Peroxisomal Disorders

- Positive HTA recommendation for reimbursement signifies an important milestone towards public funding to treat eligible patients with this rare liver disorder - LIVMARLI is the first and only approved medication to treat cholestatic pruritus in patients with Alagille syndrome in Canada FOSTER CITY, Calif.--(BUSINESS WIRE)-- Mirum Pharmaceuticals, Inc. (NASDAQ: MIRM) today announced that the Canadian Agency for Drugs and Technologies in Health (CADTH) Canadian Drug Expert Committee (CDEC) has recommended public reimbursement for LIVMARLI® (maralixibat oral solution) for the treatment of cholestatic pruritus in patients with Alagille Syndrome (ALGS), with certain conditions. This announcement follows Health Canada’s authorization of LIVMARLI in this indication in 2023. “The positive reimbursement recommendation for LIVMARLI by CADTH is an important step forward for patients suffering from the debilitating effects of cholestatic pruritus related to Alagille syndrome,” said Chris Peetz, chief executive officer at Mirum. “Accelerating access in all provinces to this meaningful treatment is critical as it is the first and only approved therapy available in this setting in Canada. These patients suffer greatly from the debilitating and disruptive effects of Alagille syndrome, which often starts in early childhood.” “CADTH’s recommendation of reimbursement for LIVMARLI provides a meaningful advancement in the treatment of cholestatic pruritus for patients with Alagille syndrome. I am pleased that LIVMARLI will now become more accessible in Canada, where I have seen the critical need for a treatment to address the itch caused by cholestasis,” said Dr. Binita Kamath, Director, Hepatology Program and Senior Associate Scientist at The Hospital for Sick Children (SickKids), Toronto, Canada. “This recommendation is incredibly meaningful as it signifies hope for patients and their families who have suffered from the disruptive and painful effects of pruritus for far too long,” said Roberta Smith, president, Alagille Syndrome Alliance and mother of a daughter with ALGS. “We are grateful to CADTH for ensuring support of this new and important medication.” The CADTH recommendation is based on data from the pivotal ICONIC study including six years of data across the LIVMARLI clinical program resulting in a robust body of evidence in patients with cholestatic pruritus in ALGS. Data from ICONIC demonstrated statistically significant and clinically meaningful reductions in pruritus compared to placebo, as well as significant reductions in serum bile acids, both of which were durably maintained over several years of treatment. LIVMARLI is also approved for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) in the U.S. and Europe, and for Progressive Familial Intrahepatic Cholestasis (PFIC) in the U.S. and in Europe. ALGS is a rare genetic disorder caused by abnormalities in bile ducts that can lead to progressive liver disease. Malformed or reduced bile ducts cause cholestasis, the accumulation of bile acids in the liver, which leads to inflammation and liver injury, and prevents the liver from working properly. Cholestasis in ALGS is associated with pruritus which is among the most common indications for liver transplant in ALGS. About LIVMARLI® (maralixibat) oral solution LIVMARLI® (maralixibat) oral solution is an orally administered, once-daily, ileal bile acid transporter (IBAT) inhibitor and the only approved medication by the U.S. Food and Drug Administration for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) three months of age and older and progressive familial intrahepatic cholestasis (PFIC) five years of age and older. LIVMARLI is also the only approved IBAT inhibitor approved by the European Commission for the treatment of cholestatic pruritus in patients with ALGS two months and older, and by Health Canada for the treatment of cholestatic pruritus in ALGS. For more information for U.S. residents, please visit LIVMARLI.com. Mirum has also submitted LIVMARLI for approval in Europe in PFIC for patients two months of age and older. LIVMARLI has received Breakthrough Therapy designation for ALGS and PFIC type 2 and orphan designation for ALGS and PFIC. To learn more about ongoing clinical trials with LIVMARLI, please visit Mirum’s clinical trials section on the