Interferon gamma-1b

THOUSAND OAKS, Calif., Feb. 6, 2024 /PRNewswire/ -- Amgen (NASDAQ:AMGN) today announced financial results for the fourth quarter and full year 2023 versus comparable periods in 2022. "2023 was another year of performance and progress for our company," said Robert A. Bradway, chairman and chief executive officer. "Our marketed products are reaching many more patients around the world, and we anticipate more than a dozen significant pipeline milestones in 2024." Key results include: For the fourth quarter, total revenues increased 20% to $8.2 billion in comparison to the fourth quarter of 2022. Product sales grew 20%, driven by 23% volume growth, partially offset by 3% lower net selling price. Nine brands(1) achieved record sales in the quarter, and Repatha® (evolocumab), EVENITY® (romosozumab-aqqg), Prolia® (denosumab) and BLINCYTO® (blinatumomab) delivered double-digit volume growth globally. U.S. volume grew 26% and ex-U.S. volume grew 15%, including 46% volume growth in the Asia Pacific region. Our performance included $954 million of sales for the period of Oct. 6 - Dec. 31 from our recent Horizon Therapeutics (Horizon) acquisition, driven by several first-in-class, early-in-lifecycle medicines such as TEPEZZA® (teprotumumab-trbw), KRYSTEXXA® (pegloticase) and UPLIZNA® (inebilizumab-cdon). Excluding the impact of these sales from Horizon, our product sales grew 5%, driven by volume growth of 9%. For the full year, total revenues increased 7% to $28.2 billion, resulting from a 9% increase in product sales. Product sales growth was driven by 15% volume growth, partially offset by 3% lower net selling price, 1% unfavorable changes from estimated sales deductions and 1% negative impact from foreign exchange. GAAP earnings per share (EPS) decreased 53% from $3.00 to $1.42 in the fourth quarter, driven by acquisition-related expenses and incremental operating expenses from Horizon, partially offset by increased revenues. For the full year, GAAP EPS increased 3% from $12.11 to $12.49 driven by net gains on our BeiGene, Ltd equity investment in 2023 and higher revenues, partially offset by higher operating expenses, including acquisition-related expenses and incremental expenses from Horizon. For the fourth quarter, GAAP operating income decreased from $2.2 billion to $1.3 billion, and GAAP operating margin decreased 17.8 percentage points to 16.2%. For the full year, GAAP operating income decreased from $9.6 billion to $7.9 billion, and GAAP operating margin decreased 9.3 percentage points to 29.3%. Non-GAAP EPS increased 15% from $4.09 to $4.71 in the fourth quarter and increased 5% from $17.69 to $18.65 for the full year, driven by increased revenues, partially offset by higher operating expenses, including incremental expenses from Horizon. Fourth quarter non-GAAP EPS was also unfavorably impacted by higher interest expense. For the fourth quarter, non-GAAP operating income increased from $3.0 billion to $3.7 billion, and non-GAAP operating margin increased 0.8 percentage points to 46.7%. For the full year, non-GAAP operating income increased from $12.8 billion to $13.4 billion, and non-GAAP operating margin decreased 1.7 percentage points to 49.8%. The Company generated $7.4 billion of free cash flow for the full year versus $8.8 billion in 2022. The decrease in 2023 was primarily driven by transaction expenses related to the Horizon acquisition and higher repatriation tax payments. (1) Includes product sales for the full fourth quarter of 2023 from UPLIZNA and KRYSTEXXA in connection with Horizon acquisition. References in this release to "non-GAAP" measures, measures presented "on a non-GAAP basis," "free cash flow" (computed by subtracting capital expenditures from operating cash flow), "EBITDA, or earnings before interest, taxes, depreciation and amortization" (computed by adding interest expense, provision for income taxes, and depreciation and amortization expense to GAAP net income) and "debt leverage ratio" (calculated as the ratio of GAAP total debt to EBITDA) refer to non-GAAP financial measures. Adjustments to the most directly comparable GAAP financial measures and other items are presented on the attached reconciliations. Refer to Non-GAAP Financial Measures below for further discussion. Product Sales Performance Total product sales increased 20% for the fourth quarter of 2023 versus the fourth quarter of 2022. Volume grew 23%, partially offset by 3% lower net selling price. Full year product sales increased 9% versus 2022, driven by 15% volume growth, partially offset by 3% lower net selling price, 1% unfavorable changes from estimated sales deductions and 1% negative impact from foreign exchange. General Medicine Repatha® sales increased 25% year-over-year for the fourth quarter, driven by 35% volume growth, partially offset by lower net selling price. Full year sales increased 26%, driven by 37% volume growth, partially offset by lower net selling price. Repatha remains the global proprotein convertase subtilisin/kexin type 9 (PCSK9) segment leader, with over 2.5 million patients treated since launch. Prolia® sales increased 12% year-over-year, to a record $1.1 billion for the fourth quarter, and 12% for the full year, primarily driven by volume growth and higher net selling price. Volume grew 10% for the quarter and 9% for the full year. In 2023, over 7.5 million patients were treated with Prolia. EVENITY® sales increased 41% year-over-year to a record $318 million for the fourth quarter and 47% for the full year, driven by strong volume growth. U.S. volume grew 44% year-over-year and volume outside the U.S. grew 55% for the full year. Aimovig® (erenumab-aooe) sales decreased 32% year-over-year for the fourth quarter and 22% for the full year, driven by lower net selling price. Oncology BLINCYTO® sales increased 47% year-over-year to a record $241 million for the fourth quarter and 48% for the full year, driven by 55% and 49% volume growth, respectively. Volume growth was supported by broad prescribing across academic and community settings for patients with B-cell precursor acute lymphoblastic leukemia. Vectibix® (panitumumab) sales increased 5% year-over-year for the fourth quarter