MacroGenics, Inc.

WILMINGTON, Del.--(BUSINESS WIRE)--Incyte (Nasdaq:INCY) today reports 2025 first quarter financial results, and provides a status update on the Company’s clinical development portfolio. "The double-digit revenue growth in the first quarter driven by the continued growth of Jakafi and Opzelura and the recent launch of Niktimvo, puts us on track to achieve our full year objectives," said Hervé Hoppenot, Chief Executive Officer, Incyte. "We also continued to advance our innovative pipeline, which will be critical for driving long-term growth. The positive Phase 3 results for povorcitinib in hidradenitis suppurativa in addition to the proof-of-concept in chronic spontaneous urticaria, strengthens the potential of povorcitinib as a multibillion-dollar product addressing patient needs across the five indications currently in development.” Key Commercial Highlights Jakafi® (ruxolitinib): Net product revenues for the first quarter 2025 of $709 million (+24% Y/Y): Opzelura® (ruxolitinib) cream: Net product revenues for the first quarter 2025 of $119 million (+38% Y/Y): Pipeline Updates Myeloproliferative Neoplasms (MPNs) and Graft-Versus-Host Disease (GVHD) – key highlights MPN and GVHD Programs Indication and status Ruxolitinib XR (QD) (JAK1/JAK2) Myelofibrosis, polycythemia vera and GVHD Ruxolitinib + INCB57643 (JAK1/JAK2 + BETi) Myelofibrosis: Phase 2 Ruxolitinib + axatilimab1 (JAK1/JAK2 + anti-CSF-1R) Chronic GVHD: Phase 2 Steroids + axatilimab1 (Steroids + anti-CSF-1R) Chronic GVHD: Phase 3 INCA33989 (mutCALR) Myelofibrosis, essential thrombocythemia: Phase 1 INCB160058 (JAK2V617Fi) Myelofibrosis: Phase 1 1 Clinical development of axatilimab in GVHD conducted in collaboration with Syndax Pharmaceuticals. Other Hematology/Oncology – key highlights Heme/Oncology Programs Indication and status Tafasitamab (Monjuvi®/Minjuvi®) (CD19) Relapsed or refractory diffuse large B-cell lymphoma (DLBCL): Phase 3 (B-MIND) First-line DLBCL: Phase 3 (frontMIND) Relapsed or refractory follicular lymphoma (FL): Phase 3 (inMIND) Retifanlimab (Zynyz®)1 (PD-1) Squamous cell anal cancer (SCAC): Phase 3 (POD1UM-303) Non-small cell lung cancer (NSCLC): Phase 3 (POD1UM-304) MSI-high endometrial cancer: Phase 2 (POD1UM-101, POD1UM-204) INCB123667 (CDK2i) Solid tumors with CCNE1 amplification/Cyclin E overexpression: Phase 1 INCB161734 (KRASG12D) Advanced metastatic solid tumors with a KRASG12D mutation: Phase 1 INCA33890 (TGFßR2×PD-1)2 Advanced or metastatic solid tumors: Phase 1 1 Retifanlimab licensed from MacroGenics. 2 Development in collaboration with Merus. Inflammation and Autoimmunity (IAI) – key highlights Ruxolitinib Cream Povorcitinib (INCB54707) IAI and Dermatology Programs Indication and status Ruxolitinib cream (Opzelura)1 (JAK1/JAK2) Atopic dermatitis: Phase 3 pediatric study (TRuE-AD3) Hidradenitis suppurativa: Phase 2; Phase 3 expected to initiate in 2025 Prurigo nodularis: Phase 3 (TRuE-PN1, TRuE-PN2) Povorcitinib (JAK1) Hidradenitis suppurativa: Phase 3 (STOP-HS1, STOP-HS2) Vitiligo: Phase 3 (STOP-V1, STOP-V2) Prurigo nodularis: Phase 3 (STOP-PN1, STOP-PN2) Chronic spontaneous urticaria: Phase 2 Asthma: Phase 2 INCA034460 (anti-CD122) Vitiligo: Phase 1 1 Novartis’ rights to ruxolitinib outside of the United States under our Collaboration and License Agreement with Novartis do not include topical administration. Other - key highlights In February 2025, Incyte and Genesis Therapeutics, Inc. (Genesis) entered into a strategic collaboration focused on the research, discovery and development of novel small molecule medicines, with an initial focus on collaboration targets selected by Incyte. Incyte receives exclusive rights to develop and commercialize collaboration products leveraged through Genesis’ GEMS artificial intelligence (AI) platform. Other Program Indication and Phase Zilurgisertib (ALK2) Fibrodysplasia ossificans progressiva: Pivotal Phase 2 2025 First Quarter Financial Results The financial measures presented in this press release for the three months ended March 31, 2025 and 2024 have been prepared by the Company in accordance with U.S. Generally Accepted Accounting Principles (“GAAP”), unless otherwise identified as a Non-GAAP financial measure. Management believes that Non-GAAP information is useful for investors, when considered in conjunction with Incyte’s GAAP disclosures. Management uses such information internally and externally for establishing budgets, operating goals and financial planning purposes. These metrics are also used to manage the Company’s business and monitor performance. The Company adjusts, where appropriate, for expenses in order to reflect the Company’s core operations. The Company believes these adjustments are useful to investors by providing an enhanced understanding of the financial performance of the Company’s core operations. The metrics have been adopted to align the Company with disclosures provided by industry peers. Non-GAAP information is not prepared under a comprehensive set of accounting rules and should only be used in conjunction with and to supplement Incyte’s operating results as reported under GAAP. Non-GAAP measures may be defined and calculated differently by other companies in our industry. As changes in exchange rates are an important factor in understanding period-to-period comparisons, Management believes the presentation of certain revenue results on a constant currency basis in addition to reported results helps improve investors’ ability to understand its operating results and evaluate its performance in comparison to prior periods. Constant currency information compares results between periods as if exchange rates had remained constant period over period. The Company calculates constant currency by calculating current year results using prior year foreign currency exchange rates and generally refers to such amounts calculated on a constant currency basis as excluding the impact of foreign exchange or being on a constant currency basis. These results should be considered in addition to, not as a substitute for, results reported in accordance with GAAP. Results on a constant currency basis, as the Company presents them, may not be comparable to similarly titled measures used by other companies and are not measures of performance presented in accordance with GAAP. Financial Highlights Financial Highlights (unaudited, in thousands, except per share amounts) Three Months Ended March 31, 2025 2024 Total GAAP revenues $ 1,052,898 $ 880,889 Total GAAP operating income 205,168 91,898 Total Non-GAAP operating income 283,641 161,183 GAAP net income 158,203 169,548 Non-GAAP net income 229,459 132,719 GAAP basic EPS $ 0.82 $ 0.76 Non-GAAP basic EPS $ 1.18 $ 0.59 GAAP diluted EPS $ 0.80 $ 0.75 Non-GAAP diluted EPS $ 1.16 $ 0.58 Revenue Details Revenue Details (unaudited, in thousands) Three Months Ended March 31, % Change (as reported) % Change (constant currency)1 2025 2024 Net product revenues: Jakafi $ 709,412 $ 571,839 24 % NA Opzelura 118,705 85,724 38 % 39 % Iclusig 29,544 30,343 (3 %) — % Pemazyre 18,440 17,676 4 % 6 % Minjuvi/ Monjuvi 29,551 23,874 24 % 25 % Niktimvo 13,613 — NM NA Zynyz 3,009 467 544 % NA Total net product revenues 922,274 729,923 26 % 27 % Royalty revenues: Jakavi 92,145 89,595 3 % 6 % Olumiant 30,800 30,589 1 % 6 % Tabrecta 6,413 5,234 23 % NA Other 1,266 548 131 % NM Total royalty revenues 130,624 125,966 4 % Total net product and royalty revenues 1,052,898 855,889 23 % Milestone and contract revenues — 25,000 — % — % Total GAAP revenues $ 1,052,898 $ 880,889 20 % NM = not meaningful NA = not applicable 1 Percentage change in constant currency is calculated using 2024 foreign exchange rates to recalculate 2025 results. Product