无 F508del CFTR 变异的囊性纤维化患者使用依伐卡托、泰它西普和埃拉卡托的法国扩大同情用药计划：一项真实世界研究。
The expanded French compassionate programme for elexacaftor-tezacaftor-ivacaftor use in people with cystic fibrosis without a F508del CFTR variant: a real-world study.
机构信息
Université Paris-Cité, Institut Cochin, CNRS, INSERM, Paris, France; Respiratory Medicine and Cystic Fibrosis National Reference Center, Hôpital Cochin, AP-HP, Paris, France; ERN-Lung CF network, Frankfurt, Germany.
ERN-Lung CF network, Frankfurt, Germany; Centre de Référence Maladies Rares, Mucoviscidose et Affections Liées à CFTR, Pneumologie Pédiatrique et Allergologie, Hôpital Necker Enfants Malades, AP-HP, Paris, France; Université Paris-Cité, Institut Necker Enfants Malades, INSERM U1151, Paris, France.
出版信息
Lancet Respir Med. 2024 Nov;12(11):888-900. doi: 10.1016/S2213-2600(24)00208-X. Epub 2024 Aug 13.
BACKGROUND
Elexacaftor-tezacaftor-ivacaftor has been approved in Europe for people with cystic fibrosis with at least one F508del CFTR variant. Additionally, it is approved by the US Food and Drug Administration (FDA) for people with cystic fibrosis with at least one of 177 rare variants. The aims of this study were to describe the clinical response to elexacaftor-tezacaftor-ivacaftor for people with cystic fibrosis without a F508del CFTR variant in France and to determine CFTR variant responsiveness to elexacaftor-tezacaftor-ivacaftor based on the observed clinical response.
METHODS
The French compassionate programme expanded access to elexacaftor-tezacaftor-ivacaftor to people with cystic fibrosis, aged 6 years and older, without a F508del variant, excluding those with two variants previously characterised as non-responsive. Participants at France's 47 cystic fibrosis centres were given a 4-6 week trial of elexacaftor-tezacaftor-ivacaftor and response was determined by a centralised committee based on evolution of clinical data, lung function, and sweat chloride concentration. Responsiveness of individual CFTR variants was derived from observed clinical responses.
FINDINGS
The first compassionnate programme was launched on May 19, 2022; by March 8, 2024, 516 people with cystic fibrosis had been identified for inclusion in this real-word study: 37 were not included due to the presence of two variants previously characterised as non-responsive to elexacaftor-tezacaftor-ivacaftor, and 479 (229 females [48%] and 250 males [52%]) received elexacaftor-tezacaftor-ivacaftor for 4-6 weeks. Among 443 participants who received no CFTR modulator before elexacaftor-tezacaftor-ivacaftor, 83 had at least one FDA-approved variant, of whom 81 (98%) were responders and continued elexacaftor-tezacaftor-ivacaftor; in responders, mean absolute change in sweat chloride was -44·5 mmol/L (95% CI -39·1 to -49·8) and percentage of predicted FEV (ppFEV) was 11·1 percentage points (95% CI 8·4 to 13·7; both comparisons p<0·0001). Among 360 participants with no FDA-approved variant and no previous CFTR modulator, 177 (49%) were responders; in responders, mean absolute change in sweat chloride was -20·5 mmol/L (-17·2 to -23·8) and ppFEV was 13·2 percentage points (11·4 to 15·0; both comparisons p<0·0001). Among 36 participants who were receiving ivacaftor before elexacaftor-tezacaftor-ivacaftor, 32 (89%) continued elexacaftor-tezacaftor-ivacaftor. Of 251 individual CFTR variants, 64 (28 FDA-approved) were classified as responsive or possibly responsive to elexacaftor-tezacaftor-ivacaftor, and 123 (two FDA-approved) as non-responsive or possibly non-responsive to elexacaftor-tezacaftor-ivacaftor.