and 10% for the full year, driven by 5% and 10% volume growth, respectively. KYPROLIS® (carfilzomib) sales increased 8% year-over-year for the fourth quarter and 13% for the full year, driven by 8% and 12% volume growth, respectively. LUMAKRAS®/LUMYKRAS™ (sotorasib) sales increased 8% year-over-year for the fourth quarter, driven by 5% volume growth and higher net selling price. Full year sales decreased 2%, driven by unfavorable changes to estimated sales deductions, including changes related to ongoing reimbursement negotiations in France. Full year sales were also impacted by lower net selling price and lower inventory levels, partially offset by 16% volume growth. XGEVA® (denosumab) sales increased 9% year-over-year for the fourth quarter and 5% for the full year, primarily driven by higher net selling price. Nplate® (romiplostim) sales decreased 18% year-over-year for the fourth quarter, driven by volume decline related to timing of orders placed by the U.S. government, partially offset by volume growth across our U.S. and ex-U.S. regions. U.S. government orders were $207 million in Q4'22 compared to $62 million in Q4'23. Full year sales increased 13%, primarily driven by volume growth, including U.S. government orders. U.S. government orders were $207 million for FY'22 compared to $286 million for FY'23. Excluding these U.S. government orders, Nplate sales grew 23% year-over-year for the fourth quarter and 8% for the full year. MVASI® (bevacizumab-awwb) sales decreased 8% year-over-year for the fourth quarter, primarily driven by lower net selling price, partially offset by 12% volume growth. Full year sales decreased 11%, primarily driven by lower net selling price, partially offset by 13% volume growth. Going forward, we expect continued net selling price erosion driven by increased competition. KANJINTI® (trastuzumab-anns) sales decreased 33% year-over-year for the fourth quarter and 50% for the full year, driven by lower net selling price and volume decline. Inflammation TEZSPIRE® (tezepelumab-ekko) generated $177 million of sales in the fourth quarter. Quarter-over-quarter sales increased 10%, driven by 18% volume growth that benefited from the pre-filled, single-use pen, which was approved for self-administration by the U.S. Food and Drug Administration (FDA) in the first quarter. Healthcare providers recognize TEZSPIRE's unique, differentiated profile and its broad potential to treat the 2.5 million patients worldwide with severe asthma who are uncontrolled, without any phenotypic or biomarker limitation. Otezla® (apremilast) sales increased 2% year-over-year for the fourth quarter, driven by favorable changes to estimated sales deductions and 3% volume growth, partially offset by lower inventory levels and lower net selling price. Full year sales decreased 4%, driven by lower net selling price and lower inventory levels, partially offset by 2% volume growth. We expect future growth for Otezla to be driven by its established efficacy and safety profile, strong payer coverage with limited prior authorization requirements and ease of administration. Otezla remains the only approved oral systemic therapy with a broad indication and is well-positioned to help the 1.5 million U.S. patients with mild-to-moderate psoriasis who cannot be optimally addressed by a topical and can benefit from a systemic treatment like Otezla. Enbrel® (etanercept) sales decreased 8% year-over-year for the fourth quarter, driven by a 4% impact from unfavorable changes to estimated sales deductions and lower net selling price. Full year sales decreased 10%, driven by lower net selling price, lower inventory levels and a 3% impact from unfavorable changes to estimated sales deductions. Year-over-year volume remained flat, with U.S. volume growing 1% in the fourth quarter, supported by an increase in new patients starting treatment as a result of improved payer coverage. Going forward, we expect net selling price to continue to decline year-over-year, driven by higher rebates to maintain broad first-line payer coverage and changes in patient mix. We expect Otezla and Enbrel to follow the historical pattern of lower sales in the first quarter relative to subsequent quarters due to the impact of benefit plan changes, insurance reverification and increased co-pay expenses as U.S. patients work through deductibles. AMJEVITA®/AMGEVITA™ (adalimumab) sales increased 34% year-over-year for the fourth quarter and 36% for the full year, primarily driven by 35% and 46% volume growth, respectively. Ex-U.S. sales increased 9% for the full year, driven by 20% volume growth, partially offset by lower net selling price. U.S. sales increased 43% quarter-over-quarter, driven by higher inventory levels and higher net selling price, partially offset by volume decline. Rare Disease Excluding TAVNEOS®, the products listed below were acquired from our Horizon transaction on Oct. 6, 2023. Sales figures reflect only sales in the period from Oct. 6 2023 through the end of the year, and not the full quarter. TEPEZZA® (teprotumumab-trbw) generated $448 million of sales for the period. TEPEZZA is the first and only FDA-approved treatment for thyroid eye disease (TED). KRYSTEXXA® (pegloticase) generated $272 million of sales for the period. KRYSTEXXA is the first and only FDA-approved treatment for chronic refractory gout. UPLIZNA® (inebilizumab-cdon) generated $65 million of sales for the period. UPLIZNA is used to treat adults with neuromyelitis optica spectrum disorders (NMOSD). TAVNEOS® (avacopan) generated $44 million of sales in the fourth quarter. Quarter-over-quarter sales increased 19%, primarily driven by volume growth. U.S. volume grew 23% quarter-over-quarter. In the U.S., approximately 2,700 patients have now been treated with TAVNEOS. Ultra rare products, which consist of RAVICTI® (glycerol phenylbutyrate), PROCYSBI® (cysteamine bitartrate), ACTIMMUNE® (interferon gamma-1b), BUPHENYL® (sodium phenylbutyrate) and QUINSAIR® (levofloxacin) generated $164 million of sales for the period. Established Products Total sales of our established products, which consist of EPOGEN® (epoetin alfa), Aranesp® (darbepoetin alfa), Parsabiv® (etelcalcetide) and