and Royalty Revenues Total net product and royalty revenues for the quarter ended March 31, 2025 increased 23% over the prior year comparative period. Total net product revenues for the quarter ended March 31, 2025 increased 26% over the prior year comparative period primarily driven by the following: Jakafi net product revenue increased 24% versus the prior year comparable period, driven by an increase in paid demand of 10% reflecting continued demand growth in all indications, the positive impact of the Part D redesign under the Inflation Reduction Act, partially offset by growth in 340B, and 7% favorable impact from less de-stocking compared to the first quarter of 2024. Jakafi inventory levels were within normal range at the end of the first quarter of 2025. Opzelura net product revenue increased 38% due to continued growth in new patient starts and refills in the U.S. with U.S. paid demand up 24% versus the first quarter of 2024, partially offset by a reduction in channel inventory, and increased contribution from ex-U.S. driven by continued uptake in Germany and France, as well as growth from the recent launches in Italy and Spain. Opzelura inventory levels were within normal range at the end of the first quarter of 2025. Minjuvi/Monjuvi net product revenue increased 24% as a result of the first quarter of 2025 reflecting three months of net product revenues in the U.S., compared to two months of net product revenue in the first quarter of 2024 due to the acquisition of U.S. rights to Monjuvi, which closed in February 2024. Niktimvo net product revenue driven by the commercial launch of the product during the first quarter of 2025. Operating Expenses Operating Expense Summary (unaudited, in thousands) Three Months Ended March 31, % Change 2025 2024 GAAP cost of product revenues $ 73,188 $ 60,956 20 % Non-GAAP cost of product revenues1 66,945 54,959 22 % GAAP research and development 437,279 429,260 2 % Non-GAAP research and development2 400,020 388,437 3 % GAAP selling, general and administrative 325,691 300,256 8 % Non-GAAP selling, general and administrative3 302,292 277,335 9 % GAAP loss (gain) on change in fair value of acquisition-related contingent consideration 11,572 (456 ) NM Non-GAAP loss (gain) on change in fair value of acquisition-related contingent consideration — — — % GAAP (profit) and loss sharing under collaboration agreements — (1,025 ) — % 1 Non-GAAP cost of product revenues excludes the amortization of licensed intellectual property for Iclusig relating to the acquisition of the European business of ARIAD Pharmaceuticals, Inc. and the cost of stock-based compensation. 2 Non-GAAP research and development expenses exclude the cost of stock-based compensation, MorphoSys transition costs, and Escient severance payments. 3 Non-GAAP selling, general and administrative expenses exclude the cost of stock-based compensation, MorphoSys transition costs, and Escient severance payments. Cost of product revenues GAAP and Non-GAAP cost of product revenues for the quarter ended March 31, 2025 increased 20% and 22% respectively, compared to the same period in 2024 primarily due to increased royalty expense. Research and development expenses GAAP and Non-GAAP research and development expense for the quarter ended March 31, 2025 increased 2% and 3%, respectively, compared to the same period in 2024, reflecting continued investment in our late stage development assets and timing of certain expenses. Selling, general and administrative expenses GAAP and Non-GAAP selling, general and administrative expenses for the quarter ended March 31, 2025 increased 8% and 9%, respectively, compared to the same period in 2024 primarily due to timing of consumer marketing activities and of certain other expenses. Other Financial Information Change in fair value of acquisition-related contingent consideration The change in fair value of contingent consideration during the quarter ended March 31, 2025, compared to the same period in 2024, was primarily due to fluctuations in foreign currency exchange rates impacting future revenue projections of Iclusig. Operating income GAAP and Non-GAAP operating income for the three months ended March 31, 2025 increased 123% and 76%, respectively, compared to the same period in 2024, driven primarily by growth in net product revenue. Cash, cash equivalents and marketable securities position As of March 31, 2025 and December 31, 2024, cash, cash equivalents and marketable securities totaled $2.4 billion and $2.2 billion, respectively. 2025 Financial Guidance Incyte's guidance for the fiscal year 2025 is summarized below. Incyte is raising its full year 2025 Jakafi revenue guidance. Guidance for Opzelura includes net product revenue for pediatric atopic dermatitis which has an anticipated approval in the second half of 2025. Guidance for other oncology net product revenues include net product revenue for Monjuvi in follicular lymphoma and Zynyz in squamous cell anal carcinoma. Approvals for these indications are anticipated in the second half of 2025. Guidance for research and development excludes the $15 million of expense for the full year 2025 related to our recently announced collaboration with Genesis. Current Previous Jakafi net product revenues $2,950 - $3,000 million $2,925 - $2,975 million Opzelura net product revenues Unchanged $630 - $670 million Other oncology net product revenues(1) Unchanged $415 - $455 million GAAP Cost of product revenues Unchanged 8.5% - 9.0% of net product revenues Non-GAAP Cost of product revenues(2) Unchanged 7.5% - 8.0% of net product revenues GAAP Research and development expenses Unchanged $1,930 - $1,960 million Non-GAAP Research and development expenses(3) Unchanged $1,780 - $1,805 million GAAP Selling, general and administrative expenses Unchanged $1,280 - $1,310 million Non-GAAP Selling, general and administrative expenses(3) Unchanged $1,160 - $1,185 million 1Pemazyre in the U.S., EU and Japan; Niktimvo, Monjuvi and Zynyz in the U.S.; and Iclusig and Minjuvi in the EU. 2Adjusted to exclude the amortization of licensed intellectual property for Iclusig relating to the acquisition of the European business of ARIAD Pharmaceuticals, Inc. and the estimated cost of stock-based compensation. 3Adjusted to exclude the estimated cost of stock-based compensation. Conference Call and Webcast Information Incyte will hold a conference call and webcast this morning at 8:00 a.m. ET. To access the conference call, please dial 877-407-3042 for domestic callers or 201-389-0864 for international callers. When prompted, provide the conference identification number, 13753168. If you are unable to participate, a replay of the conference call will be available for 90 days. The replay dial-in number for the United States is 877-660-6853 and the dial-in number for international callers is 201-612-7415. To access the replay you will need the conference identification number, 13753168. The conference call will also be webcast live and can be accessed at investor.incyte.com. About Incyte A global biopharmaceutical company on a mission to Solve On., Incyte follows the science to find solutions for patients with unmet medical needs. Through the discovery, development and commercialization of proprietary therapeutics, Incyte has established a portfolio of first-in-class medicines for patients and a strong pipeline of products in Oncology and Inflammation & Autoimmunity. Headquartered in Wilmington, Delaware, Incyte has operations in North America, Europe and Asia. For additional information on Incyte, please visit Incyte.com or follow us on social media: LinkedIn, X, Instagram, Facebook, YouTube. About Jakafi® (ruxolitinib) Jakafi® (ruxolitinib) is a JAK1/JAK2 