作者: Chen, Xing ; Fan, Shuai ; Zhai, Yunyun ; Kong, Zhengjie ; Wang, Jiang ; Zhang, Gaiping ; Han, Shichong ; He, Wenrui ; Du, Yongkun ; Yuan, Hang ; Hu, Man ; Zhang, Yuhang ; Wan, Bo

ABSTRACT:

The porcine reproductive and respiratory syndrome virus (PRRSV) can lead to severe reproductive problems in sows, pneumonia in weaned piglets, and increased mortality, significantly negatively impacting the economy. Post-translational changes are essential for the host-dependent replication and long-term infection of PRRSV. Uncertainty surrounds the function of the ubiquitin network in PRRSV infection. Here, we screened 10 deubiquitinating enzyme inhibitors and found that the ubiquitin-specific proteinase 1 (USP1) inhibitor ML323 significantly inhibited PRRSV replication in vitro . Importantly, we found that USP1 interacts with nonstructural protein 1β (Nsp1β) and deubiquitinates its K48 to increase protein stability, thereby improving PRRSV replication and viral titer. Among them, lysine at position 45 is essential for Nsp1β protein stability. In addition, deficiency of USP1 significantly reduced viral replication. Moreover, ML323 loses antagonism to PRRSV rSD16-K45R. This study reveals the mechanism by which PRRSV recruits the host factor USP1 to promote viral replication, providing a new target for PRRSV defense.

IMPORTANCE:

Deubiquitinating enzymes are critical factors in regulating host innate immunity. The porcine reproductive and respiratory syndrome virus (PRRSV) nonstructural protein 1β (Nsp1β) is essential for producing viral subgenomic mRNA and controlling the host immune system. The host inhibits PRRSV proliferation by ubiquitinating Nsp1β, and conversely, PRRSV recruits the host protein ubiquitin-specific proteinase 1 (USP1) to remove this restriction. Our results demonstrate the binding of USP1 to Nsp1β, revealing a balance of antagonism between PRRSV and the host. Our research identifies a brand-new PRRSV escape mechanism from the immune response.

2024-02-01·The FEBS journal

A genome‐wide CRISPR screen identifies USP1 as a novel regulator of the mammalian circadian clock

Article

作者: Liu, Dengfeng ; Zhang, Jing ; Hu, Ying ; Li, Jia-Da ; Lu, Renbin ; Li, Xin

The circadian clock is generated by a molecular timekeeping mechanism coordinating daily oscillations of physiology and behaviors in mammals. In the mammalian circadian clockwork, basic helix–loop–helix ARNT‐like protein 1 (BMAL1) is a core circadian component whose defects lead to circadian disruption and elicit behavioral arrhythmicity. To identify previously unknown regulators for circadian clocks, we searched for genes influencing BMAL1 protein level by using a CRISPR/Cas9‐based genome‐wide knockout library. As a result, we found that the deubiquitinase ubiquitin carboxyl‐terminal hydrolase 1 (USP1) positively affects BMAL1 protein abundance. Overexpression of wild‐type USP1, but not a deubiquitinase‐inactive mutant USP1, upregulated BMAL1 protein level, whereas genetic ablation of USP1 downregulated BMAL1 protein level in U2OS cells. Furthermore, treatment with USP1 inhibitors led to significant downregulation of BMAL1 protein in U2OS cells as well as mouse tissues. Subsequently, genetic ablation or pharmacological inhibition of USP1 resulted in reduced mRNA levels of a panel of clock genes and disrupted circadian rhythms in U2OS cells. Mechanistically, USP1 was able to de‐ubiquitinate BMAL1 and inhibit the proteasomal degradation of BMAL1. Interestingly, the expression of Usp1 was much higher than the other two deubiquitinases of BMAL1 (Usp2 and Usp9X) in the mouse heart, implying a tissue‐specific function of USP1 in the regulation of BMAL1 stability. Our work thus identifies deubiquitinase USP1 as a previously unknown regulator of the mammalian circadian clock and highlights the potential of genome‐wide CRISPR screens in the identification of regulators for the circadian clock.

2023-12-01·European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V

Inhibition of USP1 ameliorates hypertensive nephropathy through regulating oxidative stress and ferroptosis: A precise treatment via SJB3-019A nanodelivery

Article

作者: Shang, Jing ; Zheng, Jiaxin ; Gan, Lu ; Han, Yangwenxuan ; Li, Ying ; Zhang, Yunzhu ; Hao, Fangyi ; Zhang, Chunjian

Hypertensive nephropathy is second only to diabetes for the causation of chronic kidney disease worldwide. As the mortality and morbidity of hypertensive nephropathy keep increasing, it is important to elucidate its pathogenesis and develop new treatment strategies. In this study, an angiotensin II (Ang II)-induced renal cell system was established, and the expression of ubiquitin specific peptidase 1 (USP1) in human kidney (HK-2) cells was found to be regulated by Ang II treatment through quantitative RT-PCR and Western blot assay. The detection of glutathione peroxidase (GSH-Px), malondialdehyde (MDA) and lipid reactive oxygen species (ROS) levels revealed that interference with USP1 reversed Ang II-induced oxidative stress and ferroptosis, which was enhanced by overexpression of USP1. Subsequently, USP1 inhibitor SJB3-019A loaded in MIL-100 and PEGTK was modified to fabricate SJB3-019A@MIL-PEGTK nanoparticles, which was confirmed to exhibit excellent alleviation of hypertension-induced oxidative stress and ferroptosis in renal cells both in vitro and in vivo. Our study identified an important pathogenesis of hypertensive nephropathy and SJB3-019A@MIL-PEGTK nanoparticle was used to develop an effective clinical treatment for hypertensive nephropathy.

