CXCR4

4WARD Phase 3 chronic neutropenia trial in full swing; full enrollment on track for 3Q or 4Q 2025 and top-line data in 2H 2026 Additional analyses of mavorixafor clinical trial data increase confidence in successful outcome of 4WARD trial XOLREMDI® net U.S. revenues $3.5 million since May 2024 launch Conference call and webcast today at 8:30 am ET BOSTON, May 01, 2025 (GLOBE NEWSWIRE) -- X4 Pharmaceuticals (Nasdaq: XFOR), a company driven to improve the lives of people with rare diseases of the immune system, today reported financial results for the first quarter ended March 31, 2025, and highlighted key recent events and expected upcoming milestones. “The first quarter of 2025 was an extremely productive and value-adding period for X4,” said Paula Ragan, Ph.D., President and Chief Executive Officer of X4 Pharmaceuticals. “Not only did we make significant progress in activating sites and enrolling participants in our ongoing mavorixafor Phase 3 trial in chronic neutropenia, but we also continued to support U.S. commercialization of XOLREMDI (mavorixafor) in WHIM syndrome, while also significantly expanding our global potential following acceptance of our EU regulatory submission in WHIM and the announcement of two international commercialization partnerships. We look forward to continuing to deliver on our milestones in the coming year toward our goal of maximizing the potential of mavorixafor to benefit patients with rare immunodeficiencies.” Key First-Quarter 2025 and Recent Corporate Highlights Advancing Mavorixafor in Chronic Neutropenia (CN) 4WARD Trial Updates. X4 continues to enroll participants in its ongoing global, pivotal Phase 3 clinical trial (NCT06056297), evaluating oral, once-daily mavorixafor in people with congenital, acquired primary autoimmune, or idiopathic CN who are experiencing recurrent and/or serious infections. As previously reported, an amendment to the 4WARD protocol has been implemented, focusing enrollment on those with the highest unmet needs and refining the definition of ANC response, making it consistent across all trial participants. Overall, the trial seeks to demonstrate statistically significant increases in ANC response and corresponding decreases in annualized infection rate between those on mavorixafor versus placebo.To date, the demographics of the enrolled population are balanced and representative of the targeted commercial CN patient populations; baseline absolute neutrophil counts (ANC) and historical infection rates are consistent with this high unmet need population.X4 continues to expect full enrollment in the trial in the third or fourth quarter of 2025, and disclosure of top-line data in the second half of 2026. Further Data Analyses Continue to Increase Confidence in Potential 4WARD Success. X4 recently applied the 4WARD trial ANC response criteria to individual participant results in the completed mavorixafor Phase 3 4WHIM trial and the Phase 2 CN trial to further assess the likelihood of 4WARD trial success. The company believes that the results of these analyses (details of which are available in the company’s updated investor presentation) further support the potential of mavorixafor to not only elevate ANC in the 4WARD trial participants, but that these ANC elevations should correspond with significant reductions in annualized infection rates in the mavorixafor treated trial population.Mavorixafor Patent Update: In March 2025, X4 received a Notice of Allowance from the U.S. Patent and Trademark Office on its application 17/941,509, which claims include the use of mavorixafor in treating severe chronic, idiopathic, and autoimmune neutropenia in patients without a CXCR4 genetic variation. The patent is expected to expire in the U.S. in March of 2041; similar patent applications are pending in Europe, China, Japan, and Canada. Commercializing XOLREMDI® (mavorixafor) in WHIM Syndrome, a Rare Primary Immunodeficiency Revenue Update: X4 has now generated $3.5 million in U.S. sales of XOLREMDI (mavorixafor) from its mid-May 2024 launch through March 2025. The company also disclosed that newly identified patients on treatment are increasing in share of the overall current population on XOLREMDI, demonstrating the positive impact of ongoing WHIM education and awareness.Upcoming WHIM Clinical and Survey Data Presentations: Published abstracts accepted for poster presentation at the upcoming meeting of the Clinical Immunology Society (CIS) summarize the following results: Phase 3 Open Label Extension (OLE) Wart Data: Two-year data from the OLE phase of the 4WHIM Phase 3 clinical trial evaluating once-daily oral mavorixafor in people with WHIM syndrome revealed marked clinical improvement in wart severity as assessed by Clinical Global Impression of Severity across 70 defined wart areas.First-Ever WHIM Infection Burden Survey Results: Of the 20 WHIM patient respondents, 60% of those <18 years and 73% of those ≥18 years reported experiencing at least one infection in the previous 3 months, with 25% requiring overnight hospitalization due to infection. The study concludes that “the frequency and severity of infections requiring medical care and hospitalization underscores the urgency to proactively treat patients with WHIM syndrome.” Maximizing the Global Opportunity for Mavorixafor in WHIM Syndrome: MAA Acceptance. In January 2025, X4 announced that its submitted Marketing Authorization Application (MAA) for mavorixafor in the treatment of WHIM syndrome was validated for review by the European Medicines Agency (EMA), enabling possible approval in the first half of 2026.Ex-US Partnerships. In the first quarter of 2025, the company announced that it had entered into two ex-U.S. partnerships for the commercialization of mavorixafor: the first, an exclusive licensing and supply agreement under which Norgine Pharma UK will commercialize mavorixafor in Europe, Australia, and New Zealand and the second, with taiba rare to distribute and commercialize XOLREMDI for the treatment of WHIM syndrome in Saudi Arabia, United Arab Emirates, Qatar, Oman, Kuwait, Bahrain, and Egypt following the necessary regulatory approvals in those countries and/or regions. Strategic RestructuringIn February 2025, X4 announced a strategic restructuring to sharpen focus and maximize the opportunity for mavorixafor in chronic neutropenia while also optimizing its U.S. promotion of XOLREMDI. X4 continues to expect that these efforts will decrease spending by $30-35 million annually. Reverse Stock SplitOn April 24, 2025, X4 announced a one-for-thirty reverse stock split of the company’s common stock. The reverse stock split took effect at 12:01 a.m. ET on April 28, 2025, and the company’s common stock began trading on a split-adjusted basis on The Nasdaq Capital Market as of the opening of trading the same day under a new CUSIP number (98420X202). The reverse split reduced the number of outstanding shares of the company’s Common Stock from approximately 173.6 million shares to approximately 5.8 million shares. First-Quarter 2025 Financial Results Cash position: X4 had $87.7 million in cash, cash equivalents, restricted cash, and marketable securities as of March 31, 2025. The company continues to believe it has sufficient funds to support operations into the first half of 2026.Revenue and Cost of Revenue: For the first quarter ended March 31, 2025, X4 reported net revenue of $28.8 million and cost of revenue of $4.7 million. Revenue in the quarter included license and other revenues of $27.9 million associated with the completed Norgine agreement and XOLREMDI product revenue of $0.9 million. Cost of revenue included $4.5 million of sublicense royalties associated with the Norgine agreement.Research and Development (R&D) Expenses were $18.5 million for the first quarter ended March 31, 2025, as compared to $19.9 million for the comparable period in 2024. R&D expenses included $0.3 million of certain non-cash expenses for the first quarter ended March 31, 2025.Selling, General, and Administrative (SG&A) Expenses were $15.0 million for the first quarter ended March 31, 2025, as compared to $17.4 million for the comparable period in 2024. SG&A expenses included $0.3 million of certain non-cash expenses for the first quarter ended March 31, 2025.Net Income (Loss): X4 reported net income of $0.3 million for the first quarter ended March 31, 2025, as compared to a net loss of $51.8 million for the comparable period in 2024. Net income included $0.5 million of stock-based compensation expenses for the first quarter ended March 31, 2025. Conference Call and Webcast X4 will host a conference call and webcast today at 8:30 am ET to discuss these financial results and business highlights. The conference call can be accessed by dialing 1-800-343-4849 from the United States or 1-203-518-9848 internationally, followed by the conference ID: X4PHARMA. The live webcast will be accessible through the investor relations section of X4 Pharmaceuticals’ website at www.x4pharma.com. Following the conclusion of the call, a webcast replay will be available on the website. About WHIM SyndromeWHIM syndrome is a rare, combined primary immunodeficiency and chronic neutropenic disorder caused by CXCR4 receptor dysfunction that results in impaired mobilization of white blood cells from the bone marrow into peripheral circulation. WHIM syndrome is named for its four classic manifestations: warts, hypogammaglobulinemia, infections, and myelokathexis, although only a minority of patients experience all four manifestations in the acronym. People with WHIM syndrome characteristically have low blood levels of neutrophils (neutropenia) and lymphocytes (lymphopenia), and as a result, experience serious and/or frequent infections. About XOLREMDI® (mavorixafor)XOLREMDI (mavorixafor) is a selective CXCR4 receptor antagonist approved in the U.S. as a once-daily oral treatment for use in patients 12 years of age and older with WHIM syndrome to increase the number of circulating mature neutrophils and lymphocytes. XOLREMDI is the only treatment specifically approved for patients with WHIM syndrome in the U.S. About Chronic Neutropenia and MavorixaforChronic neutropenia is a primary, rare blood condition lasting more than three months, persistently or intermittently, and characterized by low levels of circulating neutrophils and increased risk of infections and reduced quality of life due to abnormally low levels of neutrophils circulating in the blood. Neutrophils are retained in the bone marrow by the CXCR4/CXCL12 axis, creating a reserve of cells. Downregulation of the CXCR4 receptor by mavorixafor, an orally active CXCR4 antagonist, has been shown to mobilize functional neutrophils from the bone marrow into the peripheral blood across multiple disease states. The level of circulating neutrophils is typically measured by drawing