Porphyria, Acute Hepatic

-More than 35 authorized treatment centers (ATCs) activated globally for CASGEVY™ and approximately 20 patients have had cells collected across all regions as of mid-July- -Clinical trials ongoing for next generation CAR T product candidates, CTX112™ and CTX131™ targeting CD19 and CD70 respectively, across multiple indications- -Clinical trials opened for CTX112 in systemic lupus erythematosus (SLE) and for CTX131 in hematological malignancies- -Clinical trials ongoing for in vivo gene editing product candidates, CTX310™ and CTX320™ targeting ANGPTL3 and LPA, respectively- -Clinical trial ongoing for CTX211™, an allogeneic, hypoimmune, gene-edited, stem cell derived product candidate for the treatment of Type 1 Diabetes (T1D)- -Strong balance sheet with approximately $2 billion in cash, cash equivalents, and marketable securities as of June 30, 2024- ZUG, Switzerland and BOSTON, Aug. 05, 2024 (GLOBE NEWSWIRE) -- CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, today reported financial results for the second quarter ended June 30, 2024. “In addition to the continued momentum of CASGEVY’s launch, we are making significant progress across the rest of our pipeline,” said Samarth Kulkarni, Ph.D., Chief Executive Officer and Chairman of CRISPR Therapeutics. “We continue to advance our next generation CD19-directed CAR T cell program, CTX112, which has the potential to be best-in-class in both oncology and autoimmune indications. We have opened the clinical trial for CTX131 in hematologic malignancies, and continue to dose-escalate with our in vivo directed programs, CTX310 and CTX320. We are making outstanding progress across our early stage discovery efforts and are well-positioned to realize our mission of bringing multiple transformative medicines to patients in need.” Recent Highlights and Outlook Hemoglobinopathies and CASGEVY™ (exagamglogene autotemcel [exa-cel]) CRISPR Therapeutics has two next generation approaches with the potential to significantly expand the addressable population with SCD and TDT. The Company continues to advance its internally developed targeted conditioning program, an anti-CD117 (c-Kit) antibody-drug conjugate (ADC), through preclinical studies. Additionally, the Company has ongoing research efforts to enable in vivo editing of hematopoietic stem cells. This work could obviate the need for conditioning altogether, expand geographic reach, and enable the treatment of multiple additional other diseases beyond SCD and TDT.Enrollment has been completed in two global Phase 3 studies of CASGEVY in people 5 to 11 years of age with SCD or TDT and the trials are ongoing.In June, positive long-term data from CLIMB-111, CLIMB-121 and the long-term follow-up study of CASGEVY were presented at the 2024 Annual European Hematology Association Congress. These long-term data from more than 100 patients dosed with CASGEVY, with the longest follow-up of more than five years, confirm the transformative, consistent, and durable clinical benefits of CASGEVY over time.The French National Authority for Health (HAS) approved Vertex’s request for the implementation of an early access program (EAP) for the use of CASGEVY in indicated patients with SCD. HAS previously approved the implementation of an EAP for CASGEVY in indicated patients with TDT in the first quarter of 2024.As of mid-July, more than 35 authorized treatment centers (ATCs) have been activated globally, including centers in all regions where CASGEVY is approved, and approximately 20 patients have had cells collected across all regions.CASGEVY is approved in the U.S., Great Britain, the European Union (EU), the Kingdom of Saudi Arabia (KSA), and the Kingdom of Bahrain (Bahrain) for the treatment of both sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT), and launches are ongoing. Regulatory submissions for CASGEVY have been completed in both SCD and TDT in Switzerland and Canada where it received Priority Review. CASGEVY is the first therapy to emerge from a strategic partnership between CRISPR Therapeutics and Vertex Pharmaceuticals established in 2015. As part of an amendment to the collaboration agreement in 2021, Vertex now leads global development, manufacturing, regulatory and commercialization of CASGEVY with support from CRISPR Therapeutics. Immuno-Oncology and Autoimmune Diseases CTX131 is currently in an ongoing clinical trial in solid tumors. In addition, the Company has opened a clinical trial for CTX131 in hematologic malignancies including T cell lymphomas (TCL). Allogeneic CAR T approaches for TCL may have greater potential to meet the unmet need in this patient population given the patients’ own T cells are not suitable for autologous manufacturing.CRISPR Therapeutics opened a clinical trial for CTX112 in systemic lupus erythematosus (SLE), with the potential to expand into additional autoimmune indications in the future. Early clinical studies conducted by third parties have shown that CD19-directed autologous CAR T therapy can produce long-lasting remissions in multiple autoimmune indications by deeply depleting B cells. The Company’s first generation allogeneic CD19-directed CAR T program has demonstrated effective depletion of B cells in oncology settings, which supports the potential for CTX112 in autoimmune diseases.CTX112 is being developed for both oncology and autoimmune indications. In oncology settings, CTX112 is in a Phase 1/2 trial for CD19 positive relapsed or refractory B-cell malignancies, and the Company expects to report preliminary clinical data this year.CRISPR Therapeutics’ next generation allogeneic CAR T candidates reflect the Company’s mission of innovating continuously to bring potentially transformative medicines to patients as quickly as possible. Clinical trials are ongoing for the Company’s next generation CAR T product candidates, CTX112™ and CTX131™, targeting CD19 and CD70, respectively, across multiple indications. CTX112 and CTX131 both contain novel potency edits which can lead to significantly higher CAR T cell expansion and cytotoxicity, potentially representing best-in-class allogeneic CAR T products for these targets. In Vivo CRISPR Therapeutics has established a proprietary lipid nanoparticle (LNP) platform for the delivery of CRISPR/Cas9 to the liver. The first two in vivo programs utilizing this proprietary platform, CTX310™ and CTX320™, are directed towards validated therapeutic targets associated with cardiovascular disease.CTX310 is currently in an ongoing Phase 1 trial targeting ANGPTL3 in patients with homozygous familial hypercholesterolemia (HoFH), severe hypertriglyceridemia (SHTG), heterozygous familial hypercholesterolemia (HeFH), or mixed dyslipidemias. Natural loss-of-function mutations in ANGPTL3 are associated with reduced low-density lipoprotein (LDL-C), triglycerides (TG) and atherosclerotic cardiovascular disease (ASCVD) risk without any negative impact on overall health.CTX320 is currently in an ongoing Phase 1 trial targeting LPA in patients with elevated lipoprotein(a) [Lp(a)], which has shown to have an independent association with major adverse cardiovascular events (MACE). Up to 20% of the global population has elevated Lp(a) levels.The Company continues to advance two additional preclinical programs, CTX340™ targeting angiotensinogen (AGT) for the treatment of refractory hypertension and CTX450™ targeting 5’ aminolevulinic acid synthase (ALAS1) for the treatment of acute hepatic porphyrias (AHP). CRISPR Therapeutics has initiated IND/CTA-enabling studies for CTX340, targeting hepatic AGT for hypertension, and expects to initiate both clinical trials in the second half of 2025. Regenerative Medicine CTX211™, an allogeneic, gene-edited, stem cell-derived beta islet cell precursor, is currently in an ongoing Phase 1 clinical trial for the treatment of Type 1 Diabetes (T1D). CRISPR Therapeutics remains committed to its goal