PDE10A

Phase 2b study will evaluate the safety and efficacy of gemlapodect (NOE-105) in patients with Tourette syndromeBASEL, Switzerland, Oct. 30, 2024 (GLOBE NEWSWIRE) -- Noema Pharma AG, a clinical-stage neuroscience-based company, today announced the first patients have been dosed in a global Phase 2b study evaluating the safety and efficacy of gemlapodect (NOE-105) in Tourette syndrome. NOE-TTS-201 (NCT06315751) is a Phase 2b, 12-week, randomized, double-blind, placebo-controlled study that is designed to examine the safety and efficacy of gemlapodect. The trial will enroll 140 patients with Tourette syndrome in multiple centers in the US and Europe. Patients will be treated with up to 15 mg of gemlapodect once daily, or a matching placebo. The primary endpoint is the Yale Global Tic Severity Scale (YGTSS) Total Tic Score. “Patients with Tourette syndrome carry an incredible burden related to the expression of motor and vocal tics with limited treatment options,” said Ilise Lombardo, M.D., Chief Executive Officer of Noema Pharma. “I am happy to announce the progression of the development of gemlapodect in Tourette syndrome with the dosing of the first patients in our Phase 2b trial.” About Tourette Syndrome Tourette syndrome is a neurodevelopmental disorder in the wider spectrum of tic disorders, consisting of motor and vocal abrupt and brief movement or sound which is preceded by a local or generalized urge/premonitory sensation. TS impacts over a half-million individuals and families in the US alone, as well as millions of individuals worldwide. About NOE-105/gemlapodect NOE-105/gemlapodect is a potential first-in-class phosphodiesterase-10A (PDE10A) inhibitor in mid-stage clinical development as a dopamine modulator for Tourette syndrome. NOE-105 has been well-tolerated in studies with healthy volunteers and in patients with Tourette syndrome. NOE-105 has the potential to achieve a more targeted effect by modulating dopamine signaling exclusively in the medium spiny neurons of the striatum in the brain, while limiting off-target effects compared to other dopamine antagonists. About Noema Pharma Noema Pharma is a clinical-stage biotech company advancing a portfolio of transformative therapeutics utilizing first-in-disease approaches targeting neuroscience-based conditions with high unmet need. Noema has four programs currently in active Phase 2 clinical trials evaluating pain in Trigeminal Neuralgia, seizures in Tuberous Sclerosis Complex, Tourette syndrome and vasomotor symptoms plus associated symptoms of menopause with readouts expected in 2025. Noema was founded by leading venture capital firm Sofinnova Partners and is supported by current investors including Forbion, Gilde Healthcare, Invus, Jeito Capital, Polaris Partners and UPMC Enterprises. Learn more at www.noemapharma.com. Investor Contact: Precision AQAlex Lobo212-698-8802alex.lobo@precisionaq.com