Neulasta® (pegfilgrastim), decreased 10% year-over-year for the fourth quarter, primarily driven by lower net selling price and volume declines, partially offset by favorable changes to estimated sales deductions. Full year sales decreased 19%, driven by lower net selling price and volume declines. In the aggregate, we expect the year-over-year net selling price and volume declines for this portfolio of products to continue. Product Sales Detail by Product and Geographic Region Operating Expense, Operating Margin and Tax Rate Analysis On a GAAP basis: Total Operating Expenses increased 50% year-over-year for the fourth quarter. For the full year, Total Operating Expenses increased 21%. Cost of Sales as a percentage of product sales increased 13.0 percentage points in the fourth quarter primarily driven by higher amortization expense from acquisition-related assets as well as higher profit share and royalties, partially offset by Puerto Rico excise tax, changes in product mix, and lower manufacturing cost. For the full year, cost of sales as a percentage of product sales increased 5.6 percentage points primarily driven by higher amortization expense from acquisition-related assets, higher profit share and royalties, and changes in product mix, partially offset by Puerto Rico excise tax. Research & Development (R&D) expenses increased 16% in the fourth quarter and increased 8% for the full year driven by higher spend in later-stage clinical programs and marketed products support, including spend from programs acquired from the Horizon acquisition. Selling, General & Administrative (SG&A) expenses increased 45% in the fourth quarter and increased 14% for the full year primarily driven by higher acquisition-related costs, in addition to commercial and general administrative expenses related to the Horizon acquisition. For the full year, this was partially offset by a decline in other marketed product spend. Other operating expenses for the full year consisted of net impairment charges for AMG 340 and Teneobio IPR&D assets in addition to expenses related to our restructuring plan initiated in the first quarter of 2023. Operating Margin as a percentage of product sales decreased 17.8 percentage points to 16.2% in the fourth quarter and decreased 9.3 percentage points for the full year to 29.3%. Tax Rate increased 2.4 percentage points in the fourth quarter and increased 3.7 percentage points for the full year, primarily driven by the 2022 Puerto Rico tax law change that replaced the excise tax with an income tax beginning in 2023. For the fourth quarter this was partially offset by the change in earnings mix. On a non-GAAP basis: Total Operating Expenses increased 18% for the fourth quarter and increased 9% for the full year. Cost of Sales as a percentage of product sales remained flat in the fourth quarter primarily driven by higher profit share and royalties, offset by Puerto Rico excise tax, changes in product mix, and lower manufacturing cost. For the full year, cost of sales as a percentage of product sales increased 1.1 percentage points primarily driven by higher profit share and royalties and changes in product mix, partially offset by Puerto Rico excise tax. R&D expenses increased 16% in the fourth quarter and increased 8% for the full year driven by higher spend in later-stage clinical programs and marketed products support, including spend from programs acquired from the Horizon acquisition. SG&A expenses increased 20% in the fourth quarter and increased 5% for the full year primarily driven by higher commercial and general administrative expenses related to the Horizon acquisition. For the full year, this was partially offset by a decline in other marketed product spend. Operating Margin as a percentage of product sales increased 0.8 pts. percentage points to 46.7% in the fourth quarter and decreased 1.7 percentage points for the full year to 49.8%. Tax Rate increased 2.5 percentage points in the fourth quarter and increased 2.7 percentage points for the full year primarily due to the 2022 Puerto Rico tax law change that replaced the excise tax with an income tax beginning in 2023. Cash Flow and Balance Sheet The Company generated $0.3 billion of free cash flow in the fourth quarter of 2023 versus $2.3 billion in the fourth quarter of 2022, primarily driven by timing of federal and repatriation tax payments. The Company generated $7.4 billion of free cash flow for the full year 2023 versus $8.8 billion in 2022. The Company's fourth quarter 2023 dividend of $2.13 per share was declared on October 24, 2023, and was paid on December 8, 2023, to all stockholders of record as of November 17, 2023, representing a 10% increase from 2022. During the fourth quarter, there were no repurchases of shares of common stock. Cash and investments totaled $10.9 billion and debt outstanding totaled $64.6 billion as of December 31, 2023. Debt leverage was approximately 4.4 times EBITDA as of December 31, 2023. 2024 Guidance For the full year 2024, the Company expects: Total revenues in the range of $32.4 billion to $33.8 billion. On a GAAP basis, EPS in the range of $8.42 to $9.87, and a tax rate in the range of 11.5% to 13.0%. On a non-GAAP basis, EPS in the range of $18.90 to $20.30, and a tax rate in the range of 16.0% to 17.0%. Capital expenditures to be approximately $1.1 billion. Share repurchases not to exceed $500 million. Fourth Quarter Product and Pipeline Update The Company provided the following updates on selected product and pipeline programs: General Medicine Maridebart cafraglutide (AMG 133) A Phase 2 study of maridebart cafraglutide, a multispecific molecule that inhibits the gastric inhibitory polypeptide receptor (GIPR) and activates the glucagon like peptide 1 (GLP-1) receptor, in overweight or obese adults with or without type 2 diabetes mellitus has completed enrollment, with topline data anticipated in late 2024. The Company recently added a Part 2 to this study which explores durable weight loss beyond 52 weeks. Planning for a comprehensive Phase 3 program across multiple indications remains on track. In February 2024, results of preclinical studies and the Phase 1 study of maridebart cafraglutide were published in Nature