AXA1125

Long COVID affects an estimated 65 million people worldwide and can damage the brain, heart, blood vessels, and immune system long after infection. Researchers now link symptoms to lingering virus, inflammation, micro-clots, and disrupted energy metabolism. While structured rehab and pacing can improve quality of life, a growing list of experimental treatments—from antivirals and metformin to microbiome therapies and biologics—shows early promise. Clear answers, however, are still limited by small studies and the lack of large, definitive trials.Long COVID is defined as symptoms that last at least two months after an initial SARS-CoV-2 infection, with no other clear medical explanation. An estimated 65 million people worldwide are now affected, yet there are still no approved, evidence-based treatments. Researchers are working to better understand what drives the condition and to test a wide range of possible therapies, from structured rehabilitation programs to antivirals, blood thinners, anti-inflammatory drugs, supplements, and new biologic treatments. Scientists believe long COVID is fueled by several overlapping biological problems. These include lingering virus in the body, ongoing low-level inflammation marked by elevated IL-1β, IL-6, and TNF-α, and the formation of tiny blood clots caused by interactions between the viral spike protein and fibrinogen. Other contributing factors include auto-immunity, disruptions in gut bacteria, and impaired mitochondrial function. Together, these processes can damage multiple organs, leading to blood vessel dysfunction, heart inflammation, neuro-inflammation, small-fiber neuropathy, ME/CFS-like fatigue, menstrual changes, problems with blood sugar regulation, and kidney or liver injury. Rehabilitation and Non-Drug Approaches For people with mild symptoms in the early stages, non-drug treatments remain the first option. Clinical trials show that online, group-based physical and mental rehabilitation programs can improve quality of life. Breathing exercises and inspiratory-muscle training have also been shown to boost heart and lung fitness. Additional strategies may include pacing daily activities, cognitive and speech therapy, smell retraining, and dietary counseling. However, exercise that is not carefully supervised can worsen inflammation. For this reason, activity programs need to be gradual and adjusted based on symptoms. Antivirals and Early Treatment Effects Antiviral drugs taken during the initial COVID-19 infection appear to slightly reduce the risk of developing long COVID. In Japan, ensitrelvir lowered long-COVID rates by 25% among out-patients. In high-risk individuals, nirmatrelvir/ritonavir and molnupiravir were linked to about a 25% reduction in risk, while favipiravir showed little benefit. Researchers are also studying monoclonal antibodies that target the spike protein for possible effects on neuro-toxicity, although phase-3 trial results are not yet available. Medications Targeting Specific Symptoms Some treatments focus on particular complications such as clotting, autonomic nervous system problems, and immune imbalance. Low-dose naltrexone has been shown to reduce fatigue and lower platelet aggregation. Apheresis can remove micro-clots and auto-antibodies from the blood, but it is expensive and its benefits tend to be short-lived. Other medications are being tested for symptom relief. β-blockers are used to treat postural-tachycardia syndrome. Famotidine, intravenous immunoglobulin, SGLT-2 inhibitors, and GLP-1 agonists are under investigation for neurological, immune-related, heart, and kidney symptoms. Targeting Inflammation at Its Source Reducing inflammation early appears to be one of the most active areas of research. When started within seven days of infection, metformin lowered the risk of long COVID by 41%, likely by reducing mTOR signaling. Plant-based supplements containing quercetin, curcumin, and piperine improved fatigue compared with placebo. Other approaches include sulphur-thermal-water inhalation and enzymatically liberated salmon oil, both of which lowered CRP levels and helped restore the lung's protective barrier. Baricitinib and rapamycin, which act on JAK and mTOR pathways, are now entering multi-centre trials aimed at interrupting widespread STAT3-driven inflammation. Gut Health, Supplements, and Energy Metabolism Adjusting the gut microbiome may also help. The synbiotic SIM01 eased overall symptoms after six months. Small randomized trials suggest that high doses of vitamins C and D, coenzyme Q10, magnesium, and creatine-glucose blends can improve cellular energy production and blood vessel function. Early-stage studies also report benefits from N-acetyl-cysteine and the amino-acid blend AXA1125, both of which improved mitochondrial respiration and reduced fatigue. Experimental Biologics and Emerging Therapies New biologic treatments are exploring the role of fibrin-driven neuro-inflammation. A humanized antibody that blocks the inflammatory region of fibrinogen is currently in phase-1 trials after animal studies showed protection against neuronal loss. Another experimental therapy, the DNA aptamer BC007, removes G-protein-coupled-receptor auto-antibodies and reversed fatigue and poor capillary blood flow in a single patient, though larger trials are still needed. Other non-drug approaches have shown potential. Hyperbaric oxygen therapy improved cognition, sleep, and pain in a six-month randomized trial. Case series of acupuncture reported reductions in brain-fog and joint pain. Vaccines and Long COVID Outcomes Vaccination provides limited protection against long COVID after breakthrough infections, lowering risk by about 15 to 41%. Among people who already had long COVID symptoms, outcomes after a booster were mixed. About 17% improved, 21% worsened, and 62% saw no change. Where the Science Stands Now Although many potential treatments are showing early promise, most evidence still comes from small or open-label studies that rely on indirect outcome measures. Large, adaptive randomized trials with consistent definitions and biomarker-based patient grouping are urgently needed. Until clearer answers emerge, experts support a flexible, team-based approach that includes early antiviral use, carefully graded exercise, targeted anti-thrombotic and anti-inflammatory treatments, gut microbiome support, and personalized rehabilitation. This strategy reflects the diverse, multi-system nature of long COVID while researchers continue searching for definitive, mechanism-based cures.

