Core Viewpoint - Agios Pharmaceuticals' shares rose 5.2% following positive results from the phase III ENERGIZE study, which evaluated mitapivat for treating non-transfusion-dependent thalassemia patients, achieving both primary and key secondary endpoints [1][3]. Group 1: Study Results - The ENERGIZE study enrolled 194 adult participants with non-transfusion-dependent alpha- or beta-thalassemia, randomized into two groups: 130 received 100mg of mitapivat and 64 received a placebo over 24 weeks [3]. - Patients treated with mitapivat showed a statistically significant hemoglobin response, with 42.3% achieving this compared to only 1.6% in the placebo group [3]. - Key secondary endpoints also showed significant improvements in average FACIT-Fatigue score and hemoglobin concentration, indicating lower fatigue levels in mitapivat patients [3]. Group 2: Market Potential - Agios estimates that the thalassemia patient population in the U.S. is around 8,000, with more than half being non-transfusion-dependent patients, highlighting a significant market opportunity as there are currently no approved therapies for this group [4]. - Mitapivat was previously approved by the FDA in November 2022 for adults with pyruvate kinase deficiency, marketed as Pyrukynd [4]. Group 3: Future Developments - Agios plans to seek regulatory approval for mitapivat as a treatment for all thalassemia sub-types, regardless of transfusion dependency, following the ENERGIZE-T study results expected in mid-2024 [5]. - If approved, mitapivat could have a competitive advantage over existing treatments, as it is an orally administered drug compared to gene therapy and injectable options [6]. - Agios is also conducting the phase II/III RISE UP study for sickle cell disease, with the phase II portion achieving its primary endpoint, and aims for approval by 2026 [6].

Agios Pharmaceuticals (AGIO) shares rallied 5.2% in the last trading session to close at $24.02. This move can be attributable to notable volume with a higher number of shares being traded than in a typical session. This compares to the stock's 1.3% gain over the past four weeks.Share price rose after management reported encouraging results from a late-stage study, evaluating orally-administered mitapivat in non-transfusion-dependent (NTD) thalassemia patients. Patients treated with mitapivat achieved demon ...

–Mitapivat Demonstrated a Statistically Significant Increase in Hemoglobin Response Rate Compared to Placebo – – Statistical Significance Also Achieved for Key Secondary Endpoints of Change From Baseline in Both FACIT-Fatigue Score and Hemoglobin Concentration – – ENERGIZE is the First Phase 3 Study to Demonstrate Efficacy of an Oral Treatment for Non-Transfusion-Dependent Alpha- and Beta-Thalassemia – – Agios to Host Investor Webcast Event Today at 8:00 a.m. ET– CAMBRIDGE, Mass., Jan. 03, 2024 (GLOBE NEWSW ...

Agios Pharmaceuticals Inc.’s stock AGIO, +2.51% soared 19.6% early Wednesday, after the biotech announced positive results from a Phase 3 trial of a treatment for a rare blood disorder. The trial dubbed Energize sought to evaluate the company’s mitapivat therapy and met its primary endpoint of hemoglobin response in patients with non-transfusion-dependent (NTD) alpha- or beta-thalassemia. The trial also met secondary endpoints of change from baseline in FACIT-Fatigue Score and hemoglobin concentration. The ...

CAMBRIDGE, Mass., Jan. 02, 2024 (GLOBE NEWSWIRE) -- Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism pioneering therapies for rare diseases, today announced that the company is scheduled to present at the 42nd Annual J.P. Morgan Healthcare Conference on Wednesday, January 10, 2024, at 7:30 a.m. PT. A live webcast of the presentation can be accessed under "Events & Presentations" in the Investors section of the company's website at www.agios.com. A replay of the webcast ...

