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▲3月15-16日 生物医药创新者峰会 · 限时免费报名中注：本文不构成任何投资意见和建议，以官方/公司公告为准；本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及），不代表平台立场。任何文章转载需得到授权。  synbio深波，专注合成生物学1989年，美国斯克里普斯研究所在《自然》杂志上发表了一篇使用烟草植物产生功能性重组抗体的文章，代表了以植物为底盘细胞的分子农业的开端。到2005 年，公开报道的的至少有 50 家公司是为了分子农业而成立，主要集中在制药领域。但由于早期技术研发管线原因以及植物平台的多样性，带来了行业研发的分散，在加上监管框架的不成熟，导致其曾一度跌入低谷。现在，分子农业正在重新受到市场的关注，可以说技术现在才真正开始起飞。2022年，世界上最古老的期刊之一THE OFFICIAL JOURNAL OF THE ROYAL PHARMACEUTICAL SOCIETY（皇家药学会期刊），发表了一篇关于分子农业的文章，详细分析了其在制药领域的应用前景。   近年来多款基于分子农业的产品获批2012年美国食品药品监督管理局（FDA）批准第一个上市的植物细胞药物Elelyso（taliglucerase alfa），由以色列生物科技公司Protalix和辉瑞研发，是治疗戈谢病的药物病，一种罕见的遗传病，影响全球 40000 人中的 1 人。患有这种疾病的人无法产生葡萄糖脑苷脂酶——这种酶可以分解细胞物质以供再利用——导致骨骼脆弱和脾脏肿大等症状。通过注射缺失的酶来治疗这种情况，Protalix 和辉瑞公司开发的药物是使用不起眼的胡萝卜细胞生产的。2022 年 2 月，生物技术公司 Medicago 宣布其两剂 COVID-19 疫苗 Covifenz 已在加拿大获得批准。III 期结果表明，该疫苗与其他几种 COVID-19 疫苗具有相似的功效，但有一个主要区别：它是世界上第一个基于植物的 COVID-19 疫苗。   更有效的替代方案在传统的制药领域，治疗性蛋白质通常使用细菌大肠杆菌( E. coli ) 或酵母（如酿酒酵母）生产。如果生物治疗药物需要包含在细菌中不可复制的修饰，通常会使用中国仓鼠卵巢细胞 (CHO)，因为它们生长迅速且蛋白质产量高。然而，所有这些方法都需要昂贵的不锈钢生物反应器和高度受控的无菌条件（见图）。此外，它们生产的蛋白质在质量和与它们模仿的人类版本的相似性方面各不相同。所有这些因素导致人们对基于植物的替代品的兴趣增加，并发现植物可能能够提供一种更便宜、更有效的生物药物生产方式——有可能生产出更优质的产品。图：开发植物性药物 阿里斯代尔麦克唐纳   在植物中生产生物药自分子农业领域出现以来，已经开发了多种利用植物细胞培养物和整株植物在植物中生产生物药物的方法。基于植物细胞培养市场上的第一种植物细胞培养药物 Elelyso（taliglucerase alfa）由 Protalix 和辉瑞公司开发，使用在液体培养基中生长的胡萝卜细胞。这些细胞在一次性 10-800 升生物反应器中生长，因此它们无需在循环之间进行清洁，从而显着降低成本。主要载体是植物愈伤组织的细胞悬浮液，再通过表达目标蛋白基因的农杆菌感染植物细胞，并将其含有该基因的 DNA 转移到植物细胞中，然后在植物细胞中“瞬时表达”。最后，从细胞培养物中提取蛋白质，并使用与生产其他生物制剂类似的过滤层析和离心步骤进行纯化。基于整株植物目前正在开发的最突出的方法之一是基于植物或者agro-infusion。这种方法不是使用细胞培养，而是从整株植物开始。生物技术公司 Medicago 于 2005 年开始使用这种方法，因为它能够快速准确地生产大量所需的蛋白质产品。该方法类似于 Protalix 和 Pfizer 开发的方法，但将用感兴趣的蛋白质设计的农杆菌培养物注入植物叶片中。这可以通过直接注入叶子或更大规模地通过将植物和培养物放在吸出空气的真空罐中，用培养基代替它来完成。然后将植物从培养物中取出晾干，大约一周后，收获叶子以便提取和纯化蛋白质。Lomonossoff 解释说，早期批发“种植”的雄心并未实现，这主要是由于需要将此类植物保存在封闭的环境中以防止外部污染。但仍有希望利用温室实现大规模种植。 另一个优点是安全；哺乳动物细胞培养的问题之一是病毒污染的风险。“对于基于植物的材料，这不是一个问题，因为植物可能感染的任何疾病都不会感染人类——没有交叉的例子，”Lomonossoff 说。出于这个原因，FDA 对生长条件出人意料地放松了，总部位于慕尼黑的 Nomad Bioscience 公司的创始人 Yuri Gleba 说。“它同意植物的生长必须在受控条件下，而不是良好生产规范 (GMP) 条件下……当您取出叶子和/或整株植物并开始研磨时，GMP 就开始了。” GMP 描述了药品制造商在其生产过程中必须满足的最低标准，并且需要进行检查以验证合规性，这会增加成本。尽管到目前为止，降低生产成本的最初承诺尚未兑现，但该方法本身已被证明是快速的。2012 年，Medicago 在一个月内生产了 1000 万剂候选流感疫苗，而且它在开发 COVID-19 疫苗方面也同样迅速。“从我们在计算机上获得序列的那一刻起，到我们 [拥有] 第一个纯化产品的那一刻，用了 19 天，”该公司执行副总裁 Marc-André D'Aoust 说。与传统的卵生疫苗相比，这种速度需要五到六个月，这对于未来潜在的大流行病来说将是非常有利的。   分子农业的主力军水生植物、苔藓、藻类，叶菜类（烟草，油菜，生菜），根茎类（马铃薯），谷物类（小麦，大麦，玉米，水稻）等等都被科研人员在实验室中应用。但随着行业的发展，谷物和本塞姆氏烟草成为了大多数公司的一致选择。本塞姆氏烟草与整株植物打交道的研究人员和公司主要选择本塞姆氏烟草( N. benthamiana )；一种澳大利亚本土植物，是烟草植物的近亲。“没有什么比[本塞姆氏猪笼草]好，”罗蒙诺索夫说。“它的最大吸引力在于它有一个有缺陷的植物沉默系统，不会尝试抵消表达水平，而许多植物自然会这样做。” 这意味着，当被细菌感染时，本塞姆氏烟草无法反击并阻止细菌劫持其蛋白质生产机器。因此，感兴趣的蛋白质的产量将特别高。本塞姆氏烟草也很容易快速生长。“植物长到大约 10-12 英尺，它们的叶子很大，”伦敦圣乔治大学感染与免疫研究所所长 Julian Ma 说。它也不是重要的粮食作物，尤其是在欧洲，那里担心转基因生物进入食物链。在开始使用紫花苜蓿植物后，由于它易于繁殖，2005 年，Medicago 也开始使用本塞姆氏烟草植物。现在，除了 COVID-19 疫苗外，它还完成了大流行性流感疫苗的 II 期临床试验以及轮状病毒和诺如病毒疫苗的 I 期临床试验。这些疫苗由植物产生的病毒样颗粒 (VLP) 组成，Lomonossoff 解释说，它具有与原始病毒相似的结构，但不具有传染性，因为它们不包含基因组。Lomonossoff 还开发了几种植物生产的 VLP 候选疫苗，包括一种用于脊髓灰质炎的疫苗。来自苔藓的生物制药然而，并不是所有的分子农业都是基于需要种植整株植物的方法，或者确实使用典型的开花植物。来自德国西南部弗莱堡大学的拉尔夫·雷斯基 (Ralf Reski) 是苔藓生物反应器的共同发明人，这种生物反应器使用一种名为Physcomitrella patens的特殊苔藓生产生物药物，雷斯基说，它结合了“两个世界的精华”。“我们有一个工厂，我们有遏制和高度控制的条件。”