Lyophilised Oxalobacter formigenes(OxThera AB)

人体是数以万计的微生物的家园。所谓微生物组是众多微生物及其基因和代谢物的复杂集合体，它们定殖在消化道、皮肤、口腔、泌尿生殖系统。而微生物组疗法则是将微生物作为活性物质用于治疗或预防疾病的一种新兴疗法。过去，制药企业一直未能开发出用于调节患者微生物组的疗法；但近期，微生物组疗法已迎来了转机：2022年11月，辉凌制药的REBYOTA获得美国FDA批准上市。2022年11月，BiomeBank Bioscience公司的BIOMICTRA获得澳大利亚医疗用品管理局（TGA）批准上市。2023年4月，Seres Therapeutics公司的Vowst（SER-109）获批上市，这也是FDA批准上市的首款口服微生物组疗法。以上三款药物均用于治疗复发性艰难梭菌感染。作为新兴疗法，微生物组疗法是否能成为新药研发的下一座“金矿”？答案是肯定的。微生物与健康，是一个宏达、且远未被了解的生物学领域。新疗法的获批上市也表明部分地区的监管机构对这一新兴疗法的处理方式已非常成熟。目前来看，新上市的第一代微生物组疗法仅切入了一个相对较小的目标市场（即复发性艰难梭菌感染），然而，微生物组疗法的涉及领域正在迎来范式的转变，自身免疫、肿瘤甚至是神经系统疾病，均有可能成为微生物组疗法的下一个突破点，一旦成功，未来将不可估量。初识微生物组疗法微生物组疗法，又被成为活体菌药物（live biotherapeutic products, LBPs），根据制造方法的不同，目前活体菌药物主要分为四大类：粪菌移植、单菌株药物、工程菌株以及小分子微生态调节剂。01粪菌移植粪菌移植（Fecal Microbiota Transplantation, FMT），是指将健康人群粪便中的微生物菌群移植到患者胃肠道内，通过重建新的肠道菌群以实现治愈疾病的疗法。目前已获批上市的3款微生物组疗法均是基于FMT开发的，此外，全球多家公司正在布局FMT新药。FMT疗法研发情况（列举）资料来源：《中国生命科学》2023年3月第3期，作者整理02单菌株药物单菌株药物，包括单菌株或者混合株药物单菌药物，也有开发少数复合菌的项目。目前的单菌疗法中有少数品种是食品益生菌菌株（例如，罗伊斯乳杆菌、动物双歧杆菌等）按药物标准进行再研发，但更多的品种是采用未有人体使用历史的新菌株（例如，脆弱拟杆菌、鹑鸡肠球菌、克里斯滕森菌等）。据统计，单菌疗法占活体生物新药研发总数的一半左右。目前，已有3款单菌株药物进入临床3期研究阶段：Infant Bacterial Therapeutics公司的IBP-9414（一种罗伊氏乳杆菌）用于治疗婴儿溃疡性结肠炎；Probi公司的LP299V（一种乳酸菌）用于治疗移植物抗宿主病；Ox Thera公司的Oxabact（一种草酸盐还原菌）用于治疗原发性高草尿酸症。03工程菌株药物工程菌株是指用基因工程方法，使外源基因获得高效表达的菌株。工程菌是采用现代生物工程技术加工出来的新型微生物，具有多功能、高效和适应性强等特点。相较于FMT和单菌株疗法，工程菌药物研发起步略晚，大部分药物处于临床早期阶段。其中，具有代表性的有 Advaxis公司的ADXS-503（一种减毒单核细胞增多性李斯特菌），联合帕博利珠单抗治疗非小细胞肺癌，目前处于临床II期阶段，I/II期试验结果显示，ADXS-503可让患者产生可观的应答率和疾病控制率，且患者的临床获益具有持续性：14名既往使用过帕博利珠单抗的患者，联合使用ADXS-503后，客观缓解率达14%，疾病控制率达36%；在另一研究中，将ADXS-503用于未接受过全身治疗、PD-L1≥50%且EGFR/ALK阴性患者，结果显示在3名接受联合治疗的新诊断的非小细胞患者中，疾病控制率为67%，两名患者疾病稳定分别达332天和94天。ADXS-503临床数据资料来源：Advaxis Corporate Presentation，202204小分子微生态调节剂小分子微生态调节剂（small molecule microbiome modulator, SMMM）是指能选择性地促进宿主肠道内的有益细菌生长繁殖的物质，通过促进有益菌的繁殖，抑制有害细菌的生长，达到调整肠道菌群，从而促进机体健康。该领域的代表公司有 Second Genome、Enterome等。Second Genome公司的SGM-1019用于治疗非酒精性脂肪性肝炎，目前处于临床II期；Enterome公司的EB8018用于治疗炎症性肠病，处于临床II期阶段。微生物组疗法的新机遇从单一疾病向多疾病领域延伸据作者不完全统计，全球进入临床阶段的微生物组药物有103个，其中：影响肠道的自身免疫类疾病是目前最常见的适应症，占全部微生物疗法研发管线的35%，其中炎症性肠病（包括溃疡性结肠炎和克罗恩病）是主要的目标疾病。复发性艰难梭菌感染是目前微生物组临床研发中最大的单一疾病领域，占比达12%。肿瘤或将成为微生物组疗法的下一个研发重点，目前占研发管线总量的20%。PD-1等免疫检查点抑制剂通过阻断免疫检查点恢复或增强机体的抗肿瘤免疫，但存在某些免疫检查点抑制剂应答率偏低、继发性耐药等不良反应。相关研究表现，肠道微生物组会影响免疫检查点抑制剂的疗效，因此，微生物组疗法联合免疫检查点抑制剂，成为目前LBP药物开发的热点之一。微生物组疗法在研管线情况资料来源：IQVIA，作者整理微生物组疗法联合免疫检查点抑制剂研发情况资料来源：广东省活体生物药工程技术研究中心此外，越来越多研究显示肠道菌群与神经系统疾病的产生存在相关关系，脑-肠轴是一个双向交流路径，通过此路径，细菌代谢物可以进入脑，影响神经发育或产生神经炎症，这些代谢物被认为与神经退行性疾病有关，例如阿尔茨海默病，帕金森病，自闭症等。综上所述，粪菌移植仅仅是第一代微生物组疗法，未来伴随着微生物组在疾病病理中的作用机制证据不断增加，微生物组疗法将有望在肿瘤、自身免疫、代谢类疾病甚至是神经系统再下一城。微生物组疗法的挑战研发失败、监管仍处于探索阶段作为新兴事物，微生物组疗法充满机遇，但同时也伴随着风险和挑战。由于大多数复杂疾病的发病机制与微生物间的因果关系尚未明确，不少企业因为临床研究效果欠佳而选择终止某些药品的临床研究或直接关停微生物组管线，例如，由于反应率过低，Seres Therapeutics公司中断了SER-401研发，Vedanta停止其VE800药物临床试验。