HDV 单药治疗的第 3 阶段数据看起来很有希望

StephenW

HDV 单药治疗的第 3 阶段数据看起来很有希望

一项新的 3 期试验的中期结果支持 bulevirtide（Hepcludex，Gilead Sciences）单药治疗丁型肝炎病毒慢性感染患者的安全性和有效性。

国际多中心调查得出结论，使用一流的进入抑制剂治疗 24 周与病毒 RNA 的显着减少和生化疾病活动的改善有关。研究人员表示，这些发现证实了欧盟委员会 2020 年 8 月对布列韦肽的有条件批准，该药物已获得美国 FDA 的突破性疗法指定。

Bulevirtide 是一种源自乙型肝炎表面抗原的肽。 “在之前的 2 期试验 [MYR202/MYR203] 中，我们表明，如果每天给丁型肝炎患者注射不同剂量的这种肽，HDV RNA 会随着时间的推移呈线性下降，这反映了感染细胞的损失，”德国汉诺威医院胃肠病学、肝病学和内分泌学系主任、医学博士 Heiner Wedemeyer 说。

目前的研究是 MYR301 3 期试验的 24 周中期分析，该试验包括 150 名同时感染乙型肝炎病毒 (HBV) 和 HDV 的患者（57% 男性；平均年龄 41.8 岁）。该试验的参与者被随机分配到三组之一：48 周未接受抗病毒治疗，然后每天 10 毫克布勒韦肽治疗 96 周（对照组 A；n=51）；每天 2 毫克布勒韦肽（B 组；n=49）；或每天 10 毫克布列韦肽（C 组；n=50）。


B 组和 C 组的患者接受了 144 周的药物治疗，无治疗随访期为 96 周。试验的主要终点是检测不到 HDV RNA 或 HDV​​ RNA 降低至少 210 IU/mL 和丙氨酸氨基转移酶 (ALT) 在第 48 周正常化的综合反应。次要终点包括检测不到 HDV RNA、HDV RNA 下降RNA 至少 210 IU/mL，ALT 正常化，HBsAg 下降至少 110 IU/mL。

在 2021 年国际肝脏大会（摘要 LBP-2730）上的演讲中，Wedemeyer 博士报告说，24 周后，对照组（A 组）中没有一个患者达到病毒学和生化联合反应，而 36.7% 的患者在 B 组和 C 组中有 28.0% 的人这样做（P<0.0001 与 A 组）。

HDV RNA 也观察到了类似的结果，在基线和第 24 周之间，A 组 3.8%、B 组 55.1% 和 C 组 68% 的患者下降至少 210 IU/mL（P<0.0001 vs. A 组） )，据研究人员称。在第 24 周，B 组 53.1% 的患者和 C 组 38% 的患者实现 ALT 正常化，而 A 组为 5.9%（P<0.0001）。研究人员报告说，在第 24 周时，除一名患者外，所有患者的 HBsAg 水平均未显示相关下降。

“重要的信息是，2 期试验的结果得到了完全证实，”韦德迈尔博士说。

安全性分析发现，在接受研究药物治疗的患者中，与治疗相关的不良事件更为常见。 “正如预期的那样，胆汁酸增加是因为布列韦肽的作用方式阻断了胆汁盐转运蛋白，”韦德迈尔博士解释说。 “尽管如此，没有出现意外的严重不良事件。”

研究人员承认，只有一小部分患者完全检测不到 HDV RNA，但他们对结果感到鼓舞。 “这证实了我们可以在现实环境中使用这种药物，”韦德迈尔博士说。 “对于丁型肝炎患者来说，这是激动人心的时刻。”

德国弗莱堡大学医院的主治医师 Tobias BÖttler 医学博士告诉 Gastroenterology & Endoscopy News，bulevitide 有可能在管理活动性丁型肝炎感染患者方面产生重大影响。 “在剂量、治疗持续时间和可能的联合疗法方面，我们仍然需要学习很多东西，因为一些数据表明，与干扰素联合使用甚至更有效，”他说。 “根据我们目前掌握的数据，它似乎耐受性良好，副作用很小。展望未来，我们甚至可以在乙型肝炎单一感染患者中使用这种药物，但这需要更多的临床试验数据。”

——迈克尔·弗莱西德斯

StephenW

  Phase 3 Data Look Promising for HDV Monotherapy

Interim results from a new phase 3 trial support the safety and efficacy of monotherapy with bulevirtide (Hepcludex, Gilead Sciences) in patients with chronic infection with the hepatitis delta virus.

