Leriglitazone

来瑞格列酮（MIN-102，Leriglitazone，Nezglyal）是Minoryx开发的一款可穿透血脑屏障的PPAR-γ激动剂。早在2020年9月，曙方医药与Minoryx Therapeutics已经达成中国地区的独家授权协议。很可惜，今年6月EMA拒绝了Nezglyal（leriglitazone）用于治疗肾上腺脑白质营养不良 (ALD)的上市许可。参考公开的审评报告MIN-102被拒绝的原因很多，其中最关键的因素是主要终点阴性，见表1 表1  Change From Baseline to Week 96 in Total Distance Walked in 6 Minutes (Meters) 可以看到MIN-102治疗后主要终点指标（6分钟步行试验）的恶化程度竟超过安慰剂组（-33.022 vs -31.840）。阴性结果不做过多分析，今天要介绍的是Minoryx采用的一种全新剂量选择方案——暴露驱动的个体化给药设计（exposure-guided dosing），即每位受试者根据血药浓度（目标AUC 200 µg·hr/mL，允许±20%浮动）调整剂量。具体实施过程由一个开放的PK专家委员会根据V1（第4周）和V2（第12周）的血药浓度数据进行剂量调整，以维持目标暴露量。初始剂量 10 mL QD，4周后根据血药浓度调整至12 mL，为保持盲态安慰剂组患者也会进行随机的“剂量调整”。 至于为什么是200µg·hr/mL，看看Minoryx是怎么说的，目标值AUCτ=200μg·hr/mL基于临床前药效学和毒理学数据确定，当药物AUC达到该水平能够产生预期的药理效应（如激活PPARγ受体，升高脂联素水平）。同时，I期多剂量递增（MAD）研究数据中发现，谷浓度（Cmin）与 AUCτ之间存在线性相关，AUCτ 是衡量药物在体内总暴露量的黄金标准，但需要密集采血来计算，而Cmin只需在给药前采一次血即可获得，通过线性回归得到了 Cmin和 AUCτ 的“最佳拟合”方程。根据这个方程，要达到暴露量 AUCτ (200 μg·hr/mL)所需要的目标 Cmin是 5716 ng/mL。从结果也能看到，整个研究期间Cmin基本能维持在目标值（图1），达到了研究的预期目的。 Dose reduced组：给予PK专家委员会推荐剂量（±10%） Dose as recommended组：给予PK专家委员会推荐剂量的10%～50% 图1    Mean (SD) Cmin for MIN-102 by Visit Number/Week 这是一种全新的剂量确定方案，以患者稳态暴露量为目标，目前只在肿瘤药物早期临床研究有探索性使用[1]，在关键临床开展尚属首例，构思之精妙、设计之大胆令小驿拜服，采用这种方案的原因其实也不复杂： 1. 个体间差异：传统临床试验通常使用固定剂量或基于体重/体表面积的换算剂量，受年龄、体重、遗传、肝肾功能、饮食习惯等多种因素影响，不同人对同一种药物吸收、分布、代谢和排泄速度可能不同，导致个体间的血药浓度（暴露量）差异巨大。确保每位患者都能达到有效的药物暴露水平，可减少因个体代谢差异导致的疗效偏倚。 2. 稳态血药浓度的意义：有研究认为[2]，神经系统药物研发失败率高的原因就是无法维持有效的血药浓度，所有患者血药暴露量都调整到目标水平，能极大地减少了“无效暴露”的数量。这对于罕见病尤为重要，因为招募每一个患者都非常不易，必须最大化从每个患者身上获得有价值数据的可能性。 3.增强安全性：PPARγ激动剂（如吡格列酮）有已知的安全风险，如液体潴留、心力衰竭等通常与剂量相关。将患者的暴露量控制在一个既有效又相对安全的窗口内，可以避免少数代谢慢的患者出现意外的高暴露和高毒性。如果某个患者出现不耐受，可以在个体水平上降低剂量，而不是停止整个研究。 可惜，天不遂人愿，MIN-102第一个关键临床没能达到预期目标。这里重点介绍EMA对剂量探索部分的意见：没有独立的剂量探索（dose-finding）研究——既缺乏基于暴露-反应（PK/PD）确定最优暴露，也缺乏更低/更安全剂量仍有有效性的证据；在试验中相当比例患者需要降剂量或停药，提示目前拟定剂量可能偏高且难以耐受。其中小驿个人觉得目标AUC的证据来源是最大的败笔，AUC目标设定完全依赖动物实验，未早期建立稳健PK/PD模型。若能开设独立的II期探索研究，建立清晰的暴露—反应（疗效与毒性）曲线以确定目标AUC，或许就不是今天的结果。 这种个体化血药浓度控制策略是一种更准确、更灵活的方法，它不是在探索一个固定的剂量，而是假设患者的血药浓度达到某个水平就能看到效果。即使目前的结果是失败的，也不妨碍其成为一次创举，虽败犹荣。 ▲本文图表源自公开的信息和文件，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 参考文献 [1] Niels Rode Kristensen, Henrik Agersø. Dose/exposure-response modeling in dose titration trials: Overcoming the titration paradox. CPT Pharmacometrics Syst Pharmacol, 2022, 11(12): 1592-1603. [2] Dario Doller , Kevin J. Hodgetts , János Fischer.  Trends in CNS Drug Discovery. ISBN: 978-3-527-35280-7

BARCELONA, Spain and DÜSSELDORF, Germany I July 23, 2025 I Minoryx Therapeutics,  a late-stage biotech company focused on the development of therapies for orphan central nervous system (CNS) disorders and Neuraxpharm Group (Neuraxpharm), a leading European specialty pharmaceutical company focused on the treatment of CNS disorders, today announce that the Marketing Authorization Application (MAA) for Minoryx’s lead candidate leriglitazone (NEZGLYAL®) has been submitted to the European Medicines Agency (EMA) for the treatment of paediatric and adult male patients with cerebral adrenoleukodystrophy (cALD). EMA has now validated the MAA file and it is under review by the Committee for Medicinal Products for Human Use (CHMP). This new MAA is based on recent data from the successfully concluded NEXUS study, a 96-week, pivotal, open-label study designed to evaluate the efficacy and safety of once-daily oral dosing of leriglitazone in paediatric patients with cALD. The study met the primary endpoint and all 20 evaluable patients remained clinically stable whilst on treatment and 7 out of 20 evaluable patients (35%) met the arrested disease criteria, which is significantly greater than the 10% self-arrest rate that would be expected from natural history (p<0.05). Leriglitazone was well tolerated with no discontinuations due to adverse events. The submission is further supported by data from the previously concluded ADVANCE study, a 116 patient, double-blind, placebo-controlled study conducted in Europe and the United States in which leriglitazone reduced  the incidence and progression of cerebral lesions in adults. Furthermore, data from the ongoing extensive compassionate use program in adult and paediatric patients with cALD have also been submitted. Leriglitazone was generally well tolerated in the ADVANCE study and compassionate use programme. “We believe the new and positive data from Nexus provide compelling evidence for the efficacy of leriglitazone