Cep290

MALVERN, Pa., Dec. 13, 2023 (GLOBE NEWSWIRE) -- Ocugen, Inc. (“Ocugen” or the “Company”) (NASDAQ: OCGN), a biotechnology company focused on discovering, developing, and commercializing novel gene and cell therapies, biologics, and vaccines, today announced that the first patient has been dosed in the ArMaDa Phase 1/2 clinical trial of OCU410 (AAV-RORA), a modifier gene therapy product candidate being developed for dry AMD (dAMD). “OCU410, our first-in-class modifier gene therapy for dAMD, addresses gaps among other therapies available and in development for dAMD as a potential one-time treatment for life,” said Dr. Shankar Musunuri, Chairman, CEO and Co-Founder of Ocugen. “We are very pleased to continue advancing our ophthalmic gene therapy pipeline, which remains the Company’s primary focus.” This Phase 1/2 trial will assess the safety and efficacy of OCU410 for geographic atrophy (GA) secondary to dAMD and will be conducted in two phases. Phase 1 is a multicenter, open-label, dose-ranging study. Phase 2 is a randomized expansion phase in which subjects will be randomized in a 1:1:1 ratio to either one of two OCU410 dose groups or to an untreated control group. OCU410 is a potential curative therapy with a single sub-retinal injection that targets multiple pathways causing dAMD, including lipid metabolism, inflammation, oxidative stress, and complement activation. Currently, the other therapeutic options available target only complement activation and require approximately 6-12 intravitreal injections annually. “Breaking new ground in the pursuit of vision restoration, our pioneering modifier gene therapy candidate, OCU410, achieves another major milestone by dosing a GA patient in a Phase 1/2 clinical trial,” said Arun Upadhyay, PhD, Chief Scientific Officer, Head of R&D at Ocugen. “OCU410 offers hope for those battling GA that are faced with limited treatment options and the real prospect of ultimately losing their vision.” “There remains a great unmet need for novel durable and effective treatments for GA, which remains one of the most common causes of vision loss globally,” said Benjamin Bakall, MD, PhD, director of clinical research at Associated Retina Consultants (ARC) and clinical assistant professor at University of Arizona, College of Medicine – Phoenix. “I am excited that we performed the first surgery with this novel therapeutic approach—designed to restore homeostasis and slow disease progression following a single treatment—at ARC in Phoenix, AZ, with the surgical team led by Dr. Mark Kwong, medical director of ARC.” The first surgery was successful in delivering the new gene underneath the retina; the light sensitive nerve tissue lining the inside of the eye. About dAMD and GAdAMD affects approximately 10 million Americans and more than 266 million people worldwide. It is characterized by the thinning of the macula. The macula is the part of the retina responsible for clear vision in one’s direct line of sight. dAMD involves the slow deterioration of the retina with submacular drusen (small white or yellow dots on the retina), atrophy, loss of macular function and central vision impairment. dAMD accounts for 85-90% of the total AMD population. GA, an advanced form of dry age-related macular degeneration, affects approximately 1 million people in the United States alone. About OCU410OCU410 utilizes an AAV delivery platform for the retinal delivery of the RORA (RAR Related Orphan Receptor A) gene. The RORA protein plays an important role in lipid metabolism, reducing lipofuscin deposits and oxidative stress, and demonstrates an anti-inflammatory role in-vitro and in-vivo (animal model) studies. These results demonstrate the ability for OCU410 to target multiple pathways linked with dAMD pathophysiology. Ocugen is developing AAV-RORA as a one-time gene therapy for the treatment of GA. Currently, the other therapeutic options available target only complement activation and require approximately 6-12 intravitreal injections annually. About Ocugen, Inc.Ocugen, Inc. is a biotechnology company focused on discovering, developing, and commercializing novel gene and cell therapies, biologics, and vaccines that improve health and offer hope for patients across the globe. We are making an impact on patient’s lives through courageous innovation—forging new scientific paths that harness our unique intellectual and human capital. Our breakthrough modifier gene therapy platform has the potential to treat multiple retinal diseases with a single product, and we are advancing research in infectious diseases to support public health and orthopedic diseases to address unmet medical needs. Discover more at www.ocugen.com and follow us on X and LinkedIn. About Associated Retina ConsultantsAssociated Retina Consultants is the largest independent retina practice in the state of Arizona, taking part in groundbreaking clinical trials to bring new treatments for the benefit of patients with diseases affecting the retina. In addition to collaborating with Ocugen on the OCU410 clinical trial, in October 2023, Associated Retina Consultants—with a surgical team led by Dr. Mark Kwong—performed gene therapy with OCU400 on a pediatric CEP290 patient. This was the first retinal gene therapy of its kind performed on a child in Arizona. Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995, which are subject to risks and uncertainties. We may, in some cases, use terms such as “predicts,” “believes,” “potential,” “proposed,” “continue,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “should,” or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. Such statements are subject to numerous important factors, risks, and uncertainties that may cause actual events or results to differ materially from our current expectations. These and other risks and uncertainties are more fully described in our periodic filings with the Securities and Exchange Commission (SEC), including the risk factors described in the section entitled “Risk Factors” in the quarterly and annual reports that we file with the SEC. Any forward-looking statements that we make in this press release speak only as of the date of this press release. Except as required by law, we assume no obligation to update forward-looking statements contained in this press release whether as a result of new information, future events, or otherwise, after the date of this press release. Contact:Tiffany HamiltonHead of CommunicationsIR@ocugen.com