项与 USP1 inhibitor(Shanghai Impact) 相关的新闻（医药）

2024-05-08

·BioSpace

Tango Therapeutics Reports First Quarter 2024 Financial Results and Provides Business Highlights

Dose expansion initiated in TNG908 phase 1/2 clinical trial Dose expansion expected to initiate in TNG462 phase 1/2 clinical trial in 2Q 2024 Clinical data expected in 2H 2024 from PRMT5 program Dose escalation ongoing in TNG260 and TNG348 clinical-stage precision oncology programs Strong cash position of $344 million as of March 31, 2024; cash runway into late 2026 expected to fund all clinical programs through proof-of-concept BOSTON--(BUSINESS WIRE)-- Tango Therapeutics, Inc. (NASDAQ: TNGX), a clinical-stage biotechnology company committed to discovering and delivering the next generation of precision cancer medicines, reported its financial results for the first quarter ended March 31, 2024, and provided business highlights. “We are progressing both TNG908 and TNG462 into dose expansion in order to accelerate our clinical development. We look forward to sharing a comprehensive clinical data update on our PRMT5 program in the second half of this year,” said Barbara Weber, M.D., President and Chief Executive Officer of Tango Therapeutics. “We continue to make substantial progress across our other programs as enrollment and dose escalation are continuing in the phase 1/2 clinical trials of TNG260 and TNG348. Finally, we welcomed the newest member of our leadership team, Julie Carretero, as Chief Human Resources Officer. She will play an instrumental role in growing the company while maintaining our culture at a pivotal time for the company.” Recent Business Highlights Pipeline Update TNG908, a blood-brain barrier penetrant, MTA-cooperative PRMT5 inhibitor Expansion cohorts have been opened in MTAP-deleted solid tumors in glioblastoma (GBM), non-small cell lung and pancreatic cancers at 600 mg BID in the TNG908 phase 1/2 clinical trial. MTAP deletions occur in approximately 10%-15% of all human cancers, including 40% of GBM. TNG462, a potentially best-in-class MTA-cooperative PRMT5 inhibitor Dose expansion is expected to initiate in the TNG462 phase 1/2 clinical trial in 2Q 2024. The safety, tolerability and pharmacokinetic profiles of TNG462 remain favorable with increasing doses. TNG260, a first-in-class, highly selective CoREST complex inhibitor Dose escalation is ongoing in the TNG260 phase 1/2 clinical trial evaluating the safety, pharmacokinetics, pharmacodynamics and efficacy of TNG260 in combination with pembrolizumab in patients with locally advanced or metastatic solid tumors with an STK11 loss-of-function mutation. To date, safety, tolerability and pharmacokinetic profiles remain favorable. STK11 mutations occur in approximately 15% of NSCLC, 15% of cervical, 10% of carcinoma of unknown primary, 5% of breast and 3% of pancreatic cancers. TNG348, a novel USP1 inhibitor Single agent dose escalation is ongoing in the TNG348 phase 1/2 clinical trial evaluating the safety, pharmacokinetics, pharmacodynamics and efficacy of TNG348 as a single agent and in combination with olaparib, a PARP inhibitor, in patients with BRCA1/2-mutant and other HRD+ (homologous recombination deficient) cancers. Early clinical data support switch to once-a-day dosing. Single agent dose escalation pharmacokinetic, pharmacodynamic, safety and tolerability data are favorable and support the opening of the combination cohort with olaparib in 2Q 2024. HRD+ cancers, including BRCA1/2 mutations, represent up to 50% of ovarian cancers, 25% of breast cancers, 10% of prostate cancers and 5% of pancreatic cancers. Upcoming Milestones Dose expansion in the TNG462 phase 1/2 clinical trial is expected to initiate in 2Q 2024. A comprehensive update of the PRMT5 program, including clinical data from the ongoing phase 1/2 clinical trials of TNG908 and TNG462, is expected in 2H 2024. Scientific Publications “Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP-Deleted Cancers,” was published in March in the Journal of Medicinal Chemistry. Leadership Update Julie Carretero joined as Chief Human Resources Officer in March. Ms. Carretero brings over 25 years of biopharmaceutical and human resources experience to this newly created role. Most recently, Ms. Carretero served as Chief People Officer at Evelo Biosciences where she oversaw growth from a clinical to a commercial-stage company. Previously she held senior human resources roles at multiple companies, including FXI, Matter Communications and Novartis. Financial Results As of March 31, 2024, the Company held $343.6 million in cash, cash equivalents and marketable securities, which the Company expects to be sufficient to fund operations into late 2026. Collaboration revenue was $6.5 million for the three months ended March 31, 2024, compared to $5.8 million for the same period in 2023. Research costs incurred under the collaboration were similar during each of the three-month periods presented which resulted in similar collaboration revenue amounts recognized. Research and development expenses were $38.1 million for the three months ended March 31, 2024, compared to $28.0 million for the same period in 2023. The change is due to increased spend relating to the advancement of our clinical programs and personnel-related costs to support our research and development activities. General and administrative expenses were $10.7 million for the three months ended March 31, 2024, compared to $8.0 million for the same period in 2023. The change was primarily due to increases in personnel-related costs. Net loss for the three months ended March 31, 2024 was $37.9 million, or $0.35 per share, compared to a net loss of $28.0 million, or $0.32 per share, in the same period in 2023. About Tango Therapeutics Tango Therapeutics is a clinical-stage biotechnology company dedicated to discovering novel drug targets and delivering the next generation of precision medicine for the treatment of cancer. Using an approach that starts and ends with patients, Tango leverages the genetic principle of synthetic lethality to discover and develop therapies that take aim at critical targets in cancer. This includes expanding the universe of precision oncology targets into novel areas such as tumor suppressor gene loss and their contribution to the ability of cancer cells to evade immune cell killing. For more information, please visit . Forward-Looking Statements Certain statements in this press release may be considered forward-looking statements. Forward-looking statements generally relate to future events, Tango’s future operating performance and goals, the anticipated benefits of therapies and combination therapies (that include a Tango pipeline product), as well as the expectations, beliefs and development objectives for Tango’s product pipeline and clinical trials. In some cases, you can identify forward-looking statements by terminology such as “may”, “should”, “expect”, “intend”, “will”, “goal”, “estimate”, “anticipate”, “believe”, “predict”, “designed,” “potential” or “continue”, or the negatives of these terms or variations of them or similar terminology. For example, implicit or explicit statements concerning the following include or constitute forward-looking statements: dose expansion expected to initiate in TNG462 phase 1/2 clinical trial in 2Q 2024; clinical data expected in 2H 2024 from PRMT5 program; Company expects cash runway into late 2026 and this cash runway is expected to fund all clinical programs through proof-of-concept; the Company is progressing both TNG908 and TNG462 into dose expansion in order to accelerate clinical development; Company expects to share a comprehensive clinical data update on our PRMT5 program in the second half of this year; Company continues to make substantial progress across other programs