Drospirenone/Estetrol

关注并星标CPHI制药在线近日，Adaptimmune Therapeutics宣布其在研工程化T细胞疗法afami-cel的关键性2期临床研究SPEARHEAD-1的积极数据发表于《柳叶刀》当中。美国FDA已接受afami-cel的生物制品许可申请（BLA），并授予其优先审评资格。该申请的PDUFA日期为2024年8月4日。如果获得批准，afami-cel将成为首款用于治疗实体瘤的工程化T细胞疗法，也是十多年来治疗滑膜肉瘤的首个有效疗法。图片来源：参考来源1       共有52名患者在北美和欧洲的23个医疗中心参与了这项2期临床试验，其中44名滑膜肉瘤患者和8名黏液样圆细胞脂肪肉瘤（MRCLS）患者。36%的患者（19/52人）对治疗有反应，肿瘤缩小或在某些情况下完全消失。该疗法对滑膜肉瘤患者比对MRCLS患者更有效。平均而言，滑膜肉瘤患者的反应持续时间略高于11个月，而MRCLS患者的反应持续时间略高于4个月。大多数患者在癌症缓解一段时间后复发。目前为止，有少数在初始治疗后肿瘤消失的患者没有复发。       在所有患者中，平均生存期略高于15个月，一年生存率为60%。在滑膜肉瘤患者中，肿瘤对初始治疗显示完全应答（即单次治疗后肿瘤完全消失），一年生存率为90%，两年生存概率为70%。       该治疗最常见的副作用涉及红细胞和白细胞计数低，这是由于为准备身体接受工程T细胞所需的化疗所致。许多患者需要通过治疗来控制细胞因子释放综合征（即细胞因子风暴），这是T细胞疗法常见的副作用。在随访期间发生的28例死亡被证明均是由于癌症最终进展而非治疗所致。       在这项国际性、开放标签的2期临床试验中，TCR-T细胞疗法afami-cel在晚期滑膜肉瘤和黏液样圆细胞脂肪肉瘤（MRCLS）患者中产生了持久缓解。这项临床试验表明，TCR-T细胞疗法可以有效地靶向实体瘤，并为将这种方法扩展到其他实体恶性肿瘤提供了理论基础。       Afami-cel是一款MAGE-A4靶向的TCR-T细胞疗法，MAGE-A4作为癌睾丸抗原，在多种肿瘤组织中高表达。尽管滑膜肉瘤和黏液样圆细胞脂肪肉瘤是两种不同的癌症，但它们具有共同的临床和生物学特征，它们都高表达癌-睾丸抗原（CT抗原），包括MAGE-A4和NY-ESO-1。该疗法从患者体内提取T细胞并使用慢病毒载体进行基因工程改造，表达靶向HLA-A*02呈递的MAGE-A4 230-239 GVYDGREHTV的高亲和力和特异性T细胞受体（TCR），该TCR引导T细胞靶向表达MAGE-A4的癌细胞并清除这些癌细胞。FDA已授予其治疗晚期软组织肉瘤的孤儿药资格（ODD）和晚期滑膜肉瘤的再生医学高级疗法（RMAT）资格。       另外，Adaptimmune 还在开发下一代TCR-T疗法ADP-A2M4CD8，这种疗法与afami-cel的区别在于，这些细胞还表达CD8α共受体以及靶向MAGE-A4的工程TCR。其临床前数据表明，CD8α的共表达可以拓宽对实体瘤的免疫反应，并通过将CD4细胞转化为CD8杀伤细胞或细胞毒性T细胞来增加抗肿瘤活性，同时保留其CD4辅助功能；此外ADP-A2M4CD8针对MAGE-A4，MAGE-A4是在多种实体瘤类型中表达的癌症评估抗原的MAGE家族成员。目前A2M4CD8的1期SURPASS临床数据显示，疗效信号支持卵巢癌、尿路上皮癌和头颈癌的进一步发展。对于患有广泛表达MAGE-A4的不可切除或转移性肿瘤的患者（包括接受纳武利尤单抗（nivolumab）联合治疗的患者），ADP-A2M4CD8继续显示出可接受的风险效益。Adaptimmune临床实体瘤T细胞治疗管线图片来源：Adaptimmune官网喜中有忧的AdaptimmuneAdaptimmune Therapeutics是一家细胞疗法公司，致力于重新定义癌症治疗方法，尤其聚焦实体瘤治疗。公司独特的工程化T细胞受体（TCR）平台使T细胞工程能够靶向摧毁多种实体瘤类型的癌症。2023年3月，Adaptimmune和TCR2  Therapeutics共同宣布，两家公司将合并成为一家新公司，进一步巩固了Adaptimmune公司在TCR-T细胞疗法领域的地位。       Adaptimmune依托其独有的Spear-T细胞技术，是最早将TCR-T疗法推进临床试验的Biotech公司。Adaptimmune的技术曾先后得到葛兰素史克、安斯泰来、基因泰克等大药企的认可，建立了合作开发的关系，但遗憾的是，最后都无疾而终了。       • 2022年10月， 葛兰素史克向Adaptimmune退还了靶向NY-ESO的TCR-T疗法的全部权益；       • 2023年4月，安斯泰来宣布终止了与 Adaptimmune的TCR-T疗法研发合作，此前该合作项目总金额达8.975亿美元；       • 2024年4月，基因泰克宣布终止了与Adaptimmune公司价值高达30亿美元的细胞疗法合作。两家公司最初计划开发针对最多五个癌症靶点的异体细胞疗法，同时建立一个个性化异体细胞疗法平台。       除了与多个MNC的合作项目告吹外，Adaptimmune公司的股价在过去两年的跌幅较大还有其他原因：       • 研发进度慢。主要资产afami-cel在递交上市进度方面较为拖拉，此前给出的预期是2021年上半年申报BLA，2022年上市，目前进度已经大为落后。       • 临床试验数据存在瑕疵。afami-cel此前发布的数据中，药物疗效的持久性存疑，入组患者中存在细胞因子释放综合征的现象，加剧了市场对药物能否获批的担忧。       • 适应症市场想象空间不足。滑膜肉瘤的发病率为2.75人/10万人，全美每年新增病例不足800人，作为一款二线疗法，afami-cel的销售潜力难以突破1亿美元。TCR-T疗法简介       TCR-T的全称是"T细胞受体工程化T细胞疗法"，同属新型细胞免疫疗法。主要通过基因编辑技术，将能特异性识别肿瘤抗原的T细胞受体（TCR）基因导入患者自身的T细胞内，使其表达外源性TCR，从而具有特异性杀伤肿瘤细胞的活性。       T淋巴细胞被誉为人体内的"战士"，在人体血液、淋巴和周围组织器官发挥免疫功能，能够抵御和消灭肿瘤细胞。但在肿瘤细胞逃逸过程中，T细胞却不能很好地识别杀伤肿瘤细胞。       TCR（T cell receptor）是T细胞表面的特异性受体，以非共价键与CD3结合，形成TCR-CD3复合物，通过识别并结合MHC呈递的抗原从而激活T细胞，促进T细胞的分裂与分化。TCR-T疗法是向正常外周血淋巴细胞上导入已知的抗原特异性TCR基因进行治疗的一种疗法。普通T细胞中引入新的基因，使得改造过的T细胞能够表达有效识别肿瘤细胞的TCR，从而引导T细胞杀死肿瘤细胞。       目前在血液瘤领域大获成功的CAR-T，由于特异性靶标的掣肘，在实体瘤领域进展缓慢。而TCR-T识别的是多肽-MHC复合体，不仅精准、范围广泛，还更容易浸润到实体瘤内部，大大拓宽了肿瘤免疫治疗的靶点。针对单个抗原靶点的TCR-T回输后，可以进一步激活患者自身针对其他肿瘤抗原表位的T细胞，具有逆转实体瘤抑制性免疫微环境的作用，有望实现更好的疗效与持久性。与此同时，TCR-T只介导少量细胞因子的释放，在安全性上具有天然优势。总体而言，TCR-T将是实体瘤治疗领域极具威力的"杀手锏"国内药企争相布局TCR-T赛道       TCR-T 研发的星星之火，已渐成燎原之态，国内外众多企业布局 TCR-T 细胞治疗。2022 年 1 月，美国食品和药物管理局（FDA）已批准全球第一个 T 细胞受体（TCR）治疗药 Kimmtrak（IMCgp100）上市，用于治疗 HLA-A*02:01 阳性不可切除性或转移性葡萄膜黑色素瘤（mUM）成人患者，为TCR 疗法治疗实体瘤奠定基础。而今第一个 TCR-T 疗法的申报上市，意味着肿瘤治疗靶点从胞外转移到胞内，开辟了全新的靶点选择空间。       根据美国临床试验注册库的数据，目前在研的 TCR-T 治疗实体瘤种类，主要包括转移性非小细胞肺癌、肝细胞癌、多发性骨髓瘤、软组织肉瘤、头颈癌、黑色素瘤、脂肪肉瘤和宫颈癌等，主要分布在美国和中国。在国内的 TCR-T 细胞治疗中，香雪制药、百吉生物、天科雅、普瑞金、深圳宾德、来恩生物、泛恩生物、华夏英泰、立凌生物、可瑞生物等多家药企布局了这一赛道。TCR-T疗法覆盖的肿瘤适应症图片来源：可瑞生物官网国内 TCR-T 细胞治疗企业与管线一览（部分）图片来源：医麦客       香雪制药的TAEST16001是中国首个获批临床试验的TCR-T细胞疗法。2023年8月15日，国际著名期刊Cell Reports Medicine刊发了TAEST16001的1期临床研究成果，该产品适应症为软组织肉瘤，I期临床研究肿瘤客观缓解率（ORR）达到41.7%，中位无进展生存期（PFS）为7.2个月，中位缓解持续时间（DOR）为13.1个月，并已进入II期临床研究。       来恩生物的First in class候选TCR-T疗法LioCyx-M004能够利用mRNA编码表达HBV抗原特异性的TCR来靶向肝癌细胞。2022年11月，来恩生物在2022年美国肝病研究协会年会上以海报形式公布了LioCyx-M004的1期临床试验数据，初步证明了该产品具有良好的靶向性和持久抗肿瘤作用。目前，LioCyx-M004正在进行2期临床试验。       星汉德生物的SCG101通过引入病毒特异性TCR基因序列重定向T细胞，使其表达针对乙肝病毒表面抗原（HBsAg）的特异性T细胞受体，定向清除HBV感染的肝细胞和肝癌细胞，还可能调节肝脏中的免疫抑制微环境。值得一提的是，这是第一个在中国获批IND治疗肝癌的TCR-T细胞治疗药物。去年6月，星汉德生物在国际细胞与基因治疗学会（ISCT）会议上展示了SCG101的最新临床数据：单剂量SCG101输注后可根除100%的HBsAg+肝细胞，使得74.5%的肝肿瘤细胞减少。       天科雅的TC-E202是一种加载抗PD-1抗体的TCR-T疗法，它在编码HPV16 E6 TCR的同时，编码抗PD-1的单链抗体可变区片段。经病毒转染，T细胞能够表达HPV16 E6 TCR并同时分泌抗PD-1的单链抗体，有效消除肿瘤微环境的抑制。当TC-E202输入患者体内，经改造的T细胞表面表达的TCR能有效识别宫颈癌肿瘤抗原HPV16 E6。目前TC-E202正在开展I/II期临床研究，旨在评估TC-E202在HPV16阳性的既往治疗失败的复发或转移性宫颈癌患者中的安全性和耐受性。       参考来源       1. Sandra P D'Angelo,et al. Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial . doi.org/10.1016/S0140-6736(24)00319-2       2. 企业官网       3. Yating Liu, et al. TCR-T Immunotherapy: The Challenges and Solutions . Front Oncol. 2022 Jan 25;11:794183.       4. Estelle Baulu, et al. TCR-engineered T cell therapy in solid tumors: State of the art and perspectives. Sci Adv. 2023 Feb 15;9(7):eadf3700.【智药研习社近期直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