blood to determine the absolute neutrophil count (ANC). About the 4WARD Clinical TrialThe 4WARD trial is a global, pivotal Phase 3 clinical trial (NCT06056297) evaluating the efficacy, safety, and tolerability of oral, once-daily mavorixafor (with or without G-CSF) in people with congenital, acquired primary autoimmune, or idiopathic chronic neutropenia who are experiencing recurrent and/or serious infections. The 52-week trial is a randomized, double-blind, placebo-controlled, multicenter study aiming to enroll 150 participants with confirmed trough ANC levels less than 1,000 cells per microliter at baseline screening and histories of two or more serious and/or recurrent infections in the prior year. The primary endpoint of the trial is based on two outcome measures: annualized infection rate and positive ANC response. About X4 PharmaceuticalsX4 is delivering progress for patients by developing and commercializing innovative therapies for those with rare diseases of the immune system and significant unmet needs. Leveraging expertise in CXCR4 and immune system biology, X4 has successfully developed mavorixafor, an orally available CXCR4 antagonist that is currently being marketed in the U.S. as XOLREMDI® in its first indication. The company is also evaluating additional uses of mavorixafor and is conducting a global, pivotal Phase 3 clinical trial (4WARD) in people with certain chronic neutropenic disorders. X4 is headquartered in Boston, Massachusetts. For more information, please visit www.x4pharma.com. X4 Forward Looking Statements This press release contains forward-looking statements within the meaning of applicable securities laws, including the Private Securities Litigation Reform Act of 1995, as amended. These statements may be identified by the words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target,” or other similar terms or expressions that concern X4’s expectations, strategy, plans, or intentions. Forward-looking statements include, without limitation, implied or express statements regarding the initiation, timing, progress, and results of our current and future preclinical studies and clinical trial; the timing and period during which the results of the trials will become available and reported, as well as our research and development programs; market opportunities for X4’s product candidates, including potential benefits from partnerships; expectations regarding the commercial potential of mavorixafor and ongoing engagement and feedback from regulatory authorities; and the sufficiency of X4’s cash resources and pro forma cash resources, including the potential impact of the 2025 strategic restructuring, and expectations regarding X4’s cash runway. Any forward-looking statements in this press release are based on management’s current expectations and beliefs. These forward-looking statements are neither promises nor guarantees of future performance, and are subject to a variety of risks and uncertainties, many of which are beyond X4’s control, which could cause actual results to differ materially from those contemplated in these forward-looking statements, including the risks that: X4’s restructuring activities may be more costly or time-consuming than expected or may not achieve their intended results and savings; X4’s future financial performance and position may not improve resulting in difficulties in implementing X4’s business strategy, and plans and objectives for future operations; the expected decrease in annual spending could negatively impact X4’s commercial plans and strategy for mavorixafor; the expected sufficiency of X4’s existing cash resources and runway may not be accurate resulting in the need for additional financing sooner than anticipated or unexpected liquidity constraints; the internal and external costs required for X4’s ongoing and planned activities, and the resulting impact on expense and use of cash, may be higher than expected, which may cause the company to use cash more quickly than expected or to change or curtail some of X4’s plans or both; the expected availability, content, and timing of clinical data from X4’s ongoing clinical trials of mavorixafor may be delayed or unavailable, including the ongoing Phase 3 clinical trial; trials, studies and research programs may be delayed and may not have satisfactory outcomes, additionally earlier trials and studies may not be predictive of later trials and studies; the design and rate of enrollment for current clinical trials may not enable successful completion of the trial(s); the commercial opportunity for mavorixafor may be smaller than anticipated; X4 may be unable to obtain and maintain regulatory approvals; adverse safety effects may arise from the testing or use of X4’s product and product candidates; the need to align with collaborators may hamper or delay development and commercialization efforts or increase costs; business may be adversely affected and costs may increase if any of the company’s key collaborators fails to perform its obligations or terminates the collaboration; X4’s may be unable to advance and commercialize and increase sales in mavorixafor to treat chronic neutropenia or to optimize the U.S. promotion of XOLREMDI® (mavorixafor), approved for the treatment of WHIM; and other risks and uncertainties, including those described in the section entitled “Risk Factors” in X4’s most recent Annual Report on X4’s Form 10-K , as well