Ultomiris regulatory submission accepted under FDA Priority Review in the US for adults with generalised myasthenia gravis

21 December 2021 07:00 GMT

Submission based on positive Phase III trial in whichUltomiris significantly improved functional activities as measured by Myasthenia Gravis-Activities of Daily Living Profile

The supplemental Biologics License Application (sBLA) forUltomiris(ravulizumab-cwvz) in adults with generalised myasthenia gravis (gMG) has been accepted for Priority Review by the US Food and Drug Administration (FDA).

The FDA set a Prescription Drug User Fee Act date during the second quarter of 2022, following use of a rare disease priority review voucher by Alexion, AstraZeneca’s Rare Disease group.

gMG is a rare, debilitating, chronic, autoimmune neuromuscular disease that leads to a loss of muscle function and severe weakness.1美国GMG的诊断患病率估计为64,000。2-10

Alexion首席执行官Marc Dunoyer说：“孤独was the first new treatment approved for this devastating disease in approximately 60 years, and this filing forUltomiris展示了Alexion继续致力于改善GMG患者的预后。第三阶段试验表明Ultomirismay help a broader range of patients including those with milder symptoms or who are earlier in their treatment journey.”

The sBLA submission in the US is based on results from the Phase III trial ofUltomirisin gMG, which wereannouncedby Alexion in July 2021, and showed efficacy as early as Week 1 and sustained for 52 weeks (26 weeks randomised controlled period + 26 weeks of open-label extension). In the trial, the safety profile ofUltomiris与在第三阶段试验中观察到的一致Ultomirisin paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS).

监管提交Ultomirisfor the treatment of gMG are also currently under review with health authorities in the European Union (EU) and Japan.

Notes

gMG
GMG是一种罕见的自身免疫性疾病，其特征是严重的肌肉无力。在GMG中，炎症会在神经细胞和控制肌肉之间的连接点（称为神经肌肉连接或NMJ）引起损害。这种损害导致大脑与肌肉之间的交流破裂，导致肌肉功能的丧失和严重的无力。1

About 85% of people with gMG produce specific antibodies that bind to the surface of the cells at the NMJ.1This binding activates the complement cascade and causes the immune system to attack the NMJ. People with gMG can suffer from initial symptoms, such as slurred speech, droopy eyelids, double vision, and lack of balance, which can often lead to more severe symptoms like choking, impaired swallowing, extreme fatigue and even episodes of respiratory failure.11,12

gMG can occur at any age, but it most commonly begins for women before the age of 40 and for men after the age of 60.13-15

Clinical trial
全球III期随机，双盲，安慰剂对照，多中心26周试验评估了的安全性和功效Ultomirisin adults with gMG who were not previously treated with a complement inhibitor medicine. The trial enrolled 175 patients across North America, Europe, Asia-Pacific and Japan. Participants were required to have a confirmed myasthenia gravis diagnosis at least six months prior to the screening visit with a positive serologic test for anti-AChR antibodies, Myasthenia Gravis-Activities of Daily Living Profile (MG-ADL) total score of at least 6 at trial entry and Myasthenia Gravis Foundation of America Clinical Classification Class II to IV at screening. There was no requirement for prior treatment failure, and patients could stay on stable standard of care medicines, with a few exceptions, for the duration of the trial.16

Patients were randomised 1:1 to receiveUltomirisor placebo for a total of 26 weeks. Patients received a single weight-based loading dose on Day 1, followed by regular weight-based maintenance dosing beginning on Day 15, every eight weeks. The primary endpoint of change from baseline in the MG-ADL total score at Week 26 was assessed along with multiple secondary endpoints evaluating improvement in disease-related and quality-of-life measures.

完成随机控制期的患者有资格继续进行开放标签的延长期，以评估安全性和有效性Ultomirisfor up to two years, which is ongoing. At the time of the preliminary analysis of the open-label extension period, 75 patients had completed 26 weeks of treatment, for a total of 52 weeks of treatment.

Ultomiris
Ultomiris（Ravulizumab）是第一个也是唯一的长效C5补体抑制剂，可立即提供，完整和持续的补体抑制作用。该药物通过抑制末端补体级联反应（人体免疫系统的一部分）中的C5蛋白来起作用。当以不受控制的方式激活时，补充级联反应过度，导致身体攻击自己的健康细胞。Ultomirisis administered intravenously every eight weeks or, for paediatric patients less than 20kg, every four weeks, following a loading dose.Ultomirisis approved in the US for the treatment of adults and children (one month of age and older) with PNH; in the EU for adults, as well as for children (with a body weight of 10kg or above) and adolescents with PNH who experience haemolysis with clinical symptom(s) indicative of high disease activity, as well as for individuals who are clinically stable after having been treated with孤独至少在过去的六个月中；在日本，作为PNH成年人的治疗。在美国，它还批准了Ahus抑制成人和儿科（一个月及以上）患者的补体介导的血栓性微血管病。，以及日本的成人和患有Ahus的儿童。