苔藓在盐水溶液中生长，并将作为药物生产的蛋白质直接表达到生长介质中，因此可以在不破坏苔藓细胞的情况下收获它，从而简化纯化过程。与哺乳动物 CHO 细胞培养不同，苔藓不需要生长调节剂或抗生素，只需要光。“我们还发现批次间的稳定性非常高，比市场上非植物系统生产的那些药物更相似，”Reski 说。他的生物技术公司 Eleva 已经完成了其第一个候选药物 moss-aGal（阿加糖酶）的I 期临床试验，用于治疗α-半乳糖苷酶缺乏症，这种酶会导致法布里病，这是一种罕见的遗传性溶酶体贮积症。他们发现他们的苔藓产生的酶具有优于哺乳动物细胞产生的相同酶的药代动力学。然而，所有基于植物的方法面临的一个问题是植物和动物细胞中糖基化模式的差异。许多生物药物都是糖蛋白，这意味着蛋白质被寡糖链（聚糖）覆盖，这是一个发生在翻译后的过程。这种表面糖涂层对于形成正确的 3D 蛋白质构象通常很重要，并且在膜蛋白中，它在控制细胞与其他细胞和分子的相互作用方面发挥作用。简而言之，糖基化模式的任何差异都会影响生物药物的功效。“有特定的糖类只能在植物中找到，而其他糖类只能在动物中找到，”Reski 解释说。为了解决这个问题，Reski 对苔藓进行了基因改造，使糖基化过程“人性化”。他删除了两个编码添加植物特有糖分的酶的基因，并添加了六个引入人类或哺乳动物糖分的基因。那些与N. benthamiana合作的人还对植物进行了改造，以更好地匹配人类糖基化模式，并提高产品产量。Lomonossoff 的实验室创造了一种称为 Hypertrans 的技术，Medicago 现在使用该技术，使他们能够每公斤植物材料生产 5 毫克至 5 克产品。Hypertrans 系统不仅提供蛋白质的遗传密码，还提供额外的遗传指令，以加速从基因产生的 RNA 的翻译。除了价格和效率的优势，Reski 还发现，有时，植物生产的产品优于 CHO 或其他细胞生产的产品。“我们认为它们有时是生物更好的，而不是生物仿制药，”他建议道。“例如，我们发现，在杀死肿瘤细胞系的抗体中，我们用苔藓制成的抗体中缺少一种非常特殊的糖残基，这有帮助——它杀死这些肿瘤细胞系的效率提高了 40 倍”。   发展中国家的生物制剂机会植物基药物可能特别重要的一个领域是发展中国家，那里获得昂贵的疫苗或抗体药物的机会有限。“种植植物需要阳光、水和土壤，不需要一些复杂的介质。你可以以低得多的投资进入制造游戏，因此发展中国家现在能够开始考虑建立生物制剂制造设施，”伦敦圣乔治大学感染与免疫研究所所长 Julian Ma 表示。一些国家已经开始以植物为基础的药物生产。一家位于泰国的初创公司 Baiya Phytopharm 使用本塞姆氏烟草开发了 COVID-19疫苗。该公司于 2021 年 9 月开始 I 期试验。在巴西，加拿大生物制药公司 PlantForm Corporation 和领先的巴西生物技术公司 Axis Biotec 正在合作开发基于植物的 pembrolizumab（Keytruda；Merck）生物类似药，pembrolizumab 是一种用于治疗多种癌症的抗体免疫治疗药物。在他的实验室中，Julian Ma 还一直致力于中和 HIV 的抗体，该抗体在本塞姆氏烟草植物的糖工程品系中表达。“我认为在南非 HIV 感染率约为 20%，你买不起目前抗体价格附近的任何东西，所以这是我们一直在努力的事情之一，我认为这是真的很令人兴奋，”他说。他补充说，研究人员还一直在试验使用谷物等可食用作物。“事实证明，玉米是一种很好的作物，因为你可以收获玉米种子，而那些玉米种子是天然的蛋白质储存器官，你可以在环境温度下以一种半加工的形式储存你的生物制品多年，只要你保持它们会变干，”Julian Ma 解释道。2021 年，东京大学的一个团队完成了其口服大米生产的霍乱疫苗 (MucoRIce-CTB) 的 I 期试验，该疫苗通过将大米磨成粉末并悬浮在磷酸盐缓冲盐溶液中饮用来给药。结果显示抗体浓度增加而没有严重的不良事件。欧洲面临的一个问题是对种植转基因生物的法律限制。Gleba 说，Nomad Bioscience 目前正在西班牙现有的温室设施中种植植物，这些设施最初是为更传统的作物而建造的：“这是唯一不反对商业规模种植转基因植物的欧盟国家”。Julian Ma担心，即使这些作物并非用于食物链，但欧洲围绕转基因生物的问题可能会减缓该技术的采用。英国脱欧后，英国现在将允许对基因编辑作物进行田间试验，前提是这些植物被种植在温室或其他封闭空间内。到目前为止，大型制药公司对基于植物的技术表现出兴趣的速度相对较慢，因为它们对当前的生产方法进行了大量投资。“这就像调转油轮，让它们转到不同的制造平台，”马云说。但是，Gleba 相信，从长远来看，植物将在生物制药的制造过程中发挥越来越重要的作用。“这是一个非常民主的技术方向，”他说。在几乎没有基础设施的情况下生产药物的能力也引起了美国国家航空航天局的注意，该局正在寻找可能有助于火星任务的技术。例如，Gleba 解释说，N. benthamiana植物的一片小叶子可以为六名丙型肝炎患者提供六个月的治疗。因此，如果这项技术不能继续在地球上起飞，也许有一天，植物会成为太空中的首选药物。  资料来源：[1] https://pharmaceutical-journal.com/article/feature/going-plant-based-how-molecular-farming-could-revolutionise-drug-development版权声明：本文转自synbio深波，如不希望被转载的媒体或个人可与我们联系，我们将立即删除线下活动（点击即可查看）点分享点点赞点在看

On Track for FY 2022 Guidance Q1 2022 revenue rises 3% to €10.3 million Completed phase out of COVID-19 Business segment in Q1 2022Positioning Pharma and Diagnostics for post-COVID recovery and growth in 2022 and beyondReaffirms FY 2022 guidance of 15-20% revenue growth CAMBRIDGE, Mass. and ROSTOCK, Germany and BERLIN, July 15, 2022 (GLOBE NEWSWIRE) -- Centogene N.V. (Nasdaq: CNTG), the commercial-stage essential biodata life science partner for rare and neurodegenerative diseases, today announced financial results for the first quarter ending March 31, 2022, reaffirmed guidance, and provided a business update. “We are on track with our renewed focus on the Core Business. The Diagnostics segment continued to show double digit growth rates year-over-year and is planned to grow faster than the market. We are on target to enhance our Pharma offering – broadening our commercial team, marketing a differentiated product portfolio, and growing the pipeline to return the Pharma segment to steady growth in 2022. We see the extension of the market access partnership with Takeda and the new contract with Agios as important proof points of our biopharma strategy,” stated Kim Stratton, Chief Executive Officer at CENTOGENE. “In the first quarter, we phased out the COVID-19 Testing Business as planned, allowing our organization to pivot and be focused on Core Business execution." First Quarter 2022 Financial Highlights Overall revenues of €10.3 million (excluding the discontinued operation) were recorded in Q1 2022, a 3% increase compared to €10.0 million in Q1 2021Diagnostics segment revenues of €7.1 million in Q1 2022, an increase of 11% compared to €6.4 million in Q1 2021, reflecting the fourth consecutive quarter of year-over-year revenues growth in the segment. The increase in revenues was primarily related to an increase in revenues from Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) of 18%Pharma segment revenues of €3.2 million in Q1 2022, a decrease of 10% compared to €3.6 million in Q1 2021The COVID-19 Testing Business was phased out in Q1 2022 and reported as discontinued operations but no longer as a segment. Revenues from the COVID-19 Business were €19.5 million in Q1 2022, compared to €55.0 million in Q1 2021. Discontinued operations in the period contributed positively to net income and cash flowNet loss of €6.4 million in Q1 2022, compared to net loss of €4.8 million in Q1 2021Total segment adjusted EBITDA of €1.9 million for the two continuing segments was recorded in Q1 2022, compared to €2.6 million in Q1 2021. This mainly reflects the lower proportion of revenues in the higher margin Pharma segmentAdjusted EBITDA from COVID-19 business for the three months ended March 31, 2022 was €6,106 thousand as compared to €10,167 thousand for the three months ended March 31, 2021. The decrease was driven by the reduction in COVID-19 test order intakes as the business was phased outCash and cash equivalents were €42.7 million as of March 31, 2022, compared to €17.8 million for the period ending December 31, 2021. The reported cash position per end of Q1 2022 reflects proceeds from the debt (first tranche) and equity financings completed in February 2022 “With the completion of the financings earlier this year, CENTOGENE is operating from a stable financial position. We rolled out multiple initiatives to extend our cash runway by closely managing margins and corporate expenses. As a result, we are expecting to show improvements in our 2022 adj. EBITDA versus the prior year,” added Miguel Coego, Chief Financial Officer of CENTOGENE. Recent Business Highlights Corporate Appointed executive and Supervisory Board leadership, including Kim Stratton as CEO, Miguel Coego as CFO, and Dr. Andreas Busch as Vice Chairman of the Supervisory BoardClosed $62 million aggregate equity and debt financings to support growth plan, including a €15 million (approx. $17 million) private placement incl. 1.3 million warrants at an exercise price of $7.72 per share from leading growth investors and a $45 million senior secured loan from Oxford