PART I. FINANCIAL INFORMATION This section provides the unaudited condensed consolidated financial statements and management's discussion and analysis for the period [Item 1. Condensed Consolidated Financial Statements (Unaudited)](index=7&type=section&id=Item%201.%20Condensed%20Consolidated%20Financial%20Statements%20%28Unaudited%29) This section presents the unaudited condensed consolidated financial statements of AVROBIO, Inc. for the period ended March 31, 2022, including balance sheets, statements of operations and comprehensive loss, statements of stockholders' equity, and statements of cash flows, along with detailed notes explaining the company's business, accounting policies, license agreements, and financial position [Balance Sheets](index=7&type=section&id=Balance%20Sheets) This section presents the company's financial position, including assets, liabilities, and equity, as of specific dates Balance Sheet Summary | Metric | March 31, 2022 (in thousands) | December 31, 2021 (in thousands) | | :----- | :---------------------------- | :------------------------------- | | Total Assets | $175,343 | $203,837 | | Total Liabilities | $32,180 | $34,361 | | Total Stockholders' Equity | $143,163 | $169,476 | | Cash and Cash Equivalents | $161,663 | $189,567 | [Statements of Operations and Comprehensive Loss](index=8&type=section&id=Statements%20of%20Operations%20and%20Comprehensive%20Loss) This section details the company's financial performance, including revenues, expenses, and net loss, over specific periods Statements of Operations Summary | Metric | Three Months Ended March 31, 2022 (in thousands) | Three Months Ended March 31, 2021 (in thousands) | Change (YoY) | | :----- | :----------------------------------------------- | :----------------------------------------------- | :----------- | | Research and Development | $19,253 | $18,527 | +$726 | | General and Administrative | $10,165 | $8,357 | +$1,808 | | Total Operating Expenses | $29,418 | $26,884 | +$2,534 | | Net Loss | $(29,833) | $(26,899) | $(2,934) | | Net Loss Per Share (Basic and Diluted) | $(0.68) | $(0.65) | $(0.03) | [Statements of Stockholders' Equity](index=9&type=section&id=Statements%20of%20Stockholders%27%20Equity) This section outlines changes in the company's equity accounts, including common stock and accumulated deficit, over specific periods Stockholders' Equity Summary | Metric | March 31, 2022 (in thousands) | December 31, 2021 (in thousands) | | :----- | :---------------------------- | :------------------------------- | | Common Stock | $4 | $4 | | Additional Paid-in Capital | $556,534 | $553,014 | | Accumulated Deficit | $(413,375) | $(383,542) | | Total Stockholders' Equity | $143,163 | $169,476 | - **Stock-based compensation expense** for the three months ended March 31, 2022, was **$3,378 thousand**, and **$4,635 thousand** for the same period in 2021[24](index=24&type=chunk) [Statements of Cash Flows](index=10&type=section&id=Statements%20of%20Cash%20Flows) This section reports the cash inflows and outflows from operating, investing, and financing activities over specific periods Cash Flow Summary | Metric | Three Months Ended March 31, 2022 (in thousands) | Three Months Ended March 31, 2021 (in thousands) | | :----- | :----------------------------------------------- | :----------------------------------------------- | | Net Cash Used in Operating Activities | $(28,014) | $(27,339) | | Net Cash Used in Investing Activities | $(32) | $(115) | | Net Cash Provided by Financing Activities | $142 | $799 | | Net Decrease in Cash, Cash Equivalents and Restricted Cash | $(27,904) | $(26,655) | | Cash, Cash Equivalents and Restricted Cash at End of Period | $162,155 | $233,519 | [Notes to Consolidated Financial Statements](index=11&type=section&id=Notes%20to%20Consolidated%20Financial%20Statements) This section provides detailed explanations and disclosures supporting the condensed consolidated financial statements [1. Nature of the Business](index=11&type=section&id=1.%20Nature%20of%20the%20Business) This note describes AVROBIO's core business as a clinical-stage gene therapy company and its financial viability - AVROBIO is a **clinical-stage gene therapy company** focused on developing potentially **curative ex vivo lentiviral gene therapies** to treat **rare diseases** following a **single dose treatment regimen**[29](index=29&type=chunk) - The company has incurred **recurring net losses since inception**, including **$29.8 million** for the three months ended March 31, 2022, and had an **accumulated deficit of $413.4 million** as of March 31, 2022[31](index=31&type=chunk) - Existing cash and cash equivalents of **$161.7 million** as of March 31, 2022, are expected to fund current planned operations and capital expenditure requirements for **at least the next twelve months**, but **future viability depends on raising additional capital**[31](index=31&type=chunk) [2. Summary of Significant Accounting Policies](index=11&type=section&id=2.