Peginterferon alfa-2a(Rhein-Minapharm)

Significant progress made advancing proprietary programs in chronic HBV and Coronavirus AB-729 data from multiple Phase 2a combination clinical trials expected in 2023 Initial Phase 1 data for oral PD-L1, AB-101, and oral RNA Destabilizer, AB-161, expected in the second half of 2023 Initiate Phase 1 clinical trial for oral Mpro coronavirus candidate, AB-343, expected in the second half of 2023 Strengthened financial position – cash runway into Q4 2024 Conference Call and Webcast Today at 8:45 AM ET WARMINSTER, Pa., March 02, 2023 (GLOBE NEWSWIRE) -- Arbutus Biopharma Corporation (Nasdaq: ABUS), a clinical-stage biopharmaceutical company leveraging its extensive virology expertise to develop novel therapeutics that target specific viral diseases, today reported fourth quarter and year end 2022 financial results and provided a corporate update. “In 2022 we focused on three key initiatives: exploring several combination therapies with AB-729, our RNAi therapeutic, as a potential cornerstone agent in a functional cure for hepatitis B virus; advancing our preclinical HBV compounds AB-101, our oral PD-L1 inhibitor, and AB-161, our oral RNA destabilizer; and identifying a clinical candidate that inhibits the SARS-CoV-2 nsp5 main protease,” said William Collier, Arbutus’ President and Chief Executive Officer. “With promising AB-729 data in-hand and plans to initiate phase 1 clinical trials with AB-101, AB-161 and our newly nominated pan-coronavirus Mpro compound, AB-343, we achieved our 2022 corporate objectives and are now well-positioned to further execute on these strategic initiatives to deliver multiple clinical milestones this year. The need for a functional cure for patients with cHBV and alternatives to treat COVID-19 and future coronavirus outbreaks remains urgent, and we look forward to advancing our pipeline to address these large global market opportunities.” Pipeline Updates and Key Milestones AB-729 (RNAi Therapeutic) In the first half of 2023, we anticipate announcing additional off-treatment data from those patients in our Phase 1b clinical trial, AB-729-001, who have discontinued both AB-729 and nucleos(t)ide analogue (NA) therapy. Recently, one of the patients has met the protocol-defined HBV DNA criteria to restart their NA therapy. We are continuing to follow the seven patients who remain off-treatment. To assess AB-729 as a potential cornerstone agent in a functional cure for cHBV, we are conducting a Phase 2a clinical trial, AB-729-201, evaluating the safety and tolerability of AB-729 in combination with ongoing NA therapy and short courses of PEG-IFNα-2a (IFN) in 43 patients with cHBV infection. Preliminary data from the lead-in phase of the trial further validated AB-729’s capacity to reduce HBsAg. We expect to announce preliminary data from patients receiving the combination of AB-729, NA therapy and IFN in the first half of 2023. We are conducting a Phase 2a clinical trial, AB-729-202, evaluating AB-729, NA therapy and Vaccitech’s antigen-specific immunotherapeutic, VTP-300. We have recently amended the clinical trial to include an additional arm with an approved PD-1 inhibitor, nivolumab (Opdivo®). Upon regulatory approval of the amendment, 20 patients will receive AB-729 (60mg every 8 weeks) plus NA therapy for 24 weeks, followed by VTP-300 plus a low dose of nivolumab in conjunction with the booster dose(s) only while remaining on their NA therapy. At week 48, all patients will be evaluated for eligibility to discontinue NA therapy and will be followed for an additional 24-48 weeks. We expect to dose the first patient in the amended arm in the first half of 2023 and announce preliminary data from patients who receive AB-729, NA and VTP-300 in the second half of 2023. Through our collaboration with Assembly Biosciences Inc., (Assembly), we are conducting a Phase 2a proof-of-concept clinical trial evaluating AB-729 in combination with Assembly’s first-generation HBV core inhibitor, vebicorvir (VBR) and NA therapy. Preliminary data from sixty-five patients in the trial showed that the addition of VBR did not positively or negatively impact the reduction of HBsAg in the triple arm combination. Accordingly, we have mutually agreed to discontinue the clinical trial following completion of the final, on-treatment visit at week 48. AB-101 (Oral PD-L1 Inhibitor) To reawaken and boost the immune system of patients with cHBV, we are developing AB-101, our oral PD-L1 inhibitor. Preclinical data generated thus far indicates that AB-101 is highly potent and mediates activation and reinvigoration of HBV-specific T-cells from cHBV patients. We expect to initiate a Phase 1 healthy subject clinical trial with AB-101 in the first half of 2023 with data from the single-ascending dose portion of this trial expected in the second half of 2023. AB-161 (Oral RNA destabilizer) AB-161 is our next-generation oral HBV specific RNA destabilizer, which is being developed to create an all-oral treatment regimen to functionally cure HBV. Preclinical data generated thus far shows that AB-161 is effective as a once-daily dose in reducing HBsAg in an HBV mouse model. We expect to initiate a Phase 1 healthy subject clinical trial with AB-161 in the first half of 2023 with single-ascending dose data expected in the second half of 2023. COVID-19 and Pan-Coronavirus Programs We have nominated, AB-343 as our lead coronavirus drug candidate that inhibits the main protease (Mpro). In pre-clinical research conducted thus far, AB-343 has shown pan-coronavirus antiviral activity, no reduction in potency against known SARS-CoV-2 variants, robust activity against SARS-CoV-2 Mpro resistant strains, and a favorable drug-drug interaction pro no need for ritonavir boosting. We expect to complete IND-enabling studies and initiate a Phase 1 clinical trial with AB-343 in the second half of 2023. Our research efforts directed to identifying an nsp12 viral polymerase clinical candidate are continuing. Such a candidate could potentially be combined with AB-343 to achieve better patient treatment outcomes and for use in prophylactic settings. We expect to nominate a nsp12 clinical candidate and initiate IND-enabling studies in the second half of 2023. Financial Results Cash, Cash Equivalents and Investments As of December 31, 2022, we had cash, cash equivalents and investments in marketable securities of $184.3 million as compared to $191.0 million as of December 31, 2021. During the year ended December 31, 2022, we received a $40.0 million (net of withholding taxes) upfront payment from Qilu Pharmaceutical Co., Ltd. (“Qilu”) related to a technology transfer and license agreement for AB-729 in greater China, $15.0 million of gross proceeds from Qilu’s equity investment in us and $20.3 million of net proceeds from the issuance of common shares under Arbutus’s “at-the-market” offering program. These cash inflows were partially offset by $79.4 million of cash used in operations. We expect a net cash burn between $95 to $100 million in 2023 and believe our cash runway will be sufficient to fund our operations into