百时美施贵宝的精神分裂症新药Cobenfy（xanomeline/trospium，即KarXT）于今年9月底顺利获得FDA批准，是几十年来精神分裂症领域首个新型作用机制的药物（M1/M4毒蕈碱激动剂）。 就在获得批准前夕，杰富瑞(Jefferies)分析师预测，Cobenfy仅精神分裂症适应症的年销售额最高将达到35亿美元，所有适应症的销售额将达到62亿美元。高盛分析师预测，到2035年，Cobenfy精神分裂症销售额将达到37亿美元。 Cobenfy作为其他精神分裂症药物的辅助药物正在进行Ⅲ期试验，预计将于2025年获得结果；治疗阿尔茨海默病精神病Ⅲ期试验预计将于2026年获得数据。百时美施贵宝还计划启动Cobenfy治疗双相情感障碍、阿尔茨海默病相关躁动和阿尔茨海默病的试验。Cobenfy已计划于2025年启动与自闭症相关的认知障碍研究项目，并计划于2025年底或2026年初启动另一个针对与自闭症相关烦躁的研究项目。 尽管精神分裂症市场有超过20种抗精神病药物可供患者选择，似乎已经非常饱和，但是患者对现有治疗药物非常不满意，主要原因是这些抗精神病药物只对大约30%的患者有效。 与传统针对多巴胺2（D2）受体的非典型抗精神病药物相比，Cobenfy具有差异化的疗效、安全性和耐受性，有望成为该治疗领域游戏规则的改变者。 延伸阅读：70年来精神分裂症First in Class新药KarXT将于9月下旬获FDA批准 与此同时，在精神分裂症新药研发管线中，除了传统抗精神病药物外，Cobenfy还面临着同类机制的追赶者、新机制的突破者以及505(b)(2)挑战者。 追赶者：直接数据PK NBI-1117568 就在今年8月底，Neurocrine公司公布了其开发的口服选择性M4毒蕈碱激动剂NBI-1117568Ⅱ期临床试验结果：尽管该药物可改善精神分裂症的症状，但只有在最低剂量达到主要终点。即每日一次 20 mg 剂量治疗第 6 周时阳性和阴性症状量表 (PANSS) 总分较基线有临床意义和统计学显着降低，安慰剂调整后平均降低 7.5 分；在此剂量水平下，疾病的严重程度也得到了改善。所有其他剂量组（30mg、40mg和60mg）均未达到试验的主要终点。 该公司股价在结果公布后下跌了20%，部分原因是其PANSS评分低于竞争对手。 Cobenfy在3项关键的Ⅲ期临床试验（EMERGENT-1、2、3）主要终点方面，EMERGENT-3中治疗第五周PANSS总分降低了8.4分，略低于EMERGENT-2中的9.6分和EMERGENT-1的11.6分。 Neurocrine仍旧计划于2025年初把NBI-1117568推进到Ⅲ期临床试验，未来试验数据有待于进一步观察。 不过，该公司还具有丰富的毒蕈碱激动剂组合：M1激动剂NBI-1117567、M4激动剂NBI-1117569和M1/M4双重激动剂NBI-1117570都正在进行Ⅰ期临床试验。Neurocrine在未来有充足的选择机会。 Emraclidine 艾伯维于2023年12月以87亿美元收购Cerevel，从而获得了M4毒蕈碱激动剂Emraclidine，目前处于II期EMPOWER - 2研究开发阶段。不过该研究因为比一般的II期试验规模大得多（招募372例患者），因此被认为具有可用于上市申请潜力。 根据2022年发表于《柳叶刀》杂志上的Ⅰb期试验结果，Emraclidine对精神分裂症成年人治疗六周后PANSS总分出现了具有临床意义和统计学意义的改善。 突破者：多种机制齐出击 ALTO-101 Alto Neuroscience正在开发的新型磷酸二酯酶4(PDE4)酶抑制剂ALTO-101来治疗精神分裂症认知症状。 PDE4抑制剂已获批上市用于治疗慢性阻塞性肺病（COPD ）和银屑病。有趣的是，PDE4酶在大脑中高表达，被认为是治疗神经系统疾病的潜在靶点。 Alto于2024年6月启动了ALTO-101的II期研究，计划招募约70名年龄在21至55岁精神分裂症和明显认知障碍的患者。预计2025年下半年将获得主要数据。 在I期研究中，该候选药物对认知和与认知功能相关的脑电图(EEG)测量结果表现出积极作用。该公司报告称，ALTO-101透皮制剂比口服制剂具有更大的全身药物暴露量。透皮ALTO-101将在Ⅱ期试验中进行测试。 MK-8189 PDE10A是一种主要存在于纹状体多巴胺能神经元中的磷酸二酯酶，可终止多巴胺与D1和D2受体结合所诱导的细胞内信号，因此，被认为是治疗精神分裂症的潜在靶点。 默沙东也在开发的治疗精神分裂症的强效选择性PDE10A抑制剂MK-8189。MK-8189在随机概念验证临床试验的初步结果表明：与安慰剂相比，MK-8189在治疗4周后患者PANSS总分相对于基线的变化呈改善趋势。目前正处于Ⅱb期临床开发阶段。 延伸阅读：辉瑞、武田、灵北“三连败”后：默沙东MK-8189初步看到更广泛潜力 Iclepertin 勃林格殷格翰正在开发一种甘氨酸转运蛋白1(GlyT1)抑制剂iclepertin，用于治疗与精神分裂症相关的认知症状。GlyT1被认为在调节抑制性和兴奋性神经传递方面发挥重要作用。 Ⅱ期临床试验结果显示，与安慰剂相比，Iclepertin 2-25 mg剂量组患者的认知功能均较基线改善，其中10 mg和25 mg组患者的认知功能改善幅度最大。所有剂量的Iclepertin总体安全性及耐受性都是良好的。 iclepertin目前正在进行三项大型随机对照Ⅲ期临床试验研究，预计将于2025年公布结果。 505(b)(2)挑战者：最直接威胁 不过，对于百时美施贵宝，Cobenfy最为直接的挑战者可能是Terran Biosciences。 由于Cobenfy两种活性成分xanomeline和trospium都属于“老药”，化合物已失去专利保护。 Terran Biosciences公司正在通过开发xanomeline和trospium前药的组合，有望在未来挑战百时美施贵宝。 为了成功克服xanomeline和trospium的药代动力学局限性，Terran组建了一支由全球药物化学专家组成的团队，设计了10000多种新型前药。Terran的PK建模团队针对各种不同的配方设计和释放曲线开发了xanomeline和trospium的预测模型，以确定最佳药代动力学参数和比例。Terran利用200名化学家组成的团队合成了500多种前药，然后进行了临床前测试，包括285项体外研究和365项体内研究。 Terran目前正在开发Cobenfy的两种前药版本，一种是每日一次的口服候选药物TerXT，另一种是数月注射剂TerXT LAI。长效注射剂可以大大改善精神分裂症患者服药依从性问题。   Terran已通过505(b)(2)审批途径将TerXT提交给FDA申请，目前正在接受FDA审查。 Terran正计划分别针对两个版本启动两项I期试验，以确认安全性和药代动力学。不过，该公司仍需要等待百时美施贵宝的五年市场独占期结束，才能将其产品推向市场。