Ceftolozane Sulfate/Tazobactam Sodium

RAHWAY, N.J.--( BUSINESS WIRE )--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced financial results for the fourth quarter and full year of 2023. “ 2023 was another very strong year for Merck. I am extremely pleased by the progress we’ve made to develop and deliver transformative therapies and vaccines that will help save and improve lives around the world. We reached more than 500 million people with our medicines last year alone, over half of which were donations, including through our program to treat river blindness,” said Robert M. Davis, chairman and chief executive officer, Merck. “ We also made investments of approximately $30 billion in research and development in our ongoing effort to discover, develop and collaborate to propel the next generation of impactful innovations. As we move forward, I’m confident that our strong momentum will continue, underpinned by the unwavering dedication of our talented global team.” Financial Summary $ in millions, except EPS amounts Fourth Quarter Year Ended 2023 2022 Change Change Ex-Exchange Dec. 31, 2023 Dec. 31, 2022 Change Change Ex-Exchange Sales $14,630 $13,830 6% 7% $60,115 $59,283 1% 4% GAAP net (loss) income 1 (1,226) 3,017 N/M N/M 365 14,519 -97% -95% Non-GAAP net income that excludes certain items 1,2* 66 4,129 -98% N/M 3,837 19,005 -80% -75% GAAP EPS (0.48) 1.18 N/M N/M 0.14 5.71 -98% -95% Non-GAAP EPS that excludes certain items 2* 0.03 1.62 -98% N/M 1.51 7.48 -80% -75% *Refer to table on page 9. N/M - Not meaningful Generally Accepted Accounting Principles (GAAP) loss/earnings per share (EPS) assuming dilution was a loss per share of $0.48 for the fourth quarter and EPS of $0.14 for the full year of 2023. Non-GAAP EPS was $0.03 for the fourth quarter and $1.51 for the full year of 2023. GAAP loss per share and non-GAAP EPS in the fourth quarter of 2023 include a charge of $1.69 per share related to the collaboration with Daiichi Sankyo. GAAP and non-GAAP EPS for the full years of 2023 and 2022 include charges of $6.21 and $0.22 per share, respectively, related to certain collaborations, licensing agreements and asset acquisitions. Non-GAAP EPS excludes acquisition- and divestiture-related costs, including pretax intangible asset impairment research and development (R&D) charges of $779 million in the fourth quarter and full year of 2023 related to gefapixant, and $780 million and $1.7 billion in the fourth quarter and full year of 2022, respectively, primarily related to nemtabrutinib. Non-GAAP EPS also excludes restructuring costs, including costs for the recently approved 2024 Restructuring Program, as well as income and losses from investments in equity securities. Fourth-Quarter Sales Performance The following table reflects sales of the company’s top products and significant performance drivers. Fourth Quarter $ in millions 2023 2022 Change Change Ex-Exchange Commentary Total Sales $14,630 $13,830 6% 7% Pharmaceutical 13,141 12,180 8% 8% Increase driven by growth in oncology, vaccines and hospital acute care, partially offset by a decline in virology, due to LAGEVRIO, and diabetes. Excluding LAGEVRIO and impact of foreign exchange, growth of 14%. KEYTRUDA 6,608 5,450 21% 22% Growth driven by increased global uptake in earlier-stage indications, including triple-negative breast cancer and renal cell carcinoma (RCC), and continued strong global demand from metastatic indications. GARDASIL/GARDASIL 9 1,871 1,470 27% 27% Growth due to strong global demand, particularly in China, and public-sector buying patterns in the U.S. JANUVIA/JANUMET 787 913 -14% -13% Decline primarily due to generic competition in several international markets, particularly in Europe, and lower demand in the U.S. PROQUAD, M-M-R II and VARIVAX 545 526 4% 3% Growth largely due to higher pricing in the U.S. BRIDION 429 441 -3% -3% Decline primarily due to generic competition in certain ex-U.S. markets, particularly in Europe, partially offset by higher demand in the U.S. Lynparza* 315 292 8% 8% Growth driven primarily by higher pricing in the U.S. Lenvima* 226 216 5% 5% Growth primarily due to higher demand in the U.S., partially offset by timing of shipments in China. LAGEVRIO 193 825 -77% -76% Decline due to nonrecurrence of sales in the U.K. and lower demand in Japan and Australia. ROTATEQ 185 139 34% 33% Growth primarily due to public-sector buying patterns in the U.S. and timing of shipments in China. VAXNEUVANCE 176 138 28% 26% Growth largely driven by launches in Europe and continued uptake for the pediatric indication in the U.S. Prior-year quarter benefited from inventory stocking in the U.S. in preparation for pediatric launch. Animal Health 1,278 1,230 4% 4% Growth primarily driven by higher demand for Companion Animal products. Livestock 808 814 -1% 0% Decline primarily due to timing of shipments for ruminant products, largely offset by higher pricing across the product portfolio and higher demand for swine products. Companion Animal 470 416 13% 12% Growth primarily due to higher demand and timing of shipments for BRAVECTO line of products, as well as higher pricing. Sales of BRAVECTO were $197 million and $168 million in the current and prior-year quarters, respectively, which represented growth of 18%, or 19% excluding the impact of foreign exchange. Other Revenues** 211 420 -50% -1% Decline primarily due to impact of revenue hedging activities. *Alliance revenue for this product represents Merck’s share of profits, which are product sales net of cost of sales and commercialization costs. **Other revenues are comprised primarily of revenues from third-party manufacturing arrangements and miscellaneous corporate revenues, including revenue-hedging activities. Full-Year Revenue Performance The following table reflects sales of the company’s top pharmaceutical products, as well as sales of Animal Health products. Year Ended $ in millions Dec. 31, 2023 Dec. 31, 2022 Change Change Ex-Exchange Total Sales $60,115 $59,283 1% 4% Pharmaceutical 53,583 52,005 3% 5% KEYTRUDA 25,011 20,937 19% 21% GARDASIL/GARDASIL 9 8,886 6,897 29% 33% JANUVIA/JANUMET 3,366 4,513 -25% -23% PROQUAD, M-M-R II and VARIVAX 2,368 2,241 6% 6% BRIDION 1,842 1,685 9% 11% LAGEVRIO 1,428 5,684 -75% -74% Lynparza* 1,199 1,116 7% 9% Lenvima* 960 876 10% 11% ROTATEQ 769 783 -2% -1% VAXNEUVANCE 665 170 N/M N/M Animal Health 5,625 5,550 1% 3% Livestock 3,337 3,300 1% 4% Companion Animal 2,288 2,250 2% 3% Other Revenues** 907 1,728 -48% -15% *Alliance revenue for this product represents Merck’s share of profits, which are product sales net of cost of sales and commercialization costs. **Other revenues are comprised primarily of revenues from third-party manufacturing arrangements and miscellaneous corporate revenues, including revenue-hedging activities. N/M - Not meaningful Full-year 2023 pharmaceutical sales grew 3% to $53.6 billion. Pharmaceutical sales growth was primarily driven by higher sales in oncology, particularly KEYTRUDA, higher sales of vaccines, reflecting strong growth of combined sales of GARDASIL/GARDASIL 9 and VAXNEUVANCE, as well as growth in hospital acute care products, including PREVYMIS and BRIDION. Pharmaceutical sales growth in 2023 was partially offset by lower sales of the COVID-19 medication LAGEVRIO, as well as lower sales of JANUVIA and JANUMET, primarily reflecting generic competition in many ex-U.S. markets and lower demand in the U.S., and lower sales of PNEUMOVAX 23 as the market continues to shift toward newer adult pneumococcal conjugate vaccines. Pharmaceutical sales growth for the full year of 2023 was 14% excluding LAGEVRIO and the unfavorable impact of foreign exchange. Full-year 2023 Animal Health sales grew 1% to $5.6 billion. Excluding the unfavorable impact of foreign exchange, Animal Health sales grew 3%, primarily due to higher pricing. Full-year sales growth was also driven by higher demand for livestock products, led by poultry and swine products, partially offset by lower demand for ruminant products. Sales of BRAVECTO were $1.1 billion in 2023, which represented growth of 4%, or 5% excluding the impact of foreign exchange, primarily reflecting higher pricing. Fourth-Quarter and Full-Year Expense, EPS and Related Information The table below presents selected expense information. $ in millions GAAP Acquisition- and Divestiture- Related Costs 3 Restructuring Costs (Income) Loss From Investments in Equity Securities Non- GAAP 2 Fourth