Sepofarsen

Preclinical and translational pipeline program data for AX-0810 for Cholestatic Diseases targeting NTCP and AX-1412 for Cardiovascular Disease targeting B4GALT1 anticipated in 2024, building further momentum toward the clinicAccelerated development of Axiomer™ for CNS applications via new research partnership with Rett Syndrome Research TrustCompleted divestment of sepofarsen and ultevursen ophthalmic programs to Laboratoires Théa€118.9 million cash and cash equivalents as of December 31, 2023 providing runway into mid-2026 LEIDEN, Netherlands & CAMBRIDGE, Mass., March 13, 2024 (GLOBE NEWSWIRE) -- ProQR Therapeutics NV. (Nasdaq: PRQR) (ProQR), a company dedicated to changing lives through transformative RNA therapies based on its proprietary Axiomer™ RNA editing technology platform, today reported its financial and operating results for the year ended December 31, 2023, and provided a business update. “Over the past year as we exclusively focused our strategy on RNA editing, ProQR made important progress with Axiomer, our ADAR-mediated RNA editing technology platform,” said Daniel A. de Boer, Chief Executive Officer of ProQR. “We announced our initial pipeline programs, AX-0810 and AX-1412, targeting NTCP and B4GALT1, respectively, and presented preclinical platform data across a variety of targets. Our platform has demonstrated robust editing, including reporting up to 70% editing of ACTB in the liver of non-human primates, as well as functional protein data with the liver target ANGPTL3 in mice. Additionally, we further strengthened our leading global IP estate for ADAR-mediated RNA editing, which was upheld when challenged by multiple parties in various jurisdictions. We continued to execute and build on the successes achieved during the first two years of our collaboration with Eli Lilly, and formed a new partnership with the Rett Syndrome Research Trust. We also completed the divestment of late-stage ophthalmic assets, sepofarsen and ultevursen, to Laboratoires Théa who will continue the development of these therapies for patients, as ProQR continues to focus exclusively on advancing our RNA editing platform and pipeline.” De Boer continued, “In 2024, we anticipate sharing in vitro, in vivo, and translational data for our initial pipeline programs using Axiomer, and remain on track to enter the clinic in late 2024/early 2025. Along with our extensive body of preclinical proof of concept data for the platform, partnership with Eli Lilly, leading IP position, and strong cash position providing runway into mid-2026, we believe that ProQR is well positioned to continue to execute on our strategy and advance our mission of changing lives through transformative RNA therapies.” Recent Progress In February, ProQR announced that it further strengthened its leading intellectual property estate for ADAR-mediated RNA editing by successfully defending against an opposition filed in Japan by a strawman against ProQR’s granted patent JP 7244922, which is related to the broad concept of using chemically modified oligonucleotides to target specific adenosines within target RNA using endogenous enzymes. The Japanese Patent Office rejected the strawman’s opposition and indicated that all claims were to be maintained as granted to ProQR.In January, ProQR highlighted its continued progress in advancing its Axiomer™ RNA editing technology platform, with new data presented