as enrollment and dose escalation are continuing in the phase 1/2 clinical trials of TNG260 and TNG348; early clinical data for TNG348 support switch to once-a-day dosing; single agent dose escalation pharmacokinetic, pharmacodynamic, safety and tolerability data for TNG348 support opening of combination with olaparib in 2Q 2024; a comprehensive update of the PRMT5 program, including clinical data from ongoing phase 1/2 clinical trials of TNG908 and TNG462, is expected in 2H 2024; Tango is committed to discovering and delivering the next generation of precision cancer medicines; and the expected timing of: (i) development candidate declaration for certain targets; (ii) initiating IND-enabling studies; (iii) filing INDs; (iv) clinical trial initiation, dose escalation and dose expansion and (v) disclosing initial, interim, additional and final clinical trial results; and the expected benefits of the Company's development candidates and other product candidates. Such forward-looking statements are subject to risks, uncertainties, and other factors which could cause actual results to differ materially from those expressed or implied by such forward-looking statements. These forward-looking statements are based upon estimates and assumptions that, while considered reasonable by Tango and its management, are inherently uncertain. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Factors that may cause actual results to differ materially from current expectations include, but are not limited to: benefits of product candidates seen in preclinical tests and analyses may not be evident when tested in later preclinical studies or in clinical trials or when used in broader patient populations (if approved for commercial sale); Tango has limited experience conducting clinical trials (and will rely on a third party to operate its clinical trials) and may not be able to commence the clinical trial (including opening clinical trial sites, dosing the first patient, and continued enrollment and dosing of an adequate number of clinical trial participants) when expected, may not be able to continue dosing, initiate dose escalation and/or dose expansion on anticipated timelines, and may not generate results (including final, initial or additional safety, efficacy data and proof-of-mechanism and proof-of-concept) in the anticipated timeframe (or at all); Tango’s pipeline products may not be safe and/or effective in humans; Tango has a limited operating history and has not generated any revenue to date from product sales, and may never become profitable; other companies may be able to identify and develop product candidates more quickly than the Company and commercially introduce the product prior to the Company; the Company’s proprietary discovery platform is novel and may not identify any synthetic lethal targets for future development; the Company may not be able to identify development candidates on the schedule it anticipates due to technical, financial or other reasons; the Company may not be able to for development candidates on time, or at all, due to technical or financial reasons or otherwise; the Company may utilize cash resources more quickly than anticipated; Tango will need to raise capital in the future and if we are unable to raise capital when needed or on attractive terms, we would be forced to delay, scale back or discontinue some of our development programs or future commercialization efforts (which may delay filing of INDs, dosing patients, initiation of dose expansion, reporting clinical trial results and filing new drug applications); Tango’s approach to the discovery and development of product candidates is novel and unproven, which makes it difficult to predict the time, cost of development, and likelihood of successfully developing any products; the Company may be unable to advance our preclinical development programs into and through the clinic for safety or efficacy reasons or commercialize our product candidates or we may experience significant delays in doing so as a result of factors beyond Tango’s control; the Company may not be able to realize the benefits of ODD or Fast Track designation (and such designations may not advance any anticipated approval timelines); Tango may not identify or discover additional product candidates or may expend limited resources to pursue a particular product candidate or indication and fail to capitalize on product candidates or indications that may be more profitable or for which there is a greater likelihood of success; the Company’s product candidates may cause adverse or other undesirable side effects (or may not show requisite efficacy) that could, among other things, delay or prevent regulatory approval; our dependence on one or a limited number third parties for conducting clinical trials and producing drug substance and drug product (including drug substance, which is currently sole sourced); government regulation may negatively impact the Company’s business, including the potential approval of the BIOSECURE Act; and our ability to obtain and maintain patent and other intellectual property protection for our technology and product candidates or the scope of intellectual property protection obtained is not sufficiently broad. Additional information concerning risks, uncertainties and assumptions can be found in Tango’s filings with the SEC, including the risk factors referenced in Tango’s Annual Report on Form 10-K for the fiscal year ended December 31, 2023, as supplemented and/or modified by its most recent Quarterly Report on Form 10-Q. You should not place undue reliance on forward-looking statements in this press release, which speak only as of the date they are made and are qualified in their entirety by reference to the cautionary statements herein. Tango specifically disclaims any duty to update these forward-looking statements. Consolidated Statements of Operations (In thousands, except share and per share data) Three Months Ended March 31, 2024 2023 Collaboration revenue $ 6,471 $ 5,766 Operating expenses: Research and development 38,065 28,039 General and administrative 10,661 8,013 Total operating expenses 48,726 36,052 Loss from operations (42,255 ) (30,286 ) Other income, net 4,381 2,278 Loss before income taxes (37,874 ) (28,008 ) Provision for income taxes (40 ) — Net loss $ (37,914 ) $ (28,008 ) Net loss per common share – basic and diluted $ (0.35 ) $ (0.32 ) Weighted average number of common shares outstanding – basic and diluted 108,171,463 88,193,917 Consolidated Balance Sheets (In thousands) March 31, 2024 December 31, 2023 Assets Current assets: Cash and cash equivalents $ 61,163 $ 66,385 Marketable securities 282,436 270,500 Restricted cash — 856 Prepaid expenses and other current assets 8,437 8,797 Total current assets 352,036 346,538 Property and equipment, net 9,522 9,908 Operating lease right-of-use assets 42,086 43,508 Restricted cash, net of current portion 2,567 2,567 Other assets 11 46 Total assets $ 406,222 $ 402,567 Liabilities and Stockholders' Equity Current liabilities: Accounts payable $ 3,898 $ 2,785 Accrued expenses and other current liabilities 13,755 15,401 Operating lease liabilities 2,066 2,082 Deferred revenue 23,070 25,670 Total current liabilities 42,789 45,938 Operating lease liabilities, net of current portion 36,169 36,838 Deferred revenue, net of current portion 62,812 66,683 Total liabilities 141,770 149,459 Total stockholders’ equity 264,452 253,108 Total liabilities and stockholders’ equity $ 406,222 $ 402,567 View source version on businesswire.com: Contacts Investors: Sam Martin/Andrew Vulis Argot Partners tango@argotpartners.com Media: Amanda Brown Galgay SVP, Corporate Communications, Tango Therapeutics media@tangotx.com Source: Tango Therapeutics, Inc. View this news release online at:

