VX-880

— Full year product revenue of $9.87 billion, an 11% increase compared to full year 2022 — — Company provides full year 2024 product revenue guidance of $10.55 to $10.75 billion — — CASGEVYTM approved in the U.S., Great Britain, the Kingdom of Saudi Arabia and Bahrain — — Vertex on track to submit new drug applications (NDAs) to the FDA by mid-2024 for both VX-548 in Acute Pain and the Vanzacaftor Triple in CF — — Broad and deep clinical-stage pipeline continues to advance across 10 disease areas — BOSTON--(BUSINESS WIRE)-- Vertex Pharmaceuticals (Nasdaq: VRTX) today reported consolidated financial results for the fourth quarter and full year ended December 31, 2023 and provided full year 2024 financial guidance. “2023 was a transformative year for Vertex as we continued our strong performance, including 11% revenue growth, combined with significant advancement across the business. We expanded our leadership in CF, diversified our commercial opportunity with CASGEVY regulatory approvals in multiple regions, and rapidly advanced a broad pipeline with multiple additional near-term potential launch opportunities in disease areas outside of CF,” said Reshma Kewalramani, M.D., Chief Executive Officer and President of Vertex. “Our progress in 2023 lays the foundation for the anticipated regulatory submissions for the vanzacaftor triple and VX-548 by mid-2024 and sets us on a path to expand our business in CF and beyond, beginning with the commercialization of CASGEVY in multiple geographies.” Fourth Quarter 2023 Results Product revenue increased 9% to $2.52 billion compared to the fourth quarter of 2022, primarily driven in the U.S. by the continued performance of TRIKAFTA, including the uptake in children with CF 2 to 5 years of age, and in ex-U.S. markets by the continued strong uptake of TRIKAFTA/KAFTRIO, including label extensions in younger age groups. Net product revenue in the fourth quarter of 2023 increased 8% to $1.57 billion in the U.S. and increased 12% to $943 million outside the U.S., compared to the fourth quarter of 2022. Combined GAAP and Non-GAAP R&D, Acquired IPR&D and SG&A expenses were $1.2 billion and $1.0 billion, respectively, compared to $984 million and $872 million, respectively, in the fourth quarter of 2022. The increases were due to increased investment in support of multiple programs that have advanced in mid- and late-stage clinical development and the costs to support launches of Vertex's therapies globally. Combined GAAP R&D, Acquired IPR&D and SG&A expenses also included increased stock-based compensation expense compared to the fourth quarter of 2022. GAAP effective tax rate was 15.6% compared to 24.0% for the fourth quarter of 2022 based on increased benefits from R&D tax credits and a lower provision from uncertain tax positions. Non-GAAP effective tax rate was 16.3% compared to 18.5% for the fourth quarter of 2022 as a result of increased benefits from R&D tax credits for the current year. Please refer to Note 1 for further details on our GAAP to Non-GAAP tax adjustments. GAAP and Non-GAAP net income increased by 18% and 12%, respectively, compared to the fourth quarter of 2022, primarily due to higher interest income and lower taxes. Full Year 2023 Results Product revenue increased 11% to $9.87 billion compared to 2022, primarily driven by the continued strong uptake of TRIKAFTA/KAFTRIO in ex-U.S. markets, including label extensions in younger age groups, and the continued performance of TRIKAFTA in the U.S, including the ongoing launch in children with CF 2 to 5 years of age. Net product revenue in 2023 increased 6% to $6.04 billion in the U.S. and increased 18% to $3.83 billion outside the U.S., compared to 2022. Combined GAAP and Non-GAAP R&D, Acquired IPR&D and SG&A expenses were $4.83 billion and $4.24 billion, respectively, compared to $3.60 billion and $3.07 billion, respectively, in 2022. The increases were due to increased investment in support of multiple programs that have advanced in mid- and late-stage clinical development, the costs to support launches of Vertex's therapies globally, and increased acquired IPR&D expenses. GAAP effective tax rate was 17.4% compared to 21.5% in 2022, largely as a result of higher U.S. R&D tax credits for the current and prior years. Non-GAAP effective tax rate was 19.4% compared to 20.8% in 2022, also largely as a result of higher U.S. R&D tax credits for the current year. Please refer to Note 1 for further details on our GAAP to Non-GAAP tax adjustments. GAAP and Non-GAAP net income increased by 9% and 3%, respectively, compared to 2022, primarily due to higher interest income and lower taxes. Cash, cash equivalents and total marketable securities as of December 31, 2023 were $13.7 billion, compared to $10.9 billion as of December 31, 2022. The increase was primarily due to income from operations that was driven by strong revenue growth, and interest income, partially offset by income tax payments and repurchases of our common stock pursuant to our