giving hope to patients and their families that a new treatment will be available in the near future,” said Marc Martinell, CEO, Minoryx . “Leriglitazone, if approved, would be the only pharmacological treatment for patients suffering from this devastating orphan disease with a major unmet medical need.” “We are very pleased that the clinical development programme and compassionate use data have shown the efficacy of leriglitazone across all age ranges” , said Arun Mistry, Chief Medical Officer, Minoryx. “We will continue to work closely with the EMA through the evaluation process to maximize the chance for this therapy to reach all patients in desperate need.” Dr. Jörg-Thomas Dierks, CEO, Neuraxpharm said: “The EMA’s validation of the leriglitazone MAA submission is a key step forward as we look to bring this much needed treatment to patients. Given the terrible impact of this devastating disease and the lack of effective options, we remain hopeful of a positive outcome from the CHMP.” The development of leriglitazone continues with the ongoing CALYX trial in adult patients with cALD and the TREE study in paediatric Rett patients. Both studies are open to recruitment. About leriglitazone (NEZGLYAL®) Leriglitazone is Minoryx Therapeutics’ novel orally bioavailable, selective PPAR gamma agonist with a potential first-in-class and best-in-class profile for CNS diseases. It has demonstrated brain penetration and a favourable safety profile. It showed robust preclinical proof-of-concept in animal models of multiple diseases by modulating pathways leading to neuroinflammation, demyelination, mitochondrial dysfunction, oxidative stress, and axonal degeneration. In clinical trials, leriglitazone showed clinical benefit in both paediatric X-ALD patients in NEXUS and adult X-ALD patients in ADVANCE. Results from NEXUS demonstrate that paediatric cALD patients are clinically and radiologically stable after over 96 weeks of treatment or at a visit prior to haematopoietic stem cell transplantation (HSCT). Data from ADVANCE showed that leriglitazone stabilises lesion growth and reduces the incidence of progressive cALD therefore delaying or preventing life threatening progression of the disease in adult patients. Another clinical trial in adult male patients with progressive cALD (CALYX2) is currently recruiting in the US, Argentina, Brazil, Europe and India. Leriglitazone has been granted orphan drug status for X-ALD from the FDA and the EMA and Fast Track and Rare Pediatric Disease designation from the FDA for the treatment of X-ALD. About NEXUS NEXUS is a 96-week, pivotal, open-label, multicentre study (NEXUS; NCT04528706) of once-daily oral leriglitazone in paediatric patients with cALD. NEXUS enrolled 23 patients and the evaluable population consisted of those patients treated for a minimum of 24 weeks (n=20). The primary endpoint assessed the proportion of evaluable patients that had clinically and radiologically arrested disease at week 96 or at a visit prior to HSCT (success criteria: one-sided 95% [CI] > 10%). Secondary endpoints included change from baseline in NFS and Loes score (LS). Change from baseline in lesion volume and plasma biomarker concentrations are exploratory endpoints. About X-ALD and cALD X-linked adrenoleukodystrophy (X-ALD) is an orphan neurodegenerative disease. The global incidence of X-ALD is approximately 6-8/100,000 live births. Boys and adult men with X-ALD can, at any point in their lifetime, develop cALD, which is characterised by demyelinating brain lesions that may become rapidly progressive, leading to acute neurological decline and death. These lesions can produce severe symptoms such as loss of voluntary movements, inability to swallow, loss of communication, cortical blindness and total incontinence and death with a mean survival of three to four years. Progressive cALD occurs in 31-35% of ALD patients in childhood with typical onset between the age of 2-12 and up to 60% of adult patients with X-ALD will develop progressive cALD over time. There is currently no pharmacological treatment available for cALD. In childhood, HSCT can arrest the disease. However, it is an aggressive procedure and is only available for a portion of patients. Gene therapy based HSCT is not globally available, and it requires myeloablative chemotherapy with