Quarter 2023 Cost of sales $3,911 $454 $117 $- $3,340 Selling, general and administrative 2,804 24 29 - 2,751 Research and development 9,628 790 - - 8,838 Restructuring costs 255 - 255 - - Other (income) expense, net 78 (35) - (61) 174 Fourth Quarter 2022 Cost of sales $3,881 $482 $38 $- $3,361 Selling, general and administrative 2,687 39 20 - 2,628 Research and development 3,775 740 - - 3,035 Restructuring costs 49 - 49 - - Other (income) expense, net (75) (69) - 80 (86) $ in millions GAAP Acquisition- and Divestiture- Related Costs 3 Restructuring Costs (Income) Loss From Investments in Equity Securities Certain Other Items Non- GAAP 2 Year Ended Dec. 31, 2023 Cost of sales $16,126 $2,018 $211 $- $- $13,897 Selling, general and administrative 10,504 86 122 - - 10,296 Research and development 30,531 819 1 - - 29,711 Restructuring costs 599 - 599 - - - Other (income) expense, net 466 (47) - (279) 573 219 Year Ended Dec. 31, 2022 Cost of sales $17,411 $2,059 $205 $- $- $15,147 Selling, general and administrative 10,042 176 94 - - 9,772 Research and development 13,548 1,676 30 - - 11,842 Restructuring costs 337 - 337 - - - Other (income) expense, net 1,501 (207) - 1,348 - 360 GAAP Expense, EPS and Related Information Gross margin was 73.3% for the fourth quarter of 2023 compared with 71.9% for the fourth quarter of 2022. The increase was primarily due to the favorable impacts of lower LAGEVRIO sales, which have a low gross margin, lower manufacturing facilities costs and product mix, partially offset by the unfavorable impacts of foreign exchange and higher restructuring costs. Gross margin was 73.2% for the full year of 2023 compared with 70.6% for the full year of 2022. The increase was primarily due to the favorable impacts of lower LAGEVRIO sales, product mix, lower manufacturing facilities costs, and lower revenue from third-party manufacturing arrangements, partially offset by the unfavorable impact of foreign exchange. Selling, general and administrative (SG&A) expenses were $2.8 billion in the fourth quarter of 2023, an increase of 4% compared with the fourth quarter of 2022. The increase was primarily due to higher administrative costs, including higher compensation and benefit costs, partially offset by lower promotional spending. Full-year 2023 SG&A expenses were $10.5 billion, an increase of 5% compared with the full year of 2022. The increase was primarily due to higher administrative costs, including higher compensation and benefit costs, and higher promotional spending, partially offset by the favorable impact of foreign exchange and lower acquisition- and divestiture-related costs. R&D expenses were $9.6 billion in the fourth quarter of 2023 compared with $3.8 billion in the fourth quarter of 2022. R&D expenses were $30.5 billion for the full year of 2023 compared with $13.5 billion for the full year of 2022. The increase in the fourth quarter and full year of 2023 reflects a $5.5 billion charge for the collaboration with Daiichi Sankyo, and higher development costs due to spending on clinical programs, including newly acquired programs, as well as higher compensation and benefit costs (reflecting in part increased headcount). The increase in R&D expenses for the full year was also due to charges of $11.4 billion in the aggregate for the acquisitions of Prometheus Biosciences, Inc. (Prometheus) and Imago BioSciences, Inc. (Imago). The increase in R&D expenses for the full year was partially offset by lower intangible asset impairment charges in 2023 and charges of $690 million in the aggregate in 2022 for collaboration and licensing agreements with Moderna, Inc. (Moderna), Orna Therapeutics (Orna) and Orion Corporation (Orion). Other (income) expense, net, was $78 million of expense in the fourth quarter of 2023 compared with $75 million of income in the fourth quarter of 2022, primarily due to higher exchange losses and higher net interest expense, partially offset by net gains from investments in equity securities for the fourth quarter of 2023 compared with net losses from investments in equity securities for the fourth quarter of 2022, and lower pension settlement costs. Other (income) expense, net, was $466 million of expense in the full year of 2023 compared with $1.5 billion of expense in the full year of 2022, primarily due to net gains from investments in equity securities in 2023 compared with net losses from investments in equity securities in 2022, and lower pension settlement costs, partially offset by a $572.5 million charge in 2023 related to settlements with certain plaintiffs in the Zetia antitrust litigation. The effective tax rate was 40.1% for the fourth quarter of 2023 compared with 14.1% in the fourth quarter of 2022. The effective tax rate for the fourth quarter of 2023 includes a 29.2 percentage point impact resulting from the charge for the Daiichi Sankyo collaboration. The effective tax rate was 80.0% for the full year of 2023 compared with 11.7% for the full year of 2022. The full-year 2023 effective tax rate reflects an aggregate 65.6 percentage point unfavorable impact, resulting from charges for asset acquisitions (for which no tax benefits were recognized) as well as the charge for the Daiichi Sankyo collaboration. GAAP loss per share was $0.48 for the fourth quarter of 2023 compared with EPS of $1.18 for the fourth quarter of 2022, primarily driven by the charge in 2023 related to the collaboration with Daiichi Sankyo, the unfavorable impact of foreign exchange and higher restructuring costs, partially offset by a beneficial impact from the tax rate and operational strength in the business. GAAP EPS was $0.14 for the full year of 2023 compared with EPS of $5.71 for the full year of 2022. The EPS decline in 2023 was primarily due to higher charges for certain business development transactions, the unfavorable impact of foreign exchange and the tax rate, as well as a charge related to settlements with certain plaintiffs in the Zetia antitrust litigation, partially offset by the beneficial impacts of operational strength in the business, better performance from equity investments and lower intangible asset impairment charges. Non-GAAP Expense, EPS and Related Information Non-GAAP gross margin was 77.2% for the fourth quarter of 2023 compared with 75.7% for the fourth quarter of 2022. Non-GAAP gross margin was 76.9% for the full year of 2023 compared with 74.4% for the full year of 2022. The non-GAAP gross margin improvement in the fourth quarter and full year of 2023 was primarily due to the favorable impacts of lower LAGEVRIO sales, which have a low gross margin, product mix, and lower manufacturing facilities costs. The increase in non-GAAP gross margin for the full year was also due to lower revenue from third-party manufacturing arrangements. The non-GAAP gross margin improvement in the fourth quarter and full year of 2023 was partially offset by the unfavorable impact of foreign exchange. Non-GAAP SG&A expenses were $2.8 billion for the fourth quarter of 2023 compared with $2.6 billion for the fourth quarter of 2022. The increase was primarily due to higher administrative costs, including higher compensation and benefit costs, partially offset by lower promotional spending. Full-year 2023 non-GAAP SG&A expenses were $10.3 billion, an increase of 5% compared with the full year of 2022. The increase was primarily due to higher administrative costs, including higher compensation and benefit costs, and higher promotional spending, partially offset by the favorable impact of foreign exchange. Non-GAAP R&D expenses were $8.8 billion in the fourth quarter of 2023 compared with $3.0 billion in the fourth quarter of 2022. Non-GAAP R&D expenses were $29.7 billion for the full year of 2023 compared with $11.8 billion for the full year of 2022. The increase in the fourth quarter and full year of 2023 reflects a $5.5 billion charge for the collaboration with Daiichi Sankyo, and higher development costs due to spending on clinical programs, including newly acquired programs, as well as higher compensation and benefit costs (reflecting in part increased headcount). The increase in non-GAAP R&D expenses for the full year was also due to charges of $11.4 billion in the aggregate for the acquisitions of Prometheus and Imago. The increase in R&D expenses for the full year was partially offset by charges of $690 million in the aggregate in 2022 for collaboration and licensing agreements with Moderna, Orna