Finance in Q1 2022, with the second tranche of the loan subject to operating covenantsAdded ~28,000 individuals to the CENTOGENE Biodatabank in Q1 2022; CENTOGENE believes its Biodatabank is the world’s largest real-world data repository for rare and neurodegenerative diseases, which includes samples as well as data and cell lines from patients from over 120 countriesAuthored 15 peer-reviewed scientific publications in Q1 2022, focused on generating critical insights into an array of diseases, including rare genetic and neurological diseases, e.g., the prevalence of Fabry disease among patients with Parkinson's diseasePhased out the COVID-19 testing services end of Q1 2022 according to plan Pharma Expanded partnership with Agios Pharmaceuticals for clinical development of PYRUKYND® (mitapivat) to treat children with rare blood diseaseExtended market access partnership with Takeda to accelerate path from diagnosis to available treatments for rare metabolic and rare neurodegenerative diseasesExpanded Data Access and Collaboration R&D Agreement with Pfizer to advance discovery and validation of novel genetic targets as candidates for the development of new therapies for rare diseasesInitiated collaboration with Insilico Medicine for Niemann-Pick disease Type C (NPC) target discovery, leveraging the CENTOGENE BiodatabankCurrently leading three observational studies for patient finding and market access in collaboration with our pharma partners in rare and neurodegenerative disorders Diagnostics Reported order intake of approximately 16,300 test requests in our diagnostics segment, representing an increase of approximately 24% as compared to approximately 13,100 test requests in the same period in 2021Launch of CENTOGENE MOx – a portfolio of single-step multiomic solutions that combines sequencing and biochemical testing to enable early diagnosis, improved prognosis, and precision medicineGlobal release of CentoCloud, a cloud-based, clinical decision support platform enabling decentralized analysis, interpretation, and quality reporting for laboratories around the worldReceived CE-mark for CentoCloud, making it one of the only decentralized SaaS and clinical decision support platforms compliant with European IVD regulatory frameworkMajor Next Generation Sequencing (NGS) panel update with more than 3,000 genes revised and 1,864 genes added to maximize the clinical utility for rare metabolic and neurodegenerative diseasesContributed to Europe-wide efforts to update guidelines for WGS in rare disease diagnostics 2022 Financial Guidance The Company has reaffirmed its previously communicated 2022 annual revenue guidance for year-over-year revenue growth of 15% to 20%. As a result, CENTOGENE expects revenues to be in the range of €50 million to €52 million. This reflects the classification of the COVID-19 Testing Business as discontinued operations. About CENTOGENE CENTOGENE (Nasdaq: CNTG) is transforming real-world clinical, genetic, and multiomic data to enable better health outcomes for patients with rare and neurodegenerative diseases. For over 15 years, CENTOGENE has been providing diagnostic insights to patients with genetic diseases through our network of nearly 30,000 active