at the 5th International Conference on Base Editing, Prime Editing & Related Enzymes (Deaminet 2024), including: Platform demonstrates robust in vivo editing capabilities reporting up to 70% editing of ACTB in the liver of non-human primates (NHPs) and mice; andFunctional effect demonstrated in mice in vivo via modulation of ANGPLT3 protein properties leading to favorable increase in LPL enzymatic activity and meaningful impact of biomarkers. In January, ProQR and the Rett Syndrome Research Trust (RSRT) formed a partnership focused on utilizing ProQR’s Axiomer™ RNA editing technology platform to design and develop editing oligonucleotides targeting an underlying genetic variant that causes Rett syndrome. RSRT awarded ProQR approximately $1 million as a research grant for the initial phase of the project, which encompasses editing oligonucleotide design and optimization, including evaluation in in vivo models for editing efficiency and MECP2 protein recovery. It is the intent of the partnership to be continued by an expanded co-funding arrangement following the initial discovery work.In December, ProQR completed the divestment of sepofarsen and ultevursen to Laboratoires Théa, who will continue the development of these programs for patients with LCA10 and Usher syndrome. The transaction agreement provided ProQR with an initial payment of €8 million and the Company may be eligible for up to €165 million in further development, regulatory, and commercial earn-out payments upon related achieved milestones, as well as double-digit royalties based on commercial sales in the US and EU. Anticipated Upcoming Events Additional Axiomer™ platform data updates throughout 2024.Preclinical and translational pipeline program data for AX-0810 for Cholestatic Diseases targeting NTCP and AX-1412 for Cardiovascular Disease targeting B4GALT1: In vitro and in vivo data for AX-0810 for Cholestatic Diseases targeting NTCP in mid 2024, and In vitro and in vivo data for AX-1412 for Cardiovascular Diseases targeting B4GALT1 in the second half of 2024. Continue to progress on key steps required to advance AX-0810 and AX-1412 to clinical trials with translational data updates ahead of entry to clinic, which is on track for late 2024/early 2025.Potential initial Trident preclinical data in late 2024 – Trident is ProQR’s early stage RNA editing pseudouridylation platform designed to enable the suppression of nonsense mutations and premature stop codons, which can edit a uridine (U) into a pseudouridine.Potential additional new pipeline target announcements in 2024.Continue to execute on partnership with Eli Lilly and Company (Lilly), with potential data updates to come in 2024 along with potential milestone income from existing partnership, and potential option to exercise for expansion of deal to 15 targets, which would result in a $50 million opt-in payment to ProQR.ProQR may selectively form new partnerships, which could include multi-target discovery alliances, or product alliances on specific programs. Year End 2023 Financial Highlights At December 31, 2023, ProQR held cash and cash equivalents of €118.9 million, compared to €94.8 million at December 31, 2022. Net cash generated by operating activities during the full year ended December 31, 2023 was €21.5 million, compared to €68.5 million net cash used in operating activities for the same period in 2022. The Company experienced a net positive