company’s website. IMPORTANT SAFETY INFORMATION LIVMARLI is not for use in PFIC type 2 patients who have a severe defect in the bile salt export pump (BSEP) protein. LIVMARLI can cause side effects, including: Liver injury. Changes in certain liver tests are common in patients with Alagille syndrome and PFIC but can worsen during treatment. These changes may be a sign of liver injury. In PFIC, this can be serious or may lead to liver transplant or death. Your healthcare provider should do blood tests and physical exams before starting and during treatment to check your liver function. Tell your healthcare provider right away if you get any signs or symptoms of liver problems, including nausea or vomiting, skin or the white part of the eye turns yellow, dark or brown urine, pain on the right side of the stomach (abdomen), bloating in your stomach area, loss of appetite or bleeding or bruising more easily than normal. Stomach and intestinal (gastrointestinal) problems. LIVMARLI can cause stomach and intestinal problems, including diarrhea and stomach pain. Your healthcare provider may advise you to monitor for new or worsening stomach problems including stomach pain, diarrhea, blood in your stool or vomiting. Tell your healthcare provider right away if you have any of these symptoms more often or more severely than normal for you. A condition called Fat Soluble Vitamin (FSV) Deficiency caused by low levels of certain vitamins (vitamin A, D, E, and K) stored in body fat is common in patients with Alagille syndrome and PFIC but may worsen during treatment. Your healthcare provider should do blood tests before starting and during treatment and may monitor for bone fractures and bleeding which have been reported as common side effects. US Prescribing Information EU SmPC Canadian Product Monograph About Mirum Pharmaceuticals, Inc. Mirum Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to transforming the treatment of rare diseases affecting children and adults. Mirum has three approved medications: LIVMARLI® (maralixibat) oral solution, CHOLBAM® (cholic acid) capsules, and CHENODAL® (chenodiol) tablets. LIVMARLI, an IBAT inhibitor, is approved for the treatment of two rare liver diseases affecting children and adults. It is approved for the treatment of cholestatic pruritus in patients with Alagille syndrome in the U.S. (three months and older), in Europe (two months and older), and in other regions globally. It is also approved in the U.S. in cholestatic pruritus in PFIC patients five years of age and older. Mirum has submitted for approval in Europe for the treatment of PFIC in patients two months of age and older. CHOLBAM is FDA-approved for the treatment of bile acid synthesis disorders due to single enzyme deficiencies and adjunctive treatment of peroxisomal disorders in patients who show signs or symptoms or liver disease. CHENODAL has received medical necessity recognition by the FDA to treat patients with cerebrotendinous xanthomatosis (CTX). Mirum’s late-stage pipeline includes two investigational treatments for debilitating liver diseases. Volixibat, an IBAT inhibitor, is being evaluated in two potentially registrational studies including the Phase 2b VISTAS study for primary sclerosing cholangitis and Phase 2b VANTAGE study for primary biliary cholangitis. Lastly, CHENODAL, has been evaluated in a Phase 3 clinical study, RESTORE, to treat patients with CTX, with positive topline results reported in 2023. To learn more about Mirum, visit mirumpharma.com and follow Mirum on Facebook, LinkedIn, Instagram and Twitter. Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include statements regarding, among other things, the potential commercial success of LIVMARLI in Canada and other approved territories and the additional improvements in disease beyond pruritus. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as “will,” “intended,” “potential” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Mirum’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks and uncertainties associated with Mirum’s business in general, the impact of geopolitical and macroeconomic events , and the other risks described in Mirum’s filings with the Securities and Exchange Commission, including its most recent Annual Report on Form 10-K, as updated by any subsequent Quarter Reports on Form 10-Q. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management’s assumptions and estimates as of such date. Mirum undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