%20Summary%20of%20Significant%20Accounting%20Policies) This note outlines the key accounting principles and methods used in preparing the financial statements - The unaudited condensed consolidated financial statements are **prepared in conformity with GAAP** and reflect all necessary adjustments for fair presentation[32](index=32&type=chunk)[33](index=33&type=chunk) - The company operates and manages its business as **one operating segment**, with all material long-lived assets residing in the United States[37](index=37&type=chunk) - As an **'emerging growth company' (EGC)**, AVROBIO has elected to use the **extended transition period for complying with new or revised accounting standards**[46](index=46&type=chunk) [3. License Agreements](index=14&type=section&id=3.%20License%20Agreements) This note details the company's exclusive worldwide license agreements for various gene therapy programs - The company holds an **exclusive worldwide license** from The University of Manchester for an ex vivo lentiviral gene therapy for Hunter syndrome (MPSII), with **potential milestone payments up to $80 million** and **mid-single digit royalties**. Incurred **$963 thousand** related to collaborative research funding in Q1 2022[53](index=53&type=chunk)[54](index=54&type=chunk)[56](index=56&type=chunk) - AVROBIO has an **exclusive worldwide license** from University Health Network (UHN) for Fabry disease, incurring **$24 thousand** in R&D expense in Q1 2022. Another **exclusive license** with UHN for Interleukin 12 patent rights incurred no R&D expense in Q1 2022[57](index=57&type=chunk)[60](index=60&type=chunk)[63](index=63&type=chunk)[65](index=65&type=chunk) - The company also holds **exclusive worldwide licenses** for Pompe disease (from BioMarin Pharmaceutical Inc.), cystinosis (from Papillon Therapeutics, Inc.), and Gaucher disease (from Lund University Rights Holders), with no related expenses recognized in Q1 2022 for these agreements[66](index=66&type=chunk)[67](index=67&type=chunk)[70](index=70&type=chunk)[71](index=71&type=chunk)[72](index=72&type=chunk)[73](index=73&type=chunk) [4. Fair Value Measurement](index=17&type=section&id=4.%20Fair%20Value%20Measurement) This note provides information on the fair value of financial instruments, particularly cash equivalents Fair Value Measurement Details | Asset | March 31, 2022 (in thousands) | December 31, 2021 (in thousands) | | :---- | :---------------------------- | :------------------------------- | | Cash equivalents — money market funds | $160,512 | $189,332 | - The **fair value of cash equivalents was determined through quoted prices by third-party pricing services (Level 1 inputs)**[77](index=77&type=chunk) [5. Supplemental Balance Sheet Information](index=18&type=section&id=5.%20Supplemental%20Balance%20Sheet%20Information) This note offers additional details on specific balance sheet accounts, such as prepaid expenses and accrued liabilities Supplemental Balance Sheet Details | Category | March 31, 2022 (in thousands) | December 31, 2021 (in thousands) | | :------- | :---------------------------- | :------------------------------- | | Prepaid expenses and other current assets | $9,258 | $9,578 | | Property and equipment, net | $3,867 | $4,126 | | Restricted cash | $492 | $492 | | Accrued expenses and other current liabilities | $12,879 | $15,638 | [6. Commitments and Contingencies](index=19&type=section&id=6.%20Commitments%20and%20Contingencies) This note discloses the company's contractual obligations, potential legal proceedings, and indemnification agreements - The company was **not subject to any material legal proceedings** during the three months ended March 31, 2022 and 2021, and no material legal proceedings are currently pending or threatened[85](index=85&type=chunk) - AVROBIO is party to various agreements requiring future milestone and royalty payments, and enters into **standard indemnification agreements with unknown maximum exposure**, but **does not anticipate significant losses**[86](index=86&type=chunk) [7. Note Payable](index=19&type=section&id=7.%20Note%20Payable) This note describes the terms and conditions of the company's term loan agreement and related obligations - In November 2021, the company entered into a **Term Loan Agreement** for up to **$50 million**, with **$15 million** advanced on the closing date. The **$20 million Milestone Funding tranche is no longer available** due to the **deprioritization of the Fabry program**[87](index=87&type=chunk)[149](index=149&type=chunk) - The note payable, net of discount, was **$15,020 thousand** as of March 31, 2022. The **loan bears interest at the greater of Prime Rate + 4.85% or 8.10%**, with an **effective interest rate of approximately 11.12%**[88](index=88&type=chunk)[90](index=90&type=chunk)[91](index=91&type=chunk) - **Interest-only payments are required through November 1, 2024**, followed by **principal and interest installments through October 1, 2026**. An **end-of-term charge of 9.00%** of the aggregate principal amount is due upon repayment[88](index=88&type=chunk)[89](index=89&type=chunk) [8. Stockholders' Equity](index=21&type=section&id=8.