the fourth quarter of 2024. Revenue Total revenue was $39.0 million for the year ended December 31, 2022 compared to $11.0 million for the same period in 2021. The increase of $28.0 million was due primarily to $26.0 million of revenue recognition from our license agreement with Qilu based on employee labor hours expended by us during 2022 to perform our manufacturing obligations under the license agreement. Operating Expenses Research and development expenses were $84.4 million for the year ended December 31, 2022 compared to $65.5 million for the same period in 2021. The increase of $18.9 million was due primarily to an increase in expenses related to our multiple ongoing AB-729 Phase 2a clinical trials, an increase in expenses for our early-stage development programs, including AB-101 and AB-161, and an increase in compensation costs due to hiring several new employees for our research and development team in early 2022, partially offset by a decrease in expenses for our AB-836 Phase 1a/1b clinical trial, which we discontinued during the fourth quarter of 2022. Net Loss For the year ended December 31, 2022, our net loss attributable to common shares was $69.5 million, or a loss of $0.46 per basic and diluted common share, as compared to a net loss of $88.4 million, or a loss of $0.83 per basic and diluted common share, for the year ended December 31, 2021. Net loss attributable to common shares for the year ended December 31, 2021 included $12.1 million of non-cash expense for the accrual of coupon on our convertible preferred shares, which converted into 22.8 million common shares in October 2021. Outstanding Shares As of December 31, 2022, we had approximately 157.5 million common shares issued and outstanding, as well as approximately 15.5 million stock options outstanding. Roivant Sciences Ltd. owned approximately 25% of our outstanding common shares as of December 31, 2022. UNAUDITED CONDENSED CONSOLIDATED STATEMENTS OF LOSS (in thousands, except share and per share data) Year ended December 31, 2022 2021 Revenue Collaborations and licenses $ 31,366 $ 4,880 Non-cash royalty revenue 7,653 6,108 Total revenue 39,019 10,988 Operating expenses Research and development 84,408 65,502 General and administrative 17,834 17,136 Change in fair value of contingent consideration 2,233 1,872 Total operating expenses 104,475 84,510 Loss from operations (65,456 ) (73,522 ) Other income (loss) Interest income 2,192 127 Interest expense (1,726 ) (2,857 ) Foreign exchange (losses) gains (22 ) 5 Total other income (loss) 444 (2,725 ) Loss before income taxes (65,012 ) (76,247 ) Income tax expense (4,444 ) — Net loss (69,456 ) (76,247 ) Items applicable to preferred shares Dividend accretion of convertible preferred shares — (12,139 ) Net loss attributable to common shares $ (69,456 ) $ (88,386 ) Net loss per common share Basic and diluted $ (0.46 ) $ (0.83 ) Weighted average number of common shares Basic and diluted 150,939,337 106,242,452 UNAUDITED CONDENSED CONSOLIDATED BALANCE SHEETS (in thousands) December 31, 2022 December 31, 2021 Cash, cash equivalents and marketable securities, current $ 146,913 $ 155,317 Accounts receivable and other current assets 4,226 5,344 Total current assets 151,139 160,661 Property and equipment, net of accumulated depreciation 5,070 5,983 Investments in marketable securities, non-current 37,363 35,688 Right of use asset 1,744 2,092 Other non-current assets 103 61 Total assets $ 195,419 $ 204,485 Accounts payable and accrued liabilities $ 16,029 $ 10,838 Deferred license revenue, current 16,456 — Lease liability, current 372 383 Total current liabilities 32,857 11,221 Liability related to sale of future royalties 10,365 16,296 Deferred license revenue, non-current 5,999 — Contingent consideration 7,531 5,298 Lease liability, non-current 1,815 2,231 Total stockholders’ equity 136,852 169,439 Total liabilities and stockholders’ equity $ 195,419 $ 204,485 UNAUDITED CONDENSED CONSOLIDATED STATEMENTS OF CASH FLOW (in thousands) Twelve Months Ended December 31, 2022 2021 Net loss $ (69,456 ) $ (76,247 ) Non-cash items 4,857 7,790 Change in deferred license revenue 22,455 — Other changes in working capital 6,788 925 Net cash used in operating activities (35,356 ) (67,532 ) Net cash used in investing activities (74,942 ) (12,678 ) Issuance of common shares pursuant to Share Purchase Agreement 10,973 — Issuance of common shares pursuant to the Open Market Sales Agreement 20,324 134,665 Cash provided by other financing activities 517 2,571 Net cash provided by financing activities 31,814 137,236 Effect of foreign exchange rate changes on cash and cash equivalents (22 ) 5 (Decrease) increase in cash and cash equivalents (78,506 ) 57,031 Cash and cash equivalents, beginning of period 109,282 52,251 Cash and cash equivalents, end of period 30,776 109,282 Investments in marketable securities 153,500 81,723 Cash, cash equivalents and marketable securities, end of period $ 184,276 $ 191,005 Conference Call and Webcast Today Arbutus will hold a conference call and webcast today, Thursday, March 2, 2023, at 8:45 AM Eastern Time to provide a corporate update. To dial-in for the conference call by phone, please register using the following link: Registration Link. A live webcast of the conference call can be accessed through the Investors section of Arbutus' website at . An archived webcast will be available on the Arbutus website after the event. About AB-729 AB-729 is an RNA interference (RNAi) therapeutic specifically designed to reduce all HBV viral proteins and antigens including hepatitis B surface antigen which is thought to be a key prerequisite to enable reawakening of a patient’s immune system to respond to the virus. AB-729 targets hepatocytes using Arbutus’ novel covalently conjugated N-Acetylgalactosamine (GalNAc) delivery technology enabling subcutaneous delivery. Clinical data generated thus far has shown single- and multi-doses of AB-729 to be generally safe and well-tolerated, while also providing meaningful reductions in hepatitis B surface antigen and hepatitis B DNA. AB-729 is currently in multiple Phase 2a clinical trials. About AB-101 AB-101 is our lead oral PD-L1 inhibitor candidate that we believe will allow for controlled checkpoint blockade and enable oral dosing, while minimizing the systemic safety issues typically seen with checkpoint antibody therapies. Immune checkpoints such as PD-1/PD-L1 play an important role in the induction and maintenance of immune tolerance and in T-cell activation. Preclinical data generated thus far indicates that AB-101 mediates activation and reinvigoration of HBV-specific T-cells from cHBV patients. We believe AB-101, when used in combination with other approved and investigational agents, could potentially lead to a functional cure in HBV chronically infected patients. We are also exploring oncology applications for our internal PD-L1 portfolio. About AB-161 AB-161 is our next generation oral small molecule RNA destabilizer, specifically designed to target the liver. Mechanistically, RNA destabilizers target the host proteins PAPD5/7, which are involved