and Orion. Non-GAAP other (income) expense, net, was $174 million of expense in the fourth quarter of 2023 compared with $86 million of income in the fourth quarter of 2022, primarily due to higher exchange losses and higher net interest expense, partially offset by lower pension settlement costs. Non-GAAP other (income) expense, net, was $219 million of expense in the full year of 2023 compared with $360 million of expense in the full year of 2022, primarily due to lower pension settlement costs. The non-GAAP effective tax rate was 114.2% for the fourth quarter of 2023 compared with 15.6% in the fourth quarter of 2022. The non-GAAP effective tax rate for the fourth quarter of 2023 includes a 101.1 percentage point unfavorable impact resulting from the charge for the Daiichi Sankyo collaboration. The non-GAAP effective tax rate was 35.8% for the full year of 2023 compared with 14.2% for the full year of 2022. The full-year 2023 non-GAAP effective tax rate reflects an aggregate 21.2 percentage point unfavorable impact, resulting from charges for asset acquisitions (for which no benefits were recognized) as well as the charge for the Daiichi Sankyo collaboration. Non-GAAP EPS was $0.03 for the fourth quarter of 2023 compared with $1.62 for the fourth quarter of 2022. The non-GAAP EPS decline in the fourth quarter was primarily due to the charge in 2023 related to the collaboration with Daiichi Sankyo and the unfavorable impact of foreign exchange, partially offset by a beneficial impact from the tax rate and operational strength in the business. Non-GAAP EPS was $1.51 for the full year of 2023 compared with $7.48 for the full year of 2022. The non-GAAP EPS decline for the full year was primarily due to higher charges for certain business development transactions, the unfavorable impact of foreign exchange and the tax rate, partially offset by operational strength in the business. A reconciliation of GAAP to non-GAAP net (loss) income and (loss) earnings per share is provided in the table that follows. Fourth Quarter Year Ended $ in millions, except EPS amounts 2023 2022 Dec. 31, 2023 Dec. 31, 2022 EPS GAAP EPS $(0.48) $1.18 $0.14 $5.71 Difference 0.51 0.44 1.37 1.77 Non-GAAP EPS that excludes items listed below 2 $0.03 $1.62 $1.51 $7.48 Net (Loss) Income GAAP net (loss) income 1 $(1,226) $3,017 $365 $14,519 Difference 1,292 1,112 3,472 4,486 Non-GAAP net income that excludes items listed below 1,2 $66 $4,129 $3,837 $19,005 Excluded Items: Acquisition- and divestiture-related costs 3 $1,233 $1,192 $2,876 $3,704 Restructuring costs 401 107 933 666 (Income) loss from investments in equity securities (61) 80 (279) 1,348 Charge for Zetia antitrust litigation settlements - - 573 - Increase to net loss/decrease to net income before taxes 1,573 1,379 4,103 5,718 Estimated income tax (benefit) expense (281) (267) (631) (1,232) Increase to net loss/decrease to net income $1,292 $1,112 $3,472 $4,486 2024 Restructuring Program Merck recently approved a new restructuring program (2024 Restructuring Program) intended to continue the optimization of the company’s Human Health global manufacturing network as the future pipeline shifts to new modalities, and also to optimize the Animal Health global manufacturing network to improve supply reliability and increase efficiency. The company recorded charges in its GAAP results of $190 million related to the 2024 Restructuring Program for the fourth quarter and full year of 2023. Pipeline and Portfolio Highlights In the fourth quarter, Merck continued to make significant progress advancing its broad portfolio and pipeline across key therapeutic areas, representing continued momentum toward addressing patient needs. In oncology, Merck received multiple U.S. Food and Drug Administration (FDA) approvals, including KEYTRUDA plus Padcev for the first-line treatment of adult patients with locally advanced or metastatic urothelial cancer and WELIREG for the treatment of certain patients with previously treated advanced RCC, among other approvals. The FDA also accepted and granted Priority Review to Merck and Daiichi Sankyo’s Biologics License Application (BLA) for patritumab deruxtecan for the treatment of certain patients with previously treated locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC). The FDA set a Prescription Drug User Fee Act (PDUFA), or target action, date of June 26, 2024. In addition, Merck showed meaningful progress in its robust oncology pipeline, initiating Phase 3 trials for four investigational medicines, including bomedemstat (LSD1 inhibitor), nemtabrutinib (BTK inhibitor), MK-2870 (anti-TROP2 antibody-drug conjugate) and MK-5684 (CYP11A1 inhibitor). In vaccines, Merck received Priority Review from the FDA for a BLA for V116, the company’s investigational, 21-valent pneumococcal conjugate vaccine specifically designed to protect adults, based on results from multiple Phase 3 trials. The FDA set a PDUFA date of June 17, 2024. If approved, V116 would be the first pneumococcal conjugate vaccine to include serotypes responsible for approximately 83 percent of adult invasive pneumococcal disease in individuals 65 and older, according to U.S. Centers for Disease Control and Prevention data from 2018-2021. In hospital acute care, the European Commission (EC) approved PREVYMIS for prevention of cytomegalovirus (CMV) disease in high-risk adult kidney transplant recipients and extended 200-day dosing in adult hematopoietic stem cell transplant (HSCT) recipients who are at high risk for late CMV infection and disease. Merck continued to augment its pipeline through business development, and in January 2024, entered into a definitive agreement to acquire Harpoon Therapeutics, Inc. (Harpoon), for an approximate total equity value of $680 million, further diversifying its oncology pipeline. Notable recent news releases on Merck’s pipeline and portfolio are provided in the table that follows. Oncology FDA Approved Expanded Indication for KEYTRUDA Plus Padcev as First-Line Treatment for Adult Patients With Locally Advanced or Metastatic Urothelial Cancer, Based on Results From Phase 3 KEYNOTE-A39 Trial (Read Announcement) FDA Approved Merck’s WELIREG as Treatment for Patients With Advanced RCC Following a PD-1 or PD-L1 Inhibitor and a VEGF-TKI, Based on Results From LITESPARK-005 Trial (Read Announcement) FDA Approved Merck’s KEYTRUDA Plus Chemoradiotherapy as Treatment for Patients With FIGO 2014 Stage III-IVA Cervical Cancer, Based on Results From Phase 3 KEYNOTE-A18 Trial (Read Announcement) FDA Approved Merck’s KEYTRUDA Plus Chemotherapy as First-Line Treatment for Locally Advanced Unresectable or Metastatic HER2-Negative Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma, Based on Results From Phase 3 KEYNOTE-859 Trial (Read Announcement) FDA Approved Merck’s KEYTRUDA Plus Gemcitabine and Cisplatin as Treatment for Patients With Locally Advanced Unresectable or Metastatic Biliary Tract Cancer, Based on Results From Phase 3 KEYNOTE-966 Trial (Read Announcement) EC Approved KEYTRUDA Plus Chemotherapy for New First-Line Indications in Advanced HER2-Negative Gastric or GEJ Adenocarcinoma in Tumors Expressing PD-L1 (CPS ≥1) and Advanced Biliary Tract Cancer, Based on Results From Phase 3 KEYNOTE-859 and KEYNOTE-966 Trials (Read Announcement) FDA Granted Priority Review to Merck and Daiichi Sankyo’s BLA for Patritumab Deruxtecan for the Treatment of Certain Patients With Previously Treated Locally Advanced or Metastatic EGFR-Mutated NSCLC, Based on Results From Phase 2 HERTHENA-Lung01 Trial; FDA Set PDUFA Date of June 26, 2024 (Read announcement) Merck Announced Phase 3 Trial Initiations for Bomedemstat, Nemtabrutinib, MK-2870 and MK-5684, Four Investigational Candidates From Promising Hematology and Oncology Pipeline (Read announcement) Merck and Moderna Initiated INTerpath-002, a Phase 3 Study Evaluating V940 (mRNA-4157) in Combination With KEYTRUDA for Adjuvant Treatment of Patients With Certain Types of Resected NSCLC (Read Announcement) KEYTRUDA Reduced the Risk of Death by 38% Versus Placebo as Adjuvant Therapy for Patients With RCC at an Increased Risk of Recurrence Following Nephrectomy, Based on Results From Phase 3 KEYNOTE-564 Trial (Read Announcement) KEYTRUDA Significantly Improved Disease-Free Survival as Adjuvant Therapy Versus Observation in High-Risk Patients With Localized Muscle-Invasive and Locally Advanced Urothelial Carcinoma After Surgery, Based on Results From Phase 