,978,000 at the end of 2022[11]. - The Company’s total short-term investments amounted to $110.571 million, with $31.297 million in commercial paper, $57.202 million in US Treasury securities, and $22.072 million in corporate debt securities[63]. - The company has filed a Registration Statement for the registration of up to $250.0 million of its common stock, with $75.0 million available for sale under an "at-the-market" offering[24]. - The company recorded a gain of $131.2 million on the sale of its manufacturing business, with cash received amounting to $130.0 million and a fair value of equity method investment at $31.2 million[80]. Lease and Operating Costs - Operating lease costs for the three months ended March 31, 2023, were $1.1 million, compared to $0.9 million for the same period in 2022[88]. - The company has a noncancelable operating lease for approximately 67,000 square feet, with an initial annual base rent of $39.50 per square foot, increasing by three percent annually[83]. - Total undiscounted lease payments amount to $43.646 million, with a present value of operating lease liabilities at $29.101 million[89]. - Cash paid for lease liabilities in Q1 2023 was $1.101 million, an increase from $0.877 million in Q1 2022[91]. Risks and Future Outlook - The company anticipates continued losses for the foreseeable future and will require additional capital to fund operations[6]. - The company is heavily dependent on the success of its product candidates, with no history of commercializing genetic medicine products, which poses significant risks[6]. - The company does not believe inflation has materially affected its financial condition as of March 31, 2023, but acknowledges potential future impacts on expenses[204]. Stock-Based Compensation - The Company recorded stock-based compensation expense of $2.369 million in Q1 2023, down from $4.051 million in Q1 2022[106]. - The Company expects to recognize $15.8 million of unrecognized compensation expense related to unvested share-based compensation over approximately 2.7 years[106]. - The fair value of stock options granted in Q1 2023 was estimated at $1.06 per share, compared to $1.78 in Q1 2022[101]. - The total intrinsic value of options exercised during Q1 2022 was insignificant, with no options exercised in Q1 2023[101]. Collaboration and Agreements - Under the Supply Agreement with OXB Solutions, the company is committed to purchase approximately $29.7 million worth of AAV-based products in 2023[117]. - The company recorded purchases from OXB Solutions of $4.9 million for drug substance and $1.2 million for process development services during the three months ended March 31, 2023[118]. - The exclusive right of first refusal (ROFR) granted to Pfizer for collaboration on HMI-102 and HMI-103 expired on May 9, 2023[111].

Clinical Trials and Product Development - The company has initiated a Phase 1 clinical trial for HMI-103, its lead gene editing candidate for classical PKU, with the first participant dosed in January 2023 and additional patients being screened across ten active sites[10]. - The HMI-103 trial is expected to enroll up to nine patients aged 18-55, with initial data anticipated by mid-2023, focusing on safety and serum phenylalanine changes[11]. - HMI-203, an investigational gene therapy for Hunter syndrome, is currently in a Phase 1 trial with initial data expected in the second half of 2023, targeting nine male patients aged 18-45[13]. - The company paused enrollment in the HMI-102 trial to prioritize the HMI-103 trial, despite observing biologic activity in the former[14]. - HMI-204 is an optimized gene therapy candidate for MLD, with IND-enabling studies completed and the company seeking a partner for advancement[86]. - The company has initiated a Phase 1 trial with HMI-103 for the treatment of classical PKU, with additional patients being screened across ten active clinical trial sites[36]. - The company plans to enroll younger patients in subsequent HMI-103 clinical trials if positive safety and efficacy results are established in adults[11]. - HMI-203 showed robust biodistribution and significant reductions in heparan sulfate GAG levels in multiple organs in preclinical studies[13]. Financial Overview and Capital Requirements - The company anticipates continued losses for the foreseeable future and will require additional capital to fund operations, which may impact its ability to commercialize product candidates[8]. - The company has raised approximately $721 million in aggregate net proceeds since its inception, including $130.0 million from the Oxford agreement[22]. - The company has incurred significant losses since inception and expects to continue incurring losses for the foreseeable future[8]. - The company requires additional capital to fund operations and may not be able to complete the development and commercialization of its product candidates if financing is not obtained[8]. Regulatory and Compliance Challenges - The regulatory approval processes for its product candidates are lengthy and unpredictable, posing a risk to the company's business[8]. - The FDA approval process for biological products requires extensive regulatory compliance, including preclinical and clinical trials, and submission of a Biologics License Application (BLA)[119]. - The company must navigate various regulatory requirements and may incur substantial time and financial resources in obtaining approvals[119]. - The FDA reviews Biologics License Applications (BLAs) to ensure products are safe, pure, potent, and effective, typically adding approximately two months to the review timeline[129]. - Orphan drug designation can be granted for drugs treating rare diseases affecting fewer than 200,000 individuals in the U.S., providing financial incentives such as grant funding and tax advantages[130]. Intellectual Property and Competitive Landscape - The company has a robust intellectual property portfolio with issued patents for its family of 15 AAVHSCs, which is considered a strategic asset[22]. - The company has exclusive worldwide rights to its technologies, including 15 issued composition of matter patents in the United States for its novel AAVHSCs[37]. - The company has entered into a license agreement with Caltech, paying an initial licensing fee of $100,000 and up to $7.2 million in milestone payments for the first licensed product[115]. - The company relies on a combination of patents, trade secrets, and confidentiality agreements to protect its intellectual property[106]. - The company faces competition from major pharmaceutical and biotechnology companies, academic institutions, and research institutions, with potential competitors including American Gene Technologies and BioMarin[103]. Manufacturing and Supply Chain - The company relies on third-party manufacturers, which increases the risk of supply issues that could delay development or commercialization efforts[8]. - The company closed a transaction with Oxford Biomedica Solutions, resulting in the transfer of assets primarily used for AAV vector manufacturing in exchange for 175,000 common equity units[18]. - The manufacturing strategy utilizes HEK293 cells, ensuring scalability and regulatory familiarity[99]. - The manufacturing capabilities established with Oxford are designed to support the pipeline programs while reducing costs and maintaining quality[37]. Gene Therapy and Technology Platforms - The company focuses on monogenic diseases, utilizing gene therapy and gene editing approaches to address these conditions[23]. - The proprietary AAVHSC platform enables nuclease-free gene editing, which is believed to provide improved safety and efficacy compared to traditional methods[31]. - The AAVHSC platform allows for high-efficiency gene editing without the use of nucleases, simplifying the manufacturing and delivery of therapeutic candidates[33]. - The AAVHSCs demonstrate gene integration efficiencies believed to be in therapeutic ranges, significantly higher than both nuclease-based and other AAV-based approaches[31]. - The AAVHSC technology allows for targeting multiple tissues, including the liver, CNS, and muscle, with a single intravenous administration[49]. Market and Treatment Landscape - The incidence of PKU in the U.S. is estimated at one in 12,707, translating to approximately 350 new cases annually[60]. - Current treatments for PKU, such as Kuvan and Palynziq, do not address the underlying genetic defect, with Kuvan sales at approximately $228 million and Palynziq at $255 million in 2022[64][67]. - The gene integration approach aims to restore PAH activity to 10% or more of normal levels, potentially normalizing serum Phe levels and improving patient quality of life[68]. - Approximately 80% of individuals lack pre-existing neutralizing antibodies against AAVHSCs, enhancing the potential patient pool for gene therapies[57]. - The company is focused on developing product candidates for monogenic diseases with significant unmet medical needs, particularly in the liver, CNS, and peripheral tissues[34].