新的制药化学实体从FDA批准开始，将获得五年的市场独占期，以防止仿制药竞争。 当药物的原始成分专利到期时，制药公司可以开发药物前体版本，以绕过原始药物配方或组合的任何其他专利。开发药物前体会创造一种新的可获得专利授权保护的分子，使公司能够重新获得该药物前体的20年专利保护。只要原始成分专利到期，药物前体就可以获得批准和上市，而不会受到原始药物配方其他专利的阻碍。 今年5月20日，Terran称已收到美国专利商标局 (USPTO) 专利权利要求保护全球首款xanomeline前药的物质成分专利申请通知。 备注：本文同时刊载于《医药经济报》，有删改。 本文由「新药前沿」微信公众号根据公开资料整理编辑，欢迎个人转发至朋友圈。媒体或机构转载授权请在「新药前沿」微信公众号留言公众号名称，审核通过后开通白名单获取转载授权，转载请标识来源。 免责声明：本文仅作信息交流之目的，非投资建议或者治疗方案推荐，「新药前沿」微信公众号不对任何主体因使用本文内容而导致的任何损失承担责任。 限于作者水平和专业知识所限，如有谬误，欢迎指正！

– Topline results from Phase 2a study – Nearly 60% of all patients treated with gemlapodect and 88% of patients completing the study at the target clinical dose range were responders based on the primary efficacy assessment The Yale Global Tics Severity Scale Total Tic Score (YGTSS-TTS) showed a statistically significant improvement of -7.8 points for all patients, and -12.8 points for patients completing the study at the target clinical dose No weight gain, events of metabolic marker increase, or serious adverse events were reported BASEL, Switzerland, Oct. 17, 2024 (GLOBE NEWSWIRE) -- Noema Pharma AG, a clinical-stage neuroscience-based company, today announced the Phase 2a ALLEVIA-1 study with NOE-105 (gemlapodect) in patients with Tourette syndrome (TS) met its primary and all key secondary endpoints. Gemlapodect is a novel and first-in-class PDE10A inhibitor currently being studied to assess its potential to reduce vocal and motor tics in people with TS with an improved tolerability profile over current treatment options. The Phase 2a study, ALLEVIA-1 (NOE-TTS-211), was a multicenter, 12-week, open-label, single-arm monotherapy study which enrolled a total of 15 patients with TS with a mean age of 26.2 (+/- 8.7) years. Patients were treated with ascending doses of gemlapodect ranging from 2.5 to 15 mg once daily, with a target dose range of 10 to 15 mg per day. The ALLEVIA-1 study achieved its primary and secondary objectives. Key findings included: 57% of patients showed tic improvement compared to baseline, with the remaining patients having no change and no patients worsening on the independently adjudicated TS Clinical Global Impression of Change (TS-CGI-C; primary endpoint) (n=14 patients taking at least one dose of study medication and having at least one post-baseline efficacy assessment).For patients who completed the study within the target clinical dose range, 87.5% showed improvement and 75% were rated as much or very much improved on the TS-CGI-C (n=8).YGTSS Total Tic Score showed a mean improvement of -7.8 points (p=0.009) from baseline to endpoint for all patients taking at least one dose and having at least one post-baseline assessment.YGTSS Total Tic Score showed a mean improvement of -12.8 points (p=0.003) from baseline to endpoint for all patients completing the study within the target clinical dose range.Adverse events were consistent with the known profile of gemlapodect, and no serious adverse events were reported during the trial.No