in regulating the stability of HBV RNA transcripts. In doing so, RNA destabilizers lead to the selective degradation of HBV RNAs, thus reducing HBsAg levels and inhibiting viral replication. To provide a proprietary all-oral treatment regimen for patients with cHBV, we believe inclusion of a small molecule RNA destabilizer is key. About AB-343 AB-343 is our lead coronavirus drug candidate that inhibits the main protease (Mpro), a validated target for the treatment of COVID-19 and potential future coronavirus outbreaks. In our pre-clinical research conducted to date, AB-343 has shown robust pan-coronavirus antiviral activity, no reduction in potency against known SARS-CoV-2 variants, and Mpro resistant strains, and a favorable drug-drug interaction pro no need for ritonavir boosting. We see an opportunity to pursue a potential combination therapeutic strategy focusing on Mpro and nsp12 viral polymerase targets to reduce hospitalizations, achieve better patient treatment outcomes and provide pre-exposure prophylactic therapy. About HBV Hepatitis B is a potentially life-threatening liver infection caused by the hepatitis B virus (HBV). HBV can cause chronic infection which leads to a higher risk of death from cirrhosis and liver cancer. Chronic HBV infection represents a significant unmet medical need. The World Health Organization estimates that over 290 million people worldwide suffer from chronic HBV infection, while other estimates indicate that approximately 2.4 million people in the United States suffer from chronic HBV infection. Approximately 820,000 people die every year from complications related to chronic HBV infection despite the availability of effective vaccines and current treatment options.  About Coronaviruses Coronaviruses are a large family of viruses that range from the common cold to more severe diseases such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19. COVID-19 has caused approximately 7.2 million deaths globally according to an analysis by the Institute for Health Metrics and Evaluation (IHME). As we strive to identify and develop new antiviral small molecules to treat COVID-19 and future coronavirus outbreaks, we have focused our research efforts on two essential targets critical for replication across all coronaviruses – nsp5 protease and nsp12 polymerase.  About Arbutus Arbutus Biopharma Corporation (Nasdaq: ABUS) is a clinical-stage biopharmaceutical company leveraging its extensive virology expertise to develop novel therapeutics that target specific viral diseases. Our current focus areas include Hepatitis B virus (HBV), SARS-CoV-2, and other coronaviruses. To address HBV, we are developing a RNAi therapeutic, an oral PD-L1 inhibitor, and an oral RNA destabilizer to potentially identify a combination regimen with the aim of providing a functional cure for patients with chronic HBV by suppressing viral replication, reducing surface antigen and reawakening the immune system. We believe our lead compound, AB-729, is the only RNAi therapeutic with evidence of immune re-awakening. AB-729 is currently being evaluated in multiple phase 2 clinical trials. We also have an ongoing drug discovery and development program directed to identifying novel, orally active agents for treating coronaviruses, (including SARS-CoV-2), for which we have nominated a compound and have begun IND-enabling pre-clinical studies. In addition, we are also exploring oncology applications for our internal PD-L1 portfolio. For more information, visit . Forward-Looking Statements and Information This press release contains forward-looking statements within the meaning of the Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, and forward-looking information within the meaning of Canadian securities laws (collectively, forward-looking statements). Forward-looking statements in this press release include statements about our future development plans for our product candidates; the expected cost, timing and results of our clinical development plans and clinical trials with respect to our product candidates; our expectations with respect to the release of data from our clinical trials and the expected timing thereof; our expectations and goals for our collaborations with third parties and any potential benefits related thereto; the potential for our product candidates to achieve success in clinical trials; and our expected financial condition, including our anticipated net cash burn, the anticipated duration of cash runways and timing regarding needs for additional capital. With respect to the forward-looking statements contained in this press release, Arbutus has made numerous assumptions regarding, among other things: the effectiveness and timeliness of preclinical studies and clinical trials, and the usefulness of the data; the timeliness of regulatory approvals; the continued demand for Arbutus’ assets; and the stability of economic and market conditions. While Arbutus considers these assumptions to be reasonable, these assumptions are inherently subject to significant business, economic, competitive, market and social uncertainties and contingencies, including uncertainties and contingencies related to the ongoing COVID-19 pandemic and patent litigation matters. Additionally, there are known and unknown risk factors which could cause Arbutus’ actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements contained herein. Known risk factors include, among others: anticipated pre-clinical studies and clinical trials may be more costly or take longer to complete than anticipated, and may never be initiated or completed, or may not generate results that warrant future development of the tested product candidate; Arbutus may elect to change its strategy regarding its product candidates and clinical development activities; Arbutus may not receive the necessary regulatory approvals for the clinical development of Arbutus’ products; economic and market conditions may worsen; uncertainties associated with litigation generally and patent litigation specifically; Arbutus and its collaborators may never realize the expected benefits of the collaborations; market shifts may require a change in strategic focus; and the ongoing COVID-19 pandemic could significantly disrupt Arbutus’ clinical development programs. A more complete discussion of the risks and uncertainties facing Arbutus appears in Arbutus’ Annual Report on Form 10-K, Arbutus’ Quarterly Reports on Form 10-Q and Arbutus’ continuous and periodic disclosure filings, which are available at and at . All forward-looking statements herein are qualified in their entirety by this cautionary statement, and Arbutus disclaims any obligation to revise or update any such forward-looking statements or to publicly announce the result of any revisions to any of the forward-looking statements contained herein to reflect future results, events or developments, except as required by law. Contact Information Investors and Media William H. Collier President and CEO Phone: 267-469-0914 Email: ir@arbutusbio.com Lisa M. Caperelli Vice President, Investor Relations Phone: 215-206-1822 Email: lcaperelli@arbutusbio.com