Mithra reports full year 2023 financial results Revenues were EUR 40.2 million, down from the 2022 result of EUR 67.0 million which was positively impacted by exceptional upfront cash payments from partnerships.Product sales were EUR 18.7 million, up +19.3% vs EUR 15.7 million in 2022.ESTELLE® product sales reached EUR 10.4 million in 2023 beating the September 2023 guidance of EUR 8.5 million and up from EUR 9.2 million in 2022.Cash position, at EUR 9.0 million at end of 2023, is down compared to previous year (EUR 28.3 million end 2022).In an effort to maximize value for all of Mithra’s stakeholders, the Company has initiated a Monetization Process to realize value from its assets involving the sale of various selected assets, particularly Estetra SRL (which includes the US DONESTA® out-licensing process), and/or the business as a whole.The delay in the DONESTA® US NDA filing negatively impacted the process to consummate a US licensing agreement, also negatively impacting expected revenues.Triggered by the monetization process, management recognized an impairment loss of EUR 74.1 million on two of those assets (namely the Mithra CDMO and ZORELINE®). This accounting conclusion does not affect the management’s commitment to continue to find the best possible outcome for those assets. Due to these impairments (non-cash items), among other factors, the net loss for the period was EUR 173.5 million.Post-closing events include the 06 February 2024 announcement of Mithra’s cash position of EUR 6.5 million, the 15 February 2024 sale of balance of shares held in Mayne Pharma for approximately EUR 12.8 million, the 05 March 2024 announcement of up to EUR 18.5 million bridge facility to initiate a monetization process of key Mithra assets, and the 05 March 2024 change of management announcement. Liege, Belgium, 08 March 2024 – 7:00 CET – Mithra (Euronext Brussels: MITRA), a company dedicated to Women’s Health, today announces its financial results for the year which ended on 31 December 2023, prepared in accordance with IFRS. Financial Highlights See "Note regarding basis of preparation" on page 5 below. FY 2023 revenues were EUR 40.2 million compared to EUR 67.0 million in 2022.Out-licencing revenues at EUR 19.0 million were mostly driven by ESTELLE® in 2023. On top of EUR 3.75 million invoiced to our partner Fuji, another EUR 12.5 million has been recognized as revenue according to our IFRS 15 accounting policy (respectively EUR 2.5 million with Gedeon Richter for China and EUR 10.0 million with Fuji). Balance of out-licencing was primarily for DONESTA® with EUR 1.5 million invoiced to our partner Searchlight and EUR 1.13 million recognized under IFRS for China and Israel.ESTELLE® product sales, at EUR 10.4 million, were above 2022 level (EUR 9.2 million) and above our latest guidance (EUR 8.5 million) given in September. This is due to, amongst other items, our first deliveries to our Japan partner Fuji Pharma.Total number of cycles of ESTELLE® (NEXTSTELLIS®) sold by our partner in the US Mayne Pharma increased +136% to 385k cycles. The increase in sales is expected to continue in 2024.ESTELLE® cycle sales in Europe (DROVELIS® and LYDISILKA® brand names) increased by 103% to 3.2 million cycles in 2023.Novalon sales of generic products, including MYRING®, TIBELIA® and DAPHNE®, were EUR 8.1 million in 2023, up by +28% compared to the previous year while R&D contracting revenue from our CDMO remained steady at EUR 2.4 million.Cash collection from out-licensing milestones totalled EUR 56.4 million in 2023; EUR 51.5 million from DONESTA® (EUR 50.0 million from Gedeon Richter, out of which EUR 39.7 million was recognized in 2022 according to IFRS 15 and EUR 1.5 million from Searchlight); EUR 4.8 million from ESTELLE® (EUR 3.8 million from Fuji Pharma and EUR 1.0 million from Gedeon Richter for two LATAM territories previously recognised