inhibitor approved by the U.S. FDA for treatment of polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea; intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF in adults; steroid-refractory acute GVHD in adult and pediatric patients 12 years and older; and chronic GVHD after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older. Jakafi is a registered trademark of Incyte. About Opzelura® (ruxolitinib) Cream Opzelura® (ruxolitinib) cream, a novel cream formulation of Incyte’s selective JAK1/JAK2 inhibitor ruxolitinib, approved by the U.S. Food & Drug Administration for the topical treatment of nonsegmental vitiligo in patients 12 years of age and older, is the first and only treatment for repigmentation approved for use in the United States. Opzelura is also approved in the U.S. for the topical short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis (AD) in non-immunocompromised patients 12 years of age and older whose disease is not adequately controlled with topical prescription therapies, or when those therapies are not advisable. Use of Opzelura in combination with therapeutic biologics, other JAK inhibitors, or potent immunosuppressants, such as azathioprine or cyclosporine, is not recommended. In Europe, Opzelura (ruxolitinib) cream 15mg/g is approved for the treatment of non-segmental vitiligo with facial involvement in adults and adolescents from 12 years of age. Incyte has worldwide rights for the development and commercialization of ruxolitinib cream, marketed in the United States as Opzelura. Opzelura and the Opzelura logo are registered trademarks of Incyte. About Monjuvi® (tafasitamab-cxix) Monjuvi® (tafasitamab-cxix) is a humanized Fc-modified cytolytic CD19 targeting monoclonal antibody. In 2010, MorphoSys licensed exclusive worldwide rights to develop and commercialize tafasitamab from Xencor, Inc. Tafasitamab incorporates an XmAb® engineered Fc domain, which mediates B-cell lysis through apoptosis and immune effector mechanism including Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP). MorphoSys and Incyte entered into: (a) in January 2020, a collaboration and licensing agreement to develop and commercialize tafasitamab globally; and (b) in February 2024, an agreement whereby Incyte obtained exclusive rights to develop and commercialize tafasitamab globally. Following accelerated approval by the U.S. Food and Drug Administration in July 2020, Monjuvi® (tafasitamab-cxix) is being commercialized in the United States by Incyte. In Europe, Minjuvi® (tafasitamab) received conditional Marketing Authorization from the European Medicines Agency in August 2021. XmAb® is a registered trademark of Xencor, Inc. Monjuvi, Minjuvi, the Minjuvi and Monjuvi logos and the “triangle” design are (registered) trademarks of Incyte. About Pemazyre® (pemigatinib) Pemazyre® (pemigatinib) is a kinase inhibitor indicated in the United States for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). Pemazyre is also the first targeted treatment approved for use in the United States for treatment of adults with relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with FGFR1 rearrangement. In Japan, Pemazyre is approved for the treatment of patients with unresectable biliary tract cancer (BTC) with a fibroblast growth factor receptor 2 (FGFR2) fusion gene, worsening after cancer chemotherapy. In Europe, Pemazyre is approved for the treatment of adults with locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement that have progressed after at least one prior line of systemic therapy. Pemazyre is a potent, selective, oral inhibitor of FGFR isoforms 1, 2 and 3 which, in preclinical studies, has demonstrated selective pharmacologic activity against cancer cells with FGFR alterations. Pemazyre is marketed by Incyte in the United States, Europe and Japan. Pemazyre is a trademark of Incyte. About Iclusig® (ponatinib) tablets Iclusig® (ponatinib) targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, which has been associated with resistance to other approved TKIs. In the EU, Iclusig is approved for the treatment of adult patients with chronic phase, accelerated phase or blast phase chronic myeloid leukemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation, or the treatment of adult patients with Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation. Click here to view the Iclusig EU Summary of Medicinal Product Characteristics. Incyte has an exclusive license from Takeda Pharmaceuticals International AG to commercialize ponatinib in the European Union and 29 other countries, including Switzerland, UK, Norway, Turkey, Israel and Russia. Iclusig is marketed in the U.S. by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. About Zynyz® (retifanlimab-dlwr) Zynyz® (retifanlimab) is an intravenous PD-1 inhibitor indicated in the U.S. for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Zynyz is marketed by Incyte in the U.S. In 2017, Incyte entered into an exclusive collaboration and license agreement with MacroGenics, Inc. for global rights to retifanlimab. Zynyz is a trademark of Incyte. About Niktimvo™ (axatilimab-csfr) Niktimvo (axatilimab-csfr) is a first-in-class colony stimulating factor-1 receptor (CSF-1R)-blocking antibody approved for use in the U.S. for the treatment of chronic graft-versus-host disease (GVHD) after failure of at least two prior lines of systemic therapy in adult and pediatric patients weighing at least 40 kg (88.2 lbs). In 2016, Syndax licensed exclusive worldwide rights to develop and commercialize axatilimab from UCB. In September 2021, Syndax and Incyte entered into an exclusive worldwide co-development and co-commercialization license agreement for axatilimab in chronic GVHD and any future indications. Axatilimab is being studied in frontline combination trials in chronic GVHD – a Phase 2 combination trial with ruxolitinib (NCT06388564) and a Phase 3 combination trial with steroids (NCT06585774) are underway. Axatilimab is also being studied in an ongoing Phase 2 trial in patients with idiopathic pulmonary fibrosis (NCT06132256). Niktimvo is a trademark of Incyte. All other trademarks are the property of their respective owners. Forward-Looking Statements Except for the historical information set forth herein, the matters set forth in this release contain predictions, estimates and other forward-looking statements, including any discussion of the following: Incyte’s potential for continued performance and growth; Incyte’s ability to achieve both its full-year and long-term objectives; Incyte’s financial guidance for 2025, including its expectations regarding sales of and demand for Jakafi and Opzelura; expected revenue contribution from Niktimvo and additional near-term launches; the potential of povorcitinib to be a multibillion-dollar product; the possibility for 2025 to be a transformational year for Incyte in terms of launches, phase 3 study initiations, pivotal readouts and proof of concept readouts; Incyte’s potential to have more than 10 high impact launches by 2030; the potential and progress of programs in our pipeline; ongoing clinical trials and clinical trials that may be initiated; expectations regarding discussions with regulators, regulatory submissions and regulatory approvals; plans to present data at upcoming medical conferences; Incyte’s exposure to potential tariffs; and 2025 newsflow items. These forward-looking statements are based on Incyte’s current expectations and subject to risks and uncertainties that may cause actual results to differ materially, including unanticipated developments in and risks related to: further research and development and the results of clinical trials possibly being unsuccessful or insufficient