3 AMBASSADOR/KEYNOTE-123 Trial (Read Announcement) Moderna and Merck Announced V940 (mRNA-4157) in Combination With KEYTRUDA Demonstrated Continued Improvement in Recurrence-Free Survival and Distant Metastasis-Free Survival in Patients With High-Risk Stage III/IV Melanoma Following Complete Resection Versus KEYTRUDA at Three Years, Based on Results From Phase 2b Randomized KEYNOTE-942/mRNA-4157-P201 Study (Read Announcement) Vaccines FDA Granted Priority Review to Merck’s New BLA for V116, an Investigational, 21-valent Pneumococcal Conjugate Vaccine Specifically Designed to Protect Adults, Based on Results From Multiple Phase 3 Trials; FDA Set PDUFA Date of June 17, 2024 (Read Announcement) Merck’s V116, an Investigational, 21-valent Pneumococcal Conjugate Vaccine Specifically Designed to Protect Adults, Demonstrated Superior Immunogenicity for 10 of 11 Unique Serotypes Compared to PCV20 in Adults 50 Years of Age and Older, Based on Results From Phase 3 STRIDE-3 Trial (Read Announcement) Full-Year 2024 Financial Outlook The following table summarizes the company’s full-year financial outlook. Full Year 2024 Sales * $62.7 to $64.2 billion Non-GAAP gross margin 2 Approximately 80.5% Non-GAAP operating expenses 2** $25.1 to $26.1 billion Non-GAAP other (income) expense, net 2 Approximately $200 million expense Non-GAAP effective tax rate 2 14.5% to 15.5% Non-GAAP EPS 2*** $8.44 to $8.59 Share count (assuming dilution) Approximately 2.54 billion *The company does not have any non-GAAP adjustments to sales. **Includes approximately $650 million of R&D expense related to the recently announced Harpoon acquisition, which is expected to close in the first half of 2024. Outlook does not assume any additional significant potential business development transactions. ***Includes a one-time charge of approximately $0.26 per share related to the Harpoon acquisition. Merck has not provided a reconciliation of forward-looking non-GAAP gross margin, non-GAAP operating expenses, non-GAAP other (income) expense, net, non-GAAP effective tax rate and non-GAAP EPS to the most directly comparable GAAP measures, given it cannot predict with reasonable certainty the amounts necessary for such a reconciliation, including intangible asset impairment charges, legal settlements, and income and losses from investments in equity securities either owned directly or through ownership interests in investment funds, without unreasonable effort. These items are inherently difficult to forecast and could have a significant impact on the company’s future GAAP results. Merck anticipates full-year 2024 sales to be between $62.7 billion and $64.2 billion, including a negative impact of foreign exchange of approximately 2% at mid-January 2024 exchange rates. The negative impact is primarily due to the devaluation of the Argentine peso, which the company expects will largely be offset by inflation-related price increases, consistent with market practice. The outlook for operating expenses reflects incremental R&D spending expected to be incurred to advance the development of promising programs related to the acquisitions of Prometheus, Imago and Harpoon, as well as the collaborations with Daiichi Sankyo and Kelun-Biotech. Merck’s full-year non-GAAP effective income tax rate is expected to be between 14.5% and 15.5%. Merck expects full-year 2024 non-GAAP EPS to be between $8.44 and $8.59, including a negative impact of foreign exchange of approximately $0.25 per share. In 2023, non-GAAP EPS of $1.51 was negatively impacted by charges of $6.21 per share related to certain acquisitions and collaboration agreements. In early January 2024, Merck announced the acquisition of Harpoon, which is expected to close in the first half of 2024, and result in a non-tax deductible charge of approximately $650 million of R&D expense included in non-GAAP results. The impact of the transaction on expected full-year non-GAAP EPS is approximately $0.26 per share, which is included in the 2024 outlook. Consistent with past practice, the financial outlook does not assume additional significant potential business development transactions. Earnings Conference Call Investors, journalists and the general public may access a live audio webcast of the earnings conference call on Thursday, Feb. 1, at 9 a.m. ET via this weblink . A replay of the webcast, along with the sales and earnings news release, supplemental financial disclosures, prepared remarks and slides highlighting the results, will be available at www.merck.com . All participants may join the call by dialing (800) 779-6561 (U.S. and Canada Toll-Free) or (773) 756-4619 and using the access code 5958465. About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter ) , Facebook , Instagram , YouTube and LinkedIn . Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of the global outbreak of novel coronavirus disease (COVID-19); the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2022, and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site ( www.sec.gov ). Appendix Generic product names are provided below. Pharmaceutical BRIDION (sugammadex) GARDASIL ( Human Papillomavirus Quadrivalent [Types 6, 11, 16 and 18] Vaccine, Recombinant ) GARDASIL 9 (Human Papillomavirus 9-valent Vaccine, Recombinant) JANUMET (sitagliptin and metformin HCl) JANUVIA (sitagliptin) KEYTRUDA (pembrolizumab) LAGEVRIO (molnupiravir) Lenvima (lenvatinib) Lynparza ( olaparib) M-M-R II (Measles, Mumps and Rubella Virus Vaccine Live) PNEUMOVAX 23 (Pneumococcal Vaccine Polyvalent) PREVYMIS ( letermovir ) PROQUAD (Measles, Mumps, Rubella and Varicella Virus Vaccine Live) ROTATEQ (Rotavirus Vaccine, Live, Oral, Pentavalent) VARIVAX (Varicella Virus Vaccine Live) VAXNEUVANCE ( Pneumococcal 15-valent Conjugate Vaccine ) WELIREG ( belzutifan ) Animal Health BRAVECTO (fluralaner) ________________________________ 1 Net (loss) income attributable to Merck & Co., Inc. 2 Merck is providing certain 2023 and 2022 non-GAAP information that excludes certain items because of the nature of these items and the impact they have on the analysis of underlying business performance and trends. Management believes that providing this information enhances investors’ understanding of the company’s results because management uses non-GAAP results to assess performance. Management uses non-GAAP measures internally for planning and forecasting purposes and to measure the performance of the company along with other metrics. In addition, senior management’s annual compensation is derived in part using a non-GAAP pre-tax income metric. This information should be considered in addition to, but not as a substitute for or superior to, information prepared in accordance with GAAP. For a description of the non-GAAP adjustments, see Table 2a attached to this release. 3 Includes expenses for the amortization of intangible assets and purchase accounting adjustments to inventories recognized as a result of acquisitions of businesses, intangible asset impairment charges and expense or income related to changes in the estimated fair value measurement of liabilities for contingent consideration. R&D expenses include intangible asset impairment charges of $779 million in both the fourth quarter and full year of 2023 related to gefapixant and $780 million and $1.7 billion in the fourth quarter and full year of 2022, respectively, largely related to nemtabrutinib. Also includes integration, transaction and certain other costs associated with acquisitions and divestitures, as well as amortization of intangible assets related to collaborations and licensing arrangements. MERCK & CO., INC. CONSOLIDATED STATEMENT OF OPERATIONS - GAAP (AMOUNTS IN MILLIONS, EXCEPT PER SHARE FIGURES) (UNAUDITED) Table 1 GAAP % Change GAAP % Change 4Q23 4Q22 Full Year 2023 Full Year 2022 Sales $ 14,630 $ 13,830 6 % $ 60,115 $ 59,283 1 % Costs, Expenses and Other Cost of sales 3,911 3,881 1 % 16,126 17,411 -7 % Selling, general and administrative 2,804 2,687 4 % 10,504 10,042 5 % Research and development 9,628 3,775 * 30,531 13,548 * Restructuring costs 255 49 * 599 337 78 % Other (income) expense, net 78 (75 ) * 466 1,501 -69 % (Loss) Income Before Taxes (2,046 ) 3,513 * 1,889 16,444 -89 % Income Tax (Benefit) Provision (821 ) 495 1,512 1,918 Net (Loss) Income (1,225 ) 3,018 * 377 14,526 -97 % Less: Net Income Attributable to Noncontrolling Interests 1 1 12 7 Net (Loss) Income Attributable to Merck & Co., Inc. $ (1,226 ) $ 3,017 * $ 