%20Stockholders%27%20Equity) This note provides details on the company's authorized and outstanding shares, and shares reserved for future issuance - As of March 31, 2022, the company had **150,000,000 authorized common shares** and **10,000,000 undesignated preferred shares**, with **no preferred stock outstanding**. **No cash dividends have been declared or paid**[95](index=95&type=chunk) Shares Reserved for Future Issuance | Shares Reserved for Future Issuance | March 31, 2022 | December 31, 2021 | | :---------------------------------- | :------------- | :---------------- | | Exercise of outstanding stock options | 9,471,305 | 7,423,777 | | Vesting of restricted stock units | 919,853 | 599,850 | | Issuance under 2018 Stock Option and Grant Plan | 1,777,657 | 2,583,736 | | Issuance under 2018 Employee Stock Purchase Plan | 1,544,308 | 1,151,010 | | Issuance under 2019 Inducement Plan | 573,944 | 412,686 | | Issuance under 2020 Inducement Plan | 1,637,000 | 1,637,000 | | Total shares reserved | 15,924,067 | 13,808,059 | [9. Stock-based Compensation](index=21&type=section&id=9.%20Stock-based%20Compensation) This note explains the accounting for stock-based awards and the related compensation expense recognized Stock-based Compensation Expense | Stock-based Compensation Expense | Three Months Ended March 31, 2022 (in thousands) | Three Months Ended March 31, 2021 (in thousands) | | :------------------------------- | :----------------------------------------------- | :----------------------------------------------- | | Research and development | $939 | $2,115 | | General and administrative | $2,439 | $2,520 | | Total | $3,378 | $4,635 | - The **weighted-average grant-date fair value of stock options granted decreased** from **$10.69** in Q1 2021 to **$1.29** in Q1 2022[102](index=102&type=chunk) - As of March 31, 2022, **total unrecognized compensation cost related to unvested stock-based awards** was **$34,360 thousand**, expected to be recognized over a **weighted-average period of 2.78 years**[107](index=107&type=chunk) [10. Net Loss Per Share](index=23&type=section&id=10.%20Net%20Loss%20Per%20Share) This note details the calculation of basic and diluted net loss per share for the reporting periods - Basic and diluted net loss per share was **$(0.68)** for the three months ended March 31, 2022, compared to **$(0.65)** for the same period in 2021[20](index=20&type=chunk) - **Potentially dilutive common stock equivalents**, including **9,471,305 options** and **919,853 restricted stock units** as of March 31, 2022, were **excluded from the diluted net loss per share calculation as their effect would be anti-dilutive**[108](index=108&type=chunk)[109](index=109&type=chunk) [11. Related Party Transactions](index=23&type=section&id=11.%20Related%20Party%20Transactions) This note discloses transactions with entities or individuals considered related parties to the company - The company recognized **$24 thousand** in research and development expense related to license agreements with University Health Network (UHN) for the three months ended March 31, 2022, down from **$39 thousand** in the prior year[110](index=110&type=chunk) - Expenses of **$794 thousand** were recorded for a sublease to rent lab space from an entity affiliated with a board member for the three months ended March 31, 2022, an increase from **$641 thousand** in the prior year[111](index=111&type=chunk) [12. Restructuring Activities](index=23&type=section&id=12.%20Restructuring%20Activities) This note describes the company's restructuring efforts, including program deprioritization and workforce reductions - In January 2022, AVROBIO **deprioritized its AVR-RD-01 Fabry disease program** due to **new clinical data showing variable engraftment patterns and a challenging market/regulatory environment**[112](index=112&type=chunk) - A **workforce reduction of approximately 23%** was approved, resulting in **total restructuring expenses of $1,369 thousand** for the three months ended March 31, 2022, **primarily for employee termination benefits**[112](index=112&type=chunk)[115](index=115&type=chunk) [Item 2. Management's Discussion and Analysis of Financial Condition and Results of Operations](index=25&type=section&id=Item%202.%20Management%27s%20Discussion%20and%20Analysis%20of%20Financial%20Condition%20and%20Results%20of%20Operations) This section provides management's perspective on AVROBIO's financial condition and operational results for the three months ended March 31, 2022, highlighting the company's focus on clinical-stage gene therapies for rare diseases, its financial performance, liquidity, and future funding requirements, including the impact of the Fabry program deprioritization and workforce reduction [Overview](index=25&type=section&id=Overview) This section provides a high-level summary of AVROBIO's business, pipeline, and financial performance - AVROBIO is a **clinical-stage gene therapy company** focused on developing potentially **curative ex vivo lentiviral-based gene therapies** for **rare diseases**, particularly lysosomal disorders[118](index=118&type=chunk) - The company's pipeline includes **five lentiviral-based gene therapy programs**: AVR-RD-04 (cystinosis), AVR-RD-02 (Gaucher disease type 1), AVR-RD-05 (Hunter syndrome), AVR-RD-06 (Gaucher disease type 3), and AVR-RD-03 (Pompe disease)[119](index=119&type=chunk) - AVROBIO has incurred **significant operating losses since inception**, with a net loss of **$29.8 million** for Q1 2022 and an **accumulated deficit of $413.4 million** as of March 31, 2022[124](index=124&type=chunk)[125](index=125&type=chunk) - Existing cash and cash equivalents of **$161.7 million** are projected to fund operating expenses and capital expenditure requirements **into the first quarter of 2024**, but **substantial additional funding will be needed**[128](index=128&type=chunk) [Components of Our Consolidated Results of Operations](index=26&type=section&id=Components%20of%20Our%20Consolidated%20Results%20of%20Operations) This section breaks down the key components contributing to the company's consolidated financial results [Operating Expenses](index=26&type=section&id=Operating%20Expenses) This section details the company's research and development and general and administrative expenses [Research and Development Expenses](index=26&type=section&id=Research%20and%20Development%20Expenses) This section analyzes the trends and drivers of the company's research and development expenditures - Research and development expenses increased by approximately **$0.7 million** to **$19.3 million** for Q1 2022, from **$18.5 million** for Q1 2021, **primarily driven by a $1.8 million increase in clinical trial consulting expenses**[141](index=141&type=chunk) - The company expects R&D expenses to **increase substantially over the next several years** as product candidates advance through clinical development, requiring increased personnel, contractor, and facilities costs[132](index=132&type=chunk) [General and Administrative Expenses](index=28&type=section&id=General%20and%20Administrative%20Expenses) This section analyzes the trends and drivers of the company's general and administrative expenditures - General and administrative expenses increased by **$1.8 million** to **$10.2 million** for Q1 2022, compared to **$8.4 million** for Q1 2021[142](index=142&type=chunk) - This increase was **attributable to a $0.7 million rise in personnel-related costs (including severance from workforce reduction) and a $1.1 million increase in other expenses** (facilities, professional, and legal fees)[142](index=142&type=chunk) [Other (Expense) Income, Net](index=28&type=section&id=Other%20%28Expense%29%20Income%2C%20Net) This section details non-operating income and expenses, primarily interest expense - Other (expense), net, was **$(0.4) million** for Q1 2022, compared to less than **$(0.1) million** for Q1 2021, **primarily due to interest expense related to the Term Loan Agreement** entered in Q4 2021[143](index=143&type=chunk) [Consolidated Results of Operations](index=28&type=section&id=Consolidated%20Results%20of%20Operations) This section provides a comparative analysis of the company's consolidated operating results [Comparison of the three months ended March 31, 2022 and 2021](index=28&type=section&id=Comparison%20of%20the%20three%20months%20ended%20March%2031%2C%202022%20and%202021) This section compares the company's financial performance for the three-month periods ended March 31, 2022 and 2021 Operating Expense Comparison | Operating Expense | 2022 (in thousands) | 2021 (in thousands) | Change (in thousands) | | :---------------- | :------------------ | :------------------ | :-------------------- | | Research and Development | $19,253 | $18,527 | $726 | | General and Administrative | $10,165 | $8,357 | $1,808 | | Total Operating Expenses | $29,418 | $26,884 | $2,534 | | Loss from Operations | $(29,418) | $(26,884) | $(2,534) | | Total Other (Expense) Income, Net | $(415) | $(15) | $(400) | | Net Loss | $(29,833) | $(26,899) | $(2,934) | [Liquidity and Capital Resources](index=29&type=section&id=Liquidity%20and%20Capital%20Resources) This section discusses the company's ability to meet its short-term and long-term financial obligations and its funding sources - Since inception, AVROBIO has **funded operations primarily through sales of preferred stock ($87.5 million)**, **common stock through IPO and follow-on offerings ($428.1 million)**, **ATM facility sales ($23.5 million)**, and **$15.0 million from a term loan**[123](index=123&type=chunk)[144](index=144&type=chunk) - As of March 31, 2022, the company had **$161.7 million** in cash and cash equivalents, which are **expected to fund operating expenses and capital expenditure requirements into the first quarter of 2024**[128](index=128&type=chunk)[150](index=150&type=chunk) - The **$20.0 million Milestone Funding tranche under the Term Loan Agreement is no longer available** due to the **deprioritization of the Fabry disease program**[149](index=149&type=chunk) [Cash Flows](index=30&type=section&id=Cash%20Flows) This section analyzes the company's cash inflows and outflows from operating, investing, and financing activities Cash Flow Summary | Cash Flow Activity | Three Months Ended March 31, 2022 (in thousands) | Three Months Ended March 31, 2021 (in thousands) | | :----------------- | :----------------------------------------------- | :----------------------------------------------- | | Net