under IFRS).R&D expenses (excluding depreciation) decreased slightly (EUR 52.9 million in 2023 versus EUR 53.7 million in 2022) coming in below the guidance of EUR 60 million given in May 2023. The stable level of spend is a product of the continued strategy to focus on core R&D projects (DONESTA® and ESTELLE®) and discontinuing or pausing other research activities outside Mithra’s core scope.REBITDA was EUR -48.2 million in 2023 compared to EUR -12.3 million in 2022 year mostly due to lower out-licencing revenue and, to a lesser extent, an increase in G&A expenses and lower other operating income.Share-based payments expenses include the one-time (non-cash) expense of EUR 4.1 million relating to the 20 million warrants issued to Armistice Capital, LLC; the remaining being the balance of costs relating to previously awarded plans.Impairment on non-current assets: due to current cash runway situation, focus for non-core assets has now shifted to short-term sale or disposal. Accordingly, an impairment loss of EUR 74.1 million for two such assets has been recorded in FY 2023 financial statements: EUR 47.7 million for Mithra CDMO and EUR 26.4 million for ZORELINE®. This accounting conclusion does not affect the management’s commitment to continue to find the best possible outcome for those assets.Deferred tax assets: Balance of deferred tax assets previously recognized within Mithra CDMO and Novalon have been reversed as essentially relating to expected future taxable profit of ZORELINE®, now most likely to be sold in the short term.Cash position, at EUR 9.0 million at end 2023, is down compared to previous year (EUR 28.3 million end 2022) as revenue cash collection, capital increases and draw-down on existing financing lines did not compensate for expenses as well as reimbursement of several credit lines with some of our lenders.Equity was EUR -103.2 million at the end of 2023, down EUR 136.9 million compared to end 2022 (EUR 33.7 million). The total comprehensive loss for the period (EUR 167.1 million) was only partially compensated by a capital increase of EUR 2.5 million with Highbridge and Whitebox, a loan conversion by a lender under the convertible loan facility (EUR 1.2 million) and several contributions in kind against the issuance of new shares for interest to the lenders for a total of EUR 3.5 million (net of transaction costs) and by the private placement in equity with Armistice Capital LLC for EUR 18.4 million (net of transaction costs of EUR 1.6 million). Operational highlights Mithra announced positive preclinical data from its CSF-1R inhibitor program following the earlier announcement of its initial pre-clinical study successes. This was achieved in partnership with BCI Pharma and focused on tyrosine kinases inhibitors, a new development axis in the treatment of many pathologies including endometriosis, oncology and inflammatory disorders. Mithra announced promising topline safety results from DONESTA® Phase 3 Study in North America positive topline safety results for its E4 COMFORT clinical trial in the United States and Canada aiming at evaluating the efficacy and safety of DONESTA® for the treatment of Vasomotor Symptoms (VMS) in post-menopausal women.Mithra and the University of Liège secure proof-of-concept for novel manufacturing process of E4 delivering an improved manufacturing methodology to boost robustness and productivity while ensuring a limited environmental footprint. The new metal-free process is based on the thermolysis of a key sulfoxide derivative of estrone.Mithra granted an additional patent for NEXTSTELLIS® (3 mg drospirenone and 14.2 mg estetrol (E4) tablets) in the United States by the United States Patent and Trademark Office. The new patent will provide NEXTSTELLIS® contraceptive with oral-dosage-unit protection in the US market until 2036. The patent is a continuation of U.S. Patent No. 11,147,771 and was listed in the FDA’s Orange Book.Mithra received guidance from the FDA for the DONESTA® NDA marketing authorization filing in the US and received positive DSMB opinion on the DONESTA® European Phase 3 trial. Mithra received feedback regarding its new drug application (NDA) marketing authorization filing for DONESTA® in the United States. This follows an agreement in principle with the FDA for Mithra to conduct additional endometrial data analyses with a formal NDA submission now planned for Q4 2024 to allow for the