Creutzfeldt-Jakob Disease, Sporadic

- PHOENIX Study Did Not Meet Prespecified Primary or Secondary Endpoints - Data From 664-Participant Study Reinforce That AMX0035 is Generally Safe and Well-Tolerated - Within the Next Eight Weeks, Amylyx Will Continue to Engage With Regulatory Authorities and the ALS Community to Share Topline Data; Amylyx Will Share Plans for RELYVRIO/ALBRIOZA in ALS Which May Include Voluntarily Withdrawing RELYVRIO/ALBRIOZA From the Market - At This Time, RELYVRIO/ALBRIOZA Will Continue to be Available for People Living With ALS; Amylyx Has Voluntarily Decided to Pause Promotion; Related Patient Support Services Will Remain in Place - Studies With AMX0035 in Wolfram Syndrome (WS) and Progressive Supranuclear Palsy (PSP) to Continue Based on Data Supporting its Potential in These Diseases - Amylyx to Host Investor Conference Call Today, March 8, at 8:00 a.m. ET CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Amylyx Pharmaceuticals, Inc. (NASDAQ: AMLX) (“Amylyx” or the “Company”) today announced topline results from PHOENIX, a global, 48-week, randomized, placebo-controlled Phase 3 clinical trial of AMX0035 (sodium phenylbutyrate and taurursodiol [also known as ursodoxicoltaurine]; RELYVRIO® in the U.S., ALBRIOZA™ in Canada) in people living with amyotrophic lateral sclerosis (ALS). PHOENIX did not meet its primary endpoint of reaching statistical significance (p=0.667) as measured by change from baseline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score at Week 48, nor was there statistical significance seen in secondary endpoints. Amylyx plans to present the data from PHOENIX at an upcoming medical meeting and will publish the results in a medical journal later this year. Amylyx will continue to engage with regulatory authorities and the broader ALS community, including ALS specialists and other multidisciplinary experts, people living with ALS, and advocates, to discuss the results from PHOENIX within the next eight weeks and make informed decisions. Amylyx intends to share plans for RELYVRIO/ALBRIOZA in ALS, which may include voluntarily withdrawing RELYVRIO/ALBRIOZA from the market. At this time, RELYVRIO/ALBRIOZA and its related patient support program will continue to be available for people living with ALS. Amylyx has voluntarily decided to pause promotion of the medication during this time. “We are surprised and deeply disappointed by the PHOENIX results following the positive data from the CENTAUR trial. Our main priority at the moment is sharing the information with people living with ALS and their treating physicians; this is part of our continued commitment to them and our mission. Over the next eight weeks, our team will continue to engage with regulatory authorities and the ALS community to discuss the results from PHOENIX. We will be led in our decisions by two key principles: doing what is right for people living with ALS, informed by regulatory authorities and the ALS community, and by what the science tells us. On behalf of the entire Amylyx team, we are grateful to the ALS community and for the dedication of trial participants, investigators, and study site teams. With data collected from 664 participants in PHOENIX, we are certain there will be important learnings that will help inform future ALS research. We are steadfast in our commitment to the ALS community and our mission, including with AMX0035 where it has shown potential in neurodegenerative diseases such as Wolfram syndrome and progressive supranuclear palsy, and with AMX0114, our investigational antisense oligonucleotide targeting calpain-2, in ALS,” said Justin Klee and Joshua Cohen, Co-CEOs of Amylyx. PHOENIX Study Results: The Phase 3 PHOENIX study enrolled 664 adults living with ALS. Participants were randomized three-to-two to receive either AMX0035 or placebo, with both treatment groups receiving standard-of-care. Continuation of a stable dosing regimen of riluzole and/or edaravone was permitted. PHOENIX did not meet the primary endpoint: There was no significant difference observed between participants treated with AMX0035 and placebo in ALSFRS-R total score change from baseline at