of developing a beta-cell replacement product that does not require chronic immunosuppression.Vertex has non-exclusive rights to certain CRISPR Therapeutics’ CRISPR/Cas9 technology to accelerate development of potentially curative cell therapies for T1D. CRISPR Therapeutics remains eligible for development milestones and would receive royalties on any future products resulting from this agreement. Other Corporate Matters In May, CRISPR Therapeutics announced the appointment of Naimish Patel, M.D., as Chief Medical Officer. Dr. Patel brings in-depth experience in successfully accelerating innovation and advancing drug candidates across a breadth of modalities and disease areas. Dr. Patel is an experienced drug developer who has worked across a wide range of disease areas, including his most recent leadership role as the Global Development Therapeutic Area Head of Immunology and Inflammation at Sanofi. In addition, the Company announced the promotions of (i) Julianne Bruno, M.B.A., to Chief Operating Officer; Ms. Bruno previously served as the Company’s Senior Vice President and Head of Programs & Portfolio Management; and (ii) Susan Kim to Senior Vice President, Investor Relations and Corporate Communications; Ms. Kim previously served as the Company’s Vice President of Investor Relations and Corporate Communications. Second Quarter 2024 Financial Results Cash Position: Cash, cash equivalents, and marketable securities were $2,012.8 million as of June 30, 2024, compared to $1,695.7 million as of December 31, 2023. The increase in cash was primarily driven by proceeds from the $280.0 million February 2024 registered direct offering, a $200.0 million milestone payment received from Vertex in connection with the approval of CASGEVY, proceeds from employee option exercises as well as interest income, offset by operating expenses.Revenue: Total collaboration revenue for the second quarter of 2024 was not material. Collaboration revenue for the second quarter of 2023 was $70.0 million. Collaboration revenue recognized in the second quarter of 2023 was primarily attributable to a research milestone achieved during the current quarter in connection with a non-exclusive license agreement with Vertex.R&D Expenses: R&D expenses were $80.2 million for the second quarter of 2024, compared to $101.6 million for the second quarter of 2023. The decrease in R&D expense was primarily driven by reduced variable external research and manufacturing costs.G&A Expenses: General and administrative expenses were $19.5 million for the second quarter of 2024, compared to $19.0 million for the second quarter of 2023.Collaboration Expense: Collaboration expense, net, was $52.1 million for the second quarter of 2024, compared to $44.6 million for the second quarter of 2023. The increase in collaboration expense, net, was primarily attributable to manufacturing and commercial costs under the CASGEVY collaboration with Vertex.Net Loss: Net loss was $126.4 million for the second quarter of 2024, compared to a net loss of $77.7 million for the second quarter of 2023. About CASGEVY™ (exagamglogene autotemcel [exa-cel]) CASGEVY™ is a non-viral, ex vivo CRISPR/Cas9 gene-edited cell therapy for eligible patients with SCD or TDT, in which a patient’s own hematopoietic stem and progenitor cells are edited at the erythroid specific enhancer region of the BCL11A gene. This edit results in the production of high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is the form of the oxygen-carrying hemoglobin that is naturally present during fetal development, which then switches to the adult form of hemoglobin after birth. CASGEVY has been shown to reduce or eliminate VOCs for patients with SCD and transfusion requirements for patients with TDT. CASGEVY is approved for certain indications in multiple jurisdictions for eligible patients. About the CRISPR Therapeutics-Vertex Collaboration CRISPR Therapeutics and Vertex entered into a strategic research collaboration in 2015 focused on the use of CRISPR/Cas9 to discover and develop potential new treatments aimed at the underlying genetic causes of human disease. CASGEVY represents the first potential treatment to emerge from the joint research program. Under an amended collaboration agreement, Vertex now leads global development, manufacturing, and commercialization of CASGEVY and splits program costs and profits worldwide 60/40 with CRISPR Therapeutics. Vertex is the manufacturer and exclusive license holder of CASGEVY™. About CTX112 CTX112 is being developed for both oncology and autoimmune indications. CTX112 is a next-generation, wholly-owned, allogeneic CAR T product candidate targeting Cluster of Differentiation 19, or CD19, which incorporates additional edits designed to enhance CAR T potency and reduce CAR T exhaustion. CTX112 is being investigated in an ongoing clinical trial designed to assess safety and efficacy of the product candidate in adult patients with relapsed or refractory CD19-positive B-cell malignancies who have received at least two prior lines of therapy. In addition, the Company has opened a clinical trial of CTX112 in systemic lupus erythematosus. About CTX131 CTX131 is being developed for both solid tumors and hematologic malignancies, including T cell lymphomas (TCL). CTX131 is a next-generation, wholly-owned, allogeneic CAR T product candidate targeting Cluster of Differentiation 70, or CD70, an antigen expressed on various solid tumors and hematologic malignancies. CTX131 incorporates additional edits designed to enhance CAR T potency and reduce CAR T exhaustion. CTX131 is being investigated in a clinical trial designed to assess the safety and efficacy of the product candidate in adult patients with relapsed or refractory solid tumors. In addition, we have opened a clinical trial of CTX131 in hematologic malignancies, including TCL. About In Vivo Programs CRISPR Therapeutics has established a proprietary LNP platform for the delivery of CRISPR/Cas9 to the liver. The Company’s in vivo portfolio includes its lead investigational programs, CTX310 (directed towards angiopoietin-related protein 3 (ANGPTL3)) and CTX320 (directed towards LPA, the gene encoding apo(a), a critical component of lipoprotein(a) [Lp(a)]), targeting two validated therapeutic targets for cardiovascular disease. CTX310 and CTX320 are in ongoing clinical trials in patients with heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, mixed dyslipidemias, or severe hypertriglyceridemia, and in patients with elevated lipoprotein(a), respectively. In addition, the Company’s research and preclinical development candidates include CTX340 and CTX450, targeting angiotensinogen (AGT) for refractory hypertension and 5’-aminolevulinate synthase 1 (ALAS1) for acute hepatic porphyria (AHP), respectively. About CTX211 CTX211 is an allogeneic, gene-edited, stem cell-derived investigational therapy for the treatment of type 1 diabetes (T1D), which incorporates gene edits that aim to make cells hypoimmune and enhance cell fitness. This immune-evasive cell replacement therapy is designed to enable patients to produce their own insulin in response to glucose. A Phase 1 clinical trial for CTX211 for the treatment of T1D is ongoing. About CRISPR Therapeutics Since its inception over a decade ago, CRISPR Therapeutics has transformed from a research-stage company advancing programs in the field of gene editing, to a company that recently celebrated the historic approval of the first-ever CRISPR-based therapy and has a diverse portfolio of product candidates across a broad range of disease areas including hemoglobinopathies, oncology, regenerative medicine, cardiovascular, autoimmune, and rare diseases. CRISPR Therapeutics advanced the first-ever CRISPR/Cas9 gene-edited therapy into the clinic in 2018 to investigate the treatment of sickle cell disease or transfusion-dependent beta thalassemia, and beginning in late 