share repurchase program. Full Year 2024 Financial Guidance Vertex today provided full year 2024 financial guidance. Vertex’s product revenue guidance of $10.55 billion to $10.75 billion includes expectations for continued growth in CF as well as the launch of CASGEVY in approved indications and geographies. Vertex’s combined Non-GAAP R&D, Acquired IPR&D and SG&A expense guidance of $4.3 billion to $4.4 billion includes expectations for continued investment in our multiple mid and late-stage clinical development programs, commercial and manufacturing capabilities, and approximately $125 million of upfront and milestone payments. Vertex’s financial guidance is summarized below: FY 2024 Total product revenues $10.55 to $10.75 billion Combined GAAP R&D, Acquired IPR&D and SG&A expenses (2) $4.9 to $5.1 billion Combined Non-GAAP R&D, Acquired IPR&D and SG&A expenses (2) $4.3 to $4.4 billion Non-GAAP effective tax rate 20% to 21% Key Business Highlights Marketed Products Cystic Fibrosis (CF) Portfolio Vertex anticipates the number of CF patients taking our medicines will continue to grow, including through new approvals and reimbursement for the treatment of younger patients. Recent and anticipated progress includes: Updated estimates for the number of patients living with CF from ~88,000 to ~92,000 in the U.S., Europe, Australia, and Canada. The European Commission granted approval in the fourth quarter of 2023 for label extension of KAFTRIO in combination with ivacaftor in children with CF 2 to 5 years of age who have at least one F508del mutation in the CFTR gene. With this approval, approximately 1,200 children are newly eligible for a medicine that could treat the underlying cause of their disease. Vertex will continue to work with reimbursement authorities across the European Union to ensure access for all eligible patients. In the U.K., the Medicines and Healthcare Products Regulatory Agency (MHRA) approved the use of KAFTRIO in children with CF 2 to 5 years of age who have at least one F508del mutation in the CFTR gene. With this approval, approximately 200 children are newly eligible for a medicine that could treat the underlying cause of their disease. Because of the existing reimbursement agreement between Vertex and the National Health Service, children ages 2 years of age and above in the U.K. already have access to KAFTRIO. The European Medicines Agency (EMA) validated the Marketing Authorization Application (MAA) extension for KAFTRIO in combination with ivacaftor to include people with CF who have a rare mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive based on clinical and/or in vitro data, including the N1303K mutation. If approved, approximately 2,800 people with CF in the European Union ages 2 years of age and above would be newly eligible for treatment. Vertex plans to submit regulatory filings for the same mutations in Australia, Brazil, Canada, New Zealand and Switzerland. Vertex also plans to submit a subset of these mutations, including N1303K and non-canonical splice mutations, not currently included in the U.S. TRIKAFTA label to the U.S. FDA. Sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT): CASGEVY Vertex received regulatory approvals for CASGEVY in the U.S., Great Britain, Bahrain, and the Kingdom of Saudi Arabia (KSA) for the treatment of both SCD and TDT. Vertex also received a positive opinion for CASGEVY for the treatment of both SCD and TDT from the EMA’s Committee for Medicinal Products for Human Use (CHMP). 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 to treat people with transfusion-dependent beta thalassemia (TDT) from 12-35 years of age for whom hematopoietic stem cell (HSC) transplantation is appropriate and a human leukocyte antigen (HLA)-matched related HSC donor is not available. Vertex is also pursuing an EAP submission for SCD in France and expects to hear the outcome of this decision in the coming months. The regulatory submission for CASGEVY in both SCD and TDT is currently under review in Switzerland, with submission in Canada planned for the first half of 2024. Vertex updated estimates for the number of patients living with severe SCD, from ~25,000 patients to ~30,000 patients in the U.S. and Europe, with additional patients in KSA and Bahrain. Vertex also updated estimates for patients with TDT, from ~7,000 to ~5,000 patients in the U.S. and Europe, with additional patients in KSA and Bahrain. Vertex has activated 12 authorized treatment centers (ATCs) in the U.S. and three in the EU, with the ultimate goal of activating approximately 50 ATCs in the U.S. and 25 in Europe. Vertex has also activated one of two planned ATCs in KSA. Vertex recently signed an agreement with Synergie Medication Collective, a medication contracting organization founded by a group of Blue Cross and Blue Shield affiliated companies covering approximately 100 million people in the U.S., to provide access to CASGEVY. On January 30th, the Biden Administration, in partnership with Centers for Medicare