Week 48 (p=0.667). No significant difference was observed in the subset of participants who met the CENTAUR trial criteria. There were also no significant differences observed across secondary endpoints. Consistent safety and tolerability profile: AMX0035 was well-tolerated in PHOENIX. There were no new safety signals, reinforcing the favorable and manageable safety pro with AMX0035 to date. European participants who completed the 48-week randomized phase had the option to enroll in an open label extension of the trial of up to two years in duration, which remains ongoing. Science of AMX0035: AMX0035, a specially formulated oral fixed-dose combination of PB and TURSO, has been shown in numerous preclinical studies to have a robust, synergistic effect in targeting two different destructive neurodegenerative disease pathways by mitigating endoplasmic reticulum stress and the associated unfolded protein response and mitochondrial dysfunction thereby reducing neuronal cell death. Additionally, AMX0035 has been shown to also reduce markers associated with neurodegenerative diseases in clinical trials, including a reduction of tau, a key protein aggregate shared across several neurodegenerative diseases, and YKL-40, a marker of neuroinflammation. Update on Ongoing AMX0035 Studies: The global, randomized, double-blind, placebo-controlled Phase 3 ORION clinical study of AMX0035 in PSP remains ongoing. The first participant was dosed in December 2023, and the Company is planning for an interim analysis. Topline results continue to be anticipated in 2025 or 2026. Data from the ongoing 12-participant, single site, open-label Phase 2 HELIOS clinical study are demonstrating evidence of clinical activity of AMX0035 in Wolfram syndrome. This study is fully recruited, and the Company plans to present preliminary data in the second quarter of 2024. Investor Conference Call Information Amylyx’ management team will host a live conference call and webcast today, March 8, 2024, at 8:00 a.m. ET to discuss the results of the PHOENIX trial. To participate in the conference call, please dial +1 (877) 870-4263 (U.S.), +1 (855) 669-9657 (Canada), or +1 (412) 317-0790 (International) at least 10 minutes prior to the start time and ask to be joined into the Amylyx Pharmaceuticals call. All interested parties are invited to access a live broadcast of the call via a webcast, which will be available on the “Events and Presentations” page in the “Investors” section of the Company’s website at investors.amylyx.com/news-events/events. An archived webcast will be available on the Company's website approximately two hours after the conference call and will be available for replay for 90 days following the call. About the PHOENIX Trial PHOENIX was a 48-week, randomized, placebo-controlled, global Phase 3 clinical trial further evaluating the safety and efficacy of AMX0035 (sodium phenylbutyrate and taurursodiol) for the treatment of ALS. The primary efficacy outcome of the trial was change from baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) total score at 48 weeks. Secondary endpoints include quality of life patient-reported outcome assessments, overall survival, and respiratory function as measured by slow vital capacity (SVC). Safety and tolerability were also assessed. European participants who completed the 48-week trial had the option to enroll in an open-label extension (OLE) phase. During this phase, all participants receive AMX0035, and continued safety and efficacy measures will be assessed. About the CENTAUR Trial CENTAUR was a multicenter Phase 2 clinical trial in 137 participants with ALS encompassing a 6-month randomized, placebo-controlled phase and an open-label long-term follow-up phase. The trial met its primary efficacy endpoint of reducing functional decline as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). Overall, reported rates of adverse events and discontinuations were similar between AMX0035 and placebo groups during the 24-week randomized phase; however, gastrointestinal events occurred with greater frequency (≥2%) in the AMX0035 group. Detailed data from CENTAUR is published in the New England Journal