365 $ 14,519 -97 % (Loss) Earnings per Common Share Assuming Dilution (1) $ (0.48 ) $ 1.18 * $ 0.14 $ 5.71 -98 % Average Shares Outstanding Assuming Dilution (1) 2,533 2,548 2,547 2,542 Tax Rate 40.1 % 14.1 % 80.0 % 11.7 % * 100% or greater (1) Because the company recorded a net loss in the fourth quarter of 2023, no potential dilutive common shares were used in the computation of loss per common share assuming dilution as the effect would have been anti-dilutive. MERCK & CO., INC. FOURTH QUARTER AND FULL YEAR 2023 GAAP TO NON-GAAP RECONCILIATION (AMOUNTS IN MILLIONS, EXCEPT PER SHARE FIGURES) (UNAUDITED) Table 2a GAAP Acquisition and Divestiture-Related Costs (1) Restructuring Costs (2) (Income) Loss from Investments in Equity Securities Certain Other Items Adjustment Subtotal Non-GAAP Fourth Quarter Cost of sales $ 3,911 454 117 571 $ 3,340 Selling, general and administrative 2,804 24 29 53 2,751 Research and development 9,628 790 790 8,838 Restructuring costs 255 255 255 – Other (income) expense, net 78 (35 ) (61 ) (96 ) 174 Loss Before Taxes (2,046 ) (1,233 ) (401 ) 61 (1,573 ) (473 ) Income Tax Provision (Benefit) (821 ) (227 ) (4 ) (67 ) (4 ) 13 (4 ) (281 ) (540 ) Net (Loss) Income (1,225 ) (1,006 ) (334 ) 48 (1,292 ) 67 Net (Loss) Income Attributable to Merck & Co., Inc. (1,226 ) (1,006 ) (334 ) 48 (1,292 ) 66 (Loss) Earnings per Common Share Assuming Dilution (5) $ (0.48 ) (0.40 ) (0.13 ) 0.02 (0.51 ) $ 0.03 Tax Rate 40.1 % 114.2 % Full Year Cost of sales $ 16,126 2,018 211 2,229 $ 13,897 Selling, general and administrative 10,504 86 122 208 10,296 Research and development 30,531 819 1 820 29,711 Restructuring costs 599 599 599 – Other (income) expense, net 466 (47 ) (279 ) 573 (3 ) 247 219 Income Before Taxes 1,889 (2,876 ) (933 ) 279 (573 ) (4,103 ) 5,992 Income Tax Provision (Benefit) 1,512 (476 ) (4 ) (155 ) (4 ) 60 (4 ) (60 ) (4 ) (631 ) 2,143 Net Income 377 (2,400 ) (778 ) 219 (513 ) (3,472 ) 3,849 Net Income Attributable to Merck & Co., Inc. 365 (2,400 ) (778 ) 219 (513 ) (3,472 ) 3,837 Earnings per Common Share Assuming Dilution $ 0.14 (0.94 ) (0.31 ) 0.08 (0.20 ) (1.37 ) $ 1.51 Tax Rate 80.0 % 35.8 % Only the line items that are affected by non-GAAP adjustments are shown. Merck is providing certain non-GAAP information that excludes certain items because of the nature of these items and the impact they have on the analysis of underlying business performance and trends. Management believes that providing non-GAAP information enhances investors’ understanding of the company’s results because management uses non-GAAP measures to assess performance. Management uses non-GAAP measures internally for planning and forecasting purposes and to measure the performance of the company along with other metrics. In addition, senior management’s annual compensation is derived in part using a non-GAAP pretax income metric. The non-GAAP information presented should be considered in addition to, but not as a substitute for or superior to, information prepared in accordance with GAAP. (1) Amounts included in cost of sales primarily reflect expenses for the amortization of intangible assets. Amounts included in selling, general and administrative expenses reflect integration, transaction and certain other costs related to acquisitions and divestitures. Amounts included in research and development expenses primarily reflect a $779 million in-process research and development (IPR&D) impairment charge related to gefapixant, which was obtained as part of the 2016 Afferent Pharmaceuticals acquisition, and expenses for the amortization of intangible assets. Amounts included in other (income) expense, net, primarily reflect royalty income related to the prior termination of the Sanofi-Pasteur MSD joint venture. Additionally, other (income) expense, net, for the full year includes a $37 million loss on the sale of a business. (2) Amounts primarily include employee separation costs and accelerated depreciation associated with facilities to be closed or divested related to activities under the company's formal restructuring programs. (3) Reflects a charge related to settlements with certain plaintiffs in the Zetia antitrust litigation. (4) Represents the estimated tax impacts on the reconciling items based on applying the statutory rate of the originating territory of the non-GAAP adjustments. (5) Because the company recorded a net loss in the fourth quarter of 2023, no potential dilutive common shares were used in the computation of loss per common share assuming dilution as the effect would have been anti-dilutive. MERCK & CO., INC. FRANCHISE / KEY PRODUCT SALES (AMOUNTS IN MILLIONS) (UNAUDITED) Table 3 2023 2022 4Q Full Year 1Q 2Q 3Q 4Q Full Year 1Q 2Q 3Q 4Q Full Year Nom % Ex-Exch % Nom % Ex-Exch % TOTAL SALES (1) $14,487 $15,035 $15,962 $14,630 $60,115 $15,901 $14,593 $14,959 $13,830 $59,283 6 7 1 4 PHARMACEUTICAL 12,721 13,457 14,263 13,141 53,583 14,107 12,756 12,963 12,180 52,005 8 8 3 5 Oncology Keytruda 5,795 6,271 6,338 6,608 25,011 4,809 5,252 5,426 5,450 20,937 21 22 19 21 Alliance Revenue – Lynparza (2) 275 310 299 315 1,199 266 275 284 292 1,116 8 8 7 9 Alliance Revenue – Lenvima (2) 232 242 260 226 960 227 231 202 216 876 5 5 10 11 Welireg 42 50 54 72 218 18 27 38 40 123 79 78 77 77 Alliance Revenue – Reblozyl (3) 43 47 52 70 212 52 33 39 41 166 69 69 28 28 Vaccines (4) Gardasil / Gardasil 9 1,972 2,458 2,585 1,871 8,886 1,460 1,674 2,294 1,470 6,897 27 27 29 33 ProQuad / M-M-R II / Varivax 528 582 713 545 2,368 470 578 668 526 2,241 4 3 6 6 RotaTeq 297 131 156 185 769 216 173 256 139 783 34 33 -2 -1 Vaxneuvance 106 168 214 176 665 5 12 16 138 170 28 26 * * Pneumovax 23 96 92 140 85 412 173 153 131 145 602 -42 -43 -32 -31 Vaqta 40 42 69 29 180 36 35 64 39 173 -24 -25 4 4 Hospital Acute Care Bridion 487 502 424 429 1,842 395 426 423 441 1,685 -3 -3 9 11 Prevymis 129 143 157 175 605 94 103 114 118 428 49 49 41 43 Dificid 65 76 74 87 302 52 66 77 67 263 30 30 15 15 Zerbaxa 50 54 53 61 218 30 46 43 49 169 25 23 29 30 Noxafil 60 55 51 46 213 57 60 62 58 238 -21 -16 -11 -4 Primaxin 80 53 41 39 213 58 64 63 54 239 -28 -28 -11 -6 Cardiovascular Alliance Revenue - Adempas/Verquvo (5) 99 68 92 108 367 72 98 88 82 341 31 31 8 8 Adempas (6) 59 65 65 66 255 61 63 57 57 238 15 11 7 8 Virology Lagevrio 392 203 640 193 1,428 3,247 1,177 436 825 5,684 -77 -76 -75 -74 Isentress / Isentress HD 123 136 119 105 483 158 147 161 167 633 -37 -37 -24 -23 Neuroscience Belsomra 56 63 58 54 231 69 69 62 59 258 -8 -6 -11 -6 Immunology Simponi 180 180 179 171 710 186 181 173 166 706 3 -2 1 - Remicade 51 48 45 43 187 61 53 49 44 207 -1 -2 -9 -8 Diabetes (7) Januvia 551 511 581 547 2,189 779 756 717 561 2,813 -2 -2 -22 -20 Janumet 329 354 255 240 1,177 454 476 417 353 1,700 -32 -32 -31 -29 Other Pharmaceutical (8) 584 553 549 595 2,283 602 528 603 583 2,319 2 2 -2 - ANIMAL HEALTH 1,491 1,456 1,400 1,278 5,625 1,482 1,467 1,371 1,230 5,550 4 4 1 3 Livestock 849 807 874 808 3,337 832 826 829 814 3,300 -1 - 1 4 Companion Animal 642 649 526 470 2,288 650 641 542 416 2,250 13 12 2 3 Other Revenues (9) 275 122 299 211 907 312 370 625 420 1,728 -50 -1 -48 -15 *200% or greater Sum of quarterly amounts may not equal year-to-date amounts due to rounding. (1) Only select products are shown. (2) Alliance Revenue represents Merck’s share of profits, which are product sales net of cost of sales and commercialization costs. (3) Alliance Revenue represents royalties and a milestone payment of $20 million received in the first quarter of 2022. (4) Total Vaccines sales were $3,133 million, $3,557 million, $4,002 million and $2,962 million in the first, second, third and fourth quarter of 2023, respectively, and $2,481 million, $2,709 million, $3,552 million and $2,554 million in the first, second, third and fourth quarter of 2022, respectively. (5) Alliance Revenue represents Merck's share of profits from sales in Bayer's marketing territories, which are product sales net of cost of sales and commercialization costs. (6) Net product sales in Merck's marketing territories. (7) Total Diabetes sales were $950 million, $951 million, $924 million and $876 million in the first, second, third and fourth quarter of 2023, respectively, and $1,305 million, $1,300 million, $1,231 million and $1,012 million in the first, second, third and fourth quarter of 2022, respectively. (8) Includes Pharmaceutical products not individually shown above. (9) Other Revenues are comprised primarily of revenues from third-party manufacturing arrangements and miscellaneous corporate revenues, including revenue-hedging activities. Other Revenues related to the receipt of upfront and milestone payments for out-licensed products were $51 million, $3 million and $65 million in the first, second and third quarter of 2023, respectively, and $114 million, $32 million, $10 million and $10 million in the first, second, third and fourth quarter of 2022, respectively.