weight gain and no clinically significant changes in laboratories (including metabolic measures such as blood glucose or lipids) were reported. “Based on these promising data, we believe gemlapodect has the potential to offer a meaningful advancement in the treatment of Tourette syndrome,” said Ilise Lombardo M.D., CEO of Noema Pharma. “I would like to thank the investigators and patients for their important contributions to the ALLEVIA-1 study.” “Tourette syndrome is a devastating disease that impacts patients and their families. Recurrent and severe tics interfere with the patient’s ability to learn, work and interact with others.” said Prof. Kirsten Mueller-Vahl, Principal Investigator, MHH, Hannover, Germany. “Current treatments, essentially antipsychotics, are associated with side effects such as significant weight gain and insulin resistance, as well as stigma. Our findings with gemlapodect are very encouraging, given that the need for new treatments and novel mechanisms in Tourette syndrome remains notably high.” Initial study data were presented at the MDS 2024 Congress, September 28, 2024. About Noema Pharma Noema Pharma is a clinical-stage biotech company advancing a portfolio of transformative therapeutics utilizing first-in-disease approaches targeting neuroscience-based conditions with high unmet need. Noema has four programs currently in active Phase 2 clinical trials evaluating pain in Trigeminal Neuralgia, seizures in Tuberous Sclerosis Complex, Tourette syndrome and vasomotor symptoms plus associated symptoms of menopause with readouts expected in 2025. Noema was founded by leading venture capital firm Sofinnova Partners and is supported by current investors including Forbion, Gilde Healthcare, Invus, Jeito Capital, Polaris Partners and UPMC Enterprises. Learn more at www.noemapharma.com. About NOE-105/gemlapodect NOE-105/gemlapodect is a potential first-in-class phosphodiesterase-10A (PDE10A) inhibitor in mid-stage clinical development as a dopamine modulator for Tourette syndrome. NOE-105 has been well-tolerated in studies with healthy volunteers and in patients with Tourette syndrome with no evidence of metabolic side effects including weight gain, hyperlipidemia and type 2 diabetes. NOE-105 has the potential to achieve a more targeted effect by modulating dopamine signaling exclusively in the medium spiny neurons of the striatum in the brain, while limiting off-target effects compared to other dopamine antagonists. About Tourette Syndrome Tourette syndrome is a neurodevelopmental disorder in the wider spectrum of tic disorders, consisting of motor and vocal abrupt and brief movement or sound which is preceded by a local or generalized urge/premonitory sensation. TS impacts over a half-million individuals and families in the US alone, as well as millions of individuals worldwide. Investors Contact and Media Contact Precision AQAlex Lobo212-698-8802alex.lobo@precisionaq.com