of Medicine (NEJM) and Muscle & Nerve. The CENTAUR trial was funded, in part, by the ALS ACT grant and the ALS Ice Bucket Challenge, and was supported by The ALS Association, ALS Finding a Cure (a program of The Leandro P. Rizzuto Foundation), the Northeast ALS Consortium, and the Sean M. Healey & AMG Center for ALS at Mass General. About AMX0114 AMX0114 is an antisense oligonucleotide designed to target the gene encoding calpain-2, a key contributor to the axonal (Wallerian) degeneration pathway. Axonal degeneration has been recognized as an important early contributor to the clinical presentation and pathogenesis of ALS and other neurodegenerative diseases. Calpain-2 has been implicated in the pathogenesis of ALS based on findings of elevated levels of calpain-2 and its cleavage products in postmortem ALS tissue, therapeutic benefit of calpain-2 modulation in animal models of ALS, and the role of calpain-2 in cleaving neurofilament, a broadly researched biomarker in ALS. Preclinical studies completed to date have shown that AMX0114 achieves potent, dose-dependent, and durable knockdown of CAPN2 mRNA expression and calpain-2 protein levels in human motor neurons. Moreover, in preclinical efficacy studies, treatment with AMX0114 reduced extracellular neurofilament light chain levels following neurotoxic insult in iPSC-derived human motor neurons, and improved survival of iPSC-derived human motor neurons harboring ALS-linked, pathogenic TDP-43 mutations. About ALS Amyotrophic lateral sclerosis (ALS, also known as motor neuron disease) is a relentlessly progressive and fatal neurodegenerative disorder caused by motor neuron death in the brain and spinal cord. Motor neuron loss in ALS leads to deteriorating muscle function, the inability to move and speak, respiratory paralysis, and eventually, death. More than 90% of people with ALS have sporadic disease, showing no clear family history. ALS affects around 30,000 people in the U.S., and more than 30,000 people are estimated to be living with ALS in Europe (European Union and United Kingdom). People living with ALS have a median survival of approximately two years from diagnosis. About HELIOS The HELIOS trial (NCT05676034) is a 12-participant, open-label proof of biology, Phase 2 trial designed to study the effect of AMX0035 on safety and tolerability, and various measures of endocrinological, neurological, and ophthalmologic function in adult participants living with Wolfram syndrome (WS). About Wolfram Syndrome Wolfram syndrome (WS) is an autosomal recessive neurodegenerative disease characterized by childhood-onset diabetes, optic nerve atrophy, and neurodegeneration. Common manifestations of WS include diabetes mellitus, optic nerve atrophy, central diabetes insipidus, sensorineural deafness, neurogenic bladder, and progressive neurologic difficulties. Genetic and experimental evidence suggest that endoplasmic reticulum (ER) dysfunction is a critical pathogenic component of WS. The prognosis of WS is poor, and many people with the disease die prematurely with severe neurological disabilities. About the ORION Trial The Phase 3 ORION trial (NCT06122662) is a global, randomized, double-blind, placebo-controlled Phase 3 clinical trial designed to assess the efficacy, safety, and tolerability of AMX0035 compared to placebo in people living with progressive supranuclear palsy (PSP). The ORION Phase 3 trial was designed and planned in collaboration with key global academic leaders, people living with PSP and their caregivers, and industry advocacy organizations. About PSP Progressive supranuclear palsy (PSP) is a sporadic, rare and adult-onset neurodegenerative disorder that affects walking and balance, eye movement, swallowing, and speech. People living with PSP have a life expectancy of six to eight years after initial diagnosis, and its epidemiology is similar to that of amyotrophic lateral sclerosis (ALS). PSP typically begins in late-middle age and rapidly progresses over time. The disease affects approximately seven in 100,000 people worldwide, and there are currently no disease-modifying therapies approved for the treatment of PSP. PSP is characterized by