and Medicaid Services (CMS) and the Department of Health and Human Services (HHS), announced the details of the Center for Medicare and Medicaid Innovation Cell and Gene Therapy (CGT) Access Demonstration Model. The demonstration model is structured as a voluntary negotiation with CMS to devise multi-state outcomes-based arrangements (OBAs) for SCD cell and genetic therapies that state Medicaid programs can participate in beginning in January 2025. In the meantime, Vertex is actively engaging with Medicaid states to secure immediate reimbursement and coverage for CASGEVY and believes the CGT Access Model may provide an additional important tool to help address longstanding inequities in care by facilitating access and funding for potentially curative therapies for the sickle cell community. Potential Near-Term Launch Opportunities Vertex is preparing for the following near-term potential new product launches: Vanzacaftor/tezacaftor/deutivacaftor, the next-in-class triple oral small molecule combination, in cystic fibrosis In the fourth quarter, Vertex completed three pivotal studies evaluating the efficacy and safety of vanzacaftor/tezacaftor/deutivacaftor ("the vanza triple") relative to TRIKAFTA in people with CF ages 6 years of age and older (ages 12+ in SKYLINE 102 and 103 studies; ages 6-11 in the RIDGELINE study). Vertex today shared positive data from the three pivotal studies for the vanza triple, showing that the studies met the primary endpoint and all key secondary endpoints. Based on these data, Vertex intends to submit global regulatory filings by mid-2024 for the vanza triple, including a New Drug Application (NDA) to the U.S. FDA using a priority review voucher and MAAs to the EMA and Health Canada, for people with CF 6 years of age and older. VX-548 for the treatment of moderate to severe acute pain: Vertex has discovered multiple selective small molecule inhibitors of NaV1.8 with the objective of creating a new class of pain medicines that have the potential to provide effective pain relief across a variety of pain states, without the limitations of opioids and other currently available medicines. In the fourth quarter of 2023, Vertex completed the pivotal program, which includes three Phase 3 trials: one randomized, controlled trial in abdominoplasty; one randomized, controlled trial in bunionectomy; and a single-arm safety and effectiveness trial. Vertex recently shared positive results from the three Phase 3 trials of VX-548 in acute pain. Based on these data, Vertex plans to submit an NDA for the treatment of moderate to severe acute pain to the U.S. FDA by mid-2024. VX-548 has Fast Track and Breakthrough Therapy designations in acute pain. Select Clinical-Stage R&D Pipeline Vertex is delivering on a diversified pipeline of potentially transformative medicines for serious diseases utilizing a range of modalities. Recent and anticipated progress for select programs in clinical development is summarized below. Cystic Fibrosis Vertex continues to pursue a nebulized mRNA therapy for the more than 5,000 patients who do not make CFTR protein and cannot benefit from CFTR modulators, as well as next-in-class, small molecule, oral CFTR modulators. Vertex completed dosing in the single ascending dose (SAD) portion of the Phase 1/2 study of VX-522 in people with CF. Vertex initiated the multiple ascending dose (MAD) portion of the study; screening, enrollment and dosing are underway. Vertex expects to share data from this study in late 2024 or early 2025. Sickle Cell Disease and Beta Thalassemia Vertex completed enrollment in two global Phase 3 studies of CASGEVY in people 5 to 11 years of age with SCD or TDT. Additionally, Vertex continues to work on preclinical assets for gentler conditioning for CASGEVY, which could broaden the eligible patient population to more than 150,000 people. Peripheral Neuropathic Pain (PNP) In December 2023, Vertex shared positive Phase 2 results with VX-548 in diabetic peripheral neuropathy, a condition that affects ~2 million Americans. Vertex will meet with regulators in the first quarter of 2024 and anticipates advancing VX-548 into pivotal development thereafter. Vertex initiated a Phase 2 study of VX-548 in lumbosacral radiculopathy (LSR), another type of peripheral neuropathic pain and the largest patient segment (over 40%) within the PNP category with high unmet need and no approved therapies. Screening, enrollment and dosing are underway. Vertex anticipates initiating a Phase 2 study with an oral formulation of VX-993, a next-generation selective NaV1.8 inhibitor, for the treatment of PNP in 2024. Acute Pain Vertex also anticipates initiating a Phase 2 study with an oral formulation of VX-993, a next-generation NaV1.8 inhibitor, for the treatment of moderate to severe acute pain in of 2024. Vertex anticipates completing IND-enabling studies and filing an IND for an intravenous formulation of VX-993 in 2024. Consistent with its commitment to serial innovation and leadership in pain, Vertex