因此，对于试图布局微生物组疗法的企业来说，仍需开展大量的基础研究，明确在疾病发生和进展中，起到关键性作用的某种或某类菌群。其次是监管方面的问题。2016年，FDA发布了《活体生物药的早期临床试验：化学､制造和控制信息》，这是首个关于LBP药物研发指南，FDA对于LBP药物的监管体系已较为成熟。然而，不同地区的监管环境存在差异化，例如，欧盟没有制定欧洲通用的“微生物组疗法”明确法规，而是交由各成员国自己来决定。国内而言，目前对于LBP药物的监管尚处于探索阶段，中华医学会仅在肠道菌群捐献者管理、治疗质量管理、减少不良事件以及促进标准化方面达成了专家共识。未来一段时期内，随着国内新LBP药物的陆续上市申报，国内LBP药物的研发、技术审评和监管也将逐步积累更多经验。微生物组疗法为疾病治疗开辟了一个新天地。大量正处于临床后期的LBP药物正在不断推进，未来几年，微生物组疗法市场将逐渐发展成熟，谁又能在这新生的、不断发展的市场中领航，我们拭目以待。参考资料《国际活体生物药临床开发进展（2019-2021年）》，广东省活体生物药工程技术研究中心《内有乾坤：微生物组疗法的不断发展》，IQVIA，2023年《活体菌药物产业化》，《中国生命科学》2023年3月第3期Advaxis Corporate Presentation，2022药物临床试验登记与信息公示平台，ClinicalTrials.gov，公司官网END👇关注药渡数据媒体矩阵

STOCKHOLM, June 11, 2021 /PRNewswire/ -- OxThera AB, a privately-held biopharmaceutical company dedicated to improving the lives of people with Primary Hyperoxaluria (PH), announces completion of its pivotal Phase 3 study and reports top line results. OxThera's 52-week OC5-DB-02 study "A Phase III Double-Blind, Randomised Study to Evaluate the Long-Term Efficacy and Safety of Oxabact® in Patients with Primary Hyperoxaluria" (ePHex) enrolled patients with all types of PH, who had to have a plasma oxalate (Pox) concentration ≥ 10 μmol/L and an eGFR < 90 ml/min/1.73 m2 during screening to be eligible for inclusion into the study. Twenty-five patients were enrolled and randomly assigned 1:1 to either Oxabact (13) or placebo (12). Almost all patients (24) had been diagnosed with PH type 1, only 1 patient with PH type 2. The mean age at baseline for all subjects was 15.5. years (range 5 to 54 years), patients in the Oxabact arm were slightly younger. Baseline mean plasma oxalate in the two treatment arms was well balanced, 14.8 µmol/L in Oxabact and 14.4 µmol/L in placebo. Urinary oxalate excretion was slightly higher in the Oxabact group vs placebo; 2.10 and 1.76 mmol/day/1.73 m2, respectively. The mean Pox concentration, the primary endpoint of the study, separated after week 24 in favor of Oxabact. The estimate of mean (SE) difference between treatment arms reached – 3.8 (2.0) μmol/L (95% CI -7.8 – 0.2) at week 52 (p=0.06), where the Oxabact group was essentially stable, and placebo increased. A trend in favor of Oxabact was observed for the overall comparison, and this was consistent across most pre-defined sub-groups. A supportive slope model demonstrated a similar magnitude of change (SE) of -6.1 (3.0) µmol/L (p=0.04). Adverse events were well balanced between the 2 treatment arms, there were slightly more severe adverse events observed in the placebo arm than in the Oxabact arm. "We are encouraged that the observed treatment effect towards the end of the study supports our hypothesis behind the mechanism of action of Oxabact, but of course disappointed that it did not reach statistical significance" said Elisabeth