as in other filings X4 makes with the Securities and Exchange Commission, including its quarterly report on Form 10-Q, from time to time. X4 undertakes no obligation to update the information contained in this press release to reflect new events or circumstances, except as required by law. (Tables Follow) X4 PHARMACEUTICALS, INC.CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS(in thousands, except per share amounts)(unaudited) Three Months Ended March 31, 2025 2024 License and other revenue $27,865 $— Product revenue, net 942 — Total revenue 28,807 — Costs and operating expenses: Cost of revenue 4,716 — Research and development 18,513 19,854 Selling, general and administrative 15,021 17,435 Total operating expenses 38,250 37,289 Loss from operations (9,443) (37,289)Other income (expense), net 9,759 (14,458)Income (loss) before provision for income taxes 316 (51,747)Provision for income taxes 34 19 Net income (loss) $282 $(51,766)Net income (loss) per share- basic $0.04 $(7.77)Weighted average common shares outstanding- basic 6,840 6,666 Net income (loss) per share- diluted $0.04 $(7.77)Weighted average common shares outstanding- diluted 6,869 6,666 X4 PHARMACEUTICALS, INC.CONDENSED CONSOLIDATED BALANCE SHEETS(in thousands)(unaudited) March 31,2025 December 31,2024Current assets: Cash and cash equivalents $40,257 $55,699 Accounts receivable 509 1,070 Marketable securities 46,694 46,361 Research and development incentive receivable 665 640 Inventory 3,089 2,817 Prepaid expenses and other current assets 4,483 5,588 Total current assets 95,697 112,175 Property and equipment, net 487 776 Goodwill 17,351 17,351 Intangible asset, net 9,813 10,000 Right-of-use assets 3,652 4,065 Other assets 3,013 2,080 Total assets $130,013 $146,447 Current liabilities: Accounts payable $11,115 $8,621 Accrued expenses 12,611 23,005 Deferred revenue 855 — Current portion of lease liability 1,303 1,251 Total current liabilities 25,884 32,877 Long-term debt, including accretion, net of discount 75,629 75,425 Lease liabilities 1,109 1,410 Warrant liability 2,925 13,755 Deferred revenue and other liabilities 1,522 831 Total liabilities 107,069 124,298 Total stockholders' equity 22,944 22,149 Total liabilities and stockholders' equity $130,013 $146,447 X4 Investor Contact:X4 Media Contact:Daniel FerryLifeSci Advisorsdaniel@lifesciadvisors.com(617) 430-7576Rhiannon JeselonisTen Bridge Communicationsrhiannon@tenbridgecommunications.com

4WARD Phase 3 chronic neutropenia trial in full swing; full enrollment on track for 3Q or 4Q 2025 and top-line data in 2H 2026 Additional analyses of mavorixafor clinical trial data increase confidence in successful outcome of 4WARD trial XOLREMDI® net U.S. revenues $3.5 million since May 2024 launch Conference call and webcast today at 8:30 am ET BOSTON , May 01, 2025 (GLOBE NEWSWIRE) -- X4 Pharmaceuticals (Nasdaq: XFOR), a company driven to improve the lives of people with rare diseases of the immune system, today reported financial results for the first quarter ended March 31, 2025 , and highlighted key recent events and expected upcoming milestones. “The first quarter of 2025 was an extremely productive and value-adding period for X4,” said Paula Ragan , Ph.D., President and Chief Executive Officer of X4 Pharmaceuticals . “Not only did we make significant progress in activating sites and enrolling participants in our ongoing mavorixafor Phase 3 trial in chronic neutropenia, but we also continued to support U.S. commercialization of XOLREMDI (mavorixafor) in WHIM syndrome, while also significantly expanding our global potential following acceptance of our EU regulatory submission in WHIM and the announcement of two international commercialization partnerships. We look forward to continuing to deliver on our milestones in the coming year toward our goal of maximizing the potential of mavorixafor to benefit patients with rare immunodeficiencies.” Key First-Quarter 2025 and Recent Corporate Highlights Advancing Mavorixafor in Chronic Neutropenia (CN) 4WARD Trial Updates. X4 continues to enroll participants in its ongoing global, pivotal Phase 3 clinical trial (NCT06056297), evaluating oral, once-daily mavorixafor in people with congenital, acquired primary autoimmune, or idiopathic CN who are experiencing recurrent and/or serious infections. As previously reported, an amendment to the 4WARD protocol has been implemented, focusing enrollment on those with the highest unmet needs and refining the definition of ANC response, making it consistent across all trial participants. Overall, the trial seeks to demonstrate statistically significant increases in ANC response and corresponding decreases in annualized infection rate between those on mavorixafor versus placebo. To date, the demographics of the enrolled population are balanced and representative of the targeted commercial CN patient populations; baseline absolute neutrophil counts (ANC) and historical infection rates are consistent with this high unmet need population. X4 continues to expect full enrollment in the trial in the third or fourth quarter of 2025, and disclosure of top-line data in the second half of 2026. Further Data Analyses Continue to Increase Confidence in Potential 4WARD Success. X4 recently applied the 4WARD trial ANC response criteria to individual participant results in the completed mavorixafor Phase 3 4WHIM trial and the Phase 2 CN trial to further assess the likelihood