Favorablesafetyandtolerabilitypro >ofOCU400investigational drug productin RP and LCA subjects to date Clinical study update suggests continued positive trends in Best-Corrected Visual Acuity (BCVA) and Multi-Luminance Mobility Testing (MLMT), as well as positive trends in Low-Luminance Visual Acuity (LLVA) among treated eyes 83% (10/12) of subjects demonstrated stabilization or improvement in treated eye either on BCVA or LLVA or MLMT scores from baseline Notably, 86% (6/7) of RHO mutation subjects experienced either stabilization of or increase in MLMT scores from baseline including a subset of 29% (2/7) that demonstrated a 3 Lux luminancelevel improvement MALVERN, Pa., Sept. 13, 2023 (GLOBE NEWSWIRE) -- Ocugen, Inc. (Ocugen or the Company) (NASDAQ: OCGN), a biotechnology company focused on discovering, developing, and commercializing novel gene and cell therapies, biologics, and vaccines, today announced a clinical study update for Retinitis Pigmentosa (RP) participants treated in the Phase 1/2 trial to assess the safety and efficacy of OCU400 for RP associated with NR2E3 and Rhodopsin (RHO) mutations and Leber congenital amaurosis (LCA) with mutation(s) in the CEP290 gene. This clinical study update is an extension of results provided by Ocugen on April 14, 2023, and includes additional subjects from the high dose group. The Company believes that OCU400—Ocugen’s therapeutic approach, utilizing a proprietary modifier gene therapy platform—has the potential to be a gene-agnostic therapeutic for RP and LCA patients with inherited retinal degeneration. “This clinical study update supports our vision to help change the lives of patients suffering from inherited retinal diseases,” said Dr. Shankar Musunuri, Chairman, Chief Executive Officer, and Co-Founder of Ocugen. “We remain dedicated to our mission of pioneering breakthroughs in biotechnology and believe that OCU400 has the potential to have an impact on the future treatment of patients with RP and LCA.” This Phase 1/2 trial is a multicenter, open-label, dose ranging study. A total of 18 subjects with vision impairment due to RP associated with RHO and NR2E3 gene mutations received a unilateral subretinal injection of either a low dose (1.66 x 1010 vg/mL), medium dose (3.33 x 1010 vg/mL), or high dose (1.66 x 1011 vg/mL) of OCU400. The study pro a diverse group of subjects aged 18-77 years old, with varied disease stages, racial and ethnic pro medical histories, and mutation subgroups. Ocugen further expanded this Phase1/2 trial to enroll LCA patients with CEP290 gene mutation and pediatric patients with NR2E3, RHO and CEP290 mutations. Inherited retinal diseases (IRDs) such as RP and LCA encompass a group of genetic disorders that affect the retina, the light-sensitive tissue at the back of the eye. These diseases often lead to a gradual loss of vision over time and can ultimately result in blindness. Stabilization of vision is crucial for patients with IRDs due to the progressive and degenerative nature of these conditions. Preserving remaining vision, slowing disease progression, or improving the vision can significantly impact patients’ quality of life. It not only enhances the quality of life for affected individuals but also provides hope for future treatments that may ultimately lead to vision restoration. Comprehensive care, early diagnosis, and access to emerging therapies are essential components of a strategy to stabilize vision in IRD patients. “I am gratified to see the progress we have made in our pursuit of developing a novel gene-agnostic therapy for RP and LCA. Our team's unwavering dedication to advancing modifier gene therapy research demonstrated positive preliminary clinical results that offer renewed hope to patients and their families. We remain resolute in our mission and vision to bring a