to meet applicable regulatory standards or warrant continued development; the ability to enroll sufficient numbers of subjects in clinical trials and the ability to enroll subjects in accordance with planned schedules; determinations made by the FDA, EMA and other regulatory agencies; Incyte’s dependence on its relationships with and changes in the plans of its collaboration partners; the efficacy or safety of Incyte’s products and the products of Incyte’s collaboration partners; the acceptance of Incyte’s products and the products of Incyte’s collaboration partners in the marketplace; market competition; unexpected variations in the demand for Incyte’s products and the products of Incyte’s collaboration partners; the effects of announced or unexpected price regulation or limitations on reimbursement or coverage for Incyte’s products and the products of Incyte’s collaboration partners; sales, marketing, manufacturing and distribution requirements, including Incyte’s and its collaboration partners’ ability to successfully commercialize and build commercial infrastructure for newly approved products and any additional products that become approved; greater than expected expenses, including expenses relating to litigation or strategic activities; variations in foreign currency exchange rates; and other risks detailed in Incyte’s reports filed with the Securities and Exchange Commission, including its annual report on form 10-K for the year ended December 31, 2024. Incyte disclaims any intent or obligation to update these forward-looking statements. INCYTE CORPORATION CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS (unaudited, in thousands, except per share amounts) Three Months Ended March 31, 2025 2024 GAAP Revenues: Product revenues, net $ 922,274 $ 729,923 Product royalty revenues 130,624 125,966 Milestone and contract revenues — 25,000 Total revenues 1,052,898 880,889 Costs, expenses and other: Cost of product revenues (including definite-lived intangible amortization) 73,188 60,956 Research and development 437,279 429,260 Selling, general and administrative 325,691 300,256 Loss (gain) on change in fair value of acquisition-related contingent consideration 11,572 (456 ) (Profit) and loss sharing under collaboration agreements — (1,025 ) Total costs, expenses and other 847,730 788,991 Income from operations 205,168 91,898 Interest income 22,929 46,770 Interest expense (660 ) (430 ) (Loss) gain on equity investments (1,343 ) 99,947 Other, net 8,096 (2,026 ) Income before provision for income taxes 234,190 236,159 Provision for income taxes 75,987 66,611 Net income $ 158,203 $ 169,548 Net income per share: Basic $ 0.82 $ 0.76 Diluted $ 0.80 $ 0.75 Shares used in computing net income per share: Basic 193,712 224,484 Diluted 198,197 227,219 INCYTE CORPORATION CONDENSED CONSOLIDATED BALANCE SHEETS (unaudited, in thousands) March 31, 2025 December 31, 2024 ASSETS Cash, cash equivalents and marketable securities $ 2,408,658 $ 2,158,092 Accounts receivable 823,134 853,154 Property and equipment, net 765,359 763,411 Finance lease right-of-use assets, net 29,892 30,803 Inventory 429,286 407,199 Prepaid expenses and other assets 243,470 181,382 Equity investments 17,463 18,814 Other intangible assets, net 107,611 113,803 Goodwill 155,593 155,593 Deferred income tax asset 768,899 762,071 Total assets $ 5,749,365 $ 5,444,322 LIABILITIES AND STOCKHOLDERS’ EQUITY Accounts payable, accrued expenses and other liabilities $ 1,849,681 $ 1,765,733 Finance lease liabilities 37,121 37,961 Acquisition-related contingent consideration 195,000 193,000 Stockholders’ equity 3,667,563 3,447,628 Total liabilities and stockholders’ equity $ 5,749,365 $ 5,444,322 INCYTE CORPORATION RECONCILIATION OF GAAP NET (LOSS) INCOME TO SELECTED NON-GAAP ADJUSTED INFORMATION (unaudited, in thousands, except per share amounts) Three Months Ended March 31, 2025 2024 GAAP Net Income $ 158,203 $ 169,548 Adjustments1: Non-cash stock compensation from equity awards (R&D)2 36,724 36,792 Non-cash stock compensation from equity awards (SG&A)2 23,399 22,373 Non-cash stock compensation from equity awards (COGS)2 859 613 Non-cash interest3 82 108 Loss (gain) on equity investments4 1,343 (99,947 ) Amortization of acquired product rights5 5,384 5,384 Loss (gain) on change in fair value of contingent consideration6 11,572 (456 ) MorphoSys transition costs7 — 4,579 Escient acquisition related compensation expense8 535 — Tax effect of Non-GAAP pre-tax adjustments9 (8,642 ) (6,275 ) Non-GAAP Net Income $ 229,459 $ 132,719 Non-GAAP net income per share: Basic $ 1.18 $ 0.59 Diluted $ 1.16 $ 0.58 Shares used in computing Non-GAAP net income per share: Basic 193,712 224,484 Diluted 198,197 227,219 1 Included within the Milestone and contract revenues line item in the Condensed Consolidated Statements of Operations (in thousands) for the three months ended March 31, 2025 are milestones of $0 earned from our collaborative partners, as compared to $25,000 of milestones earned for the three months ended March 31, 2024. Included within the Research and development expenses line item in the Condensed Consolidated Statements of Operations (in thousands) for the three months ended March 31, 2025 and 2024 are upfront consideration and milestones of $15,500 and $1,000, respectively, related to our collaborative partners. 2 As included within the Cost of product revenues (including definite-lived intangible amortization) line item; the Research and development expenses line item; and the Selling, general and administrative expenses line item in the Condensed Consolidated Statements of Operations. 3 As included within the Interest expense line item in the Condensed Consolidated Statements of Operations. 4 As included within the (Loss) gain on equity investments line item in the Condensed Consolidated Statements of Operations. 5 As included within the Cost of product revenues (including definite-lived intangible amortization) line item in the Condensed Consolidated Statements of Operations. Acquired product rights of licensed intellectual property for Iclusig is amortized utilizing a straight-line method over the estimated useful life of 12.5 years. 6 As included within the Loss (gain) on change in fair value of acquisition-related contingent consideration line item in the Condensed Consolidated Statements of Operations. 7 Included within the Research and development line item in the Condensed Consolidated Statements of Operations (in thousands) is $4,031 for the three months ended March 31, 2024, and $548 is included within the Selling, general and administrative expenses line item in the Condensed Consolidated Statements of Operations (in thousands) for the three months ended March 31, 2024. MorphoSys transition costs primarily represent employee related costs to transition research and development and selling, general and administrative activities to us under the former collaboration agreement with MorphoSys. 8 Included within the Research and development line item in the Condensed Consolidated Statements of Operations (in thousands) is $535 for the three months ended March 31, 2025. Escient acquisition related compensation expense represents non-recurring charges associated with severance payments to former Escient employees. 9 Income tax effects of Non-GAAP pre-tax adjustments are calculated using an estimated annual effective tax rate, taking into consideration any permanent items and valuation allowances against related deferred tax assets. The Non-GAAP net income for the three months ended March 31, 2024 should have been $132,719 compared to the $145,269 previously disclosed to correct a transposition error in the tax effect of Non-GAAP pre-tax adjustments. For the three months ended March 31, 2024, the tax effect of Non-GAAP pre-tax adjustments should have been ($6,275) instead of $6,275. This correction is reflected in the table above.