time required to perform these additional analyses pursuant to FDA guidance. Pending regulatory approval, DONESTA® is expected to target a US market of nearly 63 million women between the ages of 45 and 65 years-old and experiencing vasomotor symptoms of menopause (VMS). Mithra also received a positive review from the independent Data and Safety Monitoring Board (DSMB) on its phase 3 program for DONESTA®.Mithra completed its pediatric study of ESTELLE® in adolescent patients, evaluating the safety, compliance, and pharmacokinetic profile of ESTELLE® in more than 100 participants aged 12 to 17 years old. The primary endpoint of the study, which was conducted in Estonia, Finland, Georgia, Latvia, Poland and Sweden, was to evaluate the safety of ESTELLE® in post-menarchal subjects.Mayne Pharma and Mithra announced the US launch of HALOETTE®, a vaginal hormonal contraceptive ring, resulting in a EUR 1.6 million milestone payment. HALOETTE® is a generic version of NUVARING®. According to IQVIA, NUVARING® US brand and generic sales were approximately USD 564 million for the 12 months ended November 2022.Mithra signs license agreement for the commercialization of DONESTA® with Gedeon Richter, Searchlight and Rafa Laboratories expanding its potential reach to Canada, Israel, Europe, the CIS countries, Latin America, Australia and New Zealand.Mithra received EUR 3.75 million milestone payments from Fuji Pharma under its ESTELLE® licensing agreement in Japan. A payment of EUR 1.25 million was triggered by completion of the interim clinical study reports of Phase 3 trials investigating ESTELLE® for the treatment of patients with dysmenorrhea or endometriosis. An additional EUR 2.5 million payment was made in October following the submission of an application for marketing approval in Japan in a drive to help combat dysmenorrhea.Mithra and Gedeon Richter signed a supply agreement for production of API for ESTELLE® and DONESTA® in August. The agreement specifies that Gedeon Richter will manufacture and supply the Estetrol (E4) native estrogen for Mithra’s leading products.Mithra and Gedeon Richter signed a binding Head of Terms to commercialize ESTELLE® and DONESTA® in China. Upon the finalization of the license agreements, Gedeon Richter will have the exclusive commercial rights for both products in China. Under the head of terms, Gedeon Richter to perform and fund the clinical studies required to obtain marketing approvals in China; upon the closing of the two licencing agreements, Mithra to receive a combined milestone payment of EUR 4.5 million. Events beyond the reporting period Mithra provided an update on its current cash position and its plans to address its runway and creating and optimizing value for all its stakeholders on 06 February, 2024. Announced the sale of all 4,221,815 shares it held in Mayne Pharma Group Limited on 15 February 2024. The shares were sold at a price of A$ 5.03 per share for aggregate net proceeds of A$ 21,129,551 (approx. EUR 12.8 million).Reported the last patient-out in the DONESTA® C301 Endometrial Safety Study. was reached on 8 February 2024. This marks the completion of patient treatments and the initiation of the data management/reporting phase.On 05 March 2024, Mithra announced the initiation of a monetization process and signing of a new secured bridge loan facility expected to fund that process through 30 April. The monetization process and Facility are further to Mithra’s 06 February 2024 announcement on its cash position. In an effort to maximize value for all of Mithra’s stakeholders, the Company has initiated a monetization process to realize value from its assets involving the sale of various selected assets, particularly Estetra SRL, and/or the business as a whole. The Company is finalizing negotiations with an internationally recognized investment bank to help conduct the Monetization Process in collaboration with DC Advisory and Alvarez & Marsal, who are advising on liquidity management and advising on monetization, among other things. Parties interested in participating in the Monetization Process should contact Ed Kulik of DC Advisory (Ed.Kulik@dcadvisory.com) and Thomas Dillenseger of Alvarez & Marsal (TDillenseger@alvarezandmarsal.com).Management Changes: Appointment of Christophe Maréchal1 and Xavier Paoli as co-CEOs following, 05 March 2024 termination of the management agreement of former CEO. Financial results