− Achieved Fourth Quarter and Full Year 2022 Global Net Product Revenues of $262 Million and $894 Million, Respectively, Representing 35% Annual Growth Compared to 2021 (43% Using Constant Exchange Rate*) – − Submitted and Received Acceptance of Supplemental New Drug Application (sNDA) for ONPATTRO® (patisiran) for the Treatment of the Cardiomyopathy of ATTR Amyloidosis – − Provides 2023 Combined Net Product Revenue Guidance of $1,200 Million to $1,285 Million, in Addition to Collaboration and Royalty Revenue and Operating Expense Guidance – CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today reported its consolidated financial results for the fourth quarter and full year ended December 31, 2022 and reviewed recent business highlights. “2022 was another year of strong progress at Alnylam, including our continued commercial execution which delivered 35% full-year product revenue growth (43% with constant exchange rate*) compared to 2021. A key factor in these results was the approval and launch of AMVUTTRA, which is off to a great start in its first two full quarters on the market. Further to our leadership in TTR amyloidosis, we’re thrilled to have submitted our sNDA for ONPATTRO for the treatment of the cardiomyopathy of ATTR amyloidosis, which has now been accepted by the FDA, and look forward to potentially bringing this important therapy to patients, if approved,” said Yvonne Greenstreet, MBChB, Chief Executive Officer of Alnylam. “Looking ahead to 2023, we are excited for a number of important milestones across the pipeline, with 10 clinical readouts from proprietary and partner-led programs, including first-in-human results for an RNAi therapeutic in the CNS from our Phase 1 study of ALN-APP, as well as Phase 2 results from the KARDIA studies of zilebesiran. With the totality of this progress, we believe we are on track to achieve our Alnylam P5x25 goals and position Alnylam as a top-tier biotech company poised to deliver sustainable innovation.” Fourth Quarter 2022 and Recent Significant Corporate Highlights Commercial Performance Total TTR: ONPATTRO® (patisiran) & AMVUTTRA® (vutrisiran) Achieved global net product revenues for ONPATTRO and AMVUTTRA for the fourth quarter of $122 million and $69 million, respectively, representing 12% total TTR quarterly growth compared to Q3 2022, and full year 2022 revenues of $558 million and $94 million, respectively, representing 37% total TTR annual growth compared to full year 2021. Attained over 2,975 hATTR amyloidosis patients with polyneuropathy worldwide on commercial treatment with ONPATTRO or AMVUTTRA as of December 31, 2022, up from over 2,580 commercial patients as of September 30, 2022, representing 15% total TTR quarterly growth and 46% total TTR annual growth vs. 2021. Received 760 Start Forms in the U.S. for AMVUTTRA from launch through December 31, 2022, with ~53% representing new patients and ~47% representing patients switching from ONPATTRO. GIVLAARI® (givosiran) Achieved global net product revenues for the fourth quarter and full year 2022 of $47 million and $173 million, respectively, representing quarterly and annual growth of 3% and 35% compared to Q3 2022 and full year 2021, respectively. Attained over 520 patients worldwide on commercial GIVLAARI treatment as of December 31, 2022, up from over 460 commercial patients as of September 30, 2022, representing 13% quarterly growth and 47% annual growth vs. 2021. OXLUMO® (lumasiran) Achieved global net product revenues for the fourth quarter and full year 2022 of $24 million and $70 million, respectively, representing quarterly and annual growth of 45% and 17% compared to Q3 2022 and full year 2021, respectively. Attained over 280 patients worldwide on commercial OXLUMO treatment as of December 31, 2022, up from over 230 commercial patients as of September 30, 2022, representing 22% quarterly growth and 101% annual growth vs. 2021. Leqvio® (inclisiran) Launch is ongoing, with focus on patient on-boarding, removing access hurdles and enhancing medical education. R&D Highlights Patisiran (the non-proprietary name for ONPATTRO), in development for the treatment of ATTR amyloidosis. Submitted and received acceptance of the sNDA for ONPATTRO (patisiran) for the treatment of the cardiomyopathy of ATTR amyloidosis. The FDA has set an action date of October 8, 2023 under the Prescription Drug User Fee Act (PDUFA). In their letter, the FDA stated that they have not identified any review issues. The Agency also noted that they are planning to hold an advisory committee meeting to discuss the application. Vutrisiran (the non-proprietary name for AMVUTTRA), in development for the treatment of ATTR amyloidosis. Announced topline results from the Randomized Treatment Extension (RTE) of the HELIOS-A Phase 3 study evaluating a biannual dosing regimen of vutrisiran. Non-inferiority of 50 mg biannual (vs. 25 mg quarterly) was established, as measured by TTR lowering through nine months in the RTE, along with an acceptable safety profile. However, the Company announces its strategic decision not to proceed with regulatory submissions for a biannual dosing regimen of vutrisiran and instead will focus on advancing ALN-TTRsc04, which has now entered the clinic and offers the potential for more durable and potent TTR silencing via annual dosing. Received approval from the Brazilian Health Regulatory Agency (ANVISA) for AMVUTTRA for the treatment of hATTR amyloidosis in adults. Lumasiran (the non-proprietary name for OXLUMO), for the treatment of primary hyperoxaluria type 1 (PH1). Based on the successful outcome of the ILLUMINATE-C study in children and adults with advanced PH1, received approval from the U.S. FDA of an sNDA for OXLUMO, expanding the indication for the treatment of PH1 to lower urinary oxalate and plasma oxalate levels in pediatric and adult patients, and received approval from the European Medicines Agency (EMA) of a Type II variation to include the ILLUMINATE-C data in the label. Inclisiran (the non-proprietary name for Leqvio), for the treatment of hypercholesterolemia or mixed dyslipidemia, in collaboration with Novartis. New long-term data from the ORION-3 open-label study demonstrated effective and sustained reductions in LDL cholesterol over four years of treatment. At any time throughout the trial, approximately 80% of patients reached an LDL-C level of <70mg/dL. Data presented at AHA 2022. Early- and mid-stage investigational RNAi therapeutic pipeline programs and RNAi platform. Completed enrollment in the KARDIA-1 Phase 2 monotherapy study of zilebesiran in patients with mild-to-moderate hypertension. Submitted Clinical Trial Authorization (CTA) filings for ALN-KHK for the treatment of type 2 diabetes, and ALN-PNP for the treatment of NASH in collaboration with Regeneron. Regeneron announced that dosing in a Phase 1 study of ALN-PNP has been initiated. Submitted a CTA application for ALN-TTRsc04, in development for the treatment of ATTR amyloidosis. The Company announces today that dosing in a Phase 1 study has been initiated. Announced pipeline prioritization