Financial Performance - Total current assets increased to $213,204,000 as of September 30, 2022, compared to $191,909,000 as of December 31, 2021, representing a growth of 11.5%[17] - Collaboration revenue for the three months ended September 30, 2022, was $802,000, a decrease of 52.2% from $1,677,000 in the same period of 2021[19] - The net loss for the three months ended September 30, 2022, was $33,726,000, compared to a net loss of $30,608,000 for the same period in 2021, reflecting a 10.3% increase in losses[19] - The company reported a comprehensive loss of $34,142,000 for the three months ended September 30, 2022, compared to a comprehensive loss of $30,615,000 for the same period in 2021[23] - For the nine months ended September 30, 2022, the company recorded a net income of $29.3 million, primarily due to a gain from the transaction with Oxford Biomedica[38] - The company reported a net cash used in operating activities of $86.5 million for the nine months ended September 30, 2022, compared to $79.3 million for the same period in 2021[30] - The company expects to incur additional operating losses and negative operating cash flows for the foreseeable future[38] - The company has not generated any revenue from product sales and does not expect to do so in the near future[38] Assets and Liabilities - Cash and cash equivalents decreased to $43,162,000 as of September 30, 2022, from $108,382,000 as of December 31, 2021, indicating a decline of 60.2%[17] - Total liabilities increased to $53,590,000 as of September 30, 2022, compared to $42,070,000 as of December 31, 2021, marking a rise of 27.4%[17] - Stockholders' equity rose to $209,061,000 as of September 30, 2022, from $169,651,000 as of December 31, 2021, an increase of 23.2%[17] - As of September 30, 2022, the company had an accumulated deficit of $394.8 million[38] - The company’s total financial assets amounted to $201.074 million as of September 30, 2022, including cash equivalents of $43.162 million and short-term investments of $157.912 million[76] Revenue and Expenses - Total operating expenses for the nine months ended September 30, 2022, were $101,193,000, up 5.8% from $95,493,000 in the same period of 2021[19] - The company’s stock-based compensation expense for the nine months ended September 30, 2022, was $9.965 million, compared to $12.582 million in 2021[30] - The Company reported operating lease costs of $2.826 million for the nine months ended September 30, 2022, compared to $1.869 million for the same period in 2021, reflecting a year-over-year increase of approximately 51.1%[94] - Research and development expenses for the three months ended September 30, 2022, increased by $1.87 million to $25.85 million compared to $23.99 million in 2021[191] - General and administrative expenses decreased by $541,000 to $7.81 million for the three months ended September 30, 2022[191] Investments and Financing - The company completed a transaction with Oxford Biomedica, receiving $130 million in upfront cash and retaining a 20% ownership interest in the new company[35] - The Company recorded a gain of $131.249 million on the sale of its manufacturing business, with cash received amounting to $130 million and a fair value of equity method investment at $31.223 million[86] - The company has raised approximately $721 million since its inception in 2015, including $130.0 million from the Oxford transaction[158] - The company has $148.4 million of common stock available for sale under its at-the-market offerings as of September 30, 2022[37] - The company entered into a sales agreement in March 2020 to issue and sell common stock with an aggregate value of up to $150 million under the ATM program[215] Clinical Development - The Company is developing multiple clinical-stage product candidates, including HMI-103 for PKU, HMI-203 for MPS II, and HMI-104 for PNH, utilizing its proprietary AAVHSC platform[131] - HMI-103 is currently in a Phase 1 clinical trial, with enrollment expected to include up to nine patients aged 18-55 diagnosed with classical PKU[135] - HMI-203 has received orphan drug designation from both the EMA and FDA, with a Phase 1 trial expected to enroll up to nine male patients aged 18-45 diagnosed with Hunter syndrome[138] - The Company paused enrollment in the HMI-102 trial to focus resources on the HMI-103 trial, despite observing biologic activity in the HMI-102 trial[141] - The Company is actively seeking a partner to advance the preclinical development of HMI-204, an optimized gene therapy candidate for MLD[146] Legal and Compliance - The Company believes the claims in a pending securities class action lawsuit lack merit and has filed motions to transfer venue and dismiss the case[95]

UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, D.C. 20549 FORM 10-Q (Mark One) ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the quarterly period ended June 30, 2022 OR ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from ___________________ to ___________________ Commission File Number: 001-38433 Homology Medicines, Inc. (Exact Name of Registrant as Specified in its Charter) (S ...

UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, D.C. 20549 FORM 10-Q (Mark One) ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the quarterly period ended March 31, 2022 OR ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from ___________________ to ___________________ Commission File Number: 001-38433 Homology Medicines, Inc. (Exact Name of Registrant as Specified in its Charter) D ...