Metabolism. AMG 786 A Phase 1 study of AMG 786, a small molecule obesity program, is ongoing with initial data readout anticipated in H1 2024. This molecule has a different target than maridebart cafraglutide and is not an incretin-based therapy. Olpasiran (AMG 890) A Phase 3 cardiovascular outcomes study of olpasiran, a potentially best-in-class small interfering ribonucleic acid (siRNA) molecule that reduces lipoprotein(a) (Lp(a)) synthesis in the liver, in patients with atherosclerotic cardiovascular disease and elevated Lp(a) continues to enroll patients. To date, over 7,000 patients have been enrolled, with enrollment completion anticipated in H1 2024. Repatha EVOLVE-MI, a Phase 4 study of Repatha administered within 10 days of an acute myocardial infarction to reduce the risk of cardiovascular events, continues to enroll patients. A Phase 3 cardiovascular outcomes study (VESALIUS-CV) in patients at high cardiovascular risk without prior myocardial infarction or stroke is ongoing. Oncology Tarlatamab (AMG 757) The U.S. Food and Drug Administration (FDA) has granted Priority Review for the Company's Biologics License Application (BLA) for tarlatamab, a first-in-class investigational delta-like ligand 3 (DLL3) targeting BiTE® (bispecific T-cell engager) molecule. The BLA is based on the results from the Phase 2 DeLLphi-301 clinical trial, which demonstrated antitumor activity with a durable response and encouraging survival outcomes in previously treated small cell lung cancer (SCLC). The safety profile was consistent with the Phase 1 trial. Based on the Priority Review designation, the Prescription Drug User Fee Act (PDUFA) date for tarlatamab is June 12, 2024. DeLLphi-304, a Phase 3 study comparing tarlatamab with standard of care chemotherapy in second-line SCLC, continues to enroll patients. DeLLphi-306, a Phase 3 study comparing tarlatamab with placebo in limited-stage SCLC, was initiated. DeLLphi-305, a Phase 3 study comparing tarlatamab and durvalumab with durvalumab alone in first-line, extensive-stage SCLC, will be initiated in H1 2024. DeLLphi-300, a Phase 1 study of tarlatamab in relapsed/refractory SCLC, continues to enroll patients. DeLLphi-302, a Phase 1b study of tarlatamab in combination with AMG 404, an anti-programmed cell death protein 1 (PD1) monoclonal antibody, in second-line or later SCLC, is ongoing.   DeLLphi-303, a Phase 1b study of tarlatamab in combination with standard of care in first-line SCLC, continues to enroll patients. DeLLpro-300, a Phase 1b study of tarlatamab in de novo or treatment-emergent neuroendocrine prostate cancer, is ongoing. BLINCYTO The FDA granted Priority Review for the Company's supplemental BLA for BLINCYTO in early-stage, CD19-positive B-cell precursor acute lymphoblastic leukemia (B-ALL) based in part on the Phase 3 E1910 study conducted by the National Cancer Institute, the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network Cancer Research Group. Based on the Priority Review designation, the PDUFA date for BLINCYTO is June 21, 2024. Additional global regulatory authority submissions are underway. Golden Gate, a Phase 3 study of BLINCYTO alternating with low-intensity chemotherapy in older adults with newly diagnosed Philadelphia chromosome-negative (Ph-) B-ALL, continues to enroll patients. The Company is planning to amend the Golden Gate Phase 3 study to include an evaluation of blinatumomab subcutaneous administration with initiation anticipated in H2 2024. A Phase 1/2 study of subcutaneous blinatumomab in adults with relapsed or refractory Ph- B-ALL continues to enroll patients. Xaluritamig (AMG 509) A Phase 1b monotherapy and combination dose-escalation and -expansion study of xaluritamig, a first-in-class bispecific T-cell engager targeting six-transmembrane epithelial antigen of prostate 1 (STEAP1) in metastatic castrate resistant prostate cancer continues to enroll patients in the dose-expansion portion of the study, where enrollment is almost complete. A reduced monitoring cohort was also initiated. Two additional Phase 1 studies of xaluritamig to evaluate preliminary efficacy and safety in patients with early prostate cancer are planned. AMG 193 The Phase 1/1b/2 study of AMG 193, a first-in-class small molecule methylthioadenosine (MTA)-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor, continues to enroll patients with advanced methylthioadenosine phosphorylase (MTAP)-null solid tumors. To date, responses have been seen in nine patients across seven tumor types. Master protocols in thoracic and gastrointestinal malignancies exploring combinations with standard of care will be initiated in H1 2024. A Phase 1/2 study of AMG 193 in combination with IDE397, an investigational methionine adenosyltransferase 2A (MAT2A) inhibitor, is enrolling patients. Nplate A Phase 3 study of Nplate in chemotherapy-induced thrombocytopenia in gastrointestinal, pancreatic, or colorectal malignancies is fully enrolled. Data readout is anticipated in H2 2024. LUMAKRAS/LUMYKRAS A U.S. regulatory submission is planned for the Phase 3 CodeBreaK 300 trial in H1 2024. This study evaluated two doses of LUMAKRAS (960 mg or 240 mg) in combination with Vectibix in patients with chemorefractory KRAS G12C-mutated metastatic colorectal cancer (CRC). A Phase 3 study of LUMAKRAS in combination with Vectibix and FOLFIRI in first-line KRAS G12C-mutated CRC was initiated. A Phase 3 study of LUMAKRAS plus chemotherapy vs. pembrolizumab plus chemotherapy in first-line KRAS G12C-mutated and programmed cell death protein ligand-1 (PD-L1) negative advanced non-small cell lung cancer (NSCLC) is enrolling patients. Regulatory review by the European Medicines Agency (EMA) of the CodeBreaK 200 Phase 3 trial of adults with previously treated locally advanced or metastatic KRAS G12C-mutated NSCLC along with data from the Phase 2 dose-comparison substudy is ongoing. The FDA completed its review of the Company's supplemental New Drug Application seeking full approval of LUMAKRAS based on the CodeBreaK 200 trial results. The FDA issued a new postmarketing requirement for an additional confirmatory study to support full approval to be completed no later than February 2028, while also concluding