cash used in operating activities | $(28,014) | $(27,339) | | Net cash used in investing activities | $(32) | $(115) | | Net cash provided by financing activities | $142 | $799 | | Net (decrease) in cash and cash equivalents | $(27,904) | $(26,655) | - The **decrease in cash provided by financing activities** in Q1 2022 was **primarily due to lower proceeds from stock option exercises** compared to Q1 2021, **partially offset by proceeds from ESPP shares**[155](index=155&type=chunk) [Funding Requirements](index=31&type=section&id=Funding%20Requirements) This section outlines the company's anticipated future capital needs and strategies for securing additional funding - Expenses are **expected to increase substantially** with ongoing preclinical activities, clinical trials, and potential commercialization efforts for product candidates[156](index=156&type=chunk) - The company anticipates **financing future cash needs through equity offerings, debt financings, collaboration agreements, and other third-party funding**, as **product revenue is not expected for several years**[158](index=158&type=chunk) [Contractual Obligations and Commitments](index=31&type=section&id=Contractual%20Obligations%20and%20Commitments) This section refers to disclosures regarding the company's long-term contractual obligations and commitments - Disclosure of contractual obligations and commitments is set forth in the Annual Report on Form 10-K for the fiscal year ended December 31, 2021[159](index=159&type=chunk) [Critical Accounting Policies and Significant Judgments and Estimates](index=31&type=section&id=Critical%20Accounting%20Policies%20and%20Significant%20Judgments%20and%20Estimates) This section confirms no material changes to the company's critical accounting policies during the reporting period - There were **no material changes to the company's critical accounting policies** during the three months ended March 31, 2022[160](index=160&type=chunk) [Emerging Growth Company Status](index=32&type=section&id=Emerging%20Growth%20Company%20Status) This section explains the company's status as an emerging growth company and its election of certain exemptions - AVROBIO is an **'emerging growth company' (EGC)** and takes advantage of certain exemptions from reporting requirements, including an **extended transition period for new or revised accounting standards**[161](index=161&type=chunk) [Recently Issued Accounting Pronouncements](index=32&type=section&id=Recently%20Issued%20Accounting%20Pronouncements) This section refers to disclosures regarding recently issued accounting pronouncements and their potential impact - A description of recently issued accounting pronouncements that may impact financial position and results of operations is disclosed in Note 2, 'Summary of Significant Accounting Policies'[162](index=162&type=chunk) [Item 3. Quantitative and Qualitative Disclosures About Market Risk](index=32&type=section&id=Item%203.%20Quantitative%20and%20Qualitative%20Disclosures%20About%20Market%20Risk) This section discusses AVROBIO's exposure to market risks, specifically interest rate risk on its cash equivalents and foreign currency exchange risk from international operations, and the company's strategies for managing these risks [Interest Rate Risk](index=32&type=section&id=Interest%20Rate%20Risk) This section analyzes the company's exposure to interest rate fluctuations on its cash equivalents and debt obligations - AVROBIO's **primary exposure to market risk is interest rate sensitivity**, affecting its **$161.7 million** in cash and cash equivalents, primarily held in short-term money market funds[163](index=163&type=chunk) - Due to the **short-term duration and low-risk profile of its investment portfolio**, an **immediate 100 basis point change in interest rates would not materially affect the fair market value** of the portfolio[163](index=163&type=chunk) [Foreign Currency Exchange Risk](index=32&type=section&id=Foreign%20Currency%20Exchange%20Risk) This section discusses the company's exposure to foreign currency exchange rate fluctuations from international operations - The company is **exposed to foreign exchange rate risk** from research and development costs incurred by its Australian and Canadian subsidiaries in Australian and Canadian dollars, respectively[164](index=164&type=chunk) - **Foreign currency transaction losses of $46 thousand** were recognized for the three months ended March 31, 2022, compared to **$25 thousand** for the same period in 2021[164](index=164&type=chunk) - A **10% change in the exchange rate** between the U.S. dollar, Australian dollar, Great British Pound, and Canadian dollar is **not expected to have a material impact** on the company's financial position or results of operations[164](index=164&type=chunk) [Item 4. Controls and Procedures](index=33&type=section&id=Item%204.