also continues to develop NaV1.7 inhibitors, both for stand-alone use and in combination with NaV1.8 inhibitors, for both acute and peripheral neuropathic pain. APOL1-Mediated Kidney Disease (AMKD) Vertex has discovered and advanced multiple oral, small molecule inhibitors of APOL1 function, pioneering a new class of medicines that target an underlying genetic driver of kidney disease. Vertex completed enrollment in the Phase 2B dose-ranging portion of the pivotal program for inaxaplin, a single Phase 2/3 clinical trial in patients with AMKD. Vertex expects to select a dose for the Phase 3 portion and begin Phase 3 in the first quarter of 2024. Type 1 Diabetes (T1D) Vertex is evaluating cell therapies using stem cell-derived, fully differentiated, insulin-producing islet cells to replace the endogenous insulin-producing islet cells that are destroyed in people with T1D, with the goal of developing a potential one-time functional cure for this disease. VX-880, fully differentiated islet cells with standard immunosuppression: Completed enrollment in Parts A, B, and C of the Phase 1/2 study of VX-880, an allogeneic, stem cell-derived, fully differentiated, insulin-producing islet cell therapy, used in conjunction with standard immunosuppression, in people with T1D and impaired awareness of hypoglycemia and recurrent hypoglycemic events. Vertex has placed the study on a protocol-specified pause, pending review of the totality of the data by the independent data monitoring committee and global regulators. VX-264, fully differentiated islet cells encapsulated in an immunoprotective device: The clinical trial for VX-264, which encapsulates the same VX-880 cells in a novel device designed to eliminate the need for immunosuppressants, is a multi-part, Phase 1/2 study. Vertex has completed Part A of the study. Per protocol, the Independent Data Monitoring Committee reviewed the totality of the data from the patients dosed in Part A of the study and recommended advancement to Part B of the study, which has been initiated in multiple centers and countries. Hypoimmune, edited fully differentiated islet cells: Vertex’s hypoimmune cell program involves using CRISPR/Cas9 to gene edit the same stem cell-derived, fully differentiated islets used in the VX-880 and VX-264 programs to cloak the cells from the immune system. This program is progressing through the research stage. Non-GAAP Financial Measures In this press release, Vertex's financial results and financial guidance are provided in accordance with accounting principles generally accepted in the United States (GAAP) and using certain non-GAAP financial measures. In particular, non-GAAP financial results and guidance exclude from Vertex's pre-tax income (i) stock-based compensation expense, (ii) intangible asset amortization expense, (iii) gains or losses related to the fair value of the company's strategic investments, (iv) increases or decreases in the fair value of contingent consideration, (v) acquisition-related costs, (vi) an intangible asset impairment charge and (vii) other adjustments. The company's non-GAAP financial results also exclude from its provision for income taxes the estimated tax impact related to its non-GAAP adjustments to pre-tax income described above and certain discrete items. These results should not be viewed as a substitute for the company’s GAAP results and are provided as a complement to results provided in accordance with GAAP. Management believes these non-GAAP financial measures help indicate underlying trends in the company's business, are important in comparing current results with prior period results and provide additional information regarding the company's financial position that the company believes is helpful to an understanding of its ongoing business. Management also uses these non-GAAP financial measures to establish budgets and operational goals that are communicated internally and externally, to manage the company's business and to evaluate its performance. The company’s calculation of non-GAAP financial measures likely differs from the calculations used by other companies. A reconciliation of the GAAP financial results to non-GAAP financial results is included in the attached financial information. The company provides guidance regarding combined R&D, Acquired IPR&D and SG&A expenses and effective tax rate on a non-GAAP basis. Unless otherwise noted, the guidance regarding combined GAAP and non-GAAP R&D, Acquired IPR&D and SG&A expenses does not include estimates associated with any potential future business development transactions, including collaborations, asset acquisitions and/or licensing of third-party intellectual property rights. The company does not provide guidance regarding its GAAP effective tax rate because it is unable to forecast with reasonable certainty the impact of excess tax benefits related to stock-based compensation and the possibility of certain discrete items, which could be material. Vertex Pharmaceuticals Incorporated