bright future to those with inherited or age-related retinal diseases through courageous innovation and unwavering determination,” said Dr. Arun Upadhyay, Chief Scientific Officer, Head of Research, Development and Medical at Ocugen. This clinical study update is based on the currently available data from Phase 1 (dose-escalation: Cohort 1, 2 and 3) and the Phase 2 (open enrollment) portion of the study. The exploratory efficacy update includes data for 12 subjects who have completed a minimum of 6-month follow up. The data set comprised of 2 subjects [Cohort 1] with 12-month follow-up, 5 subjects [N=2 from Cohort 1 and N=3 from Cohort 2] with 9-month follow-up, and 5 subjects [N=2 from Cohort 3 and N=3 from Open Enrollment/Phase 2] with 6-month follow-up. “It is an important steppingstone for Ocugen and its mission to help the nearly 1.6 million patients affected by RP and LCA worldwide. For those suffering from these IRDs, this clinical trial update provides hope. It is encouraging to see a favorable safety and tolerability pro positive efficacy readout for OCU400 in RP patients,” said Dr. Lejla Vajzovic, Associate Professor of Ophthalmology with Tenure, Director of Duke Vitreoretinal Fellowship Program at Duke Eye Center and Duke University School of Medicine and leader in gene-therapy research. Key efficacy outcomes from 12 subjects demonstrated: BCVA: 83% (10/12) of subjects demonstrated stabilization or improvements in treated eyes in BCVA scores from baseline 42% (5/12) of OCU400 treated eyes experienced 4-letter improvement and 33% (4/12) treated eyes experienced 7-letter improvement in BCVA from baseline 57% (4/7) of RHO subjects’ treated eyes experienced 4-letter improvement and 43% (3/7) treated eyes experienced 7-letter improvement in BCVA scores from baseline LLVA: 83% (10/12) of subjects demonstrated stabilization or improvement in treated eyes in LLVA scores from baseline 42% (5/12) of OCU400 treated eyes experienced 5-letter improvement (1 line) in LLVA from baseline, with 25% (3/7) increasing by 10 letters (2 lines) 43% (3/7) of RHO subjects experienced 5-letter improvement (1 line) in treated eyes in LLVA scores from baseline, among which 29% (2/7) increased by 10 letters (2 lines) MLMT: 75% (9/12) of subjects demonstrated stabilization or improvement in treated eyes in MLMT scores from baseline 33% (4/12) of subjects in the low, medium, and high dose cohorts experienced at least 1 Lux luminance level improvement from baseline in treated eyes, among which 17% (2/12) increased by 3 Lux luminance levels 86% (6/7) of RHO subjects experienced either stabilization or increases in MLMT scores from baseline, among which 29% (2/7) improved by 3 lux levels “The RHO mutation affects more than 10,000 people in the US,” said Dr. David Birch, Scientific Director, Retina Foundation of the Southwest and Principal investigator of the study. “In my view, the clinical study update supports the gene-agnostic mechanism of action of OCU400 in RHO patients. The improvements in BCVA, LLVA and MLMT in this patient population are very exciting and encouraging because stabilization alone could be considered as a treatment benefit.” The clinical study update from the Phase 1/2 clinical trial demonstrated that OCU400 continued to be generally safe and well-tolerated in subjects across different mutations and dose levels. There were no serious adverse events (SAEs) related to the investigational