Note regarding basis of preparation: The consolidated financial results of Mithra Pharmaceuticals SA and its subsidiaries (“Mithra”) included in this release have been prepared in accordance with International Financial Reporting Standards as adopted by the European Union. These include International Financial Reporting Standards (IFRS) and the related interpretations issued by the International Accounting Standards Board (IASB), and the IFRS Interpretations Committee (IFRIC), effective at the reporting date and adopted by the European Union. These consolidated financial results have been prepared on the basis of a going concern. However, as announced on 06 February 2024 and 05 March 2024, there are material uncertainties about Mithra's ability to continue in operation beyond 30 April 2024. As of 07 March 2024, Mithra has approximately EUR 9.0 million in cash and cash equivalents including the first drawdown under the bridge facility. Its lenders have provided a committed bridge facility of up to EUR 13.5 million, plus an uncommitted "accordion" facility for a further EUR 5 million, in each case subject to milestones, as described in that 05 March 2024 press release, in order to fund a monetization process. However, as noted in that release there is a risk that Mithra will not be able to draw the full amount, for instance if it is not able to initiate a Monetization Process. Even if a Monetization Process is initiated, there is a material risk that that process will not be successful, in whole or in part, or may not significantly reduce Mithra's existing indebtedness. If Mithra is not able to draw funds under the new bridge facility or is otherwise not able to raise or generate sufficient cash, this will adversely affect Mithra's continued operations and ability to operate as a going concern. 1. Consolidated statement of profit or loss Thousands of euro (€)20232022 Revenue40,15566,997Cost of sales(21,950)(19,623)Gross profit18,20547,374Research and development expenses(63,170)(64,041)General and administrative expenses(22,085)(14,675)Selling expenses(2,271)(2,100)Impairment on non-current assets(74,147)-Other operating income4,3367,196Loss from operations(139,132)(26,245)Change in fair value of contingent consideration payable(1,510)28,335Net fair value gains/(losses) on financial assets at fair value through profit or loss--Financial income1,7459,852Financial expenses(22,899)(23,422)Loss before taxes(161,795)(11,480)Income taxes(11,707)(48,139)NET LOSS FOR THE PERIOD(173,502)(59,620) 2. Consolidated statement of financial position As at 31 DecemberThousands of euro (€)20232022ASSETS Property, plant and equipment13,40540,717Right-of-use assets38,08365,534Goodwill5,2335,233Other intangible assets108,713134,905Deferred income tax assets1,28916,354Contract assets1792.828Derivatives financial assets349-Investment in equity securities16,01521,437Other non-current assets9,8749,544Non-current assets193,139296,552 Inventories48,28950,312Contract assets19,53644,988Derivatives financial assets47-Trade and other receivables16,55622,277Other short-term deposits--Cash and cash equivalents8,98028,285Current assets93,408145,863 TOTAL ASSETS286,546442,414 As at 31 DecemberThousands of euro (€)20232022EQUITY AND LIABILITIES Share capital50,59441,228Additional paid-in-capital424,858408,647Other reserves10,586(19,934)Accumulated deficit(589,294)(396,254)Equity attributable to equity holders(103,255)33,687 Subordinated loans9,79110,710Other loans137,739127,052Lease liabilities31,63138,253Refundable government advances7,6478,127Other financial liabilities73,73174,210Derivatives financial liabilities13,63615,261Contract liabilities10,300-Provisions266266Deferred tax liabilities1,0814,420Non-current liabilities285,822278,298 Current portion of subordinated loans1,2521,252Current portion of other loans19,00145,980Current portion of lease liabilities6,4505,179Current portion of refundable government advances2,5071,417Current portion of other financial liabilities15,69815,959Derivatives financial liabilities-2,561Trade and other payables59,07258,082Current liabilities103,981130,431 TOTAL EQUITY AND LIABILITIES286,546442,414 3. Consolidated statement of cash flows As at 31 DecemberThousands of euro (€)20232022Cash and cash equivalents at beginning of year28,28532,872Net cash (used in)/ provided by operating activities(2,184)(56,819)Net cash (used in)/ provided by investing