2023, CASGEVY™ (exagamglogene autotemcel [exa-cel]) was approved in some countries to treat eligible patients with either of those conditions. The Nobel Prize-winning CRISPR science has revolutionized biomedical research and represents a powerful, clinically validated approach with the potential to create a new class of potentially transformative medicines. To accelerate and expand its efforts, CRISPR Therapeutics has established strategic partnerships with leading companies including Bayer and Vertex Pharmaceuticals. CRISPR Therapeutics AG is headquartered in Zug, Switzerland, with its wholly-owned U.S. subsidiary, CRISPR Therapeutics, Inc., and R&D operations based in Boston, Massachusetts and San Francisco, California, and business offices in London, United Kingdom. To learn more, visit www.crisprtx.com. CRISPR THERAPEUTICS® standard character mark and design logo, CTX112™, CTX131™, CTX211™, CTX310™, CTX320™, CTX340™ and CTX450™ are trademarks and registered trademarks of CRISPR Therapeutics AG. The CASGEVY™ word mark and design are trademarks of Vertex Pharmaceuticals Incorporated. All other trademarks and registered trademarks are the property of their respective owners. CRISPR Therapeutics Forward-Looking Statement Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements regarding any or all of the following: (i) CRISPR Therapeutics preclinical studies, clinical trials and pipeline products and programs, including, without limitation, manufacturing capabilities, status of such studies and trials, potential expansion into new indications and expectations regarding data, safety and efficacy generally; (ii) its strategy, goals, anticipated financial performance and the sufficiency of its cash resources; (iii) regulatory submissions and authorizations, including timelines for and expectations regarding additional regulatory agency decisions; (iv) the expected benefits of its collaborations; and (v) the therapeutic value, development, and commercial potential of CRISPR/Cas9 gene editing technologies and therapies, including as compared to other therapies. Risks that contribute to the uncertain nature of the forward-looking statements include, without limitation, the risks and uncertainties discussed under the heading “Risk Factors” in its most recent annual report on Form 10-K and in any other subsequent filings made by CRISPR Therapeutics with the U.S. Securities and Exchange Commission. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date they are made. We disclaim any obligation or undertaking to update or revise any forward-looking statements contained in this press release, other than to the extent required by law. This press release discusses CRISPR/Cas9 gene editing investigational therapies and is not intended to convey conclusions about efficacy or safety as to those investigational therapies or uses of such investigational therapies. There is no guarantee that any investigational therapy will successfully complete clinical development or gain approval from applicable regulatory authorities. Investor Contact: Susie Kim +1-617-307-7503 susan.kim@crisprtx.com Media Contact: Rachel Eides +1-617-315-4493 rachel.eides@crisprtx.com CRISPR Therapeutics AG Condensed Consolidated Statements of Operations (Unaudited, In thousands except share data and per share data) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 Revenue: Collaboration revenue $— $70,000 $— $170,000 Grant revenue 517 — 1,021 — Total revenue 517 $70,000 $1,021 $170,000 Operating expenses: Research and development 80,165 101,555 156,338 201,490 General and administrative 19,481 19,032 37,434 41,392 Collaboration expense, net 52,131 44,636 99,097 86,828 Total operating expenses 151,777 165,223 292,869 329,710 Loss from operations (151,260) (95,223) (291,848) (159,710)Total other income, net 26,139 18,406 50,860 31,148 Net loss before income taxes (125,121) (76,817) (240,988) (128,562)Provision for income taxes (1,287) (923) (2,011) (2,243)Net loss (126,408) (77,740) (242,999) (130,805)Foreign currency translation adjustment 2 28 (9) 60 Unrealized (loss) gain on marketable securities (1,329) 452 (4,783) 6,679 Comprehensive loss $(127,735) $(77,260) $(247,791) $(124,066)Net loss per common share — basic $(1.49) $(0.98) $(2.92) $(1.66)Basic weighted-average common shares outstanding 84,920,929 79,091,061 83,357,780 78,885,168 Net loss per common share — diluted $(1.49) $(0.98) $(2.92) $(1.66)Diluted weighted-average common shares outstanding 84,920,929 79,091,061 83,357,780 78,885,168 CRISPR Therapeutics AG Condensed Consolidated Balance Sheets Data (Unaudited, in thousands) As of June 30, 2024 December 31, 2023Cash and cash equivalents $484,472 $389,477Marketable securities 1,517,147 1,304,215Marketable securities, non-current 11,216 1,973Working capital 1,882,584 1,799,287Total assets 2,339,853 2,229,571Total shareholders' equity 1,980,949 1,882,803

CAMBRIDGE, Mass.--( BUSINESS WIRE )-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today reported its consolidated financial results for the second quarter ended June 30, 2024 and reviewed recent business highlights. “Alnylam delivered strong results across the business in the second quarter. We achieved a robust 34% year-over-year growth, with global net product revenues of $410 million, primarily driven by our TTR business, leading to an upward revision of our combined net product revenue guidance for the year. On the clinical side, we announced positive topline results from the HELIOS-B Phase 3 study of vutrisiran, showing that it improved cardiovascular outcomes, including an impressive 35-36% mortality benefit, in patients with ATTR cardiomyopathy,” said Yvonne Greenstreet, MBChB, Chief Executive Officer of Alnylam. “With these outstanding results in hand, and assuming successful regulatory review and approval, we believe we are positioned to deliver significant long-term topline growth, providing the capacity for strategic investment in our highly productive organic R&D platform, and further advancing us toward our Alnylam P 5 x25 goals and becoming a leading global biotech company.” Second Quarter 2024 and Recent Significant Corporate Highlights Commercial Performance Total TTR: ONPATTRO ® (patisiran) & AMVUTTRA ® (vutrisiran) Continued growth momentum in total TTR, achieving global net product revenues for ONPATTRO and AMVUTTRA for the second quarter of $77 million and $230 million, respectively, representing 16% total TTR quarterly growth compared to Q1 2024, and 37% annual growth compared to Q2 2023, including 40% annual growth in the U.S. Total Rare: GIVLAARI ® (givosiran) & OXLUMO ® (lumasiran) Achieved global net product revenues for GIVLAARI and OXLUMO for the second quarter of $62 million and $41 million, respectively, representing 2% total Rare quarterly growth compared to Q1 2024, and 25% annual growth compared to Q2 2023. R&D Highlights Announced positive topline results from the HELIOS-B Phase 3 study of vutrisiran in patients with ATTR amyloidosis with cardiomyopathy (ATTR-CM). The study met the primary endpoint, demonstrating statistically significant reductions of 28% and 33% in the composite of all-cause mortality and recurrent cardiovascular events in the overall and monotherapy populations, respectively. Reduced all-cause mortality by 36% and 35% in the overall and monotherapy populations, respectively, in a pre-specified secondary endpoint. Demonstrated clinically significant improvements vs. placebo on key measures of disease progression, including functional capacity, quality of life, and physician assessment of disease severity. Observed consistent effects in all key subgroups, including baseline tafamidis use. Demonstrated encouraging safety, consistent with vutrisiran’s established profile. Reported positive results from the KARDIA-2 Phase 2 study of investigational zilebesiran added to standard-of-care antihypertensives in patients with inadequately