School of Medicine, University of Washington, Seattle, WA.
Elson S. Floyd College of Medicine, Washington State University, Spokane, WA.
Am J Obstet Gynecol. 2023 Dec;229(6):647-655. doi: 10.1016/j.ajog.2023.07.042. Epub 2023 Jul 27.
Preterm birth remains one of the most urgent unresolved medical problems in obstetrics, yet only 2 therapeutics for preventing preterm birth have ever been approved by the United States Food and Drug Administration, and neither remains on the market. The recent withdrawal of 17-hydroxyprogesterone caproate (17-OHPC, Makena) marks a new but familiar era for obstetrics with no Food and Drug Administration-approved pharmaceuticals to address preterm birth. The lack of pharmaceuticals reflects a broad and ineffective pipeline hindered by extensive regulatory hurdles, soaring costs of performing drug research, and concerns regarding adverse effects among a particularly vulnerable population. The pharmaceutical industry has historically limited investments in research for diseases with similarly small markets, such as cystic fibrosis, given their rarity and diminished projected financial return. The Orphan Drug Act, however, incentivizes drug development for "orphan diseases", defined as affecting <200,000 people in the United States annually. Although the total number of preterm births in the United States exceeds this threshold annually, the early subset of preterm birth (<34 weeks' gestation) would qualify, which is predominantly caused by inflammation and infection. The scientific rationale for classifying preterm birth into early and late subsets is strong given that their etiologies differ, and therapeutics that may be efficacious for one subset may not work for the other. For example, antiinflammatory therapeutics would be expected to be highly effective for early but not late preterm birth. A robust therapeutic pipeline of antiinflammatory drugs already exists, which could be used to target spontaneous early preterm birth, in combination with antibiotics shown to sterilize the amniotic cavity. New applications for therapeutics targeting spontaneous early preterm birth could categorize as orphan disease drugs, which could revitalize the preterm birth therapeutic pipeline. Herein, we describe why drugs targeting early preterm birth should qualify for orphan status, which may increase pharmaceutical interest for this vitally important obstetrical condition.
早产仍然是产科领域最紧迫的未解决的医学问题之一，但美国食品和药物管理局 (FDA) 仅批准了 2 种预防早产的疗法，而且这两种疗法都已不再上市。最近，17-羟孕酮己酸酯 (17-OHPC，Makena) 的撤市标志着产科领域一个新的但却似曾相识的时代的到来，因为没有 FDA 批准的药物可用于治疗早产。缺乏药物反映了一个广泛而无效的研发管道，受到广泛的监管障碍、药物研究成本飙升以及对特定弱势群体不良影响的担忧的阻碍。制药行业历来对市场规模同样较小的疾病（如囊性纤维化）的研究投资有限，因为这些疾病的发病率较低，预计财务回报也较低。然而，孤儿药法案鼓励为“孤儿病”开发药物，定义为每年在美国影响<200,000 人的疾病。尽管美国每年的早产总数超过这一阈值，但<34 周妊娠的早产早期亚组符合条件，这主要是由炎症和感染引起的。将早产分为早期和晚期亚组的科学依据是强有力的，因为它们的病因不同，对一个亚组有效的治疗方法可能对另一个亚组无效。例如，抗炎治疗方法可能对早期早产非常有效，但对晚期早产无效。现已有针对炎症的治疗药物，可用于治疗自发性早产早期，与已证明可使羊膜腔无菌的抗生素联合使用。针对自发性早产早期的治疗药物的新应用可能被归类为孤儿病药物，这可能使早产治疗药物研发管道恢复活力。在此，我们描述了为什么针对早产早期的药物应该有资格获得孤儿药地位，这可能会增加制药公司对这种极其重要的产科疾病的兴趣。