cash flow from operating activities in 2023 primarily due to the receipt of the Lilly up-front payment of $60 million in February 2023. Research and development costs for the year ended December 31, 2023 were €25.1 million, compared to €50.9 million for the same period in 2022. Research and development costs for the year end December 31, 2022 included costs related to the winding down of ophthalmology programs, including the clinical trials. General and administrative costs for the year ended December 31, 2023 were €16.2 million, compared to €18.7 million for the same period in 2022. Net loss for the year ended December 31, 2023 was €27.7 million or €0.35 per diluted share, compared to €64.2 million, or €0.90 per diluted share for the same period ended December 31, 2022. For further financial information for the period ended December 31, 2023, please refer to our 2023 Annual Report on Form 20-F and our Statutory Annual Report which will be available on our website, www. proqr.com under Financials and Filings. About Axiomer™ ProQR is pioneering a next-generation RNA base editing technology called Axiomer™, which could potentially yield a new class of medicines for diverse types of diseases. Axiomer™ “Editing Oligonucleotides”, or EONs, mediate single nucleotide changes to RNA in a highly specific and targeted way using molecular machinery that is present in human cells called ADAR (Adenosine Deaminase Acting on RNA). Axiomer™ EONs are designed to recruit and direct endogenously expressed ADARs to change an Adenosine (A) to an Inosine (I) in the RNA – an Inosine is translated as a Guanosine (G) – correcting an RNA with a disease-causing mutation back to a normal (wild type) RNA, modulating protein expression, or altering a protein so that it will have a new function that helps prevent or treat disease. About Biliary Atresia (BA) and Primary Sclerosing Cholangitis (PSC) Cholestatic disorders refer to a group of diseases presenting excessive and toxic buildup of bile acids in the liver due to bile ducts dysfunction. This leads to liver damage and a range of debilitating symptoms. Without treatment, liver damage can progress through various stages, ultimately leading to liver failure and elevated risk of liver malignancy, affecting life expectancy. Cholestatic diseases remain leading causes of liver transplantation. There are no approved therapies for primary sclerosing cholangitis (PSC) for adults and biliary atresia (BA) for pediatrics It is estimated that 80,000 and 20,000 individuals have PSC and BA, respectively, in North America and in Europe. About AX-0810 targeting NTCP The majority of the bile acids present in the liver cells originate from the enterohepatic reuptake cycle. The key transporter responsible for hepatic uptake of bile acids from portal circulation is the sodium (Na+)-taurocholate cotransporting polypeptide (NTCP, SLC10A1 gene) expressed in the liver. AX-0810 is designed to introduce a loss of function variant in SLC10A1 RNA that has been found in human genetics to prevent re-uptake of bile acids in liver via NTCP. Based on its mechanism of action, AX-0810 has the potential to become a disease modifying treatment for PSC and BA primarily among other cholestatic diseases. About Cardiovascular Diseases Cardiovascular diseases (CVDs) are a group of health conditions that affect the heart and blood vessels, such as atherosclerosis which can lead to