product in the low and medium-dose cohorts. In the high-dose and open-enrollment cohorts, SAEs were reported for two subjects. Adverse events were mostly deemed related to the surgical procedure and resolved within a few days to weeks. “The clinical study update released by Ocugen appears to have a tangible biological impact on Retinitis Pigmentosa associated with NR2E3 and RHO mutations,” said Dr. David Boyer, Clinical Professor of Ophthalmology USC/Keck School of Medicine Los Angeles, CA and Partner, Retina Vitreous Associates Medical Group. “These findings may indicate a huge step forward in the way we approach and treat this condition. We remain optimistic and eager to continue the trial and understand the full potential of OCU400.” Ocugen will continue to monitor long-term safety and efficacy data from the treated patients and provide additional updates. A webcast and conference call will take place today at 8:30 a.m. ET: Dial-in Numbers: (800) 715-9871 for U.S. callers and (646) 307-1963 for international callers Conference ID: 7803227 Webcast: Available on the events section of the Ocugen investorsite AboutModifierGeneTherapy Modifier gene therapy is designed to fulfill unmet medical needs related to retinal diseases, including IRDs, such as RP, LCA, and Stargardt disease, as well as dry AMD. Our modifier gene therapy platform is based on the use of Nuclear hormone receptors (NHRs), master gene regulators, which have the potential to restore homeostasis — the basic biological processes in the retina. Unlike single-gene replacement therapies, which only target one genetic mutation, we believe that our modifier gene therapy platform, through its use of NHRs, represents a novel approach that has the potential to address multiple retinal diseases caused by mutations in multiple genes with one product, and to address complex diseases that are potentially caused by imbalances in multiple gene networks. Currently Ocugen has three modifier gene therapy programs OCU400 (RP, LCA), OCU410 (dry AMD), OCU410ST (Stargardt disease). AboutOCU400 OCU400 is the Company’s gene-agnostic modifier gene therapy product based on NHR gene, NR2E3. NR2E3 regulates diverse physiological functions within the retina—such as photoreceptor development and maintenance, metabolism, phototransduction, inflammation and cell survival networks. Through its drive functionality, OCU400 resets altered/affected cellular gene-networks and establishes homeostasis—a state of balance, which has the potential to improve retinal health and function in patients with inherited retinal diseases. AboutOcugen,Inc. Ocugen, Inc. is a biotechnology company focused on discovering, developing, and commercializing novel gene and cell therapies, biologics, and vaccines that improve health and offer hope for patients across the globe. We are making an impact on patients’ lives through courageous innovation—forging new scientific paths that harness our unique intellectual and human capital. Our breakthrough modifier gene therapy platform has the potential to treat multiple retinal diseases with a single product, and we are advancing research in infectious diseases to support public health and orthopedic diseases to address unmet medical needs. Discover more at and follow us on Twitter and LinkedIn. CautionaryNoteonForward-LookingStatements Thispressreleasecontainsforward-lookingstatementswithinthemeaningofThePrivateSecuritiesLitigationReformActof1995,whicharesubject