decisions at 2022 R&D Day, including discontinuation of ALN-XDH in gout and lumasiran in recurrent renal stones, and pausing development of cemdisiran in IgA nephropathy. Additional Business Updates Appointed Carolyn Bertozzi, Ph.D. to its Board of Directors. Also, Amy W. Schulman, previously the Lead Independent Director, assumed the role of Chair of the Board from Michael W. Bonney, who has continued on the Board as a non-independent director. Mr. Bonney stepped down from his interim role as Executive Chair. Ranked #1 on The Boston Globe’s 2022 list of Great Places to Work in the “Largest Employer category. Ranked #2 in Science Magazine’s 2022 Top Employer survey, marking the fourth year Alnylam was featured as one of the top three companies. Recognized on Newsweek’s 2023 list of America’s Most Responsible Companies. Upcoming Events In early 2023: Alnylam intends to complete enrollment in the KARDIA-2 Phase 2 study of zilebesiran. Alnylam intends to report preliminary topline results from the Phase 1 study of ALN-APP in patients with early onset Alzheimer’s Disease. Alnylam intends to initiate a Phase 1 study of ALN-KHK in normal healthy volunteers. Vir intends to report additional results from Part A of the MARCH trial evaluating the combination of ALN-HBV02 (VIR-2218) and VIR-3434, an anti-HBV monoclonal antibody, for the treatment of patients with chronic HBV infection in the first half of 2023. Vir also plans to report additional results from a Phase 2 study evaluating the combination of ALN-HBV02 (VIR-2218) and PEG-IFN alpha in the first half of 2023. Regeneron plans to initiate a Phase 2 study of ALN-HSD in patients with NASH. Financial Results for the Quarter and Year Ended December 31, 2022 Financial Highlights Three Months Ended December 31, Twelve Months Ended December 31, (In thousands, except per share amounts) 2022 2021 2022 2021 Net product revenues $ 261,675 $ 198,514 $ 894,329 $ 662,138 Net revenue from collaborations $ 70,645 $ 59,625 $ 134,912 $ 180,953 Royalty revenue $ 2,715 $ 396 $ 8,177 $ 1,196 GAAP Operating loss $ (188,614 ) $ (194,561 ) $ (785,072 ) $ (708,652 ) Non-GAAP Operating loss $ (145,847 ) $ (149,979 ) $ (554,423 ) $ (542,935 ) GAAP Other expense, net $ (18,407 ) $ (65,741 ) $ (341,921 ) $ (143,492 ) Non-GAAP Other expense, net $ (25,203 ) $ (60,163 ) $ (232,023 ) $ (199,187 ) GAAP Net loss $ (207,493 ) $ (258,460 ) $ (1,131,156 ) $ (852,824 ) Non-GAAP Net loss $ (171,522 ) $ (208,300 ) $ (790,609 ) $ (742,802 ) GAAP Net loss per common share – basic and diluted $ (1.68 ) $ (2.16 ) $ (9.30 ) $ (7.20 ) Non-GAAP Net loss per common share – basic and diluted $ (1.39 ) $ (1.74 ) $ (6.50 ) $ (6.27 ) Net Product Revenues Three Months Ended December 31, Twelve Months Ended December 31, (In thousands) 2022 2021 2022 2021 ONPATTRO net product revenues $ 122,221 $ 138,630 $ 557,608 $ 474,737 AMVUTTRA net product revenues 68,566 - 93,795 - Total TTR net product revenues 190,787 138,630 651,403 474,737 GIVLAARI net product revenues 47,058 40,679 173,144 127,815 OXLUMO net product revenues 23,830 19,205 69,782 59,586 Total net product revenues $ 261,675 $ 198,514 $ 894,329 $ 662,138 Year over Year % Growth Three Months Ended December 31, Twelve Months Ended December 31, As Reported At CER* As Reported At CER* Total TTR net product revenues 38% 48% 37% 46% GIVLAARI net product revenues 16% 22% 35% 41% OXLUMO net product revenues 24% 33% 17% 25% Total net product revenues 32% 41% 35% 43% * CER = Constant Exchange Rate, representing growth calculated as if the exchange rates had remained unchanged from those used in the three and twelve months ended December 31, 2021. CER is a Non-GAAP measure. Net product revenues increased 32% and 35% at actual currency during the three and twelve months ended December 31, 2022, respectively, compared to the same periods in 2021, and 41% and 43% at CER, respectively. The increases are primarily due to increased patients on our commercial TTR products as well as increased patients on GIVLAARI and OXLUMO. Net Revenues from Collaborations Net revenues from collaborations increased 18% during the fourth quarter 2022, as compared to the prior year, primarily due to increased revenue from our collaboration with Regeneron from increased manufacturing activities. Net revenues from collaborations decreased 25% for the twelve months ended December 31, 2022, as compared to the prior year, primarily due to a decrease in revenue recognized in connection with our collaboration agreements with Regeneron and Vir, attributed to reduced research and manufacturing activities and timing of reimbursable activities. Operating Expenses Three Months Ended December 31, Twelve Months Ended December 31, (in thousands) 2022 2021 2022 2021 GAAP research and development expenses $ 262,039 $ 229,050 $ 883,015 $ 792,156 Non-GAAP research and development expenses $ 245,095 $ 210,513 $ 790,854 $ 723,741 GAAP selling, general and administrative expenses $ 210,344 $ 186,382 $ 770,658 $ 620,639 Non-GAAP selling, general and administrative expenses $ 184,521 $ 160,337 $ 632,170 $ 523,337 Research & Development (R&D) Expenses GAAP and non-GAAP R&D expenses increased during the three and twelve months ended December 31, 2022, compared to the same periods in 2021, primarily due to increases in headcount to support our R&D pipeline, development expenses associated with the KARDIA-1 and KARDIA-2 zilebesiran Phase 2 studies, and manufacturing and research related expenses associated with our pre-clinical and developmental activities. GAAP R&D expenses further increased during the twelve month period due to increased stock-based compensation expense related to the accounting for certain performance-based awards that vested during the period. Selling, General & Administrative (SG&A) Expenses GAAP and non-GAAP SG&A expenses increased during the three and twelve months ended December 31, 2022, compared to the same periods in 2021, primarily due to increased headcount and other strategic investments in support of the global launch of AMVUTTRA and other expenses to support our strategic growth. GAAP SG&A expenses further increased during the twelve month period due to stock-based compensation expense related to the accounting for certain performance-based awards that vested during the period. Other Financial Highlights GAAP other expense, net, decreased during the fourth quarter 2022, as compared to the prior year, primarily due to foreign currency gains as a result of the U.S. Dollar weakening against key global currencies, increased interest income, and unrealized gains on marketable equity securities. GAAP other expense, net, increased during the twelve months ended December 31, 2022, compared to the same period in 2021, primarily due to a loss on the extinguishment of the Blackstone credit agreement, increased realized and unrealized losses on our marketable equity securities, and an increased loss from the fair value adjustment on the development derivative liability, offset by an increase in interest income. Cash, cash equivalents and marketable securities were $2.19 billion as of December 31, 2022 compared to $2.44 billion as of December 31, 2021 with the decrease primarily due to our year-to-date operating loss in 2022. This decrease was largely offset by approximately $265 million received from employee option award exercises and approximately $135 million received from the issuance of convertible debt, net of repayment borrowings, inclusive of prepayment premiums under the credit facility, the purchase of capped call transactions, and underwriter fees. The adjustments to the non-GAAP measures provided in the financial results above and in the financial guidance below are described under “Use of Non-GAAP Financial Measures” later in this press release. A reconciliation of our GAAP to non-GAAP results presented in this release is included in the tables of this press release. 