INTERPRETATION
In France, over half of the population with cystic fibrosis without a F508del variant responded to elexacaftor-tezacaftor-ivacaftor, with most responders having no FDA-approved variant. The treatment period was relatively short and further research is warranted to describe the long-term safety and effectiveness of elexacaftor-tezacaftor-ivacaftor in this population.
FUNDING
Association Vaincre la Mucoviscidose, Société Française de la Mucoviscidose, and Filière Maladies Rares MUCO-CFTR.
背景
依伐卡托与泰比卡托和艾克卡托联合制剂（elexacaftor-tezacaftor-ivacaftor）已在欧洲获批用于至少携带一种 F508del CFTR 变异的囊性纤维化患者。此外，它也被美国食品和药物管理局（FDA）批准用于至少携带 177 种罕见变异中的一种的囊性纤维化患者。本研究的目的是描述在法国，无 F508del CFTR 变异的囊性纤维化患者使用依伐卡托与泰比卡托和艾克卡托联合制剂的临床反应，并根据观察到的临床反应确定 CFTR 变异对依伐卡托与泰比卡托和艾克卡托联合制剂的反应性。
方法
法国的同情用药项目扩大了依伐卡托与泰比卡托和艾克卡托联合制剂的使用范围，纳入了年龄在 6 岁及以上、无 F508del 变异的囊性纤维化患者，但排除了之前被确定为无反应的两种变异的患者。法国 47 个囊性纤维化中心的参与者接受了依伐卡托与泰比卡托和艾克卡托联合制剂的 4-6 周试验，根据临床数据、肺功能和汗液氯化物浓度的变化，由一个中央委员会来确定反应情况。个别 CFTR 变异的反应性是从观察到的临床反应中得出的。
结果
第一个同情用药项目于 2022 年 5 月 19 日启动；截至 2024 年 3 月 8 日，已有 516 名囊性纤维化患者被确定纳入本真实世界研究：由于存在两种之前被确定为对依伐卡托与泰比卡托和艾克卡托联合制剂无反应的变异，37 名患者未被纳入；479 名（229 名女性[48%]和 250 名男性[52%]）接受了依伐卡托与泰比卡托和艾克卡托联合制剂 4-6 周治疗。在 443 名之前未接受过 CFTR 调节剂治疗的参与者中，有 83 名患者携带至少一种 FDA 批准的变异，其中 81 名（98%）为应答者并继续接受依伐卡托与泰比卡托和艾克卡托联合制剂治疗；在应答者中，汗液氯化物的绝对变化为-44.5mmol/L（95%CI -39.1 至-49.8），预计 FEV 的百分比为 11.1 个百分点（95%CI 8.4 至 13.7；两者比较 p<0.0001）。在 360 名无 FDA 批准的变异且无先前 CFTR 调节剂治疗的参与者中，有 177 名（49%）为应答者；在应答者中，汗液氯化物的绝对变化为-20.5mmol/L（-17.2 至-23.8），预计 FEV 的百分比为 13.2 个百分点（11.4 至 15.0；两者比较 p<0.0001）。在 36 名之前接受依伐卡托治疗的参与者中，有 32 名（89%）继续接受依伐卡托与泰比卡托和艾克卡托联合制剂治疗。在 251 个单独的 CFTR 变异中，有 64 个（28 个 FDA 批准）被归类为对依伐卡托与泰比卡托和艾克卡托联合制剂有反应或可能有反应，有 123 个（两个 FDA 批准）被归类为无反应或可能无反应。
解释
在法国，无 F508del 变异的囊性纤维化患者中，有一半以上对依伐卡托与泰比卡托和艾克卡托联合制剂有反应，大多数应答者没有 FDA 批准的变异。治疗期相对较短，需要进一步研究来描述依伐卡托与泰比卡托和艾克卡托联合制剂在这一人群中的长期安全性和有效性。
资金
Vaincre la Mucoviscidose 协会、法国囊性纤维化协会和 MUCO-CFTR 罕见疾病网络。
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