torisksanduncertainties,including,butnotlimitedto,statementsregardingqualitative assessments of available data, potential benefits, expectations for ongoing clinical trial results, and anticipated timing of clinical trial updates and regulatory interactions.Wemay,insomecases,usetermssuchas“predicts,”“believes,”“potential,”“proposed,”“continue,”“estimates,”“anticipates,”“expects,” “plans,”“intends,”“may,”“could,”“might,”“will,”“should,”orotherwordsthatconveyuncertaintyoffutureeventsoroutcomestoidentifytheseforward- lookingstatements.Suchstatementsaresubjecttonumerousimportantfactors,risks,anduncertaintiesthatmaycauseactualeventsorresultsto differmateriallyfromourcurrentexpectations,including,butnotlimitedto, the risks that preliminary, interim and top-line clinical trial results may not be indicative of, and may differ from, final clinical data; that unfavorable new clinical trial data may emerge in the Phase 1/2 clinical trial or through further analyses of existing clinical trial data; that earlier non-clinical and clinical data and testing of may not be predictive of the results or success of later clinical trials; and that that clinical trial data are subject to differing interpretations and assessments, including by regulatory authorities.TheseandotherrisksanduncertaintiesaremorefullydescribedinourperiodicfilingswiththeSecuritiesand ExchangeCommission(SEC),includingtheriskfactorsdescribedinthesectionentitled“RiskFactors”inthequarterlyandannualreportsthatwe theSEC.Anyforward-lookingstatementsthatwemakeinthispressreleasespeakonlyasofthedateofthispressrelease.Exceptasrequiredby law, we assume no obligation to update forward-looking statements contained in this press release whether as a result of new information, future events, or otherwise, after the date of this press release. Contact: Tiffany Hamilton Head of Communications Tiffany.Hamilton@ocugen.com

近年来FDA已批准了多款小核酸药物，主要用于治疗罕见病。截至2023年，全球小核酸药物进入临床管线的共有近80个，覆盖神经、心血管、感染和肿瘤等领域，共计有 15 款小核酸药物获批上市。但有2款早期ASO药物与1款适配体药物由于销售额过低等原因而退市，目前仍在市场的有7款ASO、5款siRNA药物。上市小核酸药物已在盘点 ｜ 小核酸药物的详细分类及上市情况中详细总结，感兴趣的朋友可以点击链接查阅，本文接着盘点小核酸药物在Ⅲ期/Ⅱ期临床阶段的进展情况。 图注：全球已上市小核酸药物（含已退市）  01  全球小核酸药物Ⅲ期临床概览 图注：全球小核酸药物Ⅲ期临床概览1.1 TivanisiranSylentis推出的Tivanisiran (SYL1001) 是一种 siRNA，用于干眼症的治疗。干眼症（DED）的特征是泪膜改变，伴有眼部炎症和神经感觉异常，这种情况的主要临床症状是泪液不稳定和眼损伤。Tivanisiran 用于沉默瞬时受体电位香草素1（TRPV1） mRNA。Tivanisiran 旨在减少眼部不适和疼痛，并被证明可以改善人类和动物模型中的眼充血和泪液质量。目前Tivanisiran处在Ⅲ期试验阶段，评估治疗治疗干眼症以及干燥综合征引起的干眼症的安全性，研究预计在2023年下半年到2024年上半年完成（NCT05310422；NCT04819269）。1.2 BepirovirsenGSK推出的Bepirovirsen作为用于治疗乙型肝炎的ASO治疗药物，Ⅱ期临床结果显示可降低乙型肝炎表面抗原（HBsAg）和乙型肝炎病毒（HBV）DNA的水平。乙型肝炎病毒利用这些RNA在受感染肝细胞中自我复制，产生病毒抗原（蛋白），而生成的病毒抗原能帮助病毒逃脱免疫系统清除，从而促使乙型肝炎疾病慢性化。ASO通过招募肝脏自身的酶将病毒RNA降解成无活性形式并将其清除。RNA水平降低使病毒和肝细胞生成的HBsAg均减少。Bepirovirsen具有通过Toll样受体8（TLR8）刺激免疫应答的特性，这可能有助于免疫系统持久清除血液循环系统中的病毒。对于Bepirovirsen有效性和安全性的Ⅲ期临床试验预计在2026年初结束（NCT05630807；NCT05630820）。1.3 Leqvio®（Inclisiran） Novartis Pharma GmbH诺华制药公司推出的Leqvio®(Inclisiran)，作为饮食控制的一种辅助手段，用于治疗成人原发性高胆固醇血症（杂合子家族性和非家族性）或混合型血脂异常。Leqvio是一款siRNA疗法。使用该药可以持续降低患者LDL-C引起的心血管疾患的发病率。Leqvio可与编码PCSK9蛋白的mRNA结合，通过RNA的干扰作用来防止肝脏生成PCSK9蛋白。PCSK9蛋白的作用是抑制LDL受体的回收和再利用。而降低体内PCSK9的水平可以让更多LDL受体回到肝细胞表面，与更多LDL结合，进而将它们从血液中清除。目前此药正在进行一项Ⅲ期临床实验以评估对已确诊心血管疾病（CVD）参与者的主要不良心血管（MACE）事件的益处。预计在2027年完成（NCT05004675）。1.4 Oxlumo®（Lumasiran）由Alnylam研发的Lumasiran 于2020年11月23日被FDA批准上市作为首个治疗原发性高草酸尿1型（PH1）的药物。PH1是一种罕见的遗传性疾病。Oxlumo获得孤儿药称号和突破性治疗指定。Lumasiran是一种靶向HAO1的siRNA，与含有N-乙酰半乳糖胺的配体共价连接，通过RNAi靶向肝细胞中的羟基酸氧化酶1 (HAO1)的mRNA，从而降低乙醇酸氧化酶(GO)酶的水平。