controlled hypertension. Initiated dosing in the cAPPricorn-1 Phase 2 study of investigational mivelsiran (ALN-APP) in patients with cerebral amyloid angiopathy (CAA). Initiated Part B of the Phase 1 study of ALN-KHK , in development for the treatment of Type 2 diabetes mellitus. Our collaboration partner, Sanofi, submitted regulatory filings for the investigational agent for hemophilia, fitusiran , in China, Brazil, and the U.S., with an FDA target action date of March 28, 2025. Our collaboration partner, Vir Biotechnology, reported new data for investigational elebsiran at the European Association for the Study of the Liver (EASL) Congress 2024. Vir also received Fast Track Designation for tobevibart and elebsiran for the treatment of hepatitis delta infection. Additional Business Updates Updated collaboration agreements with Regeneron. Amended license agreement under which Regeneron gains exclusive rights to cemdisiran as a monotherapy in exchange for a $10 million upfront payment, certain regulatory milestones, and low double-digit royalties on sales of cemdisiran as a monotherapy. Alnylam now has full global development and commercialization rights to mivelsiran in all indications, as Regeneron opted out of further co-development and co-commercialization of mivelsiran, in development for CAA and Alzheimer's disease. Regeneron will be eligible to receive low double-digit royalties on sales of mivelsiran, if approved. Published 2023 Corporate Responsibility Report Upcoming Events Alnylam announced today that detailed results from the HELIOS-B Phase 3 study of vutrisiran will be presented as a Hot Line Oral Presentation at the European Society of Cardiology (ESC) Congress on Friday, August 30, 2024, at 11:00 am BST (6:00 am ET) in London, UK. The Company will host a webcast to discuss the results at 1:00 pm BST (8:00 am ET). The Company also announced today that it will host a TTR Investor Day on October 9, 2024 in New York City. This event will feature presentations from Alnylam senior leaders and external experts related to the Company’s TTR business. A live webcast of the event will also be available. In mid- and late 2024, Alnylam intends to: Submit a supplemental New Drug Application (sNDA) for vutrisiran to the FDA using a Priority Review Voucher. Initiate a Phase 3 study of ALN-TTRsc04 in patients with ATTR-CM at or around year-end. Report interim results from Part B of the Phase 1 study of mivelsiran (ALN-APP) in patients with Alzheimer’s disease. Initiate a Phase 2 study of mivelsiran in patients with Alzheimer’s disease at or around year-end. Initiate a Phase 1 study of ALN-BCAT , in development for the treatment of hepatocellular carcinoma. File 3 Investigational New Drug (IND) applications by year-end. Financial Results for the Quarter Ended June 30, 2024 Three Months Ended June 30, (In thousands, except per share amounts) 2024 2023 Net product revenues $ 410,088 $ 305,705 Net revenue from collaborations $ 227,338 $ 5,844 Royalty revenue $ 22,399 $ 7,205 GAAP Operating income (loss) $ 48,614 $ (229,831 ) Non-GAAP Operating income (loss) $ 137,902 $ (154,029 ) GAAP Net loss $ (16,889 ) $ (276,024 ) Non-GAAP Net income (loss) $ 73,766 $ (201,622 ) GAAP Net loss per common share - basic and diluted $ (0.13 ) $ (2.21 ) Non-GAAP Net income (loss) per common share - basic $ 0.58 $ (1.62 ) Non-GAAP net income (loss) per common share - diluted $ 0.56 $ (1.62 ) For an explanation of our use of non-GAAP financial measures refer to the “Use of Non-GAAP Financial Measures” section later in this press release and for a reconciliation of each non-GAAP financial measure to the most comparable GAAP measure, see the tables at the end of this press release. Net Product Revenues Three Months Ended June 30, Year over Year % Growth (In thousands, except percentages) 2024 2023 As Reported At CER* ONPATTRO net product revenues $ 77,244 $ 91,458 (16 )% (15 )% AMVUTTRA net product revenues 230,109 132,136 74 % 77 % Total TTR net product revenues 307,353 223,594 37 % 39 % GIVLAARI net product revenues 62,127 57,899 7 % 8 % OXLUMO net product revenues 40,608 24,212 68 % 68 % Total Rare net product revenues 102,735 82,111 25 % 26 % Total net product revenues $ 410,088 $ 305,705 34 % 35 % * CER = Constant Exchange Rate, representing growth calculated as if the exchange rates had remained unchanged from those used in the second quarter 2023. CER is a non-GAAP measure. Total net product revenues increased 34% and 35% at actual currency and CER, respectively, during the three months ended June 30, 2024, as compared to the same period in 2023, due to strong growth from AMVUTTRA driven by increased patient demand, as well as increased patients on GIVLAARI and OXLUMO. Net Revenues from Collaborations Net revenues from collaborations during the three months ended June 30, 2024, included approximately $185 million of revenue, which was previously deferred, upon modifying our collaboration agreement with Regeneron. As part of the modification to the collaboration agreement, we granted Regeneron exclusive license rights to cemdisiran monotherapy. Operating Expenses Three Months Ended June 30, (In thousands, except percentages) 2024 2023 Cost of goods sold $ 67,271 $ 75,336 Cost of goods sold as a percentage of net product revenues 16.4 % 24.6 % Cost of collaborations and royalties $ 1,401 $ 10,034 GAAP research and development expenses $ 294,142 $ 248,526 Non-GAAP research and development expenses $ 246,027 $ 215,725 GAAP selling, general and administrative expenses $ 248,397 $ 214,689 Non-GAAP selling, general and administrative expenses $ 207,224 $ 171,688 Cost of Goods Sold Cost of goods sold as a percentage of net product revenues decreased during the three months ended June 30, 2024, as compared to the same period in 2023, primarily due to higher costs in 2023 associated with cancelled manufacturing commitments for ONPATTRO and other adjustments to inventory, for which similar expenses did not occur in 2024. Research & Development (R&D) Expenses GAAP and non-GAAP R&D expenses increased during the three months ended June 30, 2024, as compared to the same period in 2023, primarily due to increased costs associated with our preclinical activities, increased clinical research expenses associated with startup activities for the zilebesiran and mivelsiran clinical studies, and increased employee compensation expenses. GAAP R&D expenses further increased in the second quarter of 2024, compared with 2023, due to increased stock-based compensation expense. Selling, General & Administrative (SG&A) Expenses GAAP and non-GAAP SG&A expenses increased during the three months ended June 30, 2024, as compared to the same period in 2023, primarily due to increased marketing investment associated with promotion of our TTR therapies and increased employee compensation expenses. Other Financial Highlights Cash, cash equivalents and marketable securities were $2.62 billion as of June 30, 2024, as compared to $2.44 billion as of December 31, 2023, with the increase primarily due to increased net product revenues and increased net proceeds from the issuance of common stock in connection with stock option exercises. A reconciliation of our GAAP to non-GAAP results for the quarter is included in the tables at the end of this press release. 2024 Financial Guidance Full year 2024 financial guidance has been updated as follows: Provided 2/15/2024 Updated 8/1/2024 Combined net product revenues for ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO 1 $1,400 million - $1,500 million $1,575 million - $1,650 million Net Product Revenue Growth vs. 2023 at reported FX rates 1 13% to 21% 27% to 33% Net Product Revenue Growth vs. 2023 at CER* 13% to 21% 28% to 34% Net revenues from collaborations and royalties $325 million - $425 million $575 million - $650 million GAAP R&D and SG&A expenses $1,900 million - $2,050 million $2,000 million - $2,150 million Non-GAAP R&D and SG&A expenses 2 $1,675 million - $1,775 million $1,775 million - $1,875 million 1 Uses June 30, 2024 FX rates including: 1 EUR = 1.07 USD and 1 USD = 161 JPY 2 Primarily excludes $225 - $275 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, 2023. 