MRGPRX2

Evommune is eligible to receive up to $62 million in upfront and milestone payments Expanded collaboration adds additional non-dilutive cash to Evommune's strong balance sheet PALO ALTO, Calif., March 20, 2024 /PRNewswire/ -- Evommune, Inc., a biotechnology company discovering and developing new ways to treat immune-mediated inflammatory diseases, today announced that it has entered into an expanded strategic collaboration with Maruho Co., Ltd., to exclusively develop and commercialize EVO756 in Greater China and additional key Asian countries. The two companies previously entered into a similar agreement for Japan in September, 2023. Under the terms of the new agreement, Evommune is eligible to receive up to $62 million, including a significant upfront and customary milestone payments. EVO756, Evommune's MRGPRX2 antagonist, is an investigational therapy targeting MRGPRX2 for multiple inflammatory conditions, with the potential to be a first-in-class oral treatment for a variety of mast cell mediated disease, including chronic spontaneous urticaria. Evommune has initiated its Phase 1 first-in-human trial, evaluating EVO756 in heathy adults and adults with chronic spontaneous urticaria (CSU). The trial is a randomized, double-blind, placebo-controlled single and multiple ascending dose (SAD and MAD) study in normal healthy adults and an open label study in adults with CSU. The trial is designed to assess the safety, tolerability and pharmacokinetics, of orally administered EVO756, as well as the pharmacodynamic potential of EVO756 on mast cell degranulation via a skin challenge test, with data expected in the first half of 2024. "The collaboration with Maruho gives full recognition to the strenghths of both companies, accelerating the delivery of R&D innovation, and jointly bringing transformative medicines to benefit chronic inflammatory disease patients in Asia and globally," said Greg Moss, Chief Corporate Strategy & Legal Officer at Evommune. "Maruho's recognition of the potential of EVO756 has allowed us to attract substantial non-dilutive capital, which will be used to support our strategy to expand our pipeline with novel therapies designed to treat and halt the progression of chronic inflamatory diseases. About EVO756 EVO756 is a potent, highly selective small molecule antagonist of mas-related G-protein coupled receptor X2 (MRGPRX2). MRGPRX2 is most abundantly found on mast cells and peripheral sensory neurons. MRGPRX2 can trigger IgE-independent activation (degranulation), which can lead to a variety of symptoms depending on the tissue that is affected. This receptor is unique in that it can respond to a wide variety of ligands, including neuropeptides, proteases, cytokines, antimicrobial peptides and others. In response to MRGPRX2 activation, mast cells release histamine, tryptase, chymase, chemokines and cytokines, which can cause itchy hives, angioedema, type 2 inflammation (through engagement of the adaptive immune system) and chronic pruritus and pain. Evommune's pre-clinical data demonstrates that by blocking activation of MRGPRX2 and degranulation of mast cells, EVO756 has the potential to be a first-in-class oral treatment for a variety of mast cell mediated diseases. In addition, due to its unique function on peripheral sensory neurons, EVO756 could provide fast relief of itch associated with inflammatory diseases, such as atopic dermatitis, by blocking MRGPRX2. EVO756 represents a new, targeted approach to the treatment of these disorders with the potential for once-daily oral administration without the serious side effects observed with other approaches. About Evommune, Inc. Evommune, Inc., a Palo Alto based biotech company, is creating game-changing science to treat immune-mediated inflammatory diseases by discovering, developing, and delivering therapies that address symptoms and halt progressive disease. For more information, please visit Evommune.com.