亚历山大
亚历山大, AstraZeneca Rare Disease, is the group within AstraZeneca focused on rare diseases, created following the 2021 acquisition of Alexion Pharmaceuticals, Inc. As a leader in rare diseases for nearly 30 years, Alexion is focused on serving patients and families affected by rare diseases and devastating conditions through the discovery, development and commercialisation of life-changing medicines. Alexion focuses its research efforts on novel molecules and targets in the complement cascade and its development efforts on haematology, nephrology, neurology, metabolic disorders, cardiology and ophthalmology. Headquartered in Boston, Massachusetts, Alexion has offices around the globe and serves patients in more than 50 countries.

欧洲杯微信买球
欧洲杯微信买球阿斯利康（LSE/Sto/nasdaq：AZN）是一家全球性的，由科学领导的生物制药公司，重点介绍肿瘤学，稀有疾病和生物药物在内的发现，开发和商业化，包括心血管，肾脏，肾脏和代谢，以及包括心血管疾病和生物药物和免疫学。阿斯利康总部位于英国剑桥，在100多个国家 /地欧洲杯微信买球区运营，其创新药物被全球数百万患者使用。请拜访astrazeneca.com并在Twitter上关注公司@AstraZeneca。

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参考

  1. Howard, J. F., (2017). Myasthenia gravis: the role of complement at the neuromuscular junction. Annals of The New York Academy of Sciences, 1412(1), 113-128.
  2. Fang，F.，Sveinsson，O.，Thormar，G.，Granqvist，M.，Askling，J.，Lundberg，I.E.，。。。Piehl，F。（2015）。肌无力的肌无力谱系：一项基于瑞典人群的研究。J Intern Med，277（5），594-604。doi：10.1111/joim.12310
  3. Grob, D., Brunner, N., Namba, T., and Pagala, M. (2008). Lifetime course of myasthenia gravis. Muscle Nerve 37: 141-149.
  4. Suh, J., Goldstein, J. M., & Nowak, R. J. (2013). Clinical Characteristics of Refractory Myasthenia Gravis Patients. The Yale Journal of Biology and Medicine, 86(2), 255-260.
  5. Joensen P.（2014）。北大西洋孤立人口中的肌无力发生率。Acta Neurol Scand 130：222–228。
  6. Lefter, S., Hardiman, O., and Ryan, AM. (2016). A population-based epidemiologic study of adult neuromuscular disease in the Republic of Ireland. Neurology 88:304–313.
  7. Pallaver, F., Riviera, A. P., Piffer, S., Ricciardi, R., Roni, R., Orrico, D., & Bonifati, D. M. (2011). Change in myasthenia gravis epidemiology in Trento, Italy, after twenty years. Neuroepidemiology, 36(4), 282-287. doi:10.1159/000328863
  8. Santos, E., Coutinho, E., Moreira, I., Silva, A. M., Lopes, D., Costa, H., . . . Goncalves, G. (2016). Epidemiology of myasthenia gravis in Northern Portugal: Frequency estimates and clinical epidemiological distribution of cases. Muscle Nerve, 54(3), 413-421. doi:10.1002/mus.25068
  9. Robertson, NP., Deans, J., and Compston DAS. (1998). Myasthenia gravis: a population based epidemiological study in Cambridgeshire, England. J Neurol Neurosurg Psychiatry, 65:492–496.
  10. Zieda, A., Ravina, K., Glazere, I., Pelcere, L., Naudina, M. S., Liepina, L., . . . Kenina, V. (2018). A nationwide epidemiological study of myasthenia gravis in Latvia. Eur J Neurol, 25(3), 519-526. doi:10.1111/ene.13535
  11. Myasthenia Gravis Fact Sheet. (2020, April 27). National Institutes of Neurological Disorders and Stroke. Available这里。2021年10月访问。
  12. Ding J., Zhao, S., Ren, K., Dang, D., Li, H., Wu, F., Zhang, M., Li, Z., & Guo, J. (2020). Prediction of generalization of ocular myasthenia gravis under immunosuppressive therapy in Northwest China. BMC Neurology, 20(238).
  13. Myasthenia Gravis. National Organization for Rare Disorders (NORD). Available这里。2021年10月访问。
  14. Howard，J。F.（2015）。MG的临床概述。可用的这里。2021年10月访问。
  15. Sanders, D. B., Raja, S. M., Guptill J. T., Hobson-Webb, L. D., Juel, V. C., & Massey, J. M. (2020). The Duke myasthenia gravis clinic registry: I. Description and demographics. Muscle & Nerve, 63(2), 209-216.
  16. ClinicalTrials.gov. Safety and Efficacy Study of Ravulizumab in Adults With Generalized Myasthenia Gravis. NCT Identifier: NCT03920293. Available online. Accessed November 2021

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