PART I [Item 1. Business](index=5&type=section&id=Item%201.%20Business) 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](index=18&type=chunk) - 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](index=18&type=chunk)[20](index=20&type=chunk)[25](index=25&type=chunk)[27](index=27&type=chunk)[30](index=30&type=chunk)[31](index=31&type=chunk) - 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](index=32&type=chunk)[126](index=126&type=chunk)[128](index=128&type=chunk) - 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](index=19&type=chunk)[36](index=36&type=chunk)[38](index=38&type=chunk) [Overview](index=5&type=section&id=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](index=18&type=chunk) - AAVHSCs enable precise targeting of tissues including liver, CNS, PNS, bone marrow, cardiac and skeletal muscle, and the eye[18](index=18&type=chunk) - The product-development strategy involves parallel development of gene therapy and gene editing, leveraging gene therapy experience to advance gene editing[18](index=18&type=chunk) [Clinical-Stage Product Candidates](index=5&type=section&id=Clinical-Stage%20Product%20Candidates) 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](index=5&type=section&id=HMI-102%3A%20Investigational%20Gene%20Therapy%20for%20the%20Treatment%20of%20Adult%20Patients%20with%20PKU) [HMI-103: Gene Editing Candidate for the Treatment of Patients with PKU](index=6&type=section&id=HMI-103%3A%20Gene%20Editing%20Candidate%20for%20the%20Treatment%20of%20Patients%20with%20PKU) [HMI-203: Investigational Gene Therapy for the Treatment of Adult Patients with MPS II (Hunter Syndrome)](index=6&type=section&id=HMI-203%3A%20Investigational%20Gene%20Therapy%20for%20the%20Treatment%20of%20Adult%20Patients%20with%20MPS%20II%20%28Hunter%20Syndrome%29) - **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](index=20&type=chunk) - **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](index=23&type=chunk)[24](index=24&type=chunk) - **HMI-103**, a gene editing candidate for classical PKU, initiated a Phase 1 trial (pheEDIT) in October 2021 and received Fast Track Designation[25](index=25&type=chunk) - **HMI-203**, a gene therapy for Hunter syndrome, initiated a Phase 1 trial (juMPStart) in October 2021[27](index=27&type=chunk) [Earlier-Stage Product Candidates](index=6&type=section&id=Earlier-Stage%20Product%20Candidates) 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](index=30&type=chunk) - 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](index=31&type=chunk) [Manufacturing](index=7&type=section&id=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](index=32&type=chunk) - 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](index=32&type=chunk) - The agreement establishes Homology as a preferred client, aiming to reduce manufacturing costs and ensure dedicated capacity for its product candidates[32](index=32&type=chunk) [Management Team and Cash Raised](index=7&type=section&id=Management%20Team%20and%20Cash%20Raised) 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](index=33&type=chunk) - Homology Medicines has raised approximately **$721 million** in aggregate net proceeds since its inception in 2015[34](index=34&type=chunk) - 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](index=34&type=chunk) - The company possesses a robust intellectual property portfolio, including issued composition of matter patents in the U.S. for its 15 AAVHSCs[33](index=33&type=chunk) [Our Opportunity in Genetic Medicines](index=7&type=section&id=Our%20Opportunity%20in%20Genetic%20Medicines) 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](index=35&type=chunk) - Gene therapy (gene transfer) is used for slowly or non-dividing cells, while gene editing (gene integration) is for rapidly dividing cells[35](index=35&type=chunk) - 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](index=36&type=chunk) [DNA Repair Pathways](index=8&type=section&id=DNA%20Repair%20Pathways) 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](index=37&type=chunk)[42](index=42&type=chunk) - 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](index=37&type=chunk)[38](index=38&type=chunk) [Our Approach](index=8&type=section&id=Our%20Approach) 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)](index=8&type=section&id=Modality%20%28in%20vivo%29) [Figure 1. Our Genetic Medicines Platform.](index=8&type=section&id=Figure%201.%20Our%20Genetic%20Medicines%20Platform.) [Figure 2. How our AAVHSCs are designed to enable each therapeutic modality.](index=9&type=section&id=Figure%202.%20How%20our%20AAVHSCs%20are%20designed%20to%20enable%20each%20therapeutic%20modality.) - 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](index=39&type=chunk) - 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](index=41&type=chunk) - 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](index=43&type=chunk)[44](index=44&type=chunk) [Our Pipeline Strategy](index=10&type=section&id=Our%20Pipeline%20Strategy) 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](index=45&type=chunk) - 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](index=45&type=chunk)[46](index=46&type=chunk) - 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](index=46&type=chunk) [Our Product Pipeline](index=11&type=section&id=Our%20Product%20Pipeline) 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](index=11&type=section&id=Our%20Strategy) 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](index=49&type=chunk) - 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](index=49&type=chunk)[50](index=50&type=chunk)[52](index=52&type=chunk) - 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](index=49&type=chunk) [Our Genetic Medicines Platform](index=12&type=section&id=Our%20Genetic%20Medicines%20Platform) 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](index=51&type=chunk) - 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](index=55&type=chunk) - 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](index=51&type=chunk)[53](index=53&type=chunk) [Homologous Recombination—A Powerful Basis for Gene Editing](index=13&type=section&id=Homologous%20Recombination%E2%80%94A%20Powerful%20Basis%20for%20Gene%20Editing) 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.](index=13&type=section&id=Figure%203.%20Schematic%20of%20homologous%20recombination.) - The technology induces endogenous HR using AAVHSCs to insert replacement or corrective genes into cells with mutations[55](index=55&type=chunk) - 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](index=55&type=chunk) - This HR-based approach avoids exogenous nucleases, simplifying the process and reducing risks associated with non-HR-based repair mechanisms[54](index=54&type=chunk)[55](index=55&type=chunk) [Our Proprietary AAVHSCs](index=13&type=section&id=Our%20Proprietary%20AAVHSCs) 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](index=14&type=section&id=Single%20AAVHSC%20Platform%20for%20Both%20Gene%20Therapy%20and%20Gene%20Editing%20Modalities) [Ability to Perform In Vivo Nuclease-free Gene Editing Mediated by HR](index=14&type=section&id=Ability%20to%20Perform%20In%20Vivo%20Nuclease-free%20Gene%20Editing%20Mediated%20by%20HR) [Figure 4. In vivo gene editing proof-of-concept at the murine F8 locus.](index=14&type=section&id=Figure%204.%20In%20vivo%20gene%20editing%20proof-of-concept%20at%20the%20murine%20F8%20locus.) [Figure 5. In vivo gene editing proof-of-concept at the murine F8 locus.](index=15&type=section&id=Figure%205.%20In%20vivo%20gene%20editing%20proof-of-concept%20at%20the%20murine%20F8%20locus.) [Ability to Introduce Entire Gene into the Genome Mediated via HR](index=15&type=section&id=Ability%20to%20Introduce%20Entire%20Gene%20into%20the%20Genome%20Mediated%20via%20HR) [High Precision and Lack of Unwanted Off-target or On-target DNA Modifications](index=15&type=section&id=High%20Precision%20and%20Lack%20of%20Unwanted%20Of%20-target%20or%20On-target%20DNA%20Modifications) [Ability to Target Multiple Tissues](index=16&type=section&id=Ability%20to%20Target%20Multiple%20Tissues) [Figure 6. Our family of AAVHSCs has demonstrated the ability to target a wide variety of tissues.](index=16&type=section&id=Figure%206.