Pictured: 3D rendering of human cells and DNA/iStock/iStock, anusorn nakdee 2023 was a banner year for cell and gene therapy, with seven FDA approvals, according to the Alliance for Regenerative Medicine. And the pace doesn’t appear to be slowing at all as the second quarter of this year gets underway. The advocacy group is anticipating an even bigger year for the CGT space in 2024, with a potential 17 approvals in the U.S. and EU combined, according to ARM’s annual Cell & Gene State of the Industry Briefing in January. “It seems like the FDA is really pushing forward with accelerated approvals for cell and gene therapies, and that’s quite encouraging to see,” Jack Allen, a senior research analyst at Baird, told BioSpace. “These can be quite expensive products to develop, and if we’re able to leverage abbreviated pathways to get them to market rapidly, I think that can really reignite enthusiasm for the space.” Allen noted that cell and gene therapy is somewhat de-risked by the fact that, in many instances, these treatments involve introducing the genetic sequence for a native functional protein. “I think there will be some bumps in the road as it relates to pressing forward rapidly with the technology,” he said, but “it seems like the FDA has buy-in and is willing to ride through some of those bumps.” Here, we take a closer look at six of the more notable cell and gene therapies approved during the past year—two of them under the FDA’s accelerated approval pathway—and preview some of the decisions on the horizon. Cell Therapies BMS’s Breyanzi Chronic lymphocytic leukemia and small lymphocytic leukemia On March 14, the FDA approved Bristol Myers Squibb’s Breyanzi as the first CAR T cell therapy for relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia. In the pivotal TRANSCEND 004 trial, Breyanzi elicited a complete response—something that is “basically unheard of” in patients with relapsed/refractory CLL, according to Rosanna Ricafort, vice president and head of late development hematology and cell therapy at BMS—in 20% of recipients, with responses lasting more than 35 months. The Big Picture In November 2023, the FDA launched an investigation into the “serious risk” of secondary malignancies in patients treated with BCMA- or CD19-directed autologous CAR T cell therapies. This led to the addition of a boxed warning to all six commercial CAR-T therapies at the time, including BMS’s Breyanzi. But industry leaders and the FDA itself have been supportive of CAR-T’s risk/benefit profile. Breyanzi’s approval in two more indications, along with the recommendation of FDA advisers to move Abecma and J&J’s Carvykti into earlier lines of treatment for multiple myeloma, have cemented this tone. Iovance’s Amtagvi Melanoma In one of the year’s most anticipated decisions, the FDA in February greenlit the first one-time cell therapy for a solid tumor, Iovance Biotherapeutics’ Amtagvi for unresectable or metastatic melanoma, under the accelerated approval pathway. Iovance is currently conducting a confirmatory study to verify the therapy’s benefit. The Big Picture Amtagvi is the first tumor-infiltrating lymphocytes (TIL) therapy, a treatment modality some experts say has advantages over CAR-T. While CAR Ts recognize only a small number of proteins on the surface of tumor cells, TILs can identify tumor targets derived from intra- or extracellular tumor proteins, Sammy Farah, CEO of Turnstone Biologics, told BioSpace. As of February 2023, there were more than 75 TIL immunotherapies in preclinical or clinical studies for various indications. Gene Therapies Orchard Therapeutics’ Lenmeldy Metachromatic leukodystrophy Last month, the FDA approved Orchard Therapeutics’ Lenmeldy as the first gene therapy for metachromatic leukodystrophy (MLD), a rare, degenerative disease characterized by loss of motor and cognitive function and early death. MLD is caused by a deficiency in the arylsulfatase-A (ARSA) gene, leading to a buildup of fatty substances in the cells. Lenmeldy is a single-dose infusion made from a patient’s own hematopoietic stem cells, which have been genetically modified to include functional copies of the ARSA gene. The