that LUMAKRAS at 960 mg once-daily will remain the dose for patients with KRAS G12C-mutated NSCLC under accelerated approval. Bemarituzumab FORTITUDE-101, a Phase 3 study of bemarituzumab, a first-in-class fibroblast growth factor receptor 2b (FGFR2b) targeting monoclonal antibody, plus chemotherapy in first-line gastric cancer, continues to enroll patients. FORTITUDE-102, a Phase 1b/3 study of bemarituzumab plus chemotherapy and nivolumab in first-line gastric cancer, continues to enroll patients in the Phase 3 portion of the study. FORTITUDE-103, a Phase 1b/2 study of bemarituzumab plus oral chemotherapy regimens with or without nivolumab in first-line gastric cancer, continues to enroll patients. FORTITUDE-301, a Phase 1b/2 basket study of bemarituzumab monotherapy in solid tumors with FGFR2b overexpression, is ongoing. Inflammation TEZSPIRE In severe asthma, the WAYFINDER Phase 3b study is fully enrolled. The PASSAGE Phase 4 real-world effectiveness study and the SUNRISE Phase 3 study continue to enroll patients. A Phase 3 study of TEZSPIRE in chronic rhinosinusitis with nasal polyps is fully enrolled. Primary analysis is anticipated in H2 2024. A Phase 3 study of TEZSPIRE in eosinophilic esophagitis continues to enroll patients. A Phase 2 study of TEZSPIRE in chronic obstructive pulmonary disease is fully enrolled. Data readout is anticipated in H1 2024. Rocatinlimab (AMG 451/KHK4083) The ROCKET Phase 3 program, now composed of eight studies evaluating rocatinlimab, a first in class monoclonal antibody targeting OX40, in moderate to severe atopic dermatitis, continues to enroll adult and adolescent patients. To date, over 2,400 patients have been enrolled in the ROCKET program. The Phase 3 HORIZON study (part of the ROCKET program) evaluating rocatinlimab monotherapy vs. placebo in adults with moderate to severe atopic dermatitis is fully enrolled. Data readout is anticipated in H2 2024. A Phase 2 study of rocatinlimab in asthma will be initiated in H1 2024 and a Phase 3 study of rocatinlimab in prurigo nodularis will be initiated in H2 2024. Otezla In November 2023, data were presented from the MOSAIC and FOREMOST studies: In the MOSAIC Phase 4 study, primary and key secondary outcomes highlighted that Otezla led to better inflammatory disease control in psoriatic arthritis patients with moderate clinical disease activity than in patients with high disease activity. In the FOREMOST Phase 4 study, Otezla when added to standard of care, significantly improved disease activity in patients with early oligoarticular (few joints involved) psoriatic arthritis at 16 weeks compared to placebo. Efavaleukin alfa (AMG 592) A Phase 2b study of efavaleukin alfa, an interleukin 2 (IL 2) mutein Fc fusion protein, in ulcerative colitis continues to enroll patients. Ordesekimab (AMG 714/PRV-015) A Phase 2b study of AMG 714, a monoclonal antibody that binds interleukin-15, in nonresponsive celiac disease has completed enrollment. Rare Disease TAVNEOS In November 2023, data were presented from the Phase 3 ADVOCATE trial demonstrating that outcomes in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis favored TAVNEOS versus a prednisone taper across subgroups of patients 65 years and older, patients with kidney involvement and albuminuria, and patients with diffuse alveolar hemorrhage at baseline. TEPEZZA In December 2023, TEPEZZA received orphan drug designation in Japan for patients with moderate to severe active thyroid eye disease (TED). A New Drug Application was submitted for TEPEZZA in Japan based on the results from the OPTIC-J study evaluating TEPEZZA in patients with active TED. A Phase 3 study of TEPEZZA in Japan for chronic or low clinical activity score (CAS) TED continues to enroll patients. The Company plans to initiate a Phase 3 study evaluating the subcutaneous route of administration of TEPEZZA in patients with TED in H1 2024. UPLIZNA A Phase 3 study of UPLIZNA in myasthenia gravis is fully enrolled. Data readout is anticipated in H2 2024. A Phase 3 study of UPLIZNA for the prevention of flare in immunoglobulin G4- (IgG4) related disease is fully enrolled. Data readout is anticipated in H2 2024. Dazodalibep A Phase 3 study of dazodalibep, a cluster of differentiation 40 (CD40) ligand inhibitor fusion protein in Sjögren's syndrome is enrolling patients. Daxdilimab A Phase 2 study of daxdilimab, a fully human monoclonal antibody targeting immunoglobulin-like transcript 7 (ILT7), in moderate-to-severe active primary discoid lupus erythematosus refractory to standard of care is enrolling patients. A Phase 2 study of daxdilimab in dermatomyositis and antisynthetase inflammatory myositis is enrolling patients. Fipaxalparant (formerly AMG 670 / HZN 825) A Phase 2 study of fipaxalparant, a lysophosphatidic acid receptor 1 (LPAR1) antagonist, in idiopathic pulmonary fibrosis is enrolling patients. Data readout is anticipated in H2 2024. A Phase 2 study of fipaxalparant in diffuse cutaneous systemic sclerosis is enrolling patients. Biosimilars The clinical comparative study portion of a randomized, double-blind pivotal study evaluating pharmacokinetic (PK) similarity of ABP 206 compared with OPDIVO® (nivolumab) in resected stage III or stage IV melanoma patients in the adjuvant setting is enrolling patients. TEZSPIRE is being developed in collaboration with AstraZeneca. Rocatinlimab, formerly AMG 451/KHK4083, is being developed in collaboration with Kyowa Kirin. Ordesekimab, formerly AMG 714 and also known as PRV-015, is being developed in collaboration with Provention Bio, a Sanofi Company. For the purposes of the collaboration, Provention Bio conducts a clinical trial and leads certain development and regulatory activities for the program. Xaluritamig, formerly AMG 509, is being developed pursuant to a research collaboration with Xencor, Inc. IDE397 is an investigational MAT2A inhibitor from IDEAYA Biosciences. OPDIVO is a registered trademark of Bristol-Myers Squibb Company. Non-GAAP Financial Measures In this news release, management has presented its operating results for the fourth quarters and full years of 2023 and 2022, in accordance with U.S. Generally Accepted Accounting Principles (GAAP) and on a non-GAAP basis. In