Consolidated Statements of Income (in millions, except per share amounts)(unaudited) Three Months Ended December 31, Twelve Months Ended December 31, 2023 2022 2023 2022 Product revenues, net $ 2,517.7 $ 2,302.7 $ 9,869.2 $ 8,930.7 Costs and expenses: Cost of sales 368.0 283.3 1,262.2 1,080.3 Research and development expenses 824.6 694.1 3,162.9 2,540.3 Acquired in-process research and development expenses 17.8 22.6 527.1 115.5 Selling, general and administrative expenses 369.1 267.4 1,136.6 944.7 Change in fair value of contingent consideration (50.3 ) 1.8 (51.6 ) (57.5 ) Total costs and expenses 1,529.2 1,269.2 6,037.2 4,623.3 Income from operations 988.5 1,033.5 3,832.0 4,307.4 Interest income 179.5 86.0 614.7 144.6 Interest expense (10.6 ) (11.6 ) (44.1 ) (54.8 ) Other expense, net (9.8 ) (31.1 ) (22.8 ) (164.8 ) Income before provision for income taxes 1,147.6 1,076.8 4,379.8 4,232.4 Provision for income taxes 178.8 257.9 760.2 910.4 Net income $ 968.8 $ 818.9 $ 3,619.6 $ 3,322.0 Net income per common share: Basic $ 3.76 $ 3.19 $ 14.05 $ 12.97 Diluted $ 3.71 $ 3.15 $ 13.89 $ 12.82 Shares used in per share calculations: Basic 257.7 256.9 257.7 256.1 Diluted 260.9 260.3 260.5 259.1 Vertex Pharmaceuticals Incorporated Product Revenues (in millions)(unaudited) Three Months Ended December 31, Twelve Months Ended December 31, 2023 2022 2023 2022 TRIKAFTA/KAFTRIO $ 2,333.3 $ 2,021.5 $ 8,944.7 $ 7,686.8 Other CF products 184.4 281.2 924.5 1,243.9 Product revenues, net $ 2,517.7 $ 2,302.7 $ 9,869.2 $ 8,930.7 Vertex Pharmaceuticals Incorporated Reconciliation of GAAP to Non-GAAP Financial Information (in millions, except percentages)(unaudited) Three Months Ended December 31, Twelve Months Ended December 31, 2023 2022 2023 2022 GAAP cost of sales $ 368.0 $ 283.3 $ 1,262.2 $ 1,080.3 Stock-based compensation expense (2.1 ) (2.4 ) (7.5 ) (9.4 ) Intangible asset amortization expense (1.7 ) — (1.7 ) — Non-GAAP cost of sales $ 364.2 $ 280.9 $ 1,253.0 $ 1,070.9 GAAP research and development expenses $ 824.6 $ 694.1 $ 3,162.9 $ 2,540.3 Stock-based compensation expense (123.0 ) (68.0 ) (354.9 ) (297.9 ) Intangible asset impairment charge (3) — — — (13.0 ) Acquisition-related costs (4) (2.8 ) (2.8 ) (11.3 ) (24.9 ) Non-GAAP research and development expenses $ 698.8 $ 623.3 $ 2,796.7 $ 2,204.5 Acquired in-process research and development expenses $ 17.8 $ 22.6 $ 527.1 $ 115.5 GAAP selling, general and administrative expenses $ 369.1 $ 267.4 $ 1,136.6 $ 944.7 Stock-based compensation expense (83.5 ) (41.1 ) (218.8 ) (184.0 ) Acquisition-related costs (4) — (0.7 ) — (13.9 ) Non-GAAP selling, general and administrative expenses $ 285.6 $ 225.6 $ 917.8 $ 746.8 Combined non-GAAP R&D, Acquired IPR&D and SG&A expenses $ 1,002.2 $ 871.5 $ 4,241.6 $ 3,066.8 GAAP other expense, net $ (9.8 ) $ (31.1 ) $ (22.8 ) $ (164.8 ) Decrease in fair value of strategic investments 0.4 6.0 0.6 149.1 Non-GAAP other expense, net $ (9.4 ) $ (25.1 ) $ (22.2 ) $ (15.7 ) GAAP provision for income taxes $ 178.8 $ 257.9 $ 760.2 $ 910.4 Tax adjustments (1) 35.5 (36.3 ) 194.7 101.7 Non-GAAP provision for income taxes $ 214.3 $ 221.6 $ 954.9 $ 1,012.1 GAAP effective tax rate 15.6 % 24.0 % 17.4 % 21.5 % Non-GAAP effective tax rate 16.3 % 18.5 % 19.4 % 20.8 % Vertex Pharmaceuticals Incorporated Reconciliation of GAAP to Non-GAAP Financial Information (continued) (in millions, except per share amounts)(unaudited) Three Months Ended December 31, Twelve Months Ended December 31, 2023 2022 2023 2022 GAAP operating income $ 988.5 $ 1,033.5 $ 3,832.0 $ 4,307.4 Stock-based compensation expense 208.6 111.5 581.2 491.3 Intangible asset amortization expense 1.7 — 1.7 — Decrease (increase) in fair value of contingent consideration (3) (50.3 ) 1.8 (51.6 ) (57.5 ) Intangible asset impairment charge (3) — — — 13.0 Acquisition-related costs (4) 2.8 3.5 11.3 38.8 Non-GAAP operating income $ 1,151.3 $ 1,150.3 $ 4,374.6 $ 4,793.0 Three Months Ended December 31, Twelve Months Ended December 31, 2023 2022 2023 2022 GAAP net income $ 968.8 $ 818.9 $ 3,619.6 $ 3,322.0 Stock-based compensation expense 208.6 111.5 581.2 491.3 Intangible asset amortization expense 1.7 — 1.7 — Decrease in fair value of strategic investments 0.4 6.0 0.6 149.1 Decrease (increase) in fair value of contingent consideration (3) (50.3 ) 1.8 (51.6 ) (57.5 ) Intangible asset impairment charge (3) — — — 13.0 Acquisition-related costs (4) 2.8 3.5 11.3 38.8 Total non-GAAP adjustments to pre-tax income 163.2 122.8 543.2 634.7 Tax adjustments (1) (35.5 ) 36.3 (194.7 ) (101.7 ) Non-GAAP net income $ 1,096.5 $ 978.0 $ 3,968.1 $ 3,855.0 Net income per diluted common share: GAAP $ 3.71 $ 3.15 $ 13.89 $ 12.82 Non-GAAP $ 4.20 $ 3.76 $ 15.23 $ 14.88 Shares used in diluted per share calculations: GAAP and Non-GAAP 260.9 260.3 260.5 259.1 Vertex Pharmaceuticals Incorporated Condensed Consolidated Balance Sheets (in millions)(unaudited) December 31, 2023 December 31, 2022 Assets Cash, cash equivalents and marketable securities $ 11,218.3 $ 10,778.5 Accounts