2023 Financial Guidance1 Full year December 31, 2023 financial guidance consists of the following: Combined net product revenues for ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO1,2 $1,200 million – $1,285 million Net Product Revenue Growth vs. 2022 at reported Fx rates1 34% to 44% Net Product Revenue Growth vs. 2022 at constant exchange rates* 34% to 44% Net revenues from collaborations and royalties $100 million – $175 million GAAP R&D and SG&A expenses $1,790 million – $1,885 million Non-GAAP R&D and SG&A expenses3 $1,575 million – $1,650 million 1 Uses December 31, 2022 Fx rates including: 1 EUR = 1.07 USD and 1 USD = 131 JPY 2 Assumes U.S. sNDA approval of patisiran for ATTR amyloidosis with cardiomyopathy by the PDUFA date on October 8, 2023 3 Excludes $215-$235 million of stock-based compensation expense from estimated GAAP R&D and SG&A expenses * CER = Constant Exchange Rate, representing growth calculated as if the exchange rates had remained unchanged from those used in the twelve months ended December 31, 2022. CER is a Non-GAAP measure. Use of Non-GAAP Financial Measures This press release contains non-GAAP financial measures, including expenses adjusted to exclude certain non-cash expenses and non-recurring gains and expenses outside the ordinary course of the Company’s business. These measures are not in accordance with, or an alternative to, GAAP, and may be different from non-GAAP financial measures used by other companies. The items included in GAAP presentations but excluded for purposes of determining non-GAAP financial measures for the periods presented in this press release are stock-based compensation expenses, realized and unrealized (gains) losses on marketable equity securities and loss on the extinguishment of debt. The Company has excluded the impact of stock-based compensation expense, which may fluctuate from period to period based on factors including the variability associated with performance-based grants for stock options and restricted stock units and changes in the Company’s stock price, which impacts the fair value of these awards. The Company has excluded the impact of the realized and unrealized (gains) losses on marketable equity securities because the Company does not believe these adjustments accurately reflect the performance of the Company’s ongoing operations for the period in which such gains or losses are reported, as their sole purpose is to adjust amounts on the balance sheet. The Company has excluded the loss on the extinguishment of debt because the Company believes the item is a non-recurring transaction outside the ordinary course of the Company’s business. Percentage changes in revenue growth at CER, also a non-GAAP financial measure, are presented excluding the impact of changes in foreign currency exchange rates for investors to understand the underlying business performance. The current period’s foreign currency revenue values are converted into U.S. dollars using the average exchange rates from the prior period. The Company believes the presentation of non-GAAP financial measures provides useful information to management and investors regarding the Company’s financial condition and results of operations. When GAAP financial measures are viewed in conjunction with non-GAAP financial measures, investors are provided with a more meaningful understanding of the Company’s ongoing operating performance and are better able to compare the Company’s performance between periods. In addition, these non-GAAP financial measures are among those indicators the Company uses as a basis for evaluating performance, allocating resources and planning and forecasting future periods. Non-GAAP financial measures are not intended to be considered in isolation or as a substitute for GAAP financial measures. A reconciliation between historical GAAP and non-GAAP measures presented in this release is provided later in this press release. Conference Call Information Management will provide an update on the Company and discuss fourth quarter and year-end 2022 results as well as expectations for the future via conference call on Thursday, February 23, 2023 at 8:30 am ET. To access the call, please register online at . Participants are requested to register at a minimum 15 minutes before the start of the call. A replay of the call will be available two hours after the call and archived on the same web page for six months. A live audio webcast of the call will be available on the Investors section of the Company’s website at . An archived webcast will be available on the Alnylam website approximately two hours after the event. About ONPATTRO® (patisiran) ONPATTRO is an RNAi therapeutic that is approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. ONPATTRO is also approved in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and in Japan for the treatment of hATTR amyloidosis with polyneuropathy. ONPATTRO is an intravenously administered RNAi therapeutic targeting transthyretin (TTR). It is designed to target and silence TTR messenger RNA, thereby reducing the production of TTR protein before it is made. Reducing the pathogenic protein leads to a reduction in amyloid deposits in tissues. For more information about ONPATTRO, including full Prescribing Information, visit ONPATTRO.com. About AMVUTTRA® (vutrisiran) AMVUTTRA® (vutrisiran) is an RNAi therapeutic approved in the United States for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. It is a double‑stranded small interfering RNA (siRNA) that targets mutant and wild‑type transthyretin (TTR) messenger RNA (mRNA). Using Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, AMVUTTRA is designed for increased potency and high metabolic stability to allow for subcutaneous injection once every three months (quarterly). Results from the pivotal HELIOS-A Phase 3 study demonstrate AMVUTTRA rapidly reduces serum TTR levels, has the potential to reverse neuropathy impairment relative to baseline and improves other key measures of disease burden relative to external placebo in patients with the polyneuropathy of hATTR amyloidosis. For more information about AMVUTTRA, including the full U.S. Prescribing Information, visit AMVUTTRA.com. About GIVLAARI® (givosiran) GIVLAARI is an RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) approved in the