of 4WARD trial success. The company believes that the results of these analyses (details of which are available in the company’s updated investor presentation) further support the potential of mavorixafor to not only elevate ANC in the 4WARD trial participants, but that these ANC elevations should correspond with significant reductions in annualized infection rates in the mavorixafor treated trial population. Mavorixafor Patent Update: In March 2025 , X4 received a Notice of Allowance from the U.S. Patent and Trademark Office on its application 17/941,509, which claims include the use of mavorixafor in treating severe chronic, idiopathic, and autoimmune neutropenia in patients without a CXCR4 genetic variation. The patent is expected to expire in the U.S. in March of 2041; similar patent applications are pending in Europe , China , Japan , and Canada . As previously reported, an amendment to the 4WARD protocol has been implemented, focusing enrollment on those with the highest unmet needs and refining the definition of ANC response, making it consistent across all trial participants. Overall, the trial seeks to demonstrate statistically significant increases in ANC response and corresponding decreases in annualized infection rate between those on mavorixafor versus placebo. To date, the demographics of the enrolled population are balanced and representative of the targeted commercial CN patient populations; baseline absolute neutrophil counts (ANC) and historical infection rates are consistent with this high unmet need population. X4 continues to expect full enrollment in the trial in the third or fourth quarter of 2025, and disclosure of top-line data in the second half of 2026. Commercializing XOLREMDI® (mavorixafor) in WHIM Syndrome, a Rare Primary Immunodeficiency Revenue Update: X4 has now generated $3.5 million in U.S. sales of XOLREMDI (mavorixafor) from its mid-May 2024 launch through March 2025 . The company also disclosed that newly identified patients on treatment are increasing in share of the overall current population on XOLREMDI, demonstrating the positive impact of ongoing WHIM education and awareness. Upcoming WHIM Clinical and Survey Data Presentations: Published abstracts accepted for poster presentation at the upcoming meeting of the Clinical Immunology Society (CIS) summarize the following results: Phase 3 Open Label Extension (OLE) Wart Data: Two-year data from the OLE phase of the 4WHIM Phase 3 clinical trial evaluating once-daily oral mavorixafor in people with WHIM syndrome revealed marked clinical improvement in wart severity as assessed by Clinical Global Impression of Severity across 70 defined wart areas. First-Ever WHIM Infection Burden Survey Results: Of the 20 WHIM patient respondents, 60% of those <18 years and 73% of those ≥18 years reported experiencing at least one infection in the previous 3 months, with 25% requiring overnight hospitalization due to infection. The study concludes that “the frequency and severity of infections requiring medical care and hospitalization underscores the urgency to proactively treat patients with WHIM syndrome.” Maximizing the Global Opportunity for Mavorixafor in WHIM Syndrome: MAA Acceptance. In January 2025 , X4 announced that its submitted Marketing Authorization Application (MAA) for mavorixafor in the treatment of WHIM syndrome was validated for review by the European Medicines Agency (EMA), enabling possible approval in the first half of 2026. Ex-US Partnerships. In the first quarter of 2025, the company announced that it had entered into two ex- U.S. partnerships for the commercialization of mavorixafor: the first, an exclusive licensing and supply agreement under which Norgine Pharma UK will commercialize mavorixafor in Europe , Australia, and New Zealand and the second, with taiba rare to distribute and commercialize XOLREMDI for the treatment of WHIM syndrome in Saudi Arabia , United Arab Emirates , Qatar , Oman , Kuwait , Bahrain , and Egypt following the necessary regulatory approvals in those countries and/or regions. Phase 3 Open Label Extension (OLE) Wart Data: Two-year data from the OLE phase of the 4WHIM Phase 3 clinical trial evaluating once-daily oral mavorixafor in people with WHIM syndrome revealed marked clinical improvement in wart severity as assessed by Clinical Global Impression of Severity across 70 defined wart areas. First-Ever WHIM Infection Burden Survey Results: Of the 20 WHIM patient respondents, 60% of those <18 years and 73% of those ≥18 years reported experiencing at least one infection in the previous 3 months, with 25% requiring overnight hospitalization due to infection. The study concludes that “the frequency and severity of infections requiring medical care and hospitalization underscores the urgency to proactively treat patients with WHIM syndrome.” MAA Acceptance. In January 2025 , X4 announced that its submitted Marketing Authorization Application (MAA) for mavorixafor in the treatment of WHIM syndrome was validated for review by the European Medicines Agency (EMA), enabling possible approval in the first half of 2026. Ex-US Partnerships. In the first quarter of 2025, the company announced that it had entered into two ex- U.S. partnerships for the commercialization of mavorixafor: the first, an exclusive licensing and supply agreement under which Norgine Pharma UK will commercialize mavorixafor in Europe , Australia, and New Zealand and the