这篇综述文章于2024年发表在《Cell Culture and Tissue Engineering》。主要调研并阐述了抗体开发的应对措施，并在相关情况下对比了复杂分子开发的挑战，以提供有关开发CHO生产细胞系所需的典型时间和精力的全面行业观点。摘要：细胞系开发（CLD）是生物药物开发过程中一个复杂但高度关键的过程。为了阐明这一关键的工作流程，BioPhorum成员（作者）团队开发并执行了调查，重点关注典型CLD活动所涉及的活动和努力。参与BioPhorum CLD工作组的来自不同公司的27名成员平均回答了涵盖标准CLD流程三个可区分阶段的调查：（1）预转染，包括载体设计和构建;（2）转染，包括最初将载体引入细胞中以及随后的混合池选择和分析;（3）单细胞克隆和先导克隆选择，包括分离单细胞和确认克隆来源的方法、随后的扩增和筛选过程，以及鉴定和储存先导克隆的方法。调查范围非常广泛，共涉及341个问题，分为抗体和复杂分子CLD过程。在这篇调查综述中，作者解释并强调了抗体开发的应对措施，并在相关情况下对比了复杂分子开发的挑战，以提供有关开发CHO生产细胞系所需的典型时间和精力的全面行业观点。1 综述背景将生物药物带到临床进行首次人体（FIH）研究是一个漫长而复杂的过程。化学、制造和控制（CMC）开发过程的第一步是生成表达治疗蛋白的细胞系。因此，细胞系开发（CLD）小组受到了很多关注，因为他们负责创建克隆衍生的生产细胞系（本文也称为克隆），这是一项位于整体开发时间表的关键路径上的活动。除了对FIH候选药物的热情外，人们还希望尽快将药物推向市场，这导致了一个不可避免的问题：我们什么时候会有克隆？生成克隆来源的细胞系所需的时间一直是一个长期存在的问题。最近，它已成为许多科学会议和出版物的主题，因为重点已转移到加快 CLD时间表以应对COVID-19大流行。BioPhorum CLD工作组是一个由生物制药行业的CLD主题专家（SME）组成的联盟，其成员花费了大量时间分析和讨论决定开发稳定表达生物制剂的哺乳动物细胞系所需时间的因素和工艺步骤。尽管每家公司都有快速生成高性能、克隆衍生的生产细胞系的相同目标，但人们认为整个行业的工艺各不相同，因为每家公司都有自己定义明确的生物制剂开发和生产工艺（也称为平台或平台工艺）。然而，小组讨论揭示了不同公司之间共享的关键流程步骤的许多相似之处。因此，本文的作者（BioPhorum CLD工作组的一个子团队）研究了共性，以描述克隆衍生细胞系开发的“典型时间表”，该细胞系可用于创建用于临床生产的主细胞库（MCB）。在典型的平台过程中，CLD从生成DNA表达构建体（或载体）开始，到选择先导克隆结束。先导克隆的选择基于最合适的CMC特性，通常包括细胞培养生长、生产率、细胞系稳定性和表达的治疗性蛋白的理想产品质量。为了在本次调查中保持一致，我们将冷冻保存的主要候选者称为研究细胞库（RCB），并将问题集中在其开发上，而不是从RCB种子库生成 MCB所需的时间和精力。调查设计的一个主要考虑因素是区分开发标准单克隆抗体（mAb）和复杂分子，复杂分子是所有其他非标准抗体生物制剂（例如，多特异性抗体、抗体片段、蛋白质融合和糖蛋白）的统称。为了解决这一差异，我们将调查一分为二，并针对单克隆抗体和复杂分子提出了每个问题。根据调查受访者的说法，本文的重点是开发抗体表达细胞系的时间和精力，当表达的蛋白质对给定工艺步骤的时间或包含有相当大的影响时，引用和区分复杂分子。离线调查表明，大多数工作组成员使用CHO宿主细胞（95%;n=19）和随机积分向量（68%;n=19），因此这些过程变量建立了解释调查结果的基线。图1：根据标准细胞系发育阶段进展进行3项调查。每个调查都包含阶段输出和描述。作者的方法是调查整个BioPhorum CLD工作组（见表1）关于选择先导克隆和开发可用作创建MCB的种子库的RCB所涉及的时间、精力和步骤。该调查分为三个部分，代表CLD流程的典型阶段，如图 1 所示。这些阶段是（1）预转染阶段，包括表达载体的构建，（2）转染池的生成，以及（3）从转染池中选择先导克隆和开发RCB。作者一致认为，这三个阶段代表可以独立且具有离散停止点或可交付成果（例如，表达载体、混合细胞库和克隆细胞库）的作单元。后一个克隆选择阶段有两个不同的阶段，即单细胞克隆和在板式容器中的克隆扩增，一直到摇瓶和/或小型生物反应器，直到产生RCB。小规模扩增阶段是从单细胞克隆到第一个细胞库被冻存的连续体，我们称之为pre-RCB（或安全库），然后是作为RCB保存的顶级细胞的选择。由于这三个阶段有明确的停止点，因此可以根据需要轻松暂停FIH发展计划的进展，但这将导致潜在的进度差距。这些差距通常是由管理评审和决策驱动的;因此，它们超出了本文的范围。讨论了三个阶段中每个阶段的单独时间表，并且可以将它们相加以产生从DNA序列到先导克隆选择的典型时间表，从而避免工作流程中的空白。附录S1中介绍了每个阶段的调查问题和结果。鉴于受访工业组织的数量和多样性，本手稿中总结的收集结果可以被认为对整个生物制药行业具有高度代表性。表1.调查受访者调查主题（数字）预转染（1）转染（2）单细胞克隆和克隆选择（3）响应号码23受访者（19家公司）31受访者（27公司）27受访者（26公司）公司响应艾伯维，阿尔克梅斯，拜耳，百时美施贵宝，勃林格殷格翰，康泰伦特，费森尤斯卡比，吉利德，葛兰素史克，免疫原，杨森，共和麒麟公司，MacroGenics，默克公司，默克公司，默克公司，Seagen Inc.，武田，赛默飞世尔制药服务，UCB艾伯维，亚历克森，阿尔克姆斯，拜耳，百时美施贵宝，勃林格殷格翰，康泰伦特，CSL，吉利德，葛兰素史克，免疫原，Incyte，杨森，协和麒麟公司，MacroGenics，默克公司，默克公司，默克集团，诺和诺德，辉瑞，罗氏，三星生物制药，Seagen Inc.，武田，Thermo Fisher Pharma Services，UCB，公司A艾伯维，Alkermes，APC Limited，拜耳，Biogen，BMS，勃林格殷格翰，Ferring，Fresenius Kabi，GSK，Immunogen，Incyte，Janssen，MacroGenics，Merck & Co. Inc.，Merck KGaA，诺和诺德，辉瑞，罗氏，Seagen Inc.，武田，Thermo Fisher Pharma Services，UCB，公司A，公司B注：调查结果中的支持信息S1，包括哪些公司做出了回应，可以在本文的支持S1中找到。2 结果和讨论：调查#1（转染前阶段）新的FIH开发计划从转染前阶段开始，此时CLD组接收到预期候选药物的DNA序列。大多数FIH生物制剂通常是单克隆抗体，这是本文的重点。与此一致，几乎所有受访公司（99%）都开发抗体，而只有85%的受访者生产复杂分子（抗体和复杂分子的三项调查（S）和问题（Q）的累积百分比;缩写为S1Q3、S1Q34、S2Q3、S2Q42、S3Q3和S3Q4）。将 DNA序列通过预转染阶段所涉及的步骤相当复杂。它们包括在CLD组（或支持组）内部执行的步骤，以及通过外包给合同实验室在外部执行的步骤，并且对于抗体或复杂分子基本相同（图2a）。图2：转染前阶段调查回复。a） S1Q5&S1Q35：通常进行的活动以及谁执行它们。b） S1Q11&S1Q41：在相同或多个质粒上转染重链和轻链的受访者。c） S1Q28&S1Q58：分配给基因和质粒设计、基因合成和质粒/宿主细胞制备（预转染活性）的时间。该过程从通常在公司内部进行的可开发性评估开始（图2a）。该调查没有具体说明该评估包括哪些内容，但作者认为这是对初级蛋白质序列的审查，以确定CMC风险因素，例如有问题的氨基酸残基（例如脱酰胺位点）、蛋白质的快速和小规模表达，以及可能影响可开发性的蛋白质理化特性的表征。该分析通常在基因和质粒设计开始之前进行，以生成稳定细胞系，因此，作为CLD预转染阶段的一部分，所消耗的时间未被捕获。尽管在此过程中使用了不同的DNA序列元件（例如，启动子、可选标记物、信号序列等），但各行各业对载体构建的担忧是相似的。大多数受访者（82%） 使用计算机模拟建模进行质粒设计，以促进DNA克隆并改善基因表达（例如，密码子优化、S1Q21、S1Q51）。在单克隆抗体的情况下，绝大多数（78%） 表示它们表达来自同一质粒/载体的重链和轻链多肽，而复合物分子表达是项目依赖性的（图2b）。作者一致认为，由于链比率的滴定，多个质粒可能有利于复杂分子提高分子质量。一旦载体设计完成，几乎所有受访者都将蛋白质编码区的基因合成外包（图 2a）。在S1Q27中查询的基因合成的典型周转时间为3周（30%）和4周或更长时间（39%），但这可能取决于地缘政治因素，因为一些作者表示运输和海关可能会延迟接收外国货物。在复杂分子（S1Q57）中观察到了类似的结果，这些答案代表了在完成预转染活动之前分配给基因和质粒设计、基因合成和质粒/宿主细胞制备的总预算时间的相当大比例（图2c）。由于大多数受访者在4到6周之间回答了所有这些活动，因此可以肯定地说，转染前阶段的大部分时间都花在了等待DNA合成上，这是进入下一阶段的主要瓶颈。预转染阶段所需的工作量在很大程度上取决于每个开发程序进入流程的候选分子数量。在抗体开发计划的情况下，分子是指识别特定靶标的抗体重链和轻链多肽序列的独特组合。大多数受访公司（74%）为给定靶标（S1Q7）开发多个分子（氨基酸序列）。然而，大多数受访者（61%）只是为每个抗体分子（S1Q8）开发了一个编码序列，包括信号肽。为复杂分子开发单个编码序列的数量下降到38%（S1Q38）。表达载体骨架也出现了类似的趋势，其中70%的受访者开发了用于转染的单一抗体质粒变体（S1Q10），但只有44%的受访者开发了用于复杂分子的单一变体（S1Q40）。总之，与标准单克隆抗体相比，这些趋势可能会降低尝试表达复杂分子时的不确定性风险，因为标准单克隆抗体的载体设计知识可以很容易地从一种mAb转移到另一种mAb。生成表达质粒所需的实际工作量取决于设计，设计因公司而异，并且未进行调查。参与者被问及用于确认正确质粒组装的方法，大多数人回答了抗体构建体的重链和轻链基因的DNA测序（S1Q12）。在加速的时间表中，这种DNA测序可以在转染开始时同时进行，但存在一些额外的程序风险 （S1Q44）。在每个分子中创建和验证多个质粒会增加质粒设计/创建阶段的工作量，并将增加后续转染阶段的工作量。生成多表达质粒的决定是为了降低与创建新的转染池相关的不确定性风险，因为如果不进行实验工作，很难预测新抗体在稳定细胞系中的表达情况。然而，在完善的CLD平台中生产抗体通常会在预期的时间范围内提供一致的结果，如以下阶段所示。这不是对复杂分子的期望，作者同意需要对工作进行更深思熟虑的考虑并延长典型的时间表。转染前，必须制备表达载体和宿主细胞系。这可能包括质粒线性化，这可能需要几天时间，但被认为包含在图2c中查询的总体转染前时间表中。转染前必须培养宿主细胞，主要问题是细胞的年龄。大多数受访者同意宿主细胞的制备方式对转染有影响（S1Q23、S1Q53），并指定了宿主细胞培养时间的标准（S1Q64），表明转染前的典型最大值为10-20代（S1Q25、S1Q55）。转染前解冻和培养宿主细胞所需的时间不会影响整个时间表，因为它可以在载体构建阶段并行进行。3 结果和讨论：调查#2（转染阶段）转染阶段的特点是将目标异源基因（GOI） 引入宿主细胞并选择表达GOI的稳定细胞库所需的时间和精力。生物制药行业通常使用中国仓鼠卵巢（CHO） 细胞作为表达宿主，因为它们能够在这种严酷的发育过程中存活、在化学定义的悬浮培养物中茁壮成长、易于稳定基因作、对病毒感染的抵抗力，以及产生具有类似人类翻译后修饰的治疗性蛋白质的能力。CHO细胞也得到卫生当局的普遍认可和接受。大多数公司认为表达载体的转染是细胞系开发时间表的起点（S2Q4;S2Q43）。作者一致认为，转染是一个明确定义的起点，主要依赖于CLD小组的努力，并且具有不同的终止点和可交付成果（例如，冻存的池库）。因此，它作为一个有用的初始阶段，通过不同生物制药公司的先导克隆选择来比较整个CLD平台的时间表。然而，由于开发可以停止在池库的冷冻保存或直接继续到细胞系克隆，因此作者在调查#2中只关注池生成的时间表。调查#3涵盖了从单细胞克隆开始到先导克隆选择的时间，包括影响两个阶段之间过渡点时间的因素。与调查#1一样，转染阶段调查的审查主要集中在抗体表达反应上。两家公司主要采用两种方法将表达载体引入宿主细胞，即电穿孔和脂质辅助转染（脂质转染）。大多数受访者（84%） 正在使用电穿孔来生成抗体池 （S2Q6），复杂分子也是如此（85%，S2Q45）。转染后，通常在选择前将细胞在非选择性培养基中回收1-2天（S2Q14、S2Q53）。这可确保转染的培养物在受到导致许多细胞死亡的选择条件之前生长，只留下那些稳定掺入并表达载体选择标记基因的细胞。许多公司包括评估转染有效性的对照品（S2Q18、S2Q57），例如不含DNA的空载转染，以评估不表达可选标记物的池中的细胞杀伤性，或转染效率对照品，例如具有已知特性的标准抗体或荧光蛋白。相当多的受访者在转染过程中不使用效率控制，这表明这是一种基于风险的方法。包括对照不应延长整个时间表，但需要一些额外的努力和功能来执行（例如，荧光细胞检测和定量）。省略此对照可能是由于先前知道合适的转染效率。随着进入发育阶段的分子数量和/或每个分子的混合池数量的增加，生成稳定转染库所需的工作量会增加。几乎所有受访者通常每个表达分子生成多个池（S2Q8、S2Q47），并且大多数受访者在同一实验（S2Q10、S2Q49）中每个分子（S2Q9、S2Q48）进行六次或更多次重复。作者一致认为，增加每次转染的重复数会增加工作量，但不应影响时间表，因为转染池的回收和选择受细胞生长速率的控制，对于使用相同表达载体表达相同分子的池，细胞生长速率通常相似。如果池由于各种原因（例如，回收率差、溢出、污染等）而丢失，则添加重复转染可降低必须重复转染的风险，而重复转染会直接延长开发时间。重复还可能导致表达表型（例如，生长、滴度和产品质量）略有不同，这可能会影响未来的使用。其他可能影响时间和工作的因素包括转染不同的表达载体骨架（例如，含有不同启动子的质粒）、不同的编码序列（例如，密码子优化的序列）和/或不同的宿主细胞。对于有关这些选项的问题（S2Q11、S2Q50），受访者的回答不一，这更多地说明了识别高表达池的方法多种多样，而较少说明了所需的时间。然而，公司似乎重视这些变异的潜在益处，以改善后期细胞系的性能和/或质量，尤其是对于复杂分子表达。作者讨论了反应，并同意使用不同质粒的大多数变量对时间表的影响很小，但需要增加努力，CLD和分析组分别根据开发中的构建体数量来生产和分析表达的蛋白质。使用不同的CHO宿主细胞系可能会增加时间，具体取决于转染池的回收率和生长速率。进行顺序转染（增加转基因拷贝数和可能的蛋白质表达的超级转染）会增加开发池所需的时间。这可能是获得具有特定表达载体和平台工艺的高表达池所必需的，但通常只有一个受访者对抗体和复杂分子进行连续转染。稳定细胞系的开发通常从将转染质粒整合到宿主基因组中开始。接受质粒并将其成功整合到基因组中的细胞可以表达可选择的标记物，从而提供生存优势。通过这种方式，表达选择标记物的细胞长得比群体中的其他非表达细胞多，成为池中的主要细胞系成分。所有受访者在转染后、细胞系开发期间（S2Q22）施加选择压力，主要是某种形式的营养缺陷吸收因子剥夺或抗性基因表达的抗生素选择（图3a）。在复杂分子开发过程中，抗生素耐药性的使用更多，这可能是由于在独立载体上表达多个亚基或使用新型细胞系。在用不同的选择标记物转染多个表达载体的情况下，选择压力通常平行施加，而不是按顺序施加，这不应增加CLD平台过程的时间（S2Q26、S2Q65）。蛋氨酸亚砜胺（MSX）和甲氨蝶呤（MTX）通常用于增加谷氨酰胺合成酶（GS）或二氢叶酸还原酶（DHFR）缺陷型 CHO宿主细胞营养剥夺的选择压力。然而，大多数受访者在表征或克隆之前不会扩增其转染池（抗体为89%，S2Q27;复杂分子为100%，S2Q66）。池扩增是随着时间的推移增加选择试剂浓度以提高克隆选择严格性的连续过程，过去更为常见，但现代CLD平台过程不依赖于扩增来获得FIH开发计划可接受的滴度。基因扩增还有一个缺点，即时间增加，突变或细胞系不稳定的风险增加。转染选择阶段的另一个变量是批量池或小型池的生成：与小型池（抗体S2Q20为14%;复杂分子S2Q59为 20%）相比，更多的受访者生成了大量池（抗体S2Q20为59;复杂分子S2Q59为52%），其余大多数受访者表示他们的选择取决于项目。微型池的生成需要更多的劳动力，并且会对CLD时间表产生影响，因为与生成批量池相比，微型池的恢复、筛选和扩展更加耗时。在单细胞克隆之前应用微型池似乎是公司特定的，并且可能有利于在面临克隆优势风险的平台上选择产量最高的克隆，并导致批量池中种群多样性减少。转染阶段的特点是将目标异源基因（GOI）引入宿主细胞并选择表达GOI的稳定细胞库所需的时间和精力。生物制药行业通常使用中国仓鼠卵巢（CHO）细胞作为表达宿主，因为它们能够在这种严酷的发育过程中存活、在化学定义的悬浮培养物中茁壮成长、易于稳定基因作、对病毒感染的抵抗力，以及产生具有类似人类翻译后修饰的治疗性蛋白质的能力。CHO细胞也得到卫生当局的普遍认可和接受。图3：转染池条件和特征调查回复。a） S2Q23 & S2Q62：应用的选择类型。b） S2Q30 & S2Q69：在进行下一步之前应用的转染细胞的测试/标准。c） S2Q32 & S2Q71：转染细胞的测试/标准与下一步并行进行。d） S2Q35 & S2Q74：从转染开始到从大量池中克隆的时间。一旦转染池经过选择，它就可以直接进入单细胞克隆，并且可以并行完成池的表征。这种方法可以节省时间，但如果没有蛋白质生产知识，克隆会面临风险。或者，可以在生产过程中运行混合池，并在克隆之前评估每个混合池的细胞生长、蛋白质滴度和产品质量。