Lindner, Chief Operating Officer of OxThera. "Oxabact is an oral formulation of the bacterium Oxalobacter formigenes metabolizing oxalate that enters the GI tract through active and passive secretion from plasma. The hypothesis is that treatment with Oxabact could stop or delay disease progression. It appears that the study was not long enough to detect a difference in clinical endpoints, and OxThera is now seeking a partner to further develop Oxabact." Key secondary endpoints of the study, kidney function (estimated glomerular filtration rate, eGFR) and the number of adjudicated kidney stone events during the study, did not show a significant difference between treatment groups. During the 3 years pre-dose, 9 patients in the Oxabact arm reported in total 18 or more stone events, and 7 patients in placebo reported in total 16 or more stone events. On study, 7 stone events occurred in 13 Oxabact patients and 8 stone events in 12 placebo patients. "As a physician treating patients with PH, it is of primary importance to me that my patients are stable." said Dr. Gema Ariceta, Principal Investigator at Val d'Hebron hospital, Barcelona, Spain, and highest recruiter of patients in the ePHex study. Six out of 8 enrolled patients at her study site were randomized to Oxabact during the study. "Even if I am disappointed that the study did not meet significance, I think it is important to look at individual patients in such a rare disease and to see if treatment effects can be seen. The safety profile of Oxabact, as well as oral administration, would make it a good background treatment candidate for patients." The study results have been accepted for oral presentation at the upcoming European Society of Pediatric Nephrology meeting, 16-19. September 2021, Amsterdam, and will be presented by Dr. Ariceta on Saturday, 18. September, in Session 16 (Hall 2) between 16:45 - 18:30. For further information, please contact: Elisabeth Lindner, COO E-mail: Elisabeth.lindner@oxthera.com About Oxabact® Oxabact is a bi-modal enteric biotherapy containing a lyophilized formulation of Oxalobacter formigenes, a non-pathogenic, oxalate-degrading commensal bacterium. Oxabact is administered orally as a coated capsule. By promoting active and passive secretion of oxalate from the plasma into the gut, Oxabact is able to increase excretion of oxalate. Oxabact is a registered trademark of OxThera Intellectual Property AB. About OxThera OxThera AB is a Swedish biopharmaceutical company developing a new treatment for primary hyperoxaluria (PH) - a rare genetic and devastating disease with fatal outcomes. This information was brought to you by Cision The following files are available for download: View original content: SOURCE OxThera