%20Controls%20and%20Procedures) This section details management's evaluation of the company's disclosure controls and procedures and reports on any changes in internal control over financial reporting [Evaluation of Disclosure Controls and Procedures](index=33&type=section&id=Evaluation%20of%20Disclosure%20Controls%20and%20Procedures) This section details management's assessment of the effectiveness of the company's disclosure controls and procedures - Management, with the participation of the CEO and CFO, evaluated the **effectiveness of disclosure controls and procedures as of March 31, 2022, and concluded they were effective at the reasonable assurance level**[167](index=167&type=chunk) [Changes in Internal Control over Financial Reporting](index=33&type=section&id=Changes%20in%20Internal%20Control%20over%20Financial%20Reporting) This section reports on any material changes in the company's internal control over financial reporting - **No change in internal control over financial reporting occurred** during the three months ended March 31, 2022, that materially affected, or is reasonably likely to materially affect, internal control over financial reporting[168](index=168&type=chunk) PART II. OTHER INFORMATION This section provides additional disclosures including legal proceedings, risk factors, and other required information [Item 1. Legal Proceedings](index=34&type=section&id=Item%201.%20Legal%20Proceedings) This section confirms the absence of any material legal proceedings against the company - As of March 31, 2022, AVROBIO was **not subject to any pending or threatened litigation that, if determined adversely, would reasonably be expected to have a material adverse effect on its business**[170](index=170&type=chunk) [Item 1A. Risk Factors](index=34&type=section&id=Item%201A.%20Risk%20Factors) This section outlines the significant risks and uncertainties that could adversely affect AVROBIO's business, financial condition, and results of operations, covering aspects from financial viability and product development to manufacturing, commercialization, intellectual property, and stock ownership [Risks related to our business, financial position and need for additional capital](index=34&type=section&id=Risks%20related%20to%20our%20business%2C%20financial%20position%20and%20need%20for%20additional%20capital) This section highlights risks associated with the company's financial viability, ongoing losses, and future funding requirements - AVROBIO has incurred **net losses since inception** and expects to continue incurring losses for the foreseeable future, potentially **never achieving or maintaining profitability**[172](index=172&type=chunk)[174](index=174&type=chunk) - The company will need **substantial additional funding, which may not be available on acceptable terms**, potentially **forcing delays, limitations, or termination of product development efforts**[177](index=177&type=chunk)[180](index=180&type=chunk) - The **Term Loan Agreement contains restrictions limiting operational flexibility**, and the **$20.0 million Milestone Funding tranche is no longer available** due to the **deprioritization of the Fabry program**[181](index=181&type=chunk)[182](index=182&type=chunk) [Risks related to the discovery and development of our product candidates](index=37&type=section&id=Risks%20related%20to%20the%20discovery%20and%20development%20of%20our%20product%20candidates) This section outlines risks inherent in the discovery, development, and regulatory approval of the company's gene therapy product candidates - The **ongoing COVID-19 pandemic has caused and may continue to cause disruptions to clinical trial programs**, clinical supply, and business operations, impacting patient enrollment and data collection[187](index=187&type=chunk)[188](index=188&type=chunk)[189](index=189&type=chunk)[191](index=191&type=chunk) - **Lentiviral-based gene therapy is a novel technology**, making it **difficult to predict the time and cost of product candidate development and regulatory approval**, which can be **more expensive and lengthy**[193](index=193&type=chunk)[194](index=194&type=chunk) - Product candidates and their administration process may cause **undesirable side effects, including delayed adverse events**, which could **delay or prevent regulatory approval, limit commercial potential, or result in significant negative consequences**[199](index=199&type=chunk)[200](index=200&type=chunk)[201](index=201&type=chunk)[203](index=203&type=chunk)[204](index=204&type=chunk) - **Success in preclinical studies or early clinical trials may not be indicative of later trial results**; the **deprioritization of the Fabry program due to variable engraftment patterns in later-stage patients highlights this risk**[211](index=211&type=chunk) - **Difficulty enrolling patients in clinical trials, especially for rare diseases and international patients**, could **delay or prevent the progression of product candidates**[217](index=217&type=chunk)[218](index=218&type=chunk)[219](index=219&type=chunk)[221](index=221&type=chunk)[222](index=222&type=chunk) - The company faces **significant competition from larger pharmaceutical and biotechnology companies with greater resources and established therapies**[233](index=233&type=chunk)[234](index=234&type=chunk)[235](index=235&type=chunk)[236](index=236&type=chunk) [Risks