addition, management has presented its full year 2024 EPS and tax guidance in accordance with GAAP and on a non-GAAP basis. These non-GAAP financial measures are computed by excluding certain items related to acquisitions, divestitures, restructuring and certain other items from the related GAAP financial measures. Beginning January 1, 2022, following industry guidance from the U.S. Securities and Exchange Commission, the Company no longer excludes adjustments for upfront license fees, development milestones and in-process research and development (IPR&D) expenses of pre-approval programs related to licensing, collaboration and asset acquisition transactions from its non-GAAP financial measures. Management has presented Free Cash Flow (FCF), which is a non-GAAP financial measure, for the fourth quarters and full years of 2023 and 2022. FCF is computed by subtracting capital expenditures from operating cash flow, each as determined in accordance with GAAP. Management has also presented Earnings Before Interest, Taxes, Depreciation and Amortization (EBITDA) and debt leverage ratio for 2023, both of which are non-GAAP financial measures. EBITDA is computed by adding interest expense, provision for income taxes, and depreciation and amortization expense to GAAP net income. Debt leverage ratio is calculated as the ratio of GAAP total debt to EBITDA. The Company believes that its presentation of non-GAAP financial measures provides useful supplementary information to and facilitates additional analysis by investors. The Company uses certain non-GAAP financial measures to enhance an investor's overall understanding of the financial performance and prospects for the future of the Company's normal and recurring business activities by facilitating comparisons of results of normal and recurring business operations among current, past and future periods. The Company believes that FCF provides a further measure of the Company's liquidity. The Company believes its debt leverage ratio provides a supplemental operating metric for the full year period as it compares the amount of cash generated by our operations for the year. The Company uses the non-GAAP financial measures set forth in the news release in connection with its own budgeting and financial planning internally to evaluate the performance of the business, including to allocate resources and to evaluate results relative to incentive compensation targets. The non-GAAP financial measures are in addition to, not a substitute for, or superior to, measures of financial performance prepared in accordance with GAAP. About Amgen Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology. Amgen focuses on areas of high unmet medical need and leverages its expertise to strive for solutions that improve health outcomes and dramatically improve people's lives. A biotechnology pioneer since 1980, Amgen has grown to be one of the world's leading independent biotechnology companies, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential. Amgen is one of the 30 companies that comprise the Dow Jones Industrial Average and is also part of the Nasdaq-100 index. In 2023, Amgen was named one of "America's Greatest Workplaces" by Newsweek, one of "America's Climate Leaders" by USA Today and one of the "World's Best Companies" by TIME. For more information, visit Amgen.com and follow us on X (formerly known as Twitter), LinkedIn, Instagram, TikTok, YouTube and Threads. Forward-Looking Statements This news release contains forward-looking statements that are based on the current expectations and beliefs of Amgen. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements, including any statements on the outcome, benefits and synergies of collaborations, or potential collaborations, with any other company (including BeiGene, Ltd. or Kyowa Kirin Co., Ltd.), the performance of Otezla® (apremilast) (including anticipated Otezla sales growth and the timing of non-GAAP EPS accretion), our acquisitions of Teneobio, Inc., ChemoCentryx, Inc., or Horizon (including the prospective performance and outlook of Horizon's business, performance and opportunities and any potential strategic benefits, synergies or opportunities expected as a result of such acquisition, and any projected impacts from the Horizon acquisition on our acquisition-related expenses going forward), as well as estimates of revenues, operating margins, capital expenditures, cash, other financial metrics, expected legal, arbitration, political, regulatory or clinical results or practices, customer and prescriber patterns or practices, reimbursement activities and outcomes, effects of pandemics or other widespread health problems on our business, outcomes, progress, and other such estimates and results. Forward-looking statements involve significant risks and uncertainties, including those discussed below and more fully described in the Securities and Exchange Commission reports filed by Amgen, including our most recent annual report on Form 10-K and any subsequent periodic reports on Form 10-Q and current reports on Form 8-K. Unless otherwise noted, Amgen is providing this information as of the date of this news release and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise. No forward-looking statement can be guaranteed and actual results may differ materially from those we project. Our results may be affected by our ability to successfully market both new and existing products domestically and internationally, clinical and regulatory developments involving current and future products, sales growth of recently launched products, competition from other products including biosimilars, difficulties or delays in manufacturing our products and global economic conditions. In addition, sales of our products are affected by pricing pressure, political and public scrutiny and reimbursement policies imposed by third-party payers, including governments, private insurance plans and managed care providers and may be affected by regulatory, clinical and guideline developments and domestic and international trends toward managed care and healthcare cost containment. Furthermore, our research, testing, pricing, marketing and other operations are subject