receivable, net 1,563.4 1,442.2 Inventories 738.8 460.6 Prepaid expenses and other current assets 623.7 553.5 Total current assets 14,144.2 13,234.8 Property and equipment, net 1,159.3 1,108.4 Goodwill and intangible assets, net 1,927.9 1,691.6 Deferred tax assets 1,812.1 1,246.9 Operating lease assets 293.6 347.4 Long-term marketable securities 2,497.8 112.2 Other long-term assets 895.3 409.6 Total assets $ 22,730.2 $ 18,150.9 Liabilities and Shareholders' Equity Accounts payable and accrued expenses $ 3,020.2 $ 2,430.6 Other current liabilities 527.2 311.5 Total current liabilities 3,547.4 2,742.1 Long-term finance lease liabilities 376.1 430.8 Long-term operating lease liabilities 348.6 379.5 Other long-term liabilities 877.7 685.8 Shareholders' equity 17,580.4 13,912.7 Total liabilities and shareholders' equity $ 22,730.2 $ 18,150.9 Common shares outstanding 257.7 257.0 Notes and Explanations 1: In the three and twelve months ended December 31, 2023 and 2022, "Tax adjustments" included the estimated income taxes related to non-GAAP adjustments to the company's pre-tax income and excess tax benefits related to stock-based compensation. “Tax adjustments” for the twelve months ended December 31, 2023 also included a $75 million discrete benefit related to prior tax years resulting from a R&D tax credit study that was completed during the third quarter of 2023. “Tax adjustments” for the twelve months ended December 31, 2022 included $60 million of net discrete tax expense related to our uncertain tax positions associated with intercompany transfer pricing matters partially offset by changes in our estimated prior-year tax liabilities. 2: The difference between the company’s full year 2024 combined GAAP R&D, Acquired IPR&D and SG&A expenses and combined non-GAAP R&D, Acquired IPR&D and SG&A expenses guidance relates primarily to $600 million to $700 million of stock-based compensation expense. Unless otherwise noted, the guidance regarding combined GAAP and non-GAAP R&D, Acquired IPR&D and SG&A expenses does not include estimates associated with any potential future business development transactions, including collaborations, asset acquisitions and/or licensing of third-party intellectual property rights. 3: In the three months ended December 31, 2023, the company determined that additional pre-clinical studies for DMD will be required, which resulted in a decrease in the associated fair value of contingent consideration. In the three months ended June 30, 2022, the company revised the scope of certain acquired programs, resulting in a decrease in the associated fair value of contingent consideration and a $13 million “Intangible asset impairment charge.” 4: "Acquisition-related costs" in the three and twelve months ended December 31, 2023 and 2022 related to costs associated with the company's acquisition of Exonics and ViaCyte. Note: Amounts may not foot due to rounding. About Vertex Vertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has approved medicines that treat the underlying causes of multiple chronic, life-shortening genetic diseases — cystic fibrosis, sickle cell disease and transfusion-dependent beta thalassemia — and continues to advance clinical and research programs in these diseases. Vertex also has a robust clinical pipeline of investigational therapies across a range of modalities in other serious diseases where it has deep insight into causal human biology, including APOL1-mediated kidney disease, acute and neuropathic pain, type 1 diabetes, myotonic dystrophy type 1 and alpha-1 antitrypsin deficiency. Vertex was founded in 1989 and has its global headquarters in Boston, with international headquarters in London. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia, Latin America and the Middle East. Vertex is consistently recognized as one of the industry's top places to work, including 14 consecutive years on Science magazine's Top Employers list and one of Fortune’s 100 Best Companies to Work For. For company updates and to learn more about Vertex's history of innovation, visit or follow us on LinkedIn, Facebook, Instagram, YouTube and Twitter/X. Special Note Regarding Forward-Looking Statements This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, Dr. Kewalramani's statements in this press release, the information provided regarding future financial performance and operations, the section captioned “Full Year 2024 Financial Guidance” and statements regarding (i) expectations for continued growth in the number treated with our CF medicines, including through new approvals and reimbursements for eligible younger children, our continued work with reimbursement authorities to ensure access for eligible patients, and expectations for expansion of treatment options for patients that have a rare mutation of the CFTR gene, including the N1303K and non-canonical splice mutations, (ii) expectations associated with the recent and anticipated regulatory approvals for CASGEVY, including plans to pursue additional EAPs