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 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 and realized and unrealized losses on marketable equity securities. 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 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. Percentage changes in revenue growth at CER 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 GAAP and non-GAAP measures is provided later in this press release. Conference Call Information Management will provide an update on the Company and discuss second quarter 2024 results as well as expectations for the future via conference call on Thursday, August 1, 2024 at 8:30 am ET. A live audio webcast of the call will be available on the Investors section of the Company’s website at investors.alnylam.com/events . 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 adults with hATTR amyloidosis with polyneuropathy. 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 adults with hATTR amyloidosis with polyneuropathy. 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 (givosiran) 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, GIVLAARI 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 profile consistent 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 lipid nanoparticle (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 in 2002, 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 P 5 x25 ” 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 www.alnylam.com and engage with us on X (formerly Twitter) at @Alnylam , or on LinkedIn , Facebook , or 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, statements regarding Alnylam’s aspiration to become a leading global biotech company, 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 commercial products, and Alnylam’s projected commercial and financial performance, including the expected range of net product revenues and net revenues from collaborations and royalties for 2024, the expected range of aggregate annual GAAP and non-GAAP R&D and SG&A expenses for 2024, the potential submission of a sNDA for AMVUTTRA for patients with ATTR amyloidosis with cardiomyopathy by mid- to late 2024 for FDA review, the use of a Priority Review Voucher in connection with the submission of a sNDA for AMVUTTRA for patients with ATTR amyloidosis with cardiomyopathy, and the advancement towards its “Alnylam P 5 x25” strategy, 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, risks and uncertainties relating to: Alnylam’s ability to successfully execute on its “ Alnylam P 5 x25 ” 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 vutrisiran, zilebesiran and mivelsiran; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, including 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 approved indications for 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 profile in 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 Roche, Novartis, Sanofi, Regeneron and Vir; the outcome of litigation; the risk of future government investigations; and unexpected expenditures; as well as those risks and uncertainties more fully discussed in the “Risk Factors” filed with Alnylam’s 2023 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 other filings that Alnylam makes with the SEC. 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. Vutrisiran 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. CONDENSED CONSOLIDATED BALANCE SHEETS (In thousands, except per share amounts) June 30, 2024 December 31, 2023 ASSETS (Unaudited) Current assets: Cash and cash equivalents $ 968,492 $ 812,688 Marketable debt securities 1,646,268 1,615,516 Marketable equity securities 9,889 11,178 Accounts receivable, net 309,481 327,787 Inventory 83,981 89,146 Prepaid expenses and other current assets 154,745 126,382 Total current assets 3,172,856 2,982,697 Property, plant and equipment, net 517,159 526,057 Operating lease right-of-use assets 198,303 199,732 Restricted investments 49,391 49,391 Other assets 71,925 72,003 Total assets $ 4,009,634 $ 3,829,880 LIABILITIES AND STOCKHOLDERS’ DEFICIT Current liabilities: Accounts payable $ 73,980 $ 55,519 Accrued expenses 808,643 713,013 Operating lease liability 41,656 41,510 Deferred revenue 69,009 102,753 Liability related to the sale of future royalties 61,963 54,991 Total current liabilities 1,055,251 967,786 Operating lease liability, net of current portion 239,352 243,101 Deferred revenue, net of current portion 2,402 188,175 Convertible debt 1,022,688 1,020,776 Liability related to the sale of future royalties, net of current portion 1,342,580 1,322,248 Other liabilities 350,428 308,438 Total liabilities 4,012,701 4,050,524 Commitments and contingencies (Note 13) Stockholders’ deficit: Preferred stock, $0.01 par value per share, 5,000 shares authorized and no shares issued and outstanding as of June 30, 2024 and December 31, 2023 — — Common stock, $0.01 par value per share, 250,000 shares authorized; 128,021 shares issued and outstanding as of June 30, 2024; 125,794 shares issued and outstanding as of December 31, 2023 1,281 1,259 Additional paid-in capital 7,122,704 6,811,063 Accumulated other comprehensive loss (34,637 ) (23,375 ) Accumulated deficit (7,092,415 ) (7,009,591 ) Total stockholders’ deficit (3,067 ) (220,644 ) Total liabilities and stockholders’ deficit $ 4,009,634 $ 3,829,880 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, 2023. ALNYLAM PHARMACEUTICALS, INC. CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS (In thousands, except per share amounts) (Unaudited) Three Months Ended Six Months Ended June 30, 2024 June 30, 2023 June 30, 2024 June 30, 2023 Statements of Operations Revenues: Net product revenues $ 410,088 $ 305,705 $ 775,251 $ 582,033 Net revenues from collaborations 227,338 5,844 345,886 42,306 Royalty revenue 22,399 7,205 33,021 13,705 Total revenues 659,825 318,754 1,154,158 638,044 Operating costs and expenses: Cost of goods sold 67,271 75,336 121,884 116,768 Cost of collaborations and royalties 1,401 10,034 12,764 23,471 Research and development 294,142 248,526 555,137 479,095 Selling, general and administrative 248,397 214,689 459,194 398,348 Total operating costs and expenses 611,211 548,585 1,148,979 1,017,682 Income (loss) from operations 48,614 (229,831 ) 5,179 (379,638 ) Other (expense) income: Interest expense (33,258 ) (30,035 ) (68,511 ) (58,990 ) Interest income 29,182 21,075 58,827 39,730 Other expense, net (55,705 ) (35,418 ) (70,249 ) (47,673 ) Total other expense, net (59,781 ) (44,378 ) (79,933 ) (66,933 ) Loss before income taxes (11,167 ) (274,209 ) (74,754 ) (446,571 ) Provision for income taxes (5,722 ) (1,815 ) (8,070 ) (3,554 ) Net loss $ (16,889 ) $ (276,024 ) $ (82,824 ) $ (450,125 ) Net loss per common share - basic and diluted $ (0.13 ) $ (2.21 ) $ (0.66 ) $ (3.62 ) Weighted-average common shares used to compute basic and diluted net loss per common share 126,733 124,659 126,435 124,387 ALNYLAM PHARMACEUTICALS, INC. RECONCILIATION OF SELECTED GAAP MEASURES TO NON-GAAP MEASURES (In thousands, except per share amounts) (Unaudited) Three Months Ended June 30, 2024 June 30, 2023 Reconciliation of GAAP to Non-GAAP Research and development: GAAP Research and development $ 294,142 $ 248,526 Less: Stock-based compensation expenses (48,115 ) (32,801 ) Non-GAAP Research and development $ 246,027 $ 215,725 Reconciliation of GAAP to Non-GAAP Selling, general and administrative: GAAP Selling, general and administrative $ 248,397 $ 214,689 Less: Stock-based compensation expenses (41,173 ) (43,001 ) Non-GAAP Selling, general and administrative $ 207,224 $ 171,688 Reconciliation of GAAP to Non-GAAP Operating