财报高管变更快速通道临床研究

2024-04-30

·PRNewswire

MEDIVIR AB - INTERIM REPORT JANUARY - MARCH 2024

STOCKHOLM, April 30, 2024 /PRNewswire/ -- Preparations for the planned phase 2b study continue according to plan after the completed Type C meeting with the FDA, strengthened by the fact that the median time to progression with fostrox + Lenvima increased to 7 months. January – March Financial summary for the quarter Net turnover amounted to SEK 0.5 (0.4) million. The loss before interest, tax, depreciation and amortization (EBITDA) amounted to SEK -26.7 (-18.9) million. Basic and diluted earnings per share amounted to SEK -0.23 (-0.34) and SEK -0.23 (-0.34) respectively. Cash flow from operating activities amounted to SEK -35.0 (-16.1) million. Cash and cash equivalents at the end of the period amounted to SEK 153.4 (100.8) million Significant events during the quarter In January Tango Therapeutics announced that it has dosed the first patient with TNG348, a new USP1-inhibitor from the preclinical USP1 program in-licensed from Medivir in 2020. Positive results from the ongoing phase 1b/2a study in advanced liver cancer (HCC) showing further improved response and time to progression were presented at the ASCO GI Symposium in San Francisco. In January, a directed issue to Hallberg Management AB was carried out amounting to approximately SEK 20 million before deduction of issuance costs. In February, a change in Medivir's nomination committee announced as Anders Hallberg, appointed by Healthinvest Partners, leaves the nomination committee and is replaced by Stefan Bengtsson, appointed by CA Fastigheter AB. Events after the end of the period In April it was announced that Medivir's partner Vetbiolix, a veterinary biotechnology company based in France, reported positive results from a proof-of-concept clinical trial in canine periodontitis with its drug candidate VBX-1000, formerly known as MIV-701. In April it was announced that Medivir has completed a so-called Type C meeting with the FDA and that the company's preparations for the planned phase 2b study are continuing as planned, with a couple of adjustments in study design with limited impact on the timeline and size of the study. In April MIV-711 was granted Rare Pediatric Disease Designation (RPDD) and Orphan Drug Designation (ODD) from the FDA for the treatment of Legg-Calvé-Perthes disease (LCPD), an uncommon hip disorder affecting children aged 2-12 years. Conference call for investors, analysts and the media The Interim Report January - March 2024 will be presented by Medivir's CEO, Jens Lindberg. Time: Tuesday, April 30, 2024, at 10.00 (CET). To access the webcast and find information about the teleconference, please click HERE! The conference call will also be streamed via a link on the website: The presentation will be available on Medivir's website after completion of the conference. CEO's message "Our goal is that the combination of fostrox and Lenvima® shall become the first approved alternative in second-line for patients with primary liver cancer. Preparations for our planned phase 2b study continue after the Type C meeting with the FDA, strengthened by the fact that patients in the ongoing phase 1b/2a study continue to benefit from treatment with fostrox + Lenvima longer than expected and that the outcome continues to improve. Medivir's proprietary candidate drug fostrox is a targeted, smart chemotherapy that selectively kills cancer cells in the liver. Fostrox + Lenvima constitutes a unique, potential combination of complementary medicines that is showing promising results in Medivir's ongoing phase 1b/2a study. At the international ASCO-GI congress in San Francisco in January, results were presented for fostrox + Lenvima showing that the proportion of patients achieving a clinically relevant reduction in their liver tumor is greater than what would be expected with a second-line treatment. Data evaluated by investigators and local radiologists showed that the Objective Response Rate (ORR) was 25 percent (RECIST v1.1), a significantly higher rate than the 5–10 percent shown for second-line treatment of HCC in previous studies. The update also showed continued good tolerability without any new unexpected side effects. As the patients remain on treatment longer than expected, the clinical efficacy has continued to improve. At the time of writing, ~30 percent of patients remain on treatment in the study. The median time to progression has now increased further to 7 months, compared to 5 months at ASCO GI, significantly longer than previous studies in second-line HCC have shown. The patient who has benefited the longest remains on treatment after 20 months with continued partial response. The readout of the study as a whole is expected to be completed by the end of 2024, depending on how long the last patients continue to benefit from the treatment. Our data has been met with great interest and the discussions with leading global experts, not least at ASCO GI, have confirmed what the combination fostrox + Lenvima could mean in the second-line treatment of HCC, where patients today are without any approved treatment alternative. With the increasingly exciting data from the study, the opportunity emerges to become the first approved drug treatment in a market worth ~$2.5 billion annually. We have therefore put in a higher gear to ensure maximum speed forward in fostrox's development program to create the possibility of a so-called accelerated approval. Somewhat simplified, it can be described as a conditional regulatory approval that enables prescribing to patients where the data must later be substantiated in a follow-up confirmatory phase 3 study. This means an opportunity for fostrox to reach patients up to three years faster than would otherwise be the case. During the quarter, we also had a Type C meeting with the FDA to discuss the study design. The FDA provided clarifying guidance, which means we are now approaching the final study design for the planned phase 2b study, which is proceeding as previously planned. Parallel to these measures, the discussions we are having with potential cooperation partners for fostrox continue. Also, when it comes to the projects Medivir previously licensed out to partners, the development is exciting. In January, Tango Therapeutics initiated a phase 1/2 study and dosed the first patient with TNG348, a USP-1 inhibitor developed from the preclinical USP1 program in-licensed from Medivir in 2020. In April, our partner Vetbiolix, a veterinary biotech company based in France, could report positive results from a clinical Proof-of-Concept study in canine periodontitis disease with its drug candidate VBX-1000, formerly known as MIV-701 which was out-licensed to Vetbiolix in 2019. In addition, our project for partnership MIV-711 was granted Rare Pediatric Disease Designation and Orphan Drug Designation for the treatment of Legg-Calvé-Perthes Disease from the FDA. Aside from that this creates opportunity for partnerships and future revenue, it also demonstrates the quality of Medivir's research. The continued clinical development of fostrox is our focus and the promising data showing further improvement in clinical efficacy in second-line HCC reinforces our belief that fostrox can become an effective anti -cancer drug that makes a real difference to patients. There is a clear need and an obvious place for fostrox in the treatment landscape. The goal is to become the first approved alternative in second-line for patients with primary liver cancer. I look forward to keeping you informed of Medivir's continued development." Jens Lindberg Chief Executive Officer For further information, please contact Magnus Christensen, CFO Phone: +46 (0)8 5468 3100 E-mail: [email protected] This report has not been subject to auditors' review. The information was submitted for publication at 08.30 CET on April 30, 2024 This information was brought to you by Cision The following files are available for download: SOURCE Medivir