Big Picture Lenmeldy joins a growing list of gene therapy firsts in pediatric diseases, including Sarepta’s Elevidys for Duchenne muscular dystrophy and bluebird bio’s Skysona for cerebral adrenoleukodystrophy. It is also the first FDA-approved treatment for MLD patients, “who previously had no treatment options beyond supportive and end-of-life care,” Orchard CEO Bobby Gaspar said in a statement. Vertex and CRISPR Therapeutics’ Casgevy Sickle cell disease, beta thalassemia Possibly the most celebrated approval of 2023 went to Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy, which in December became the first-ever CRISPR-based gene editing therapy in the U.S., for sickle-cell disease (SCD). Just one month later, Casgevy was also approved for transfusion-dependent beta thalassemia, more than two months ahead of its PDUFA date. The Big Picture Casgevy’s SCD approval came just over a decade after the publication of the Nobel Prize-winning CRISPR-Cas9 technology—a timeline many industry experts have deemed faster than what would normally be expected of a new modality. But CRISPR is not without its risks. Researchers have cited cell toxicity and genomic instability as potential side effects, which could potentially trigger tumor development. Scientists are now working to improve on the technology with new modalities, including base editing and epigenetic editing. Bluebird bio’s Lyfgenia Sickle-cell disease While the historic nature of Casgevy’s approval won the day, bluebird bio’s Lyfgenia, a lentiviral gene therapy, also got the FDA’s nod for SCD on Dec. 8, 2023. Treatment with Lyfgenia led to the complete resolution of vaso-occlusive events 6 to 18 months after infusion, making it another promising option for patients. The Big Picture Allen said Lyfgenia may have a couple of advantages in the SCD market. “Both [therapies] are incredibly transformative in that they effectively eliminate sickle-cell disease–induced pain crises. Lyfgenia I think is quite interesting in that there’s a longer durability of data . . . and they also have some data in stroke patients, which I think is going to be differentiating in the commercial marketplaces” given the prevalence of stroke in SCD. Lyfgenia also has the upper hand over Casgevy in terms of developing the infrastructure needed to deliver treatment to patients. Sarepta’s Elevidys Duchenne muscular dystrophy In one of 2023’s more controversial decisions, the FDA approved Sarepta Therapeutics’ Elevidys as the first gene therapy for Duchenne muscular dystrophy (DMD). Elevidys missed the primary functional endpoint in a randomized trial but won accelerated approval based on data showing it increased the expression of the micro-dystrophin protein—a biomarker the agency determined is “reasonably likely to predict clinical benefit” in DMD patients 4 to 5 years of age. The FDA’s green light followed an adcomm meeting where its advisers narrowly recommended the gene therapy for approval. Then, just four months after the approval, Elevidys failed a confirmatory trial. The Big Picture Elevidys’ approval kicked off a wave of momentum in the DMD space. In October 2023, the FDA authorized Santhera Pharmaceuticals’ Agamree, and just last month, Italfarmaco won approval for Duvyzat, the first nonsteroidal drug approved to treat patients with all genetic variants of the disease. On the Horizon Rocket’s Kresladi Leukocyte adhesion deficiency-I Rocket Pharmaceuticals had expected a decision on its gene therapy Kresladi, in development for the rare disease leukocyte adhesion deficiency-I, in March, but the FDA pushed the date back to June 30, 2024 in order to allow for more review time. BMS’s Breyanzi Follicular lymphoma and mantle cell lymphoma It’s a big year for BMS’s Breyanzi, as the company is expecting the FDA to decide on the CAR T cell therapy as a treatment for patients with relapsed or refractory follicular lymphoma on May 23 and for those with relapsed or refractory mantle cell lymphoma who have been treated with a Bruton tyrosine kinase inhibitor therapy on May 31. Pfizer’s Beqvez Hemophilia B After winning approval in Canada in January, Pfizer’s adeno-associated virus-based gene therapy fidanacogene elaparvovec—marketed as Beqvez in Canada—has a PDUFA date in the second quarter of 2024. Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.