United States and Brazil for the treatment of adults with acute hepatic porphyria (AHP). GIVLAARI is also approved in the European Union for the treatment of AHP in adults and adolescents aged 12 years and older. In the pivotal study, givosiran was shown to significantly reduce the rate of porphyria attacks that required hospitalizations, urgent healthcare visits or intravenous hemin administration at home compared to placebo. GIVLAARI is Alnylam’s first commercially available therapeutic based on its Enhanced Stabilization Chemistry ESC-GalNAc conjugate technology to increase potency and durability. GIVLAARI is administered via subcutaneous injection once monthly at a dose based on actual body weight and should be administered by a healthcare professional. GIVLAARI works by specifically reducing elevated levels of ALAS1 messenger RNA (mRNA), leading to reduction of toxins associated with attacks and other disease manifestations of AHP. For more information about GIVLAARI, including the full U.S. Prescribing Information, visit GIVLAARI.com. About OXLUMO® (lumasiran) OXLUMO (lumasiran) is an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1). HAO1 encodes glycolate oxidase (GO). Thus, by silencing HAO1 and depleting the GO enzyme, OXLUMO inhibits production of oxalate – the metabolite that directly contributes to the pathophysiology of PH1. OXLUMO utilizes Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index. OXLUMO has received regulatory approvals from the U.S. Food and Drug Administration (FDA) for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary and plasma oxalate levels in pediatric and adult patients and from the European Medicines Agency (EMA) for the treatment of PH1 in all age groups. In the pivotal ILLUMINATE-A study, OXLUMO was shown to significantly reduce levels of urinary oxalate relative to placebo, with the majority of patients reaching normal or near-normal levels. In the ILLUMINATE-B pediatric Phase 3 study, OXLUMO demonstrated an efficacy and safety pro to that observed in ILLUMINATE-A. In the ILLUMINATE-C study, OXLUMO resulted in substantial reductions in plasma oxalate in patients with advanced PH1. Across all three studies, injection site reactions (ISRs) were the most common drug-related adverse reaction. OXLUMO is administered via subcutaneous injection once monthly for three months, then once quarterly beginning one month after the last loading dose at a dose based on actual body weight. For patients who weigh less than 10 kg, ongoing dosing remains monthly. OXLUMO should be administered by a healthcare professional. For more information about OXLUMO, including the full U.S. Prescribing Information, visit OXLUMO.com. About LNP Technology Alnylam has licenses to Arbutus Biopharma LNP intellectual property for use in RNAi therapeutic products using LNP technology. About RNAi RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines known as RNAi therapeutics is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing or disease pathway proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases. About Alnylam Pharmaceuticals Alnylam Pharmaceuticals (Nasdaq: ALNY) has led the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare and prevalent diseases with unmet need. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach yielding transformative medicines. Since its founding 20 years ago, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylam’s commercial RNAi therapeutic products are ONPATTRO® (patisiran), AMVUTTRA® (vutrisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran), which is being developed and commercialized by Alnylam’s partner, Novartis. Alnylam has a deep pipeline of investigational medicines, including multiple product candidates that are in late-stage development. Alnylam is executing on its “Alnylam P5x25” strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram. Alnylam Forward Looking Statements This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than historical statements of fact regarding Alnylam’s expectations, beliefs, goals, plans or prospects including, without limitation, expectations regarding Alnylam’s aspiration to become a leading biotech company and the planned achievement of its “Alnylam P5x25” strategy, the potential for Alnylam to identify new potential drug development candidates and advance its research and development programs, Alnylam’s ability to obtain approval for new commercial products or additional indications for its existing products, and Alnylam’s projected commercial and financial performance, should be considered forward-looking statements. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam’s business, results of operations and financial condition and the effectiveness or timeliness of Alnylam’s efforts to mitigate the impact of the pandemic; Alnylam’s ability to successfully execute on its “Alnylam P5x25” strategy; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for Alnylam’s product candidates, including patisiran and vutrisiran; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, including patisiran and vutrisiran, as well as favorable pricing and reimbursement; successfully launching, marketing and selling Alnylam’s approved products globally; delays, interruptions or failures in the manufacture and supply of Alnylam’s product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to successfully expand the indication for ONPATTRO or AMVUTTRA in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial pro the future without the need for future equity financing; Alnylam’s ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Sanofi, Regeneron and Vir; the outcome of litigation; the potential impact of a current government investigation and the risk of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam's 2022 Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as may be updated from time to time in Alnylam’s subsequent Quarterly Reports on Form 10-Q, and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements. This release discusses investigational RNAi therapeutics and uses of previously approved RNAi therapeutics in development and is not intended to convey conclusions about efficacy or safety as to those investigational therapeutics or uses. Patisiran has not been approved by any regulatory agency for the treatment of ATTR amyloidosis with cardiomyopathy. No conclusions can or should be drawn regarding its safety or effectiveness in treating cardiomyopathy in this population. There is no guarantee that any investigational therapeutics or expanded uses of commercial products will successfully complete clinical development or gain health authority approval. ALNYLAM PHARMACEUTICALS, INC. CONSOLIDATED STATEMENTS OF OPERATIONS (In thousands, except per share amounts) (Unaudited) Three Months Ended December 31, Twelve Months Ended December 31, 2022 2021 2022 2021 Revenues: Net product revenues $ 261,675 $ 198,514 $ 894,329 $ 662,138 Net revenues from collaborations 70,645 59,625 134,912 180,953 Royalty revenue 2,715 396 8,177 1,196 Total revenues 335,035 258,535 1,037,418 844,287 Operating costs and