临床2期孤儿药临床结果财报

2024-04-30

·BioSpace

Exelixis Announces First Quarter 2024 Financial Results and Provides Corporate Update

- Total Revenues of $425 million, Cabozantinib Franchise U.S. Net Product Revenues of $379 million - - Restructuring Expenses of $32.8 million Recorded - - GAAP Diluted EPS of $0.12, Non-GAAP Diluted EPS of $0.17 - - Conference Call and Webcast Today at 5:00 PM Eastern Time - ALAMEDA, Calif.--(BUSINESS WIRE)-- Exelixis, Inc. (Nasdaq: EXEL) today reported financial results for the first quarter of 2024, provided an update on progress toward achieving key corporate objectives, and detailed its recent and anticipated commercial, clinical and pipeline development milestones. “In the first quarter of 2024, Exelixis made important progress to advance a diverse, multi-product portfolio of small molecules and biotherapeutics with the potential to improve standards of care for patients with cancer,” said Michael M. Morrissey, Ph.D., President and Chief Executive Officer, Exelixis. “The team continued to execute across our three ongoing pivotal trials for zanzalintinib, as well as the phase 1 studies of our tissue-factor targeting ADC, XB002, and our small molecule USP1 inhibitor, XL309. We expect to provide updates from these programs as clinical data mature. In addition, we are on track for up to three Investigational New Drug filings this year, pending continued supportive preclinical data.” Dr. Morrissey continued: “We also continued to pursue our label expansion plans for cabozantinib to drive future potential revenue growth of our flagship franchise and will provide additional updates on our regulatory strategies for both neuroendocrine tumors and metastatic castration-resistant prostate cancer, when appropriate. We believe the recent restructuring of our business, announced in January, further enhances our integrated research, development and commercial capabilities to deliver an innovative pipeline of cancer therapies for patients, while continuing to return capital back to our shareholders through our 2024 share repurchase program. As we drive the commercial and pipeline components of our business forward, we remain steadfast in our defense of cabozantinib’s intellectual property and anticipate a ruling on the second bench trial for our ongoing litigation with MSN Pharmaceuticals in the spring timeframe of this year.” First Quarter 2024 Financial Results Total revenues for the quarter ended March 31, 2024 were $425.2 million, as compared to $408.8 million for the comparable period in 2023. Total revenues for the quarter ended March 31, 2024 included net product revenues of $378.5 million, as compared to $363.4 million for the comparable period in 2023. The increase in net product revenues was primarily due to an increase in sales volume, partially offset by a decrease in average net selling price. Collaboration revenues, composed of license revenues and collaboration services revenues, were $46.7 million for the quarter ended March 31, 2024, as compared to $45.4 million for the comparable period in 2023. The increase in collaboration revenues was primarily due to higher royalty revenues for the sales of cabozantinib outside of the U.S. generated by Exelixis’ collaboration partners, Ipsen Pharma SAS and Takeda Pharmaceutical Company Limited, partially offset by a decrease in development cost reimbursements earned. Research and development expenses for the quarter ended March 31, 2024 were $227.7 million, as compared to $234.2 million for the comparable period in 2023. The decrease in research and development expenses was primarily related to a decrease in license and other collaboration costs, partially offset by an increase in clinical trial costs. Selling, general and administrative expenses for the quarter ended March 31, 2024 were $114.0 million, as compared to $131.4 million for the comparable period in 2023. The decrease in selling, general and administrative expenses were primarily related to decreases in corporate giving and legal and advisory fees. Restructuring expenses for the quarter ended March 31, 2024 were $32.8 million. The restructuring expenses primarily consist of severance and employee-related costs, asset impairment and contract termination costs. Provision for income taxes for the quarter ended March 31, 2024 was $12.0 million, as compared to $8.3 million for the comparable period in 2023. GAAP net income for the quarter ended March 31, 2024 was $37.3 million, or $0.12 per share, basic and diluted, as compared to GAAP net income of $40.0 million, or $0.12 per share, basic and diluted, for the comparable period in 2023. GAAP net income per share for the quarter ended March 31, 2024 was favorably impacted by lower weighted-average common shares outstanding for the quarter ended March 31, 2024, as compared to the comparable period in 2023, as a result of the stock repurchase programs. Non-GAAP net income for the quarter ended March 31, 2024 was $52.0 million, or $0.17 per share, basic and diluted, as compared to non-GAAP net income of $52.8 million, or $0.16 per share, basic and diluted, for the comparable period in 2023. Non-GAAP Financial Measures To supplement Exelixis’ financial results presented in accordance with U.S. Generally Accepted Accounting Principles (GAAP), Exelixis presents non-GAAP net income (and the related per share measures), which excludes from GAAP net income (and the related per share measures) stock-based compensation expense, adjusted for the related income tax effect for all periods presented. Exelixis believes that the presentation of these non-GAAP financial measures provides useful supplementary information to, and facilitates additional analysis by, investors. In particular, Exelixis believes that these non-GAAP financial measures, when considered together with its financial information prepared in accordance with GAAP, can enhance investors’ and analysts’ ability to meaningfully compare Exelixis’ results from period to period, and to identify operating trends in Exelixis’ business. Exelixis has excluded stock-based compensation expense, adjusted for the related income tax effect, because it is a non-cash item that may vary significantly from period to period as a result of changes not directly or immediately related to the operational performance for the periods presented. Exelixis also regularly uses these non-GAAP financial measures internally to understand, manage and evaluate its business and to make operating decisions. These non-GAAP financial measures are in addition to, not a substitute for, or superior to, measures of financial performance prepared in accordance with GAAP. Exelixis encourages investors to carefully consider its results under GAAP, as well as its supplemental non-GAAP financial information and the reconciliation between these presentations, to more fully understand Exelixis’ business. Reconciliations between GAAP and non-GAAP results are presented in the tables of this release. 