Financial Performance - The company reported a net loss of $256.1 million for the nine months ended September 30, 2023, compared to a net loss of $268.3 million for the same period in 2022[91]. - As of September 30, 2023, the company had an accumulated deficit of $726.7 million[91]. - Net loss for the three months ended September 30, 2023, was $91.3 million, compared to a net loss of $81.7 million for the same period in 2022, driven by a $17.5 million up-front payment associated with the agreement with Alnylam[118]. - Total revenue for the nine months ended September 30, 2023, was $19.7 million, up $9.8 million from the same period in 2022, primarily due to increased product revenue from PYRUKYND®[109]. - PYRUKYND® product revenue for Q3 2023 was $7.4 million, an increase of $3.9 million compared to Q3 2022, attributed to its FDA approval in February 2022[108]. - Net cash used in operating activities was $223.6 million for the nine months ended September 30, 2023, compared to $243.3 million for the same period in 2022[124]. - Cash, cash equivalents, and marketable securities balance was $872.4 million at September 30, 2023, down from $1.1 billion at December 31, 2022[137]. Research and Development - The lead product candidate, PYRUKYND®, received FDA approval on February 17, 2022, for the treatment of hemolytic anemia in adults with PK deficiency[93]. - The company expects to incur significant expenses and net losses as it continues to advance clinical development activities for PYRUKYND® and AG-946[91]. - The company continues to invest in late-stage research programs, including a PAH stabilizer for the treatment of phenylketonuria[83]. - AG-946, a novel PK activator, is in a phase 1 trial with topline results expected by the end of 2023[103]. - The company expects to report topline data from the ENERGIZE trial in the first half of 2024, which evaluates PYRUKYND® for non-transfusion-dependent thalassemia[101]. - The ENERGIZE-T trial has completed enrollment, with topline data expected in the second half of 2024, focusing on transfusion-dependent thalassemia patients[101]. - Total research and development expenses increased by $8.4 million for the nine months ended September 30, 2023, primarily due to an $18.4 million increase in direct expenses, partially offset by a $9.9 million decrease in indirect expenses[114]. - Research and development expenses for Q3 2023 were $81.8 million, an increase of $16.9 million compared to Q3 2022, driven by higher direct expenses related to PYRUKYND® and in-process research and development[113]. Commercialization and Sales - The company anticipates significant commercialization expenses related to product sales, marketing, manufacturing, and distribution as it continues to develop and commercialize PYRUKYND®[130]. - The company has initiated a global managed access program for PYRUKYND® in the EU and Great Britain, providing free access to eligible patients[100]. - The company anticipates generating future revenue from product sales, royalties, and potential collaborations or licensing agreements[94]. - The company recognized income of $127.9 million from the sale of rights to future contingent payments related to its oncology business[86]. - The sale of the oncology business to Servier included a payment of approximately $1.8 billion in cash at closing, with additional contingent payments based on future approvals[84]. Agreements and Milestones - The company made an upfront payment of $17.5 million to Alnylam Pharmaceuticals for the development and commercialization rights of a novel siRNA targeting TMPRSS6[88]. - The company is responsible for up to $130.0 million in potential development and regulatory milestones related to the licensed product from Alnylam[88]. - A license agreement with Alnylam for the development of products targeting the TMPRSS6 gene was established in July 2023, with an IND filing expected by the end of 2023[104]. - The company entered into a license agreement with Alnylam, which may require up to $130.0 million in potential development and regulatory milestones[136]. Cash Flow and Investments - Cash provided by investing activities was $144.1 million for the nine months ended September 30, 2023, primarily due to higher proceeds from maturities and sales of marketable securities[126]. - The company expects to fund its operating expenses and capital expenditures through existing cash, anticipated product revenue, and potential milestone payments through at least 2026[131]. - Interest income increased significantly due to rising interest rates, with net interest income of $24.7 million for the nine months ended September 30, 2023, compared to $6.3 million in 2022[115]. - The company sold its rights to future contingent payments associated with royalties on U.S. net sales of TIBSOVO® for $131.8 million in October 2022[121]. Market Risks - The company is exposed to market risk related to changes in foreign currency exchange rates due to contracts with CROs in Asia and Europe[138]. - As of September 30, 2023, and December 31, 2022, liabilities denominated in foreign currencies were immaterial[138].