expenses: Cost of goods sold 46,172 33,635 140,174 115,005 Cost of collaborations and royalties 5,094 4,029 28,643 25,139 Research and development 262,039 229,050 883,015 792,156 Selling, general and administrative 210,344 186,382 770,658 620,639 Total operating costs and expenses 523,649 453,096 1,822,490 1,552,939 Loss from operations (188,614 ) (194,561 ) (785,072 ) (708,652 ) Other (expense) income: Interest expense (29,913 ) (36,816 ) (155,968 ) (143,021 ) Other (expense) income, net 11,506 (28,925 ) (109,367 ) (471 ) Loss on the extinguishment of debt — — (76,586 ) — Total other (expense) income, net (18,407 ) (65,741 ) (341,921 ) (143,492 ) Loss before income taxes (207,021 ) (260,302 ) (1,126,993 ) (852,144 ) Provision for income taxes (472 ) 1,842 (4,163 ) (680 ) Net loss $ (207,493 ) $ (258,460 ) $ (1,131,156 ) $ (852,824 ) Net loss per common share — basic and diluted $ (1.68 ) $ (2.16 ) $ (9.30 ) $ (7.20 ) Weighted-average common shares used to compute basic and diluted net loss per common share 123,266 119,773 121,689 118,451 ALNYLAM PHARMACEUTICALS, INC. RECONCILIATION OF SELECTED GAAP MEASURES TO NON-GAAP MEASURES (In thousands, except per share amounts) (Unaudited) Three Months Ended December 31, Twelve Months Ended December 31, 2022 20211 2022 20211 Reconciliation of GAAP to Non-GAAP research and development: GAAP Research and development $ 262,039 $ 229,050 $ 883,015 $ 792,156 Less: Stock-based compensation expenses (16,944 ) (18,537 ) (92,161 ) (68,415 ) Non-GAAP Research and development $ 245,095 $ 210,513 $ 790,854 $ 723,741 Reconciliation of GAAP to Non-GAAP selling, general and administrative: GAAP Selling, general and administrative $ 210,344 $ 186,382 $ 770,658 $ 620,639 Less: Stock-based compensation expenses (25,823 ) (26,045 ) (138,488 ) (97,302 ) Non-GAAP Selling, general and administrative $ 184,521 $ 160,337 $ 632,170 $ 523,337 Reconciliation of GAAP to Non-GAAP operating loss: GAAP operating loss $ (188,614 ) $ (194,561 ) $ (785,072 ) $ (708,652 ) Add: Stock-based compensation expenses 42,767 44,582 230,649 165,717 Non-GAAP Operating loss $ (145,847 ) $ (149,979 ) $ (554,423 ) $ (542,935 ) Reconciliation of GAAP to Non-GAAP Other (expense) income: GAAP Total other expense, net $ (18,407 ) $ (65,741 ) $ (341,921 ) $ (143,492 ) (Less) Add: Realized and unrealized (gain) loss on marketable equity securities (6,796 ) 5,578 33,312 (55,695 ) Add: Loss on the extinguishment of debt — — 76,586 — Non-GAAP Other expense, net $ (25,203 ) $ (60,163 ) $ (232,023 ) $ (199,187 ) Reconciliation of GAAP to Non-GAAP net loss: GAAP Net loss $ (207,493 ) $ (258,460 ) $ (1,131,156 ) $ (852,824 ) Add: Stock-based compensation expenses 42,767 44,582 230,649 165,717 (Less) Add: Realized and unrealized (gain) loss on marketable equity securities (6,796 ) 5,578 33,312 (55,695 ) Add: Loss on the extinguishment of debt — — 76,586 — Non-GAAP Net loss $ (171,522 ) $ (208,300 ) $ (790,609 ) $ (742,802 ) Reconciliation of GAAP to Non-GAAP net loss per common share-basic and diluted: GAAP Net loss per common share - basic and diluted $ (1.68 ) $ (2.16 ) $ (9.30 ) $ (7.20 ) Add: Stock-based compensation expenses 0.35 0.37 1.90 1.40 (Less) Add: Realized and unrealized (gain) loss on marketable equity securities (0.06 ) 0.05 0.27 (0.47 ) Add: Loss on the extinguishment of debt — — 0.63 — Non-GAAP Net loss per common share - basic and diluted $ (1.39 ) $ (1.74 ) $ (6.50 ) $ (6.27 ) 1 Beginning in 2022, presentations of non-GAAP financial measures will not include adjustments for upfront payment on license and collaboration agreement. Non-GAAP financial measures for three- and twelve-months ended December 31, 2021 have been adjusted to reflect this updated presentation. Please note that the figures presented above may not sum exactly due to rounding ALNYLAM PHARMACEUTICALS, INC. RECONCILIATION OF GAAP TO NON-GAAP PRODUCT REVENUE GROWTH AT CONSTANT CURRENCY (Unaudited) December 31, 2022 Three Months Ended Twelve Months Ended Total TTR net product revenue growth, as reported 38% 37% Add: Impact of foreign currency translation 10 9 Total TTR net product revenue growth at constant currency 48% 46% GIVLAARI net product revenue growth, as reported 16% 35% Add: Impact of foreign currency translation 6 6 GIVLAARI net product revenue growth at constant currency 22% 41% OXLUMO net product revenue growth, as reported 24% 17% Add: Impact of foreign currency translation 9 8 OXLUMO net product revenue growth at constant currency 33% 25% Total net product revenue growth, as reported 32% 35% Add: Impact of foreign currency translation 9 8 Total net product revenue growth at constant currency 41% 43% Total revenue growth, as reported 30% 23% Add: Impact of foreign currency translation 7 6 Total revenue growth at constant currency 37% 29% ALNYLAM PHARMACEUTICALS, INC. CONSOLIDATED BALANCE SHEETS (In thousands, except per share amounts) December 31, 2022 December 31, 2021 ASSETS Current assets: Cash and cash equivalents $ 866,394 $ 819,975 Marketable debt securities 1,297,890 1,548,617 Marketable equity securities 28,122 66,972 Accounts receivable, net 237,963 198,571 Inventory 128,962 86,363 Prepaid expenses and other current assets 132,916 88,078 Total current assets 2,692,247 2,808,576 Property, plant and equipment, net 523,494 501,958 Operating lease right-of-use assets 215,136 231,675 Restricted investments 49,390 40,891 Other assets 66,092 60,204 Total assets $ 3,546,359 $ 3,643,304 LIABILITIES AND STOCKHOLDERS’ (DEFICIT) EQUITY Current liabilities: Accounts payable $ 98,094 $ 73,426 Accrued expenses 545,460 395,174 Operating lease liability 41,967 40,548 Deferred revenue 42,105 149,483 Liability related to the sale of future royalties 40,289 37,079 Total current liabilities 767,915 695,710 Operating lease liability, net of current portion 261,339 281,347 Deferred revenue, net of current portion 193,791 152,360 Convertible debt 1,016,942 — Long-term debt — 675,697 Liability related to the sale of future royalties, net of current portion 1,252,015 1,151,024 Other liabilities 212,580 98,963 Total liabilities 3,704,582 3,055,101 Commitments and contingencies (Note 14) Stockholders’ (deficit) equity: Preferred stock, $0.01 par value per share, 5,000 shares authorized and no shares issued and outstanding as of December 31, 2022 and December 31, 2021 — — Common stock, $0.01 par value per share, 250,000 shares authorized as of December 31, 2022 and December 31, 2021, respectively; 123,925 shares issued and outstanding as of December 31, 2022; 120,182 shares issued and outstanding as of December 31, 2021 1,240 1,202 Additional paid-in capital 6,454,540 6,058,453 Accumulated other comprehensive loss (44,654 ) (33,259 ) Accumulated deficit (6,569,349 ) (5,438,193 ) Total stockholders’ (deficit) equity (158,223 ) 588,203 Total liabilities and stockholders’ equity $ 3,546,359 $ 3,643,304 This selected financial information should be read in conjunction with the consolidated financial statements and notes thereto included in Alnylam’s Annual Report on Form 10-K which includes the audited financial statements for the year ended December 31, 2021.