%20Our%20family%20of%20AAVHSCs%20has%20demonstrated%20the%20ability%20to%20target%20a%20wide%20variety%20of%20tissues.) [In Vivo Administration with a Single Component Delivery System](index=16&type=section&id=In%20Vivo%20Administration%20with%20a%20Single%20Component%20Delivery%20System) [Figure 7. Our nuclease-free AAVHSC single component gene editing construct vs. nuclease-based multiple component gene editing construct for gene editing applications.](index=17&type=section&id=Figure%207.%20Our%20nuclease-free%20AAVHSC%20single%20component%20gene%20editing%20construct%20vs.%20nuclease-based%20multiple%20component%20gene%20editing%20construct%20for%20gene%20editing%20applications.) [Ability to Target a Broad Range of Patients Given Low Frequency of Pre-Existing Neutralizing Antibodies](index=17&type=section&id=Ability%20to%20Target%20a%20Broad%20Range%20of%20Patients%20Given%20Low%20Frequency%20of%20Pre-Existing%20Neutralizing%20Antibodies) - The platform utilizes a family of **15 proprietary AAVHSCs**, isolated from human stem cells, for both gene therapy and gene editing modalities[57](index=57&type=chunk)[58](index=58&type=chunk) - 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](index=59&type=chunk)[60](index=60&type=chunk)[63](index=63&type=chunk) - 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](index=67&type=chunk)[68](index=68&type=chunk)[102](index=102&type=chunk) - 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](index=69&type=chunk)[70](index=70&type=chunk) - The single-component delivery system for gene editing simplifies manufacturing and delivery compared to nuclease-based approaches requiring multiple vectors[69](index=69&type=chunk)[74](index=74&type=chunk) - Approximately **80% of individuals** lack pre-existing neutralizing antibodies to AAVHSCs, suggesting a broad patient population can be targeted[71](index=71&type=chunk) [Our Product Candidates](index=17&type=section&id=Our%20Product%20Candidates) 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](index=17&type=section&id=HMI-102%20for%20Treatment%20of%20PKU%20in%20Adult%20Patients%20and%20HMI-103%20for%20Treatment%20of%20PKU%20in%20Pediatric%20Patients) [PKU Disease Overview](index=18&type=section&id=PKU%20Disease%20Overview) [Current Treatments](index=19&type=section&id=Current%20Treatments) [Our Gene Therapy and Gene Editing Approaches to PKU](index=19&type=section&id=Our%20Gene%20Therapy%20and%20Gene%20Editing%20Approaches%20to%20PKU) [HMI-102: Our Gene Therapy Approach for PKU](index=20&type=section&id=HMI-102%3A%20Our%20Gene%20Therapy%20Approach%20for%20PKU) [Preclinical Studies with HMI-102](index=21&type=section&id=Preclinical%20Studies%20with%20HMI-102) [Optimized HMI-103: Our Gene Editing Approach for PKU](index=22&type=section&id=Optimized%20HMI-103%3A%20Our%20Gene%20Editing%20Approach%20for%20PKU) [Additional Product Opportunities](index=24&type=section&id=Additional%20Product%20Opportunities) [CNS Diseases](index=24&type=section&id=CNS%20Diseases) [HMI-203: Our Gene Therapy Approach for Hunter Syndrome](index=24&type=section&id=HMI-203%3A%20Our%20Gene%20Therapy%20Approach%20for%20Hunter%20Syndrome) [HMI-202: Our Gene Therapy Approach for MLD](index=25&type=section&id=HMI-202%3A%20Our%20Gene%20Therapy%20Approach%20for%20MLD) [HMI-104: Our Gene Therapy Approach for PNH](index=26&type=section&id=HMI-104%3A%20Our%20Gene%20Therapy%20Approach%20for%20PNH) [Other CNS Diseases](index=27&type=section&id=Other%20CNS%20Diseases) [Other Liver Diseases and Therapeutics](index=27&type=section&id=Other%20Liver%20Diseases%20and%20Therapeutics) [Hemoglobinopathies](index=27&type=section&id=Hemoglobinopathies) [Ophthalmological Diseases](index=28&type=section&id=Ophthalmological%20Diseases) - **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](index=73&type=chunk)[74](index=74&type=chunk) - **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](index=89&type=chunk)[90](index=90&type=chunk)[93](index=93&type=chunk)[95](index=95&type=chunk) - 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](index=96&type=chunk)[97](index=97&type=chunk)[98](index=98&type=chunk) - **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](index=100&type=chunk)[102](index=102&type=chunk)[103](index=103&type=chunk)[104](index=104&type=chunk) - **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](index=106&type=chunk)[107](index=107&type=chunk)[109](index=109&type=chunk) - **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](index=111&type=chunk)[113](index=113&type=chunk)[115](index=115&type=chunk) - **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](index=116&type=chunk)[120](index=120&type=chunk) [Manufacturing](index=28&type=section&id=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](index=28&type=section&id=Oxford%20Biomedica%20Solutions%20Transaction) - 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](index=124&type=chunk)[125](index=125&type=chunk) - 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](index=126&type=chunk)[128](index=128&type=chunk) - This transaction aims to reduce Homology's manufacturing costs and maintain dedicated capacity for its product candidates[126](index=126&type=chunk) [Competition](index=29&type=section&id=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](index=131&type=chunk) - 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](index=133&type=chunk) - 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](index=135&type=chunk)[136](index=136&type=chunk) - Many competitors have significantly greater financial resources and expertise in R&D, manufacturing, clinical trials, and marketing[137](index=137&type=chunk) [Intellectual Property](index=30&type=section&id=Intellectual%20Property) 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](index=139&type=chunk) - 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](index=140&type=chunk) - 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](index=141&type=chunk)[143](index=143&type=chunk)[144](index=144&type=chunk) - 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](index=147&type=chunk)[148](index=148&type=chunk)[149](index=149&type=chunk)[150](index=150&type=chunk) [Strategic Collaborations](index=32&type=section&id=Strategic%20Collaborations) 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](index=152&type=chunk) - 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](index=153&type=chunk)[154](index=154&type=chunk) - 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](index=156&type=chunk)[158](index=158&type=chunk) - 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](index=160&type=chunk) [Government Regulation and Product Approval](index=33&type=section&id=Government%20Regulation%20and%20Product%20Approval) 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](index=33&type=section&id=FDA%20Approval%20Process) [U.S. Biological Products Development Process](index=34&type=section&id=U.S.%20Biological%20Products%20Development%20Process) [U.S. Review and Approval Processes](index=36&type=section&id=U.S.