2024 Financial Guidance Exelixis is maintaining the previously provided financial guidance for fiscal year 2024 (1): Total revenues $1.825 billion - $1.925 billion Net product revenues (2) $1.650 billion - $1.750 billion Cost of goods sold 4% - 5% of net product revenues Research and development expenses (3) $925 million - $975 million Selling, general and administrative expenses (4) $425 million - $475 million Effective tax rate 20% - 22% ____________________ (1) 2024 financial guidance excludes expenses related to the restructuring plan announced in January 2024. (2) Exelixis’ 2024 net product revenues guidance range includes the impact of a U.S. wholesale acquisition cost increase of 2.2% for both CABOMETYX and COMETRIQ effective on January 1, 2024. (3) Includes $40 million of non-cash stock-based compensation expense. (4) Includes $60 million of non-cash stock-based compensation expense. Cabozantinib and Pipeline Highlights Cabozantinib Franchise Net Product Revenues and Royalties. Net product revenues generated by the cabozantinib franchise in the U.S. were $378.5 million during the first quarter of 2024, with net product revenues of $376.4 million from CABOMETYX® (cabozantinib) and $2.1 million from COMETRIQ® (cabozantinib). Based upon cabozantinib-related net product revenues generated by Exelixis’ collaboration partners during the quarter ended March 31, 2024, Exelixis earned $39.6 million in royalty revenues. Detailed Results from Phase 3 CONTACT-02 Pivotal Trial Evaluating Cabozantinib in Combination with Atezolizumab in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Presented at the American Society of Clinical Oncology 2024 Genitourinary Cancers Symposium (ASCO GU). In January, positive results from the primary progression-free survival (PFS) analysis in the global phase 3 CONTACT-02 pivotal trial were presented during an oral abstract session at ASCO GU. The results demonstrated a statistically significant improvement in PFS, as assessed by a blinded independent radiology committee (BIRC), for cabozantinib in combination with atezolizumab in the first 400 randomized patients in the intent-to-treat (PFS ITT) population and per protocol. A PFS benefit was observed across all subgroups of high-risk populations who have a poor prognosis and a high unmet need for additional treatment options, notably in patients with liver metastases or those who had received prior docetaxel chemotherapy. A statistically significant improvement in PFS was also observed by BIRC both in the ITT population (n=507) and according to Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. An interim analysis for overall survival (OS), conducted at the time of the primary PFS analysis, demonstrated a trend favoring the combination of cabozantinib and atezolizumab. The study continues toward the next analysis of OS, which is anticipated in 2024. CONTACT-02 is evaluating cabozantinib in combination with atezolizumab compared with a second novel hormonal therapy (NHT) in patients with mCRPC and measurable soft-tissue disease who have progressed on one prior NHT. The safety pro the combination regimen was consistent with the known profiles of each single agent, and no new safety findings were identified. Four-Year Follow-up Results from Phase 3 CheckMate -9ER Trial Evaluating CABOMETYX in Combination with Nivolumab (OPDIVO®) in Previously Untreated Renal Cell Carcinoma (RCC) Presented at ASCO GU. In January, four-year follow-up results from the CheckMate -9ER trial were featured in an oral presentation at ASCO GU. Results continued to show superior PFS and objective response rates in patients treated with the combination of CABOMETYX and nivolumab over sunitinib, the comparator studied in the trial, regardless of risk classification. Superior OS was also observed in patients treated with the combination. The presentation included data showing health-related quality-of-life benefits with the combination as compared to sunitinib. No new safety concerns were identified in the follow-up analysis. Cabozantinib and Zanzalintinib Data Presentations at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. Cabozantinib and zanzalintinib will be the subject of 10 presentations at this year’s ASCO Annual Meeting, which is being held from May 31 through June 4 in Chicago. Notably, presentations will include a biomarker analysis from the clear cell RCC cohort of the phase 1b/2 STELLAR-001 study of zanzalintinib in advanced solid tumors. Corporate Highlights Announcement of Key Priorities and Anticipated Milestones for 2024. In January, Exelixis announced its key priorities and anticipated milestones for 2024, including: implementation of a corporate restructuring to prioritize the advancement of the company’s deep pipeline of clinical and near-clinical programs; potential U.S. regulatory filings for cabozantinib in advanced NET and mCRPC indications; the anticipated outcome of the cabozantinib Abbreviated New Drug Application litigation with MSN Pharmaceuticals in the Spring timeframe of 2024; expansion of zanzalintinib’s pivotal development program with priorities defined by emerging phase 1b/2 data and potential clinical co-funding opportunities; advancing JEWEL-101, the phase 1 study of XB002, a next-generation tissue factor-targeting antibody-drug conjugate (ADC), alone and in combination with immunotherapy in a variety of solid tumor settings with the goal of prioritizing sensitive tumor types for full development; accelerating the phase 1 development of XL309, a potentially best-in-class small molecule