income (loss): GAAP Operating income (loss) $ 48,614 $ (229,831 ) Add: Stock-based compensation expenses 89,288 75,802 Non-GAAP Operating income (loss) $ 137,902 $ (154,029 ) Reconciliation of GAAP Net loss to Non-GAAP Net income: GAAP Net loss $ (16,889 ) $ (276,024 ) Add: Stock-based compensation expenses 89,288 75,802 Add (Less): Realized and unrealized loss (gain) on marketable equity securities 1,367 (1,400 ) Non-GAAP Net income (loss) $ 73,766 $ (201,622 ) Reconciliation of GAAP Net loss to Non-GAAP Net income (loss) per common share- basic: GAAP Net loss per common share - basic $ (0.13 ) $ (2.21 ) Add: Stock-based compensation expenses 0.70 0.61 Add (Less): Realized and unrealized loss (gain) on marketable equity securities 0.01 (0.01 ) Non-GAAP Net income (loss) per common share - basic $ 0.58 $ (1.62 ) Reconciliation of GAAP Net loss to Non-GAAP Net income (loss) per common share- diluted: GAAP net loss per common share - diluted $ (0.13 ) $ (2.21 ) Add: Stock-based compensation expenses 0.70 0.61 Add (Less): Realized and unrealized loss (gain) on marketable equity securities 0.01 (0.01 ) Less: Impact to earnings per common share as a result of diluted weighted-average common shares outstanding during the period* (0.02 ) — Non-GAAP net income (loss) per common share - diluted* $ 0.56 $ (1.62 ) *Diluted non-GAAP net income per share is calculated by dividing the non-GAAP net income by the weighted-average number of common shares and dilutive potential common share equivalents then outstanding during the period. The diluted weighted-average common shares outstanding for the three-months ended June 30, 2024 would be 132,061,000. 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) June 30, 2024 Three Months Ended ONPATTRO net product revenue growth, as reported (16 )% Add: Impact of foreign currency translation 1 ONPATTRO net product revenue growth at constant currency (15 )% AMVUTTRA net product revenue growth, as reported 74 % Add: Impact of foreign currency translation 3 AMVUTTRA net product revenue growth at constant currency 77 % Total TTR net product revenue growth, as reported 37 % Add: Impact of foreign currency translation 2 Total TTR net product revenue growth at constant currency 39 % GIVLAARI net product revenue growth, as reported 7 % Add: Impact of foreign currency translation 1 GIVLAARI net product revenue growth at constant currency 8 % OXLUMO net product revenue growth, as reported 68 % Add: Impact of foreign currency translation — OXLUMO net product revenue growth at constant currency 68 % Total net product revenue growth, as reported 34 % Add: Impact of foreign currency translation 1 Total net product revenue growth at constant currency 35 %

-More than 25 authorized treatment centers (ATCs) activated globally for CASGEVY™ and multiple patients have already had cells collected- -Clinical trials ongoing for next generation CAR T product candidates, CTX112™ and CTX131™ targeting CD19 and CD70 respectively, across multiple indications- -Clinical trials ongoing for in vivo gene editing product candidates, CTX310™ and CTX320™ targeting ANGPTL3 and Lp(a), respectively- -Expands pipeline with new preclinical programs utilizing lipid nanoparticle (LNP) mediated delivery to the liver for refractory hypertension targeting angiotensinogen (AGT) and acute hepatic porphyria (AHP) targeting 5’-aminolevulinate synthase 1 (ALAS1)- -Clinical trial ongoing for CTX211™, an allogeneic, hypoimmune, gene-edited, stem cell derived product candidate for the treatment of Type 1 Diabetes (T1D)- -Strong balance sheet with approximately $2.1 billion in cash, cash equivalents, and marketable securities as of March 31, 2024- ZUG, Switzerland and BOSTON, May 08, 2024 (GLOBE NEWSWIRE) -- CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, today reported financial results for the first quarter ended March 31, 2024. “This quarter, in addition the robust launch of CASGEVY, we are pleased to have nominated additional in vivo programs targeting both rare and common diseases to our portfolio based on promising preclinical data,” said Samarth Kulkarni, Ph.D., Chief Executive Officer and Chairman of CRISPR Therapeutics. “Additionally, we continue to advance our portfolio of clinical trials across oncology, autoimmune, diabetes and cardiovascular indications in a capital efficient manner. With multiple data read-outs in the next 12-18 months, we are poised to broaden the number of patients that could potentially benefit from transformative gene-editing based therapies.” Recent Highlights and Outlook Hemoglobinopathies and CASGEVY™ (exagamglogene autotemcel [exa-cel]) CASGEVY is approved in the U.S., Great Britain, the European Union (EU), the Kingdom of Saudi Arabia (KSA), and the Kingdom of Bahrain (Bahrain) for the treatment of both sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT). Regulatory submissions for CASGEVY have been completed in both SCD and TDT in Switzerland and Canada; the submission in Canada was granted priority review. CASGEVY is the first therapy to emerge from a strategic partnership between CRISPR Therapeutics and Vertex Pharmaceuticals established in 2015. As part of an amendment to the collaboration agreement in 2021, Vertex now leads global development, manufacturing, regulatory and commercialization of CASGEVY with support from CRISPR Therapeutics.As of mid-April, more than 25 authorized treatment centers (ATCs) have been activated globally, including centers in all regions where CASGEVY is approved, and multiple patients have already had cells collected. Vertex has signed multiple agreements with both commercial and government health insurance providers in the U.S. to provide access to CASGEVY. Vertex has also secured reimbursed access for eligible people with SCD or TDT in KSA and Bahrain, as well as for people with TDT in France through an early access program.CRISPR Therapeutics has two next-generation approaches with the potential to significantly expand the addressable population with SCD and TDT. CRISPR Therapeutics continues to advance its internally developed targeted conditioning program, an anti-CD117 (c-Kit) antibody-drug conjugate (ADC), through preclinical studies. Additionally, the Company has ongoing research efforts to enable in vivo editing of hematopoietic stem cells. This work could obviate the need for conditioning altogether, expand geographic reach, and enable the treatment of multiple additional other diseases beyond SCD and TDT. Immuno-Oncology and Autoimmune Diseases CRISPR Therapeutics’ next-generation allogeneic CAR T candidates reflect the Company’s mission of innovating continuously to bring potentially transformative medicines to patients as quickly as possible. Clinical trials are ongoing for the Company’s next-generation CAR T product candidates, CTX112™ and CTX131™, targeting CD19 and CD70, respectively, across multiple indications. CTX112 and CTX131 both contain novel potency edits which can lead to significantly higher CAR T cell expansion and cytotoxicity, potentially representing best-in-class allogeneic CAR T products for these targets. CTX112 is being developed for both oncology and autoimmune indications. In oncology settings, CTX112 is in a Phase 1/2 trial for CD19 positive relapsed or refractory B-cell malignancies, and the Company expects to report preliminary clinical data this year.The Company remains on track to initiate a clinical trial for CTX112 in systemic lupus erythematosus (SLE) in the first half of this year, with the potential to expand into additional autoimmune indications in the future. Early clinical studies have shown that CD19-directed autologous CAR T therapy can produce long-lasting remissions in multiple autoimmune indications by deeply depleting B cells. The Company’s first generation allogeneic CD19-directed CAR T program has demonstrated effective depletion of B cells in oncology settings, which supports