%20Review%20and%20Approval%20Processes) [Orphan Drug Designation](index=37&type=section&id=Orphan%20Drug%20Designation) [Rare Pediatric Disease Priority Review Voucher Program](index=37&type=section&id=Rare%20Pediatric%20Disease%20Priority%20Review%20Voucher%20Program) [Expedited Development and Review Programs](index=38&type=section&id=Expedited%20Development%20and%20Review%20Programs) [Post-Approval Requirements](index=39&type=section&id=Post-Approval%20Requirements) [Biosimilars and Exclusivity](index=40&type=section&id=Biosimilars%20and%20Exclusivity) [Other Healthcare Laws and Compliance Requirements](index=40&type=section&id=Other%20Healthcare%20Laws%20and%20Other%20Legal%20Compliance%20Matters) [Coverage and Reimbursement](index=40&type=section&id=Coverage%20and%20Reimbursement) [Healthcare Reform](index=40&type=section&id=Healthcare%20Reform) [Data Privacy and Security Laws](index=41&type=section&id=Data%20Privacy%20and%20Security%20Laws) [Additional Regulation](index=42&type=section&id=Additional%20Regulation) [Government Regulation Outside of the United States](index=42&type=section&id=Government%20Regulation%20Outside%20of%20the%20United%20States) [Non-clinical Studies and Clinical Trials](index=42&type=section&id=Non-clinical%20Studies%20and%20Clinical%20Trials) [Marketing Authorization](index=43&type=section&id=Marketing%20Authorization) [Data and Marketing Exclusivity](index=44&type=section&id=Data%20and%20Marketing%20Exclusivity) [Orphan Medicinal Products](index=45&type=section&id=Orphan%20Medicinal%20Products) [Pediatric Development](index=45&type=section&id=Pediatric%20Development) [Post-Approval Requirements](index=45&type=section&id=Post-Approval%20Requirements) - 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](index=161&type=chunk)[162](index=162&type=chunk) - 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](index=165&type=chunk)[166](index=166&type=chunk)[168](index=168&type=chunk)[169](index=169&type=chunk)[170](index=170&type=chunk)[172](index=172&type=chunk) - 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](index=188&type=chunk)[189](index=189&type=chunk)[190](index=190&type=chunk)[191](index=191&type=chunk)[193](index=193&type=chunk) - 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](index=183&type=chunk)[184](index=184&type=chunk)[185](index=185&type=chunk)[235](index=235&type=chunk) - 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](index=194&type=chunk)[197](index=197&type=chunk)[198](index=198&type=chunk) - 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](index=216&type=chunk)[217](index=217&type=chunk)[219](index=219&type=chunk)[223](index=223&type=chunk)[224](index=224&type=chunk)[225](index=225&type=chunk)[226](index=226&type=chunk)[227](index=227&type=chunk)[228](index=228&type=chunk)[230](index=230&type=chunk)[231](index=231&type=chunk)[232](index=232&type=chunk)[233](index=233&type=chunk)[234](index=234&type=chunk)[235](index=235&type=chunk)[236](index=236&type=chunk)[237](index=237&type=chunk)[238](index=238&type=chunk)[239](index=239&type=chunk)[240](index=240&type=chunk)[241](index=241&type=chunk)[242](index=242&type=chunk)[243](index=243&type=chunk)[244](index=244&type=chunk) [Employees](index=46&type=section&id=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](index=246&type=chunk) - 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](index=246&type=chunk) [Corporate Information](index=46&type=section&id=Corporate%20Information) 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](index=247&type=chunk) - The principal executive offices are located at One Patriots Park, Bedford, MA 01730[247](index=247&type=chunk) [Available Information](index=46&type=section&id=Available%20Information) 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](index=248&type=chunk) - 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](index=47&type=section&id=Item%201A.%20Risk%20Factors) 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](index=47&type=section&id=Risks%20Related%20to%20Our%20Financial%20Position%20and%20Need%20for%20Additional%20Capital) [Risks Related to Discovery, Development, Clinical Testing, Manufacturing and Regulatory Approval](index=51&type=section&id=Risks%20Related%20to%20Discovery%2C%20Development%2C%20Clinical%20Testing%2C%20Manufacturing%20and%20Regulatory%20Approval) [Risks Related to Healthcare Laws and Other Legal Compliance Matters](index=64&type=section&id=Risks%20Related%20to%20Healthcare%20Laws%20and%20Other%20Legal%20Compliance%20Matters) [Risks Related to Commercialization](index=69&type=section&id=Risks%20Related%20to%20Commercialization) [Risks Related to Our Dependence on Third Parties](index=73&type=section&id=Risks%20Related%20to%20Our%20Dependence%20on%20Third%20Parties) [Risks Related to Our Intellectual Property](index=77&type=section&id=Risks%20Related%20to%20Our%20Intellectual%20Property) [Risks Related to Employee Matters and Managing Growth and Other Risks Related to Our Business](index=84&type=section&id=Risks%20Related%20to%20Employee%20Matters%20and%20Managing%20Growth%20and%20Other%20Risks%20Related%20to%20Our%20Business) [Risks Related to Our Common Stock](index=86&type=section&id=Risks%20Related%20to%20Our%20Common%20Stock) [General Risk Factors](index=89&type=section&id=General%20Risk%20Factors) - 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](index=251&type=chunk)[252](index=252&type=chunk)[255](index=255&type=chunk)[256](index=256&type=chunk) - 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](index=264&type=chunk) - 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](index=274&type=chunk)[275](index=275&type=chunk) - 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](index=284&type=chunk)[285](index=285&type=chunk)[287](index=287&type=chunk) - Adverse public perception of genetic medicine, particularly gene editing, could negatively impact regulatory approval or demand for products[294](index=294&type=chunk)[295](index=295&type=chunk)[296](index=296&type=chunk)[297](index=297&type=chunk) - 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](index=319&type=chunk)[320](index=320&type=chunk)[325](index=325&type=chunk)[412](index=412&type=chunk)[413](index=413&type=chunk)[414](index=414&type=chunk)[415](index=415&type=chunk)[418](index=418&type=chunk)[419](index=419&type=chunk)[420](index=420&type=chunk)[421](index=421&type=chunk) - 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](index=435&type=chunk)[436](index=436&type=chunk)[437](index=437&type=chunk)[438](index=438&type=chunk)[439](index=439&type=chunk)[441](index=441&type=chunk)[442](index=442&type=chunk)[443](index=443&type=chunk)[444](index=444&type=chunk)[445](index=445&type=chunk)[446](index=446&type=chunk)[447](index=447&type=chunk)[448](index=448&type=chunk)[449](index=449&type=chunk)[450](index=450&type=chunk)[451](index=451&type=chunk)[452](index=452&type=chunk)[453](index=453&type=chunk)[454](index=454&type=chunk)[455](index=455&type=chunk)[456](index=456&type=chunk)[457](index=457&type=chunk)[458](index=458&type=chunk)[459](index=459&type=chunk)[460](index=460&type=chunk)[461](index=461&type=chunk)[462](index=462&type=chunk)[463](index=463&type=chunk)[464](index=464&type=chunk)[465](index=465&type=chunk)[466](index=466&type=chunk)[467](index=467&type=chunk)[468](index=468&type=chunk)[469](index=469&type=chunk)[470](index=470&type=chunk)[471](index=471&type=chunk)[472](index=472&type=chunk)[473](index=473&type=chunk) - The COVID-19 pandemic has caused and could continue to cause delays in clinical trials, disruptions in supply chains, and increased cybersecurity risks[474](index=474&type=chunk)[475](index=475&type=chunk)[476](index=476&type=chunk)[477](index=477&type=chunk)[478](index=478&type=chunk) [Item 1B. Unresolved Staff Comments](index=95&type=section&id=Item%201B.%20Unresolved%20Staff%20Comments) The company reported no unresolved staff comments from the SEC - There are no unresolved staff comments[502](index=502&type=chunk) [Item 2. Properties](index=95&type=section&id=Item%202.%20Properties) 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](index=503&type=chunk) - This space is held under a sublease agreement with OXB Solutions, which expires in **2024**[503](index=503&type=chunk) - Management believes current facilities are sufficient and additional space will be available as needed[503](index=503&type=chunk) [Item 3. Legal Proceedings](index=95&type=section&id=Item%203.