SAN CARLOS, Calif., March 14, 2024 (GLOBE NEWSWIRE) -- Allakos Inc. (the “Company”) (Nasdaq: ALLK), a biotechnology company developing antibodies for the treatment of allergic, inflammatory and proliferative diseases, today provided a business update and reported financial results for the fourth quarter and full year ended December 31, 2023. Recent Allakos Events Completed dosing in the single ascending dose (SAD) cohorts and continued dosing in the multiple ascending dose (MAD) cohorts of the randomized, double-blind, placebo-controlled Phase 1 trial of Intravenous (IV) AK006 in healthy volunteers.Initiated the randomized, double-blind, placebo-controlled subcutaneous (SC) AK006 cohort in healthy volunteers.Published preclinical research in Allergy showing that AK006 controls mast cell function through interaction with multiple activating receptors and key signaling pathways.Presented preclinical data at the American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting 2024 highlighting AK006’s mechanism of action and ability to reduce MRGPRX2-induced skin inflammation.Reported topline data from the Phase 2 study of SC lirentelimab in patients with atopic dermatitis and Phase 2b study of SC lirentelimab in patients with chronic spontaneous urticaria.Halted lirentelimab-related development activities and announced a restructuring plan to reduce costs and focus on AK006 clinical development. As a result of the restructuring, Allakos expects its cash runway to extend into mid-2026. Upcoming Allakos Anticipated Milestones Report safety, pharmacokinetics (PK), and pharmacodynamic (PD) results from the Phase 1 trial of IV AK006 in healthy volunteers, including data to confirm Siglec-6 receptor occupancy in skin biopsy samples in Q2 2024.Initiate the randomized, double-blind, placebo-controlled Phase 1 trial of IV AK006 in patients with chronic spontaneous urticaria in Q2 2024.Report safety, PK, and PD results from the Phase 1 trial of SC AK006 in healthy volunteers, including data to confirm Siglec-6 receptor occupancy in skin biopsy samples in Q3 2024.Report topline data from the Phase 1 trial of IV AK006 in patients with CSU at year end 2024 Cash Guidance The Company expects that the restructuring activities will extend the cash runway into mid-2026. The Company ended the fourth quarter of 2023 with approximately $170.8 million in cash, cash equivalents and investments. The Company’s outlook for 2024 cash, cash equivalents and investments is as follows: Cash, cash equivalents and investments at year end 2023$171 millionEstimated 2024 net cash used in operating activities (GAAP)($85 to $90 million)Estimated cash, cash equivalents and investments at year end 2024$81 to $86 million Components of estimated 2024 net cash used in operating activities for the year ended December 31, 2024 are as follows: Estimated net cash used in operating activities (GAAP)$85 to $90 millionLess: estimated lirentelimab closeout, severance and other costs 1($30 million)Estimated adjusted net cash used in operating activities (non-GAAP) 2$55 to $60 million 1 The Company anticipates that the significant majority of the restructuring expenditures, including approximately $4 million of severance, will be paid in the first half of 2024. 2 For additional information on the Company’s use of non-GAAP financial information, please see the section titled “Non-GAAP Financial Measure” below. Fourth Quarter 2023 Financial Results Research and development expenses were $53.8 million in the fourth quarter of 2023 compared to $35.4 million in the fourth quarter of 2022, an increase of $18.4 million. This quarter over quarter increase is attributed to $15.0 million of increased manufacturing costs and $3.4 million of increased other research and development expenses related primarily to our clinical studies. General and administrative expenses were $11.2 million for the fourth quarter of 2023 compared to $10.8 million for the fourth quarter of 2022, an increase of $0.4 million. The quarter over quarter change included $0.3 million of increase stock-based compensation expenses and $0.1 million increase in other general and administrative expenses. Allakos reported a net loss of $62.6 million in the fourth quarter of 2023 compared to $43.0 million in the fourth quarter of 2022. The fourth quarter of 2023 included noncash expenses for stock-based compensation of $10.2 million, compared to $9.3 million in the same period in 2023, and depreciation expense of $1.5 million in each of the