activities3,452(25,490)Net cash (used in)/provided by financing activities(20,538)77,869Net increase/(decrease) in cash and cash equivalents(19,270)(4,440)Effects of exchange rate changes on cash and cash equivalents(35)(147)Cash and cash equivalents at end of period8,98028,285 Statement of profit and loss The Group reported a net loss of EUR 173.5 million in 2023, compared to a net loss of EUR 59.6 million in 2022. The main contributor to this difference was an impairment loss of EUR 74.1 million registered on the value of Mithra CDMO and ZORELINE® assets. Revenues were EUR 40.2 million compared with EUR 67.0 million in 2022. The revenues breakdown as follows: Overall product sales of EUR 18.7 million were largely driven by ESTELLE® (EUR 10.4 million), which are higher than in 2022 (EUR 9.2 million) and MYRING® (EUR 6.0 million) that improves the revenue on our generic portfolio to EUR 8.3 million compared to EUR 6.5 million in 2022.Out-licensing revenue for the year was EUR 19 million from ESTELLE® and DONESTA® milestones (EUR 16.3 million and EUR 2.6 million, respectively). For ESTELLE®, on top of EUR 3.75 million invoiced to our Partner Fuji, another EUR 12.5 million has been recognized as revenue according to our IFRS 15 accounting policy (respectively EUR 2.5 million with Gedeon Richter for China and EUR 10.0 million with Fuji). Balance of out-licencing was primarily for DONESTA® with EUR 1.5 million invoiced to our partner Searchlight and EUR 1.13 million recognised under IFRS for China and Israel.Revenues from the R&D contracting activities of the CDMO were stable at EUR 2.4 million compared to EUR 2.3 million in 2022. R&D expenses (including depreciation) decreased slightly to EUR 63.2 million. The stable level of research expenses is due to the continued focus on our core R&D projects, namely the DONESTA® Phase II and III clinical studies and the ESTELLE® post-approval safety study (PASS). G&A and selling expenses increased +44% to EUR 24.4 million due to a higher impact of share-based payments accounting entries (charge of EUR 4.5 million compared to charge of EUR 2.0 million in 2022); increase in professional services to assist us in our attempt to strengthen our balance sheet and refocus on innovative R&D, but also relating to administration of our financial liabilities and uncomfortable cash position; and, to a lesser extent, an increase in insurance costs and salaries indexation. Impairment on non-current assets: as focus for non-core assets has now shifted to short-term sale or disposal of those assets, an impairment loss of EUR 74.1 million for two such assets has been recorded in FY 2023 financial statements: EUR 47.7 million for Mithra CDMO and EUR 26.4 million for ZORELINE®. Other operating income of EUR 4.3 million (compared to EUR 7.2 million in 2022) mostly consists of an R&D tax credit for EUR 1.3 million which is directly related to R&D expenses level and of EUR 1.4 million exemption from the withholding tax on professional income for R&D staff. Main reason for lower other operating income is that last year included a reinvoicing of costs of EUR 2.2 million that did not repeat in 2023. The negative impact of approximately EUR -1.5 million for change in fair value related to contingent consideration payable ESTELLE® is the consequence of the update of both the discount rate and the timing effect. The decrease in financial income to EUR 1.7 million from EUR 9.9 million in 2022 is explained by the lower impact of the remeasurement of refundable government advances measured at amortized cost following the update of forecasts (EUR 0.5 million in 2023 vs EUR 3.6 million last year). Last year also included EUR 3.0 million of dividend from Mayne Pharma as well as a realized gain of EUR 2.5 million following the early repurchase of EUR 34.1 million tranche of our convertible bonds due in 2025 at a discount to par, via the convertible loan signed with Highbridge Capital Management, LLC (“Highbridge“) and funds managed by Whitebox Advisors, LLC (“Whitebox”). Financial expenses remained stable compared to last year, albeit at a high level. The group recorded a tax loss of EUR -11.7 million for 2023 as the balance of deferred tax assets previously recognised within Mithra CDMO and Novalon have been reversed as essentially relating to expected future taxable profit of ZORELINE® now most likely to be sold in the short term. Statement of financial position