PART I. FINANCIAL INFORMATION [Item 1. Financial Statements (Unaudited)](index=3&type=section&id=Item%201.%20Financial%20Statements%20(Unaudited)) Unaudited condensed consolidated financial statements are presented, detailing the company's financial position and performance [Condensed Consolidated Balance Sheets](index=3&type=section&id=Condensed%20Consolidated%20Balance%20Sheets) Total assets decreased to **$1.09 billion** as of June 30, 2023, driven by reduced cash and marketable securities Condensed Consolidated Balance Sheet Highlights (in thousands) | Account | June 30, 2023 | December 31, 2022 | | :--- | :--- | :--- | | **Assets** | | | | Cash and cash equivalents | $84,753 | $139,259 | | Marketable securities | $862,170 | $957,734 | | Total current assets | $757,239 | $832,772 | | **Total assets** | **$1,085,153** | **$1,238,718** | | **Liabilities & Equity** | | | | Total current liabilities | $55,141 | $62,629 | | **Total liabilities** | **$120,917** | **$137,904** | | **Total stockholders' equity** | **$964,236** | **$1,100,814** | [Condensed Consolidated Statements of Operations](index=4&type=section&id=Condensed%20Consolidated%20Statements%20of%20Operations) Total revenue increased to **$12.3 million**, while net loss narrowed to **$164.8 million** for the six months ended June 30, 2023 Statement of Operations Summary (in thousands, except per share data) | Metric | Three Months Ended June 30, 2023 | Three Months Ended June 30, 2022 | Six Months Ended June 30, 2023 | Six Months Ended June 30, 2022 | | :--- | :--- | :--- | :--- | :--- | | Product revenue, net | $6,712 | $3,082 | $12,321 | $3,914 | | Total revenue | $6,712 | $5,582 | $12,321 | $6,414 | | Research and development | $68,895 | $74,523 | $136,196 | $144,646 | | Total operating expenses | $100,412 | $103,222 | $196,634 | $205,199 | | Loss from operations | ($93,700) | ($97,640) | ($184,313) | ($198,785) | | Net loss | ($83,806) | ($91,806) | ($164,824) | ($186,580) | | Net loss per share | ($1.51) | ($1.68) | ($2.97) | ($3.41) | [Condensed Consolidated Statements of Cash Flows](index=7&type=section&id=Condensed%20Consolidated%20Statements%20of%20Cash%20Flows) Net cash used in operating activities improved to **$161.9 million**, resulting in a **$54.5 million** net decrease in cash Cash Flow Summary (in thousands) | Activity | Six Months Ended June 30, 2023 | Six Months Ended June 30, 2022 | | :--- | :--- | :--- | | Net cash used in operating activities | ($161,931) | ($171,964) | | Net cash provided by investing activities | $104,721 | $56,240 | | Net cash provided by financing activities | $2,704 | $1,141 | | **Net change in cash and cash equivalents** | **($54,506)** | **($114,583)** | | Cash and cash equivalents at end of period | $84,753 | $88,543 | [Notes to Condensed Consolidated Financial Statements](index=8&type=section&id=Notes%20to%20Condensed%20Consolidated%20Financial%20Statements) The notes provide detailed information on the company's operations, accounting policies, and key financial statement items - The company's lead product is **PYRUKYND® (mitapivat)**, an activator of pyruvate kinase enzymes, approved for hemolytic anemia in adults with **PK deficiency** in the U.S., EU, and Great Britain, and is also in clinical trials for **thalassemia**, **sickle cell disease (SCD)**, and **pediatric PK deficiency**[25](index=25&type=chunk) - The company is also developing **AG-946**, another **PK activator**, for **lower-risk myelodysplastic syndrome (LR MDS)** and **hemolytic anemias**, and has a late-stage research program for a **PAH stabilizer** for **phenylketonuria (PKU)**[25](index=25&type=chunk)[26](index=26&type=chunk) - On July 28, 2023, Agios entered into a license agreement with **Alnylam Pharmaceuticals** to develop and commercialize a preclinical **siRNA targeting TMPRSS6** for **polycythemia vera (PV)**, involving a **$17.5 million upfront payment** and up to **$130.0 million in potential development and regulatory milestones**[75](index=75&type=chunk) - As of June 30, 2023, the company had **$946.9 million in cash, cash equivalents, and marketable securities** and expects this to be **sufficient to fund operations for at least the next twelve months**[35](index=35&type=chunk) [Item 2. Management's Discussion and Analysis of Financial Condition and Results of Operations](index=18&type=section&id=Item%202.%20Management%27s%20Discussion%20and%20Analysis%20of%20Financial%20Condition%20and%20Results%20of%20Operations) Management discusses financial condition and results, highlighting revenue growth, expense control, and liquidity into 2026 [Results of Operations](index=23&type=section&id=Results%20of%20Operations) Total revenue increased, operating expenses decreased, and net loss narrowed to **$164.8 million** for the six months ended June 30, 2023 Revenue Comparison (in thousands) | Revenue Type | Six Months Ended June 30, 2023 | Six Months Ended June 30, 2022 | | :--- | :--- | :--- | | Product revenue, net | $12,321 | $3,914 | | Milestone revenue | $0 | $2,500 | | **Total revenue** | **$12,321** | **$6,414** | Operating Expense Comparison (in thousands) | Expense Category | Six Months Ended June 30, 2023 | Six Months Ended June 30, 2022 | | :--- | :--- | :--- | | Cost of sales | $1,662 | $774 | | Research and development | $136,196 | $144,646 | | Selling, general and administrative | $58,776 | $59,779 | | **Total operating expenses** | **$196,634** | **$205,199** | - The **$8.5 million decrease in R&D expenses** for the six-month period was primarily due to an **$8.7 million decrease in indirect expenses** (lower compensation and facilities costs), partially offset by a **$0.2 million increase in direct expenses** driven by higher costs for **PYRUKYND® trials** in **thalassemia** and **SCD**[108](index=108&type=chunk) - The **decrease in net loss to $164.8 million** for the first six months of 2023 from **$186.6 million** in 2022 was driven by **higher interest income**, **lower R&D expenses**, and **increased revenue**, partially offset by the **elimination of royalty income** from the sale of TIBSOVO® rights[113](index=113&type=chunk) [Liquidity and Capital Resources](index=25&type=section&id=Liquidity%20and%20Capital%20Resources) The company had **$946.9 million** in cash, cash equivalents, and marketable securities, expected to fund operations into 2026 - The company's cash, cash