fourth quarters of 2023 and 2022. Net loss per basic and diluted share was $0.71 for the fourth quarter of 2023 compared to $0.50 in the fourth quarter of 2022. Allakos ended the fourth quarter of 2023 with $170.8 million in cash, cash equivalents and investments resulting in a net decrease in cash, cash equivalents and investments of $23.1 million during the fourth quarter of 2023. About Allakos Allakos is a clinical stage biotechnology company developing therapeutics that target immunomodulatory receptors present on immune effector cells involved in allergy, inflammatory and proliferative diseases. Activating these immunomodulatory receptors allows for the direct targeting of cells involved in disease pathogenesis and, in the setting of allergy and inflammation, has the potential to result in broad inhibition of inflammatory cells. The Company’s most advanced product candidate is AK006. AK006 targets Siglec-6, an inhibitory receptor expressed on mast cells. Mast cells are widely distributed in the body and play a central role in the inflammatory response. Inappropriately activated mast cells have been identified as key drivers in a number of severe diseases affecting the gastrointestinal tract, eyes, skin, lungs and other organs. In preclinical studies, AK006 appears to provide deep mast cell inhibition and, in addition to its inhibitory activity, reduce mast cell numbers. For more information, please visit the Company’s website at www.allakos.com. Non-GAAP Financial Measure In this press release, Allakos’ estimated net cash used in operating activities is provided in accordance with generally accepted accounting principles (GAAP) in the United States and also on a non-GAAP basis. Non-GAAP estimated adjusted net cash used in operating activities excludes estimated lirentelimab closeout, severance and other costs. Non-GAAP estimated adjusted net cash used in operating activities is provided as a complement to estimated net cash used in operating activities provided in accordance with GAAP because management believes the non-GAAP financial measure is useful to investors in assessing the Company’s operating performance. Management also uses the non-GAAP financial measure to establish operational goals that are communicated internally and externally, to manage the Company’s business and to evaluate its performance. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 as contained in Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Such forward-looking statements include, but are not limited to, Allakos’ progress, business plans and areas of focus; the expected timing of reporting data from its clinical trial of AK006; the clinical potential of AK006; and Allakos’ anticipated clinical milestones. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from current expectations and beliefs, including but not limited to: Allakos’ stages of clinical drug development; Allakos’ ability to timely initiate and complete clinical trials for AK006; Allakos’ ability to obtain required regulatory approvals for its clinical trials; uncertainties related to the enrollment of patients in its clinical trials; Allakos’ ability to demonstrate sufficient safety and efficacy of its product candidates in its clinical trials; uncertainties related to the success of clinical trials, regardless of the outcomes of preclinical testing or early-stage trials; Allakos’ ability to obtain regulatory approvals to market its product candidates; market acceptance of Allakos’ product candidates; uncertainties related to the projections of the size of patient populations suffering from the diseases Allakos is targeting; Allakos’ ability to advance additional product candidates beyond AK006; uncertainties related to Allakos’ ability to realize the contemplated benefits of its restructuring and related reduction in force; Allakos’ ability to accurately forecast financial results; Allakos’ ability to obtain additional capital to finance its operations, research and drug development; general economic and market conditions, both domestic and international; domestic and international regulatory obligations; and other risks. Information regarding the foregoing and additional risks may be found in the section entitled “Risk Factors” in documents that Allakos files from time to time to with the SEC. These documents contain and identify important factors that could cause the actual results for Allakos to differ materially from those contained in Allakos’ forward-looking statements. Any