related to manufacturing](index=50&type=section&id=Risks%20related%20to%20manufacturing) This section details risks associated with the complex manufacturing processes for gene therapies, including production interruptions and quality control - **Gene therapies are novel, complex, and difficult to manufacture**, posing risks of **production interruptions, equipment malfunctions, facility contamination, raw material shortages, and human error**[256](index=256&type=chunk)[257](index=257&type=chunk) - Even **minor deviations in the manufacturing process could result in product defects, lot failures, product recalls, or insufficient inventory**, **delaying clinical trials or commercial launches**[257](index=257&type=chunk)[258](index=258&type=chunk) [Risks related to our reliance on third parties](index=50&type=section&id=Risks%20related%20to%20our%20reliance%20on%20third%20parties) This section discusses risks arising from the company's dependence on third-party contractors for critical aspects of its operations - AVROBIO **relies on third parties for vector production, product manufacturing, protocol development, research, and preclinical/clinical testing**, which **reduces control and poses risks if these parties do not perform satisfactorily**[259](index=259&type=chunk)[260](index=260&type=chunk)[261](index=261&type=chunk)[262](index=262&type=chunk)[263](index=263&type=chunk) - The company **depends on sole source suppliers** for its **automated, closed cell processing system, vector supply, plasmid supply, cell culture media, and drug product manufacturing**, creating **significant supply chain risks**[264](index=264&type=chunk)[265](index=265&type=chunk)[266](index=266&type=chunk)[268](index=268&type=chunk)[269](index=269&type=chunk) - **Contract manufacturers are subject to extensive cGMP regulations**, and **failure to meet these requirements could lead to delays, regulatory sanctions, or facility closures**[271](index=271&type=chunk)[272](index=272&type=chunk)[273](index=273&type=chunk)[274](index=274&type=chunk) - **Reliance on third parties necessitates sharing trade secrets**, **increasing the risk of competitors discovering them or unauthorized disclosure**, which could **impair the company's competitive position**[275](index=275&type=chunk)[276](index=276&type=chunk)[277](index=277&type=chunk) [Risks related to commercialization of our product candidates](index=53&type=section&id=Risks%20related%20to%20commercialization%20of%20our%20product%20candidates) This section addresses risks concerning market acceptance, reimbursement, and regulatory hurdles for commercializing product candidates - If AVROBIO is **unable to establish its own sales, distribution, and marketing capabilities or enter into agreements with third parties**, it will be **unable to generate product revenue**[278](index=278&type=chunk)[279](index=279&type=chunk) - The **commercial success of any product candidate depends on market acceptance by physicians, patients, and third-party payors**, which is **uncertain for novel gene therapy products**[281](index=281&type=chunk)[282](index=282&type=chunk)[284](index=284&type=chunk) - The **insurance coverage and reimbursement status of newly-approved products are uncertain**, and **failure to obtain or maintain adequate coverage could limit marketability and revenue**[286](index=286&type=chunk)[287](index=287&type=chunk)[288](index=288&type=chunk)[289](index=289&type=chunk)[290](index=290&type=chunk) - **Healthcare legislative reform measures and cost containment initiatives, both domestically and internationally**, could **adversely affect demand, pricing, and profitability of product candidates**[291](index=291&type=chunk)[292](index=292&type=chunk)[294](index=294&type=chunk)[295](index=295&type=chunk)[296](index=296&type=chunk) - **Negative public opinion and increased regulatory scrutiny of gene therapy and genetic research** may **damage public perception of product candidates or adversely affect business operations and regulatory approvals**[302](index=302&type=chunk) [Risks related to our intellectual property](index=64&type=section&id=Risks%20related%20to%20our%20intellectual%20property) This section covers risks related to protecting the company's intellectual property, including patents and license agreements - **Third-party claims of intellectual property infringement may prevent or delay AVROBIO's development and commercialization efforts**, potentially requiring **substantial litigation expense or licensing fees**[331](index=331&type=chunk)[332](index=332&type=chunk)[334](index=334&type=chunk)[335](index=335&type=chunk)[336](index=336&type=chunk) - **Rights to develop and commercialize product candidates are subject to license agreements**, and **termination or disputes over these licenses could significantly harm the ability to commercialize products**[338](index=338&type=chunk)[339](index=339&type=chunk)[341](index=341&type=chunk)[342](index=342&type=chunk) - **Inability to obtain and maintain patent protection, or if the scope is insufficient**, could **allow competitors to develop similar products, adversely affecting