大会由扬州市人民政府主办，同写意专业策划，以“打造生物医药新质生产力”为主题，邀请众多行业领袖和先锋人物一起取势明道，就如何打造中国医药新质生产力，面向未来创新药如何立项，资本寒冬下的创新药BD与出海，GLP-1&小核酸药物以及抗体药的质量与生产四大主题展开深度研讨，为行业发展提供方向性指引。审核：王永增，合源生物CTO在过去一年中，FDA启动了多项举措以支持细胞和基因疗法的临床开发和监管审查，以应对长期悬而未决的挑战：即大量的细胞和基因疗法临床试验处于临床搁置状态。FDA将此归因于CBER发布的临床搁置数量的整体增加，而这又是因为计划中或已启动的细胞和基因疗法临床试验数量在不断增加。不过，最近的一项分析指出，细胞和基因疗法临床试验在FDA临床搁置总数中占比高达40%，而它们在ClinicalTrials.gov上公示的临床试验中占比仅2%。虽然这种不平衡可能部分反映了细胞和基因疗法领域科学的新颖性，以及许多细胞和基因疗法产品是“first in class”的事实，但搁置率似乎不成比例。如果没有其他原因，我们需要评估一下在产品本身之外，是什么导致了这些临床搁置，以期避免未来的临床搁置。特别需要指出的是，如果长期搁置，可能会延迟患者获得潜在有益的临床试验用药，并不可避免地对公司产生财务影响。更令人担忧的是，在后一种情况下，公司可能会由于缺乏资金而放弃临床试验，而进一步剥夺患者和医生获得有前景的潜在治疗地选择。在细胞和基因治疗开发中，医疗需求很大，技术发展迅速，而其商业模式却如此不确定，因此申办方和FDA应一起努力来减少临床搁置。作为产品开发者的监管顾问，我们经常与大大小小寻求帮助企业合作，帮助解决导致临床搁置的问题。在本文中，我们为申办方提供了一些前瞻性地战略建议，以提高其临床试验能够顺利进行而不被搁置的可能性。我们也给FDA提出了相应地措施建议，以确保仅在必要时和不可避免的情况下才叫停细胞和基因治疗临床试验 - 临床搁置。1细胞和基因疗法的临床搁置：感知与现实细胞和基因治疗临床试验的搁置有多普遍？我们很难确定确切数字。但根据公开披露的信息可以估计，自2020年1月以来，至少有136项细胞和基因治疗临床试验被搁置。大家可能认为这个数字非常大，但根据the Pink Sheet对通过FOIA申请获得的数据进行的分析，每年的搁置数量已经从2018年的峰值——147个，下降到2022年的70个——近年来的最低点。如果想了解眼下临床搁置地格局，那就必须审视被搁置的具体原因。大多数临床搁置是为了应对不良事件或患者死亡而实施的，其中许多不可预测。第二大常见原因是CMC数据缺失或存在问题，包括在检查生产设施期间的发现的问题。生产制造基因和细胞疗法有特殊挑战，因此FDA也尤为关注。细胞和基因治疗领域的申办方通常是学术研究人员或小公司，他们几乎没有FDA法规和程序的操作经验，这使得在做商业生产设施和工艺规模放大时特别具有挑战性，常常导致难以确定临床试验产品和拟议的商业化产品之间的可比性，并最终导致CMC数据包的前后不一致。在一项临床试验被搁置后，项目开发会发生什么？一项研究发现，在2020-2022年间被搁置临床试验项目（n=33）中，约有80%的项目在平均6.2个月后被解除搁置，但有些持续了19个月以上（包括两个30天的时间段，用于CBER发布正式意见，并随后审核申办方的完整回复）。结局差异很大：有几项被搁置的临床试验，在问题得到解决后，随即得以恢复并且取得了显著的积极结果。相比之下，一项临床试验在取消搁置之前因安全问题而终止，另外三项临床试验在取消搁置重启之后不久，很快就终止了。蓝鸟生物的经验为解析这些数据提供了一些见解。该公司的慢病毒基因治疗产品已经获得了三个批准，但每一个都是在临床搁置之后获批的。其中两个产品使用相同的慢病毒载体，即Zynteglo（betibeglogene autotemcel，适用于β地中海贫血）和Skysona （elivaldogene autotemcel，适用于大脑型肾上腺脑白质营养不良），在数名受试者发生骨髓增生异常综合征（MDS）后，于2021年被临床搁置。