abnormal tau inclusions and is consequently also known as a tauopathy. Similar to other neurodegenerative diseases, pathophysiologic changes underlying PSP are multifactorial with several genetic and environmental factors likely contributing to tau dysfunction and aggregation. Multiple pathways, including genetic mutations, endoplasmic reticulum (ER) stress and the activation of unfolded protein response, mitochondrial dysfunction, and neuroinflammation have been implicated as contributors to tau dysfunction and aggregation. About AMX0035 / RELYVRIO® / ALBRIOZA™ AMX0035 is an oral, fixed-dose combination of sodium phenylbutyrate and taurursodiol (known as ursodoxicoltaurine outside of the U.S.). It is approved as RELYVRIO® to treat amyotrophic lateral sclerosis (ALS) in adults in the U.S. and approved with conditions as ALBRIOZA™ for the treatment of ALS in Canada. AMX0035 is being studied for the potential treatment of other neurodegenerative diseases, and Amylyx is exploring its treatment in other populations and regions. The formulation of RELYVRIO, ALBRIOZA, and AMX0035 is identical. RELYVRIO® (sodium phenylbutyrate and taurursodiol) Safety Information for United States WARNINGS AND PRECAUTIONS Risk in Patients with Enterohepatic Circulation Disorders, Pancreatic Disorders, or Intestinal Disorders RELYVRIO contains taurursodiol, which is a bile acid. In patients with disorders that interfere with bile acid circulation, there may be an increased risk for worsening diarrhea, and patients should be monitored appropriately for this adverse reaction. Pancreatic insufficiency, intestinal malabsorption, or intestinal diseases that may alter the concentration of bile acids may also lead to decreased absorption of either of the components of RELYVRIO. Because different enterohepatic circulation, pancreatic, and intestinal disorders have varying degrees of severity, consider consulting with a specialist. Patients with disorders of enterohepatic circulation (e.g., biliary infection, active cholecystitis), severe pancreatic disorders (e.g., pancreatitis), and intestinal disorders that may alter concentrations of bile acids (e.g., ileal resection, regional ileitis) were excluded from the study; therefore, there is no clinical experience in these conditions. Use in Patients Sensitive to High Sodium Intake RELYVRIO has a high salt content. Each initial daily dosage of 1 packet contains 464 mg of sodium; each maintenance dosage of 2 packets daily contains 928 mg of sodium. In patients sensitive to salt intake (e.g., those with heart failure, hypertension, or renal impairment), consider the amount of daily sodium intake in each dose of RELYVRIO and monitor appropriately. ADVERSE REACTIONS The most common adverse reactions (at least 15% and at least 5% greater than placebo) with RELYVRIO were diarrhea, abdominal pain, nausea, and upper respiratory tract infection. Gastrointestinal-related adverse reactions occurred throughout the study but were more frequent during the first 3 weeks of treatment. Please click here for RELYVRIO Full U.S. Prescribing Information. About Amylyx Pharmaceuticals Amylyx Pharmaceuticals, Inc. is committed to supporting and creating more moments for the neurodegenerative disease community through the discovery and development of innovative new treatments. Amylyx is headquartered in Cambridge, Massachusetts and has operations in Canada, EMEA, and Japan. For more information, visit amylyx.com and follow us on LinkedIn and X, (formerly Twitter). For investors, please visit investors.amylyx.com. Forward-Looking Statements Statements contained in this press release and related comments in our earnings conference call regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, Amylyx’ expectations regarding: interactions with regulatory authorities; the continued availability of RELYVRIO/ALBRIOZA for people living with ALS while such interactions are ongoing; the pausing of promotion of RELYVRIO/ALBRIOZA; pathways for continued access for patients if RELYVRIO/ALBRIOZA are withdrawn from the market; the possibility for Amylyx to voluntarily withdraw RELYVRIO/ALBRIOZA from the market; the continued evaluation