second, with taiba rare to distribute and commercialize XOLREMDI for the treatment of WHIM syndrome in Saudi Arabia , United Arab Emirates , Qatar , Oman , Kuwait , Bahrain , and Egypt following the necessary regulatory approvals in those countries and/or regions. Strategic RestructuringIn February 2025 , X4 announced a strategic restructuring to sharpen focus and maximize the opportunity for mavorixafor in chronic neutropenia while also optimizing its U.S. promotion of XOLREMDI. X4 continues to expect that these efforts will decrease spending by $30-35 million annually. Reverse Stock SplitOn April 24, 2025 , X4 announced a one-for-thirty reverse stock split of the company’s common stock. The reverse stock split took effect at 12:01 a.m. ET on April 28, 2025 , and the company’s common stock began trading on a split-adjusted basis on The Nasdaq Capital Market as of the opening of trading the same day under a new CUSIP number (98420X202). The reverse split reduced the number of outstanding shares of the company’s Common Stock from approximately 173.6 million shares to approximately 5.8 million shares. First-Quarter 2025 Financial Results Cash position: X4 had $87.7 million in cash, cash equivalents, restricted cash, and marketable securities as of March 31, 2025 . The company continues to believe it has sufficient funds to support operations into the first half of 2026. Revenue and Cost of Revenue: For the first quarter ended March 31, 2025 , X4 reported net revenue of $28.8 million and cost of revenue of $4.7 million . Revenue in the quarter included license and other revenues of $27.9 million associated with the completed Norgine agreement and XOLREMDI product revenue of $0.9 million . Cost of revenue included $4.5 million of sublicense royalties associated with the Norgine agreement. Research and Development (R&D) Expenses were $18.5 million for the first quarter ended March 31, 2025 , as compared to $19.9 million for the comparable period in 2024. R&D expenses included $0.3 million of certain non-cash expenses for the first quarter ended March 31, 2025 . Selling, General, and Administrative (SG&A) Expenses were $15.0 million for the first quarter ended March 31, 2025 , as compared to $17.4 million for the comparable period in 2024. SG&A expenses included $0.3 million of certain non-cash expenses for the first quarter ended March 31, 2025 . Net Income (Loss): X4 reported net income of $0.3 million for the first quarter ended March 31, 2025 , as compared to a net loss of $51.8 million for the comparable period in 2024. Net income included $0.5 million of stock-based compensation expenses for the first quarter ended March 31, 2025 . Conference Call and Webcast X4 will host a conference call and webcast today at 8:30 am ET to discuss these financial results and business highlights. The conference call can be accessed by dialing 1-800-343-4849 from the United States or 1-203-518-9848 internationally, followed by the conference ID: X4PHARMA. The live webcast will be accessible through the investor relations section of X4 Pharmaceuticals’ website at www.x4pharma.com. Following the conclusion of the call, a webcast replay will be available on the website. About WHIM SyndromeWHIM syndrome is a rare, combined primary immunodeficiency and chronic neutropenic disorder caused by CXCR4 receptor dysfunction that results in impaired mobilization of white blood cells from the bone marrow into peripheral circulation. WHIM syndrome is named for its four classic manifestations: warts, hypogammaglobulinemia, infections, and myelokathexis, although only a minority of patients experience all four manifestations in the acronym. People with WHIM syndrome characteristically have low blood levels of neutrophils (neutropenia) and lymphocytes (lymphopenia), and as a result, experience serious and/or frequent infections. About XOLREMDI® (mavorixafor)XOLREMDI (mavorixafor) is a selective CXCR4 receptor antagonist approved in the U.S. as a once-daily oral treatment for use in patients 12 years of age and older with WHIM syndrome to increase the number of circulating mature neutrophils and lymphocytes. XOLREMDI is the only treatment specifically approved for patients with WHIM syndrome in the U.S. About Chronic Neutropenia and MavorixaforChronic neutropenia is a primary, rare blood condition lasting more than three months, persistently or intermittently, and characterized by low levels of circulating neutrophils and increased risk of infections and reduced quality of life due to abnormally low levels of neutrophils circulating in the blood. Neutrophils are retained in the bone marrow by the CXCR4/CXCL12 axis, creating a reserve of cells. Downregulation of the CXCR4 receptor by mavorixafor, an orally active CXCR4 antagonist, has been shown to mobilize functional neutrophils from the bone marrow into the peripheral blood across multiple disease states. The level of circulating neutrophils is typically measured by drawing blood to determine the absolute neutrophil count (ANC). About the 4WARD Clinical TrialThe 4WARD trial is a global, pivotal Phase 3 clinical trial (NCT06056297) evaluating the efficacy, safety, and tolerability of oral, once-daily mavorixafor (with or without G-CSF) in people with congenital, acquired primary autoimmune, or idiopathic chronic neutropenia who are experiencing recurrent and/or serious infections. The 52-week trial is a randomized, double-blind, placebo-controlled, multicenter