inhibitor of USP1, as a potential therapy for tumors that have become refractory to PARP inhibitor (PARPi) therapy, including forms of ovarian, breast and prostate cancers, and pursuing potential PARPi combinations; potentially filing three Investigational New Drug applications for XB010 (5T4-MMAE ADC), XB628 (PD-L1 + NKG2A bispecific antibody), and XL495 (small molecule PKMYT1 inhibitor) if preclinical data continue to be supportive; and advancing two new programs to development candidate status, including a small molecule PLK4 inhibitor and an additional ADC. Exelixis presented the details of its key priorities and anticipated milestones at the 42nd Annual J.P. Morgan Healthcare Conference. Share Repurchase Program. As of March 31, 2024, Exelixis has repurchased $190.7 million of the company’s common stock, at an average price of $22.08 per share. In January, Exelixis announced that the company’s Board of Directors authorized the repurchase of up to an additional $450 million of the company’s common stock before the end of 2024. Upon fulfillment of the 2024 share repurchase program, the company expects to have returned $1 billion to shareholders over two years along with the 2023 program successfully completed in December 2023. Share repurchases under the 2024 program may be made from time to time through a variety of methods, which may include open market purchases, in block trades, accelerated share repurchase transactions, exchange transactions, or any combination of such methods. The timing and amount of any share repurchases under the share repurchase program will be based on a variety of factors, including ongoing assessments of the capital needs of the business, alternative investment opportunities, the market price of Exelixis’ common stock and general market conditions. Appointments of Two New Board Members with Extensive Drug Development and Corporate Governance Expertise. In January, Exelixis announced the appointments of Mary C. Beckerle, Ph.D., and S. Gail Eckhardt, M.D., to the Exelixis Board of Directors, effective January 5, 2024. Dr. Beckerle is Chief Executive Officer of the Huntsman Cancer Institute and Associate Vice President for Cancer Affairs and Distinguished Professor of Biology and Oncological Sciences at the University of Utah. Since 2006, she has had responsibility for the vision, strategic direction and management of the University’s oncology programs, including research, care, education and community outreach. Dr. Eckhardt is Associate Dean of Experimental Therapeutics at Baylor College of Medicine and Associate Director of Translational Research at the College’s Dan L. Duncan Comprehensive Cancer Center. A recognized leader in translational medicine relative to oncology, she has focused her career on the preclinical and early clinical development of molecularly targeted therapies and combination regimens to treat colorectal and other gastrointestinal cancers. European Patent Office (EPO) Rules in Favor of Exelixis on Formulation Patent Covering Cabozantinib Tablets. In January, Exelixis successfully defended European Patent number EP2593090 (c-MET Modulator Pharmaceutical Compositions) against three opponents, STADA Arzneimittel AG, Teva Pharmaceutical Industries Ltd. and Generics (U.K.) Ltd., in a hearing before the Opposition Division of the EPO. The patent at issue, which expires on July 18, 2031, covers tablet formulations of cabozantinib, including the tablet formulation approved as CABOMETYX (cabozantinib) tablets by the European Medicines Agency. The decision is specific to the European patent at issue and is subject to appeal to the EPO Technical Boards of Appeal. Basis of Presentation Exelixis has adopted a 52- or 53-week fiscal year that generally ends on the Friday closest to December 31st. For convenience, references in this press release as of and for the fiscal period ended March 29, 2024 is indicated as being as of and for the period ended March 31, 2024. Conference Call and Webcast Exelixis management will discuss the company’s financial results for the first quarter of 2024 and provide a general business update during a conference call beginning at 5:00 p.m. ET / 2:00 p.m. PT today, Tuesday, April 30, 2024. To access the conference call, please register using this link. Upon registration, a dial-in number and unique PIN will be provided to join the call. To access the live webcast link, log onto and proceed to the Event Calendar page under the Investors & News heading. A webcast replay of the conference call will also be archived on for one year. About Exelixis Exelixis is a globally ambitious oncology company innovating next-generation medicines and regimens at the forefront of cancer care. Powered by drug discovery and development excellence, we are rapidly evolving our product portfolio to target an expanding range of tumor types and indications with our clinically differentiated pipeline of small molecules, antibody-drug conjugates and other biotherapeutics. This comprehensive approach harnesses decades of robust investment in our science and partnerships to advance our investigational programs and extend the impact of our flagship commercial product, CABOMETYX® (cabozantinib). Exelixis is driven by a bold scientific pursuit to create transformational treatments that give more patients hope for the future. For information about the company and its mission to help cancer patients recover stronger and live longer, visit , follow @ExelixisInc on X (Twitter), like Exelixis, Inc. on Facebook and follow Exelixis on LinkedIn. Forward-Looking Statements This press release contains forward-looking statements, including, without limitation, statements related to: the potential for Exelixis’ portfolio of small molecules and biotherapeutics to improve standards of care for patients with cancer; Exelixis’ expectation to submit Investigational New Drug filings for up to three development candidates in 2024, pending continued supportive preclinical data, and to provide updates for the zanzalintinib, XB002 and XL309 development programs as clinical data mature; Exelixis’ plans to advance its regulatory strategies for cabozantinib label expansions into NET and mCRPC indications, which could drive future potential revenue growth of the