A Phase 3, Randomized, Double-Blind, Placebo-controlled, Efficacy and Safety Study of Pitolisant Followed by an Open-Label Extension in Patients With Prader-Willi Syndrome

This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, global clinical study to assess the efficacy and safety of pitolisant in patients living with Prader-Willi syndrome.
The primary objective of this study is to evaluate the efficacy of pitolisant in treating excessive daytime sleepiness (EDS) in patients ≥6 years of age with Prader-Willi syndrome.
Secondary objectives include assessing the impact of pitolisant on:
Irritable and disruptive behaviors
Hyperphagia
Other behavioral problems including social withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech

开始日期2024-04-30

申办/合作机构

Harmony Biosciences LLC

NCT05953389 / Not yet recruiting临床2期

An Exploratory, Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Effect and Safety of Pitolisant in Children and Adolescents With Autism Spectrum Disorders

Proof of concept, multicenter, randomized, double-blind, placebo-controlled, parallel-group, study to investigate the effect, safety, tolerability and pharmacokinetics of pitolisant in male children and adolescents with Autism Spectrum Disorders.

开始日期2023-10-01

申办/合作机构

Bioprojet Pharma SARL

DRKS00031339 / RecruitingN/A

Non-interventional Study with Ozawade® in patients with obstructive sleep apnea syndrome - Oz-leap

开始日期2023-08-18

申办/合作机构

Bioprojet Deutschland GmbH

100 项与盐酸替洛利生相关的临床结果

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100 项与盐酸替洛利生相关的转化医学

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100 项与盐酸替洛利生相关的专利（医药）

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306

项与盐酸替洛利生相关的文献（医药）

2024-02-01·Pharmacology research & perspectives

Is pitolisant safe for clinical use? A retrospective pharmacovigilance study focus on the post‐marketing safety

Article

作者: Qian, Jiancheng ; Jiang, Cheng ; Zhang, Shuohan ; Wang, Hongwei ; Jiang, Xin ; Zheng, Junxian

Abstract:

Pitolisant, a novel histamine H3‐receptor antagonist, holds significant promise for treating narcolepsy. However, a petition, which highlighted that pitolisant was associated with deaths during clinical trials, has propelled it into the spotlight of widespread societal attention on April 3, 2023. Till now, the clinical safety of pitolisant remains a heatedly debated topic. This study aimed to offer a comprehensive assessment of the safety profile of pitolisant in real‐world clinical settings. Adverse event reports where pitolisant was the primary suspect drug were extracted from the FDA Adverse Event Reporting System database. The clinical characteristics and concomitant drugs of the pitolisant‐associated adverse events were analyzed. The potential adverse event signals of pitolisant were explored using four disproportionality analysis methods. Furthermore, the difference in pitolisant‐associated adverse event signals was investigated concerning sex, age, weight, and dose. A total of 526 reports and 1695 adverse events with pitolisant as the primary suspected drug were identified. The most significant adverse event signals were generally mild and of short duration. The concomitant drugs of pitolisant were highly intricate, mainly included drugs for treating narcolepsy as well as antidepressants. Seven new significant adverse event signals emerged. The safety profile of pitolisant exhibited no significant differences across age and dose groups, although slight variations were observed in relation to sex and weight. The findings from reports of death and life‐threatening outcomes underscore the importance of enhanced monitoring for cardiac and respiratory adverse reactions when utilizing pitolisant. This study provided a broader understanding of the safety profile of pitolisant.

2024-02-01·Stem cells and development

Role of Histamine H₃ Receptor Antagonist Pitolisant in Early Neural Differentiation of Mouse Embryonic Stem Cells

Article

作者: Qi, Jiayu ; Liu, Nuoya ; Xu, Genghua ; Zhu, Danyan ; Qiu, Yaqing

The histamine H₃ receptor, prominently expressed in neurons with a minor presence in glial cells, acts as both an autoreceptor and an alloreceptor, controlling the release of histamine and other neurotransmitters. The receptor impacts various essential physiological processes. Our team's initial investigations had demonstrated that the histamine H₃ receptor antagonists could facilitate nerve regeneration by promoting the histamine H₁ receptors on primary neural stem cells (NSCs) in the traumatic brain injury mouse, which suggested the potential of histamine H₃ receptor as a promising target for treating neurological disorders and promoting nerve regeneration. Pitolisant (PITO) is the only histamine H₃ receptor antagonist approved by the Food and Drug Administration (FDA) for treating narcolepsy. However, there is no report on Pitolisant in neural development or regeneration, and it is urgent to be further studied in strong biological activity models in vitro. The embryonic stem (ES) cells were differentiated into neural cells in vitro, which replicated the neurodevelopmental processes that occur in vivo. It also provided an alternative model for studying neurodevelopmental processes and testing drugs for neurological conditions. Therefore, we aimed to elucidate the regulatory role of Pitolisant in the early differentiation of ES cells into neural cells. Our results demonstrated that Pitolisant could promote the differentiation of ES cells toward NSCs and stimulated the formation of growth cones. Furthermore, Pitolisant was capable of inducing the polarization of NSCs through the cAMP-LKB1-SAD/MARK2 pathway, but had no significant effect on later neuronal maturation. Pitolisant altered mitochondrial morphology and upregulated the levels of mitochondrion-related proteins TOM20, Drp1, and p-Drp1, and reversed the inhibitory effect of Mdivi-1 on mitochondrial fission during the early neural differentiation of ES cells. In addition, Pitolisant induced the increase in cytosolic Ca²⁺. Our study provided an experimental foundation for the potential application of histamine H₃ receptor-targeted modulators in the field of neuroregeneration.

2023-12-01·Sleep medicine

Pitolisant-supported bridging during drug holidays to deal with tolerance to modafinil in patients with narcolepsy

Article

作者: Groppa, Sergiu ; Winter, Yaroslav ; Fleischer, Vinzenz ; Kallweit, Ulf ; Lang, Christina ; Ellwardt, Erik ; Apel, David

STUDY OBJECTIVES:

Modafinil is a common treatment for excessive daytime sleepiness (EDS) in narcolepsy. The long-term use of modafinil can lead to tolerance with the loss of efficacy and the continuous increase of its dose. Pharmacological strategies to deal with the tolerance to modafinil are lacking. We investigated the efficacy and safety of pitolisant-supported bridging during drug holidays in patients with tolerance to modafinil.

METHODS:

Narcolepsy patients on monotherapy with modafinil who developed symptoms of tolerance were eligible. The following alternating therapy regimen was established: Monday to Friday patients continued on modafinil whereas Saturday and Sunday they switched to pitolisant to "bridge" the EDS symptoms. Patients were assessed at baseline and after three months with the Epworth Sleepiness Scale (ESS) and the Ullanlinna Narcolepsy Scale (UNS). Health-related quality of life (HrQol) was evaluated by EuroQol5D. Adverse events were documented in the patients' diaries.

RESULTS:

41 patients aged 30.9 ± 5.6 years were included. After three months of the alternating therapy regimen, the symptoms of tolerance decreased and the modafinil dose could be reduced by 41% (p < 0.01) resulting in better safety. The EDS improved on ESS (baseline: 18.2 ± 4.2, follow-up: 12.6 ± 4.0, p < 0.0001) and UNS (baseline: 25.8 ± 7.9, follow-up: 18.9 ± 5.9, p < 0.0001). The HrQol increased significantly.

CONCLUSION:

Patients with tolerance to modafinil could benefit from pitolisant-supported bridging during drug holidays. This alternating pharmacological strategy proved to be safe and helped to reduce EDS and to decrease the modafinil dose. Further randomized controlled studies are required to evaluate the different strategies to deal with the tolerance to modafinil.

CLINICAL TRIAL REGISTRATION NUMBER:

Clinical Trials.gov Identifier NCT05321355.

100

项与盐酸替洛利生相关的新闻（医药）

2024-06-17

·BioSpace

FDA Action Alert: Merck, BMS, Sarepta and More

Pictured: A scientist with pill bottles in front of FDA headquarters/Taylor Tieden for BioSpace With six target action dates lined up, the FDA has a very busy week ahead. The regulator is expected to release decisions on drug applications for a pneumococcal vaccine, a gene therapy for Duchenne muscular dystrophy and a label expansion for one of cancer’s cornerstone therapies. Read below for more. Merck Awaits Verdict on Pneumococcal Shot Merck is seeking approval for its investigational 21-valent vaccine, dubbed V116, to prevent invasive pneumococcal disease and pneumococcal pneumonia in adults. The FDA is expected to release its verdict on June 17. The pharma is backing its regulatory bid with data from the Phase III STRIDE-3 trial, which in November 2023 showed that V116 induced non-inferior immune responses as compared with a 20-valent comparator vaccine. Merck is also supporting V116’s application with several other studies, including STRIDE-3, STRIDE-4, STRIDE-5 and STRIDE-6. Data from additional studies will be shared at future medical meetings. If approved, Merck’s vaccine would become the first pneumococcal conjugate shot designed specifically for use in adults. Argenx Seeks Approval for Vyvgart Hytrulo in CIDP Argenx is proposing to use its antibody fragment Vyvgart Hytrulo (efgartigimod alfa and hyaluronidase-qvfc) to treat the rare autoimmune disease chronic inflammatory demyelinating polyneuropathy (CIDP). The FDA’s decision is due on June 21. The Netherlands-based biotech is supporting its supplemental Biologics License Application (sBLA) with data from the Phase II ADHERE study, which demonstrated a 61% reduction in the risk of relapse after treatment with Vyvgart Hytrulo versus placebo. In ADHERE’s open-label phase, 67% of patients showed evidence of clinical improvement. Vyvgart Hytrulo is a subcutaneous formulation of the human IgG1 antibody fragment efgartigimod alfa, combined with the recombinant human hyaluronidase PH20, which allows its subcutaneous administration. The drug was approved in June 2023 for the treatment of generalized myasthenia gravis. BMS Targets Krazati Expansion into CRC In February 2024, the FDA accepted Bristol Myers Squibb’s supplemental New Drug Application (sNDA) for its KRAS blocker Krazati (adagrasib), in combination with cetuximab, for the treatment of locally advanced or metastatic colorectal cancer (CRC). The deadline for the regulator’s decision is June 21. The application, which seeks to make Krazati a treatment option for CRC patients with KRAS G12C-mutated CRC, is supported by data from the KRYSTAL-1 study. BMS reported data from this trial in March 2024, touting a 34% objective response rate at a median follow-up of 11.9 months. Median progression-free survival was 6.9 months, while median overall survival reached 15.9 months. Krazati is an orally available small molecule inhibitor of G12C-mutated KRAS that won the FDA’s accelerated approval in December 2022. It was originally developed by Mirati Therapeutics, which BMS acquired in October 2023 for $4.8 billion. Harmony Aims for Wakix Expansion into Pediatric Narcolepsy Harmony Biosciences is proposing its oral drug Wakix (pitolisant) as a treatment for excessive daytime sleepiness in pediatric narcolepsy patients aged 6 years and above. The FDA’s deadline for a decision is June 21. In its sNDA, Harmony provided data from a Phase III multicenter, randomized and placebo-controlled study evaluating the efficacy and safety of Wakix in narcolepsy patients ages six through 17 with or without cataplexy. The FDA granted the application its priority review status. Wakix is an orally available histamine 3 receptor antagonist. It was approved by the FDA in August 2019 for the treatment of excessive daytime sleepiness of adult narcolepsy. Merck Targets Addition to Growing List of Keytruda Indications By June 21, the FDA is expected to release its verdict on Merck’s sBLA proposing to use its blockbuster PD-1 inhibitor Keytruda, in combination with standard of care chemotherapy, as a treatment for primary advanced or recurrent endometrial carcinoma. Merck is supporting its bid for the additional indication with results from the Phase III NRG-GY018 study, which found that the Keytruda-based investigational regimen cut the risk of disease progression or death by 46% in patients whose disease was mismatch repair proficient. Meanwhile, those with mismatch repair deficient disease saw a 70% reduction in the risk of progression or death versus chemotherapy alone. If approved, Keytruda would become the “first immunotherapy indicated for the frontline treatment of advanced endometrial cancer regardless of mismatch repair status,” Gursel Aktan, vice president of global clinical development at Merck Research Laboratories, said in a statement accompanying the sBLA’s acceptance in February 2024. Sarepta Seeks Full Approval for DMD Gene Therapy Despite Shaky Data In February 2024, the FDA accepted an efficacy supplement to Sarepta Therapeutics’ sBLA seeking to convert the accelerated approval of its gene therapy Elevidys (delandistrogene moxeparvovec-rokl) into traditional approval, as well as broaden its label to include all Duchenne muscular dystrophy (DMD) patients with confirmed DMD gene mutations. The FDA’s decision is due on June 21. Currently, Elevidys is only indicated for ambulatory pediatric patients aged 4 through 5 years of age. The FDA granted Elevidys accelerated approval in June 2023, a decision that has recently come under fire, particularly as the gene therapy failed its primary efficacy endpoint in part 1 of the SRP-9001-102 study, unable to significantly outdo placebo in terms of patients’ functional performance. Sarepta’s bid for full approval is supported by the Phase III EMBARK study, which in October 2023 also fell short of its primary endpoint. In patients treated with Elevidys, scores on the North Star Ambulatory Assessment tool at 52 weeks were only 0.65 points higher than placebo comparators, an effect that did not satisfy statistical significance. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

临床3期临床结果上市批准临床2期优先审批

2024-06-14

·药渡Daily

【药渡药闻报告-创新药篇】-2024年第21期/总第142期

全球药物批准/研发动态 01 全球新药批准情况根据药渡数据统计分析，本次统计周期（2024.05.25-05.31）全球（不含中国）共有7个新药获批上市。其中，NDA批准1个，BLA批准3个，新适应症批准1个，新剂型批准2个。与上个统计周期相比，本次增加2个批准新药。 5月29日，TEVA宣布，FDA已批准AUSTEDO XR作为每日一次的单粒治疗选择（现在有四种新的片剂规格：30、36、42、48毫克），适用于成人TD和HD舞蹈病。服用AUSTEDO XR的TD患者最早可以在两周内获得症状改善，而HD舞蹈症患者的TMC评分可能会显著降低。AUSTEDO XR及其每日两次的对应药物AUSTEDO（氘代丁苯那嗪）是唯一一种对CYP3A4/5诱导剂或抑制剂使用没有限制的VMAT2抑制剂治疗药物。同日，BMY宣布EC已批准奥迪沃®（纳武利尤单抗）联合顺铂和吉西他滨一线治疗不可切除或转移性尿路上皮癌（UC）成人患者。在CheckMate-901试验中，Opdivo与顺铂和吉西他滨的组合提高了总生存期，与单独化疗相比，疾病进展或死亡的风险降低了28%，并且与单独化疗相比，表现出深刻而持久的反应。全球（不含中国）新药批准情况（部分） 02 全球新药申报进展根据药渡数据统计分析，本次统计周期（2024.05.25-05.31）全球（不含中国）共有12个新药申报上市。其中，NDA申报进展4个，BLA申报进展6个，疫苗2个。与上次统计周期相比，本次增加9个NDA/BLA申报。 5月27日，Sanofi宣布Sarclisa接受FDA优先审评，用于治疗不符合移植条件的新诊断多发性骨髓瘤。Sarclisa是一种单克隆抗体，可与多发性骨髓瘤细胞上CD38受体的特定表位结合，诱导不同的抗肿瘤活性。如果获得批准，Sarclisa将成为第一个与标准护理VRd联合的抗CD38疗法。 NDA/BLA申报根据药渡数据统计分析，本次统计周期（2024.05.25-05.31）全球（不含中国）共有11个物获监管机构特殊资格认定。其中，化学药4个，生物药6，细胞疗法1个。与上次统计周期相比，本次增加3获监管机构特殊资格认定的药物。 5月29日，Alentis宣布FDA已授予Lixudebart（ALE.F02）用于治疗特发性肺纤维化（IPF）的孤儿药认定。Lixudebart是针对肝、肺和肾纤维化开发的首创单克隆抗体。该研究抗体旨在通过特异性靶向暴露于纤维化组织中的独特CLDN1表位来逆转器官纤维化。在I期研究中，Lixudebart耐受性良好。目前，Lixudebart正在临床试验中测试晚期肝纤维化（NCT05939947）和ANCA相关血管炎（NCT06047171）。 5月31日，万邦德制药宣布乙酰胆碱酯酶抑制剂（石杉碱甲）获得FDA授予的治疗新生儿缺氧缺血性脑病（HIE）的孤儿药资格认定。石杉碱甲具有抗炎、抗氧化应激与神经保护等作用，适用于良性记忆障碍，对痴呆患者和脑器质性病变引起的记忆障碍有改善作用，亦用于重症肌无力的治疗。万邦德制药是国内主要的石杉碱甲原料药供应商，同时有石杉碱甲注射液在售，并与中科院上海药物研究所共同开发石杉碱甲控释片，正在开展治疗阿尔茨海默病的患者临床研究。特殊资格认定情况（部分） 03 全球新药研发进展根据药渡数据统计分析，本次统计周期（2024.05.25-05.31）全球（不含中国）新药临床研发状态更新共计67条，涉及肿瘤、血液和淋巴疾病、遗传代谢病、精神疾病、神经疾病以及皮肤病等共计15个领域。其中，肿瘤临床进展更新居各领域之首，为26条：肿瘤领域涉及化学药9条，生物药14条，细胞疗法2条，疫苗1条。 5月28日，信达生物宣布重组抗白介素23p19亚基抗体注射液匹康奇拜单抗在中国中重度斑块状银屑病受试者中开展的III期临床研究中达成主要终点和所有关键次要终点。匹康奇拜单抗为重组抗白介素23p19亚基抗体注射液，是一种单克隆抗体，通过阻止IL-23与细胞表面受体结合，阻断IL-23受体介导信号通路发挥抗炎作用。 5月30日，药明巨诺在EULAR2024上公布了瑞基奥仑赛注射液（Relma-cel）在中国成人活动性系统性红斑狼疮患者中的最新临床数据。Relma-cel是靶向CD19的自体CAR-T细胞免疫治疗产品，参与试验的患者均呈现良好的安全性和耐受性，仅出现1例3级CRS，没有出现3级及以上神经毒性，仅2例患者出现3级感染，所有不良事件均能在经过相应治疗后恢复。全球新药研发进展详情（部分） 04 全球医药交易事件本次统计周期（2024.05.25-05.31）全球（含中国）医药交易时间共计53起，涉及药物权益转让、公司并购等多起交易事件。全球医药交易时间汇总表（部分）国内药物批准/研发动态 01 国内新药批准情况根据药渡数据统计分析，本次统计周期（2024.05.25-05.31）国内共有2个新药获NMPA批准上市。其中，新适应症批准2个。与上次统计周期相比，本次减少9个NMPA批准新药。 5月27日，博安生物宣布地舒单抗注射液（120mg）——博洛加®正式获得NMPA上市批准，用于治疗不可手术切除或者手术切除可能导致严重功能障碍的骨巨细胞瘤，包括成人和骨骼发育成熟（定义为至少1处成熟长骨且体重≥45kg）的青少年患者。同时，博洛加®用于实体肿瘤骨转移和多发性骨髓瘤适应症的上市申请工作也在推进中。此外，博安生物也在欧洲、美国、日本开展博洛加®的国际多中心III期临床试验。 5月28日，琅钰集团宣布NMPA正式批准盐酸替洛利生片（铧可思®）用于治疗发作性睡病（Narcolepsy）青少年和6岁及以上儿童患者的日间过度嗜睡（EDS）或猝倒。这是替洛利生在成人发作性睡病之外，在我国获批的第二个适应症。替洛利生是全球首个成药的选择性组胺3（H3）受体反向激动剂，无成瘾性，单药使用可改善发作性睡病的多个核心症状。替洛利生在EMA和FDA分别获得了孤儿药认定，并被FDA认定为突破性治疗药物。中国新药批准情况（部分） 02 国内新药临床默示许可进展根据药渡数据统计分析，本次统计周期（2024.05.25-05.31）国内共有17个新药获临床默示许可，涉及27个受理号。其中，化学药9个，治疗用生物制品7个，预防性生物用品1个。与上个统计周期相比，本次减少24个临床默示许可获批受理号。本周国内新药临床默示许可进展（部分） 03 国内新药申报进展根据药渡数据统计分析，本次统计周期（2024.05.25-05.31）国内共有1个新药申报上市，涉及4个受理号。其中，治疗用生物制品1个。与上个统计周期相比，本次减少4个新药申报上市受理号。国内新药申报上市情况根据药渡数据统计分析，本次统计周期（2024.05.25-05.31）国内共有35个新药申报临床，涉及53个受理号。其中，化学药16个，治疗用生物制品18个，预防用生物制品1个。与上个统计周期相比，本次增加12个临床申报受理号。国内新药临床申报情况（部分）。根据药渡数据统计分析，本次统计周期（2024.05.25-05.31）无国内药物获NMPA特殊资格认定。与上个统计周期相比，本次减少4个获监管机构特殊资格认定的药物。 04 国内新药研发进展根据药渡数据统计分析，本次统计周期（2024.05.25-05.31）国内新药临床研发状态更新共计10条，涉及肿瘤、血液和淋巴疾病共计2个领域。其中，化学药8个，生物药2个。 5月27日，先声再明在ASCO公布Endostar联合同步放化疗与单独同步放化疗治疗局部区域晚期鼻咽癌（LA-NPC）的一项III期实验数据。结果：2016年11月至2020年7月期间，随机分配了300例LA-NPC患者（CCRT+E组，150例；CCRT组，150例）。截至数据2023年12月，中位随访时间为66个月。意向性治疗分析显示，CCRT+E组患者在放疗后3个月获得更好的CR率（90.0% vs. 80.7%，P=0.022）。CCRT+E组的3年PFS为84.8%，CCRT组为75.1%，3年OS为89.2%vs. 85.3%，3年DMFS为89.7% vs. 80.5%，3年LRRFS为91.5% vs. 90.8%，CCRT+E组和CCRT组患者的3-4级急性和晚期毒性特征相似（61.7% vs. 65.3%）。结论：在标准CCRT中加入Endostar可显着改善具有良好安全性的LA-NPC患者的3年PFS。国内新药研发进展情况 05 国内新药研发领域政策法规动态国家药监局药审中心关于发布《在罕见疾病药物临床研发中应用去中心化临床试验的技术指导原则》的通告（2024年第25号）为深化“以患者为中心”的临床试验新理念，助力罕见疾病药物临床研发，在国家药品监督管理局的部署下，药审中心组织制定了《在罕见疾病药物临床研发中应用去中心化临床试验的技术指导原则》。根据《国家药监局综合司关于印发药品技术指导原则发布程序的通知》（药监综药管〔2020〕9号）要求，经国家药品监督管理局审查同意，现予发布，自发布之日起施行。 06 国内新药研发领域热点新闻 2024ASCO国产ADC药物临床新进展 2024ASCO年会上，国产ADC在各瘤种的临床进展再度收到广泛关注，本期我们来看看国产ADC药物的临床数据更新。科伦博泰芦康沙妥珠单抗（SKB264/MK-2870）用于既往接受过治疗的局部复发或转移性三阴性乳腺癌（TNBC）患者的III期研究（OptiTROP-Breast01）结果……更多资讯，请阅读原文赛诺菲调转船头近日，赛诺菲「艾沙妥昔单抗注射液」的2.2类上市申请获CDE受理。这是艾沙妥昔单抗在国内递交的第二项上市申请，2023年12月其在国内递交的首个上市申请获CDE受理。艾沙妥昔单抗（Isatuximab，Sarclisa）是一种IgG1嵌合单克隆抗体，靶向浆细胞CD38受体的特定表位，能够触发多种独特的作用机制，包括促进程序性肿瘤细胞死亡（凋亡）和免疫调节活性。目前，该药已在美国获批两项适应症：联合泊马度胺和地塞米松（pom-dex）治疗至少接受过2种治疗方案(包括来那度胺和一种蛋白酶抑制剂)的复发或难治性多发性骨髓瘤（R/R MM）成人患者（2020.03）；联合卡非佐米和地塞米松（Kd）治疗既往接受过1-3线治疗的R/R MM成人患者（2021.04）。更多资讯，请阅读原文第一三共ADC，未达到NSCLC试验的OS终点 2024年5月27日，阿斯利康和第一三共报告了其TROP-2 ADC Datopotamab deruxtecan（Dato-DXd），在晚期非鳞状非小细胞肺癌（NSCLC）患者中的III期研究TROPION-Lung01的OS进展。这项随机、全球、多中心、开放标签的III期临床试验，在既往接受过治疗的局部晚期/转移性NSCLC成人患者（无论可操作的基因组改变状态如何）中，评估Dato-DXd与多西他赛化疗的疗效和安全性。该项研究设立了双重主要终点，分别为PFS和OS。关键次要终点包括ORR、研究者评估的PFS、DOR、DCR和安全性。更多资讯，请阅读原文国内第五款三代EGFR抑制剂获批上市 5月20日，根据国家药监局官网公示，上海倍而达药业有限公司申报的1类创新药三代EGFR抑制剂甲磺酸瑞齐替尼胶囊（研发代码BPI-7711，商品名：瑞必达）获批上市，适应症为既往经表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）治疗时或治疗后出现疾病进展，并且经检测确认存在EGFR T790M突变阳性的局部晚期或转移性非小细胞肺癌（NSCLC）成人患者的治疗。从药渡数据库检索可知，瑞齐替尼是国内第五款获批上市的三代EGFR抑制剂，2021年3月9日，石药集团宣布，其全资附属公司石药（上海）有限公司已与上海倍而达药业订立产品授权及商业化协议，通过股权认购获得第三代EGFR-TKI（BPI-7711胶囊）独家产品授权及商业化权利。更多资讯，请阅读原文 III期成功，信达生物计划提交“匹康奇拜单抗”上市申请 2024年5月28日，信达生物宣布其自主研发的IL-23p19抗体注射液匹康奇拜单抗（IBI112），在中国中重度斑块状银屑病受试者中开展的III期临床研究（CLEAR-1）中，达到主要终点和所有关键次要终点。根据新闻稿，信达生物正在计划向监管机构递交匹康奇拜单抗的银屑病适应症的上市申请。 CLEAR-1研究，是一项多中心、随机、双盲、安慰剂对照的III期临床试验，共纳入了500例患有中重度斑块型银屑病的患者，评估匹康奇拜单抗的有效性和安全性。受试者按照1:2:2的比例随机接受安慰剂、匹康奇拜单抗200mg（0，4，8周3次给药）后，在20周开始接受200mg或者100mg每12周1次给药的长期维持。更多资讯，请阅读原文男人的“难言之隐”撑起了多大的市场随着社会压力内卷、环境恶化及生活节奏过快等变化，男人们的性健康问题开始浮现。然而，一项针对国内男性的调研显示，在出现问题后，会主动采取措施解决的人仅有20.9%。大多数男人在对待这一障碍时，首先采取的是回避的心理。这也可以理解，毕竟涉及到男人最重视的尊严问题，宁可默默承受，也不能公开承认自己不行。但随着男性的性健康问题日益凸显，相关治疗药物市场规模开始膨胀，正逐渐受到各大药企的关注。逐渐膨胀的市场男性的性健康问题主要包括勃起功能性障碍（ED）、早泄、慢性前列腺炎、前列腺增生……更多资讯，请阅读原文咨询、合作请联系作者小D有话说为方便读者阅读及保存，我们将周报原文整理成了PDF版本，如需获取全文，可点击最上方蓝字，在药渡Daily公众号后台回复“0613创新药周报”，即可下载。

上市批准孤儿药优先审批疫苗申请上市

2024-06-05

·BioSpace

HARMONY BIOSCIENCES PRESENTS POSITIVE DATA FOR PITOLISANT IN THE TREATMENT OF EXCESSIVE DAYTIME SLEEPINESS AND FATIGUE IN MYOTONIC DYSTROPHY TYPE 1

Phase 2 signal detection study presented at the annual meeting of the Associated Professional Sleep Societies, "SLEEP 2024" [05-June-2024] PLYMOUTH MEETING, Pa., June 5, 2024 /PRNewswire/ -- Harmony Biosciences (Nasdaq: HRMY) presented data from its Phase 2 signal detection study showing that pitolisant reduced excessive daytime sleepiness (EDS) and fatigue in adults with Myotonic dystrophy Type 1 (DM1). "More than 80 percent of DM1 patients experience EDS and fatigue, which patient-reported outcomes research has shown to be nearly as debilitating as the primary symptoms of DM1, namely myotonia and muscle weakness,"1 said Kumar Budur, M.D., M.S., Chief Medical and Scientific Officer of Harmony Biosciences. "The findings from our signal detection study evaluating pitolisant, which is believed to promote wakefulness through histamine, present an exciting opportunity to develop new treatments for EDS and fatigue in DM1, narcolepsy, and the other sleep/wake disorders we are investigating through our lifecycle management programs that will involve Next-Generation formulations of pitolisant." Notably, there was greater mean improvement from baseline to Week 11 in both EDS (as measured by the Daytime Sleepiness Scale) and fatigue (as measured by the Fatigue Severity Scale) compared to placebo. The overall disease burden also signaled greater improvement for pitolisant compared to placebo, with the higher dose pitolisant group showing a stronger efficacy signal. This study was designed for signal detection and was not powered to demonstrate statistical significance. Estimates suggest there are 40,000 people currently diagnosed with DM1 in the U.S. with up to 90% of them reporting EDS and fatigue. "Given the potential opportunity of pitolisant for treating EDS and fatigue in patients with DM1, we plan to progress our DM1 development program through a pivotal Phase 3 study using the Next-Generation 2 (NG2) formulation of pitolisant, which is designed to deliver an optimized pharmacokinetic pro higher dosage strength," Budur added. "The NG2 formulation could be promising given the positive findings we observed across the EDS and fatigue endpoints within the higher dose pitolisant treatment arm. These efforts are integral to our broader life cycle management programs, which, if successful, could benefit over 100,000 patients living with unmet medical needs." Poster 378: Primary Efficacy and Safety Results of a Phase 2, Double-Blind, Placebo-Controlled, Proof of Concept, Signal Detection Study of Pitolisant in Myotonic Dystrophy The Phase 2 signal detection study was a randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of pitolisant in the treatment of EDS and other non-muscular symptoms in adults with DM1. Eligible patients were confirmed to have DM1 and enrolled in an 11-week double-blind treatment phase that included a 3-week titration period and an 8-week stable dose period. Participants were randomized to receive higher or lower dose pitolisant, or a matching placebo. The primary efficacy endpoint was the change from baseline to Week 11 in Daytime Sleepiness Scale score. Additional efficacy endpoints included the change from baseline to Week 11 in Epworth Sleepiness Scale score, Fatigue Severity Scale score, Clinical Global Impression of Severity (for EDS) score, and Myotonic Dystrophy Health Index score. Results from the study include: Mean improvement on the Daytime Sleepiness Scale (primary endpoint) was greater for pitolisant. Compared with placebo, a dose-response relationship was observed from baseline to Week 11: Higher Dose Pitolisant (n=8): -2.5 Lower Dose Pitolisant (n=8): -1.0 Placebo (n=9): -0.2 Mean improvement on the other secondary efficacy endpoints (EDS, fatigue, disease burden) was also greater for pitolisant versus placebo, with higher dose pitolisant showing a stronger efficacy signal from baseline to Week 11. Epworth Sleepiness Scale: Higher Dose Pitolisant (n=8): -4.9 Lower Dose Pitolisant (n=9): 1.3 Placebo (n=10): -0.1 Fatigue Severity Scale: Higher Dose Pitolisant (n=8): -0.9 Lower Dose Pitolisant (n=9): -0.4 Placebo (n=10): -0.1 Clinical Global Impression of Severity (for EDS): Higher Dose Pitolisant (n=8): -0.9 Lower Dose Pitolisant (n=9): -0.2 Placebo (n=10): -0.1 Myotonic Dystrophy Health Index Higher Dose Pitolisant (n=8): -9.1 Lower Dose Pitolisant (n=9): -2.9 Placebo (n=10): 0.4 The rate of adverse events was similar for pitolisant and placebo. The safety and tolerability of pitolisant in patients with DM1 were consistent with its known safety profile. Pitolisant is marketed as WAKIX® in the U.S. and is FDA approved to treat EDS or cataplexy in adult patients with narcolepsy. Pitolisant is not approved for use in patients with DM1 and is currently being evaluated as an investigational agent in this patient population. 1 Heatwole C, Bode R, Johnson N, et al. Patient-reported impact of symptoms in myotonic dystrophy type 1 (PRISM-1). Neurology. 2012; 79(4):348-57. Erratum in: Neurology. 2012; 79(13):1411. About Myotonic Dystrophy Type 1 Myotonic dystrophy Type 1 (DM1) is the most common form of adult-onset muscular dystrophy. It is a genetic disorder inherited in an autosomal-dominant pattern. Latest estimates suggest a prevalence of about one per 2,100 people with the genetic defect for DM1. This equates to about 150,000 people in the U.S. with the genetic defect for DM1. About WAKIX® (pitolisant) Tablets WAKIX, a first-in-class medication, is approved by the U.S. Food and Drug Administration for the treatment of excessive daytime sleepiness or cataplexy in adult patients with narcolepsy and has been commercially available in the U.S. since Q4 2019. It was granted orphan drug designation for the treatment of narcolepsy in 2010, and breakthrough therapy designation for the treatment of cataplexy in 2018. WAKIX is a selective histamine 3 (H₃) receptor antagonist/inverse agonist. The mechanism of action of WAKIX is unclear; however, its efficacy could be mediated through its activity at H₃ receptors, thereby increasing the synthesis and release of histamine, a wake promoting neurotransmitter. WAKIX was designed and developed by Bioprojet (France). Harmony has an exclusive license from Bioprojet to develop, manufacture and commercialize pitolisant in the United States. Indications and Usage WAKIX is indicated for the treatment of excessive daytime sleepiness or cataplexy in adult patients with narcolepsy. Important Safety Information Contraindications WAKIX is contraindicated in patients with known hypersensitivity to pitolisant or any component of the formulation. Anaphylaxis has been reported. WAKIX is also contraindicated in patients with severe hepatic impairment. Warnings and Precautions WAKIX prolongs the QT interval; avoid use of WAKIX in patients with known QT prolongation or in combination with other drugs known to prolong the QT interval. Avoid use in patients with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval. The risk of QT prolongation may be greater in patients with hepatic or renal impairment due to higher concentrations of pitolisant; monitor these patients for increased QTc. Dosage modification is recommended in patients with moderate hepatic impairment and moderate or severe renal impairment (see full prescribing information). WAKIX is not recommended in patients with end-stage renal disease (ESRD). Adverse Reactions In the placebo-controlled clinical trials conducted in patients with narcolepsy with or without cataplexy, the most common adverse reactions (≥5% and at least twice placebo) for WAKIX were insomnia (6%), nausea (6%), and anxiety (5%). Other adverse reactions that occurred at ≥2% and more frequently than in patients treated with placebo included headache, upper respiratory tract infection, musculoskeletal pain, heart rate increased, hallucinations, irritability, abdominal pain, sleep disturbance, decreased appetite, cataplexy, dry mouth, and rash. Drug Interactions Concomitant administration of WAKIX with strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold. Reduce the dose of WAKIX by half. Concomitant use of WAKIX with strong CYP3A4 inducers decreases exposure of pitolisant by 50%. Dosage adjustments may be required (see full prescribing information). H1 receptor antagonists that cross the blood-brain barrier may reduce the effectiveness of WAKIX. Patients should avoid centrally acting H1 receptor antagonists. WAKIX is a borderline/weak inducer of CYP3A4. Therefore, reduced effectiveness of sensitive CYP3A4 substrates may occur when used concomitantly with WAKIX. The effectiveness of hormonal contraceptives may be reduced when used with WAKIX and effectiveness may be reduced for 21 days after discontinuation of therapy. Use in Specific Populations WAKIX may reduce the effectiveness of hormonal contraceptives. Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method during treatment with WAKIX and for at least 21 days after discontinuing treatment. There is a pregnancy exposure registry that monitors pregnancy outcomes in women who are exposed to WAKIX during pregnancy. Patients should be encouraged to enroll in the WAKIX pregnancy registry if they become pregnant. To enroll or obtain information from the registry, patients can call 1-800-833-7460. The safety and effectiveness of WAKIX have not been established in patients less than 18 years of age. WAKIX is extensively metabolized by the liver. WAKIX is contraindicated in patients with severe hepatic impairment. Dosage adjustment is required in patients with moderate hepatic impairment. WAKIX is not recommended in patients with end-stage renal disease. Dosage adjustment of WAKIX is recommended in patients with moderate or severe renal impairment. Dosage reduction is recommended in patients known to be poor CYP2D6 metabolizers; these patients have higher concentrations of WAKIX than normal CYP2D6 metabolizers. Please see the Full Prescribing Information for WAKIX for more information. To report suspected adverse reactions, contact Harmony Biosciences at 1-800-833-7460 or the FDA at 1-800-FDA-1088 or . About Harmony Biosciences At Harmony Biosciences, we specialize in developing and delivering treatments for rare neurological diseases that others often overlook. We believe that where empathy and innovation meet, a better life can begin for people living with neurological diseases. Established by Paragon Biosciences, LLC, in 2017 and headquartered in Plymouth Meeting, PA, our team of experts from a wide variety of disciplines and experiences is driven by our shared conviction that innovative science translates into therapeutic possibilities for our patients, who are at the heart of everything we do. For more information, please visit .  Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including statements regarding our full year 2024 net product revenue, expectations for the growth and value of WAKIX, plans to submit an sNDA for pitolisant in idiopathic hypersomnia; our future results of operations and financial position, business strategy, products, prospective products, product approvals, the plans and objectives of management for future operations and future results of anticipated products. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: our commercialization efforts and strategy for WAKIX; the rate and degree of market acceptance and clinical utility of pitolisant in additional indications, if approved, and any other product candidates we may develop or acquire, if approved; our research and development plans, including our plans to explore the therapeutic potential of pitolisant in additional indications; our ongoing and planned clinical trials; our ability to expand the scope of our license agreements with Bioprojet Société Civile de Recherche ("Bioprojet"); the availability of favorable insurance coverage and reimbursement for WAKIX; the timing of, and our ability to obtain, regulatory approvals for pitolisant for other indications as well as any other product candidates; our estimates regarding expenses, future revenue, capital requirements and additional financing needs; our ability to identify, acquire and integrate additional products or product candidates with significant commercial potential that are consistent with our commercial objectives; our commercialization, marketing and manufacturing capabilities and strategy; significant competition in our industry; our intellectual property position; loss or retirement of key members of management; failure to successfully execute our growth strategy, including any delays in our planned future growth; our failure to maintain effective internal controls; the impact of government laws and regulations; volatility and fluctuations in the price of our common stock; the significant costs and required management time as a result of operating as a public company; the fact that the price of Harmony's common stock may be volatile and fluctuate substantially; statements related to our intended share repurchases and repurchase timeframe and the significant costs and required management time as a result of operating as a public company. These and other important factors discussed under the caption "Risk Factors" in our Annual Report on Form 10-K filed with the Securities and Exchange Commission (the "SEC") on February 22, 2024, and our other filings with the SEC could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management's estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change. Harmony Biosciences Media Contact: Cate McCanless 202-641-6086 cmccanless@harmonybiosciences.com Harmony Biosciences Investor Contact: Luis Sanay, CFA 445-235-8386 lsanay@harmonybiosciences.com Company Codes: NASDAQ-NMS:HRMY

临床2期临床结果孤儿药引进/卖出突破性疗法

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KEGG	Wiki	ATC	Drug Bank
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适应症	国家/地区	公司	日期
白天过度嗜睡	加拿大	Endo Ventures Ltd.	2021-12-31
阻塞性睡眠呼吸暂停综合征	欧盟	Bioprojet Pharma SARL	2021-09-01
阻塞性睡眠呼吸暂停综合征	冰岛	Bioprojet Pharma SARL	2021-09-01
阻塞性睡眠呼吸暂停综合征	列支敦士登	Bioprojet Pharma SARL	2021-09-01
阻塞性睡眠呼吸暂停综合征	挪威	Bioprojet Pharma SARL	2021-09-01
猝倒症	美国	Harmony Biosciences LLC	2020-10-13
发作性睡病	欧盟	Bioprojet Pharma SARL	2016-03-31
发作性睡病	冰岛	Bioprojet Pharma SARL	2016-03-31
发作性睡病	列支敦士登	Bioprojet Pharma SARL	2016-03-31
发作性睡病	挪威	Bioprojet Pharma SARL	2016-03-31

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适应症	最高研发状态	国家/地区	公司	日期
特发性睡眠过度	临床3期	美国	Harmony Biosciences LLC	2022-05-25
自闭症谱系障碍	临床2期	-	Bioprojet Pharma SARL	2023-10-01
肌强直性营养不良	临床2期	美国	Harmony Biosciences LLC	2021-06-28
肌强直性营养不良	临床2期	加拿大	Harmony Biosciences LLC	2021-06-28
普拉德-威利综合症	临床2期	美国	Harmony Biosciences LLC	2020-12-09
Ehlers-Danlos 综合征伴纤连蛋白异常引起的血小板功能障碍	临床2期	法国	Bioprojet Pharma SARL	2010-10-01
帕金森病	临床2期	法国	Bioprojet Pharma SARL	2007-10-01
药物滥用	临床1期	加拿大	Bioprojet Pharma SARL	2017-03-15

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04596267 (CTgov)	临床1期	酗酒	9	Pitolisant (Pitolisant)	網顧艱鹽築鏇獵獵窪蓋(衊糧窪築繭簾遞夢壓簾) = 鹽鏇選構積範糧網艱膚蓋餘餘壓廠廠鹽網製鏇 (壓願壓鹽範鏇鏇構網遞, 窪鬱齋選鹹襯餘鹹簾膚 ~ 糧願鹽廠製積艱壓鏇淵) 更多	-	2023-12-04
				Placebo (Placebo)	網顧艱鹽築鏇獵獵窪蓋(衊糧窪築繭簾遞夢壓簾) = 壓艱獵顧鑰築廠製選窪蓋餘餘壓廠廠鹽網製鏇 (壓願壓鹽範鏇鏇構網遞, 獵廠壓顧蓋衊醖觸鏇鹹 ~ 觸顧鑰網膚廠簾鹹網鹹) 更多
WSC2023	N/A	发作性睡病	41	Modafinil	顧齋醖鹹繭糧願獵襯鹹(艱顧鬱繭積淵鏇選鬱糧) = adverse events of modafinil therapy, such as arterial hypertension and insomnia, ameliorated 艱鹹醖鏇艱憲鑰遞淵蓋 (簾構餘襯艱淵淵鬱夢選 )	积极	2023-10-23
WSC2023	N/A	发作性睡病	110	Pitolisant	網壓艱築獵網膚範壓衊(繭餘鏇衊鬱構餘積憲鏇) = 鬱繭夢淵壓積鹹鹹鹹遞簾壓繭糧糧願鑰餘艱鬱 (糧遞窪構製膚壓衊獵繭 )	积极	2023-10-23
				Placebo	網壓艱築獵網膚範壓衊(繭餘鏇衊鬱構餘積憲鏇) = 蓋築艱衊遞築鹹窪構鏇簾壓繭糧糧願鑰餘艱鬱 (糧遞窪構製膚壓衊獵繭 )
NEWS 人工标引	N/A	发作性睡病1型	30	盐酸替洛利生	蓋獵齋鹽願範糧齋憲膚(襯夢憲遞製製餘願鑰鹽) = 餘遞糧範淵構願襯壓膚製憲糧壓選衊願鑰遞襯 (餘糧糧構齋鹹鹹獵廠衊 ) 更多	积极	2023-08-04
WSC2022	N/A	发作性睡病	191	Pitolisant	壓選積醖襯衊範衊廠鹹(淵糧艱艱範鹽襯憲選網) = 糧醖願壓鹽襯窪鏇鑰壓醖範鹹夢廠鬱築糧膚壓 (製網膚壓範艱選襯選獵 ) 更多	积极	2022-03-11
WSC2022	N/A	白天过度嗜睡	-	Pitolisant 20mg/day	鏇構廠積觸繭簾鏇網遞(製願構艱範餘衊鹹積觸) = Side effect incidence was similar in both groups. 築築遞餘壓憲網艱製鹹 (鏇醖積膚糧鹹鏇製窪淵 )	积极	2022-03-11
ERS2021	N/A	阻塞性睡眠呼吸暂停综合征	-	Pitolisant 20mg/day	齋製艱獵願構窪遞憲醖(構蓋繭積鑰構廠願窪蓋): ratio = 1.18 (95% CI, 1.02 ~ 1.35), P-Value = 0.022 更多	积极	2021-09-05
				Placebo
ADA2021	N/A	1型糖尿病	5	Pitolisant	繭鹽醖遞鏇繭繭糧選鹽(夢餘簾遞窪觸醖蓋淵築) = patients on pitolisant had numerically higher mean glucose on CGM during the on-drug period 餘憲蓋範顧顧積構鹽醖 (構願糧範蓋蓋夢鑰範憲 )	-	2021-06-01
				Placebo
1472 (AAN2021)	N/A	发作性睡病	166	Pitolisant	鏇願鑰糧窪鏇構構簾範(繭觸製製廠網廠醖鬱築) = n=1 膚醖製鏇獵憲鹹觸憲網 (膚壓築鏇鹹鑰餘淵衊衊 ) 更多	积极	2021-04-13
				Placebo
4701 (AAN2020)	N/A	睡眠	15	Pitolisant	繭衊鬱衊鹹築鹹齋構廠(鏇淵簾醖齋製網襯鏇簾) = 壓淵繭選淵襯築製鏇選願築艱範繭選壓觸壓窪 (鏇蓋觸窪築鹽襯鬱鹹淵 ) 更多	-	2020-04-14