equivalents, and marketable securities balance was **$946.9 million** at June 30, 2023[116](index=116&type=chunk) - The company expects its **existing cash**, anticipated product revenue, interest income, and the **potential vorasidenib milestone payment** to **fund operating expenses and capital expenditures at least into 2026**[123](index=123&type=chunk) - Future capital requirements depend on factors like **PYRUKYND® sales**, **contingent payments from Servier**, **clinical trial costs**, and **potential in-licensing activities**, including **payments to Alnylam**[124](index=124&type=chunk)[203](index=203&type=chunk) Cash Flow Summary (in thousands) | Activity | Six Months Ended June 30, 2023 | Six Months Ended June 30, 2022 | | :--- | :--- | :--- | | Net cash used in operating activities | ($161,931) | ($171,964) | | Net cash provided by investing activities | $104,721 | $56,240 | | Net cash provided by financing activities | $2,704 | $1,141 | [Item 3. Quantitative and Qualitative Disclosures About Market Risk](index=27&type=section&id=Item%203.%20Quantitative%20and%20Qualitative%20Disclosures%20About%20Market%20Risk) Primary market risk is interest rate sensitivity on the **$946.9 million** cash portfolio, with immaterial foreign currency risk - The primary market risk is **interest rate sensitivity** on the company's **$946.9 million portfolio of cash, cash equivalents, and marketable securities** as of June 30, 2023[129](index=129&type=chunk) - The company has some exposure to **foreign currency exchange rate fluctuations** due to contracts with CROs in Europe and Asia, but this risk is considered **immaterial** as of June 30, 2023[130](index=130&type=chunk) [Item 4. Controls and Procedures](index=27&type=section&id=Item%204.%20Controls%20and%20Procedures) Management concluded that disclosure controls and procedures were **effective** as of June 30, 2023, with no material changes to internal control - Management concluded that as of June 30, 2023, the company's disclosure controls and procedures were **effective**[131](index=131&type=chunk) - **No changes** occurred during the fiscal quarter ended June 30, 2023, that have **materially affected**, or are reasonably likely to materially affect, the company's internal control over financial reporting[133](index=133&type=chunk) PART II. OTHER INFORMATION [Item 1A. Risk Factors](index=29&type=section&id=Item%201A.%20Risk%20Factors) Significant risks include heavy dependence on **PYRUKYND®**, intense competition, reliance on third parties, and healthcare reform impacts - The company's success is **heavily dependent** on the successful commercialization of **PYRUKYND®** and the clinical development of its other product candidates, where failure or significant delays would **materially harm the business**[137](index=137&type=chunk)[139](index=139&type=chunk) - The company faces **substantial competition** from major pharmaceutical and biotech companies like Merck, BMS, Novartis, and Vertex, which have **greater resources** and are developing therapies for the same or similar indications[168](index=168&type=chunk)[170](index=170&type=chunk) - The company **relies on third parties** (CROs and manufacturers) for **clinical trials** and **product supply**, which introduces risks related to performance, regulatory compliance, and potential **supply chain disruptions**[212](index=212&type=chunk)[219](index=219&type=chunk) - The business is subject to risks from **healthcare reform**, including the **Inflation Reduction Act (IRA)**, which could lead to **government price negotiations**, and other **downward pricing pressures** that could **harm profitability**[277](index=277&type=chunk)[286](index=286&type=chunk)[287](index=287&type=chunk) - As a **smaller, less diversified company** focused on rare diseases after selling its oncology business, Agios is **more susceptible to market fluctuations and risks** specific to this sector[197](index=197&type=chunk)[198](index=198&type=chunk) [Item 5. Other Information](index=61&type=section&id=Item%205.%20Other%20Information) This section details a significant exclusive worldwide **license agreement with Alnylam Pharmaceuticals** for a preclinical siRNA candidate - Agios entered into a **license agreement with Alnylam** on July 28, 2023, for an **exclusive worldwide license** to develop and commercialize an **siRNA candidate targeting the TMPRSS6 gene**[320](index=320&type=chunk)[321](index=321&type=chunk) Alnylam License Agreement Financial Terms | Payment Type | Amount | | :--- | :--- | | Upfront Payment | $17.5 million | | Potential Development & Regulatory Milestones | Up to $130.0 million | | Royalties | Tiered percentages from mid-single digits to mid-teens on annual net sales | [Item 6. Exhibits](index=62&type=section&id=Item%206.%20Exhibits) Exhibits filed include corporate governance documents, stock incentive agreements, and officer certifications - Exhibits filed include forms of **stock option** and **restricted stock unit agreements** under the **2023 Stock Incentive Plan**[328](index=328&type=chunk) - **Certifications from the CEO and CFO** pursuant to the **Securities Exchange Act of 1934** and the **Sarbanes-Oxley Act of 2002** are included as exhibits[328](index=328&type=chunk)