%20Legal%20Proceedings) 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](index=504&type=chunk) [Item 4. Mine Safety Disclosures](index=95&type=section&id=Item%204.%20Mine%20Safety%20Disclosures) This item is not applicable to Homology Medicines, Inc - Not Applicable[505](index=505&type=chunk) PART II [Item 5. Market for Registrant's Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities](index=96&type=section&id=Item%205.%20Market%20for%20Registrant%27s%20Common%20Equity%2C%20Related%20Stockholder%20Matters%20and%20Issuer%20Purchases%20of%20Equity%20Securities) 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](index=508&type=chunk) - As of March 11, 2022, there were **57,385,285 shares** of common stock outstanding with **17 holders of record**[509](index=509&type=chunk) - The company has never declared or paid cash dividends and plans to retain future earnings for business development[510](index=510&type=chunk) [Item 6. [Reserved]](index=97&type=section&id=Item%206.%20%5BReserved%5D) This item is reserved and contains no information [Item 7. Management's Discussion and Analysis of Financial Condition and Results of Operations](index=98&type=section&id=Item%207.%20Management%27s%20Discussion%20and%20Analysis%20of%20Financial%20Condition%20and%20Results%20of%20Operations) 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](index=98&type=section&id=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](index=520&type=chunk) - The platform allows precise targeting of diverse tissues, including liver, CNS, PNS, bone marrow, cardiac and skeletal muscle, and the eye[520](index=520&type=chunk) - The company's HR-driven gene editing approach aims for efficient gene integration without unwanted on- and off-target modifications, avoiding exogenous nucleases[521](index=521&type=chunk) [Clinical-Stage Product Candidates](index=98&type=section&id=Clinical-Stage%20Product%20Candidates) 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](index=98&type=section&id=HMI-102%3A%20Investigational%20Gene%20Therapy%20for%20the%20Treatment%20of%20Adult%20Patients%20with%20PKU) [HMI-103: Gene Editing Candidate for the Treatment of Patients with PKU](index=99&type=section&id=HMI-103%3A%20Gene%20Editing%20Candidate%20for%20the%20Treatment%20of%20Patients%20with%20PKU) [HMI-203: Investigational Gene Therapy for the Treatment of Adult Patients with MPS II (Hunter Syndrome)](index=99&type=section&id=HMI-203%3A%20Investigational%20Gene%20Therapy%20for%20the%20Treatment%20of%20Adult%20Patients%20with%20MPS%20II%20%28Hunter%20Syndrome%29) - **HMI-102**, a gene therapy for adult PKU, is in Phase 2 of the pheNIX clinical trial and has received Fast Track Designation[522](index=522&type=chunk) - 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](index=525&type=chunk) - **HMI-103**, a gene editing candidate for classical PKU, initiated a Phase 1 trial (pheEDIT) in October 2021 and received Fast Track Designation[526](index=526&type=chunk) - **HMI-203**, an investigational gene therapy for Hunter syndrome, initiated a Phase 1 trial (juMPStart) in October 2021[528](index=528&type=chunk) [Earlier-Stage Product Candidates](index=99&type=section&id=Earlier-Stage%20Product%20Candidates) 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](index=531&type=chunk) - 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](index=532&type=chunk) - 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](index=533&type=chunk) [Oxford Biomedica Solutions Transaction](index=100&type=section&id=Oxford%20Biomedica%20Solutions%20Transaction) 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](index=534&type=chunk) - Homology assigned and transferred its manufacturing assets and team to OXB Solutions in exchange for **175,000 common equity units**[535](index=535&type=chunk) - 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](index=536&type=chunk) - Homology is a preferred client of OXB Solutions, aiming to reduce costs and maintain dedicated manufacturing capacity[534](index=534&type=chunk) [Corporate Headquarters Lease](index=100&type=section&id=Corporate%20Headquarters%20Lease) 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](index=539&type=chunk)[540](index=540&type=chunk) - 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](index=540&type=chunk) - The lease for the corporate headquarters has been assigned to OXB Solutions, with Homology subleasing a portion of lab and office space back[540](index=540&type=chunk) [License Agreements](index=101&type=section&id=License%20Agreements) 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](index=541&type=chunk)[548](index=548&type=chunk) - Upon termination, Homology regained worldwide exclusive rights to the ophthalmic target[541](index=541&type=chunk) - 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](index=542&type=chunk) [Management Team and Financial Overview](index=101&type=section&id=Management%20Team%20and%20Financial%20Overview) 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](index=543&type=chunk) - 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](index=543&type=chunk) - 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](index=544&type=chunk) 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](index=552&type=chunk) [Impact of the COVID-19 Pandemic](index=103&type=section&id=Impact%20of%20the%20COVID-19%20Pandemic) 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](index=556&type=chunk) - 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](index=557&type=chunk)[558](index=558&type=chunk)[559](index=559&type=chunk) - 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](index=560&type=chunk) [Components of Our Results of Operations](index=104&type=section&id=Components%20of%20Our%20Results%20of%20Operations) 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](index=104&type=section&id=Revenue) [Operating Expenses](index=104&type=section&id=Operating%20Expenses) [Research and Development Expenses](index=104&type=section&id=Research%20and%20Development%20Expenses) [General and Administrative Expenses](index=106&type=section&id=General%20and%20Administrative%20Expenses) [Interest Income](index=106&type=section&id=Interest%20Income) [Income Taxes](index=106&type=section&id=Income%20Taxes) - The company has not generated product sales revenue and does not expect to in the foreseeable future[561](index=561&type=chunk) - 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](index=564&type=chunk) - G&A expenses are expected to increase due to higher personnel headcount, public company operating costs, and professional fees[569](index=569&type=chunk) - Interest income decreased in 2021 due to lower invested balances and yields[570](index=570&type=chunk) - 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](index=571&type=chunk) [Critical Accounting Policies and Use of Estimates](index=106&type=section&id=Critical%20Accounting%20Policies%20and%20Use%20of%20Estimates) 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](index=106&type=section&id=Revenue%20Recognition) [Accrued Research and Development Expenses](index=107&type=section&id=Accrued%20Research%20and%20Development%20Expenses) [Emerging Growth Company Status](index=107&type=section&id=Emerging%20Growth%20Company%20Status) [Recent Accounting Pronouncements](index=107&type=section&id=Recent%20Accounting%20Pronouncements) - 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](index=574&type=chunk)[575](index=575&type=chunk)[578](index=578&type=chunk)[579](index=579&type=chunk) - 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](index=581&type=chunk) - ASU 2016-13 (Financial Instruments - Credit Losses) is effective for the company starting January 1, 2023, and its impact is currently being evaluated[582](index=582&type=chunk) [Results