study aiming to enroll 150 participants with confirmed trough ANC levels less than 1,000 cells per microliter at baseline screening and histories of two or more serious and/or recurrent infections in the prior year. The primary endpoint of the trial is based on two outcome measures: annualized infection rate and positive ANC response. About X4 Pharmaceuticals X4 is delivering progress for patients by developing and commercializing innovative therapies for those with rare diseases of the immune system and significant unmet needs. Leveraging expertise in CXCR4 and immune system biology, X4 has successfully developed mavorixafor, an orally available CXCR4 antagonist that is currently being marketed in the U.S. as XOLREMDI® in its first indication. The company is also evaluating additional uses of mavorixafor and is conducting a global, pivotal Phase 3 clinical trial (4WARD) in people with certain chronic neutropenic disorders. X4 is headquartered in Boston, Massachusetts . For more information, please visit www.x4pharma.com. X4 Forward Looking Statements This press release contains forward-looking statements within the meaning of applicable securities laws, including the Private Securities Litigation Reform Act of 1995, as amended. These statements may be identified by the words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target,” or other similar terms or expressions that concern X4’s expectations, strategy, plans, or intentions. Forward-looking statements include, without limitation, implied or express statements regarding the initiation, timing, progress, and results of our current and future preclinical studies and clinical trial; the timing and period during which the results of the trials will become available and reported, as well as our research and development programs; market opportunities for X4’s product candidates, including potential benefits from partnerships; expectations regarding the commercial potential of mavorixafor and ongoing engagement and feedback from regulatory authorities; and the sufficiency of X4’s cash resources and pro forma cash resources, including the potential impact of the 2025 strategic restructuring, and expectations regarding X4’s cash runway. Any forward-looking statements in this press release are based on management’s current expectations and beliefs. These forward-looking statements are neither promises nor guarantees of future performance, and are subject to a variety of risks and uncertainties, many of which are beyond X4’s control, which could cause actual results to differ materially from those contemplated in these forward-looking statements, including the risks that: X4’s restructuring activities may be more costly or time-consuming than expected or may not achieve their intended results and savings; X4’s future financial performance and position may not improve resulting in difficulties in implementing X4’s business strategy, and plans and objectives for future operations; the expected decrease in annual spending could negatively impact X4’s commercial plans and strategy for mavorixafor; the expected sufficiency of X4’s existing cash resources and runway may not be accurate resulting in the need for additional financing sooner than anticipated or unexpected liquidity constraints; the internal and external costs required for X4’s ongoing and planned activities, and the resulting impact on expense and use of cash, may be higher than expected, which may cause the company to use cash more quickly than expected or to change or curtail some of X4’s plans or both; the expected availability, content, and timing of clinical data from X4’s ongoing clinical trials of mavorixafor may be delayed or unavailable, including the ongoing Phase 3 clinical trial; trials, studies and research programs may be delayed and may not have satisfactory outcomes, additionally earlier trials and studies may not be predictive of later trials and studies; the design and rate of enrollment for current clinical trials may not enable successful completion of the trial(s); the commercial opportunity for mavorixafor may be smaller than anticipated; X4 may be unable to obtain and maintain regulatory approvals; adverse safety effects may arise from the testing or use of X4’s product and product candidates; the need to align with collaborators may hamper or delay development and commercialization efforts or increase costs; business may be adversely affected and costs may increase if any of the company’s key collaborators fails to perform its obligations or terminates the collaboration; X4’s may be unable to advance and commercialize and increase sales in mavorixafor to treat chronic neutropenia or to optimize the U.S. promotion of XOLREMDI® (mavorixafor), approved for the treatment of WHIM; and other risks and uncertainties, including those described in the section entitled “Risk Factors” in X4’s most recent Annual Report on X4’s Form 10-K , as well as in other filings X4 makes with the Securities and Exchange Commission , including its quarterly report on Form 10-Q, from time to time. X4 undertakes no obligation to update the information contained in this press release to reflect new events or circumstances, except as required by law. (Tables Follow) Source: X4 Pharmaceuticals