to extensive regulation by domestic and foreign government regulatory authorities. We or others could identify safety, side effects or manufacturing problems with our products, including our devices, after they are on the market. Our business may be impacted by government investigations, litigation and product liability claims. In addition, our business may be impacted by the adoption of new tax legislation or exposure to additional tax liabilities. If we fail to meet the compliance obligations in the corporate integrity agreement between us and the U.S. government, we could become subject to significant sanctions. Further, while we routinely obtain patents for our products and technology, the protection offered by our patents and patent applications may be challenged, invalidated or circumvented by our competitors, or we may fail to prevail in present and future intellectual property litigation. We perform a substantial amount of our commercial manufacturing activities at a few key facilities, including in Puerto Rico, and also depend on third parties for a portion of our manufacturing activities, and limits on supply may constrain sales of certain of our current products and product candidate development. An outbreak of disease or similar public health threat, such as COVID-19, and the public and governmental effort to mitigate against the spread of such disease, could have a significant adverse effect on the supply of materials for our manufacturing activities, the distribution of our products, the commercialization of our product candidates, and our clinical trial operations, and any such events may have a material adverse effect on our product development, product sales, business and results of operations. We rely on collaborations with third parties for the development of some of our product candidates and for the commercialization and sales of some of our commercial products. In addition, we compete with other companies with respect to many of our marketed products as well as for the discovery and development of new products. Discovery or identification of new product candidates or development of new indications for existing products cannot be guaranteed and movement from concept to product is uncertain; consequently, there can be no guarantee that any particular product candidate or development of a new indication for an existing product will be successful and become a commercial product. Further, some raw materials, medical devices and component parts for our products are supplied by sole third-party suppliers. Certain of our distributors, customers and payers have substantial purchasing leverage in their dealings with us. The discovery of significant problems with a product similar to one of our products that implicate an entire class of products could have a material adverse effect on sales of the affected products and on our business and results of operations. Our efforts to collaborate with or acquire other companies, products or technology, and to integrate the operations of companies or to support the products or technology we have acquired, may not be successful. There can be no guarantee that we will be able to realize any of the strategic benefits, synergies or opportunities arising from the Horizon acquisition, and such benefits, synergies or opportunities may take longer to realize than expected. We may not be able to successfully integrate Horizon, and such integration may take longer, be more difficult or cost more than expected. A breakdown, cyberattack or information security breach of our information technology systems could compromise the confidentiality, integrity and availability of our systems and our data. Our stock price is volatile and may be affected by a number of events. Our business and operations may be negatively affected by the failure, or perceived failure, of achieving our environmental, social and governance objectives. The effects of global climate change and related natural disasters could negatively affect our business and operations. Global economic conditions may magnify certain risks that affect our business. Our business performance could affect or limit the ability of our Board of Directors to declare a dividend or our ability to pay a dividend or repurchase our common stock. We may not be able to access the capital and credit markets on terms that are favorable to us, or at all. ### CONTACT: Amgen, Thousand Oaks Jessica Akopyan, 805-440-5721 (media) Justin Claeys, 805-313-9775 (investors) * The known adjustments are presented net of their related tax impact, which amount to approximately $2.60 per share. (a) The adjustments include noncash amortization of intangible assets and fair value step-up of inventory acquired in business combinations. Our GAAP diluted EPS guidance does not include the effect of GAAP adjustments triggered by events that may occur subsequent to this press release such as acquisitions, asset impairments, litigation, changes in fair value of our contingent consideration obligations and changes in fair value of our equity investments. SOURCE Amgen

近期，赛诺菲发布了半年报，其明星产品度普利尤单抗销售额再创新高，半年全球销售额高达48.78亿欧元（约53.66亿美元），全年销售额有望突破百亿欧元大关。度普利尤单抗是一款靶向IL-4R的单抗药物，自上市以来，销售额节节攀升，在多种适应症中表现良好，今年在欧盟相继获批嗜酸性粒细胞性食管炎和6个月到5岁的儿童特应性皮炎新适应症，在中国获批成人结节性痒疹和6个月到5岁的儿童特应性皮炎新适应症，以及FDA接受了用于治疗12岁及以上青少年和成人的慢性自发性荨麻疹的补充生物制品许可证申请（sBLA）的审查。但并不是每个IL-4R药物都是这么幸运的，阿斯利康的elarekibep近期就因达不到临床效果而被阿斯利康抛弃。Elarekibep的初衷是开发吸入型靶向IL-4R药物，改善度普利尤单抗皮下注射的缺点，然而事与愿违，elarekibep的临床并没有发现积极效果，反而存在与剂量无关的炎症介导引起的肺组织损伤问题。国内也有很多企业在布局IL-4R靶点，其中康诺亚的CM310进展最快，处于临床3期，近期在柳叶刀子刊上报道了CM310减少鼻息肉大小和改善缓解鼻塞达到主要疗效终点，首次在国际上证明CM310治疗后可显著降低eCRSwNP患者鼻息肉组织嗜酸性粒细胞的数量以及下调2型炎症水平。1IL4信号通路过敏性鼻炎（allergic rhinitis，AR）是上呼吸道的常见疾病，而哮喘是一种影响下呼吸道的疾病，这两种疾病通常是合并症，且都由辅助性T细胞2（Th2）炎症过程介导，其中Th2细胞因子如白细胞介素（IL）-4，IL-5和IL-13在其发病机制中起关键作用，靶向IL-4/IL-13信号通路已成为AR和哮喘患者群体中很有希望的靶向治疗。IL-4诱导血浆细胞产生IgE和上调肥大细胞、嗜碱性粒细胞、单核细胞、巨噬细胞和B细胞中FcεRI和MHC II类分子的表达过程中起关键作用。IL-4被认为是Th2主要开关，也可驱动过敏性疾病中Th2细胞产生其他促过敏细胞因子，如IL-5和IL-13。IL-4与I型受体（由IL-4Rα和普通γ链组成）和II型受体（由IL-4Rα和IL-13Rα1组成）结合。IL-13与II型受体结合，IL-13Rα2充当诱饵受体。I型或II型受体结合配体导致Janus家族激酶（JAK1，JAK2 / TYK2和JAK3）的激活，然后信号转导器和激活剂转录6（STAT6）的磷酸化（图1）[1]。图1. IL-4和IL-13受体复合物以及信号通路2赛诺菲：度普利尤单抗上半年大卖48.78亿欧元近期，赛诺菲公布了第二季度财报，全球销售额99.65亿欧元，根据之前的报道第一季度全球销售额102.22亿欧元，至此，赛诺菲上半年销售额达到201.87亿欧元，同比增长4.4%。