of Operations](index=108&type=section&id=Results%20of%20Operations) 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](index=108&type=section&id=Comparison%20of%20Years%20Ended%20December%2031%2C%202021%20and%202020) [Collaboration Revenue](index=108&type=section&id=Collaboration%20Revenue) [Research and Development Expenses](index=108&type=section&id=Research%20and%20Development%20Expenses) [General and Administrative Expenses](index=109&type=section&id=General%20and%20Administrative%20Expenses) [Interest Income](index=109&type=section&id=Interest%20Income) [Net Loss](index=109&type=section&id=Net%20Loss) 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](index=585&type=chunk) - 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](index=586&type=chunk) - 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](index=588&type=chunk) - Interest income decreased by **$1.4 million** in 2021 due to lower invested balances and significantly lower yields[589](index=589&type=chunk) [Liquidity and Capital Resources](index=109&type=section&id=Liquidity%20and%20Capital%20Resources) 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](index=109&type=section&id=Equity%20Of%20erings%20and%20ATM%20Program) [Oxford Biomedica Solutions Transaction](index=110&type=section&id=Oxford%20Biomedica%20Solutions%20Transaction) [Strategic Collaborations and Investments](index=110&type=section&id=Strategic%20Collaborations%20and%20Investments) [Cash Flows](index=110&type=section&id=Cash%20Flows) [Cash Flows for the year ended December 31, 2021](index=111&type=section&id=Cash%20Flows%20for%20the%20year%20ended%20December%2031%2C%202021) [Cash Flows for the year ended December 31, 2020](index=111&type=section&id=Cash%20Flows%20for%20the%20year%20ended%20December%2031%2C%202020) [Funding Requirements](index=111&type=section&id=Funding%20Requirements) [Contractual Obligations](index=113&type=section&id=Contractual%20Obligations) - The company has incurred significant operating losses and requires additional capital for preclinical and clinical development[591](index=591&type=chunk) - Cash, cash equivalents, and short-term investments were **$155.9 million** as of December 31, 2021[599](index=599&type=chunk) - 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](index=592&type=chunk)[608](index=608&type=chunk) - 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](index=594&type=chunk)[595](index=595&type=chunk) 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](index=613&type=chunk) [Item 7A. Quantitative and Qualitative Disclosures About Market Risk](index=113&type=section&id=Item%207A.%20Quantitative%20and%20Qualitative%20Disclosures%20About%20Market%20Risk) 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](index=615&type=chunk) 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](index=615&type=chunk) - The company had no debt outstanding as of December 31, 2021 and 2020[615](index=615&type=chunk) [Item 8. Financial Statements and Supplementary Data](index=113&type=section&id=Item%208.%20Financial%20Statements%20and%20Supplementary%20Data) 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](index=616&type=chunk) [Item 9. Changes in and Disagreements with Accountants on Accounting and Financial Disclosure](index=114&type=section&id=Item%209.%20Changes%20in%20and%20Disagreements%20with%20Accountants%20on%20Accounting%20and%20Financial%20Disclosure) 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](index=617&type=chunk) [Item 9A. Controls and Procedures](index=114&type=section&id=Item%209A.%20Controls%20and%20Procedures) 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](index=619&type=chunk) - Management concluded that internal control over financial reporting was effective as of December 31, 2021[620](index=620&type=chunk) - As an 'emerging growth company,' the company is exempt from the auditor attestation report on internal control over financial reporting[621](index=621&type=chunk) - No material changes in internal control over financial reporting occurred during the quarter ended December 31, 2021[621](index=621&type=chunk) [Item 9B. Other Information](index=114&type=section&id=Item%209B.%20Other%20Information) No other information required to be disclosed in this item - None[622](index=622&type=chunk) [Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections](index=114&type=section&id=Item%209C.%20Disclosure%20Regarding%20Foreign%20Jurisdictions%20that%20Prevent%20Inspections) This item is not applicable to Homology Medicines, Inc - Not applicable[623](index=623&type=chunk) PART III [Item 10. Directors, Executive Officers and Corporate Governance](index=115&type=section&id=Item%2010.%20Directors%2C%20Executive%20Officers%20and%20Corporate%20Governance) This section details executive officers, directors, corporate governance, Section 16(a) compliance, and director independence [Directors and Executive Officers](index=115&type=section&id=Directors%20and%20Executive%20Officers) [Delinquent Section 16(a) Reports](index=117&type=section&id=Delinquent%20Section%2016%28a%29%20Reports) [Code of Ethics](index=118&type=section&id=Code%20of%20Ethics) [Audit Committee and Audit Committee Financial Expert](index=118&type=section&id=Audit%20Committee%20and%20Audit%20Committee%20Financial%20Expert) [Family Relationships](index=118&type=section&id=Family%20Relationships) Executive Officers and Directors | Name | Age | Position |

[PART I. FINANCIAL INFORMATION](index=5&type=section&id=PART%20I.%20FINANCIAL%20INFORMATION) [Item 1. Financial Statements](index=5&type=section&id=Item%201.%20Condensed%20Consolidated%20Financial%20Statements%20(Unaudited)) The unaudited financial statements show decreased assets and a significantly reduced net loss for the nine-month period Condensed Consolidated Balance Sheet Data (in thousands) | Metric | Sep 30, 2021 | Dec 31, 2020 | | :--- | :--- | :--- | | Cash and cash equivalents | $95,829 | $217,431 | | Total Assets | $230,816 | $263,737 | | Total Liabilities | $32,245 | $67,742 | | Total Stockholders' Equity | $198,571 | $195,995 | Condensed Consolidated Statements of Operations Data (in thousands) | Metric | Three Months Ended Sep 30, 2021 | Three Months Ended Sep 30, 2020 | Nine Months Ended Sep 30, 2021 | Nine Months Ended Sep 30, 2020 | | :--- | :--- | :--- | :--- | :--- | | Collaboration Revenue | $1,677 | $567 | $33,169 | $1,722 | | Research and Development | $23,987 | $20,417 | $69,439 | $77,197 | | General and Administrative | $8,351 | $8,423 | $26,054 | $24,986 | | Net Loss | $(30,608) | $(28,232) | $(62,181) | $(98,903) | | Net Loss per Share | $(0.54) | $(0.62) | $(1.14) | $(2.19) | - For the nine months ended September 30, 2021, net cash used in operating activities was **$79.3 million**, while net cash provided by financing activities was **$52.2 million**[29](index=29&type=chunk) - The company's collaboration agreement with Novartis was terminated, resulting in the recognition of approximately **$26.9 million** in collaboration revenue[102](index=102&type=chunk)[103](index=103&type=chunk) [Management's Discussion and Analysis of Financial Condition and Results of Operations](index=27&type=section&id=Item%202.