the potential for CTX112 in autoimmune diseases. CTX131, CRISPR Therapeutics’ next generation CAR T targeting CD70, is currently in an ongoing clinical trial in solid tumors. The Company remains on track to initiate a clinical trial for CTX131 in hematologic malignancies in the first half of this year. In Vivo CRISPR Therapeutics has established a proprietary lipid nanoparticle (LNP) platform for the delivery of CRISPR/Cas9 to the liver. The first two in vivo programs utilizing this proprietary platform, CTX310™ and CTX320™, are directed towards validated therapeutic targets associated with cardiovascular disease, and are in ongoing clinical trials. Earlier today, the Company announced the addition of two additional preclinical programs, CTX340™ and CTX450™, utilizing this LNP delivery system, demonstrating the modularity and scalability of the platform. Refractory hypertension is a serious unmet medical need affecting approximately 1.5 million patients in the U.S. alone. CTX340 is designed to inhibit production of hepatic angiotensinogen (AGT), a validated target to modulate the renin-angiotensin-aldosterone system (RAAS) and normalize blood pressure durably with a one-time treatment. In preclinical studies, CTX340 showed ~60% liver editing and ~90% AGT protein reduction, resulting in sustained ~30 mmHg blood pressure (BP) reduction out to 3 months in the spontaneously hypertensive rat (SHR) model.Acute hepatic porphyria (AHP) is a group of rare genetic diseases of heme biosynthesis. Symptomatic patients have acute attacks, characterized by debilitating neurovascular symptoms, as well as multiple chronic symptoms, such as pain. There are approximately 5,000 patients diagnosed with AHP in the U.S., although the disease remains underdiagnosed. CTX450 is specifically designed to inhibit production of ALAS1 in the liver, preventing accumulation of neurotoxic aminolevulinic acid (ALA) and porphobilinogen (PBG). In preclinical studies, CTX450 showed ~70% liver editing and ~97% ALAS1 protein reduction, resulting in reduction of ALA and PBG disease biomarkers to normal levels in an AHP mouse model. CRISPR Therapeutics has initiated IND/CTA-enabling studies for CTX340 and CTX450 and expects to initiate both clinical trials in the second half of 2025.In addition to the pipeline updates expanding the liver-targeted in vivo pipeline, CRISPR Therapeutics reported initial data at the American Society of Gene and Cell Therapy Annual Meeting demonstrating its proprietary capabilities to deliver to and edit genes in the eye, opening a potential new focus area. Regenerative Medicine CRISPR Therapeutics continues to advance a Phase 1 clinical trial for CTX211™ for the treatment of Type 1 Diabetes (T1D). CRISPR Therapeutics remains committed to its goal of developing a beta-cell replacement product that does not require chronic immunosuppression.Vertex has non-exclusive rights to certain CRISPR Therapeutics’ CRISPR/Cas9 technology to accelerate development of potentially curative cell therapies for T1D. CRISPR Therapeutics remains eligible for development milestones and would receive royalties on any future products resulting from this agreement. Other Corporate Matters In March, CRISPR Therapeutics announced its proposal to elect Christian Rommel, Ph.D., to its Board of Directors at the Company’s annual general meeting to be held this year. Dr Rommel brings in-depth experience in successfully accelerating innovation and advancing drug candidates across a breadth of modalities and disease areas. In February, CRISPR Therapeutics announced that it had entered into an investment agreement for the sale of approximately $280 million of its common shares to a select group of institutional investors in a registered direct offering. First Quarter 2024 Financial Results Cash Position: Cash, cash equivalents, and marketable securities were $2,108.1 million as of March 31, 2024, compared to $1,695.7 million as of December 31, 2023. The increase in cash was primarily driven by proceeds from the February 2024 registered direct offering, a $200.0 million milestone payment received from Vertex in connection with the approval of CASGEVY, proceeds from employee option exercises as well as interest income, offset by operating expenses.R&D Expenses: R&D expenses were $76.2 million for the first quarter of 2024, compared to $99.9 million for the first quarter of 2023. The decrease in R&D expense was primarily driven by reduced variable external research and manufacturing costs.G&A Expenses: General and administrative expenses were $18.0 million for the first quarter of 2024, compared to $22.4 million for the first quarter of 2023. The decrease in G&A expense was primarily driven by a decrease in employee related and stock-based compensation expense.Collaboration Expense: Collaboration expense, net, was $47.0 million for the first quarter of 2024, compared to $42.2 million for the first quarter of 2023. The increase in collaboration expense, net, was primarily attributable to commercial and manufacturing costs.Net Loss: Net loss was $116.6 million for the first quarter of 2024, compared to a net loss of $53.1 million for the first quarter of 2023. About CASGEVY™ (exagamglogene autotemcel [exa-cel]) CASGEVY™ is a non-viral, ex vivo CRISPR/Cas9 gene-edited cell therapy for eligible patients with SCD or TDT, in which a patient’s own hematopoietic stem and progenitor cells are edited at the erythroid specific enhancer region of the BCL11A gene. This edit results in the production of high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is the form of the oxygen-carrying hemoglobin that is naturally present during fetal development, which then switches to the adult form of hemoglobin after birth. CASGEVY has been shown to reduce or eliminate VOCs for patients with SCD and transfusion requirements for patients with TDT. CASGEVY is approved for certain indications in multiple jurisdictions for eligible patients. About the CRISPR Therapeutics-Vertex Collaboration CRISPR Therapeutics and Vertex entered into a strategic research collaboration in 2015 focused on the use of CRISPR/Cas9 to discover and develop potential new treatments aimed at the underlying genetic causes of human disease. CASGEVY (exa-cel) represents the first potential treatment to emerge from the joint research program. Under an amended collaboration agreement, Vertex now leads global development, manufacturing, and commercialization of CASGEVY and splits program costs and profits worldwide 60/40 with CRISPR Therapeutics. Vertex is the manufacturer and exclusive license holder of CASGEVY™. About CTX112 CTX112 is a next-generation, wholly-owned, allogeneic CAR T product candidate targeting Cluster of Differentiation 19, or CD19, which incorporates additional edits designed to enhance CAR T potency and reduce CAR T exhaustion. CTX112 is being investigated in an ongoing clinical trial designed to assess safety and efficacy of the product candidate in adult patients with relapsed or refractory CD19-positive B-cell malignancies who have received at least two prior lines of therapy. About CTX131 CTX131 is a next-generation, wholly-owned, allogeneic CAR T product candidate targeting Cluster of Differentiation 70, or CD70, an antigen expressed on various solid tumors and hematologic malignancies. CTX131 incorporates additional edits designed to enhance CAR T potency and reduce CAR T exhaustion. CTX131 is being investigated in a clinical trial designed to assess the safety and efficacy of the product candidate in adult patients with relapsed or refractory solid tumors. About In Vivo ProgramsCRISPR Therapeutics has established a proprietary LNP platform for the delivery of CRISPR/Cas9 to the liver. The Company’s in vivo portfolio includes its lead investigational in vivo programs, CTX310 (directed towards angiopoietin-related protein 3 (ANGPTL3)) and CTX320 (directed towards