forward-looking statements contained in this press release speak only as of the date hereof, and Allakos specifically disclaims any obligation to update any forward-looking statement, except as required by law. These forward-looking statements should not be relied upon as representing Allakos’ views as of any date subsequent to the date of this press release. Source: Allakos Inc. Investor Contact:Adam Tomasi, PresidentAlex Schwartz, VP Strategic Finance and Investor Relationsir@allakos.com Media Contact:Denise Powelldenise@redhousecomms.com ALLAKOS INC. UNAUDITED STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS (in thousands, except per share data) Three Months Ended Twelve Months Ended December 31, December 31, 2023 2022 2023 2022 Operating expenses Research and development $53,801 $35,388 $150,908 $265,081 General and administrative 11,182 10,828 45,148 57,348 Total operating expenses 64,983 46,216 196,056 322,429 Loss from operations (64,983) (46,216) (196,056) (322,429)Interest income 2,382 2,775 10,347 3,673 Other income (expense), net 50 452 8 (1,196)Net loss (62,551) (42,989) (185,701) (319,952)Unrealized gain (loss) on investments 122 (220) 334 (131)Comprehensive loss $(62,429) $(43,209) $(185,367) $(320,083)Net loss per common share: Basic and diluted $(0.71) $(0.50) $(2.14) $(5.06)Weighted-average number of common shares outstanding: Basic and diluted 87,567 85,262 86,798 63,284 ALLAKOS INC. UNAUDITED CONDENSED BALANCE SHEETS (in thousands) December 31, 2023 2022 Assets Current assets: Cash and cash equivalents $66,440 $87,217 Investments 104,354 192,569 Prepaid expenses and other current assets 9,095 29,057 Total current assets 179,889 308,843 Property and equipment, net 33,369 39,144 Operating lease right-of-use assets 24,136 30,225 Other long-term assets 6,216 8,208 Total assets $243,610 $386,420 Liabilities and stockholders’ equity Current liabilities: Accounts payable $1,764 $4,832 Accrued expenses and other current liabilities 34,814 25,206 Total current liabilities 36,578 30,038 Operating lease liabilities, net of current portion 38,215 45,949 Total liabilities 74,793 75,987 Stockholders’ equity: Common stock 88 85 Additional paid-in capital 1,287,156 1,243,408 Accumulated other comprehensive loss 50 (284)Accumulated deficit (1,118,477) (932,776)Total stockholders’ equity 168,817 310,433 Total liabilities and stockholders’ equity $243,610 $386,420

引言胆汁成分如外泌体或蛋白质可以帮助诊断或预测胆管癌(CCA)的进展，但胆汁代谢物的作用尚未研究。组胺(HA)参与CCA的进展，但HA诱导的进展机制尚不清楚，HA在CCA中的产生和清除尚不清楚。肥大细胞(MC)是肿瘤微环境中一个被忽视的成员。MC在CCA微环境中的作用研究很少。2024年3月8日，山东大学徐云飞、张宗利及吉林大学吕国悦共同通讯在Gut（IF 25）在线发表题为“Function of mast cell and bile-cholangiocarcinoma  interplay in cholangiocarcinoma microenvironment”的研究论文，该研究揭示了胆管癌微环境中肥大细胞与胆管癌功能的相互作用。胆汁酸在CCA中升高，表明预后较差。癌症相关成纤维细胞(CAFs)衍生干细胞因子(SCF)募集MCs，胆汁N,N-二甲基-1,4-苯二胺(DMPD)通过G蛋白偶联受体亚型2 (MRGPRX2)-Gαq信号通路刺激MCs释放HA。胆汁诱导的MCs释放血小板衍生生长因子亚单位B (PDGF-B)和血管生成素1/2 (ANGPT1/2)，促进CCA血管生成和淋巴管生成。组胺受体H1 (HRH1)和HRH2分别在CCA细胞和CAFs中主要表达。HA通过激活HRH1-Gαq信号通路促进CCA细胞增殖，通过激活HRH2-Gαs信号通路促进CAFs分泌肝细胞生长因子。溶质载体家族22成员3 (SLC22A3)通过将胆汁HA导入细胞降解抑制HA诱导的CCA增殖，SLC22A3缺失导致HA积累。因此，胆汁HA通过DMPD刺激从MCs中释放，并通过SLC22A3导入降解。不同的HA受体在CCA中表现出不同的表达谱，并产生不同的致癌作用。MCs通过CCA-胆汁相互作用模式促进CCA进展。胆管癌(CCA)是一种起源于胆管的高度侵袭性癌症。体液检查，如尿液检查，对疾病的诊断是重要的，但由于胆汁不能以无创的方式获得，对胆汁检测的研究很少。许多CCA合并胆道狭窄的患者必须进行胆道引流以减少黄疸，使得胆汁含量谱分析成为鉴别恶性或良性胆道狭窄的一种有希望的方法。之前证明了几种蛋白质，如成纤维细胞生长因子7 (FGF7)和高迁移率组盒1 (HMGB1)，或胆汁外泌体中的miRNA，在CCA胆汁中上调，，胆汁成分可以促进CCA进展。然而，小分子在胆汁和CCA进展中的作用很少被研究。组胺(HA)是一种内源性生物胺，参与许多生理功能，特别是局部免疫反应。它还作为大脑、脊髓和子宫的神经递质发挥作用HA存在于所有组织中，含量不同，从小于1到大于100 μg/g不等。皮肤、结缔组织、肺和胃肠道都富含透明质酸。HA主要由组氨酸脱羧酶(HDC)产生，由组胺N-甲基转移酶(HNMT)或胺氧化酶B (MAO-B)代谢透明质酸的清除是一个重要的生理过程，因为透明质酸的积累会导致过度的过敏、炎症或神经元活动。然而，透明质酸如何从组织液转运到细胞中进行清除还没有得到很好的研究。有三种已知的多特异性转运体负责HA转运，它们是溶质载体家族22成员2 (SLC22A2)， SLC22A3和SLC29A4这些受体是低亲和力，高容量和Na+/Cl−不依赖的，但这些受体的组织特异性尚不清楚。CCA中胆汁HA的生成、功能和清除示意图（Credit: Gut）HA通过与其受体，组胺受体(HRH)1/2/3/4相互作用，具有不同的组织特异性表达，具有多种功能HA受体是G蛋白偶联受体(GPCRs)，刺激HA受体可通过偶联不同的G蛋白激活不同的下游信号通路。大多数研究表明，HA-HRH信号的异位刺激具有促肿瘤作用在CCA中，HRH1和HRH2先前被报道参与CCA的肿瘤发生，而HRH3和HRH4被证明抑制CCA的进展。然而，HA受体在CCA中的这些相反作用是有争议的。肥大细胞(MC)是HA储存和释放的主要位置在胆汁淤存或胆管损伤的情况下，MCs可浸润到胆管组织中，据报道MCs可通过释放HA促进CCA进展。此外，先前的研究表明MC来源的HA可促进CCA细胞增殖和分化，但HA的确切功能和触发的信号通路尚未完全揭示。该研究表明，CCA用CAF衍生的SCF募集MCs，胆汁DMPD激活MCs上的MRGPRX2，诱导除HA外PDGF-B和ANGPT1/2的释放。PDGF-B和ANGPT1/2促进血管生成和淋巴管生成。HA通过刺激HRH1 -Gαq信号通路，促进CCA细胞的增殖。另一方面，HA激活HRH2 -Gαs信号，促进CAFs分泌HGF。SLC22A3是HA转运和清除的关键因素。研究发现胆汁HA是一种预测CCA的生物标志物，也是胆汁驱动的CCA进展和胆汁-CCA相互作用的关键效应因子。这些结果表明，胆汁检测是CCA诊断和个体化治疗的新方法。MCs和HA在CCA中的重要性可能有助于发现CCA治疗的新潜在疗法。原文链接https://doi.org/10.1136/gutjnl-2023-331715责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述