physicians. CENTOGENE now believes its Biodatabank is the world’s largest real-world data repository of corresponding patients from more than 120 countries. Simplified logistics solutions, including CentoCard® for sending biosamples, and our ISO, CAP, & CLIA certified state-of-the-art multiomic reference labs offer patients rapid and reliable diagnoses to support the identification and personalization of their treatments. Ultimately, offering the best treatment for patients involves developing new or better therapies. We are de-risking orphan drug discovery and development by partnering with more than 30 biopharma in target & drug screening, clinical development, market access and expansion. CENTOGENE engages in biodata partnerships with our Biodata Licenses and Insight Reports. To discover more about our products, pipeline, and patient-driven purpose, visit www.centogene.com and follow us on LinkedIn. Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the U.S. federal securities laws. Statements contained herein that are not clearly historical in nature are forward-looking, and the words “anticipate,” “believe,” “continues,” “expect,” “estimate,” “intend,” “project,” and similar expressions and future or conditional verbs such as “will,” “would,” “should,” “could,” “might,” “can,” and “may,” are generally intended to identify forward-looking statements. Such forward-looking statements involve known and unknown risks, uncertainties, and other important factors that may cause CENTOGENE’s actual results, performance, or achievements to be materially different from any future results, performance, or achievements expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, negative economic and geopolitical conditions and instability and volatility in the worldwide financial markets, possible changes in current and proposed legislation, regulations and governmental policies, pressures from increasing competition and consolidation in our industry, the expense and uncertainty of regulatory approval, including from the U.S. Food and Drug Administration, our reliance on third parties and collaboration partners, including our ability to manage growth and enter into new client relationships, our dependency on the rare disease industry, our ability to manage international expansion, our reliance on key personnel, our reliance on intellectual property protection, fluctuations of our operating results due to the effect of exchange rates, our ability to streamline cash usage, our requirement for additional financing, or other factors. For further information on the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to CENTOGENE’s business in general, see CENTOGENE’s risk factors set forth in CENTOGENE’s Form 20-F filed on March 31, 2022, with the Securities and Exchange Commission (the “SEC”) and subsequent filings with the SEC. Any forward-looking statements contained in this press release speak only as of the date hereof, and CENTOGENE’s specifically disclaims any obligation to update any forward-looking statement, whether as a result of new information, future events, or otherwise. Centogene N.V.Unaudited interim condensed consolidated statements of comprehensive loss for the three months ended