在细胞、组织和基因疗法办公室（OCTGT）以获益超过风险为基础投票建议批准后，这些搁置被取消，该产品于2022年获得批准。蓝鸟生物最近批准的慢病毒基因疗法Lyfgenia（lovotibeglogene autotemcel，适用于镰状细胞病）也有过2次临床搁置——第一次发生在2021年，也是由于一名受试者被诊断为MDS。第二次是对18岁以下的患者的部分搁置，原因是该年龄组的一名患者出现持续性、非输血依赖型贫血。但最终确定病因是一种潜在的遗传疾病，后续在建立了对患者筛查这一疾病的程序后，取消了搁置。虽然蓝鸟克服临床搁置的经验令人鼓舞，但申办方的目标应该仍然是避免临床搁置。以下部分的建议将进一步实现这一目标，并且为临床项目的整体成功提供支持。2申办方：了解你的监管机构从一开始，申办方应可以预见到与其产品类别和技术相关的不良事件和其他问题，尽管人身体对产品的反应总会出乎所料。但随着该领域的发展，某些产品类别的风险可能会变得更加可预测，但目前这些信息仅限于参与临床试验的研究人员、公司和监管机构。不幸的是，由于数据的商业机密性，监管机构往往无法将这些信息公之于众。但我们建议申办方和研究者多多了解FDA的想法。• 标签和评论。新申办方可以从标签上的语言中很好地了解可能面临的临床试验决策。同样，做出批准决定后发表的综述是申办方获得FDA可接受的非临床和临床试验设计的宝贵资源。• FDA咨询委员会提供了丰富的信息和见解。2021年9月，FDA召开了OCTGT会议，讨论了与基于AAV载体的基因治疗产品相关的各种毒性风险，OCTGT关于个别产品的BLAs还提供关于风险的信息，以及监管机构和专业团体如何将这些风险与潜在益处的证据联系起来。• 尽可能多地了解其他产品被搁置的原因。申办方应寻求有关其技术和产品类别的所有信息，以及其产品特有的风险。FDA在会议上的报告通常会提供大量他们关注的信息，例如，在基因编辑技术方面，FDA对脱靶编辑的可能性表示担忧，至少有一种基因编辑疗法被临床搁置，部分原因是FDA希望看到这一领域的更多分析。• 指南很重要，即使是草稿的形式。FDA已经提供了关于开发利用人类基因组编辑的基因治疗产品的指南草案，以及关于CAR-T细胞产品和用于多个疾病类别的基因治疗产品的指南草案。该机构在撰写指导文件时非常谨慎，以现有的经验为重点，即使有些产品还未被批准。• 在细胞和基因疗法中，临床前数据甚至更重要，要好好利用。在临床前研究中，应全面评估已知的风险和问题，并将其纳入IND申请中提交的风险评估计划，以及如何解决临床试验中出现安全性问题时的方案。• CMC是第一要务。虽然大多数临床搁置是由安全性事件导致的，但也有一部分是由CMC缺陷（过去3年中至少有9种疗法）、临床前数据或项目的其他因素引起。就解决问题所需的时间而言，CMC缺陷引起的问题尤其“昂贵”。上述2023年的研究发现，CMC问题平均需要8.4个月才能解决，而评估不良事件或处理FDA要求修改的方案或提供临床前信息的平均时间为4-6个月。在许多情况下，通过现有指南更好地理解FDA的期望和要求，可以使申办方在提交申请之前就解决可能导致搁置的问题。效价测定就是一个很好的例子。为了避免CMC问题，效价测定必须在临床前和早期临床阶段进行开发和完善。最近的一份指南草案《细胞和基因治疗产品的效力保证》（Potency Assurance for Cellular and Gene Therapy Products）提供了确保产品在已发布的每一批产品中达到预期疗效的效力或特定能力的策略。指南草案还规定了FDA在基于综合风险的效力中对效力试验选择和设计、控制和变更管理以及接受标准的建议。指南草案指出，如果不能保证试验用药的效力，或者说如果IND没有包含足够的信息来保证效力，那么该研究可能被临床搁置。此外，指南解释道，如果用于II期或III期临床试验的IND不能保证产品的效力，说明临床试验设计在支持上市许可产品的有效性上有缺陷，这也会是FDA叫停临床试验的理由。• 与FDA和其他机构合作。