“全球药物研发进展一周速递”精选本周新药研发领域最新动态，新药研发进展、竞争格局、前沿技术等信息一文速览。药物研发进展1.针对慢性阻塞性肺病！赛诺菲/再生元度普利尤单抗新适应症即将报上市11 月 27 日，赛诺菲宣布，度普利尤单抗（Dupixent）治疗慢性阻塞性肺病（COPD）的 III 期临床 NOTUS 研究达到主要终点。这是针对 Dupixent 治疗中重度 COPD 开展的第 2 项 III 期临床试验，此前，首项 III 期临床 BOREAS 研究已取得积极结果。赛诺菲表示将在今年年底递交该适应症的上市申请，有望成为首款 COPD 生物制剂创新药。NOTUS 研究旨在评估 Dupixent 在目前接受最大标准吸入治疗（三联治疗）且伴发 2 型炎症（血液嗜酸性粒细胞 ≥ 300 个/μL）的成年 COPD 患者的疗效、安全性和耐受性。该研究共纳入 935 例患者，该类患者曾经或目前吸烟。研究结果显示达到主要终点，接受 Dupixent 治疗 52 周，中重度COPD 的急性发作减少 34%（p=0.0002）。此外，第 12 周时，Dupixent 治疗组患者肺功能（通过支气管扩张剂前 FEV1 评估肺功能）较基线提高 139 mL，安慰剂组为 57 mL（p=0.0001），益处持续到第 52 周，Dupixent 组为 115 mL，安慰剂组则为 54 mL（p=0.0182）。在安全性方面，与 Dupixent 在已批准适应症的安全性数据基本一致。Dupixent 不良事件（AE）发生率为 67%，安慰剂组为 66%，常见 AE 包括鼻咽炎、头痛等。度普利尤单抗（Dupixent）是赛诺菲与再生元合作开发的一款人源性单克隆抗体，靶向 IL-4Rα。通过结合 IL-4Rα，度普利尤单抗可同时阻断 IL-4 和 IL-13 信号通路，IL-4 和 IL-13 被认为是特应性皮炎持续性炎症的主要驱动因子。2.默沙东抗生素二联复方注射用头孢洛生他唑巴坦钠在华申报上市11月27日，CDE网站显示，默沙东抗生素复方注射用头孢洛生他唑巴坦钠申报上市。根据临床试验进展，推测此次申报的适应症为腹腔感染。该复方（研发代号：MK-7625A）于2014年12月首次在美国获批上市，商品名为Zerbaxa，用于联合甲硝唑治疗指定易感微生物引起的复杂性腹腔感染和复杂性尿路感染（包括肾盂肾炎）。后来，其适应症又扩大至医院获得性细菌性肺炎（HABP）和呼吸机相关性细菌性肺炎（VABP）。2022年8月，默沙东在International Journal of Infectious Diseases期刊上发表了注射用头孢洛生他唑巴坦钠治疗复杂性腹腔感染的中国III期MK-7625A-015研究结果。该研究共纳入268例患者，评估了该复方（1500mg，每日3次）联合甲硝唑（500mg，每日3次）对比美罗培南（1000mg，每日3次）的疗效和安全性。研究的主要终点为在临床可评价（CE）人群中，治愈评价（TOC）访视时的临床疗效（临床治愈或临床失败）。结果显示，复方组和美罗培南组患者的临床治愈率分别为95.2%和93.1%，达到非劣效性标准。此外，在次要终点的微生物学应答指标方面，该复方也显示出了治疗优势（应答率94.4% vs. 93.2%）。三联复方（二丙酸倍他米松+克霉唑+庆大霉素）和二联复方（亚胺培南+西司他丁）已在中国上市。今年7月，默沙东的另一款抗生素三联复方（亚西瑞来）也在中国提交了上市申请。细菌感染患者有望迎来更多的治疗选择。3.开拓药业外用男性雄激素脱发药物III期研究疗效不佳11 月 27 日，开拓药业发布公告，称其在研 KX-826 外用治疗男性雄激素性脱发（AGA）的中国 III 期临床试验已读出顶线数据。该项 III 期临床试验是一项多中心、随机、双盲、安慰剂对照的研究，以评估外用 0.5% 浓度每日使用两次 KX-826 治疗中国成年男性脱髮患者的有效性和安全性。该项研究的主要终点为 24 周结束时目标区域内非毳毛数（TAHC/cm2）对比基线的平均变化。安全性指标包括不良事件的发生类型、发生率和严重程度。分析结果显示，该试验整体安全性优良，KX-826 展示了极佳的安全性能，试验过程未报告任何重大不良反应。治疗 24 周后，KX-826 组 TAHC 结果显示，KX-826 与基线相比促进了毛髮生长，具有统计学意义（P<0.000 1）。与安慰剂相比，KX-826 组 TAHC 在各个访视点均有提高，差异在统计学上未达到显著性，但显示疗效趋势。开拓药业表示将继续分析该项 III 期临床试验的结果，并开展 KX-826 外用治疗脱髮及痤疮的多项临床试验，持续探索 KX-826 上市的可能性。此前公布的 KX826 男性脱发中国 II 期试验数据显示：治疗 24 周时，KX-826 的 0.5% 剂量组在达到 TAHC 主要终点，与安慰剂组相比，每平方厘米增加 15.34 根（P = 0.024）。安全性方面，KX-826 的整体安全性良好可控。未发生严重不良事件（SAE）、不良药物反应（ADR）及死亡。此外，男性脱发美国 II 期临床试验以及女性中国 II 期临床试验均已达到主要研究终点。4.默沙东18.5亿美元收购公司所得，IL-2激动剂在中国申报临床11月27日，中国国家药监局药品审评中心（CDE）官网公示，默沙东（MSD）申报了1类新药MK-6194注射液的临床试验申请并获得受理。公开资料显示，MK-6194（PT101）是一款选择性IL-2激动剂。2021年2月，默沙东宣布以18.5亿美元收购Pandion Therapeutics公司，从而获得后者主要在研疗法，即PT101。公开资料显示，在自身免疫性疾病中，免疫系统会不恰当地攻击宿主细胞，而靶向调节性T细胞（Tregs）可以让免疫系统重新获得控制并恢复体内平衡。Tregs作为免疫系统内的一个控制节点，可以抑制多种不同促炎免疫细胞类型的活性。多个第三方临床试验表明，通过低剂量IL-2扩增Tregs，可以使自身免疫性疾病患者受益。MK-6194正是一种经过工程化改造的IL-2突变体，拟开发用于治疗自身免疫性疾病。它能够选择性与Tregs表面包含IL-2Ra亚基的IL-2受体三聚体结合，而不是与常规T细胞和自然杀伤细胞上的IL-2受体二聚体结合，从而特异性激活和扩增Tregs。该产品此前已经完成了一项1a期临床试验，表现出良好的安全性和耐受性，并且得到作用机制的概念验证。2021年2月，默沙东宣布通过子公司以总计约18.5亿美元的数额收购Pandion公司，后者是一家致力于开发治疗自身免疫性疾病创新疗法的生物技术公司，搭建了包含IL-2激动剂PT101以及多款PD-1激动剂在研疗法的管线。根据ClinicalTrials官网，默沙东目前正在海外开展MK-6194治疗中度至重度特应性皮炎患者的1期临床研究，以及治疗非节段性白癜风患者的2期临床研究。5.科伦博泰宣布新一代RET抑制剂KL590586获FDA孤儿药资格11月27日，科伦博泰发布新闻稿称，其海外合作伙伴Ellipses Pharma引进的RET小分子激酶抑制剂KL590586（EP0031，简称A400），获得了美国FDA授予的孤儿药资格，用于治疗RET融合阳性实体瘤。RET融合和突变存在于非小细胞肺癌、甲状腺髓样癌和其他类型甲状腺癌、以及结直肠癌等多种肿瘤中，因此，针对RET基因改变的治疗有望成为一种不限癌种的治疗方式。而针对RET基因改变的患者，传统化疗和免疫治疗效果有限，尤其使用第一代RET抑制剂治疗后产生耐药的患者，可接受的治疗选择有限，且预后较差，依然存在未能满足的临床需求。A400是新一代选择性RET抑制剂（SRI），对常见的RET基因融合和突变具有广泛活性，且具有克服第一代SRI耐药的潜力。在临床前研究中，A400在体外和体内对RET激酶表现出良好的抑制活性，在动物模型中也表现出良好的血脑屏障穿透性。目前，科伦博泰正在中国开展A400针对晚期RET阳性非小细胞肺癌的关键临床研究。2021年3月，科伦博泰将A400包括美国和欧洲在内的部分地区独家授权给Ellipses Pharma，科伦博泰保留大中华区、韩国、新加坡和马来西亚等部分亚太地区的权利。2022年6月，A400获得FDA批准的新药临床研究申请（IND），进行RET基因改变的恶性肿瘤患者的1/2期临床研究。科伦博泰在新闻稿中表示，获得孤儿药资格对于新药研发具有重要意义，本次A400获得FDA孤儿药资格，有望加快推进在美国的临床试验及上市注册的进度，同时，可享受一定的政策支持，包括但不限于临床试验费用的税收抵免、免除新药申请费等。6.石药集团高选择性SOS1抑制剂获批临床11月27日，石药集团发布公告称，该公司申报的1类新药高选择性SOS1抑制剂SYH2038获批临床，拟开发治疗晚期恶性肿瘤。公开资料显示，SOS1是间接抑制KRAS活性的主要靶点之一。KRAS作为一个非常重要的细胞信号通路开关，是目前所有癌症发生发展过程中突变率最高的基因之一。在细胞内，KRAS蛋白在失活和激活状态之间转变，当KRAS与鸟苷二磷酸（GDP）结合时，它处于失活状态，当它与鸟苷三磷酸（GTP）结合时，它处于激活状态，并且可以激活下游信号通路。KRAS在失活与激活状态之间的转换受到两类因子的调节。一类是鸟嘌呤核苷酸交换因子（GEF），这类蛋白催化KRAS与GTP的结合，从而促进KRAS的激活，其中包括SOS蛋白；另一类是GTP酶激活蛋白（p120GAP），这类蛋白能够促进与KRAS结合的GTP水解成为GDP，从而抑制KRAS的活性。研究显示，SOS1抑制剂可阻断鸟嘌呤核苷酸交换因子（GEF）SOS1蛋白与处于失活状态的KRAS结合，防止三磷酸鸟苷（GTP）替换二磷酸鸟苷（GDP），从而抑制KRAS的活性。根据石药集团公告，SYH2038正是一种高选择性SOS1抑制剂，通过抑制KRAS蛋白与SOS1蛋白相互作用，抑制肿瘤细胞的恶性进程。目前全球尚无同类产品上市。临床前研究显示，该产品对药效靶点选择性高，具有良好的体内外活性和良好的安全性，极具临床开发价值。7.复宏汉霖PD-L1靶向ADC在美国获批临床11月27日，复宏汉霖宣布，基于与宜联生物的合作，该公司开发的靶向PD-L1的抗体偶联药物（ADC）注射用HLX43的新药临床试验（IND）申请已经获得美国FDA许可，拟用于晚期/转移性实体瘤的治疗。与此同时，HLX43用于晚期/转移性实体瘤治疗的1期临床研究已于近期在中国完成首例受试者给药。HLX43一款靶向PD-L1的新型ADC候选药物，由高度特异性的全人lgG1 PD-L1抗体分子、可裂解的新型连接子-荷载毒素偶联制备而成，其药物抗体比（DAR）约为8。HLX43的荷载毒素为一种新型DNA拓扑异构酶I（Topoisomerase I）小分子抑制剂，通过造成DNA双链断裂，阻断DNA复制，从而导致肿瘤细胞凋亡。静脉输注后，HLX43的连接子-毒素能够在肿瘤微环境中特异性裂解释放，具备较强的旁观者杀伤效应，独特的作用机制使得HLX43具有更大的治疗窗口，增强ADC在实体肿瘤中的治疗效果。由于兼具抗体分子的高度靶向性和细胞毒素的强大杀伤力，HLX43已经在临床前研究、药代动力学研究及安全性评价中展现出良好的抗肿瘤活性和安全性。在抗PD-1单抗耐药的非小细胞肺癌、结直肠癌、三阴性乳腺癌、鳞状细胞癌等肿瘤模型中，HLX43显示出良好的肿瘤杀伤效果。值得一提的是，HLX43及HLX42（EGFR靶向ADC）的临床前研究数据同步入选了2023欧洲肿瘤内科学会（ESMO）大会，以壁报形式进行展示。复宏汉霖新闻稿表示，作为该公司首批进入临床阶段的ADC产品之一，HLX43致力于解决PD-1/L1免疫疗法不响应或耐药问题，填补更多晚期/转移性实体瘤患者未满足的临床需求。8.针对系统性红斑狼疮！亘喜生物FasTCAR-T疗法在美国获批临床11月27日，亘喜生物宣布其CD19/BCMA双靶点自体FasTCAR-T细胞疗法GC012F的又一项新药临床试验（IND）申请获得美国FDA批准，将在美国启动治疗难治性系统性红斑狼疮（rSLE）的1/2期临床试验。系统性红斑狼疮（SLE）是一种由B细胞介导的自身免疫性疾病，主要表现为免疫系统产生的自身抗体攻击患者自身组织，造成全身多脏器损伤。免疫抑制剂是当前的标准治疗手段，但效果欠佳，SLE仍然是一种难以控制的慢性疾病，严重影响患者生活质量，且无法治愈。因此，尤其是针对难治性SLE患者，业界亟待探索出更有效、乃至治愈性的疗法来改变临床用药窘境。GC012F是一款基于亘喜生物专有的FasTCAR次日生产平台开发的B细胞成熟抗原（BCMA）和CD19双靶点自体CAR-T候选产品。此前学术界展示的一些患者病历研究显示，将CD19 CAR-T细胞疗法应用于包括SLE在内的多种自身免疫性疾病在临床上具有可行性，相关数据也初步展示出了耐受性和不错的有效性。亘喜生物新闻稿表示，通过同时靶向CD19和BCMA双靶点，他们相信GC012F有望更深入、广泛地清除致病性B细胞及浆细胞，达到免疫重建，有潜力成为rSLE的一种疗效更强且更持久的治疗方案。此外，在临床前研究中，与CD19单靶点CAR-T疗法相比，GC012F展示出了更有效地清除抗体分泌细胞的能力。9.不一样的基因疗法——基因校正表皮获FDA优先审评资格11月28日，Abeona Therapeutics宣布，美国FDA已接受其在研疗法pz-cel（prademagene zamikeracel，EB-101）的生物制品许可申请（BLA），并授予优先审评资格，该疗法是一款自体、COL7A1基因校正表皮片，用于隐性营养不良性大疱性表皮松解症（RDEB）患者的治疗。美国FDA已设定该申请的PDUFA目标日期为2024年5月25日。该BLA申请主要获关键3期VIITAL研究以及另一项1/2a期研究的临床疗效和安全性数据支持。两项研究均显示，在大型和慢性伤口上单次应用pz-cel治疗可实现持续伤口愈合和疼痛减轻。分析显示，该疗法在VIITAL试验中达成两项主要终点，大多数（81%）pz-cel治疗的伤口显示出≥50%的愈合程度，并且与对照伤口相比，pz-cel治疗的伤口中观察到疼痛严重程度有更大程度的减轻。即使对于较早的时间点，与对照伤口相比，使用pz-cel治疗的伤口显示愈合的百分比（≥50%、≥75%和完全）和疼痛严重程度的降低也更大。该疗法安全且耐受性良好，未报告患者水平或伤口特异性严重的治疗相关不良反应（TEAE），仅报告了少量非严重pz-cel相关TEAE，与既往临床试验结果一致。Pz-cel是Abeona的在研自体COL7A1基因校正表皮片，目前正在开发用于治疗RDEB，这是一种罕见的结缔组织疾病，由COL7A1基因缺陷引起，导致无法产生VII型胶原。Pz-cel旨在将功能性、产生胶原的COL7A1基因整合到患者自身的皮肤细胞中，并通过使用逆转录病毒载体稳定整合到分裂的靶细胞基因组中，实现长期基因表达。10.首款！FDA批准突破性小分子癌症疗法，治疗硬纤维瘤患者11月28日，美国FDA宣布批准批准OgsiveoOgsiveo（nirogacestat）片剂用于需要全身治疗的进展性硬纤维瘤成人患者。根据FDA新闻稿，Ogsiveo是首个被批准用于治疗硬纤维瘤患者的药物，硬纤维瘤是一种罕见的软组织肉瘤亚型。此次Ogsiveo的获批是基于3期DeFi试验此前取得的积极结果。结果显示，DeFi试验达到了改善无进展生存期（PFS）的主要终点，Ogsiveo比安慰剂治疗有统计学上显著的改善，将疾病进展风险降低71%。基于RECIST v1.1的确认客观缓解率（完全缓解+部分缓解），Ogsiveo组为41%，安慰剂组为8%；Ogsiveo组的完全缓解率为7%，安慰剂组的完全缓解率为0%。此外，Ogsiveo在患者报告的结局（PROs）方面也显示出统计学意义和临床意义的改善。Ogsiveo在试验中还显示出可控的安全性，95%的治疗不良事件（TEAE）报告为1级或2级。试验中发生在至少15%患者的最常见副作用是腹泻、卵巢毒性、皮疹、恶心、疲乏、口腔炎、头痛、腹痛、咳嗽、脱发、上呼吸道感染和呼吸困难。Ogsiveo是一款口服特异性γ-分泌酶小分子抑制剂。γ-分泌酶能够切割多种跨膜蛋白复合体，其中包括Notch蛋白。而Notch蛋白被认为能够激活导致硬纤维瘤生长的信号通路。Ogsiveo曾获得美国FDA授予快速通道资格、突破性疗法认定与优先审评资格，用以治疗进行性、不可切除复发或难治性硬纤维瘤或深部纤维瘤病成人患者。除了针对成人硬纤维瘤，SpringWorks公司还正在开发Ogsiveo作为卵巢颗粒细胞肿瘤患者和多发性骨髓瘤患者的潜在治疗方法，作为几种B细胞成熟抗原（BCMA）联合治疗方案的一部分。11.PFS显著优于标准疗法，BCMA抗体偶联药物3期临床结果积极11月28日，GSK宣布了3期临床试验DREAMM-7计划中的中期疗效分析的积极顶线结果。结果显示，抗体偶联药物belantamab mafodotin作为2线疗法，治疗复发或难治性多发性骨髓瘤达到了无进展生存期（PFS）的主要终点。Belantamab mafodotin与硼替佐米加地塞米松（BorDex）联合使用，与目前用于该病的标准治疗方案相比，显著延长了无疾病进展或死亡的时间。此外，在此次分析时观察到了显著且临床意义重大的总生存期（OS）趋势，该试验仍在进行，以进一步监测OS结果。在DREAMM-7试验中，494名参与者以1:1的比例随机分配接受belantamab mafodotin与BorDex联合治疗或daratumumab与BorDex的联合治疗。所有参与者都接受过至少一线多发性骨髓瘤治疗，并在最近的治疗期间或之后显示出疾病进展。试验的主要终点是由独立审查委员会确定的无进展生存期。关键的次要终点包括总生存期、缓解持续时间等。Belantamab mafodotin是一种抗体偶联药物，由靶向B细胞成熟抗原（BCMA）的单克隆抗体与毒性载荷auristatin F通过不可切断的连接子连接而成。Belantamab mafodotin方案的安全性和耐受性与组合疗法中药物已知的安全性概况一致。这些中期分析结果将在即将召开的科学会议上展示，并与监管机构共享。12.金赛药业2款创新药获NMPA临床批准11月28日，长春高新发布公告称，其控股子公司金赛药业两款创新药均收到了中国国家药品监督管理局（NMPA）的《药物临床试验批准通知书》，分别是NK3R小分子拮抗剂GS1-144片和重组人促卵泡激素-CTP融合蛋白注射液。其中，GS1-144片是金赛药业自主研发NK3R小分子拮抗剂，为化药1类创新药。该产品本次获批就绝经期血管舒缩症适应症开展临床试验。血管舒缩症状（VMS）以潮热、夜间盗汗为特征，是典型的妇女停经后症状。神经激肽3受体（NK3R）参与大脑调节体温的机制。研究显示，针对NK3R的拮抗剂可以阻断神经激肽B（NKB）的信号通路，调控下视丘温度调节中心的神经活动，进而降低中重度停经血管舒缩症状的频率与严重程度。据长春高新公告介绍，目前中国尚无NK3R靶点药物上市，GS1-144作为绝经期血管舒缩症的非激素口服疗法，有望为患者提供更好的治疗选择。