GO酶水平的降低可以降低乙醛酸的可利用量，乙醛酸是产生草酸的底物。由于谷氨酸脱羧酶位于导致PH1的丙氨酸：乙醛酸氨基转移酶(AGT)缺陷酶的上游，Lumasiran的作用机制与潜在的AGXT基因突变无关。此药目前正在进行多项Ⅲ期临床试验（NCT04152200；NCT04152200），旨在评估 Lumasiran 在原发性高草酸尿症 1 型婴幼儿、儿童、成人以及晚期原发性PH1患者中的疗效、安全性、药代动力学和药效学。1.5 QR-110QR-110 是一种基于 RNA 的寡核苷酸，旨在解决 CEP290 基因中 p.Cys998X 突变引起的Leber先天性黑朦10（LCA10）的根本原因。LCA是儿童遗传病导致的失明的最常见原因，由一组疾病组成，其中LCA 10是更严重的形式之一。p.Cys998X突变是前mRNA中一个核苷酸的取代，导致mRNA和非功能性CEP290 mRNA的异常剪接。QR-110 旨在恢复正常（野生型）CEP290 mRNA，通过结合前 mRNA 中的突变位置导致前 mRNA 正常剪接，从而产生正常的 CEP290 蛋白。ProQR Therapeutics正在进行一项双盲、随机、对照、多剂量Ⅱ/Ⅲ期临床研究，目的是评估通过玻璃体内注射给予的QR-110在治疗 LCA受试者的疗效、安全性、耐受性和全身暴露。1.6 UltevursenProQR Therapeutics正在进行关于Ultevursen（以前称为QR-421a）的Ⅱ/Ⅲ期临床试验，本研究的目的是评估通过玻璃体内注射（IVT）给予Ultevursen的疗效安全性和耐受性，用于由于USH13A基因外显子2突变引起的视网膜色素变性（RP）受试者。此项研究预计在2024年完成。Ultevursen是一种基于单链 RNA的寡核苷酸，可以阻止因USH2A基因(编码 usherin 蛋白)的第13外显子突变而导致的色素性视网膜炎患者的视力下降。它通过眼睛玻璃体内注射给药，并已在美国和欧盟获得孤儿药指定，并获得了 FDA 的快速通道和罕见儿科疾病指定。研究预计在2024年底完成（NCT03913143；NCT04855045）。  02  全球小核酸药物Ⅱ期临床概览 图注：全球小核酸药物Ⅱ期临床概览2.1 SYL1801SYL1801Ⅱ期临床试验由Sylentis公司发起。SYL1801是一种靶向NRARP（NOTCH Regulated Ankyrin Repeat Protein）的siRNA，使用Sylentis专有的SirFinderTM进行工程设计，用于预防和/或控制湿性年龄相关性黄斑变性（AMD）的进展。SYL1801作为滴眼液给药，以转录下调NRARP的表达，NRARP在控制视网膜中新血管生成中起重要作用，这与基于抗VEGF药物的常规抗血管生成疗法所针对的靶标不同。目前该药正在进行Ⅱ期临床招聘，该临床试验的目的是比较三种不同剂量的SYL1801滴眼液的安全性和对视力的影响，预计在2022年11月22日完成（NCT05637255）。2.2 ALN-HSD由Regeneron和Alnylam发起的关于ALN-HSD的Ⅱ期临床研究，ALN-HSD作为皮下注射 RNAi 治疗药物，靶向HSD17B13基因，用于治疗 NASH。此项研究以非酒精性脂肪性肝炎（NASH）患者为对象，旨在评估ALN-HSD在患有NASH伴有遗传危险因素的纤维化（NASHGEN-2）的成年患者中的疗效和安全性（NCT05519475）。NASH是非酒精性脂肪性肝病（NAFLD）的一种形式，当脂肪在肝细胞中积聚，损害它们，并使肝脏因纤维化（疤痕组织）而发炎和僵硬时，就会发生NASH。NASH可以进展为肝硬化（长期疤痕）和肝衰竭，预计2026年12月09日完成。2.3 OLX10010由OliX公司发起的一项随机、双盲、受试者内、安慰剂对照的Ⅱa期临床实验，评估OLX10010作为辅助疗法减少疤痕修复手术后肥厚性疤痕复发的疗效。OLX10010是一种穿透细胞的不对称siRNA（cp asiRNA），可干扰结缔组织生长因子（CTGF）的表达。这项研究的目的是确定OLX10010在减少肥厚性疤痕复发方面的疗效，该研究将评估疤痕整复手术后肥厚性疤痕的减少和复发情况。预计在2023年9月份完成（NCT04877756）。2.4 ALN-KHKALN-KHK是一种靶向酮己糖激酶（KHK）的研究性RNAi治疗药物，用于治疗2型糖尿病（T2DM）。ALN-KHK采用Alnylam的增强稳定化学增强型（ESC+）GalNAc偶联物技术，该技术能够以更高的选择性和广泛的治疗指数进行皮下给药。2型糖尿病是一种全球性疾病，影响着世界6%以上的人口，全世界的发病率和流行率正在上升，估计有超过450.55亿人受到影响。Alnylam于2023年3月发起随机、双盲、安慰剂对照、由两部分组成的Ⅰ/Ⅱ 期研究，研究单剂量 ALN-KHK 对肥胖成年健康志愿者超重和多剂量 ALN-KHK 在肥胖 2 型糖尿病患者中的安全性、耐受性、有效性、药代动力学和药效学。此项研究预计在2024年上半年完成（NCT05761301）。2.5 ALN-AGT01同样由Alnylam发起，以评估RNAi疗法药物ALN-AGT01在轻度至中度高血压（KARDIA-1）患者中的有效性和安全性的一项随机、双盲、安慰剂对照、剂量范围多中心研究Ⅱ 期研究正在开展，此项研究预计在2025年完成（NCT04936035）。2.6 SQY512023年4月份由SQY Therapeutics发起一项单中心、开放标签Ⅰ/Ⅱa 期研究，旨在评估 SQY51 在杜氏肌营养不良症患者中的安全性、药代动力学和药效学。杜氏肌营养不良症（DMD）是一种遗传性疾病，导致身体所有肌肉进行性退化。它是由位于X染色体上的DMD基因（突变）异常引起的，该基因编码肌营养不良蛋白，肌营养不良蛋白是一种对肌肉纤维正常运作至关重要的蛋白质。SQY51是一种反义寡核苷酸，旨在杂交到DMD基因的pre-mRNA转录本上的特定位点，以便在mRNA成熟（外显子跳跃）期间去除突变基因的某些元素，以恢复功能性截短肌营养不良蛋白的产生。SQY51使用“三环DNA”家族的非天然核苷酸，它们的优点是非常稳定，并且比天然对应物更有效地与RNA靶标杂交。12名患者(6岁以上)将被纳入试验。研究的第1阶段，将持续13周，他们都将接受6次递增剂量的 SQY51静脉注射。对于第2a 阶段，第1阶段的参与者将被分为3个队列，每个队列用不同剂量的 SQY51治疗32周，此项研究预计在2025年完成（NCT05753462）。 图注：SQY51建模2.7 K3228836GlaxoSmithKline研发的ASO化合物GSK3228836，目前正在开展一项单盲、随机、对照的Ⅱ期研究，旨在量化序贯治疗的疗效，并确定序贯治疗相对于GSK3228836治疗在接受NA治疗的CHB患者中的附加值。此项研究从2022年3月份开始，预计2026年结束（NCT05276297）。2.8 STK-001Stoke Therapeutics推出的STK-001用于治疗儿童和青少年Dravet综合征。STK-001为一种反义寡核苷酸药物，有可能成为第一种针对Dravet综合征根本病因的改善性疗法。Dravet综合征是一种严重的进行性遗传性癫痫，特征表现为出生后一年内开始频繁、持续和难治性的癫痫发作。由于该疾病可导致相关发育迟缓和认知障碍，因此被归类为发育性和癫痫性脑病。STK-001通过利用SCN1A基因的非突变（野生型）拷贝来恢复生理性NaV1.1基因表达，进而上调NaV1.1蛋白的表达，从而减少癫痫发作和显著非发作性并发症的发生。Stoke目前的临床前数据已经证明STK-001的作用机制和概念。FDA已授予STK-001孤儿药称号，作为治疗Dravet综合征的新的潜在疗法。目前Stoke Therapeutics正在评估Dravet综合征患者单次和多次递增剂量STK-001的安全性和耐受性，预计2027年和2025年完成（NCT04740476；NCT04442295）。