outside of the U.S., plans to submit additional regulatory filings for CASGEVY, expectations for potential CASGEVY revenue, expectations around the plans to activate ATCs in the U.S., Europe and KSA, expectations associated with our agreement with Synergie Medication Collective, as well as our beliefs regarding the potential benefits of the CGT Access Model, (iii) expectations, plans, and status of the potential near-term commercial launch of vanzacaftor/tezacaftor/deutivacaftor in CF, including our plans to submit regulatory filings in the U.S., Europe and Canada in mid-2024 and plans to use a priority review voucher in the U.S., (iv) expectations, plans, and status of the potential near-term commercial launch of VX-548 for the treatment of moderate to severe acute pain, including expectations regarding the potential benefits of VX-548, and our plans to submit regulatory filings by mid-2024, (v) expectations, development plans, and anticipated timelines for the company's products, product candidates and pipeline programs, including expectations for multiple additional near-term clinical milestones, study designs, patient enrollment, data availability, potential launches and timing thereof, (vi) expectations for the expansion of treatment options for patients who cannot benefit from CFTR modulators alone, our collaboration with Moderna to develop CFTR mRNA therapeutics and the status of the MAD portion of the study for VX-522 and expectations to share data from this study in late 2024 or early 2025, (vii) expectations regarding our SCD and TDT program and clinical trials including expectations that a gentler conditioning for CASGEVY could broaden the eligible patient population to more than 150,000 people, (viii) expectations regarding our PNP program, including expectations to meet with regulators and advance VX-548 for PNP into pivotal development and timing thereof, the status of our Phase 2 study of VX-548 in LSR, and our plans to initiate a Phase 2 study with an oral formulation of VX-993 in 2024, (ix) expectations regarding our acute pain program, including plans to initiate a Phase 2 study with an oral formulation of VX-993 in 2024, expectations around completing IND-enabling studies and filing an IND for an intravenous formulation of VX-993 in 2024, and plans to continue to develop NaV1.7 and NaV1.8 inhibitors for both acute pain and PNP, (x) expectations regarding the potential benefits of our AMKD program and plans to select a dose for the Phase 3 portion and begin the Phase 3 study of inaxaplin in the first quarter of 2024, and (xi) expectations regarding our T1D programs, including the potential benefits of our T1D programs that use stem-cell derived, fully differentiated islet cells, and expectations for the advancement of our T1D programs, including clinical trial designs and clinical progress. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that the company's expectations regarding its 2024 full year product revenues, expenses and effective tax rates may be incorrect (including because one or more of the company's assumptions underlying its expectations may not be realized), that the company may not be able to receive adequate reimbursement or additional regulatory approval for CASGEVY on the expected timeline, or at all, that we are unable to successfully develop, obtain approval or commercialize VX-548 as a treatment for acute or neuropathic pain, that external factors may have different or more significant impacts on the company's business or operations than the company currently expects, that data from preclinical testing or clinical trials, especially if based on a limited number of patients, may not be indicative of final results or available on anticipated timelines, that patient enrollment in our trials may be delayed, that the company may not realize the anticipated benefits from our collaborations with third parties, that data from the company's development programs may not support registration or further development of its potential medicines in a timely manner, or at all, due to safety, efficacy or other reasons, that anticipated commercial launches may be delayed, if they occur at all, and other risks listed under the heading “Risk Factors” in Vertex's annual report and subsequent quarterly reports filed with the Securities and Exchange Commission (SEC) and available through the company's website at and on the SEC’s website at . You should not place undue reliance on these statements, or the scientific data presented. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available. Conference Call and Webcast The company will host a conference call and webcast at 4:30 p.m. ET. To access the call, please dial (833) 630-2124 (U.S.) or +1(412) 317-0651 (International) and reference the “Vertex Pharmaceuticals Fourth Quarter 2023 Earnings Call.” The conference call will be webcast live and a link to the webcast can be accessed through Vertex's website at in the "Investors" section. To ensure a timely connection, it is recommended that participants register at least 15 minutes prior to the scheduled webcast. An archived webcast will be available on the company's website. (VRTX-E)