Financial Performance - The company reported a net loss of $81.0 million for the three months ended March 31, 2023, compared to a net loss of $94.8 million for the same period in 2022, with an accumulated deficit of $551.6 million as of March 31, 2023 [84]. - Total revenue for the three months ended March 31, 2023, increased by $4.8 million to $5.6 million compared to $0.8 million in the same period in 2022, primarily due to increased product revenue from PYRUKYND® [101]. - Total operating expenses decreased by $5.8 million to $96.2 million for the three months ended March 31, 2023, compared to $102.0 million in 2022, driven by a reduction in selling, general and administrative expenses and research and development expenses [102]. - Research and development expenses totaled $67.3 million for the three months ended March 31, 2023, down from $70.1 million in 2022, reflecting a decrease in direct and indirect expenses [103]. - Interest income for the three months ended March 31, 2023, increased to $8.1 million, up from $0.7 million in 2022, primarily due to rising interest rates [105]. - The net loss for the three months ended March 31, 2023, decreased to $81.0 million from $94.8 million in 2022, attributed to increased revenue and lower operating expenses [106]. - Net cash used in operating activities for the three months ended March 31, 2023, was $95.2 million, slightly improved from $97.7 million in the same period of 2022 [111]. - Cash provided by investing activities was $57.6 million for the three months ended March 31, 2023, compared to a cash outflow of $26.6 million in the same period of 2022 [112]. - As of March 31, 2023, the company's cash, cash equivalents, and marketable securities balance was $1.0 billion, down from $1.1 billion at the end of 2022 [121]. Product Development and Clinical Trials - PYRUKYND® received FDA approval on February 17, 2022, for treating hemolytic anemia in adults with PK deficiency, leading to the generation of product revenue [85]. - PYRUKYND® is currently being evaluated in clinical trials for thalassemia, sickle cell disease, and pediatric patients with PK deficiency [92]. - The company is conducting multiple clinical trials for PYRUKYND®, including phase 3 trials ENERGIZE and ENERGIZE-T, which have closed screening for patient enrollment [93]. - The phase 2 portion of the RISE UP trial for PYRUKYND® has been fully enrolled, with data expected to be announced by mid-year 2023 [93]. - AG-946, a novel PK activator, is currently in a phase 1 trial with healthy volunteers and SCD patients, with a phase 2a study initiated in adults with LR MDS expected to complete enrollment by year-end 2023 [95]. - The company expects to file an IND for a PAH stabilizer for the treatment of PKU by year-end 2023 [96]. Business Transactions and Revenue - The sale of the oncology business to Servier Pharmaceuticals was completed on March 31, 2021, for approximately $1.8 billion in cash, with additional contingent payments based on future drug approvals [79]. - The company recognized income of $127.9 million from the sale of future contingent payments related to its oncology business in 2022 [81]. - The company completed the sale of its oncology business to Servier for approximately $1.8 billion in cash, with additional potential payments of $200 million and royalties of 5% and 15% on U.S. net sales of TIBSOVO® and vorasidenib, respectively [108][110]. - The company retains rights to potential milestone payments and royalties from Servier if vorasidenib is approved by the FDA [81]. - The company is focused on expanding its intellectual property portfolio and may pursue collaborations and licensing arrangements for pipeline growth [84]. Future Outlook and Expenses - The company expects significant increases in research and development expenses as clinical development activities for PYRUKYND® and AG-946 progress [88]. - The company anticipates an increase in selling, general and administrative expenses to support ongoing research and commercialization activities related to PYRUKYND® and other product candidates [98]. - The company expects expenses to increase as it continues research and development, clinical trials, and commercialization of its product candidates, including PYRUKYND® [114]. - Future capital requirements will depend on factors such as revenue from commercial sales of PYRUKYND® and contingent consideration from Servier [115][116]. - The company plans to finance cash needs primarily through existing cash, potential milestone payments, and royalties from Servier if vorasidenib is approved [118]. - The company may pursue opportunistic debt offerings and equity transactions to raise additional capital, which could dilute existing stockholder interests [119]. Market Risks - The company is exposed to market risks related to interest rates and foreign currency exchange rates, with no current hedging strategies in place [121][122].

[Business Overview](index=6&type=section&id=Item%201.%20Business) [Company Profile and Strategy](index=6&type=section&id=General) Agios Pharmaceuticals refocused on rare diseases after selling its oncology business for approximately **$1.8 billion**, aiming for cash-flow positivity by 2026 with its lead product PYRUKYND® and a refined research strategy - On March 31, 2021, the company sold its oncology business to Servier for approximately **$1.8 billion** in cash, plus potential **$200.0 million** milestone and royalties on TIBSOVO® and vorasidenib sales[21](index=21&type=chunk) - In October 2022, Agios sold TIBSOVO® royalty rights for **$127.9 million**, retaining vorasidenib milestone and royalty rights[23](index=23&type=chunk) - The company's 2026 strategic vision includes establishing a hematology franchise with PYRUKYND® approvals, portfolio expansion, and achieving **cash-flow positivity**[31](index=31&type=chunk) - In May 2022, the company restructured its research to focus on late-stage programs and in-licensing, reducing 45 roles and projecting annual cost savings of **$40-$50 million** from 2023-2026[24](index=24&type=chunk)[26](index=26&type=chunk) [Development Pipeline](index=9&type=section&id=Our%20Development%20Programs) Agios's pipeline, focused on cellular metabolism and hematology, is