severe problems like heart attacks, heart failure, and stroke. CVDs represent the leading cause of disability and death in the world. Approximately 18 million people die every year from CVDs representing one third of all the global deaths. Despite available lipid lowering therapies and hypertension medications, the risk of CVDs is still projected to increase rapidly over the coming years. About AX-1412 targeting B4GALT1 Gene–based analysis of rare beta-1,4-galactosyltransferase 1 (B4GALT1) missense variant (p.Asn352Ser) is known to lead to B4GALT1 protein loss of function and showed an association with decreased coronary artery disease. These beneficial effects are mediated by hypo-galactosylation of the apolipoprotein B100 and fibrinogen, known – independent – drivers of increased risk of CVDs. AX-1412 introduces a protective variant into B4GALT1 RNA to address the remaining residual risk of developing cardiovascular diseases. ProQR intends to advance AX-1412 targeting B4GALT1 to early clinical proof of concept stage, then would seek to partner this program. About ProQR ProQR Therapeutics is dedicated to changing lives through the creation of transformative RNA therapies. ProQR is pioneering a next-generation RNA technology called Axiomer™, which uses a cell’s own editing machinery called ADAR to make specific single nucleotide edits in RNA to reverse a mutation or modulate protein expression and could potentially yield a new class of medicines for both rare and prevalent diseases with unmet need. Based on our unique proprietary RNA repair platform technologies we are growing our pipeline with patients and loved ones in mind. Learn more about ProQR at www.proqr.com. Forward Looking Statements This press release contains forward-looking statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as “continue,” "anticipate," "believe," "could," "estimate," "expect," "goal," "intend," "look forward to", "may," "plan," "potential," "predict," "project," "should," "will," "would" and similar expressions. Such forward-looking statements include, but are not limited to, statements regarding our business, preclinical model data, our initial pipeline targets and the upcoming strategic priorities and milestones related thereto, our Axiomer™ platform, including the continued development and advancement of our Axiomer platform, the therapeutic potential of our Axiomer RNA editing oligonucleotides and our ability to expand preclinical in vivo and in vitro data, the timing, progress and results of our preclinical studies and other development activities, including the release of data related thereto, our patent estate, including our anticipated strength and our continued investment in it, as well as the timing of our clinical development, the potential of our technologies and product candidates, the collaboration with Lilly and the intended benefits thereof, and our financial position and cash-runway. Forward-looking statements are based on management's beliefs and assumptions and on information available to management only as of the date of this press release. Our actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including, without limitation, the risks, uncertainties and other factors in our filings made with the Securities and Exchange Commission, including certain sections of our annual report filed on Form 20-F. These risks and uncertainties include, among others, the