近日，Cell期刊上公布了一篇名为“Strategies to boost antibody selectivity in oncology”的文章。文章题目该文章主要探讨了提高治疗性抗体的选择性，以减少对健康组织的损害并提高疗效的策略。    01  研究背景用于肿瘤治疗的抗体被配备了有毒的载荷和效应功能，能够在极低浓度下杀死细胞。但是，大多数癌细胞上的靶点也存在于一些健康细胞上。共享的靶点可能导致非肿瘤部位的结合，从而降低药物的安全性和治疗潜力。为了解决这一问题，研究人员最初引入了单特异性的治疗性抗体，但往往疗效不足且容易产生耐药性。而目前使用的新一代抗体则具有更高的细胞毒性潜力，包括抗体-药物偶联物（ADCs）和多特异性抗体。在ADCs中，抗体被用作载体，将细胞毒性化学载荷递送至肿瘤。这些载荷通常对患者来说毒性过大，若不与抗体结合则无法使用，甚至还有更具毒性的载荷正在研究中。多特异性抗体能够同时结合不同的表位，包括T细胞衔接器，它们能够将免疫细胞招募至肿瘤细胞。在这种情况下，一个T细胞衔接器分子就足以杀死整个细胞。鉴于其具有高细胞毒性潜力，许多ADCs和多特异性抗体存在剂量限制性毒性，这可能会限制到达肿瘤的生物制剂的量及其治疗效果。此外，即使是非肿瘤部位的轻微结合，也可能导致严重的副作用伤害。例如，针对B细胞恶性肿瘤中CD19的双特异性抗体还可能影响健康的B细胞，引发B细胞再生障碍和感染风险增加。因此，提高治疗性抗体药物对肿瘤的选择性，对于其安全、有效地应用于癌症治疗至关重要，同时也有助于它们在联合疗法中的应用。  02  提高抗体选择性的策略鉴于此，该文章提出了多种策略来，主要分为三类：三类提高抗体选择性的策略一、利用肿瘤细胞的独特特征1. 肿瘤特异性抗原（TSAs）提供高选择性靶点癌细胞可能会表达在健康细胞中沉默的基因，或者表达基因突变产生的蛋白质变体（新抗原），这些新抗原构成了肿瘤特异性抗原（TSAs）。具有高突变负荷的肿瘤，如黑色素瘤和肺癌，往往拥有更多的新抗原，尽管其中很少有能在许多患者之间共享（所谓的“公共新抗原”）。为了利用这些TSAs，可能需要个性化疗法，如疫苗或基于细胞的疗法。不幸的是，TSAs往往在细胞内，而传统的生物制剂通常无法被动地穿过脂质双层，包括细胞膜，来与它们结合。那么，针对这一缺陷，作者总结了三种靶向细胞内TSAs的策略。图1.利用抗体（Abs）靶向细胞内癌症靶点的多种方法。利用主要组织相容性复合体（MHC）：抗原呈递是一种针对细胞内威胁的自然监视机制（图1A），蛋白质的片段被展示给T细胞，T细胞使用T细胞受体（TCR）来检查它们，并对其作出反应。类似地，治疗性抗体可以模仿TCR并与特定的肽-MHC复合物结合。以这种方式利用TSAs，需要识别一种能够与特定构象表位结合的生物制剂，即肽-MHC，它需要包含足够的内容以确保特异性和安全性。此外，靶肽-MHC的潜在低丰度以及患者人群中MHC等位基因的自然变异可能会给增加额外的治疗复杂性。利用细胞内表达生物制剂：生物制剂通常是单链抗体片段（scFv），其以核酸的形式被递送到细胞中，随后在其中表达并结合细胞内靶点（图1B）。利用跨膜生物制剂送入细胞：生物制剂跨越膜的能力可以通过多种方式实现，包括通过包囊、某些肽基序的整合、与细胞穿透肽（CPPs）或其他载体的结合，或膜不稳定剂的控制释放（图1C）。例如，一种能够通过组织蛋白酶B诱导释放1,2-乙二胺（一种膜不稳定剂）的生物制剂。一些癌细胞系具有高活性的组织蛋白酶B，这有利于膜不稳定剂在内质网释放和生物制剂的选择性递送。除了直接到达细胞质外，还可以利用自然循环于细胞中的受体的结合，以更好地接触细胞内靶点。例如，利用IGF-1受体在上皮细胞中的转胞吞作用，使用二聚体IgA靶向KRASG12D。2. 肿瘤相关抗原更为常见，但选择性较低癌症蛋白质组的变化倾向于定量而非定性变化，大多数在肿瘤细胞中富集的抗原也存在于一些健康细胞上，这些被称为肿瘤相关抗原（TAAs）。鉴于此，提高对肿瘤细胞的选择性需要利用其他特征，例如靶点密度的差异或多个靶点的共表达。图2. 生物制剂的多价性和几何形状可以被利用来提高其对特定抗原密度的选择性。利用靶点密度差异：通过多价性（multivalency）和多特异性抗体，可以提高对肿瘤细胞的选择性。多价性提供了一种利用靶点密度差异并提高对肿瘤细胞上富集的单一TAA的结合选择性的方法。拥有多个具有适当亲和力的结合位点可以使治疗药物优先集中在表面抗原密度高的细胞上（图2），这种现象被称为“超选择性”。整体的结合亲和力或结合力可以通过单个结合臂的亲和力以及生物制剂的价态和几何形状来调节。通过包括IgM在内的形式以及IgG六聚体化等策略，可以实现比IgG更高的价态和结合力。同样，catenation和AvidiMabs通过在结合时引入抗体恒定区之间的非共价相互作用，增加了它们在肿瘤细胞上的停留时间。另一种可能性是，多价融合蛋白纳米颗粒可以围绕二价阳离子自组装，并且可以在体内以显著的选择性靶向CXCR4+和PDGFR+细胞。多价性也可以引入到抗体的恒定区，这可能允许调节其效应功能和药代动力学。利用多个靶点共表达：通过靶向同一肿瘤细胞上的多个TAAs，也可以提高生物制剂对肿瘤细胞的选择性。在顺式方向上同时靶向多个抗原可以缩小生物制剂积累的位置。相关的方法涉及蛋白酶靶向抗体（PROTABs），这些是多特异性抗体，它们利用肿瘤细胞上富集的E3泛素连接酶来加速附近生物分子的降解。靶向多个细胞途径也可以实现更强大的抗肿瘤反应。最大化生物制剂对其靶点的结合亲和力并不总是最佳策略。如果抗体强烈结合健康细胞上少量的TAAs，或者增加毒性，那么在体内可能会表现不佳。过高的结合亲和力还可能增加抗体的内化速率，减少其从晚期内体的回收，并加速其降解，从而限制其半衰期和肿瘤穿透。高亲和力的另一个潜在问题是与细胞内信号传导有关：紧密的结合可能会减少受体聚集和信号传导。实际上，对T细胞衔接器的研究发现，在中等结合亲和力时，其效力和选择性达到最佳。二、利用肿瘤微环境特征的策略肿瘤微环境（TME）是一个动态的生态系统，它与肿瘤相互塑造，随着时间的推移形成双向关系。TME通常表现出一些表型特征，包括持续的炎症、细胞外基质（ECM）的重塑、异常的血管生成、坏死等。这些独特的特征可能会促进恶性表型的发展，但也可以被利用来设计选择性的生物制剂。图3. 抗体被设计为可以在肿瘤微环境（TME）中选择性结合，而不是在健康微环境中结合。1. 肿瘤微环境的特征可作为选择性抗体的合适靶点肿瘤微环境（TME）的一个特征是存在免疫细胞。抗体可用于减少TME中的免疫抑制或增强免疫激活。例如，针对CTLA-4和PD-1/PD-L1的免疫检查点抑制剂能够重新激活一些效应细胞，并已被证明对某些患者非常有效。Tocilizumab和Siltuximab分别靶向IL-6R和IL-6，旨在增强树突状细胞的抗原呈递能力。此外，一些针对TME的免疫抑制剂也正在研究中。2. 肿瘤微环境的其他特征可作为选择性抗体的合适靶点肿瘤微环境（TME）的另一个特征是存在癌症相关成纤维细胞（CAFs）。CAFs是TME的主要组成部分，在肿瘤的免疫调节和侵袭性方面发挥着关键作用。通过使用fresolimumab等抗体靶向TGF-β信号通路，可以干扰CAFs的功能。研究人员也在探索针对CAFs分泌的基质金属蛋白酶以及在CAFs中经常过表达的CAF标志物——成纤维细胞激活蛋白-α（fibrilastin-α）的抗体。异常血管生成也是实体瘤的一个常见特征。肿瘤部位代谢需求高，可以通过新生血管生成（neoangiogenesis）和血管生成（vasculogenesis）招募新的血管。因此，干扰患者的血管生成可以优先影响肿瘤的生长。一些抗体已被批准用于规范化肿瘤血管并抑制新生血管生成，包括靶向VEGF-A的bevacizumab和靶向其受体VEGFR-2的ramucirumab。坏死区域是晚期实体瘤的另一个特征性标志。晚期实体瘤的核心区域可能营养物质、氧气和代谢废物交换不良，导致细胞坏死。可以设计抗体靶向坏死时暴露的分子，这种方法被称为肿瘤坏死疗法（TNT）。研究人员发现了几种与坏死靶点高度特异性结合的抗体，包括来自细胞核的DNA/组蛋白H1复合物、单链DNA和RNA以及核糖体蛋白。由于TNT不与活细胞结合，因此需要能够扩散或远距离杀伤的药物，如放射性核素、免疫调节剂和释放的化疗药物。3. 生物制剂可被设计为在TME中选择性激活构建在TME中选择性激活的抗体前药：这些分子也被称为前体抗体或条件性活性生物制剂。通过使生物制剂与TME中丰富的分子发生反应，触发药物的局部释放或选择性地暴露抗体的互补决定区（CDRs）（见图3），可以实现选择性激活。例如，Amunix制药公司的双特异性抗体，能够结合HER2或EGFR以及T细胞上的CD3共受体的分子。为了提高肿瘤选择性，将具有特定切割位点的XTEN多肽融合到双特异性scFv的两端。在非肿瘤部位，XTEN掩蔽物可防止抗原结合。然而，在TME中，丰富的蛋白酶会特异性识别这些切割位点，切割掩蔽物，从而使双特异性抗体能够结合其抗原。值得注意的是，这种策略使该分子在食蟹猴中的最大耐受浓度比未掩蔽的双特异性抗体提高了400倍以上。此外，还可以利用酶促切割通过可切割连接子从抗体药物偶联物（ADCs）中选择性释放载荷。对于能够影响邻近细胞的膜可渗透载荷（旁观者效应），可切割ADCs可能特别适用。这种效应可能提高在抗原丢失或减少的异质性肿瘤中ADCs的有效性。优化抗体以在特定pH下发挥作用，提高其选择性：通过赋予Fc区pH敏感性结合，有利于将效应细胞招募到通常呈酸性的TME（图3D），或者通过FcRn介导的抗体回收来延长抗体的半衰期。具有pH敏感性结合的CDRs（图3C）也可以增加治疗肿瘤的价值。通过精心设计蛋白序列来实现pH敏感性结合，其中组氨酸的离子化（pKa约为6）通常起着重要作用。相互作用的pH敏感性可能涉及抗体、靶点或两者质子化状态的变化，也可能涉及介质中存在的第三种物质，如碳酸氢盐。将抗体设计为依赖于TME中特征性的其他分子：TME中某些肿瘤的细胞外ATP浓度显著增加。这种增加被研究人员巧妙地利用来识别需要ATP才能与CTLA-4和CD137结合的CDRs。在这些情况下，ATP实际上起到了分子胶的作用，补充了抗原和CDR之间的界面（图3B）。也可以设计生物制剂，使其结合在第三种分子存在时被阻止。这些方法可以扩展到其他靶点和代谢物。三、利用外部干预的策略除了设计生物制剂以利用肿瘤或TME的特征外，还可以通过外部干预来选择性地增加肿瘤中活性药物的浓度，或减少肿瘤外的药物浓度。构建用于生成特异性结合分子的替代性非抗体蛋白支架的结构。其中β-折叠以绿色显示，α-螺旋结构以黄色显示，二硫键以红色显示。增加肿瘤中活性药物的浓度改变给药途径：给药策略会影响生物制剂的运输和积累。生物制剂的给药途径，如静脉注射、动脉内注射、脑脊液内注射、胸膜内注射或腹膜内注射，会影响其在肿瘤部位的浓度。此外，正在研究新的给药途径，例如皮肤癌的局部抗体给药、呼吸道或中枢神经系统的鼻内抗体给药、淋巴系统的皮内给药以及直接的瘤内给药。一项研究显示，与静脉注射相比，腹膜内注射抗PD-L1分子在腹膜播散性癌模型中使生物制剂在肿瘤中的积累量增加了8倍。利用外部刺激：可在空间或时间上控制活性治疗药物的浓度，从而提高其选择性。可以使用辐射仅在照射区域触发抗体功能。还有报道称，通过微束辐射暂时提高治疗药物的局部血管通透性，以及将免疫检查点阻断与光热疗法相结合。外部刺激还可能涉及额外分子的给药。通过诱导表型变化的预处理也可以提高生物制剂对肿瘤的选择性。减少肿瘤外活性药物的浓度：减少治疗药物的非肿瘤结合有许多可行的方法。一种是使用治疗药物的非毒性类似物来阻断非肿瘤结合。这种方法非常适合抗体药物偶联物（ADCs），在实际给药ADC之前，可以先给药不含载荷的抗体，从而使更高比例的ADC定位到肿瘤。第二种是利用非肿瘤部位靶点密度通常较低的事实。在间接主动靶向（INTACT）中，研究人员预先给药以结合脂质体表面的靶点来控制抗体的浓度。脂质体上的靶点丰度减少了抗体向非肿瘤区域的损失，这些区域的靶点浓度较低，与脂质体相比，它们的释放更集中在肿瘤部位，靶点浓度较高。第三种是利用治疗药物在非肿瘤部位更高的可及性和更快的清除。例如，可以在非肿瘤结合清除后延迟给药某种分子。OncoOne的PreTarg-it平台涉及一种放射性核素，该放射性核素仅在ADC在肿瘤中浓集并从血液中清除后才与ADC结合。反向靶向是另一种与ADC兼容的方法，涉及（延迟）给药针对ADC化学载荷的抗体，以加速其在非肿瘤部位的清除。同样，最近的研究还展示了通过给药小分子药物使双特异性T细胞衔接器脱离的能力，从而减轻非肿瘤毒性。   03   未来展望文章最后提出了未来研究的方向，包括：整合实验、动物模型和人工智能：以更快地开发选择性治疗药物。评估分子靶点的质量：确定哪些靶点最适合用于癌症治疗。预测非肿瘤结合的次级效应：了解药物对不同细胞和组织的潜在影响。结合不同的分子设计策略：以最大化安全性和疗效。预测新型生物制剂的行为：在人体中的表现。生成分子设计的合理预期：基于当前的数据和知识，确定哪些目标是可行的。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。