associated comorbidities. In adults, experience with HSCT is very limited and this intervention is often not recommended. In addition, all X-ALD patients reaching adulthood develop adrenomyeloneuropathy (AMN). This form progresses chronically and cALD patients with advanced AMN are largely ineligible to HSCT due to the poor prognosis of the treatment. About TREE TREE2 is a 36-week, phase 2a, randomised 1:1, placebo-controlled study of once-daily oral leriglitazone in female paediatric patients aged 5-12 with Rett syndrome conducted at Hospital Sant Joan de Déu, Barcelona, Spain. The study will enroll 24 patients that will undergo 36 weeks of treatment and 4 weeks of follow-up. The primary endpoint is safety. In addition, the study assesses a number of secondary and exploratory endpoints including the Rett Syndrome Behaviour Questionnaire (RSBQ), the Vineland Adaptive Behaviour Scale (VABS), and the Rett Syndrome Motor Evaluation Scale (RESMES) including various biomarkers. About Rett Syndrome Rett syndrome is a rare genetic neurological and developmental disorder that primarily affects females. It is almost exclusively caused by a de-novo genetic mutation in the MECP2 gene on the X-chromosome. The disorder causes a progressive loss of motor skills and language. Babies born with Rett syndrome initially seem to develop as expected, however they subsequently lose the skills they previously had such as the ability to crawl, walk, communicate and use of their hands. Over time, these children experience increasing problems with the use of muscles that control movement, coordination and communication. Most patients also experience seizures and have intellectual disabilities. Rett syndrome affects about 1 in 10-20.000 females and natural history suggest that many patients live into middle age. About Minoryx Minoryx Therapeutics is a registration stage biotech company focusing on the development of novel therapies for orphan central nervous system (CNS) diseases with high unmet medical needs. The company’s lead programme, leriglitazone (MIN-102), a novel, brain penetrant and selective PPAR gamma agonist, is being developed to treat X-linked adrenoleukodystrophy (X-ALD) and other orphan CNS diseases. The company is backed by a syndicate of experienced investors, which includes Columbus Venture Partners, CDTI Innvierte, Criteria BioVentures, Fund+, Ysios Capital, Roche Venture Fund, Kurma Partners, Chiesi Ventures, S.R.I.W, Idinvest Partners / Eurazeo, SFPI-FPIM, HealthEquity, Sambrinvest and Herrecha, and has support from a network of other organisations. Minoryx was founded in 2011, is headquartered in Spain with Belgian facilities and has so far raised more than €120 million. For more information, please visit https://www.minoryx.com/ . About the Neuraxpharm Group Neuraxpharm is a leading European specialty pharmaceutical company focused on the treatment of the central nervous system (CNS), including both psychiatric and neurological disorders. It has a unique understanding of the CNS market built over 40 years. Neuraxpharm is constantly innovating, with new products and solutions to address unmet patient needs and is expanding its portfolio through its pipeline, partnerships and acquisitions. The company has c. 1,000 employees and develops and commercialices CNS products through a direct presence in more than 20 countries in Europe, two in Latin America, one in the Middle East, one in Australia and globally via partners in more than 50 countries. Neuraxpharm is backed by funds advised by Permira. Neuraxpharm manufactures many of its pharmaceutical products at Neuraxpharm Pharmaceuticals (formerly Laboratorios Lesvi) in Spain. For more information, please visit www.neuraxpharm.com Neuraxpharm, has licensed the rights to leriglitazone in Europe and Sperogenix has licensed the rights to China. 1 ADVANCE, a pivotal phase 2/3 randomised, double-blind, placebo-controlled, clinical study with an open-label extension, was designed to assess the efficacy and safety of leriglitazone in male patients with X-ALD. 2 CALYX, a phase 3, multicentre, randomised (1:1), double-blind, placebo-controlled, clinical study, has been designed to compare the efficacy and safety of leriglitazone in male adult patients with progressive cALD ( https://clinicaltrials.gov/study/NCT05819866) . SOURCE: Minoryx