led by PYRUKYND® for PK deficiency, thalassemia, and sickle cell disease, alongside AG-946 for MDS and a preclinical PKU program [PYRUKYND® (mitapivat)](index=12&type=section&id=PYRUKYND%C2%AE%20(mitapivat)%3A%20First-in-Class%20PK%20Activator) PYRUKYND®, an oral PK activator, received 2022 approvals for PK deficiency and is in pivotal trials for thalassemia, sickle cell disease, and pediatric PK deficiency - PYRUKYND® received marketing approval in the U.S. (Feb 2022), EU (Nov 2022), and Great Britain (Dec 2022) for adults with PK deficiency[52](index=52&type=chunk) PYRUKYND® Clinical Trial Status | Trial Name | Indication | Phase | Status / Next Milestone | | :--- | :--- | :--- | :--- | | **ENERGIZE** | Non-transfusion-dependent Thalassemia | 3 | Enrolling; expect to complete enrollment by mid-year 2023 | | **ENERGIZE-T** | Transfusion-dependent Thalassemia | 3 | Enrolling; expect to complete enrollment by mid-year 2023 | | **RISE UP** | Sickle Cell Disease (SCD) | 2/3 | Phase 2 fully enrolled; data and Phase 3 initiation decision expected by mid-year 2023 | | **ACTIVATE-kids / kidsT** | Pediatric PK Deficiency | 3 | Enrolling; expect to enroll at least half of patients by year-end 2023 | [AG-946 and Other Programs](index=13&type=section&id=AG-946%20and%20Other%20Programs) Agios is developing AG-946 for LR MDS with Phase 2a enrollment expected by year-end 2023, and plans an IND filing for a PKU PAH stabilizer by year-end 2023 - A Phase 2a study of AG-946 in adults with LR MDS is underway, with enrollment expected to complete by **year-end 2023**[55](index=55&type=chunk) - The company plans to file an IND for its PAH stabilizer program for PKU by **year-end 2023**[56](index=56&type=chunk) [Intellectual Property](index=13&type=section&id=Intellectual%20Property) Agios protects its PK activator program, including PYRUKYND® and AG-946, with 11 issued U.S. and 190 foreign patents expiring from 2030 to 2042 - As of February 1, 2023, the PK activator program patent portfolio includes **11 issued U.S. patents** and **190 issued foreign patents**[59](index=59&type=chunk) - Patents covering the PK activator program have statutory expiration dates ranging from at least **2030 to 2042**, with potential for extensions[60](index=60&type=chunk) [Competition](index=15&type=section&id=Competition) Agios faces intense competition in rare diseases, particularly for hemolytic anemias and PKU, from major pharmaceutical companies and developers of gene therapies and other PK activators - Key competitors include **BMS, BioMarin, bluebird bio, Merck, Novartis, Pfizer, Rocket Pharma, and Vertex**[67](index=67&type=chunk) - Specific competitive threats include gene therapies for PK deficiency (Rocket Pharma) and SCD (Vertex), and a PKR activator from Novo Nordisk for hemolytic anemias[68](index=68&type=chunk) [Manufacturing and Supply](index=16&type=section&id=Manufacturing%20and%20Supply%20Chain) Agios relies entirely on third-party contract manufacturers for all supply, with redundant raw material and API sources for PYRUKYND® but no redundant finished drug product supply - The company relies on **third parties for all manufacturing** and has no plans to establish its own facilities[73](index=73&type=chunk) - For PYRUKYND®, Agios has redundant supply for raw materials and API but not for the final drug product, though it maintains a safety stock[75](index=75&type=chunk) [Government Regulation](index=16&type=section&id=Government%20Regulation%20and%20Product%20Approvals) Agios's products are subject to extensive government regulation, including rigorous testing, manufacturing, and approval processes, with the regulatory landscape impacted by healthcare reforms like the U.S. Inflation Reduction Act - The U.S. drug approval process involves preclinical testing, IND filing, Phase 1-3 clinical trials for safety and efficacy, and NDA submission to the FDA[78](index=78&type=chunk) - The Inflation Reduction Act of 2022 (IRA) will impact Medicare pricing through negotiations for high-cost drugs starting in **2026** and inflation-based rebates, potentially affecting future profitability[149](index=149&type=chunk)[150](index=150&type=chunk) - In the EU, marketing authorization can be obtained via centralized, decentralized, or mutual recognition procedures, with the centralized procedure compulsory for orphan drugs like PYRUKYND®[160](index=160&type=chunk)[161](index=161&type=chunk) [Human Capital](index=35&type=section&id=Employees%20and%20Human%20Capital) As of December 31, 2022, Agios had **393 U.S.-based employees**, with a 59% female and 31% ethnically diverse workforce, supported by a flexible work policy - As of December 31, 2022, the company had **389 full-time** and **4 part-time employees**[178](index=178&type=chunk) - The workforce is **59% female** and **31% ethnically diverse**, with continued emphasis on Black and Latino representation[181](index=181&type=chunk) - The company has a flexible work policy, with **67% of 2022 new hires** choosing to work remotely[184](index=184&type=chunk) [Risk Factors](index=39&type=section&id=Item%201A.