The international, multicenter investigation concluded that 24 weeks of treatment with the first-in-class entry inhibitor was associated with significant decreases in viral RNA, and improvements in biochemical disease activity. The researchers said the findings affirm the August 2020 conditional approval by the European Commission of bulevirtide, which has received a breakthrough therapy designation from the FDA in the United States.

Bulevirtide is a peptide derived from the hepatitis B surface antigen. “In previous phase 2 trials [MYR202/MYR203], we showed that if you inject hepatitis D patients with this peptide on a daily basis with different doses, you get a linear decline in HDV RNA over time, which reflects a loss of infected cells,” said Heiner Wedemeyer, MD, the chair of the Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical Hospital, in Germany.

The current study was a 24-week interim analysis of the MYR301 phase 3 trial, which comprised 150 patients (57% men; mean age, 41.8 years) coinfected with hepatitis B virus (HBV) and HDV. Participants in the trial were randomized to one of three groups: no antiviral treatment for 48 weeks followed by 10 mg daily of bulevirtide for 96 weeks (control arm A; n=51); 2 mg daily of bulevirtide (arm B; n=49); or 10 mg daily of bulevirtide (arm C; n=50).


Patients in arms B and C received the drug for 144 weeks, with a treatment-free follow-up period of 96 weeks. The primary end point of the trial was a combined response of undetectable HDV RNA or HDV RNA reduction of at least 210 IU/mL and normalization of alanine aminotransferase (ALT) at week 48. Secondary end points included undetectable HDV RNA, a fall in HDV RNA of at least 210 IU/mL, normalization of ALT, and a decline in HBsAg of at least 110 IU/mL.

In a presentation at the 2021 International Liver Congress (abstract LBP-2730), Dr. Wedemeyer reported that after 24 weeks, none of the patients in the control group (arm A) achieved a combined virologic and biochemical response, whereas 36.7% of patients in arm B and 28.0% of those in arm C did so (P<0.0001 vs. arm A).

Similar results were observed for HDV RNA, which fell by at least 210 IU/mL between baseline and week 24 in 3.8% of patients in arm A, 55.1% in arm B and 68% in arm C (P<0.0001 vs. arm A), according to the researchers. At week 24, normalization of ALT was achieved by 53.1% of patients in arm B and 38% in arm C, compared with 5.9% in arm A (P<0.0001). Levels of HBsAg did not show relevant declines in all but one patient at week 24, the researchers reported.

“The important message is that the findings of the phase 2 trials were exactly confirmed,” Dr. Wedemeyer said.

Safety analyses found that treatment-related adverse events were much more common in patients treated with the study drug. “As was expected, bile acids increased because bulevirtide’s mode of action blocks a bile salt transporter,” Dr. Wedemeyer explained. “Nevertheless, there were no unexpected serious adverse events.”

The researchers acknowledged that only a small proportion of patients had completely undetectable HDV RNA, but they were encouraged by the results. “This confirms that we can use the drug in a real-world setting,” Dr. Wedemeyer said. “These are exciting times for hepatitis delta patients.”

Tobias BÖttler, MD, an attending physician at the University Hospital Freiburg, in Germany, told Gastroenterology & Endoscopy News that bulevirtide has the potential to make a significant difference in managing patients with active hepatitis delta infection. “We still need to learn a lot with regard to dosing, treatment duration and possible combination therapies, as some data suggest that combination with interferon is even more potent,” he said. “It appears to be well tolerated with little side effects, based on the data we currently have. Going forward, we might even be able to use the drug in hepatitis B–monoinfected patients, but that requires a lot more data from clinical trials.”

—Michael Vlessides