在基因疗法生产和控制领域，CBER主任最近指出，企业不仅需要直接与FDA接触，而且需要与整个行业和学术界接触，以便确定有可能固化到标准化生产流程和平台中的最佳实践。为了预防潜在的CMC和临床前并发风险，申办方应在研发前的早期阶段，通过对CBER产品监管建议的初步有目标的沟通（Initial Targeted Engagement for Regulatory Advice on CBER Products，INTERACT）计划召开会议，在pre-IND阶段进行pre-IND会议。虽然会议请求过程可能很长，但是这笔投资是值得的。这些会议为申办方提供了向FDA工作人员询问有关其项目具体问题的机会，并寻求对FDA指南的解释。• 寻求帮助。小型学术中心和新兴公司可能缺乏资源来了解FDA的所有指南，这些指南数量众多且相当细致，更不用说这些指南如何相互衔接，或者在与该机构的互动过程中预期会发生什么。除了直接与FDA会面外，与了解并深刻理解FDA指导和期望的有经验的监管顾问合作通常是最有效的成功途径。就时间和财务资源而言，比起临床搁置，在一开始就获得战略性指导可能是一项明智的投资。顾问还可以向申办方建议其产品可能适合获得哪些认定（例如RMAT、突破性疗法），并指导申办方完成申请特殊认定的过程。如果一个产品满足需求（包括初步的临床证据），申请方将获得与CBER评审人员更早、更密切的互动的优势。鉴于潜在疗效的早期证据，FDA会将额外的资源和注意力用于这些指定的产品。但请注意，组织和先进疗法办公室收到的90%的申请是针对严重或危及生命的疾病，一半是针对罕见疾病，因此该办公室的资源限制仍然适用。此外，认定并不能保证所有可能导致临床搁置的问题都能提前发现。获RMAT或突破疗法认定的临床试验也有被搁置的。• 这不是针对个人。申办方必须接受FDA在IND前和INTERACT会议上提供的反馈，并将建议纳入他们的IND中。FDA可能会根据另一个申办方的经验来给你建议，但细节不会分享。• 关注细节。最后，在最基本的层次上，IND和会议包数据必须完整和详细。不止一项CAR-T细胞疗法临床试验因IND缺乏足够的信息来支持受试者安全性风险评估而被搁置。3FDA：考虑风险CBER主任Peter Marks承认，在某种程度上，临床搁置数量的增加是由于该机构目前审核员的数量难以处理细胞和基因疗法的大量IND申请。我们意识到这个问题的重要性和加强CBER的审查能力需求，不仅仅是因为一个更有能力的审核员就能在最初的30天IND周期中处理好申请需求，还因为更有能力的审核员会有能力与申办方在30天内进行互动并解决问题，而不至于在没有这样的时间和精力的情况下导致默认的临床搁置。此外，正如我们在上面所建议的那样，CBER是否有能力举行INTERACT和pre-IND会议也取决于现有工作人员的数量。我们赞赏FDA最近采取的措施，增加其专门负责细胞和基因疗法的审核人员，并努力为其流程注入更大的灵活性，这些努力主要得益于最近将之前的OTAT重组为治疗产品办公室（Office of Therapeutic Products， OTP）。随着OTP的成立，FDA打算聘用132名专门负责细胞和基因治疗产品审核的新审核人员；然而，由于政府和生物技术行业之间的工资差异，这些职位的招聘是个挑战。同样的现实也影响了高级审评人员的留职。近年来，随着细胞和基因治疗产品数量的增加，FDA有大量专业知识人才流失。最后，为了确保创新和开发继续以相同的速度进行，我们鼓励FDA在不损害IND持有者机密的情况下，继续分享关于特定治疗类别的安全性问题的信息，以便申办方能够提前做好准备（例如通过与公众和申办方会议、咨询委员会、会议述评或出版物评论以及指南），避免临床搁置。参考文献：Reducing The Number Of Clinical Holds On Cell And Gene Therapies: Approaches For Sponsors And The FDA；cell&gene更多优质内容，欢迎关注↓↓↓