cost, timing and results of preclinical studies and clinical trials and other development activities by us and our collaborative partners whose operations and activities may be slowed or halted shortage and pressure on supply and logistics on the global market; the likelihood of our preclinical and clinical programs being initiated and executed on timelines provided and reliance on our contract research organizations and predictability of timely enrollment of subjects and patients to advance our clinical trials and maintain their own operations; our reliance on contract manufacturers to supply materials for research and development and the risk of supply interruption from a contract manufacturer; the potential for future data to alter initial and preliminary results of early-stage clinical trials; the unpredictability of the duration and results of the regulatory review of applications or clearances that are necessary to initiate and continue to advance and progress our clinical programs; the ability to secure, maintain and realize the intended benefits of collaborations with partners, including the collaboration with Lilly; the possible impairment of, inability to obtain, and costs to obtain intellectual property rights; possible safety or efficacy concerns that could emerge as new data are generated in research and development; general business, operational, financial and accounting risks, and risks related to litigation and disputes with third parties; and risks related to macroeconomic conditions and market volatility resulting from global economic developments, geopolitical instability and conflicts. Given these risks, uncertainties and other factors, you should not place undue reliance on these forward-looking statements, and we assume no obligation to update these forward-looking statements, even if new information becomes available in the future, except as required by law. ProQR Therapeutics N.V. Investor contact:Sarah KielyProQR Therapeutics N.V.T: +1 617 599 6228skiely@proqr.comorPeter KelleherLifeSci AdvisorsT: +1 617 430 7579 pkelleher@lifesciadvisors.com Media contact:Robert StanislaroFTI ConsultingT: +1 212 850 5657robert.stanislaro@fticonsulting.com

前言在21世纪初，人类基因组计划完成后，人们发现许多疾病是由基因突变导致功能蛋白表达不足引起的。然而，在药物开发中，开发具有抑制或拮抗作用的药物更容易。随着大规模重组蛋白生产和纯化技术的创新，蛋白质替代疗法，即重组蛋白在临床上取得了成功，如治疗糖尿病的胰岛素。然而，这种方法主要适用于分泌的蛋白质或酶，并且受到这些分子复杂的药代动力学和成本相关问题的阻碍。此外，合成蛋白不太可能完全代表由选择性剪接、翻译后修饰和其他调节机制引起的蛋白质内源性功能的多样性。近年来，多种基于核酸的治疗（NBT）方式已成为内源性基因表达的有效和特异性激活剂。与基因治疗补充基因表达的方法不同，RNA靶向疗法通过选择性调节内源性RNA介导的细胞机制（如转录、剪接、翻译、mRNA稳定性和亚细胞定位）增强蛋白质生产的能力。目前，美国食品药品监督管理局（FDA）和欧洲药品管理局已经批准了几种靶向剪接机制以调节突变外显子的疗法。这些方法可以特异性和可控地增加编码和非编码基因的表达，降低开发和制造成本，从而增加可治疗疾病的范围。基于已证明的治疗潜力和巨大的未满足的医疗需求，NBT在未来将迎来更加快速的发展。蛋白表达上调的生物学治疗性蛋白的上调可以通过调节细胞中蛋白质生产的任何阶段的生物过程来实现，包括转录、剪接、翻译或翻译后修饰。由于这些过程中的许多涉及DNA或mRNA，并由ncRNA网络调节，因此它们特别容易受到NBT的调节。转录激活是增加蛋白质表达丰度研究最多的方法。远端增强子元件通过染色体环与活性基因启动子的物理相互作用募集转录因子、染色质修饰物、中介复合体和RNA聚合酶II（Pol II），导致转录激活。启动子区和增强子的双向转录分别产生非编码启动子RNA（pRNA）和增强子RNA（eRNA）。从蛋白质编码基因座、反式作用的长非编码RNA（lncRNA）、pRNA和eRNA的反义链转录的天然反义转录物（NAT）可以对靶基因进行表观遗传修饰和转录调控。NAT的一个关键特征是，它们可以特异性地以顺式或反式的方式调节其正义基因的转录、RNA加工和翻译。此外，NAT还具有多种调节功能，包括吸附miRNA和与mRNA配对以提高其稳定性。但它们中的大部分是通过协调抑制因子来抑制其靶基因的表达。因此，用反义寡核苷酸（ASOs）靶向NAT可以导致正义基因的去抑制和蛋白表达的增加。此外，天然存在的修饰核苷酸，如N6-甲基腺苷、5-甲基胞嘧啶、N1甲基腺苷、假尿苷和2′-O-甲基化核糖，发生在mRNA和lncRNA的转录过程中。通过NBTs可以调节这些修饰从而影响转录和蛋白表达。翻译效率还可能受到mRNA结构特征的影响，使用NBTs阻断或增强这些结构的活性可能导致治疗性蛋白表达上调。临床阶段的NBT在过去的5-7年里，NBT经历了爆炸性的增长，其中一些已经获得批准，而其他多种NBT正在进行临床试验中进行探索，下表显示了已获批的NBT。