%20Risk%20Factors) [Risks Related to Product Development and Commercialization](index=39&type=section&id=Risks%20Related%20to%20the%20Discovery%2C%20Development%2C%20and%20Commercialization%20of%20our%20Products%20and%20Product%20Candidates) Agios's success depends on PYRUKYND® commercialization and pipeline advancement, facing risks of clinical trial failures, patient enrollment challenges, intense competition, market acceptance issues, and ongoing COVID-19 disruptions - The company's prospects are substantially harmed if it does not successfully commercialize **PYRUKYND®**, its first approved rare disease product[191](index=191&type=chunk) - The company depends heavily on its clinical product candidates, with trials facing risks of efficacy failure, side effects, or enrollment challenges, especially for orphan diseases[193](index=193&type=chunk)[196](index=196&type=chunk) - The COVID-19 pandemic may continue to disrupt clinical trials, regulatory activities, and commercial infrastructure[200](index=200&type=chunk)[201](index=201&type=chunk) - PYRUKYND® and other candidates face substantial competition from companies like **Rocket Pharma, Vertex, Novo Nordisk, and Pfizer** developing therapies for the same indications[209](index=209&type=chunk)[223](index=223&type=chunk) [Financial and Operational Risks](index=48&type=section&id=Risks%20Related%20to%20Our%20Financial%20Position) As a smaller, rare disease-focused company post-oncology sale, Agios faces financial risks from historical operating losses, potential need for dilutive capital, uncertain milestone payments, cybersecurity breaches, and stringent data privacy compliance - As a smaller company focused on rare diseases after the oncology sale, Agios is more susceptible to changing market conditions[251](index=251&type=chunk)[253](index=253&type=chunk) - The company has a history of operating losses, with a net loss of **$231.8 million** in 2022, and profitability depends on successful commercialization[18](index=18&type=chunk)[259](index=259&type=chunk) - The receipt of a **$200.0 million** milestone payment and future royalties from Servier for vorasidenib is contingent on uncertain regulatory approval and commercial success[264](index=264&type=chunk)[265](index=265&type=chunk) - The company's internal systems are vulnerable to cyber incidents, and it is subject to stringent data privacy laws (HIPAA, GDPR, CCPA) with significant non-compliance penalties[236](index=236&type=chunk)[240](index=240&type=chunk) [Risks Related to Third Parties and Intellectual Property](index=52&type=section&id=Risks%20Related%20to%20Our%20Dependence%20on%20Third%20Parties) Agios heavily relies on third-party CROs and CMOs, posing operational risks, and its success depends on robust intellectual property protection, facing risks of patent infringement and validity challenges - The company relies on third-party CROs for clinical trials and is responsible for their cGCP compliance, as failure could render data unreliable[269](index=269&type=chunk)[271](index=271&type=chunk) - Agios depends on third-party manufacturers for all product supply, with performance failures, disruptions, or cGMP non-compliance risking development and commercialization delays[276](index=276&type=chunk)[277](index=277&type=chunk)[279](index=279&type=chunk) - Successful commercialization depends on obtaining and maintaining patent protection, which may be challenged, invalidated, or circumvented by competitors[285](index=285&type=chunk)[291](index=291&type=chunk)[292](index=292&type=chunk) [Regulatory and Legal Risks](index=57&type=section&id=Risks%20Related%20to%20Regulatory%20Approval%20of%20Our%20Product%20Candidates%20and%20Other%20Legal%20Compliance%20Matters) Agios faces significant regulatory and legal risks, including uncertain and costly marketing approvals, pricing and reimbursement pressures intensified by healthcare reforms, and strict compliance with anti-kickback and fraud laws - The regulatory approval process is uncertain, potentially delaying or preventing commercialization, as authorities have discretion and may require additional costly trials[301](index=301&type=chunk)[304](index=304&type=chunk) - Even if approved, products may face unfavorable pricing and reimbursement, intensified by the Inflation Reduction Act and other healthcare reforms, harming the business[332](index=332&type=chunk)[338](index=338&type=chunk)[346](index=346&type=chunk) - The company is subject to strict healthcare laws, including the federal Anti-Kickback Statute and False Claims Act, risking criminal sanctions, civil penalties, and reputational harm[326](index=326&type=chunk)[327](index=327&type=chunk) [Financial Condition and Results of Operations (MD&A)](index=76&type=section&id=Item%207.%20Management%27s%20Discussion%20and%20Analysis%20of%20Financial%20Condition%20and%20Results%20of%20Operations) [Overview of Financial Performance](index=76&type=section&id=Financial%20Operations%20Overview) Agios reported a **$231.8 million net loss** in 2022, a shift from **$1.6 billion net income** in 2021 due to the oncology business sale, reflecting its rare disease focus with initial PYRUKYND® revenues and increased R&D Consolidated Statements of Operations Data (in thousands) | (In thousands) | 2022 | 2021 | 2020 | | :--- | :--- | :--- | :--- | | **Total Revenue** | $14,240 | $— | $— | | **Total Operating Expenses** | $403,287 | $378,418 | $335,916 | | **Net Loss from Continuing Operations** | $(231,801) | $(356,510) | $(329,305) | | **Net Income from Discontinued Operations, Net of Tax** | $— | $1,961,225 | $1,935 | | **Net (Loss) Income** | **$(231,801)** | **$1,604,715** | **$(327,370)** | [Results of Operations (2020-2022)](index=84&type=section&id=Results%20of%20Operations) In 2022, total revenue reached **$14.2 million** from PYRUKYND® launch, R&D expenses increased to **$279.9 million**, and a **$127.9 million gain** from TIBSOVO® royalty rights reduced net loss from continuing operations to **$231.8 million** Revenue Breakdown (in thousands) | (In thousands) | 2022 | 2021 | | :--- | :--- | :--- | | Product Revenue, Net | $11,740 | $— | | Milestone Revenue | $2,500 | $— | | **Total Revenue** | **$14,240** | **$—** | Research and Development Expenses (in thousands) | (In thousands) | 2022 | 2021 | 2020 | | :--- | :--- | :--- | :--- | | PK Activator (PYRUKYND®) | $83,271 | $73,999 | $48,669 | | Novel PK Activator (AG-946) | $15,747 | $10,658 | $8,378 | | Other Research and Platform Programs | $26,837 | $22,959 | $13,790 | | Indirect R&D Expenses | $154,055 | $149,357 | $149,974 | | **Total R&D Expense** | **$279,910** | **$256,973** | **$220,811** | - In 2022, the company recognized a **$127.9 million gain** on the sale of its rights to future TIBSOVO® royalty payments to Sagard[409](index=409&type=chunk)[460](index=460&type=chunk) [Liquidity and Capital Resources](index=86&type=section&id=Liquidity%20and%20Capital%20Resources) As of December 31, 2022, Agios held **$1.1 billion** in cash and equivalents, bolstered by the oncology sale, with management expecting sufficient capital to reach cash-flow positivity without additional equity - As of December 31, 2022, the company had cash, cash equivalents, and marketable securities of **$1.1 billion**[470](index=470&type=chunk)[492](index=492&type=chunk) Cash Flow Summary (in thousands) | (In thousands) | 2022 | 2021 | 2020 | | :--- | :--- | :--- | :--- | | Net Cash Used in Operating Activities | $(309,478) | $(407,320) | $(290,759) | | Net Cash Provided by Investing Activities | $243,261 | $1,248,778 | $75,746 | | Net Cash Provided by (Used in) Financing Activities | $2,350 | $(765,768) | $261,518 | - The company expects existing cash and anticipated revenues will enable it to execute its operating plan to **cash-flow positivity** without additional equity[483](index=483&type=chunk) [Contractual Obligations](index=89&type=section&id=Contractual%20Obligations) As of December 31, 2022, Agios had approximately **$109.4 million** in contractual obligations, primarily **$99.2 million** for operating leases, alongside manufacturing and service arrangements Contractual Obligations (in thousands) | (In thousands) | Total | Less than 1 year | 1-3 years | 3-5 years | More than 5 years | | :--- | :--- | :--- | :--- | :--- | :--- | | Operating Lease Obligations | $99,203 | $16,651 | $38,167 | $40,906 | $3,479 | | Manufacturing Arrangements | $904 | $301 | $603 | $— | $— | | Service Arrangements | $9,300 | $1,860 | $3,720 | $3,720 | $— | [Financial Statements and Notes](index=90&type=section&id=Item%208.%20Financial%20Statements%20and%20Supplementary%20Data) [Consolidated Financial Statements](index=102&type=section&id=Consolidated%20Financial%20Statements) The audited consolidated financial statements for 2022 reflect Agios's financial position, including **$1.1 billion** in cash and equivalents, and the reclassification of the oncology business as a discontinued operation Consolidated Balance Sheet Data (in thousands) | (In thousands) | Dec 31, 2022 | Dec 31, 2021 | | :--- | :--- | :--- | | **Assets** | | | | Cash, Cash Equivalents & Marketable Securities | $1,097,000 | $1,300,000 | | Total Assets | $1,238,718 | $1,437,736 | | **Liabilities & Equity** | | | | Total Liabilities | $137,904 | $145,761 | | Total Stockholders' Equity | $1,100,814 | $1,291,975 | [Key Notes to Financial Statements](index=107&type=section&id=Notes%20to%20Consolidated%20Financial%20Statements) Key notes detail the **$1.98 billion** pre-tax gain from the oncology business sale, PYRUKYND® product revenue, the **$1.2 billion** share repurchase program, and the **$296.0 million** valuation allowance against deferred tax assets - **Discontinued Operations (Note 15):** The March 31, 2021, sale of the oncology business to Servier resulted in a pre-tax gain of **$1,989.1 million**, with historical results reported separately[682](index=682&type=chunk)[684](index=684&type=chunk)[686](index=686&type=chunk) - **Product Revenue (Note 8):** For 2022, gross product sales were reduced by **$1.5 million** for adjustments, resulting in net revenue of **$11.7 million**[639](index=639&type=chunk)[641](index=641&type=chunk) - **Share Repurchase Program (Note 14):** As of Dec 31, 2022, the company repurchased **16.2 million shares** for **$802.5 million** under its **$1.2 billion** authorization, with the program currently paused[678](index=678&type=chunk)[679](index=679&type=chunk)[680](index=680&type=chunk) - **Income Taxes (Note 11):** The company maintains a full valuation allowance of **$296.0 million** against its deferred tax assets as of Dec 31, 2022, due to uncertainty of realization[667](index=667&type=chunk)[670](index=670&type=chunk) [Other Information](index=74&type=section&id=PART%20II%20Other%20Information) [Market for Common Equity and Shareholder Matters](index=74&type=section&id=Item%205.%20Market%20for%20Registrant%27s%20Common%20Equity%2C%20Related%20Stockholder%20Matters%20and%20Issuer%20Purchases%20of%20Equity%20Securities) Agios's common stock trades on Nasdaq under "AGIO"; the company has never paid dividends and has paused its **$1.2 billion** share repurchase program after repurchasing **$802.5 million** in shares - A share repurchase program of up to **$1.2 billion** was authorized in March 2021, with **16.2 million shares** repurchased for **$802.5 million** as of December 31, 2022[398](index=398&type=chunk)[399](index=399&type=chunk) - The company has paused share repurchases to prioritize capital for development and business opportunities[400](index=400&type=chunk) [Corporate Governance and Controls](index=90&type=section&id=Item%209A.%20Controls%20and%20Procedures) Management and PricewaterhouseCoopers LLP concluded that Agios's disclosure controls and internal control over financial reporting were effective as of December 31, 2022 - Management concluded that the company's disclosure controls and procedures were **effective** as of December 31, 2022[497](index=497&type=chunk) - Management and PricewaterhouseCoopers LLP concluded that the company's internal control over financial reporting was **effective** as of December 31, 2022[501](index=501&type=chunk)