后一个过程显然需要更多时间，但降低了从表达不佳的池中克隆的风险。在几个问题中调查了生成和表征转染池所需的时间，以确定典型过程并区分从新选择的池克隆与表征池。在从任一途径进行克隆之前，转染池都需要经过选择，大多数受访者同意这大约需要2-3周（S2Q29、S2Q68）。报告称，在选择后和克隆前测试表达mAb的池的典型时间为2-3周 （S2Q34），大多数受访者在进入克隆阶段之前评估了池生长和活力（图3b）。复杂分子的克隆时间略长（S2Q73），与mAb相比，克隆后的生产率和产品质量评估显著提高（图3c）。增加复杂分子的表征是有道理的，但对于从转染池转向克隆的时间和方法没有明确的共识。我们试图在调查#3中澄清这一点，发现受访者在抗体细胞系（S3Q21） 的单细胞克隆之前、期间或之后对mAb 库的表征大致平分秋色。然而，更大比例的受访者（61%）在克隆 （S3Q118）之前表征了表达复杂分子的池，这与调查#2的回答和表达复杂蛋白质的挑战一致。关于从转染到开始从大量混合池中克隆单细胞的总体时间范围，略多于一半的受访者认为抗体或复杂分子需要3-4周（图3d），较少但大致相等的受访者需要或多或少的时间。虽然本文侧重于基于随机转基因整合的CLD过程的典型时间表，但值得一提的是，新的替代转基因整合技术，例如转座酶介导或位点特异性整合，可以加快生成稳定转染库的时间表，并可能通过使用毒理学池来缩短项目时间表。然而，考虑到从转染到先导克隆选择的整个过程，这些（半）靶向整合库的早期可用性并不能显著加快整体CLD时间表。正如预期的那样，当使用小型池时，从转染到开始单细胞克隆需要更多时间，尤其是对于复杂分子（S2Q36、S2Q75）。只有48%的人回答了这个问题，这可能是由于转染选择阶段小型池的使用较少。微型池开发将增加筛选其他池所需的工作量，并可能使用于克隆的池的选择复杂化。据推测，这些挑战已经被纳入一个平台流程中，以改善那些使用迷你池的受访者的克隆选择。转染池可作为单细胞克隆的细胞来源，将在下一节中讨论，它们也可用于生产用于各种应用的重组蛋白。新的转染池可以在平台生产工艺中运行，以确定可能需要修改或改进的工艺挑战。凭借合适的性能，转染池可以扩大规模以运行大型生产生物反应器，为早期分析方法和配方开发提供工艺中间体（例如，用于纯化开发的未加工散装）和平台纯化的蛋白质。大多数受访者通常使用转染池进行工艺和分析方法开发（S2Q40、S2Q78）。配方开发也被认为是一项重要的早期开发需求。一些受访者 （16%）在临床前毒性研究中使用纯化的混合蛋白，但没有受访者表示他们将混合蛋白用于标准开发项目的1期临床研究。值得注意的是，一个例外是在大流行情况下使用稳定池制造临床1/2期研究材料，以开发抗 SARS-CoV2中和抗体。在这里，公司可以大大加快开发时间，为临床紧急应用提供GMP级原料药。虽然这在今天可能不是一个标准的开发场景，但这些开发程序可以用于确定未来标准CLD程序的加速潜力。先前关注加速CLD的出版物强调了使用转染库进行GLP毒性研究，以加快监管申报时间。然而，本评估未涵盖生产用于发育和毒性研究的蛋白质所需的时间，但可能与CLD活性同时发生，并且不会直接影响克隆选择。4 结果与讨论：调查#3（单细胞克隆和先导克隆选择阶段）单细胞克隆和先导克隆选择是CLD工作流程的两个阶段，它们通过利用小规模细胞培养和发酵技术的无缝过渡连接在一起。这些阶段作为一个连续体进行生产和稳定性评估，以选择最佳克隆。因此，这个阶段很漫长，需要付出相当大的努力才能将许多单个细胞培养成大量克隆衍生的培养物，同时实施各种选择和方法，将候选细胞从数千个减少到单个先导细胞系。克隆选择阶段的目标在整个行业中是一致的，即从转染子库中选择最佳的克隆来源细胞系进行生物生产。在本节中，我们探讨了公司为实现这一目标而采用的不同方法，重点关注程序上的时间和精力。所有受访者在开发抗体或复杂分子（S3Q11） 时，都在标准CLD项目中进行单细胞克隆。这与监管指南一致，即重组产物的细胞底物应从单细胞祖细胞克隆。第一步涉及从转染池中分离和培养单细胞。大多数受访者在克隆步骤之前或期间对转染池进行表征（例如，分批或补料分批的生产率评估;生长、活力、滴度和产品质量分析），尤其是在生产复杂分子时（S3Q21、S3Q118）。作者怀疑，由于平台先验知识，抗体更有可能在没有事先池表征的情况下做出风险克隆的决定，而复杂分子可能不存在。有风险的克隆还可以节省时间，因为几乎所有直接从转染池中克隆而不进行表征的受访者都表示，克隆可以在转染后3-4周开始（S3Q23），而持续时间各不相同，并且随着表征而更长（S3Q22）。单个细胞通常从多个重复转染池（100%： S3Q34） 中克隆，这些池未混合（80%： S3Q35），并且是迷你池上的批量池 （74%： S3Q43）。这些混合细胞通常具有高活力（S3Q37、S3Q38），但没有特定的生长速率要求 （S3Q39）即可进行单细胞克隆。大约一半的受访者在克隆产生抗体的细胞系（S3Q41）之前为其池设定了预定义的阈值（例如滴度和产品质量）。当克隆表达复杂分子的池时，这个数字增加到75% （S3Q102）。同样，对平台在复杂分子上表达抗体的能力的信心很可能推动了这种差异。20%的受访者表示，他们在单细胞克隆 （S3Q45） 之前使用转染池上的细胞分选（批量分选）来富集高表达细胞群，而42%的受访者表示他们在单细胞克隆过程中识别出高产者 （S3Q58）。几年前，生物制药界就单克隆性对生物制剂生产细胞系的重要性进行了讨论，已经开发出大量新的单细胞克隆仪器并实现了商业化。因此，公司现在在选择设备时有更广泛的选择，以确保其生产细胞系的单克隆性。根据调查结果，工业CLD实验室中主要使用两种类型的设备进行抗体细胞系的单细胞克隆（图4a）：38%使用Beacon（Berkeley Lights;Emeryville， CA） 和27%使用某种形式的单细胞打印（例如，Cytena， GmbH;Breisgau， Germany）。其余公司使用各种其他可用的单细胞克隆选项。从事复杂分子研究的公司也存在类似的比例。如前所述，几种单细胞克隆设备可以在仪器内的克隆或初始细胞扩增过程中识别高产细胞。其余58%的Sla在克隆（S3Q58）期间未识别高生产者，将初始滴度筛选留给克隆扩增过程的后期阶段。在本文中，我们不比较方法的适用性，但试图说明方法如何影响典型的时间表。作者承认，克隆阶段单细胞的生长可能取决于所使用的设备（例如，荧光激活细胞分选 （FACS） 会对细胞健康产生负面影响），但这应该不会对整体时间表产生重大影响，因为CHO细胞可以从克隆中快速恢复，然后恢复正常的CHO倍增时间。但是，克隆效率可能会降低，这将影响获得所需数量的克隆以进行正向处理所需的工作量，如下所述。图4：单细胞克隆和成像调查回复。a） S3Q48 & S3Q145：用于单细胞克隆的主要仪器。b） S3Q64 & S3Q161：用于保证单细胞性和单细胞分离后细胞生长的成像仪器。c） S3Q66 & S3Q163：生长成菌落的单细胞（孔）的百分比（克隆效率）。d） S3Q69 & S3Q166：在最终审查中审查以确认克隆衍生的克隆图像数量。从一致性和调控的角度来看，开发生产细胞系的更重要步骤之一是分离和扩增单细胞祖细胞，并证明克隆衍生的高概率和/或保证。为此，77%的受访者已经确定了克隆性的可能性（S3Q54），62%的受访者已经确定了他们的单细胞克隆仪器（S3Q56）。为了进一步保证克隆性，96% 的受访者对单细胞生长成集落（S3Q62）进行成像，并在第0天及以后 （S3Q63）进行成像。所有受访者对复杂分子（S3Q159、S3Q160）的成像方式相同，证明了这一步骤作为克隆性评估的一部分的重要性。如前所述，许多受访者正在使用Beacon进行克隆（图4a）。他们还回答说，Beacon被用来对生长物进行成像以确保克隆性（38%），而其他人则经常使用CELLAVISTA （27%：Synentec GmbH;Elmshorn，德国）、Cell Metric（19%：Solentim;Wimborne， UK）和其他图像来评估克隆生长（图4b）。传统的克隆方法包括将单个细胞沉积到细胞培养级微孔板的单个孔中。大多数受访者使用两种微孔板尺寸中的一种，其中约一半使用 96 孔，四分之一使用384孔（S3Q52）。其余四分之一的受访者使用纳米笔或纳米孔。作者怀疑这些受访者正在使用Beacon或CellCelector仪器进行克隆。单细胞克隆的主要问题之一是细胞生长的稳健性。对于使用微孔板的患者，大多数在接种板（S3Q50）之前不会用任何特殊的粘合剂处理板。然而，大多数研究使用特殊的克隆培养基（S3Q91）以及补充剂、条件培养基和/或生长因子（S3Q93）的混合物来制备抗体和复杂分子。克隆培养基通常是一种精而专有的营养混合物，可在特定平台过程中促进成功、一致的菌落生长。预计克隆期间的单细胞生长在任何不同的平台特定条件下都不会有意义地加速。然而，培养基组成和生长因子确实会影响长成菌落的接种细胞的百分比。这可能解释了图4c中克隆效率的一些变化，并会影响获得所需克隆数量所需的努力。从克隆容器到悬浮培养的过渡可以通过多种途径进行，并且公司之间的过渡差异很大，如下所述。克隆板进展的主要标准包括生长、生产率和单克隆性（S3Q67），大多数受访者在单细胞克隆（S3Q60）期间没有筛选产品质量。更多的受访者评估克隆板中的生长优于单克隆性。这可能表明他们相信自己的方法可以生产克隆来源的细胞系，然后在选择顶级克隆时查看图像以确认单细胞来源。成像仪可以在此阶段识别集落，而无需对单细胞来源进行彻底审查。事实上，超过一半的受访者正在目视审查50个或更少克隆的单克隆图像 （58%;图4d），表明这确实发生在平台流程的后期，当克隆数量减少到可管理的数量时。CLD工作组的一项离线民意调查显示，Beacon和CELLAVISTA 用户占筛选超过50种细胞系克隆性的大多数受访者 （88%;n=8）。这突出了设备在平台流程的设计和执行中可以发挥的作用。大量单细胞接种到克隆容器中。如S3Q53所示，近一半（46%） 的受访者每个分子接种多达2000个孔。其余受访者（54%）正在播种 4000到10000多口井。作者怀疑后一组正在使用Beacon、FACS设备或 CellCelector，因为这些仪器（或方法）可以处理更多的细胞。在这个阶段可以确定菌落生长的百分比或克隆效率，受访者的克隆效率差异很大，如图4c所示。与复杂分子相比，表达mAb的细胞系的克隆效率似乎更好。目前尚不清楚是什么导致了这种差异，但单细胞克隆是一个困难的步骤，可能会受到表达复杂分子挑战的负面影响。克隆来源的细胞系需要扩增以增加细胞质量，以便在离心管、摇瓶或生物反应器等培养容器中进行生产评估。这需要从单个细胞祖细胞系统地增加培养容器的大小和细胞数量，并且因公司而异，如下所示。S3Q73 显示了初始克隆板后在过渡到搅拌培养之前从0到4个容器的静态克隆筛选步骤的数量，大多数受访者对 mAb 和复杂分子都使用一两个步骤。生长和滴度都用于选择克隆以进入搅拌培养（92%），而只有12%评估产品质量（S3Q74）。进入搅动的时间范围是可变的，但中位时间为单细胞克隆后3周（图5a）。搅拌（悬浮）培养的中位时间为8-9周 （S3Q85）。虽然许多受访者在96个深孔板中进行搅拌培养，但类似数量的受访者在多孔板的静态培养条件下扩增细胞，直到细胞质量足够大，可以进入试管离心或摇瓶（图5b）。这种二分法表明行业内使用了不同的平台方法来扩增细胞系，并且可能取决于每个阶段进展的克隆数量（图5c、图5d）。由于深孔板和/或试管离心/摇瓶中的表征方法不同，因此在此阶段很难确定克隆在不同平台工艺中进行的时间和选择（有关整体时间表的讨论，请参见下文）。然而，进展到试管离心/摇瓶的典型数字范围为21到100（图5d），作者同意这是后续活动的可管理数字。几乎所有受访者都使用受控的微型生物反应器筛选仪器（例如，AMBR15/AMBR250：Sartorius GmbH;德国哥廷根）进行工艺性能（滴度）和产品质量评估，以选择他们的先导克隆用于研究细胞库（图6a），这表明这是先导克隆选择的最终方法。一些受访者表示（填写回复）下一代测序（NGS） 方法正在用于细胞系表征（S3Q16、S3Q72、S3Q113、S3Q184）。NGS方法有可能提供广泛的细胞系转基因序列信息，这些信息可用于克隆筛选和选择。尽管很少有受访者表示目前使用 NGS，但作者一致认为，未来NGS应用可能会增加，以降低选择不需要的克隆的风险。图5：单细胞扩增过程调查回复。a） S3Q76 & S3Q173：单细胞克隆后数周转为搅拌培养。b） S3Q77 & S3Q174：用于首次搅拌培养的容器。c） S3Q78 & S3Q175：进入搅拌培养物以在深孔板中进行表征的克隆数量（每个铅分子）。d） S3Q79 & S3Q176：进入搅拌培养物的克隆数量（每个先导分子）在管式离心/摇瓶中进行表征。图6：单细胞筛选和选择调查回复。a） S3Q83 & S3Q180：进入搅拌培养后进行的步骤，以选择主要研究细胞库（选择所有适用的选项）。b） S3Q15 & S3Q112：从单细胞克隆到最终选择主要克隆的时间跨度中包含的活动（选择所有适用的选项）。c） S3Q101 & S3Q198：用于研究细胞库冷冻的单细胞克隆每个分子预算的FTE数量。d） S3Q14 & S3Q111：从单细胞克隆到选择主要（最终）克隆的预期时间框架。在接受调查的公司中，从单细胞克隆到研究细胞库（RCB）冷冻的典型时间范围相对较大，最短为4-5周，最长为>13周（S3Q84）。一项后续民意调查显示，37%的患者需要不到12周，47%的患者在12-13周、14-15周和16-17周之间紧密分布，其余16%的患者需要20周以上 （n=19）。这将范围从4到5周扩展到20周以上，这表明在CLD工作流程的这一点上，平台非常多样化，并且可能相当长。重要的是，单细胞克隆和扩增在放置RCB之前处于风险中进行，因为在此期间的失败意味着单细胞克隆的开始。为了降低这种风险，一些公司会尽快冻结安全银行（RCB 之前），以便在需要时可以从这些银行进行筛查。这些pre-RCB文库的要求是足够的细胞来冷冻并继续繁殖。这将取决于扩增方法，大多数受访者可以在单细胞克隆开始后的4到9周内创建RCB前安全库（S3Q47）。大多数受访者将5-6个克隆作为RCB冷冻，而其他公司则冷冻保存了更多的克隆 （S3Q97），RCB库大小为每个克隆约11-30个小瓶（S3Q98）。从单细胞沉积到RCB的克隆开发是一个漫长而密集的过程，通过研究细胞库每个抗体分子需要1.5个FTE，而当开发复杂分子时，预算的FTE 会增加（图6c）。为了提高克隆开发过程中的效率，大多数受访者都采用了自动化。这包括单细胞沉积、板成像和扩增过程中的克隆挑取（S3Q81）的自动化。一些受访者已经实施了克隆扩增和产能分析的自动化。大多数在RCB创建（S3Q86）之前将生长、生产率、单克隆性和产品质量参数作为克隆选择参数。有趣的是，只有大约三分之一的受访者在研究细胞库之前进行了稳定性评估。由于生产稳定性是GMP生产细胞系生命周期的重要特征，因此需要在某个时候解决这个问题。正如怀疑的那样，更多的受访者（77%）在先导克隆选择之前进行稳定性评估（图6b）。作者将这种时间差异归因于过程知识，该过程知识允许延迟稳定性研究，以便在细胞老化期间进行平行活动以加快整体时间框架。使用非随机整合技术还可以提供克隆性能的可信度和一致性，从而降低延迟稳定性研究以加快时间表的风险。mAb从单细胞克隆到最终克隆选择的预期中位时间为17-20周（图6d），并且包括许多单元作（图6b）。复杂分子的单位作稍长（图 6d），但抗体和复杂分子的单位作相似（图6b）。几乎所有受访者都进行了发酵评估和产品质量评估，并准备了研究细胞库（RCB）。大多数受访者使用微型生物反应器 （<1L） 来评估工艺平台的适用性、生产率和产品质量（图6a）。这些活动在整个行业中的一致性并不奇怪，因为它们是生物生产细胞系的关键特征。图6b中观察到的其余活性的可变性很可能是由于不同平台中存在的小规模克隆扩增和筛选方法的差异。5 总结BioPhorum细胞系开发工作组由高度协作的主题专家组成，他们合作共享信息并更好地了解开发生物治疗药物生产细胞系的过程。尽管拥有创造高产克隆衍生细胞系的共同目标，但许多公司通过不同的方法实现这一目标。工作组的一个子团队，即本文的作者，对更广泛的小组进行了调查，以确定导致建立 GMP 级生产细胞系的潜在共性。调查结果确实突出了为典型CLD计划建立框架的常见和必要做法（表2）。表 2. 抗体程序的典型细胞系开发工作量。阶段载体构建转染到克隆细胞克隆到先导克隆努力取决于每个程序生成的表达载体的数量。取决于每个靶标的分子数 （S2Q11） 和每个分子的重复数 （S2Q9）。从单细胞克隆到 RCB （S3Q101） 的每分子中位数为1.5FTE。大多数受访者回答 2.0FTE。范围每个分子0.5至3.0 FTE。瓶颈重链和轻链基因 （S1Q27） 的DNA合成（外包）。在补料分批生产中全面表征转染池所需的时间和精力。使用的方法、设备和原材料差异很大（参见S3Q15、S3Q48、S3Q83、S3Q89至 93）。加速和风险表达载体序列确认与转染同时进行（S1Q12、S1Q14）。混合细胞直接进入单细胞克隆，无需生产模型表征（S2Q30）。平台可变性考虑了所需的资源和时间。每个步骤的特征化程度决定了时间和精力。复杂分子问题每个靶标有更多的表达载体变体，以确保生物生产（S1Q38、S1Q39、S1Q40）。在克隆之前需要更多时间来测试复杂分子池 （S2Q73）。在进行单细胞克隆（S3Q22）之前，池表征 （S3Q21）必须满足既定标准 （S3Q41）。典型的细胞系开发过程从分子的内部成影性评估开始。这有助于确定 mAb或复杂分子的适用性，并就如何最好地设计分子以进行重组蛋白表达提供指导。有趣的是，一些受访者表示他们使用建模方法 （12%; S3Q5），以及更多计划实施模型 （54%; S3Q6） 来协助克隆选择 （S3Q5）。使用计算机模型设计编码序列已被证明可以降低抗体聚集倾向，从而改善生物治疗分子的CMC特性。这种方法虽然仍处于起步阶段，但未来可能会更多地关注降低分子选择的风险，并有望减少克隆开发过程中的返工。