2.9 IGV-001Imvax目前正在进行一项随机、多中心、双盲、安慰剂对照的 Ⅱb 期研究，旨在评估 IGV-001（一种靶向 IGF-001R 的反义寡核苷酸 （IMV-1） 的自体细胞免疫疗法）在新诊断的胶质母细胞瘤（GBM）患者中的安全性和有效性。IGV-001是一款针对多形性胶质母细胞瘤的疫苗，由三种物质组成：患者的肿瘤细胞、IGF-1R反义寡核苷酸（IMV-001）、渗透室（ bio-diffusion chamber，其允许大分子渗出）。IGV-001首先从收集GBM患者手术切除的肿瘤细胞开始，然后经过IGF-1R反义寡核苷酸（IMV-001）处理，将肿瘤细胞推向受控细胞死亡。最后将这些处理过的细胞再次混合过量的IMV-001（作为佐剂）置于渗透室中，最后在手术后的24小时内植入患者的腹部。植入时间达到48小时后，将其取出，完成疫苗接种全过程。这一创新疫苗已经被美国FDA授予孤儿药资格。此项试验于2023年3月开始，预计2027年完成研究（NCT04485949）。2.10 BP1001 Bio-Path Holdings目前正在进行一项 IIa 期开放标签临床试验，旨在评估 BP1001（脂质体 Grb2 反义寡核苷酸）与维奈托克加地西他滨联合用于不适合强化诱导治疗的难治性/复发性急性髓性白血病（AML）患者的安全性、药代动力学、药效学和疗效。生长因子受体结合蛋白-2（Grb2）对癌基因信号传导和肿瘤进展至关重要。BP1001是一种脂质体掺入的Grb2反义寡核苷酸，可抑制Grb2表达。I/Ib 期单中心研究表明，BP1001 的安全性高达 90 mg/m2BP1001与低剂量阿糖胞苷（LDAC）联合治疗AML患者的剂量和疗效。本次研究的主要目的是评估：（1） BP1001 加维奈托克加地西他滨的组合是否比维奈托克加地西他滨在不能或选择不接受更高强度化疗的未经治疗的 AML 受试者中提供更大的疗效（完全缓解 [CR]、完全缓解伴不完全血液学恢复 [CRi]、完全缓解伴部分血液学恢复 [CRh]）;（2）基于BP1001的治疗是否比强化化疗（通过历史比较）对难治性/复发性AML的受试者提供更大的疗效（CR，CRi，CRh）。研究预计于2024年底结束（NCT04196257；NCT02781883）。2.11 QR-1123ProQR Therapeutics发起的一项前瞻性首次人体研究，评估 QR-1123 在因视紫红质（RHO）基因 P23H 突变而导致的常染色体显性视网膜色素变性 （adRP） 受试者中的安全性和耐受性。QR-1123是一种反义寡核苷酸，旨在特异性靶向突变型P23H mRNA，以选择性降低P23H蛋白的表达，同时保留野生型（WT）RHO蛋白的表达。据推测，突变P23H mRNA的减少将减少显性阴性蛋白的有害作用，并应导致WT视紫红质蛋白在光感受器中的功能增加。WT RHO功能的恢复有望改善因P23H突变引起的adRP患者的视力（NCT04123626）。2.12 PRAX-222Praxis Precision Medicines推出的PRAX-222是一种反义寡核苷酸，旨在选择性地降低SCN2A功能获得性癫痫患者SCN2A基因编码蛋白的表达水平。PRAX-222在体外研究中可降低SCN2A的基因表达和蛋白质的水平。在SCN2A小鼠模型中，PRAX-222可显著且剂量依赖性地减少小鼠癫痫发作、改善小鼠的行为和运动活动，并增加存活率，有望成为首个能够缓解该疾病的疗法。目前，PRAX-222已获得FDA的孤儿药资格和罕见儿科疾病资格，以及欧洲药品管理局（EMA）的用于治疗SCN2A-DEE的孤儿药资格。目前此药正在进行Ⅱ期临床试验，旨在研究多剂量PRAX-222在早发性SCN2A发育性和癫痫性脑病儿童参与者中的安全性和有效性（NCT05737784）。2.13 BNT112BNT112由信使核糖核酸（mRNA [或RNA]）组成，靶向在新生和转移性前列腺癌中表达的5种抗原，这些抗原分别与脂质体复合以形成血清稳定的RNA脂复合物（RNA-LPX）。BioNTech SE正在进行Ⅰ/Ⅱ期临床试验以评估 BNT112 癌症疫苗单药治疗或与西米普利单抗联合治疗转移性去势抵抗性前列腺癌（mCRPC：第 1 部分和第 2 部分 Arm 1A 和 1B）和高风险局部前列腺癌 （LPC） 患者的安全性、耐受性、免疫原性和初步疗效。此项研究预计在2023年下半年结束（NCT04382898）。2.14 mRNA-3705 & mRNA-3927mRNA-3705是一款治疗甲基丙二酸血症（MMA）的在研mRNA疗法，通过静脉输注给药，用于治疗因为甲基丙二酸单酰辅酶A变位酶（MUT）缺失引起的MMA患者。mRNA-3927旨在指导机体恢复导致丙酸血症（PA）的缺失或功能失调的蛋白质。旨在评估mRNA-3705的长期安全性和评估mRNA-3927对先前参加过研究mRNA-3927-P101（NCT04159103）的丙酸血症（PA）参与者施用mRNA-3927的长期安全性的Ⅱ期临床试验由ModernaTX公司发起，两项试验均预计在2030年以后收官（NCT05295433；NCT04899310）。2.15 Sapablursen由专注小核酸技术研发和创新技术的Ionis公司推出的Sapablursen，原名ISIS 702843，IONIS-TMPRSS6-LRx，是一种在研配体偶联反义（LICA）药物，旨在靶向TMPRSS6基因以调节铁调素的产生。铁调素是铁稳态的关键调节因子。通过调节铁调素的表达，Sapablursen有可能对以缺铁为特征的疾病产生积极影响，例如真性红细胞增多症（PV）。目前此药处于 Ⅱa 期临床研究阶段，研究旨在评估 Sapablursen用于静脉切开术依赖性真性红细胞增多症 （PD-PV） 患者的疗效、安全性、耐受性、药代动力学和药效学。研究预计在2025年初完成（NCT05143957）。  小结  除了以上15种处于Ⅱ期临床试验和6种Ⅲ期临床阶段的小核酸药物之外，还有近40种处于Ⅰ期临床研究阶段，涵盖siRNA、mRNA、ASO等。小核酸药物技术在企业分布上形成了两类具有代表性的企业，一类是专注小核酸技术研发和创新技术的公司，例如Ionis、Alnylam等，另一类是生物医药巨头公司通过合作开发布局小核酸药物领域，例如罗氏、阿斯利康、诺华等。小核酸药物具有靶向特异性强、药物作用长效、研发周期短、靶点丰富以及高效性，与传统药物相比，具有多重技术优势，多样化的研发模式也使得小核酸药物研发资源的使用更加高效。目前小核酸药物行业整体具有较高景气度、良好竞争格局、较大潜在市场规模的特性，逐步稳健快速发展。参考资料：1.Moreno-Montañés J, Bleau AM, Jimenez AI. Tivanisiran, a novel siRNA for the treatment of dry eye disease. Expert Opin Investig Drugs. 2018;27(4):421-426. doi:10.1080/13543784.2018.14576472.Girach A, Audo I, Birch DG, et al. RNA-based therapies in inherited retinal diseases. Therapeutic Advances in Ophthalmology. 2022;14. doi:10.1177/251584142211346023.Ana Isabel Jimenez, Veronica Ruz, Laura Rico, Tamara Martinez, Susana Monteiro, Ascension Cuesta, Amor Guerra, Alba Cuenca, Victoria Gonzalez; SYL1801: Preclinical Efficacy and Safety of a siRNA-based eye drops treatment for Age Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5389.