March 31, 2022 and 2021(in EUR k) For the three months ended March 31 Note 2022 2021*Revenue 4, 5 10,327 9,981 Cost of sales 6,450 6,208 Gross profit 3,877 3,773 Research and development expenses 4,614 4,335 General administrative expenses 7,906 11,596 Selling expenses 2,394 1,949 Impairment of financial assets 8 154 95 Other operating income 6.1 733 366 Other operating expenses 6.2 1 34 Operating loss (10,459) (13,870)Changes in fair value of warrants 11.2 238 — Interest and similar income 1 — Interest and similar expense 859 259 Financial costs, net (620) (259)Loss before taxes from continuing operations (11,079) (14,129)Income tax expenses 4 — Loss for the period from continuing operations (11,083) (14,129)Net income from discontinued operations, net of tax 7 4,601 9,240 Loss for the period (6,482) (4,889)Other comprehensive income, all attributable to equity holders of the parent 94 121 Total comprehensive loss (6,388) (4,768)Attributable to: Equity holders of the parent (6,415) (4,803)Non‑controlling interests from continuing operations — — Non‑controlling interests from discontinued operations 27 35 (6,388) (4,768)Net loss per share - Basic and diluted from (in EUR) Continuing operations (0.48) (0.63)Loss attributable to parent (0.28) (0.22) *The comparative numbers have been re-presented as a result of the discontinued operations. Refer to Note 7- Discontinued Operations. The accompanying notes form an integral part of these unaudited interim condensed consolidated financial statements. Centogene N.V.Unaudited interim condensed consolidated statements of financial position as of March 31, 2022 and December 31, 2021(in EUR k) Assets Note Mar 31, 2022 Dec 31, 2021 RevisedNon‑current assets Intangible assets 8,183 9,194Property, plant and equipment* 2.2 7,674 9,464Right-of-use assets 17,972 18,904Other assets 8 2,972 2,972 36,801 40,534Current assets Inventories 2,067 3,869Trade receivables and contract assets 8 21,125 24,337Other assets 8 5,443 5,453Cash and cash equivalents 9 42,666 17,818 71,301 51,477 108,102 92,011 Equity and liabilities Note Mar 31, 2022 Dec 31, 2021 RevisedEquity Issued capital 10 3,250 2,708 Capital reserve 10 143,456 133,897 Retained earnings and other reserves (114,120) (107,705)Non‑controlling interests 220 193 32,806 29,093 Non‑current liabilities Non‑current loans 11,1 21,890 — Lease liabilities* 11,1 14,540 15,394 Deferred tax liabilities 59 79 Government grants 11,2 7,506 8,028 Warrants liability 11,2 2,603 — 46,598 23,501 Current liabilities Government grants 11,2 1,517 1,368 Current loans 11,1 3,574 3,815 Lease liabilities* 2.2, 11.1 2,953 3,330 Trade payables 11,2 5,897 11,252 Liabilities from income taxes 11,2 198 178 Other liabilities 11,2 14,559 19,474 28,698 39,417 108,102 92,011 *Property, plant and equipment and lease liabilities as of December 31, 2021 have been revised. Refer to Note 2.2 – Revision of selected assets and liabilities in the consolidated statement of financial position and selected income and expenses in the consolidated statement of comprehensive loss. The accompanying notes form an integral part of these unaudited interim condensed consolidated financial statements. Centogene N.V.Unaudited interim condensed consolidated