Assets As of 31 December 2023, the statement of financial position shows a total of EUR 193.1 million in non-current assets-- the majority of which are other intangible assets (EUR 108.7 million); right-of-use assets (EUR 38.1 million); investments in equity securities (EUR 16.0 million); property, plant and equipment (EUR 13.4 million) and deferred tax assets (EUR 1.3 million). In 2023, new additions to the other intangible assets have been limited to a total of EUR 4.2 million (EUR 33.3 million in 2022) and almost offset by EUR 3.5 million of depreciation. Main change of 2023 was the result of the impairment testing of our CDMO and ZORELINE® that led to a one-time depreciation of EUR 27.0 million (EUR 0.6 million and EUR 26.4 million respectively for the CDMO and ZORELINE®). The same impairment testing also led to a one-time depreciation of EUR -47.2 million on our CDMO Tangible fixed assets (Property, plant and equipment and the right-of-use assets). Otherwise, limited additions during the year (EUR 1.2 million) were more than offset by depreciation of the period (EUR 8.2 million). Deferred tax assets decreased to EUR 1.3 million as balance of deferred tax assets previously recognised within Mithra CDMO and Novalon have been reversed as essentially relating to expected future taxable profit of our complex therapeutics products now most likely to be sold in the short term. Contract assets amount decreased to EUR 19.7 million (non-current and current) versus EUR 47.8 million in 2022. New contract assets recognized (essentially EUR 10 million for Fuji and EUR 3.5 million relating to ESTELLE® & DONESTA® in China) were more than offset by unbilled revenues recognised in prior year(s) and invoiced in 2023 (EUR 40.7 million for Gedeon Richter). Current assets at the end of 2023 are about EUR 93.4 million and include, besides contract assets explained here above, Cash and cash equivalents of EUR 9.0 million, Trade & other receivables of EUR 16.6 million, and Inventories of EUR 48.3 million. Equity and liabilities Total equity at year-end is negative at EUR -103.3 million as the total comprehensive loss for the period (EUR 167.1 million) was only partially compensated by several capital increases for a total amount of EUR 25.6 million (net of transaction costs). Non-current liabilities increased to EUR 285.8 million at the end of 2023, compared to EUR 278.3 million end of 2022. The main changes during the period relate to the access in June 2023 to a new tranche of the amended loan facility concluded with funds managed by Highbridge and Whitebox (“Convertible loans” in the above table) for an amount of EUR 12.5 million and the recognition of a contract liability of EUR 10.3 million with Gedeon Richter for DONESTA®. Current liabilities decreased to EUR 104.0 million at the end of 2023, compared to EUR 130.4 million in 2022. The decrease of the Current liabilities is mainly explained by the reimbursement of straight loans at maturity for an amount of EUR 26.8 million. Alternative performance measures Mithra uses some alternative performance measures (APMs) that are not defined in IFRS but that provide helpful additional information to better assess how the business has performed over the period. Mithra decided to use REBITDA and EBITDA in order to provide information on recurring items, but those measures should not be viewed in isolation or as an alternative to the measures presented in accordance with IFRS. REBITDA is an alternative performance measure calculated by excluding the non-recurring items and the depreciation & amortization from EBIT (loss from operations) from the consolidated statement of profit or loss prepared in accordance with IFRS. The Group considers share-based payments as non-recurring item above EBITDA. EBITDA is an alternative performance measure calculated by excluding the depreciation and amortization from EBIT (loss from operations) from the consolidated statement of profit or loss prepared in accordance with IFRS. Financial highlights are presented as follows in the first section of this press release (management figures): Year ended 31 DecemberThousands of euro (€)20232022 Revenue40,15566,997Cost of sales(21,189)(19,112)Gross profit18,96647,886Research and development expenses(52,869)(53,668)General and administrative expenses(16,450)(11,707)Selling expenses(2,213)(2,029)Other operating income4,3367,196REBITDA(48,231)(12,322)Share-based