在计算机模型成为主流之前，公司将依赖先验知识和平台方法通过克隆选择进行载体构建。表达质粒构建有许多步骤，这项工作可以在内部资源和外部供应商（例如 CRO）之间分配。确认表达载体的核苷酸序列以识别正确的生物开放阅读框非常重要，大多数公司在转染前都会这样做。根据需要，可以通过并行执行转染和序列确认来加速程序。基因和质粒的设计和构建的总时间表在4到8周或更长时间之间（图2c），其中大部分时间用于外部基因合成。大多数公司都在4周内完成整个过程，这似乎是基因合成交付时间达到预期的典型时间表。对于大多数公司来说，转染通常被认为是细胞系开发的起点。这可能是由于在程序开始之前就选择了用于程序开发和质粒构建的特定分子，因此在程序开始之前就存在风险。然而，这将取决于领导层的决策和商业模式，例如，根据合同工作的公司（例如CMO、CRO）似乎更典型的做法是从预转染开始。构建质粒（可以是可变的和序列依赖性的）后，转染将遵循平台程序，通常需要2到3周的时间进行细胞回收和选择，达到合适的活力以进入下一步。调查受访者在单细胞克隆之前、之前或期间对转染池进行表征方面几乎持平分歧，但更多的公司在开发复杂分子时会在克隆之前对池进行表征。如前所述，矿池特征化降低了风险，但需要时间。选择直接进入单细胞克隆的受访者表示，从转染到开始克隆的典型时间总共为3-4周。大多数公司在克隆阶段（S3Q24）为每个靶标（每个程序）开发一个分子。然而，当每个靶标的多个分子开始克隆阶段时，分子数量通常在 RCB （S3Q25）之前减少。这可以在细胞培养板、摇瓶或微型生物反应器（S3Q26）中进行，并且可能取决于每个系统产生的数据质量，从而能够选择最佳分子。有趣的是，CLD和非CLD数据几乎同样用于影响减少每个靶标分子的决定（S3Q28）。书面回答（S3Q30）表明，在克隆开始时可能无法牢固确定每种分子作为治疗药物的适用性，需要更多时间进行临床前评估和/或需要克隆生产的材料来帮助确定分子的有效性。在大多数情况下，CLD组不对减少每个靶标分子的决定（S3Q32）负责。这可能会影响时间表，因为CLD和负责选择决策的小组之间需要有效的沟通。单细胞克隆开始后，开发将继续不间断，直到创建细胞库。克隆细胞库提供了在需要时暂停的机会，并通过在灾难性克隆丢失的情况下为重新建立克隆开发提供中间点来降低开发过程中持续细胞系作的风险。首次安全库的时间是可变的，但可能需要长达>11周，如果发生克隆丢失，这将是相当多的开发时间。更多的公司可以提前（4-5周）建立银行以减轻这种风险。如前所述，用于克隆开发和表征的方法差异很大（图6），但所需的总体时间和精力通常相似，从单细胞克隆到先导克隆选择的中位时间需要17-20周（图 6d），从克隆到RCB每个分子的中位CLD FTE（图 6c）。一开始，作者的方法是调查CLD工作组制定RCB所涉及的时间、精力和步骤，较少关注过程中涉及的具体方法。正如所怀疑的那样，方法差异很大，但主要步骤相似，包括载体开发、转染池生成、单细胞沉积、克隆来源成像、生长以增加细胞数量以转移到细胞培养板、过渡到悬浮生长、细胞质量放大以及在合适的按比例缩小的生物反应器模型中评估克隆生产性能和稳定性。在此过程中，通过评估生长和生产率以及后期产品质量的选择过程，克隆数量被减少到可管理的数量。由于用于执行这些步骤的实际方法因公司而异，因此我们在“单细胞克隆和先导克隆选择阶段”部分纳入并讨论了相关的调查回复图表以及可能影响时间和精力的变量。我们讨论了使用NGS等新技术进行细胞系表征，这肯定会提高克隆的质量，以及自动化的实施，这应该可以减少工作量并可能加快开发时间。作者承认，有许多方法可以实现创建高产克隆衍生细胞系的共同目标，但加快开发和产生更好克隆的总体推动导致大多数受访者在24-28周内完成CLD（即基因到先导克隆），范围更广<14->46 周（图7）。作者将这个广泛的时间范围归因于可能的CLD单元作的可变性。例如，35%的受访者在生成RCB之前完成了稳定性研究，但在选择先导克隆之前，这一数字增加到77%。延迟稳定性评估的决定是一个潜在的加速杠杆，可能会增加更多风险，从而影响时间表。CLD集团为加快开发时间而承担的独特风险在很大程度上取决于平台的先验知识和管理层对风险的接受程度。图7：单克隆抗体开发的调查阶段和总结时间表从细胞系开发人员的角度来看，作者同意大多数公司都在以与细胞生长速率一致的速度推进项目。换句话说，从单个细胞转变为适合生物反应器生产的细胞团取决于细胞在平台过程中的生长能力，使用相同宿主细胞种类的公司之间也是如此。没有受访者愿意等待超过2周，让生长缓慢的抗体克隆达到可以进行评估的程度，大多数人表示他们根本不会等待 （S3Q88）。回复表明愿意为复杂分子克隆等待更长的时间，这可能是由于与生产非抗体分子相关的不确定性。这凸显了细胞生长速率在确定时间表方面的重要性，以及细胞系开发人员在平衡不确定性风险的同时快速推进项目的愿望。因此，总体时间的可变性更多地与用于评估和从众多候选细胞系中选择最佳细胞系的方法、使用有限数据做出决策所涉及的风险以及这些决策的方式和人员有关。这是所有CLD小组都面临的挑战。因此，回到标题问题“我们什么时候会有克隆？这实际上取决于做出克隆选择决策需要多少数据，这导致了另一个问题：“我们愿意承担多少风险？识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！请注明：姓名+研究方向！本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

With its ability to specifically inhibit the mutant IDH1 enzyme, TIBSOVO addresses an unmet need in personalized cancer treatment, offering new hope for patients with limited options. As clinical evidence continues to support its efficacy and safety, TIBSOVO is positioned for strong growth in the oncology market, especially with expanding indications and global market penetration. LAS VEGAS, April 8, 2025 /PRNewswire/ -- DelveInsight's " TIBSOVO Market Size, Forecast, and Market Insight Report" highlights the details around TIBSOVO, the first and only targeted therapy approved for patients with previously treated IDH1-mutated cholangiocarcinoma. The report provides product descriptions, patent details, and competitor products (marketed and emerging therapies) of TIBSOVO. The report also highlights the historical and forecasted sales from 2020 to 2034 segmented into 7MM [the United States, the EU4 (Germany, France, Italy, and Spain), the United Kingdom, and Japan]. Servier's TIBSOVO (ivosidenib) Overview TIBSOVO (ivosidenib) is a small molecule developed by Servier, acts as an isocitrate dehydrogenase-1 (IDH1) inhibitor. It is indicated for patients with a susceptible IDH1 mutation, which is identified through an FDA-approved test. Currently, TIBSOVO is approved for the treatment of newly diagnosed acute myeloid leukemia (AML), relapsed or refractory AML, relapsed or refractory myelodysplastic syndromes (MDS), and locally advanced or metastatic cholangiocarcinoma. According to Servier's pipeline, TIBSOVO is also being actively investigated for a range of additional indications, with key areas of exploration including solid tumors and hematological malignancies. Learn more about TIBSOVO projected market size for AML, cholangiocarcinoma, and MDS @ TIBSOVO Market Potential The oncology market has experienced significant growth in recent years, driven by advances in cancer research, the development of targeted therapies, and the increasing global prevalence of cancer. As the second-leading cause of death worldwide, cancer continues to pose a major public health challenge, creating a substantial demand for innovative treatments. The market is marked by a shift toward personalized medicine, where therapies are tailored to an individual's genetic profile, allowing for more effective and less toxic treatments. Immunotherapies, such as checkpoint inhibitors, CAR-T cell therapies, and oncolytic virus therapies, are at the forefront of these advancements, offering new hope to patients with previously untreatable cancers. Moreover, the oncology market is expanding due to the growing adoption of precision oncology and molecular diagnostics, which enable earlier and more accurate detection of cancer. This has led to increased investments in research and development, especially in areas like liquid biopsies, companion diagnostics, and next-generation sequencing. The demand for more effective and accessible cancer treatments is fueling innovation in both the pharmaceutical and biotechnology sectors, with numerous new drugs and therapies entering clinical trials and moving toward commercialization. As a result, the oncology market is poised to continue growing, with significant opportunities for breakthrough therapies in immuno-oncology, targeted treatments, and gene therapies. DelveInsight has expertise in the oncology market with an experienced team handling the oncology domain proficiently. DelveInsight has released a series of epidemiology-based market reports on Acute Myeloid Leukemia, Cholangiocarcinoma, and Myelodysplastic Syndrome. These reports include a comprehensive understanding of current treatment practices, emerging drugs, market share of individual therapies, and current and forecasted market size from 2020 to 2034, segmented into 7MM [the United States, the EU4 (Germany, France, Italy, and Spain), the United Kingdom, and Japan]. Gain deeper insights into these diseases with a customized report tailored to your needs. Connect with us today—our experts are ready to assist you! Emerging Competitors of TIBSOVO TIBSOVO faces significant competition in the newly diagnosed AML market from several alternative treatments. Oral therapies like VENCLEXTA (venetoclax), which inhibits BCL-2, and DAURISMO (glasdegib), which targets the hedgehog pathway, present strong contenders. Additionally, emerging therapies such as Lisaftoclax (Ascentage Pharma), another BCL-2 inhibitor, and gilteritinib (Astellas), a kinase inhibitor, are expected to further challenge TIBSOVO in the newly diagnosed AML space. In the R/R AML market, TIBSOVO competes with several therapies, including XOSPATA (gilteritinib), IDHIFA (enasidenib), and others. Emerging therapies such as Ziftomenib (Kura Oncology) and RVU-120 (Ryvu Therapeutics) are also expected to compete with TIBSOVO upon their approval. Ziftomenib, a small molecule developed by Kura Oncology, is currently in Phase I/II trials. In the relapsed/refractory (R/R) MDS market, TIBSOVO faces competition from therapies such as RYTELO (Imetelstat), an IV injection that inhibits oligonucleotide telomerase, and REBLOZYL (Luspatercept), a subcutaneous injection, among other treatment options. In the metastatic cholangiocarcinoma market, TIBSOVO faces relatively less competition, as there are few approved therapies. One such competitor is PEMAZYRE (pemigatinib), a kinase inhibitor that was approved in the US in 2020 