statements of cash flows for the three months ended March 31, 2022 and 2021(in EUR k) For the three months ended March 31 Note 2022 2021*Operating activities Loss before taxes from continuing operations (11,079) (14,129)Income before taxes from discontinued operations 7 4,614 9,240 Loss before taxes (6,465) (4,889) Adjustments to reconcile loss to cash flow from operating activities Amortization and depreciation 5 3,808 3,286 Interest expense 859 259 Expected credit loss allowances on trade receivables and contract assets 8 146 95 Gain on disposal of property, plant and equipment (527) — Share‑based payment (true up)/ expenses 12 (1,957) 2,042 Fair value adjustments of warrants (238) — Other non‑cash items (141) (184) Changes in operating assets and liabilities Inventories 1,802 2,083 Trade receivables and contract assets 8 3,066 500 Other assets 8 10 (941)Trade payables 11.2 (5,355) (6,638)Other liabilities 11.2 (4,908) 4,629 Thereof cash flow used in continuing operating activities (12,735) (8,720)Thereof cash flow from discontinued operating activities 7 2,835 8,962 Net cash flow (used in)/ from operating activities (9,900) 242 Investing activities Cash paid for investments in intangible assets 5 (44) (1,326)Cash paid for investments in property, plant and equipment (79) (1,970)Cash received for disposal of property, plant and equipment 575 — Thereof cash flow from continuing investing activities (123) (1,526)Thereof cash flow from discontinued investing activities 7 575 (1,770)Cash flow from/ (used in) investing activities 452 (3,296) Financing activities Cash received from issuance of shares 10 12,058 — Cash received from issuance of warrants 2,833 — Cash received from loans 11.1 21,695 1,587 Cash repayments of loans 11.1 (200) (185)Cash repayments of lease liabilities 11.1 (1,231) (1,222)Interest paid (859) (61) Thereof net cash flow from continuing financing activities 34,705 394 Thereof net cash flow used in discontinued financing activities (409) (275)Net cash flow from financing activities 34,296 119 Changes in cash and cash equivalents 24,848 (2,935)Cash and cash equivalents at the beginning of the period 17,818 48,156 Cash and cash equivalents at the end of the period 42,666 45,221 *The comparative numbers have been re-presented as a result of the discontinued operations. Refer to Note 7- Discontinued Operations. The accompanying notes form an integral part of these unaudited interim condensed consolidated financial statements. Reconciliation of segment Adjusted EBITDA to Group loss before taxes from continuing operations For the three months ended March 31 2022 2021 Reported segment Adjusted EBITDA 1,911 2,551 Corporate expenses (11,964) (12,020) (10,053) (9,469)Share-based payment (true-up)/ expenses (Note 12) 1,957 (2,042)Depreciation and amortization (2,363) (2,359)Operating loss from continuing operations (10,459) (13,870)Financial costs, net (620) (259)Loss before taxes from continuing operations for the three months ended March 31 (11,079) (14,129) Media Contact:CENTOGENELennart StreibelInvestor RelationsInvestor.Relations@centogene.com Ben LeggCorporate CommunicationsPress@centogene.com Stern IRSuzanne Messere+1 (212) 698-8801suzanne.messere@sternir.com