调节拼接的NBT突变引起的RNA剪接异常经常导致非功能转录物被无义介导的降解（NMD）迅速破坏，导致受影响蛋白质的短缺，这是许多疾病的基础。此外，前mRNA的正常选择性剪接可以包含所谓的“有毒外显子”，导致转录物通过NMD快速降解，从而降低蛋白质水平。ASOs与调节剪接事件的前mRNA上的特定序列结合，可以防止突变或天然非生产性转录物的产生，并提高靶蛋白表达水平。Vesleteplirsen（SRP-5051），是针对外显子跳跃治疗的下一个寡核苷酸新药，其针对的是可以使用外显子51跳跃治疗的杜氏进行性肌营养不良（DMD）患者。在一项临床试验（NCT04004065）中，vesleteplirsen治疗导致外显子跳跃增加18倍，肌营养不良蛋白水平增加8倍。然而由于观察到严重的低镁血症，该试验暂时搁置，后来随着对尿液生物标志物和镁补充的扩大监测而恢复。WVE-N531，这是一种新型的全身给药反义寡核苷酸疗法，目前正在15名易发生外显子53跳跃的DMD患者中进行临床试验（NCT04906460）。中期结果表明，该药物的肌肉浓度很高，平均外显子跳跃率为53%。药代动力学数据显示半衰期为25天，这可能支持每月给药。WVE-N531的初步临床结果表明，与亨廷顿舞蹈症项目中的第一代DMD剪接转换NBT和敲低NBT相比，其可能具有药理学改善。在用于治疗其他疾病的剪接调节NBT中，sepofarsen（QR-110）在Leber先天性黑蒙的早期临床试验中显示出阳性结果（NCT03913143）。Sepofarsen靶向CEP290内含子26中的c.2991+1655A>G变体。STK-001是Stoke Therapeutics开发的用于Dravet综合征的SCN1A靶向剪接切换的寡核苷酸，目前正处于I/IIa期临床试验（NCT04442295和NCT04740476）。mRNA的递送与注射纯化蛋白相比，将外源性mRNA引入病变细胞具有几个优势，包括产生的蛋白产物的正确翻译后修饰和亚细胞定位、较低的免疫原性、更简单的制造过程和更低的成本。治疗性mRNA递送技术的代表性临床应用之一是由Translate Bio/Sanofi开发的用于囊性纤维化的CFTR mRNA疗法MRT5005，该疗法在II期临床试验（NCT03375047）中进行了测试。MRT5005由体外转录的、未修饰的CFTR mRNA组成，包裹在脂质纳米颗粒中，经雾化以允许吸入输送到肺部。MRT5005在囊性纤维化患者中的I/II期临床试验的中期结果显示出良好的耐受性。肺功能结果参差不齐，部分患者的ppFEV1没有明显改善，而16毫克剂量组的3名患者从基线到第8天，平均最大增幅为15.7%。由Moderna公司开发的mRNA-3927为丙酸血症患者提供丙酰辅酶A羧化酶亚基α和β的双重mRNAs。在进行的I/II期临床试验（NCT04159103）中，10名患者的耐受性良好，初步数据显示，在疾病的自然过程中发生的临床危机数量有所减少。促进核糖体翻译的小分子NBT与RNA的相互作用是基于它们的序列互补性，而RNA靶向小分子（rSM）靶向RNA的3D结构。使用rSMs调节RNA靶点的优点包括口服可用性，以及在某些情况下的血脑屏障通透性。RIBOTACs是一种类似于蛋白水解靶向嵌合体（PROTACs）进行蛋白酶体降解的小分子机制，其设计了与RNase募集部分相连的rSM，该募集部分可以靶向RNA进行降解，能够上调疾病相关蛋白。有设计团队通过在线计算平台INFORNA鉴定了一种获批的药物，受体酪氨酸激酶抑制剂dovitinib是致癌前miR-21的选择性结合物。通过将dovitinib改造为RIBOTAC，这种dovitinib-RIBOTACs能够在小鼠模型中抑制乳腺癌症细胞向肺部的转移。此外，DT-216是治疗弗里德里希共济失调的一种rSM，在I/II期临床试验中（NCT05285540和NCT05573698），DT-216显示出良好的耐受性，单剂量给药后，可使frataxin（FXN）mRNA在24小时内增加1.2至2.6倍。miRNA靶向NBT近年来，miRNA已成为非常吸引力的治疗靶点。合成寡核苷酸已被用于干扰该途径，如miRNA模拟物（promirs）和miRNA阻断剂（antagomirs）。根据miRNA的作用机制，这两种干预类型都可能导致靶蛋白上调。Remlarsen (MRG-201)是一种 miR-29的promirs，研究发现肺部疤痕组织的积累与miR-29的减少有关。因此，创造一种类似miR-29的分子的可能会逆转这种疤痕。然而，由于高毒性，在人类的研究很快终止。随后，miRagen/Viridian开发了新的、改进后的MRG-229分子，他们对该分子进行了化学改进，使其更加稳定，并添加了一种肽，使其能够更有针对性地传递。MRG-229在动物模型中耐受性良好，没有产生任何不良反应。miRNA阻断剂的开发也已经进行了很长时间，但该领域一直受到多次失败的困扰。Regulus停止了RGLS4326的临床试验，RGLS4326抑制miR-17，用于治疗常染色体显性遗传性多囊肾病。然后又开发了下一代候选分子RGLS8429取代，RGLS8429没有观察到RGLS4326的脱靶中枢神经系统事件，目前，正在进行Ib期临床试验（NCT02855268）。另外，在罕见肾脏疾病Alport综合征（NCT05521191）的II期临床试验中，对一种抗miR-21的抗病毒药物lademirsen进行了测试。尽管该药物耐受性良好，但中期无效性分析结果导致研究终止。NBT的优势与挑战NBT的一些优点使其非常适合于治疗许多已知疾病导致的蛋白表达不足。NBT的特点是靶点特异性高，稳定性好，半衰期大大延长（如数周或数月），不用频繁给药。已批准NBT的多项临床试验证明了其良好的耐受性。NBT的开发时间周期短、成本低，可以对快速发展的癌症和罕见遗传疾病进行个性化治疗。然而，与传统的治疗模式相比，NBT也都面临着一些挑战。目前NBT的一个常见缺点是它们无法穿过肠壁或血脑屏障。目前，这个问题可以通过静脉、皮下、脑内、侧脑室或鞘内给药来解决。然而，这些方法是侵入性的，尤其是对中枢神经系统的递送，有一定的可能造成不良影响。因此，需要进行更广泛的研究，以开发化学修饰以及载体的给药技术，从而减少侵入性递送途径。此外，与大多数小分子相比，NBT具有复杂且目前知之甚少的药代动力学和药效学。尽管存在这些限制，但据报道，NBT开发的总体成功率与制药行业的平均水平持平或高于平均水平。对2006年至2015年间进行的7455项药物开发计划的分析表明，进入临床试验的新分子实体药物中只有约6%获得批准。在这项分析中，新型生物制剂的成功率为11.5%。小结最近，NBT的进展为蛋白质表达上调治疗疾病开辟了巨大的新机会。新冠肺炎mRNA疫苗的成功将RNA靶向蛋白上调技术推到聚光灯下，并可能加速该领域的重大突破。基因测序技术的改进，以及NBT在遗传疾病中的可行性所激发的新希望，将导致遗传研究的扩展。人类基因组学的重大进展使已知遗传病因的疾病数量不断增加。而这些都增加了NBT上调蛋白的适用性。随着对疾病基因组学和病理生理学理解的不断发展，以及NBT技术、制造和监管基础设施的改进，NBT的临床应用将不断扩大，为更好地治疗“罕见”疾病和个体化精准医学开辟道路。参考文献：1.Amplifying gene expression with RNA-targeted therapeutics. Nat Rev Drug Discov.2023 May 30.封面图来源：123rf版权声明/免责声明本文为授权转载文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢!药时代官方网站:www.drugtimes.cn联系方式:电话:13651980212微信:27674131邮箱:contact@drugtimes.cn全球首款端粒酶抑制剂能否获批？为什么这场ODAC会议值得关注默克终止BTK抑制剂开发！啃不动“自免”的骨头，肝损伤风险谁来验证……Ferring首席科学家杨翼博士：肥胖症疫苗离我们还有多远？点击这里，欣赏更多精彩内容！