of AMX0035 in other neurodegenerative diseases, including the timing for expected data readouts in the ORION and HELIOS studies; and the evidence of biological activity of AMX0035 in Wolfram syndrome. Any forward-looking statements in this press release and related comments in the Company's conference call are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include the risks and uncertainties set forth in Amylyx’ United States Securities and Exchange Commission (SEC) filings, including Amylyx’ Annual Report on Form 10-K for the year ended December 31, 2023, and subsequent filings with the SEC. All forward-looking statements contained in this press release and related comments in our conference call speak only as of the date on which they were made. Amylyx undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

撰文丨王聪1957年，美国科学家丹尼尔·盖杜谢克（Daniel Gajdusek）发现在巴布新几内亚发现一个土著部落Fore族有很多人得了一种被称为库鲁病的怪病，这种怪病潜伏期较长，但在发病后几个月内就会死亡。他经过研究发现，这种怪病是因为Fore族的一种特殊的习俗——在葬礼上食用死者的组织以示哀悼，这导致了一种未知致病因子的疾病传播。在盖杜谢克的劝说下，Fore族废除了这一习俗，库鲁病从此绝迹。后来我们知道，库鲁病的致病源正是大名鼎鼎的朊病毒（Prion），实际上，绝大多数人类朊病毒病其实是一种晚发性散发性疾病——散发性克雅氏病，还有少数是遗传性朊病毒病，例如致死性家族性失眠。像库鲁病这样获得性朊病毒病非常罕见，20世纪90年代出现了一种新型获得性朊病毒病——变异型克雅氏病，这是因为通过饮食接触了患有疯牛病（一种牛的朊病毒病）的牛肉。还有极少数案例，因为医疗原因（例如尸体来源的人类脑垂体生长激素治疗、脑硬膜移植等）而感染了朊病毒病。此外，还曾发生过科研人员在进行朊病毒实验时刺伤手指导致朊病毒感染并因此死亡。近年来的研究表明，常见的人类神经退行性疾病（例如阿尔茨海默病和帕金森病），也涉及错误折叠蛋白的积累和扩散，这与朊病毒类似。而通过医源性途径传播β-淀粉样蛋白（Aβ）导致医源性脑淀粉样血管病（CAA）的发现，提示了医源性阿尔茨海默病的可能性。2024年1月29日，伦敦大学学院朊病毒病研究所 John Collinge 团队在 Nature Medicine 期刊发表了题为：Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone 的研究论文【1】。该研究提供了第一个证据，在人类中发现了因为医学治疗而获得的阿尔茨海默病，并且是由β-淀粉样蛋白（Aβ）传播引起。研究团队发现，五名儿童时期曾经接受尸体来源的人类脑垂体生长激素治疗的人，出现了早发的进行性认知障碍，符合阿尔茨海默病的诊断标准。这些发表表明了阿尔茨海默病有潜在传播性，阿尔茨海默症可能有医源性的形式。朊病毒并不是一种病毒，它不含有任何DNA或RNA，而是完全由蛋白质组成。各种类型的人类朊病毒病，都是有同一种分子机制导致，编码朊病毒蛋白（PrP）的PRNP基因突变，导致朊病毒蛋白的构象从其固有折叠形式（PrPC）变为错误折叠形式（PrPSc）。而PrPSc能够让其接触的正常的PrPC蛋白转变为致病的PrPSc形式，最终导致发病和死亡。在1959-1985年间，英国至少有1848名病患接受了从尸体的脑垂体腺中提取的人类生长激素（c-hGH）治疗。在一些人得到了受朊病毒污染的c-hGH并在之后死于克雅氏病（CJD）以后，这一产品在全球召回并停止使用，之后被合称生长激素所取代。在其中一些人的大脑中，尸检发现了β-淀粉样蛋白（Aβ）病理异常，这是阿尔茨海默症的标志之一。但还不清楚这些人是否在死前出现了阿尔茨海默症的症状，因为有可能被他们的克雅氏病（CJD）症状所掩盖。2018年12月，John Collinge 团队在 Nature 期刊发表论文【2】，表明了一些存档批次的c-hGH中含有可检测量的β-淀粉样蛋白（Aβ），并且能够会将病状传递给小鼠。在这项研究中，研究团队描述了8名曾经在儿童时期接受c-hGH治疗但没有出现克雅氏病（CJD）的人。其中5人出现了与早发性痴呆（症状出现于38-55岁）一致的症状，符合阿尔茨海默病的诊断标准，即在两个或以上认知领域出现进展性障碍，严重程度足以影响日常活动。其余三人中，一人出现了符合中度认知障碍的诊断标准的症状（开始于42岁），另一人仅有主观认知症状，第三人无症状。生物标志物分析在无症状时不能用于诊断这种疾病，但支持了两名确诊患者的阿尔茨海默病诊断，并指明另一人有阿尔茨海默病的迹象。研究团队还对两名研究期间去世的人做了尸检，包括大量脑组织取样，其中一名患者也显示出阿尔茨海默病的病理。此外，在五名有样本的患者中，对导致早发性阿尔茨海默病的基因进行遗传检测，结果显示阴性。总而言之，该研究描述的所有患者的唯一共同因素就是都使用了从尸体的脑垂体腺中提取的人类生长激素（c-hGH）治疗，鉴于相关存档c-hGH批次中β-淀粉样蛋白（Aβ）传播的有力实验证据，可以得出最合理的解释就是，这些患者出现的临床综合征可以被称为医源性阿尔茨海默病。因此，类似于克雅氏病（CJD），阿尔茨海默病或许也有散发、遗传和后天获得的不同形式，阿尔茨海默病现在应该被认为是一种潜在的传染性疾病。考虑到阿尔茨海默病的发病率远高于克雅氏病，因此，从尸体的脑垂体腺中提取的人类生长激素（c-hGH）受到β-淀粉样蛋白（Aβ）污染的可能性比受到朊病毒污染的可能性要高得多。认识到Aβ的传播可能导致医源性阿尔茨海默病，这凸显了审核措施的必要性，以预防通过医疗或手术导致的阿尔茨海默病的传播。这些发现可能对驱动其他类型阿尔茨海默病的过程有所启示，也可能为治疗策略带来新见解。论文链接：https://www.nature.com/articles/s41591-023-02729-2https://www.nature.com/articles/s41586-018-0790-y免责声明“药渡”公众号所转载该篇文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。微信公众号的推送规则又双叒叕改啦，如果您不点个“在看”或者没设为"星标"，我们可能就消散在茫茫文海之中~点这里，千万不要错过药渡的最新消息哦！

MeiraGTx’s gene therapy was able to rescue movement function or prevent motor neuron loss in several rodent models of amyotrophic lateral sclerosis. New data from mouse and rat studies show that MeiraGTx’s gene therapy for amyotrophic lateral sclerosis, or ALS, can repair a key cell-killing process that’s common in both genetic and sporadic forms of the disease. In a presentation Oct. 27 at the European Society of Cell and Gene Therapy conference in Brussels, the company showed that a single treatment with its gene therapy AAV-UPF1 prevented the loss of motor neurons in mouse and rat models with genetic and cellular defects seen in ALS, thereby improving clinical symptoms. The type of defect the treatment corrects is present in the vast majority of ALS patients, suggesting it could have wide-ranging benefit if validated in future studies. ALS is a progressive neurodegenerative disease where multiple aberrant cell processes destroy motor neurons. It’s more common in men than in women, though the gap closes with age, and comes in two forms: familial and sporadic. The familial form, or fALS, accounts for about 5% to 10% of cases, while the rest of patients have no obvious family history. Both types typically arise in people's late 40s through early 60s, with fALS starting slightly earlier. Though the timeline varies, patients usually progress from subtle muscle weakness to paralysis, respiratory failure and death within two to 10 years after the disease begins. There is currently no cure for ALS. Seven drugs have been approved by the FDA to treat the disease, including a new antisense oligonucleotide drug from Biogen and Ionis called tofersen, sold as Qalsody. The therapy targets a mutation in the gene SOD1, which affects about 10% to 20% of inherited or fALS patients. The SOD1 mutation leads to protein misfolding and aggregation within motor neurons, ultimately killing them. MeiraGTx’s new therapy also impacts the pathways that lead to protein misfolding and aggregation in motor neurons, but not the type that’s caused by SOD1. Instead, it targets a different cytotoxic, or cell damaging, process where a motor neuron protein called TAR DNA-binding protein 43, or TDP-43, incorrectly moves from the nucleus to the cytoplasm and builds up. While the TDP-43 pathology isn’t found in patients who have the SOD1 mutation, it is present in those who have the most common form of fALS, which is linked with the gene C9ORF72. It’s also found in nearly all patients with sporadic ALS, bringing its prevalence to more than 95% of ALS patients overall. To counteract TDP-43’s effects, MeiraGTx’s gene therapy increases the expression of the gene UPF1, which is important to RNA metabolism and several pathways that are dysregulated in ALS. Activating UPF1 seems to ameliorate the effects of TDP-43, along with other pathways leading to ALS pathology. The new data come from experiments in four models: one neonate and one adult model with reflex impairments induced by TDP-43 toxicity; a mouse model with a mutation in the C9ORF72 gene; and a mouse model with a mutation in the gene FUS, which is primarily associated with fALS but is also seen in some patients with sporadic disease. For the studies in the neonate rats with the induced TDP-43 dysfunction, the researchers measured whether AAV-UPF1 prevented them from developing forelimb impairment. Over the course of 12 weeks, forelimb function remained intact in all seven of the treated rats, while around 75% of the seven untreated rats showed impairments by Week 4. In the adult rats with induced TDP-43 dysfunction, the researchers looked at how well the treatment reduced the degree of impairments in hindlimb reflexes. While the untreated rats’ reflexes degraded to 25% of normal by Week 6 of the study—and fell further as the study progressed—the treated rats’ reflexes degraded to only about 75% of normal, even by Week 24. For the mice with genetic disease, the researchers measured whether the treatment could protect against motor neuron loss. In the FUS model, treated mice had nearly the same amount of motor neurons as controls, while the untreated mice exhibited motor neuron loss. The same was true for mice in the C9ORF72 model: The treated animals were protected from cell loss, while those that didn’t receive the treatment were not. In addition to the rodent studies, the MeiraGTx team presented data on AAV-hUPF1, a version of AAV-UPF1 that had been made smaller and more potent to optimize it for the clinic. They showed that it improved survival in human neurons derived from induced pluripotent stem cells with mutations in the TDP43 or C9ORF72 genes and rescued motor neuron loss in mice with the FUS gene mutation. Finally, the researchers also presented data on a new capsid, AAV2-retro, to deliver the ALS gene therapy as well as other neuronal indications. It was able to transduce the therapy in the brains and spinal cords of primates and also showed an effect in ALS patient-derived neurons harboring different disease-causing mutations.   MeiraGTx is continuing to optimize the vector for the clinic and plans to start studies for an investigational new drug application in 2024, presentation documents said.