提到赛诺菲，不得不提它的明星产品度普利尤单抗（Dupilumab注射液，Dupixent），它是一种免疫球蛋白G4亚类的全人源单克隆抗体，其靶向IL-4Rα并结合IL-4及IL-13亚基，同时阻断IL-4及IL-13的信号传导。度普利尤单抗第一季度销售额23.16亿欧元，第二季度销售额25.62亿欧元，上半年销售额达到48.78亿欧元，全年销售额有望突破百亿欧元大关（图2）[2]。图2. 赛诺菲上半年主要增长产品作为赛诺菲明星产品，度普利尤单抗的销售和研发自然受到极大地重视，赛诺菲一方面积极探索新的适应症，一方面推广它在全球的应用。今年1月份，度普利尤单抗被欧盟委员会批准为首个也是唯一一种用于嗜酸性粒细胞性食管炎的靶向药物。此次批准基于下面关键性试验结果，每周接受300mg Dupixent治疗的12岁及以上患者中约有60%经历了组织学疾病缓解以及与安慰剂相比，患者的吞咽能力也显着提高。今年3月份，FDA接受度普利尤单抗的补充生物制品许可证申请（sBLA）的审查，以治疗12岁及以上青少年和成人的慢性自发性荨麻疹（CSU），目前的护理标准H1抗组胺药治疗没有得到充分控制。FDA决定的处方药使用者付费法案（PDUFA）日期是2023年10月22日。此次sBLA得到了两项3期试验（LIBERTY-CUPID研究A和B）的数据的支持，这些试验评估了度普利尤单抗在两个不同的CSU不受控制的患者群体中治疗效果。研究A是在标准治疗抗组胺药不受控制的CSU患者中进行的，其疗效和安全性数据支持提交，而研究B是在标准治疗抗组胺药不受控制且奥马珠单抗无效的CSU患者中进行的，结果提供了额外的支持数据。3月份，度普利尤单抗用于治疗成人结节性痒疹新适应症的上市申请获NMPA受理。今年上半年度普利尤单抗相继在欧洲和中国获批新适应症，用于治疗6个月到5岁的儿童特应性皮炎（Atopic Dermatitis，AD）适应症。今年新英格兰医学杂志多篇文章相继报道了Dupixent在不同疾病中的应用。其中一篇报道了度普利尤单抗治疗 COPD 伴 2 型炎症，在一项3期双盲随机试验中（NCT03930732），将939名血嗜酸性粒细胞计数至少为每微升300且尽管使用标准三联疗法但仍加重风险升高的COPD患者皮下注射度普利尤单抗（300mg）或安慰剂（468名为度普利尤单抗组，471名为安慰剂组），每 2 周一次。试验结果表明：度普利尤单抗组中度或重度加重的年化率为0.78，安慰剂组为1.10（比率，0.70；95% CI，0.58 至 0.86；P<0.001）（图3）。支气管扩张剂FEV1从基线到第12周增加，接受度普利尤单抗最小二乘（LS）平均值为160 mL，安慰剂组为77 mL，这一差异一直持续到第52周，总的来说在患有2型炎症的COPD患者中，与接受安慰剂的患者相比，接受度普利尤单抗治疗的患者恶化更少，肺功能和生活质量更好，呼吸道症状更轻 [3]。图3. 中度或重度 COPD 加重和支气管扩张剂FEV1随时间的变化另外一篇报道了度普利尤单抗治疗成人中度至重度特应性皮炎治疗效果（NCT01259323, NCT01385657, NCT01639040和NCT01548404）。在为期 4 周的单药治疗研究中，度普利尤单抗在临床指标、生物标志物水平和转录组方面实现了快速和剂量依赖性的改善。度普利尤单抗单药治疗的12周研究结果再现并扩展了4周的研究结果：度普利尤单抗组85%的患者与安慰剂组的35%相比，EASI评分降低了50%（EASI-50，EASI评分越高表明湿疹的严重程度越高）；在研究者的整体评估中，度普利尤单抗组40%的患者与安慰剂组的7%相比，得分为0至1（表明皮肤病变清除或接近清除）；度普利尤单抗组瘙痒评分降低55.7%（表明瘙痒减轻），安慰剂组下降15.1%（图4）。在联合研究中，度普利尤单抗组100%的患者符合EASI-50标准（P=0.002），尽管接受度普利尤单抗加糖皮质激素的患者使用的局部糖皮质激素量不到接受安慰剂加局部药物的患者使用的一半（P=0.16），鼻咽炎和头痛是度普利尤单抗最常见的不良事件[4]。图4. 度普利尤单抗治疗成人中度至重度特应性皮炎主要临床终点另一篇报道了度普利尤单抗在中度至重度未控制哮喘中的疗效和安全性（NCT02414854），他们2：2：1：1的比例随机分配了1902名12岁或以上的哮喘不受控制的患者，以200或300mg的剂量接受额外的皮下注射度普利尤单抗或匹配体积安慰剂，每 2 周一次，持续 52 周。每2周给予200mg度普利尤单抗的患者严重哮喘发作的年化率为0.46，在匹配安慰剂组中为0.87，度普利尤单抗的发生率低于安慰剂47.7%（P<0.001），每2周300mg接受度普利尤单抗剂量的结果与之类似。在第 12 周，分配到较低剂量度普利尤单抗的患者中，FEV1 增加了 0.32 升（安慰剂组为0.14升）；较高剂量也观察到类似的结果（图5）。在血嗜酸性粒细胞计数为每立方毫米300或更多的患者中，接受低剂量度普利尤单抗的患者严重哮喘发作的年化率为0.37，接受匹配安慰剂的患者为1.08（度普利尤单抗的发生率比安慰剂低65.8%）；较高剂量也观察到类似的结果[5]。图5. 在意向治疗人群的 52 周干预期内，支气管扩张剂 FEV1 与基线相比的变化。总体来说，在该试验中，接受度普利尤单抗治疗的患者严重哮喘恶化的发生率明显低于接受安慰剂的患者，以及更好的肺功能和哮喘控制。在嗜酸性粒细胞基线水平较高的患者中观察到更大的益处。3阿斯利康终止与Pieris合作开发elarekibep哮喘由 IL-4 和 IL-13 信号通过 IL-4R驱动，IL-4R在气道上皮、气道平滑肌和呼吸道黏膜中的免疫细胞上高度表达，表明可吸入拮抗剂的潜在优势。尽管度普利尤单抗有很多优点，但是它是皮下注射给药方式，相对于皮下注射，可吸入喷雾剂给药方式更能被患者接受。此前，Pieris Pharmaceuticals研发的吸入性IL-4Rα抑制剂elarekibep（PRS-060）是临床进展最快的，进入临床2期，它是将脂钙蛋白 1（Lcn1）通过蛋白系统修饰诱变产生高亲和力、缓慢解离、长效的IL-4Rα抑制剂，其性质类似于度普利尤单抗，在体外竞争性拮抗 IL-4Rα依赖性细胞增殖、粘液诱导和嗜酸性蛋白表达。脂钙蛋白 1是一种富含人睫状体液的 16 kDa 蛋白，具有强大的药物样结构，非常适合蛋白质工程，但它从未用于制造吸入的Anticalin蛋白治疗剂。此前，Gabriele等人报道PRS-060强烈抑制三重人源化小鼠急性过敏性炎症指数，持续时间作用时间长于其体积清除时间，表明它可能在肺部局部起作用。2017年阿斯利康与Pieris就elarekibep达成了合作协议，阿斯利康向Pieris支付了近6000万美元。根据协议条款，Pieris将推动PRS-060进入I期试验，而阿斯利康将资助临床开发和商业化项目。然而今年6月份，Pieris宣布阿斯利康终止PRS-060的临床开发（图6）[6]，因为阿斯利康开展的一项为期13周的非人类灵长类动物研究表明，在三个活性剂量组下都没有观察到elarekibep的治疗效果，但存在与剂量无关的炎症介导引起的肺组织损伤。图6. 阿斯利康终止PRS-060的临床开发阿斯利康的决定独立于2a期研究的任何数据。Pieris将加快审查数据的影响和阿斯利康对该计划的决定，并将在分享进一步更新之前审查其整体公司优先事项。最终于7月18日，Pieris Pharmaceuticals根据公司发展情况宣布将裁员70%以延长现金流。4其它临床在研的IL-4R抑制剂目前为止全球范围内有4款靶向IL-4R药物获批上市，分别是甲磺司特、度普利尤单抗、吡美莫司以及Actimmune，其中度普利尤单抗是全球首款获批的IL-4R单抗药物，除此之外临床上也有很多在研的IL-4R抑制剂（图7）。图7. 部分临床在研的靶向IL-4R药物国产IL-4Rα拮抗剂中康诺亚的CM310重组人源化单克隆抗体注射液进展最快，截至目前，CM310注射液针对慢性鼻窦炎和中重度特应性皮炎的适应症研发进展最快，均推进至临床3期试验阶段。2023年7月，CM310用于治疗重度嗜酸性粒细胞型慢性鼻窦炎鼻息肉（eCRSwNP）的多中心随机、双盲、安慰剂对照II期临床试验（CROWNS-1研究）结果发表在柳叶刀子刊《EClinicalMedicine》上。56 名符合条件的重度伴有鼻息肉的严重嗜酸性慢性鼻-鼻窦炎（eCRSwNP） 成年患者在糠酸莫米松鼻喷雾剂（MFNS）的背景治疗下，以1：1的比例随机分配，每2周皮下接受CM310（300 mg）或安慰剂治疗16周，随访8周。在2021年4月6日至2022年3月18日期间，CM310 组和安慰剂组分别有27名患者完成了研究。结果表明，与安慰剂相比，CM310减少鼻息肉大小（NPS）和缓解鼻塞（NCS）达到主要疗效终点（图8）[7]。图8. 基于MMRM的NPS（A）和NCS（B）随时间的变化本次研究是全球首个采用病理学嗜酸性粒细胞计数（鼻息肉组织嗜酸性粒细胞计数≥55个/高倍镜视野或嗜酸性粒细胞百分比≥27%）作为入组标准的生物制剂治疗eCRSwNP的多中心RCT研究。在国际上首次证明CM310治疗后可显著降低eCRSwNP患者鼻息肉组织嗜酸性粒细胞的数量，下调2型炎症水平，从而揭示了其产生疗效的内在机制。— 小结—过敏性疾病主要是由IgE介导的Ⅰ型变态反应，包括过敏性鼻炎、过敏性支气管哮喘、特应性皮炎和食物过敏等。根据发病机制来看，2型炎症通路（一种主要由Th2细胞介导的）在过敏性疾病发病过程中扮演关键角色，Th2细胞可分泌IL-4、IL-5和IL-13并刺激2型免疫，以2型炎症通路中受体为靶点的抑制剂被广泛应用于治疗过敏性疾病。其中赛诺菲/再生元的度普利尤单抗是典型的靶向IL-4R的药物，自上市以来，受到广泛关注，销售额逐年上升，在不同国家获批不同的适应症，今年NEJM上更是多篇文献报道了度普利尤单抗的临床积极结果，未来前景一片大好，今年全球销售额高达48.78亿欧元，全年销售额有望突破百亿欧元大关。有人欢喜有人愁，今年6月份，Pieris宣布阿斯利康终止elarekibep（PRS-060）的临床开发，因为阿斯利康开展的一项为期13周的非人类灵长类动物研究表明，在三个活性剂量组下都没有观察到elarekibep的治疗效果，但存在与剂量无关的炎症介导引起的肺组织损伤。国内也有很多药企加入布局IL-4R靶点，包括康诺亚，康乃德生物和三生国健药业等，其中进展最快的是康诺亚的CM310，处于临床三期，有望成为国产首款获批靶向IL-4R药物。参考文献：（上下滑动查看更多）1.Siti Muhamad Nur Husna, Norasnieda Md Shukri, Noor Suryani Mohd Ashari and Kah Keng Wong, IL-4/IL-13 axis as therapeutic targets in allergic rhinitis and asthma, PeerJ. 2022 May 30;10:e13444.2.https://www.sanofi.com/assets/dotcom/content-app/events/quaterly-results/2023/2023-q2-2023-results/q2-2023-presentation-en.pdf3.S.P. Bhatt, K.F. Rabe, N.A. Hanania, C.F. Vogelmeier, J. Cole, M. Bafadhel, S.A. Christenson, A. Papi, D. Singh, E. Laws, L.P. Mannent, N. Patel, H.W. Staudinger, G.D. Yancopoulos, E.R. Mortensen, B. Akinlade, J. Maloney, X. Lu, D. Bauer, A. Bansal, L.B. Robinson, and R.M. Abdulai, Dupilumab for COPD with Type 2 Inflammation Indicated by Eosinophil Counts, N Engl J Med 2023;389:205-14.4.Lisa A. Beck, M.D., Diamant Tha.i, M.D., Jennifer D. Hamilton, Ph.D., et.al, Dupilumab Treatment in Adults with Moderate-to-Severe Atopic Dermatitis, N Engl J Med 2014;371:130-9.5.M. Castro, J. Corren, I.D. Pavord, J. Maspero, S. Wenzel, K.F. Rabe, W.W. Busse, L. Ford, L. Sher, J.M. FitzGerald, C. Katelaris, Y. Tohda, B. Zhang, H. Staudinger, G. Pirozzi, N. Amin, M. Ruddy, B. Akinlade, A. Khan, J. Chao, R. Martincova, N.M.H. Graham, J.D. Hamilton, B.N. Swanson, N. Stahl, G.D. Yancopoulos, and A. Teper, Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma, N Engl J Med 2018; 378:2486-24966.https://d1io3yog0oux5.cloudfront.net/_beba4e8ea60d7760d2cdd730ae78df3f/pierisag/news/2023-06-21_Pieris_Pharmaceuticals_Announces_AstraZeneca_702.pdf7.Yuan Zhang,a,y Bing Yan,b,c,d,y Shen Shen, et.al, Efficacy and safety of CM310 in severe eosinophilic chronic rhinosinusitis with nasal polyps (CROWNS-1): a multicentre, randomised, double-blind, placebo-controlled phase 2 clinical trial, eClinicalMedicine 2023;61: 102076.