在后新冠时代，那些曾经在疫情期间销售额攀上神坛的药物逐渐走向没落，而取而代之的是一类以治疗新冠后遗症Long COVID（长新冠）为代表的药物。 以这一概念为卖点的Biotech公司仍然能在2024年这个时间点获取一定的融资和NIH层面上的补贴（NIH在去年启动它自己关于长新冠的一揽子试验，用来测试潜在的长冠状病毒肺炎疗法，会给予参与企业一定补贴），但在最近这一概念似乎在逐步走向破灭。 越来越多的相关公司在这一概念的尝试中受到重挫。 GeNeuro：“黑暗”势力遭横扫出局 GeNeuro公司的卖点是利用人类基因组中未解明的黑暗区域来治疗Long-Covid，去年10月该公司宣布与Alphabet（谷歌母公司）旗下的精准健康技术公司Verily合作，研究与SARS-CoV-2感染中促炎HERV-W包膜蛋白（W-ENV）激活相关的生物标志物。 而通过这一研究的产物就是该公司的长新冠疗法——抗HERV-W-Env抗体temelimab，GeNeuro也因此在瑞士、西班牙和意大利招募了203名长冠状病毒肺炎患者进行II期临床研究。 然而，II期临床并不顺利，上上周五该公司告诉投资者它并没有达到主要终点和大多数次要终点。现在这家公司的母公司GeNeuro SA已经裁减了该公司九份雇佣协议中的七份，所有的高级管理人员都被裁撤。 Axcella：错误的战略决策 Axcella本身是知名风投Flagship Pioneering孵化的产物之一，但这家公司却没有Moderna那样的好运气。 这家公司主要开发的是内源性调节剂，核心管线AXA1125。实际上最开始这一管线在其他领域的表现不算很糟糕，是Axcella错误的战略决策彻底葬送了AXA1125的未来。 AXA1125在NASH领域一度取得积极进展，最开始也一直针对这一领域布局。2022年2月，AXA1125获得FDA授予治疗NASH的快速通道资格。同年9月，Axcella公布了AXA1125治疗NASH的全球IIb期临床研究中期结果，显示多项积极数据。然而，仅3个月后，Axcella突然决定停止AXA1125针对NASH的II期临床研究，掉头开发Long COVID。 然后结果也看到了，AXA1125在Long COVID的IIa期试验中未能达到主要终点。 2023年12月4日，Axcella向美国证券交易委员会（SEC）提交文件，将进行财产清算并解散公司。其股东以压倒性多数批准了解散和清算的决议。 Virios Therapeutics：长新冠失败甩锅毒株 Virios Therapeutics这家公司管线主要是抗病毒药物IMC-1（泛昔洛韦+塞来昔布），这里主要针对的是协同抑制单纯疱疹病毒HSV-1的激活和复制，最终降低HSV-1介导的疾病症状。HSV-1是疱疹病毒科中感染人类的病毒，在人群中普遍存在且通过接触传染。由HSV-1激活的过度免疫应答被认为是如纤维肌痛（FM）、肠易激疾病（IBS）、慢性疲劳综合征（CFS）等慢性疾病的发病原因。 而长新冠的一种理论就认为是新冠诱导了HSV-1激活的过度免疫应答导致患者纤维肌痛。 有趣的是，Virios Therapeutics在IMC-1临床失败时，给出的理由过于离谱。 说是不同的COVID-19毒株与HSV-1激活之间的相互作用造成了不同时期入组患者疗效上的差异？？？ 这一过于离谱的理由毫无证据，市场也完全不信，这导致这家公司股价跌至0.2美元，基本丧失了流动性。 现在这家公司基本在破产边缘徘徊…… Tonix：山穷水尽 Tonix Pharmaceuticals对纤维肌痛样长冠状病毒肺炎的治疗也同样未能作为疼痛治疗而脱颖而出。去年9月，该公司药物TNX-102 SL的在对长冠状病毒肺炎患者的2期试验中，与安慰剂相比，在疼痛症状方面没有显示出统计学上的显著改善。 笼罩着Tonix的是一条快速萎缩的现金跑道，目前该公司的现金流赛道几乎耗竭，根据今年第一季度披露只剩下了704.90万美元，现在只能靠着和美国政府之间的一些合同获得微薄的收入，也不知道这家公司要如何渡过这个2024年…… 总结 许多Biotech看到了去研究长新冠的补贴而选择了开设相应管线，但是却忽视了管线开设是否合理，毕竟长新冠概念本身其实就很抽象，之前也有研究指出长新冠的发生率其实没想象的那么高，开发难度可能也较为困难。例如辉瑞的Paxlovid实际上就在这种从治疗新冠延伸到治疗长新冠的过程中失败了。 类似的Biotech公司还有Tevogen Bio，NLS Pharmaceutics，AIM ImmunoTech，Laurent Pharmaceuticals等等。他们未来是否会出现类似的情况值得一看。