and in Europe in 2021. Whereas, Tyra Biosciences' TYRA-200, an FGFR1/2/3 inhibitor, is in phase I stage of development that might be a threat to TIBSOVO one approved. To know more about the number of competing drugs in development, visit @ TIBSOVO Market Positioning Compared to Other Drugs Key Developmental Activities of TIBSOVO In October 2023, Servier announced that the FDA has approved TIBSOVO (ivosidenib tablets) for the treatment of IDH1-mutated R/R MDS. In May 2023, Servier announced that the European Commission has approved TIBSOVO as a targeted therapy in two indications: in combination with azacitidine for the treatment of adult patients with newly diagnosed AML with an isocitrate dehydrogenase-1 R132 mutation who are not eligible to receive standard induction chemotherapy; as well as in monotherapy for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 R132 mutation who were previously treated by at least one prior line of systemic therapy. In May 2022, Servier announced FDA approval of TIBSOVO (ivosidenib tablets) in combination with azacitidine for patients with newly diagnosed IDH1-mutated acute myeloid leukemia. In August 2021, Servier announced FDA approval for TIBSOVO (ivosidenib tablets) for the treatment of adult patients with previously treated, locally advanced, or metastatic cholangiocarcinoma with an IDH1 mutation as detected by an FDA-approved test. TIBSOVO is the first and only targeted therapy approved for patients with previously treated IDH1-mutated cholangiocarcinoma. In May 2019, Agios announced FDA approval of TIBSOVO (ivosidenib tablets) as monotherapy for newly diagnosed adult patients with IDH1 mutant acute myeloid leukemia not eligible for intensive chemotherapy. In July 2018, the FDA approved TIBSOVO (ivosidenib) for relapsed or refractory acute myeloid leukemia with an idh1 mutation. In February 2018, the FDA accepted a new drug application and granted priority review for ivosidenib in relapsed or refractory AML with an IDH1 mutation. In December 2017, Agios submitted an NDA to the FDA for ivosidenib for the treatment of patients with relapsed/refractory aml and an IDH1 mutation. TIBSOVO Patent Details TIBSOVO is a drug owned by Servier Pharmaceuticals. Currently, it is protected by 10 Orange book-listed patents filed from 2018 to 2023, out of which none have expired yet. It is also protected by ODE exclusivity for various indications. Discover how TIBSOVO is shaping the blood cancer treatment landscape @ TIBSOVO Side Effects TIBSOVO Market Dynamics In recent years, the therapeutic landscape has undergone significant changes, with promising approaches including immunotherapy, chemotherapy combined with targeted treatments, and the regulation of immune checkpoint-mediated signaling pathways. One such treatment, Ivosidenib, works by inducing the bone marrow to develop normal blood cells, helping to reduce the frequency of blood transfusions. Investment in the research and development of drugs has surged, contributing to a rich pipeline and forecasting promising opportunities in the treatment markets for AML and cholangiocarcinomas. Therapies like TIBSOVO have the potential to capture market attention due to their efficacy and innovation. As healthcare spending continues to rise globally, the pharmaceutical market is expected to expand, providing greater opportunities for market penetration by manufacturers and facilitating the development and distribution of new treatments. Despite progress in cancer treatment, significant gaps remain in understanding the full process that governs carcinogenesis and resistance to treatments, particularly in cancers like acute myeloid leukemia (AML). This highlights the need for more advanced research to address these challenges. Additionally, the limited biomarker testing for patients with the IDH1 mutation restricts the targeted patient pool, posing a challenge for therapies like TIBSOVO to achieve their expected market share. The increasing competition from emerging therapies, such as KEYTRUDA (pembrolizumab), IMFINZI (durvalumab), and the combination of Azacitidine + Venetoclax, further intensifies the pressure on TIBSOVO. Moreover, the difficulty in obtaining sufficient patient pools and diagnostic samples during disease recurrence presents significant hurdles to the effective development of translational research, potentially slowing progress in optimizing treatments. Dive deeper to get more insight into TIBSOVO's strengths & weaknesses relative to competitors @ TIBSOVO Market Drug Report Table of Contents Related Reports Acute Myeloid Leukemia Market Acute Myeloid Leukemia Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key AML companies including Agios Pharmaceuticals, Abbvie, Jazz Pharmaceuticals, Astellas Pharma, Pfizer, Novartis Oncology, Daiichi Sankyo, AstraZeneca, Astex Pharmaceuticals, Inc., Chimerix, Takeda, Rafael Pharmaceuticals Inc., Delta-Fly Pharma, GlycoMimetics Incorporated, BerGenBio ASA, MacroGenics, Syndax Pharmaceuticals, Arog Pharmaceuticals, Forma Therapeutics, Sellas Life Sciences Group, Actinium Pharmaceuticals, Clear Creek Bio Inc., CellCentric Ltd., Biosight Ltd., Astex Pharmaceuticals, Inc., Curis, Inc., NexImmune Inc., Immunomedics, Inc., Sumitomo Dainippon Pharma Co., Ltd., Incyte Corporation, Aprea Therapeutics, Immunicum, DCPrime BV, GT Biopharma, Inc., Hanmi Pharmaceutical Company Limited, Cardiff Oncology, Bio-Path Holdings, Actinium Pharmaceuticals, Aptevo Therapeutics, Synimmune GmbH, GEMoaB Monoclonals, ImmunoGen, Inc., AGC Biologics S.p.A., Precigen, Inc., Novartis Pharmaceuticals, Xencor, Inc., Novartis, Celgene, Bristol Myers Squibb, among others. Relapsed/Refractory Acute Myeloid Leukemia Market Relapsed/Refractory Acute Myeloid Leukemia Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key R/R AML companies including Agios Pharmaceuticals, Abbvie, Jazz Pharmaceuticals, Astellas Pharma, Pfizer, Novartis Oncology, Daiichi Sankyo, AstraZeneca, Astex Pharmaceuticals, Inc., Chimerix, Takeda, Rafael Pharmaceuticals Inc., Delta-Fly Pharma, GlycoMimetics Incorporated, BerGenBio ASA, MacroGenics, Syndax Pharmaceuticals, Arog Pharmaceuticals, Forma Therapeutics, Sellas Life Sciences Group, Actinium Pharmaceuticals, Clear Creek Bio Inc., CellCentric Ltd., Biosight Ltd., Astex Pharmaceuticals, Inc., Curis, Inc., NexImmune Inc., Immunomedics, Inc., Sumitomo Dainippon Pharma Co., Ltd., Incyte Corporation, Aprea Therapeutics, Immunicum, DCPrime BV, GT Biopharma, Inc., Hanmi Pharmaceutical Company Limited, Cardiff Oncology, Bio-Path Holdings, Actinium Pharmaceuticals, Aptevo Therapeutics, Synimmune GmbH, GEMoaB Monoclonals, ImmunoGen, Inc., AGC Biologics S.p.A., Precigen, Inc., Novartis Pharmaceuticals, Xencor, Inc., Novartis, Celgene, Bristol Myers Squibb, among others. Myelodysplastic Syndrome Market Myelodysplastic Syndrome Market Insight, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of market trends, market drivers, market barriers, and key MDS companies such as Bristol-Myers Squibb, Astex Pharmaceutical, Taiho Oncology, Fibrogen, AbbVie, Gilead Sciences, Novartis, Syros Pharmaceuticals, Takeda, Pfizer, Geron Corporation, Karyopharm Therapeutics, Antengene Corporation, BerGenBio ASA, Jazz Pharmaceuticals, Aprea Therapeutics, Sanofi, Medac, among others. Cholangiocarcinoma Market Cholangiocarcinoma Market Insight, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of market trends, market drivers, market barriers, and key cholangiocarcinoma companies such as AstraZeneca, Decalth Systems, Basilea Pharmaceutica, Taiho Oncology, Eisai Pharmaceuticals, TransThera Sciences, Incyte Corporation, Roche, Agios Pharmaceuticals, Servier Pharma, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED