Rilzabrutinib

Taylor Tieden for BioSpace Arguably the FDA’s most anticipated decision this month is for a subcutaneous induction formulation of Biogen and Eisai’s Alzheimer’s drug Leqembi, which, according to Eisai, could “help reduce the burden on healthcare professionals and patients.” August is shaping up to be another busy and back-heavy month for the FDA, with at least eight target action dates lined up, including for some drugs that could open up completely new treatment pathways for rare diseases. Read below for more. Insmed Builds Up to First Bronchiectasis Approval New Jersey’s Insmed is proposing its oral DPP1 blocker brensocatib for the treatment of bronchiectasis, a chronic lung disease involving inflamed airways. The FDA is expected to decide on the matter on or before Aug. 12. If approved, brensocatib will be the first drug for bronchiectasis, and will open up the inhibition of DPP1 as a therapeutic mechanism. Insmed’s application is backed by the Phase III ASPEN study. Toplined in May 2024 , ASPEN showed that 10-mg brensocatib cut the annualized pulmonary exacerbation rate by 21.1% versus placebo. A 25 mg dose, meanwhile, led to a 19.4% drop. Brensocatib also hit the study’s secondary outcomes, including lung function, time to first exacerbation event and risk of exacerbations over 52 weeks. Tonix’s Fibromyalgia Drug Nears Verdict By Aug. 15, the FDA will release its decision on Tonix Pharmaceuticals’ non-opioid candidate TNX-102 SL, being proposed for the management of fibromyalgia. If it gets the go-ahead, TNX-102 SL would be the first therapy approved for this indication in more than 15 years, according to a March press release from the company. Designed to be taken orally via a tablet under the tongue, TNX-102 SL is a novel formulation of cyclobenzaprine hydrochloride, a non-opioid drug. Data from two pivotal trials, published in April, showed that the drug candidate can significantly reduce pain and elicit other clinical improvements, while also being tolerable. PTC Pushes Vatiquinone Forward in Friedrich’s Ataxia Despite Phase III Fail Fresh off the approval of its phenylketonuria therapy Sephience, PTC Therapeutics is approaching another decision date, this time for vatiquinone, an investigational drug for Friedreich’s ataxia. The FDA’s verdict is due Aug. 19. Vatiquinone is an investigational small-molecule drug that selectively blocks the 15-lipoxygenase enzyme, which regulates pathways involved in oxidative stress that are dysfunctional in Friedreich’s ataxia. The registration-directed late-stage MOVE-FA trial fell short of its primary endpoint, unable to significantly slow disease progression versus placebo. This study, nonetheless, formed part of PTC’s application for vatiquinone. Two long-term studies in pediatric and adult patients also support vatiquinone’s application. Ionis Targets HAE Prophylaxis Nod for Donidalorsen By Aug. 21, the FDA will release its decision on Ionis Pharmaceuticals’ proposal to use the RNA-targeting therapy donidalorsen to prevent attacks in patients with hereditary angioedema (HAE), a rare genetic disease that manifests as recurring episodes of severe swelling throughout the body. Ionis is backing its application with data from the Phase III OASIS-HAE and OASISplus trials. Data from the first trial, published in May 2024 , showed that monthly treatment with donidalorsen could cut HAE attacks by 81% versus placebo over a 25-week observation period. The second study, meanwhile, demonstrated that switching to donidalorsen from other prophylactics reduced the monthly HAE attack rate by 62%, as per a July readout . Donidalorsen works by reducing levels of the prekallikrein protein, which is involved in the inflammatory cascade. Outlook Eyes AMD Approval for New Avastin Formulation Outlook Therapeutics is advancing ONS-5010, an eye drop formulation of the anti-VEGF antibody bevacizumab—approved as an intravenous infusion under the brand name Avastin for various cancers—for the treatment of wet age-related macular degeneration. The FDA is scheduled to release its decision on Aug. 27. To support its regulatory application, Outlook conducted the Phase III NORSE EIGHT study, which in January showed that ONS-5010 could match Roche’s Lucentis in terms of improving visual acuity at 8 weeks. Retinal thickness, an indicator of anatomic response, was likewise comparable between patients treated with ONS-5010 and Lucentis. The FDA previously rejected ONS-5010, flagging in August 2023 a lack of evidence to support the drug’s efficacy. If approved, Outlook plans to market ONS-5010 under the brand name Lytenava. Precigen Anticipates First Approval in Recurrent Respiratory Papillomatosis Maryland’s Precigen is advancing the gene therapy PRGN-2012, also called zopapogene imadenovec, for the treatment of recurrent respiratory papillomatosis (RRP). The FDA is expected to render a verdict on Aug. 27. RRP is a rare and lifelong neoplastic lung disease affecting the upper and lower respiratory tract after HPV infection. Patients suffer from benign tumors growing in their air passages, causing voice hoarseness, difficulty swallowing and breathing problems. RRP can be fatal, according to Precigen, and there are currently no cures. PRGN-2012 induces the immune system to target cells infected with HPV 6 or HPV 11. Data from a pivotal Phase I/II study showed that the gene therapy can elicit more than a 50% complete response in RRP patients, while more than 85% of patients saw reductions in surgical interventions. If approved, PRGN-2012 will be the first treatment for RRP. Sanofi Targets Rare Disease Approval for Rilzabrutinib The FDA is currently reviewing Sanofi’s application for BTK inhibitor rilzabrutinib for the treatment of immune thrombocytopenia (ITP). A regulatory decision is expected on Aug. 29. ITP is a rare autoimmune disorder that manifests as low platelet counts arising from both heightened destruction and reduced production of platelets. Common symptoms include bruising and bleeding that, in more severe instances, can become life-threatening, such as in the case of intracranial hemorrhage. Rilzabrutinib, an orally available BTK blocker, helps address ITP by tamping down several inflammatory and immune pathways. Phase III data presented at the 2024 meeting of the American Society of Hematology last December showed that 65% of treated patients demonstrated platelet response , defined as a doubling of platelets from baseline and hitting a certain count threshold. This response was durable for at least eight of the last 12 weeks of the study in 23% of patients. Rilzabrutinib likewise resulted in bleeding improvements and lowered the need for rescue therapy versus placebo. Biogen, Eisai’s Subcutaneous Leqembi Could Reduce Treatment Burden The FDA will cap off the month with arguably its most closely watched regulatory action: A verdict , due on Aug. 31, for Biogen and Eisai’s proposed subcutaneous maintenance formulation of their anti-amyloid Alzheimer’s therapy Leqembi. If approved, the partners expect an under-the-skin delivery method could minimize the need for hospital visits and, in turn, “help reduce the burden on healthcare professionals and patients,” according to a February 2025 company presentation from Eisai. The companies are also planning a regulatory filing for a subcutaneous induction formulation of Leqembi next year. Data from the open-label extension phase of the Phase III Clarity AD study supported the subcutaneous application. Results in October 2023 showed that weekly injections under the skin were able to remove 14% more amyloid plaques than biweekly infusions. Subcutaneous Leqembi also appeared to be as safe as the intravenous formulation, with comparable rates of amyloid-related imaging abnormalities.

编者按：过去的2024年，美国FDA批准了超过60款创新疗法和疫苗。作为创新赋能者、客户信赖的合作伙伴以及全球医药及生命科学行业的贡献者，药明康德将持续通过独特的“CRDMO”业务模式，助力更多合作伙伴，为全球病患带来突破性创新疗法。根据PDUFA的目标日期，预计2025年8月，美国FDA将对8款创新药物的批准做出监管决定。截至当前（8月8日），已有两款新药率先获批。本文将对这些疗法进行相关介绍。 ▲8月美国FDA可能批准的新药（点击可见大图） 活性成分：Pegzilarginase 适应症：精氨酸酶缺乏症（ARG1-D） 公司名称：Immedica Pharma Pegzilarginase是一种重组人体精氨酸酶，可促进体内精氨酸代谢。这种酶替代疗法可快速、持续地降低血浆中精氨酸及其毒性代谢物的水平，同时改善临床症状。Pegzilarginase已在欧盟和英国获得批准，用于治疗成人、青少年和2岁及以上儿童的精氨酸酶缺乏症。 根据2024年2月发表在eClinicalMedicine杂志上的3期临床研究结果，共有32名患者入组该研究并接受随机分组，其中21名患者接受了pegzilarginase治疗，11名患者接受了安慰剂治疗。研究结果显示，在第24周时，接受pegzilarginase治疗的患者血浆精氨酸（pArg）的几何平均值从354.0 μmol/L显著降低至86.4 μmol/L，而安慰剂组患者的pArg水平仅从464.7 μmol/L降至426.6 μmol/L（95% CI：-67.1%至-83.5%；p<0.0001）。此外，pegzilarginase治疗使90.5%的患者pArg水平恢复正常，而安慰剂组中这一比例为0%。在功能性活动能力方面，pegzilarginase治疗也显示出显著的临床改善效果。这些疗效在随后的24周持续治疗中得以长期维持。在安全性方面，pegzilarginase耐受性良好，不良事件大多为一过性且严重程度为轻度或中度。 活性成分：醋克立定（aceclidine） 适应症：老花眼 公司名称：LENZ Therapeutics 醋克立定是一种小分子乙酰胆碱受体激动剂，可引起瞳孔收缩，产生针孔效应，从而改善近视力。但与其它胆碱受体激动剂相比，它对控制瞳孔大小的虹膜肌肉的作用更具特异性，从而在缩小瞳孔的同时减少睫状体肌肉的收缩，降低晶状体的屈光变化，进而避免影响患者的远视力。2024年10月，美国FDA接受了醋克立定（1.75% aceclidine）眼药水配方LNZ100用于治疗老花眼的新药申请（NDA）。该药在7月31日获FDA批准，商品名为Vizz。 FDA的批准主要基于关键3期CLARITY试验积极数据的支持。分析显示，LNZ100达成试验主要终点和关键次要终点，即在近视力测量上，表现出视力表上3行（15个字母）以上的阅读改善，同时并不丧失1行（5个字母）的远视力。在载体对照的CLARITY 2试验中，试验第1天结果显示LNZ100展现以下效果： 快速起效：71%患者在30分钟内实现视力表上三行或更大的改善（p<0.0001）。 达主要终点：71%的患者在3小时内取得视力表上三行或更多的改善（p<0.0001）。 持续时间长：40％的患者在10小时后仍维持视力表上三行或更多的改善（p<0.0001）。 在为期四周的研究期间，CLARITY 1和2试验中所显示患者的近视力改善具有可重复性与一致性。LNZ100耐受性良好，在三项CLARITY试验中未观察到严重的治疗相关不良事件。 活性成分：Dordaviprone 适应症：复发性H3 K27M突变弥漫性中线胶质瘤 公司名称：Jazz Pharmaceuticals Dordaviprone可通过两种信号通路产生抗癌作用，作为多巴胺受体抑制剂，它可以减弱多巴胺受体介导的RAS信号通路的激活，而RAS信号通路的激活与癌细胞增殖相关。此外，它可以过度激活ClpP，导致线粒体蛋白质的选择性降解，让癌细胞因能量供应短缺而死亡。Dordaviprone已获得针对H3 K27M突变胶质瘤的罕见儿科疾病认定。今年2月，美国FDA受理了该疗法的NDA用于治疗复发性H3 K27M突变弥漫性中线胶质瘤患者，并同时授予该申请优先审评资格，预计在2025年8月18日之前完成审评。这款药物已在8月6日获得FDA批准，商品名为Modeyso。 Dordaviprone的新药申请得到2期临床试验主要分析结果的支持，此前发布的数据显示，在使用RANO 2.0（一种神经肿瘤学缓解评估标准）进行评估时，dordaviprone在H3 K27M突变弥漫性中线胶质瘤患者中达到28%的客观缓解率（ORR），中位缓解持续时间为10.4个月。 活性成分：Vatiquinone 适应症：弗里德里希共济失调（Friedreich ataxia，FA） 公司名称：PTC Therapeutics Vatiquinone是一种选择性15-脂氧合酶（15-LO）小分子抑制剂。作为调控能量代谢与氧化应激通路的关键酶，15-LO在弗里德里希共济失调患者体内存在异常激活或功能失调，而这一病理特征与疾病进展密切相关。通过抑制15-LO的活性，可有效缓解因线粒体功能障碍及氧化应激引发的多重损害，实现缓解细胞炎症反应，抑制氧化应激损伤，促进神经元存活。 今年2月，美国FDA正式受理了vatiquinone用于治疗儿童及成人弗里德里希共济失调的NDA，并同步授予该申请优先审评资格，预计将于2025年8月19日前完成审批。此次NDA的提交主要基于三项核心研究数据：包括关键性3期MOVE-FA研究，以及两项纳入儿童与成人弗里德里希共济失调患者的长期研究数据。这些研究共同证实，vatiquinone在延缓疾病进展方面展现出显著、持久且具有临床意义的疗效；此外，跨年龄组（涵盖儿童与成人）的受试者数据均显示，vatiquinone具有良好的安全性和耐受性特征。 活性成分：Zongertinib 适应症：非小细胞肺癌（NSCLC） 公司名称：勃林格殷格翰（Boehringer Ingelheim） Zongertinib是一种口服、不可逆HER2酪氨酸激酶抑制剂。由于该药物不与野生型EGFR结合，因而相关毒性较低。Zongertinib于2023年获得美国FDA授予快速通道资格，并随后于2024年获得美国FDA和中国国家药监局药品审评中心（CDE）授予的突破性疗法认定，用于治疗曾接受过全身性疗法、携带HER2突变的晚期NSCLC成人患者。 今年2月，美国FDA已正式受理zongertinib用于治疗既往接受过全身治疗的不可切除或转移性NSCLC成人患者的NDA，这些患者的肿瘤携带HER2突变。FDA同时授予这一申请优先审评资格，预计在今年第三季度完成审评。该申请基于1b期临床试验Beamion LUNG-1的积极数据。研究中，患者队列1（N=75）的数据显示，在携带HER2酪氨酸激酶结构域突变的患者中，客观缓解率达到71%，中位无进展生存期为12.4个月。 活性成分：Donidalorsen 适应症：遗传性血管性水肿（HAE） 公司名称：Ionis Pharmaceuticals Donidalorsen是一款反义寡核苷酸配体偶联（LICA）药物，旨在精确靶向以沉默前激肽释放酶（PKK）的表达，中断导致HAE发作的信号通路。PKK在激活与HAE急性发作相关的炎症介质中起重要作用。2024年11月，美国FDA宣布正式受理donidalorsen的NDA，用于预防12岁及以上成人和儿童患者的HAE发作。该申请的PDUFA日期为8月21日。 3期OASISplus研究结果显示，从既往预防性治疗方案切换至donidalorsen的患者，在此过程中未观察到疾病发作增加。治疗16周后，患者的平均HAE发作频率相较于既往治疗进一步显著降低。分析显示，从既往预防性治疗方案切换至donidalorsen的患者，其平均每月HAE发作次数进一步减少62%。血管性水肿控制测试（AECT）评分亦显示，药物切换后报告疾病控制良好的患者比例从67%升至93%，不论使用哪种既往治疗，患者的生活质量评估也获得普遍改善。此外，84%的受访患者表示更倾向于选择donidalorsen，主要原因包括疾病控制更佳、用药更便捷、注射部位不适反应更少等。 活性成分：Zopapogene imadenovec（PRGN-2012） 适应症：复发性呼吸道乳头状瘤病（RRP） 公司名称：Precigen PRGN-2012是一款利用Precigen公司的腺病毒载体平台开发的现货型（off-the-shelf）基因疗法，旨在激发针对感染HPV6或HPV11细胞的免疫反应。PRGN-2012已获得FDA授予的突破性疗法认定和孤儿药资格，并获得欧盟委员会的孤儿药资格。 2025年2月，美国FDA正式受理该公司为PRGN-2012递交的生物制品许可申请（BLA），用于治疗成人RRP。FDA同时授予该申请优先审评资格，预计在2025年8月27日之前完成审评。新闻稿指出，如果获批，PRGN-2012将成为首个获得FDA批准用于治疗成人RRP的疗法。此次BLA的支持数据来自关键性1/2期临床试验，试验数据已在2024年美国临床肿瘤学会（ASCO）年会中展示，并发表在The Lancet Respiratory Medicine上。该关键性研究达到了其主要安全性和疗效终点，超过50%的患者获得完全缓解，且超过85%的患者在PRGN-2012治疗后一年内的手术干预次数较治疗前一年有所减少。PRGN-2012耐受性良好，无剂量限制性毒性反应，也无大于2级的治疗相关不良事件。 活性成分：Rilzabrutinib 适应症：免疫性血小板减少症（ITP） 公司名称：赛诺菲（Sanofi） Rilzabrutinib是一款口服、可逆的共价BTK抑制剂，有望成为多种免疫介导疾病的潜在“first-in-class”与“best-in-class”疗法。BTK在B细胞、肥大细胞及其他先天免疫系统细胞中表达，在炎症通路和多种免疫介导疾病的病理过程中起关键作用。该药物是赛诺菲通过在2020年以37亿美元收购Principia Biopharma所获得，此前曾获得美国FDA授予快速通道资格与孤儿药资格，用于治疗ITP。 Rilzabrutinib目前正在美国、欧盟和中国接受监管审查，用于治疗免疫性血小板减少症。美国FDA的监管决策目标日期为2025年8月29日，该药物已获得快速通道资格。 3期临床研究LUNA 3的分析结果显示，接受每日两次口服400 mg rilzabrutinib治疗的ITP患者中，达到持久血小板应答这一主要终点的比例显著更高。此外，关键次要终点的积极结果也凸显rilzabrutinib为患有持续性和慢性ITP的患者带来具有临床意义的益处的潜力。Rilzabrutinib的安全性与既往研究报告的一致，没有观察到新的安全性问题。 参考资料： 各公司官网 免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新