commercialization**[343](index=343&type=chunk)[344](index=344&type=chunk)[345](index=345&type=chunk) - **Changes in U.S. patent law, including Supreme Court decisions**, could **diminish the value of patents and impair the ability to protect product candidates**[359](index=359&type=chunk)[360](index=360&type=chunk)[361](index=361&type=chunk)[362](index=362&type=chunk)[363](index=363&type=chunk) - **Failure to obtain patent term extension and data exclusivity for product candidates** could **materially harm the business by allowing competitors to enter the market sooner**[365](index=365&type=chunk) [Risks related to ownership of our common stock](index=71&type=section&id=Risks%20related%20to%20ownership%20of%20our%20common%20stock) This section outlines risks associated with the volatility of the company's stock price and corporate governance matters - The **market price of AVROBIO's common stock is highly volatile** and may be influenced by various factors, potentially **preventing investors from reselling shares at or above purchase price**[371](index=371&type=chunk)[372](index=372&type=chunk) - **Concentration of ownership among existing executive officers, directors, and principal stockholders** may prevent new investors from influencing significant corporate decisions[376](index=376&type=chunk) - As an **'emerging growth company' (EGC)**, AVROBIO's **reduced disclosure requirements** may **make its common stock less attractive to investors, potentially leading to a less active trading market and more volatile stock price**[378](index=378&type=chunk)[379](index=379&type=chunk)[380](index=380&type=chunk) - **Failure to maintain an effective system of internal control over financial reporting** could **lead to inaccurate financial reports, fraud, loss of investor confidence, and a decline in stock price**[384](index=384&type=chunk)[385](index=385&type=chunk)[386](index=386&type=chunk)[387](index=387&type=chunk) - **Provisions in the company's amended and restated certificate of incorporation and by-laws, along with Delaware law**, could **make it more difficult or costly for a third party to acquire the company**[392](index=392&type=chunk)[394](index=394&type=chunk) [General Risk Factors](index=76&type=section&id=General%20Risk%20Factors) This section presents broader risks, including economic conditions, cybersecurity, and changes in tax law, affecting the company - **Unfavorable global economic conditions, such as those caused by the COVID-19 pandemic or geopolitical events like the war in Ukraine**, could **adversely affect AVROBIO's business, financial condition, or results of operations**[397](index=397&type=chunk) - The **company's internal computer systems, or those of its collaborators, are vulnerable to security breaches (e.g., cyberattacks)**, which could **disrupt product development programs and harm business operations**[400](index=400&type=chunk) - **Changes in tax law could adversely affect AVROBIO's business and financial condition, impacting cash flow and results of operations**[401](index=401&type=chunk) [Item 2. Unregistered Sales of Equity Securities and Use of Proceeds](index=77&type=section&id=Item%202.%20Unregistered%20Sales%20of%20Equity%20Securities%20and%20Use%20of%20Proceeds) This item is marked as "Not applicable," indicating no information to report regarding unregistered sales of equity securities or use of proceeds for the period - Not applicable[402](index=402&type=chunk) [Item 3. Defaults Upon Senior Securities](index=77&type=section&id=Item%203.%20Defaults%20Upon%20Senior%20Securities) This item is marked as "Not applicable," indicating no information to report regarding defaults upon senior securities for the period - Not applicable[402](index=402&type=chunk) [Item 4. Mine Safety Disclosures](index=77&type=section&id=Item%204.%20Mine%20Safety%20Disclosures) This item is marked as "Not applicable," indicating no information to report regarding mine safety disclosures for the period - Not applicable[402](index=402&type=chunk) [Item 5. Other Information](index=77&type=section&id=Item%205.%20Other%20Information) This item is marked as "Not applicable," indicating no other information to report for the period - Not applicable[402](index=402&type=chunk) [Item 6. Exhibits](index=78&type=section&id=Item%206.%20Exhibits) This section lists all exhibits filed as part of the Form 10-Q, including corporate documents, certifications, and interactive data files - Exhibits include the Fourth Amended and Restated Certificate of Incorporation, Amended and Restated By-laws, and various certifications (e.g., Section 302, Section 906)[405](index=405&type=chunk) - Interactive Data Files (Inline XBRL) are furnished as part of the report[405](index=405&type=chunk) [Signatures](index=79&type=section&id=Signatures) This section contains the required signatures of the registrant's authorized officers, confirming the submission of the report - The report was signed by Geoff MacKay (President, Chief Executive Officer, and Principal Executive Officer) and Erik Ostrowski (Chief Financial Officer and Principal Financial and Accounting Officer) on May 10, 2022[408](index=408&type=chunk)