本次金赛药业另一款获批临床的产品为重组人促卵泡激素-CTP融合蛋白注射液，其获批开展临床试验针对适应症包括：1）与人绒毛膜促腺性激素（hCG）联用，用于治疗符合特发性低促性腺激素性性腺功能减退症（IHH）诊断，有意愿进行生精治疗的中国成年男性患者；2）与hCG联用，用于治疗14~18岁（不包括18岁）患有IHH的青少年男性。男性IHH属于生殖发育领域的罕见病，患有该疾病会影响患者生育功能和患者生活质量，患者需要长达1~2年甚至终身的激素补充治疗。据长春高新公告介绍，重组人促卵泡激素-CTP融合蛋白注射液属于长效周制剂，也是治疗IHH的长效重组促性腺激素制剂，针对该产品的研究将为IHH患者提供更好的治疗方案。13.药捷安康不可逆FGFR抑制剂最新研究结果入选ESMO Asia11月28日，药捷安康发布新闻稿称，该公司在研FGFR1/2/3抑制剂TT-00434针对晚期实体瘤的1期试验初步结果，将在2023年欧洲肿瘤内科学会亚洲年会（ESMO Asia）上壁报展示。FGFR是成纤维细胞生长因子酪氨酸激酶受体家族，在调节细胞增殖和细胞存活方面起着关键作用。FGFR基因异常出现在多种癌症中，包括肝内胆管细胞癌、尿路上皮（膀胱）癌、乳腺癌、胃癌和肺癌等等。在这些癌症中，约有5％~30％的患者携带FGFR基因变异。选择性地结合并抑制FGFR的泛FGFR抑制剂可以阻断FGFR相关信号通路，从而控制肿瘤细胞增殖和死亡。TT-00434是一款高活性、高选择性的不可逆FGFR1/2/3小分子抑制剂，拟用于携带FGFR基因变异的胃癌及其他实体瘤的治疗。目前，该产品已在中国台湾地区完成1期试验，初步结果显示其针对子宫内膜癌、膀胱癌、FGFR变异的胆管癌等晚期实体瘤疗效积极，并且具有良好的安全性和耐受性。临床前数据显示，TT-00434具有与其它小分子靶向药或化疗药联用的巨大潜力。此次TT-00434即将展示的1期临床试验是一项开放标签、剂量递增、多中心研究，入组患者均为已接受过所有可及标准治疗的晚期实体瘤患者。该试验目标包括确定临床2期推荐剂量（RP2D），探索该产品药代动力学（PK）、药效动力学（PD）、初步抗肿瘤活性和安全性。研究结果显示，TT-00434疗效积极，1例携带FGFR基因变异的胆管癌患者在接受80mg TT-00434治疗后，获得肿瘤部分缓解（PR）。该患者的治疗时间超过了203天，且仍在治疗中。试验观察到2例患者获得疾病稳定（SD），其中子宫内膜癌和膀胱癌患者各有1例。14.JAMA主刊发表！君实生物公布特瑞普利单抗3期临床结果11月28日，君实生物宣布，由中山大学肿瘤防治中心徐瑞华教授牵头开展的JUPITER-02研究的预设总生存分析结果（3年生存随访）获得全球权威期刊《美国医学会杂志》（JAMA）发表。本文的共同通讯作者是中山大学肿瘤防治中心徐瑞华教授和麦海强教授，共同第一作者是该院的麦海强教授和陈秋燕教授。基于该研究，特瑞普利单抗于今年10月获得美国FDA批准上市，用于鼻咽癌治疗。鼻咽癌（NPC）是中国尤其是南方地区常见的恶性肿瘤之一，病例约占全球一半。虽然以放化疗为主的综合治疗显著改善了鼻咽癌患者的生存获益，但仍有部分患者疾病复发或转移（RM）。据统计，5%-10%的初诊患者以及15%-30%的经治NPC患者会出现远处转移，且一旦出现转移，预后往往较差。含铂双药化疗是RM-NPC既往常用治疗手段，但其疗效并不理想。对于一线接受吉西他滨+顺铂（GP化疗）治疗的RM-NPC患者，其中位无进展生存期（mPFS）为7.0个月，中位OS为22.1个月。因此，临床迫切需要新的一线治疗策略来进一步改善RM-NPC患者的预后。目前，以特瑞普利单抗为代表的PD-1抑制剂联合化疗已逐步在全球层面取代单纯化疗，成为RM-NPC一线治疗的新标准治疗方案。JUPITER-02研究结果表明，与单纯化疗相比，特瑞普利单抗联合GP化疗一线治疗RM-NPC可获得显著更优的OS、PFS和客观缓解率（ORR），且安全性良好可控。15.潜在首款！默沙东疫苗3期STRIDE-3试验积极结果公布11月28日，默沙东（MSD）宣布3期试验STRIDE-3的积极结果。该试验在既往未接种肺炎球菌疫苗的成人中，评估其在研21价肺炎球菌结合疫苗V116与活性对照疫苗相比的免疫原性、耐受性和安全性。根据新闻稿，默沙东将向全球监管单位递送该试验结果，若获批，V116将成为首个专门为成人设计的肺炎球菌结合疫苗。STRIDE-3试验的详细结果将在即将举行的世界疫苗大会（World Vaccine Congress West Coast）中公布。该试验主要终点的分析显示，根据第30天血清型特异性调理吞噬活性（OPA）几何平均滴度（GMTs）的测量结果，在50岁及以上成人（队列1）中，V116与活性对照疫苗PCV20（肺炎球菌20价结合疫苗）共有的所有10种血清型中，V116引起的免疫应答呈现非劣效性。根据第30天OPA GMT的测定结果以及从第1天至第30天OPA升高≥4倍的患者比例，V116中包含的其中11种血清型中有10种展现良好的免疫应答，活性对照疫苗不包含这11种血清型。此外，根据接种后30天血清型特异性OPA GMTs的评估，与50-64岁的成人相比，18-49岁的成人（队列2）中V116引起的免疫应答展现非劣效性。在两个队列中，V116的安全性特征与活性对照组相当。V116是一种在研21价肺炎球菌结合疫苗。V116专门设计用于解决主要导致成人肺炎球菌疾病的肺炎链球菌血清型，包括8种独特的血清型：15A、15C、16F、23A、23B、24F、31和35B。根据2018-2021的美国疾病控制中心（CDC）数据，这些血清型约占成人疾病的30%。根据相同的CDC数据，V116涵盖的血清型占了约83%的65岁及以上患有侵袭性肺炎球菌疾病患者。16.药明巨诺CAR-T产品瑞基奥仑赛注射液新适应症拟纳入优先审评11月28日，中国国家药监局药品审评中心（CDE）官网公示，药明巨诺CAR-T产品瑞基奥仑赛注射液一项新适应症拟纳入优先审评，拟用于治疗成人复发或难治性套细胞淋巴瘤。瑞基奥仑赛注射液是一款靶向CD19的自体CAR-T细胞免疫治疗产品。作为药明巨诺的首款产品，瑞基奥仑赛注射液已被中国国家药品监督管理局（NMPA）批准两项适应症，包括治疗经过二线或以上系统性治疗后成人患者的复发或难治性大B细胞淋巴瘤（r/r LBCL），以及治疗经过二线或以上系统性治疗的成人难治性或24个月内复发的滤泡性淋巴瘤（r/r FL）。此次瑞基奥仑赛注射液拟纳入优先审评，针对适应症为复发/难治性套细胞淋巴瘤（r/r MCL）。套细胞淋巴瘤（MCL）是一种罕见的血液肿瘤，属于非霍奇金淋巴瘤（NHL）的一种。该病经常源自于位于淋巴结外缘外套层（mantle zone）的B细胞。随着癌症的进展，这些癌细胞可能扩散至骨髓、脾脏、肝脏或消化道。2022年12月，药明巨诺已在第64届美国血液学会（ASH）年会上公布了瑞基奥仑赛注射液针对r/r MCL的2期临床数据。这项单臂开放研究旨在中国成人r/r MCL患者中评估瑞基奥仑赛的初步安全性和有效性。该研究纳入了接受了至少2线治疗（靶向CD20抗体、蒽环类或苯达莫司汀、BTK抑制剂）的MCL患者。患者在清淋化疗后接受了100×106 CAR-T细胞。截至2021年11月30日，11例患者的初步数据显示，瑞基奥仑赛在r/r MCL高危患者中的临床疗效良好，最佳客观缓解率（ORR）为81.8%，最佳完全缓解率（CRR）为54.5%；安全性方面，≥3级的细胞因子释放综合征（CRS）和免疫效应细胞相关神经毒性综合征（ICANS）的发生率较低。17.“合成致死”靶点！正大天晴ATR激酶抑制剂获批临床11月28日，正大天晴宣布，该公司自主研发的1类创新药ATR激酶抑制剂TQB3015片已经获中国国家药监局药品审评中心（CDE）批准开展药物临床试验，拟用于治疗晚期恶性肿瘤。近年来，我国的癌症总体5年存活率有了一定程度的改善，但对于难治性肿瘤，如晚期胃癌、胰腺癌等，以及铂类、PARP抑制剂或免疫检查点抑制剂耐药等患者目前仍然缺乏有效的治疗手段，亟需开发新型抗肿瘤药物，以满足临床需求。ATR全称为共济失调毛细血管扩张突变Rad3相关蛋白，是DNA损伤修复的关键酶之一。ATR激活后可通过多种信号调控，从而产生细胞周期阻滞、促进脱氧核苷酸合成、启动复制叉以及修复DNA双链断裂等作用。靶向抑制ATR可阻断肿瘤细胞的DNA损伤应答，高效杀死肿瘤细胞。此外，ATR是ATM突变的“合成致死”靶点。在临床研究中，ATR抑制剂在ATM突变肿瘤中已显示了概念性验证疗效数据。ATR已被业界认为是继PARP后最有希望的合成致死靶点之一。根据正大天晴新闻稿，TQB3015是以ATR激酶作为靶点的小分子抑制剂，通过抑制细胞周期检测点激酶CHK1的磷酸化，触发细胞周期阻滞，并抑制由ATR激酶介导的修复通路，从而阻断肿瘤细胞的DNA损伤应答，达到“合成致死”的效果，高效杀死肿瘤细胞。临床前研究显示，TQB3015片具有良好的抗肿瘤活性和安全性。同时，针对常见的化疗、放疗和免疫治疗，TQB3015片具有良好的联用潜力，有望在临床上为恶性肿瘤患者带来更多的治疗选择。18.治疗失眠障碍，京新药业1类新药地达西尼胶囊获批上市11月29日，药监局官网显示，京新药业1类创新药地达西尼胶囊上市。该药适用于失眠障碍患者的短期治疗。地达西尼胶囊（EVT201胶囊）是治疗失眠障碍的1类小分子新药，属于新型GABAa受体部分正向别构调节剂（Partial positive allosteric modulator, pPAM），通过与α1-亚型结合导致GABAa受体的变构调节而中度激活该受体并导致下游信号转导，从而抑制中枢神经系统，发生睡眠作用。与GABAa受体的完全激活剂相比，EVT201胶囊对GABAa受体产生了较低的最大激活效价强度（Maximal activation potency），这种作用机制使EVT201胶囊既能对GABAa受体产生激活作用，而对神经系统发生迅速抑制，又能避免对GABAa受体过度激活而产生深度抑制引发神经副作用。此外，与传统GABA受体完全激动剂相比，EVT201胶囊在运动障碍、后遗效应、耐受性、乙醇相互作用、身体依赖性、记忆力损伤等不良反应方面，具有明显的优势。EVT201最初由德国Evotec公司开发，2010年10月，两家公司签署合作协议，京新药业获得EVT201在中国区域的独家专利许可和开发权。2021年11月，京新药业完成该药品的III期JX202001-EVT201-III研究，研究结果显示达到主要终点和次要终点。JX202001-EVT201-III研究是一项评价EVT201胶囊对比安慰剂在失眠障碍患者中疗效和安全性的多中心、随机、双盲III期临床试验。基于统计分析模型，以第13/14晚PSG监测的平均TST值为反应变量，基线TST、年龄为协变量，组别为自变量计算，EVT201胶囊组相对于安慰剂组的优效性成立，EVT201胶囊可快速起效、提高睡眠效率，同时改善次日嗜睡等残留效应。19.济民可信KRAS抑制剂拟纳入突破性治疗品种11月29日，中国国家药监局药品审评中心（CDE）官网公示，济民可信全资子公司杭煜制药申请的JMKX001899（又称JMKX1899）片拟纳入突破性治疗品种，拟用于治疗至少接受过一种系统性治疗的KRAS G12C突变的晚期或转移性非小细胞肺癌患者。公开资料显示，JMKX1899是济民可信旗下子公司上海济煜小分子创新中心自主研发的一款KRAS抑制剂。RAS基因突变是人类癌症中最常见的激活突变之一，其发生约在30%的人类肿瘤中。KRAS是RAS蛋白家族中最常见的亚型，该特定突变已被确定为多种实体瘤的致癌驱动因素，如胰腺癌、子宫内膜癌、结肠癌、膀胱癌、卵巢癌和小细胞肺肿瘤等。JMKX1899是一款KRAS抑制剂，它通过与KRAS（G12C）特异地、不可逆的结合，阻止GDP转化为GTP，维持在失活状态，从而抑制下游通路的激活，抑制胞外调节蛋白激酶（ERK）磷酸化，阻止肿瘤细胞的增殖和生长，促进细胞凋亡。临床前研究数据显示，与同靶点产品相比，JMKX1899具有较强的脑通透性，且没有心脏毒性和药物-药物相互作用风险。体内外研究结果表明，JMKX1899抗肿瘤作用明确，在多个肿瘤模型中均表现出显著的抑瘤效果，可显著抑制肿瘤细胞生长，且量效关系明显。此外，该产品给药后快速分布至靶器官，安全性好，治疗窗宽。20.艾伯维公布潜在首创c-Met ADC治疗NSCLC II期数据11月29日，艾伯维公布了其c-Met靶向的潜在首创ADC药物telisotuzumab-vedotin（Teliso-V）治疗c-Met蛋白过表达、表皮生长因子受体（EGFR）野生型、晚期/转移性非鳞状非小细胞肺癌（NSCLC）患者的单臂II期LUMINOSITY研究的初步结果。结果显示，根据独立中央审查，c-Met高表达和c-Met中等表达患者的总体缓解率分别为35%和23%。此外，其他终点也显示了有意义的临床结果，c-Met高表达和c-Met中等表达患者的中位缓解持续时间分别为9个月和7.2个月，其中位总生存期分别为14.6个月和14.2个月。Teliso-V的安全性与之前的研究结果一致，没有发现新的安全性问题。Teliso-V单药治疗的不良反应一般都得到了很好的控制和耐受。LUMINOSITY研究的全部数据将在未来的医学会议上公布，艾伯维表示将与全球监管机构讨论支持加速审批的可能性。此外，艾伯维透露III期TeliMET NSCLC-01研究目前正在招募患者，该研究旨在评估Teliso-V作为一种单一疗法对既往接受过治疗的c-Met过度表达、EGFR野生型非鳞状NSCLC患者的治疗效果。Teliso-V是一款抗体偶联药物（ADC），该药物靶向c-Met，以微管蛋白抑制剂MMAE作为毒性有效载荷。该疗法在2022年1月获FDA突破性疗法认定，治疗非小细胞肺癌。21.精神分裂症新药KarXT在美申报上市，再鼎医药拥有中国权益11月29日，再鼎医药与其合作伙伴Karuna Therapeutics共同宣布FDA已受理KarXT（xanomeline trospium）的新药上市申请，用于治疗成人精神分裂症。该申请的PDUFA日期为2024年9月26日。如获得批准，KarXT将成为数十年来第一个具有新的药理机制，治疗精神分裂症的方法。KarXT是一种在研的毒蕈碱类抗精神病药物，用于治疗与阿尔茨海默症相关的精神分裂症和精神疾病。通过新的作用机制，KarXT在中枢神经系统中充当M1/M4毒蕈碱乙酰胆碱受体激动剂，被认为可以改善精神分裂症的阳性、阴性和认知症状。与现有疗法不同，KarXT不会直接阻断多巴胺受体，提供了一个治疗精神分裂症的潜在新方法。新药上市申请的递交获得了评估KarXT用于治疗精神分裂症的EMERGENT研究的有效性和长期安全性数据的支持，EMERGENT系列研究包括三项已完成的、对比安慰剂的EMERGENT-1、EMERGENT-2和EMERGENT-3研究，这三项研究均取得阳性的有效性和安全性结果，以及评估KarXT长期安全性的EMERGENT-4和EMERGENT-5研究。所有三项安慰剂对照研究中，KarXT都达到了主要终点，阳性和阴性综合征量表（PANSS）总分上与安慰剂相比，精神分裂症症状有统计学意义和临床意义的改善。KarXT通常耐受性良好，最常见的不良事件为轻至中度胆碱能不良事件。值得注意的是，KarXT与现有抗精神病药物的常见副作用（包括体重增加、嗜睡和运动障碍）无关。22.亚虹医药膀胱癌诊断和管理药物APL-1706申报上市11月29日，亚虹医药宣布其用于膀胱癌诊断和管理的药物APL-1706（通用名：灌注用盐酸氨酮戊酸己酯）的新药上市申请（NDA）已获得中国国家药品监督管理局（NMPA）受理。APL-1706此前已在海外获批，为辅助膀胱癌诊断和管理的显影剂类药物，其联合使用蓝光膀胱镜作为非肌层浸润性膀胱癌（NMIBC）管理的方法已被纳入全球专家共识指南及《中国泌尿外科和男科疾病诊断治疗指南》。公开资料显示，APL-1706是一款新一代荧光显影剂类药物，其活性成分为5-氨基酮戊酸己酯（HAL）。由于其可以被肿瘤组织高度选择性吸收，通过与蓝光膀胱镜的联合使用可以提高NMIBC的检出率，使切除手术更完全，以降低肿瘤复发率。2021年1月，亚虹医药从Photocure公司引进了APL-1706在中国大陆及台湾地区的独家注册及商业化权利。亚虹医药在今年10月举行的国际泌尿外科学会年会（SIU）上以口头报告形式首次发布了APL-1706的3期临床试验数据，且该临床结果入选Late-Breaking Abstract（LBA）。该研究证实了在中国患者中，APL-1706联合蓝光膀胱镜（BLC）在膀胱癌检测方面优于白光膀胱镜（WLC），尤其是原位癌的检出，并且其耐受性良好。23.神州细胞抗PD-1单抗菲诺利单抗上市申请获受理11月30日，神州细胞发布新闻稿称，其控股子公司神州细胞工程收到中国国家药品监督管理局（NMPA）下发的关于公司在研产品菲诺利单抗注射液（产品代号：SCT-I10A）境内生产药品注册上市许可申请的《受理通知书》。SCT-I10A产品为该公司自主研发的重组人源化抗PD-1 IgG4型单克隆抗体注射液，本次申报的适应症为头颈部鳞状细胞癌。头颈部鳞状细胞癌（HNSCC）是全球常见癌症，该病侵袭性强，遗传背景复杂并且难于治疗，HNSCC通常与高度心理压力和生活质量降低相关。复发/难治性HNSCC患者预后较差，在接受一线铂类标准治疗失败后，目前二线标准治疗的中位生存期仅为8个月左右，临床需求亟待满足。菲诺利单抗为抗PD-1的功能性单克隆抗体，可通过阻断PD-1与其配体的结合，增加肿瘤部位的T细胞和炎性细胞因子供给量，减少肿瘤微环境中的调节性T细胞和髓系来源的抑制细胞的比例，改变肿瘤微环境，恢复和提高T细胞的免疫杀伤功能，从而抑制肿瘤的生长。神州细胞在新闻稿中表示，该公司拥有完善的生物药生产技术平台，已在商业化规模的生产线成功完成SCT-I10A的试生产。公开资料显示，菲诺利单抗拟用于治疗多种实体瘤，包括淋巴瘤、头颈鳞癌、食管鳞癌、结直肠癌、胃腺癌和鳞状非小细胞肺癌等。根据中国药物临床试验登记与信息公示平台，该产品已开展多项临床试验，其中包括一线治疗复发性和/或转移性头颈部鳞状细胞癌的3期临床研究、一线治疗晚期肝细胞癌的2/3期试验、二线治疗晚期肺鳞癌的3期临床研究等。24.罗氏“first-in-class”双抗疗法mosunetuzumab在中国拟纳入优先审评！11月30日，中国国家药监局药品审评中心（CDE）官网公示，罗氏（Roche）申报的mosunetuzumab（RO7030816）拟纳入优先审评，适用于治疗既往接受过至少两种系统性治疗的复发或难治性滤泡性淋巴瘤（FL）成人患者。公开资料显示，这是罗氏的“first-in-class”双特异性抗体疗法Lunsumio，此前已经在欧盟和美国获批用于治疗经过两种或多种前期系统治疗后复发或难治FL成年患者。该产品是一款CD20/CD3 T细胞衔接双特异性抗体，代表着一种无化疗、现货型（off-the-shelf）新免疫治疗选择。mosunetuzumab是一款靶向B细胞表面的CD20抗原和T细胞表面的CD3受体的T细胞衔接双特异性抗体。它可以引导患者体内的T细胞迁移到目标B细胞附近，并且释放细胞毒性的蛋白消灭B细胞。Mosunetuzumab以静脉输注的形式给药，持续时间固定，允许休息治疗，也可以在门诊输液。此前，该药还曾获FDA授予突破性疗法认定和孤儿药资格。Mosunetuzumab已经在一项2期GO29781研究中取得积极结果，该试验结果显示出该产品对于复发或难治滤泡性淋巴瘤患者具有较高且持久的应答率。在接受mosunetuzumab治疗的患者中，80%的患者出现了客观反应（包括完全反应和部分反应），大多数患者至少18个月内保持了反应（57%）。应答者的中位应答持续时间接近2年。据GO29781研究研究者Elizabeth Budde博士早先曾在新闻稿中表示，这一批准对复发或难治性滤泡性淋巴瘤患者来说是一个重要的里程碑，mosunetuzumab的高应答率和固定持续时间可能会改变晚期滤泡性淋巴瘤的治疗方式。