lipoprotein(a) (Lp(a)), two validated therapeutic targets for cardiovascular disease, are in ongoing clinical trials. In addition, the Company’s research and preclinical development candidates include CTX340 and CTX450, targeting angiotensinogen (AGT) for refractory hypertension and 5’-aminolevulinate synthase 1 (ALAS1) for acute hepatic porphyria (AHP), respectively. About CTX211 CTX211 is an allogeneic, gene-edited, stem cell-derived investigational therapy for the treatment of T1D, which incorporates gene edits that aim to make cells hypoimmune and enhance cell fitness. This immune-evasive cell replacement therapy is designed to enable patients to produce their own insulin in response to glucose. About CRISPR TherapeuticsSince its inception over a decade ago, CRISPR Therapeutics has transformed from a research-stage company advancing programs in the field of gene editing, to a company that recently celebrated the historic approval of the first-ever CRISPR-based therapy and has a diverse portfolio of product candidates across a broad range of disease areas including hemoglobinopathies, oncology, regenerative medicine, cardiovascular, autoimmune, and rare diseases. CRISPR Therapeutics advanced the first-ever CRISPR/Cas9 gene-edited therapy into the clinic in 2018 to investigate the treatment of sickle cell disease or transfusion-dependent beta thalassemia, and beginning in late 2023, CASGEVY™ (exagamglogene autotemcel) was approved in some countries to treat eligible patients with either of those conditions. The Nobel Prize-winning CRISPR science has revolutionized biomedical research and represents a powerful, clinically validated approach with the potential to create a new class of potentially transformative medicines. To accelerate and expand its efforts, CRISPR Therapeutics has established strategic partnerships with leading companies including Bayer and Vertex Pharmaceuticals. CRISPR Therapeutics AG is headquartered in Zug, Switzerland, with its wholly-owned U.S. subsidiary, CRISPR Therapeutics, Inc., and R&D operations based in Boston, Massachusetts and San Francisco, California, and business offices in London, United Kingdom. To learn more, visit www.crisprtx.com. CRISPR THERAPEUTICS® standard character mark and design logo, CTX112™, CTX131™, CTX211™, CTX310™, CTX320™, CTX340™ and CTX450™ are trademarks and registered trademarks of CRISPR Therapeutics AG. The CASGEVY™ word mark and design are trademarks of Vertex Pharmaceuticals Incorporated. All other trademarks and registered trademarks are the property of their respective owners. CRISPR Therapeutics Forward-Looking Statement This press release may contain a number of “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including statements made by Dr. Kulkarni in this press release, as well as statements regarding CRISPR Therapeutics’ expectations about any or all of the following: (i) its plans for and its preclinical studies, clinical trials and pipeline products and programs, including, without limitation, manufacturing capabilities, status of such studies and trials, potential expansion into new indications and expectations regarding data generally; (ii) the data that will be generated by ongoing and planned clinical trials, and the ability to use that data for the design and initiation of further clinical trials; (iii) plans and expectations for the commercialization of, and anticipated benefits of, CASGEVY, including the anticipated patient populations eligible for CASGEVY in jurisdictions where it has been or may be approved; (iv) the sufficiency of its cash resources; (v) the expected benefits of its collaborations; and (vi) the therapeutic value, development, and commercial potential of CRISPR/Cas9 gene editing technologies and therapies. Without limiting the foregoing, the words “believes,” “anticipates,” “plans,” “expects” and similar expressions are intended to identify forward-looking statements. You are cautioned that forward-looking statements are inherently uncertain. Although CRISPR Therapeutics believes that such statements are based on reasonable assumptions within the bounds of its knowledge of its business and operations, forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Actual performance and results may differ materially from those projected or suggested in the forward-looking statements due to various risks and uncertainties. These risks and uncertainties include, among others: the efficacy and safety results from ongoing clinical trials will not continue or be repeated in ongoing or planned clinical trials or may not support regulatory submissions; regulatory authorities may not approve exa-cel on a timely basis or at all; adequate pricing or reimbursement may not be secured to support continued development or commercialization of exa-cel following regulatory approval; clinical trial results may not be favorable; one or more of its product candidate programs will not proceed as planned for technical, scientific or commercial reasons; future competitive or other market factors may adversely affect the commercial potential for its product candidates; initiation and completion of preclinical studies for its product candidates is uncertain and results from such studies may not be predictive of future results of future studies or clinical trials; regulatory approvals to conduct trials or to market products are uncertain; uncertainties inherent in the operation of a manufacturing facility; it may not realize the potential benefits of its collaborations; uncertainties regarding the intellectual property protection for its technology and intellectual property belonging to third parties, and the outcome of proceedings (such as an interference, an opposition or a similar proceeding) involving all or any portion of such intellectual property; and those risks and uncertainties described under the heading "Risk Factors" in CRISPR Therapeutics’ most recent annual report on Form 10-K, quarterly report on Form 10-Q and in any other subsequent filings made by CRISPR Therapeutics with the U.S. Securities and Exchange Commission, which are available on the SEC's website at www.sec.gov. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date they are made. CRISPR Therapeutics disclaims any obligation or undertaking to update or revise any forward-looking statements contained in this press release, other than to the extent required by law. Investor Contact:Susan Kim+1-617-307-7503susan.kim@crisprtx.com Media Contact:Rachel Eides+1-617-315-4493rachel.eides@crisprtx.com CRISPR Therapeutics AGCondensed Consolidated Statements of Operations(Unaudited, In thousands except share data and per share data) Three Months Ended March 31, 2024 2023 Revenue: Collaboration revenue $— $100,000 Grant revenue 504 — Total revenue 504 $100,000 Operating expenses: Research and development 76,172 99,935 General and administrative 17,953 22,360 Collaboration expense, net 46,966 42,192 Total operating expenses 141,091 164,487 Loss from operations (140,587) (64,487)Total other income, net 24,720 12,742 Net loss before income taxes (115,867) (51,745)Provision for income taxes (724) (1,320)Net loss (116,591) (53,065)Foreign currency translation adjustment (11) 32 Unrealized (loss) gain on marketable securities (3,454) 6,227 Comprehensive loss $(120,056) $(46,806)Net loss per common share — basic $(1.43) $(0.67)Basic weighted-average common shares outstanding 81,794,630 78,676,986 Net loss per common share — diluted $(1.43) $(0.67)Diluted weighted-average common shares outstanding 81,794,630 78,676,986 CRISPR Therapeutics AGCondensed Consolidated Balance Sheets Data(Unaudited, in thousands) As of March 31, 2024 December 31, 2023 Cash and cash equivalents $707,427 $389,477 Marketable securities 1,400,698 1,304,215 Marketable securities, non-current — 1,973 Working capital 2,000,634 1,799,287 Total assets 2,439,017 2,229,571 Total shareholders' equity 2,083,936 1,882,803