%20Management's%20Discussion%20and%20Analysis%20of%20Financial%20Condition%20and%20Results%20of%20Operations) This analysis covers financial results, clinical program progress, the impact of the Novartis collaboration, and the company's liquidity position [Overview](index=27&type=section&id=Overview) - Homology Medicines is a clinical-stage company using its proprietary AAVHSC platform for in vivo gene therapy and nuclease-free gene editing[114](index=114&type=chunk) - Key clinical programs include HMI-102 for PKU gene therapy, HMI-103 for PKU gene editing, and HMI-203 for Hunter syndrome gene therapy[114](index=114&type=chunk)[121](index=121&type=chunk)[122](index=122&type=chunk) - The company operates a 25,000-square-foot GMP manufacturing facility and has produced GMP material at the 500-liter scale[116](index=116&type=chunk) - The collaboration and license agreement with Novartis was terminated, with Homology regaining worldwide exclusive rights to the remaining ophthalmic target[127](index=127&type=chunk) [Results of Operations](index=34&type=section&id=Results%20of%20Operations) Comparison of Nine Months Ended September 30, 2021 and 2020 (in thousands) | Metric | 2021 | 2020 | Change | | :--- | :--- | :--- | :--- | | Collaboration Revenue | $33,169 | $1,722 | $31,447 | | Research and Development Expenses | $69,439 | $77,197 | $(7,758) | | General and Administrative Expenses | $26,054 | $24,986 | $1,068 | | Net Loss | $(62,181) | $(98,903) | $36,722 | - Collaboration revenue for the nine months ended Sep 30, 2021, increased to **$33.2 million**, primarily due to recognizing **$28.5 million** upon Novartis's termination notice[168](index=168&type=chunk) - Research and development expenses for the nine months ended Sep 30, 2021, decreased by **$7.8 million**, mainly due to a **$12.7 million** reduction in HMI-102 external costs[169](index=169&type=chunk) [Liquidity and Capital Resources](index=39&type=section&id=Liquidity%20and%20Capital%20Resources) - As of September 30, 2021, the company had **$187.6 million** in cash, cash equivalents, and short-term investments[179](index=179&type=chunk) - Management believes existing cash will fund operations and capital expenditures into the **first quarter of 2023**[189](index=189&type=chunk) - In April 2021, the company completed a follow-on public offering, raising net proceeds of approximately **$49.7 million**[177](index=177&type=chunk) - Net cash used in operating activities for the nine months ended September 30, 2021, was **$79.3 million**, driven by the net loss and a decrease in deferred revenue[181](index=181&type=chunk) [Quantitative and Qualitative Disclosures About Market Risk](index=43&type=section&id=Item%203.%20Quantitative%20and%20Qualitative%20Disclosures%20About%20Market%20Risk) The company's primary market risk is interest rate sensitivity on its cash and investments, with no outstanding debt as of September 30, 2021 - The company's primary market risk is interest rate sensitivity related to its **$187.6 million** in cash, cash equivalents, and short-term investments[196](index=196&type=chunk) - The company had **no debt outstanding** as of September 30, 2021[196](index=196&type=chunk) [Controls and Procedures](index=43&type=section&id=Item%204.%20Controls%20and%20Procedures) Management concluded that disclosure controls and procedures were effective, with no material changes to internal controls during the quarter - Based on an evaluation as of the end of the period, the CEO and CFO concluded that the company's disclosure controls and procedures were **effective**[198](index=198&type=chunk) - There were **no material changes** in internal control over financial reporting during the quarter[199](index=199&type=chunk) [PART II. OTHER INFORMATION](index=44&type=section&id=PART%20II.%20OTHER%20INFORMATION) [Legal Proceedings](index=44&type=section&id=Item%201.%20Legal%20Proceedings) The company is not currently a party to any material legal proceedings - The company is **not party to any material legal proceedings**[201](index=201&type=chunk) [Risk Factors](index=44&type=section&id=Item%201A.%20Risk%20Factors) The company faces risks related to its history of losses, capital needs, dependence on lead candidates, and uncertainties in development and regulation [Financial and Capital Risks](index=44&type=section&id=Risks%20Related%20to%20Our%20Financial%20Position%20and%20Need%20for%20Additional%20Capital) - The company has a history of significant losses, with an accumulated deficit of approximately **$390.5 million** as of September 30, 2021[203](index=203&type=chunk) - Additional capital is required to fund operations, and failure to obtain financing could prevent the development and commercialization of product candidates[207](index=207&type=chunk) - The business is heavily dependent on the success of **HMI-102**, its most advanced product candidate[217](index=217&type=chunk) [Discovery, Development, and Regulatory Risks](index=48&type=section&id=Risks%20Related%20to%20Discovery%2C%20Development%2C%20Clinical%20Testing%2C%20Manufacturing%20and%20Regulatory%20Approval) - The company's novel genetic medicines platform makes it difficult to predict development timelines and costs[225](index=225&type=chunk) - The regulatory landscape for gene therapy and gene editing is uncertain and evolving, which could delay or prevent approval[227](index=227&type=chunk) - Clinical trials are expensive and time-consuming, and delays in patient enrollment for rare diseases could adversely affect development[233](index=233&type=chunk)[259](index=259&type=chunk) - Product candidates may cause serious adverse events, which could lead to trial halts or denial of regulatory approval[262](index=262&type=chunk) [Commercialization Risks](index=69&type=section&id=Risks%20Related%20to%20Commercialization) - The company faces significant competition from major pharmaceutical and biotechnology companies with greater financial resources[305](index=305&type=chunk)[309](index=309&type=chunk) - Successful commercialization depends on obtaining adequate coverage and reimbursement from payors, which is uncertain[311](index=311&type=chunk)[312](index=312&type=chunk) - The company lacks infrastructure for sales, marketing, and distribution and must build these capabilities or collaborate with third parties[321](index=321&type=chunk) [Intellectual Property Risks](index=76&type=section&id=Risks%20Related%20to%20Our%20Intellectual%20Property) - Success depends on obtaining and maintaining patent protection for its technology, but the patent position of biotech companies is highly uncertain[352](index=352&type=chunk)[355](index=355&type=chunk) - The company may face third-party claims of patent infringement, which could result in substantial costs or delay development[357](index=357&type=chunk) - Changes in U.S. patent laws, such as the transition to a "first-to-file" system, could diminish the value of patents[365](index=365&type=chunk)[366](index=366&type=chunk) [General Business and Employee Risks](index=85&type=section&id=Risks%20Related%20to%20Employee%20Matters%20and%20Managing%20Growth%20and%20Other%20Risks%20Related%20to%20Our%20Business) - The **COVID-19 pandemic** could adversely impact business operations, including clinical trial enrollment and supply chain[386](index=386&type=chunk)[387](index=387&type=chunk) - Future success is highly dependent on the ability to attract and retain key executive, scientific, and clinical personnel[390](index=390&type=chunk)[391](index=391&type=chunk) - As an "emerging growth company," the company is subject to reduced disclosure requirements, which may make its stock less attractive to investors[396](index=396&type=chunk) [Other Information](index=93&type=section&id=Item%205.%20Other%20Information) The company amended its lease to expand its corporate headquarters and extend the lease term to June 30, 2030 - On November 9, 2021, the company amended its lease for its corporate headquarters, expanding the premises by approximately **23,011 square feet**[416](index=416&type=chunk)[417](index=417&type=chunk) - The amendment extends the lease term for the existing premises from February 28, 2027, to **June 30, 2030**[417](index=417&type=chunk) [Exhibits](index=94&type=section&id=Item%206.%20Exhibits) This section lists all exhibits filed with the Form 10-Q, including corporate documents and officer certifications - Lists exhibits filed with the report, including corporate governance documents, the amended lease agreement, and officer certifications[421](index=421&type=chunk)