25.预防破伤风！泰诺麦博抗体新药TNM002拟纳入优先审评11月30日，中国国家药监局药品审评中心（CDE）官网公示，泰诺麦博申请的TNM002注射液拟被纳入优先审评，针对的适应症为：作为被动免疫制剂，用于成人破伤风紧急预防。公开资料显示，TNM002是一款重组抗破伤风毒素（TT）天然全人源单克隆抗体，此前已在中国被纳入突破性治疗品种，并被美国FDA授予快速通道资格。破伤风是由破伤风梭状芽孢杆菌通过皮肤或粘膜破口侵入人体后，在厌氧环境中繁殖并产生外毒素，侵袭神经系统的运动神经元而引起的以全身骨骼肌强直性收缩和阵发性痉挛为特征的急性感染性、中毒性疾病。目前，临床上用来预防和治疗破伤风的被动免疫制剂包括“马破”（马破伤风免疫球蛋白）和“人破”。其中，“马破”是来源于马的血液制品，过敏反应率高达5%~30%，主要临床表现为过敏性休克和血清病，并且临床使用前需要先进行“皮试”。而“人破”虽然过敏反应发生率低，但存在传播艾滋病和乙肝等已知或者未知传染病的风险，同时血浆供应短缺等因素限制了“人破”的生产和临床应用。TNM002是泰诺麦博利用HitmAb技术平台开发的重组抗破伤风毒素全人源单克隆抗体，具有较高的中和破伤风毒素的能力。已有的临床数据结果显示，该产品安全性和耐受性良好，给药后能达到较高的破伤风抗体保护水平。TNM002注射液通过肌肉注射给药，用于破伤风的预防治疗，无需额外皮试。泰诺麦博曾在新闻稿表示，TNM002有望为临床提供更安全、高效、适合大规模生产、可及性更高的药物。26.恒瑞JAK1抑制剂艾玛昔替尼新适应症申报上市，治疗类风湿关节炎11月30日，CDE官网显示，恒瑞JAK1抑制剂艾玛昔替尼（SHR0302）新适应症的上市申请获得受理，推测本次申报上市的适应症为类风湿关节炎。类风湿关节炎是一种以侵蚀性、对称性多关节炎为主要临床表现的慢性、全身性自身免疫性疾病，确切发病机制不明，基本病理改变为关节滑膜的慢性炎症、血管翳形成，并逐渐出现关节软骨和骨破坏，最终导致关节畸形和功能丧失，早期诊断、早期治疗至关重要。SHR0302是恒瑞医药自主研发的高选择性的JAK1抑制剂，国家1类新药，是国内自主研发的具有一类知识产权的口服小分子创新药物，可通过抑制JAK1信号传导发挥抗炎和抑制免疫的生物学效应。SHR0302目前已开展了包括类风湿性关节炎、溃疡性结肠炎、特应性皮炎、斑秃、银屑病关节炎等多领域的临床研究。2021年1月，SHR0302被国家药监局授予了突破性疗法，用于治疗成人及12岁以上青少年的中重度特应性皮炎，恒瑞已于今年6月递交了该适应症的上市申请。今年8月，SHR0302用于活动性强直性脊柱炎的新适应症上市申请也已获受理。2018年1月，恒瑞医药就SHR0302与美国Arcutis公司达成了合作协议，按照协议的内容，Arcutis获得SHR0302项目在美国、欧盟和日本的独家临床开发、注册和市场销售的权利，研发和销售的SHR0302的许可剂型范围为用于皮肤疾病治疗的局部外用制剂；恒瑞医药最多可获得共2.23亿美元的首付款和里程碑款，外加销售提成。27.Cybin重度抑郁症新药CYB003 II期研究积极11月30日，Cybin宣布旗下专有的一款氘代裸盖菇素类似物CYB003治疗重度抑郁症（MDD）的II期临床试验取得积极结果，2次12mg剂量治疗后79%患者病情缓解。据Cybin官网介绍，CYB003使用同位素氘取代了氢原子，可以更好地结合5-HT受体，减少代谢变异性，使得药物更安全且有效，目前正在开展用于治疗重度抑郁症的临床研究。II期研究结果显示，CYB003达到了由蒙哥马利抑郁评定量表（MADRS）评估的主要疗效终点，即与安慰剂相比，CYB003（12mg）治疗3周后MADRS评分较基线下降了14分（p=0.0005）；第6周时，79%患者服用两剂12mg CYB003后抑郁症状缓解并且MADRS评分逐渐降低。具体而言，单剂量CYB003治疗后可观察到患者抑郁症状快速大幅改善：MADRS平均得分为13.75分（12mg和16mg组），3周时与安慰剂相比具有显著性差异（p<0.0001）（CYB003组 n=24；安慰剂组 n=10）。第二剂CYB003治疗后益处增加明显：6周时，第二剂CYB003（12mg）的MADRS总分进一步提高5.8分，79%的患者抑郁症得到缓解（CYB003组 n=22；安慰剂组 n=10）。此外，12mg和16mg剂量组均具有良好的安全性和耐受性，未出现治疗相关的严重不良事件。该公司表示，与已批准的抗抑郁药和最近报告的其他药物数据相比，CYB003改善抑郁症状的幅度要好得多，同时本次临床试验数据支持其进入III期研究。28.Altimmune减肥新药pemvidutide II期研究成功，48周体重减轻15.6%！11月30日，Altimmune宣布在研胰高血糖素样肽-1受体（GLP-1R）/胰高血糖素受体（GCGR）双激动剂pemvidutide用于治疗肥胖的为期48周的II期MOMENTUM研究取得积极结果，第48周时患者使用2.4mg剂量治疗后平均体重减轻15.6%，治疗结束时体重减轻仍在继续。受此消息影响，Altimmune股价大涨34%。Pemvidutide是一种GLP-1R/GCGR双重激动剂，其结合了GLP-1受体激动剂减少热量摄入的作用和胰高血糖素受体激动剂增加肝脏能量消耗和脂肪代谢的作用。Pemvidutide包含EuPort结构域，这是一项专有技术，可延长每周给药的血清半衰期，减慢 pemvidutide进入血液的速度，这可能会提高其耐受性。II期MOMENTUM研究招募了391名患有肥胖或超重，且至少有一种合并症且无糖尿病的受试者。受试者按照1:1:1随机分配，分别接受pemvidutide 1.2mg、1.8mg、2.4mg或安慰剂治疗，每周用药1次，共48周，同时辅以饮食和运动。受试者平均年龄约为50岁，基线时平均体重指数（BMI）约为37kg/m2，平均体重约为104kg，此大约75%的受试者是女性。结果显示，在第48周，1.2mg、1.8mg和2.4mg pemvidutide剂量组以及安慰剂组患者的平均体重减轻分别为10.3%、11.2%、15.6%和2.2%。此外，在2.4mg剂量组，超过50%的受试者实现了至少15%的体重减轻，超过30%的受试者实现了至少20%的体重减轻。29.云顶新耀etrasimod中重度活动性溃疡性结肠炎III期研究结果积极12月1日，云顶新耀宣布伊曲莫德（etrasimod）治疗中重度活动性溃疡性结肠炎（UC）的亚洲多中心III期临床研究诱导期取得积极结果。Etrasimod是一款口服选择性1-磷酸鞘氨醇（S1P）受体调节剂，采用优化的药理学设计，与S1P受体1、4和5结合，可用于治疗包括胃肠道和皮肤病在内的一系列免疫炎性疾病。今年10月，该产品已获FDA批准上市，用于治疗中度至重度活动性溃疡性结肠炎（UC）成人患者。到2030年，中国的溃疡性结肠炎患者人数预计将比2019年增加一倍以上，达到约100万人，这表明中国市场对于该疾病的创新疗法存在巨大未满足需求。Etrasimod由Arena Pharmaceuticals公司开发，辉瑞于2022年完成了对Arena的收购，云顶新耀于2017年从Arena获得了在大中华区和韩国开发、生产和商业化etrasimod的独家权利。云顶新耀本次公布的结果显示，诱导治疗期之后，etrasimod组在主要终点、所有关键次要终点以及其他次要终点（包括粘膜愈合、症状缓解和内镜改善）均达到了具有临床意义和统计学显著性的改善。此外，etrasimod 2mg治疗耐受性良好，未观察到新的安全性信号。云顶新耀是一家专注于创新药和疫苗开发、制造及商业化的生物制药公司，致力于满足亚洲市场尚未满足的医疗需求。30.通化东宝药业GLP-1类似物利拉鲁肽注射液上市申请已获批准12月1日，中国国家药品监督管理局（NMPA）官网最新公示，通化东宝药业以注册分类3.3类申报的GLP-1类似物利拉鲁肽注射液生物类似药的上市申请已获得批准。根据通化东宝药业公开资料，利拉鲁肽注射液为该公司糖尿病研发管线中以GLP-1受体为靶点的降糖药物。人胰高糖素样肽-1（GLP-1）是肠道细胞分泌的一种多肽类激素，它通过与GLP-1受体相结合，刺激胰岛素的分泌，并且抑制胰高血糖素的分泌，从而促进葡萄糖的代谢。同时，它还能够能起到延缓胃排空和抑制食欲的效果。天然的GLP-1在人们用餐之后，受到葡萄糖的刺激而分泌。而在2型糖尿病患者中，GLP-1的分泌水平显著下降，这也是导致患者血糖控制不佳的重要原因之一。利拉鲁肽原研药由诺和诺德（Novo Nordisk）公司开发。该药是一种GLP-1类似物，可激活人GLP-1受体，促进胰腺分泌胰岛素。利拉鲁肽原研药（商品名：诺和力）于2011年进入中国市场，被批准用于成人2型糖尿病患者控制血糖。另外，利拉鲁肽还有明显的减轻体重的作用。2014年，美国FDA已批准利拉鲁肽注射液用于超重和肥胖症成人长期体重管理。通化东宝药业开发的利拉鲁肽注射液于2018年获批临床。中国药物临床试验登记与信息公示平台显示，通化东宝药业已完成一项3期临床试验，该研究旨在比较利拉鲁肽注射液和诺和力在2型糖尿病患者中的疗效和安全性。根据通化东宝药业公告，该公司已于2021年10月获得3期临床试验的总结报告。31.再折戟！辉瑞终止推进小分子GLP-1R激动剂Danuglipron III期开发12月1日，辉瑞公布了口服小分子胰高血糖素样肽-1受体激动剂（GLP-1RA）Danuglipron（PF-06882961）用于成人肥胖（非2型糖尿病）患者的IIb期临床试验（NCT04707313）的数据。该研究达到了主要终点，患者体重较基线有统计学上的显著变化。不过辉瑞表示，不计划将这款每日口服两次的药物推进至III期临床阶段。Danuglipron的给药频率为每日两次（BID），结果显示，其所有剂量组患者体重均较基线有统计学意义上的显著减轻，在第32周时，Danuglipron组体重平均减少范围为-6.9%至-11.7%，而安慰剂组为+1.4%；在第26周时，Danuglipron组体重平均减少范围为-4.8%至-9.4%，而安慰剂组为+0.17%。经安慰剂调整后，Danuglipron组第32周平均体重下降幅度为-8%至-13%，第26周为-5%至-9.5%。根据滴定计划，参与者从第6至24周内处于目标剂量水平。与作用机制相关的胃肠道副反应发生率较高（恶心：73%；呕吐：47%；腹泻：25%）。所有剂量的停药率均高于50%，而安慰剂约为40%。没有新的安全性信号报道，与安慰剂相比，接受Danuglipron治疗与肝酶升高发生率增加无关。这项研究的数据将在未来的科学会议上发表，或发表在同行评议期刊上。不过辉瑞表示Danuglipron的未来开发将集中在每日一次的配方上，药代动力学数据预计将在2024年上半年公布。而Danuglipron每日两次的制剂将不会被推进至III期研究阶段。32.百济神州HPK1抑制剂获批临床12月1日，中国国家药监局药品审评中心（CDE）官网公示，百济神州申报的1类新药BGB-26808片获批临床，拟定适应症为单药治疗晚期实体瘤。根据百济神州公开资料，这是一款HPK1抑制剂，正在海外开展1期临床研究。HPK1又称MAP4K1，是MAP4K家族的成员之一，属于丝氨酸/苏氨酸激酶。HPK1对肿瘤免疫有抑制作用。在T细胞中，T细胞受体（TCR）信号通路活化导致胞质内的HPK1被招募到细胞膜，与接头蛋白SLP76结合并对其磷酸化，促进SLP76与E3连接酶14-3-3的结合，导致SLP76/LAT信号体的降解，进而对TCR通路进行负调节，抑制T细胞活化和效应T细胞功能。此外，HPK1也是B细胞和树突细胞活化的负调控因子，并对Treg细胞功能维持起重要作用。因此，HPK1是肿瘤免疫治疗和自身免疫疾病的潜在靶点。研究发现，HPK1与多种恶性肿瘤发生发展相关，如胰腺癌、乳腺癌、结直肠癌等。HPK1抑制剂可以单用或者与免疫检查点抑制剂（例如抗PD-1抗体）联用产生协同效应。根据百济神州2023年投资者研发日资料，HPK1靶点产品为该公司下一波免疫疗法项目产品，拟与抗PD-1单抗替雷利珠单抗联用并形成协同。根据ClinicalTrials官网，百济神州正在澳大利亚、新西兰开展一项1期开放标签、多中心、非随机剂量递增和剂量扩展研究，旨在评估BGB-26808单药治疗或与替雷利珠单抗联合治疗，在晚期实体瘤患者中的安全性、耐受性、药代动力学和初步抗肿瘤活性。合作动态1.BMS布局抗体寡核苷酸偶联物11月28日，Avidity Bioscience宣布与百时美施贵宝（BMS）达成许可和研究合作协议，以针对多个心血管疾病靶点发现、开发和商业化抗体寡核苷酸偶联物（AOC）药物，潜在交易总额高达23亿美元。Avidity的AOC技术平台旨在将单克隆抗体的特异性与寡核苷酸疗法的精确性相结合，以靶向以前用RNA疗法无法治疗的疾病的根本原因。根据协议条款，Avidity将获得1亿美元预付款，其中包括6000万美元的现金支付以及以7.88美元/股的价格购买约4000万美元的Avidity普通股。Avidity还有资格获得高达13.5亿美元的研发里程碑付款、高达8.25亿美元的商业里程碑付款以及高达低两位数的净销售额分级特许权使用费。BMS未来将资助此次合作触发的所有临床开发、监管和商业化活动。Avidity表示，此次与BMS的合作区分于其内部发现管线。目前，Avidity管线中共包括6款在研药物，其中3款罕见病药物的研发进展最快，即AOC 1001（用于治疗1型强直性肌营养不良症（DM1））、AOC 1020（用于治疗面肩肱肌营养不良症（FSHD））和AOC 1044（用于治疗携带外显子44跳跃突变的杜氏肌营养不良症（DMD））。早在2021年，BMS的子公司MyoKardia即与Avidity达成过研究合作协议，以证明AOC药物在心脏组织中的潜在疗效。此次与BMS达成的新协议扩大了双方在心血管疾病方面的研究合作，也证明了AOC技术平台的广泛实用性。2.礼来与PRISM合作开发蛋白-蛋白相互作用小分子抑制剂11月28日，礼来与PRISM BioLab达成许可和合作协议，以开发针对蛋白-蛋白相互作用（PPI）靶点的小分子抑制剂。根据协议，PRISM将利用其专有的PepMetics技术平台在礼来选择的PPI靶点中开发小分子抑制剂。礼来可以选择在合作中增加另外两个靶点，并负责由此产生的所有临床开发和商业化工作。PRISM将获得未指明金额的预付款，并有资格获得高达6.6亿美元的临床前、临床和商业开发里程碑付款，以及销售特许权使用费。PRISM是一家处于发现阶段的生物技术公司，利用专有的PepMetics® 技术开发靶向蛋白质-蛋白质相互作用 (PPI) 的口服小分子抑制剂，并改变患有癌症、自身免疫、纤维化和其他疾病的患者的生活。PepMetics® 开发一类独特的小分子，可模拟 α 螺旋和 β 转角的三维结构，这是细胞内 PPI 间期和受体-配体相互作用中常见的肽结构。PRISM的专有文库包括20,000多个分子，涵盖各种氨基酸序列进行筛选。根据PRISM的说法，该技术可以将以前无法成药的PPI转化为易于用小分子成药的靶点，同时还可以为生物制剂的注射版本开发口服版本。此前，PRISM也与罗氏、施维雅、卫材和Ohara Pharmaceutical达成了合作。3.超5亿美元！AI助力发现难治性癌症新靶点11月30日，Phenomic AI公司宣布，与勃林格殷格翰达成战略合作及许可协议，旨在发现在富含间质（stroma rich）的癌症中重要的靶点。该合作将利用Phenomic在靶标识别和间质生物学方面的专长，运用其scTx单细胞转录组学平台。这一合作将增强勃林格殷格翰开发潜在“first-in-class”药物的努力，改变癌症治疗。富含间质的癌症（如结直肠癌和胰腺癌）部分因为肿瘤间质的存在而难以治疗。这种复杂的组织不仅保护癌细胞免受现有疗法的影响，还促进癌症的生长和转移。Phenomic的创新平台旨在通过识别新的靶点，打破肿瘤间质的屏障，显著提高患者的生存期。Phenomic的独特scTx平台整合了庞大的人类组织单细胞RNA数据集以及一系列分析和验证工具。该平台利用先进的人工智能和机器学习算法分析包括成像、RNA测序和空间转录组学数据在内的多样化数据库，以解码复杂多细胞系统中单个细胞的复杂性。Phenomic的独特间质模型和实验能力使其能够通过数字筛选和实验验证的循环过程，识别新的治疗靶点。根据这项协议，勃林格殷格翰有权对Phenomic发现并验证的靶点进行开发，这些靶点可能成为新癌症治疗药物的基础。勃林格殷格翰还将负责所有非临床和临床开发，以及相关癌症疗法的商业化。Phenomic将收到约900万美元的前期和近期付款，包括研究资金和合作里程碑。此外，Phenomic还有资格获得超过5亿美元的临床、监管和商业里程碑付款。4.艾伯维101亿美元收购ImmunoGen！囊获”first-in-class”ADC！12月1日，艾伯维（AbbVie）与ImmunoGen宣布达成最终协议，艾伯维将以总额达约101亿美元收购ImmunoGen，获得其“first-in-class”抗体偶联药物（ADC）Elahere（mirvetuximab soravtansine）。ImmunoGen专注于开发抗肿瘤的下一代ADC，其管线包括用于多种不同实体瘤和血液恶性肿瘤治疗的潜在项目。其所开发的Elahere是一款叶酸受体α（FRα）靶向的ADC，该药物将与FRα结合的人源化单克隆抗体，与能够产生细胞毒性的DM4分子通过二硫键连接起来。当ADC与FRα结合之后，FRα能够将ADC转移到细胞内部，ADC携带的细胞毒性分子从而抑制肿瘤细胞的有丝分裂。2022年11月，美国FDA加速批准Elahere上市，作为单药疗法，治疗FRα高表达、对含铂疗法耐药的经治晚期卵巢癌患者。值得一提的是，2020年10月，华东医药以超3亿美元获得了该药在大中华区的独家开发和商业化权益。ImmunoGen的IMGN-151目前处于1期临床，是用于治疗卵巢癌的新一代FRα靶向ADC，具潜力扩展到其他实体瘤适应症。目前处于2期临床的pivekimab sunirine是一种靶向母细胞性浆细胞样树突状细胞肿瘤（BPDCN）的CD123靶向ADC，该药物被美国FDA授予突破性疗法认定，用于治疗复发/难治性BPDCN。根据协议，艾伯维以101亿美元收购ImmunoGen，并获得Elahere。根据新闻稿，ImmunoGen对Elahere的后期开发计划有望将该疗法扩展至卵巢癌早期治疗以及其他患者群体，艾伯维预计通过此交易加速其在卵巢癌治疗领域的发展。此外，ImmunoGen的新一代ADC管线亦补充艾伯维现有ADC平台与管线。体验智慧芽新药情报库更丰富完整功能请pc端点击打开或拷贝下方链接至浏览器打开：https://synapse-zhihuiya-com.libproxy1.nus.edu.sg/关于新药情报库由智慧芽生物医药团队于 2022 年初推出，凭借首创的“全球大数据AI实时挖掘+药学专家团队校验” 情报处理机制，新药情报库已建立全球范围内的实时数据更新体系，覆盖超过4.5万+个靶点，7.5万+种新药，88万+个机构，83万+个临床试验，6000万+篇精选文献以及1300万+份药物专利。智慧芽新药情报库致力于为生物医药行业全产业链提供全面、精准、实时且标准化的全生命周期数据服务；新药情报库能够满足用户在规划新药管线、设定公司战略方向、寻找新药研发机会、评估项目引进价值、选择投资标的、追踪竞品策略、开发新客户等方面的数据情报获取需求。版权声明本文内容均由智慧芽生物医药小编收集于公开网络平台，版权由智慧芽所有，未经智慧芽授权不得转载。已获授权的应在授权范围内使用，并注明来源，违反上述声明者，智慧芽将追究其相关法律责任。如您发现相关信息有任何版权侵扰或者信息错误，请及时联系我们进行删改处理。授权相关事宜请联系：phs@patsnap.com