franchise, and to provide additional updates when appropriate; Exelixis’ belief that its restructuring will further enhance the company’s integrated research, development and commercial capabilities to deliver an innovative pipeline of cancer therapies for patients; Exelixis’ anticipation of a ruling in the second bench trial for its ongoing litigation with MSN Pharmaceuticals in the spring timeframe of 2024; Exelixis’ 2024 financial guidance; Exelixis’ anticipated timing of 2024 for the next analysis of OS from CONTACT-02; Exelixis’ plans to present cabozantinib and zanzalintinib data at the 2024 ASCO Annual Meeting, including a biomarker analysis from the clear cell RCC cohort of the phase 1b/2 STELLAR-001 study of zanzalintinib in advanced solid tumors; Exelixis’ key priorities and anticipated milestones for 2024; Exelixis’ plans to repurchase up to an additional $450 million of its common stock before the end of 2024, and Exelixis’ expectation to have returned $1 billion to shareholders over two years along with the successfully completed 2023 share repurchase program; and Exelixis’ scientific pursuit to create transformational treatments that give more patients hope for the future. Any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements and are based upon Exelixis’ current plans, assumptions, beliefs, expectations, estimates and projections. Forward-looking statements involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of these risks and uncertainties, which include, without limitation: the degree of market acceptance of CABOMETYX and other Exelixis products in the indications for which they are approved and in the territories where they are approved, and Exelixis’ and its partners’ ability to obtain or maintain coverage and reimbursement for these products; the effectiveness of CABOMETYX and other Exelixis products in comparison to competing products; the level of costs associated with Exelixis’ commercialization, research and development, in-licensing or acquisition of product candidates, and other activities; Exelixis’ ability to maintain and scale adequate sales, marketing, market access and product distribution capabilities for its products or to enter into and maintain agreements with third parties to do so; the availability of data at the referenced times; the potential failure of cabozantinib, zanzalintinib and other Exelixis product candidates, both alone and in combination with other therapies, to demonstrate safety and/or efficacy in clinical testing; uncertainties inherent in the drug discovery and product development process; Exelixis’ dependence on its relationships with its collaboration partners, including their pursuit of regulatory approvals for partnered compounds in new indications, their adherence to their obligations under relevant collaboration agreements and the level of their investment in the resources necessary to complete clinical trials or successfully commercialize partnered compounds in the territories where they are approved; complexities and the unpredictability of the regulatory review and approval processes in the U.S. and elsewhere; Exelixis’ continuing compliance with applicable legal and regulatory requirements; unexpected concerns that may arise as a result of the occurrence of adverse safety events or additional data analyses of clinical trials evaluating cabozantinib and other Exelixis product candidates; Exelixis’ dependence on third-party vendors for the development, manufacture and supply of its products and product candidates; Exelixis’ ability to protect its intellectual property rights; market competition, including the potential for competitors to obtain approval for generic versions of Exelixis’ marketed products; changes in economic and business conditions; and other factors detailed from time to time under the caption “Risk Factors” in Exelixis’ most recent Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q, and in Exelixis’ other future filings with the Securities and Exchange Commission. All forward-looking statements in this press release are based on information available to Exelixis as of the date of this press release, and Exelixis undertakes no obligation to update or revise any forward-looking statements contained herein, except as required by law. Exelixis, the Exelixis logo, CABOMETYX and COMETRIQ are registered trademarks of Exelixis, Inc. OPDIVO® is a registered trademark of Bristol-Myers Squibb Company. EXELIXIS, INC. CONDENSED CONSOLIDATED STATEMENTS OF INCOME (in thousands, except per share amounts) (unaudited) Three Months Ended March 31, 2024 2023 Revenues: Net product revenues $ 378,523 $ 363,400 License revenues 44,676 38,292 Collaboration services revenues 2,027 7,096 Total revenues 425,226 408,788 Operating expenses: Cost of goods sold 21,256 14,315 Research and development 227,689 234,246 Selling, general and administrative 113,984 131,397 Restructuring 32,835 — Total operating expenses 395,764 379,958 Income from operations 29,462 28,830 Interest income 19,894 19,502 Other expense, net (89 ) (54 ) Income before income taxes 49,267 48,278 Provision for income taxes 11,950 8,250 Net income $ 37,317 $ 40,028 Net income per share: Basic $ 0.12 $ 0.12 Diluted $ 0.12 $ 0.12 Weighted-average common shares outstanding: Basic 300,757 324,420 Diluted 305,530 326,279 EXELIXIS, INC. RECONCILIATION OF GAAP NET INCOME TO NON-GAAP NET INCOME (in thousands, except per share amounts) (unaudited) Three Months Ended March 31, 2024 2023 GAAP net income $ 37,317 $ 40,028 Adjustments: Stock-based compensation - research and development expenses (1) 3,892 3,252 Stock-based compensation - selling, general and administrative expenses (1) 15,221 13,409 Income tax effect of the above adjustments (4,448 ) (3,861 ) Non-GAAP net income $ 51,982 $ 52,828 GAAP net income per share: Basic $ 0.12 $ 0.12 Diluted $ 0.12 $ 0.12 Non-GAAP net income per share: Basic $ 0.17 $ 0.16 Diluted $ 0.17 $ 0.16 Weighted-average common shares outstanding: Basic 300,757 324,420 Diluted 305,530 326,279 ____________________ (1) Non-cash stock-based compensation expense used for GAAP reporting in accordance with Accounting Standards Codification Topic 718, Compensation—Stock Compensation.

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