转眼2023年已划上句号，尽管过去一年创新药资本“寒冬”未尽，但是新技术、新疗法的发展并未停下脚步。辞旧迎新之际，医药魔方Pro《回望2023》专栏邀请了不同细分技术赛道的标杆性企业，以领域最前线的视角，回顾所在赛道2023年的里程碑进展，并展望2024年相关赛道有望取得的突破，为行业发展提振信心。06期嘉宾：霍德生物 创始人、CEO 范靖博士赛道：iPSC细胞疗法范靖，霍德生物创始人、CEO；北京大学学士，加拿大UBC神经学博士，前JHU博士后；在多能干细胞培养及定向诱导分化、神经疾病模型、细胞信号通路、药物靶点发现等领域有17年以上的研发经验，带领团队进行了多项自主知识产权及底层技术的全球布局，建立了iPSC衍生细胞产品的CMC及开发平台，以及多个疾病领域的产品研发管线；其中首个人前脑神经前体细胞hNPC01的中国IND申请已获批并完成低剂量组给药，美国IND申请即将提交，是目前国际开发速度最快的同类iPSC细胞产品，可针对脑卒中、颅脑损伤后遗症等重大的未被满足的临床需求。2023年对于iPSC细胞疗法赛道而言是快速发展的一年。一方面，国际上多个iPSC细胞疗法的临床试验公布积极结果，包括神经退行性疾病、肿瘤和代谢疾病等，均进一步显示了iPSC细胞疗法的安全性与潜在疗效。另一方面，国内获得注册临床默许的iPSC细胞疗法企业达到6家，针对心脑血管、膝骨关节炎、神经退行性疾病等10个适应症的多个细胞产品进入或即将进入临床。同时，各国政府与监管机构也在积极制定iPSC细胞疗法相关法规和政策，更好地支持iPSC细胞疗法的可持续发展。此外，即使在资本寒冬下，2023年iPSC细胞疗法赛道的多家初创企业仍然完成了亿元以上融资。总体而言，过去一年，我们看到iPSC细胞疗法已成为新一代CGT疗法中强劲崛起的重要新生力量。2023年里程碑赛道里程碑近年来，在iPSC细胞疗法领域，全球范围内多家生物医药公司都在积极布局iPSC相关管线，涵盖多种适应症。过去一年，印象比较深的里程碑进展包括：1）2023年10月，Vertex Pharmaceuticals公布了其干细胞衍生疗法VX-880的I/II期临床试验A阶段和B阶段的长期结果。所有接受VX-880治疗的患者在超过90天的随访中都实现了胰岛细胞存活和葡萄糖响应性胰岛素产生。该临床结果证明了体外分化的胰岛组织具有体内产生胰岛素且能受血糖调节的功能，为异体胰岛移植供源不足问题提供了可能的解决方案，具有突破性的意义。当然由于临床的复杂性，该治疗结合长期免疫抑制剂对于患者人群的安全性和长期有效性还有待观察。2）2023年8月，拜耳旗下的BlueRock Therapeutics宣布其研究药物Bemdaneprocel（BRT-DA01）治疗帕金森病的I期临床试验显示了良好的耐受性和安全性，12名患者在一年内均未出现重大安全问题，且对移植的可行性以及细胞在大脑中存活植入一年以并显示出初步的治疗潜力的证据进行了展示。3）澳大利亚Cynata Therapeutics公司的同种异体、iPSC衍生间充质干细胞产品CYP-004，率先进入III期临床，是全球首个进入III期临床的iPSC衍生细胞疗法。这意味着首个iPSC细胞疗法的应用与商业化已经近在眼前。这些令人欣喜的临床结果进一步证明了iPSC细胞疗法在不同疾病治疗领域的安全性与疗效潜力。相信更多创新iPSC细胞疗法进入临床和商业化，将能为全球患者提供更多安全、稳定、可负担的治疗选择和希望。霍德生物里程碑2023年对于霍德生物是具有里程碑意义的一年。管线方面，2023年6月21日，公司首个中美双报的针对缺血性脑卒中偏瘫后遗症的iPSC衍生hNPC01注射液获得中国CDE的临床试验默示许可。这是全球首个获批注册临床的多能干细胞衍生前脑神经前体细胞产品，也是中国首个获得CDE临床默许的神经类iPSC细胞产品。12月7日，该I期临床试验已完成首例受试者给药并已观察到肌力和评分的初步改善，目前已完成所有低剂量组给药。同时，hNPC01在拓展脑瘫适应症的动物药效实验中显示出显著的治疗效果，其他在研产品也在悬浮封闭工艺开发和药学研究中也有非常好的进展，预计近期将有更多适应症逐步进入临床。资金方面，公司通过2021及2022年的多轮融资，可以为hNPC01产品的临床开发和其他管线提供至少至2026年的资金保障，基于2024年的临床进展将会考虑接收新的融资，为后期临床和商业化做好准备。BD方面，公司持续接收到和在洽谈多个海内外合作开发、GMP细胞株授权的合作需求。根据公司当前的战略规划，一些非核心的在研产品管线考虑可以通过对外授权或共同开发进行加速，近期新建成的研发中心也可以为未来的合作开发需求提供更多可能性。挑战与机遇关键挑战iPSC细胞疗法目前亟需克服的挑战，我认为主要包括以下几点：1）CMC：匹配产品阶段的规模化生产和相应的质量体系，也即符合阶段需求的CMC和GMP，是所有细胞产品、甚至CGT产品都需要克服的重要挑战，这当然也包括了大家比较关心的iPSC细胞产品的安全性。虽然iPSC通用型细胞治疗产品相对自体或原代来源的细胞治疗产品而言，在建立稳定的符合质量标准的细胞库和生产工艺后，理论上能更好地进行多批次的规模化生产、批次间可比、质量和成本更加可控。但实际上，由于多能干细胞定向分化技术出现较晚，且工艺较为复杂，不同产品分化技术和生产工艺差异较大，早期主要为贴壁、开放/半开放，依赖人工的细胞培养工艺，难以支持GMP规模化放大生产和质量保障。对于一些临床使用剂量较高且扩增较难的品类，如NK细胞、胰岛细胞等（单剂用量在10的9次方，也即数十亿细胞），一般规模的贴壁工艺生产去除用于质量检测放行、质量和稳定性研究等样品用量后所剩无几，单剂量成本高达上百万人民币，满足临床和商业化需求具有很大挑战。2）安全性：确保不同规模的生产工艺下iPSC细胞及其衍生细胞的安全性是CMC的首要挑战问题。以安全性中大家最为关注的iPSC衍生细胞的成瘤性为例，目前正式进入临床的多能干细胞衍生产品，包括长达8年的临床观察中没有观察到成瘤，但如果没有充分评估和把控捐赠者筛查、重编程后单克隆筛选、基因组突变分析，iPSC细胞库、生产中间品及成品细胞的质量和遗传稳定性，如是否有核型异常、肿瘤突变，及成品中是否有潜在的多能细胞残留等，那在使用这些未进行充分药学和非临床研究的iPSC细胞产品治疗患者时，是有一定风险的。3）分化效率：对一些分化较难和分化效率不高的特定细胞类型而言，获得足够纯度和高模拟体内细胞组成以及功能成熟度的产品仍然是一个挑战。有时，一些特定分化类型的细胞可能需要特定的刺激因子、甚至特定细胞/系统的促进，才能真正成熟和具备目标细胞的特征和功能，而这些有时是和well-defined xeno-free等临床GMP产品要求、稳定性和规模生产相矛盾的。4）其他：通用型iPSC细胞产品异体移植的免疫原性和目前大部分产品稳定性效期较短，快速放行和运输、储存等都有一定挑战。应对策略为克服以上挑战，包括霍德生物在内的iPSC细胞疗法赛道同仁做了大量的尝试及探索：首先，任何一个创新的产品类型都需要大量企业的研究积累，配合阶段开发需求，不断完善CMC和GMP体系，这是一个漫长和持续投入的过程，最终目标是能保障上市产品的质量稳定、安全性和有效性，同时也要兼顾产量和成本的可负担性。为克服这些挑战，全球iPSC细胞疗法赛道的企业和监管方、产业链伙伴等一直都在持续探讨和探索，并在临床中逐步验证和完善。霍德生物也从开发早期就非常重视悬浮封闭自动化工艺和设备的探索，随着阶段和供应链的成熟，目前也已经实现多个产品的3D悬浮生产工艺的开发，以及一些产品的悬浮封闭自动化生产和进一步放大生产规模，可以更好地支持临床后期及商业化生产和质量保障的需要。公司也很早开始进行了大量的质量研究工作，开发了多个创新的针对iPSC细胞产品的质量分析、检测方法和初步的质量标准，包括二代测序基因组突变分析、单克隆筛选标准和源性分析、数字PCR法检测多能细胞残留、克隆形成法检测多能细胞残留、单细胞转录组测序（scRNAseq）细胞组成分析等等。这些持续积累的数据、检测和方法能够帮助更好地理解现有工艺生产的iPSC细胞产品的质量和安全性，与常规的质量控制项、非临床研究的免疫缺陷动物的长期体内成瘤实验等结合，保障临床产品的安全性和一致性。对于难分化、成熟或扩增的细胞类型，领域内通常通过筛选或优化定向分化因子、调控的小分子、培养条件、采用生物材料、人血清替代物、人源工程化细胞株、磁珠纯化、刺激活化因子、基因编辑等，提高定向分化和扩增效率、产品纯度以及功能性。以hNPC01为例，公司开发的促成熟专利配方和特有的RONA物理纯化方法使得产品的稳定性、分化效率、产品纯度、批次间一致性、细胞组成、功能成熟度、产量成本、安全性等都具有极大优势，通过快速筛选命运调控因子、小分子与特有的纯化RONA技术也可以实现其他产品xeno-free的3D悬浮培养、高纯度、更高的扩增和功能促进成熟。解决异体细胞治疗的免疫排斥问题，确保细胞移植后的长期存活与功能，目前界内采用的策略有长期使用免疫抑制剂、HLA配型、生物材料包裹移植物、基因编辑iPSC得到低免细胞株等。对于非免疫豁免的移植或高免疫原性产品，霍德生物采用的是基因编辑iPSC低免细胞株的策略，并已在建立GMP细胞株和细胞库。未来展望目前全球范围内，已有包括霍德生物在内的不少公司的iPSC细胞疗法进入临床阶段，适应症包括神经疾病、肿瘤、眼科、糖尿病、心血管疾病和骨关节疾病等。十分期待2024年，这些iPSC细胞治疗公司能有更多突破性临床试验结果公布，为整个领域带来积极的信号。更长远来看，3-5年后，iPSC细胞疗法应该会有多个产品申报商业化上市，以及更多细胞类型的产品在更多疾病领域展开临床应用，包括基因编辑、通用型低免iPSC细胞产品等。此外，自动化生产等会成为趋势。我比较期待一些针对没有任何治疗手段的适应症的创新iPSC细胞的药效和机制在临床得到验证，通用型、甚至自体iPSC细胞治疗产品可以极大降低现在细胞治疗的成本，惠及更多患者。未来几年，霍德生物将重点推进hNPC01不同适应症的中美临床试验和加速审评，其次是陆续推进其他产品的IND申报和临床。此外，公司将通过GMP细胞株授权、部分管线的共同开发、专利授权等合作共赢的方式，逐步实现公司的国际化布局与发展。推荐阅读标新生物杨小宝：突破制药边界，蛋白降解剂前景无限本导基因蔡宇伽：基因编辑疗法的“终极目标”——体内编辑圣诺医药陆阳：RNAi疗法逆势而上，实体瘤是下一个高地滨会生物刘滨磊：癌症免疫疗法下一张王牌——溶瘤病毒沙砾生物刘雅容：TIL细胞疗法突破不断，2024将是「关键年」- 上下滑动查看参考资料 - [1]https://news.vrtx.com/news-releases/news-release-details/vertex-presents-positive-updated-vx-880-results-ongoing-phase-12[2]https://www.bluerocktx.com/bluerocks-phase-i-study-with-bemdaneprocel-in-patients-with-parkinsons-disease-meets-primary-endpoint/医药魔方Pro新靶点 新技术 新疗法商务合作：13502093012媒体合作：15895423126版权所有 © 2024 PHARMCUBE。保留所有权利。欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。