payments expenses(4,540)(1,983)EBITDA(52,771)(14,305)Depreciation(12,214)(11,940)Non-recurring items(74,147)-Loss from operations(139,132)(26,245)Change in fair value of contingent consideration payable(1,510)28,335Net fair value gains/(losses) on financial assets at fair value through profit or loss--Financial income1,7459,852Financial expenses(22,899)(23,422)Loss before taxes(161,795)(11,480)Income taxes(11,707)(48,139)NET LOSS FOR THE PERIOD(173,502)(59,620) Please refer to the table below for the reconciliation to loss from operations as presented within consolidated statement of profit or loss: Year ended 31 DecemberThousands of euro (€)20232022Loss from operations(139,132)(26,245)Depreciation12,21411,940Non-recurring items – impairment charges on non-current assets74,147-Share-based payments expenses4,5401,983REBITDA(48,231)(12,322)Share-based payments expenses(4,540)(1,983)EBITDA(52,771)(14,305) Annual report 2023The auditor, BDO Réviseurs d’Entreprises SRL, has stated that the statutory audit is still ongoing as of the date of this press release. Based on the unfinished status of the audit procedures and the uncertainty about the evolution of the group in the coming weeks, the auditor is not yet able to provide information on the audit opinion he intends to issue on the consolidated financial statements. Financial CalendarThe following are anticipated dates in the Company's 2024 financial calendar and subject to change: 16 April 2024: 2023 Annual Report16 May 2024: Annual General Shareholders’ Meeting26 September 2024: Half Year Report 2024 For more information, please contact: Mithra Pharmaceuticals SAAlex Sokolowski, PhDHead of IR & Communicationsinvestorrelations@mithra.com +32 (0)4 349 28 22Frédérique Depraetere Communications Directorinfo@mithra.com+32 (0)4 349 28 22 About Mithra Mithra Pharmaceuticals SA (Euronext: MITRA) is a Belgian biopharmaceutical company dedicated to transforming women’s health by offering new choices through innovation, with a particular focus on contraception and menopause. Mithra’s goal is to develop products offering better efficacy, safety and convenience, meeting women’s needs throughout their life span. Mithra explores the potential of the unique native estrogen estetrol in a wide range of applications in women health and beyond. After having successfully launched the first estetrol-based product in 2021, the contraceptive pill ESTELLE®, Mithra is now focusing on its second product DONESTA®, the next-generation hormone therapy. Mithra also offers partners a complete spectrum of solutions from early drug development, clinical batches and commercial manufacturing of complex polymeric products (vaginal ring, implants) and complex liquid injectables and biologicals (vials, pre-filled syringes or cartridges) at its technological platform Mithra CDMO. Active in more than 100 countries around the world, is headquartered in Liège, Belgium. www.mithra.com ESTELLE®, NEXTSTELLIS®, LYDISILKA®, MYRING®, HALOETTE®, ZORELINE®, TIBELIA® and DONESTA® are registered trademarks of Mithra Pharmaceuticals or one of its affiliates. DROVELIS® is a registered trademark of Richter Gedeon Nyrt. DAPHNE® is a registered trademark of Ceres Pharma. NUVARING® is a registered trademark of Organon NV. Important informationThe contents of this announcement include statements that are, or may be deemed to be, "forward-looking statements". These forward-looking statements can be identified by the use of forward-looking terminology, including the words "believes", "estimates," "anticipates", "expects", "intends", "may", "will", "plans", "continue", "ongoing", "potential", "predict", "project", "target", "seek" or "should", and include statements the Company makes concerning the intended results of its strategy. By their nature, forward-looking statements involve risks and uncertainties, and readers are cautioned that any such forward-looking statements are not guarantees of future performance. The Company's actual results may differ materially from those predicted by the forward-looking statements. The Company undertakes no obligation to publicly update or revise forward-looking statements, except as may be required by law. Subscribe to our mailing list on investors.mithra.com to receive press releases by email or follow us on social media:LinkedIn • X • Facebook 1 Acting through CMM&C SRL. Attachment 2024-03-08_Mithra_Press-release_FY2023-Results_FR