The glucagon and GLP-1 receptor dual agonist DD01 for metabolic dysfunction-associated steatotic liver disease and steatohepatitis (DD01-DN-02): 12-week results from a randomised, double-blind, multicentre, placebo-controlled, phase 2 trial.

DD01 is a liver-targeted GLP-1 receptor and glucagon dual agonist being investigated for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) and MASH.

DD01是一种正在研究中的针对肝脏的GLP-1受体和胰高血糖素双重激动剂，用于治疗代谢功能障碍相关性脂肪肝病（MASLD）和MASH。

The DD01-DN-02 trial aimed to evaluate the efficacy and safety of DD01 in adults with MASLD or MASH; this initial analysis reports prespecified 12-week outcomes to assess early hepatic effects.

DD01-DN-02试验旨在评估DD01在成人MASLD或MASH患者中的疗效和安全性；这项初步分析报告了预先设定的12周结果，以评估早期肝脏效应。

Methods

DD01-DN-02 is an ongoing, randomised, double-blind, multicentre, placebo-controlled, phase 2 trial conducted at 12 outpatient clinical sites in the USA.

DD01-DN-02是一项正在进行的、随机的、双盲的、多中心的、安慰剂对照的、2期试验，该试验在美国的12个门诊临床站点进行。

Adults aged 18-70 years with obesity or who were overweight (BMI ≥25 kg/m2) were included in the study.

研究包括了年龄在18-70岁之间的肥胖或超重（BMI ≥25 kg/m2）的成人。

Patients with MASLD or MASH underwent liver biopsy and MRI-proton density fat fraction (PDFF) and were eligible if liver fat content was 10% or higher with metabolic risk factors, or if the biopsy confirmed MASH with a non-alcoholic fatty liver disease activity score of at least 4.

MASLD或MASH患者进行了肝活检和MRI-质子密度脂肪分数（PDFF），如果肝脏脂肪含量为10%或更高且具有代谢风险因素，或者活检确认为MASH且非酒精性脂肪肝病活动评分至少为4，则符合入选条件。

Participants were randomly assigned (1:1) to receive once-weekly subcutaneous DD01 40 mg or matched placebo over 48 weeks, dose-escalated over 2 weeks, using a centrally administered interactive response technology system.

参与者被随机分配（1:1）接受每周一次的皮下注射DD01 40 mg或匹配安慰剂，持续48周，剂量在2周内逐渐增加，使用中心管理的交互式响应技术系统。

The randomisation sequence was computer-generated by an independent statistician.

随机序列是由一名独立的统计学家通过计算机生成的。

Participants, investigators, study staff, outcome assessors, and the sponsor were masked to treatment assignment.

参与者、研究人员、研究工作人员、结果评估者和赞助商对治疗分配情况均不知情。

The primary endpoint was the proportion of participants having at least a 30% relative reduction in liver fat by MRI-PDFF at week 12, which was analysed in all randomly assigned participants receiving at least one dose of study drug or placebo.

主要终点是参与者在第12周通过MRI-PDFF测量的肝脏脂肪至少减少30%的比例，这在所有至少接受一次研究药物或安慰剂的随机分配参与者中进行了分析。

Safety analyses included all participants who received at least one dose of study drug.

安全性分析包括所有至少接受一次研究药物的参与者。

Missing primary endpoint data were handled using multiple imputation under a missing-at-random assumption.

缺失的主要终点数据在假设数据缺失是随机的情况下，使用多重插补法进行处理。

This trial is registered with ClinicalTrials.gov (NCT06410924) and is ongoing but closed to new participants.

这项试验已在ClinicalTrials.gov注册（NCT06410924），目前正在进行中，但已停止接受新参与者。

Results

Between June 13, 2024, and Jan 30, 2025, 67 eligible participants were enrolled, of whom 33 were randomly assigned to DD01 and 34 to placebo.

在2024年6月13日至2025年1月30日期间，共有67名符合条件的参与者被纳入研究，其中33人被随机分配到DD01组，34人被分配到安慰剂组。

The mean age of participants was 48·4 years (SD 10·6), 42 (63%) were female, 25 (37%) were male, 57 (85%) were White, and 52 (78%) participants had biopsy-confirmed MASH.

参与者的平均年龄为48.4岁（标准差10.6），42人（63%）为女性，25人（37%）为男性，57人（85%）为白人，52人（78%）的参与者有活组织检查确认的MASH。

At week 12, 25 (76%) of 33 participants receiving DD01 had a 30% or higher reduction in liver fat versus four (12%) of 34 participants receiving placebo (adjusted common odds ratio 28·8 [95% CI 7·2-115·2]; adjusted relative risk 6·3 [95% CI 2·5-15·9]; p<0·0001).

在第12周，接受DD01治疗的33名参与者中有25人（76%）的肝脏脂肪减少了30%或更多，而接受安慰剂的34名参与者中只有4人（12%）达到了这一水平（调整后的共同优势比为28.8 [95% CI 7.2-115.2]；调整后的相对风险为6.3 [95% CI 2.5-15.9]；p<0.0001）。

Treatment-emergent adverse events occurred in 28 (85%) of 33 participants receiving DD01 and 23 (68%) of 34 participants receiving placebo.

在接受DD01治疗的33名参与者中，有28人（85%）出现了治疗后不良事件，而在接受安慰剂的34名参与者中，有23人（68%）出现了治疗后不良事件。

The most common adverse events were nausea (18 [55%] of 33 participants assigned DD01; six [18%] of 34 participants assigned placebo), diarrhoea (nine [27%] of 33; six [18%] of 34), and vomiting (ten [30%] of 33; four [12%] of 34).

最常见的不良事件是恶心（在被分配DD01的33名参与者中有18人[55%]；在被分配安慰剂的34名参与者中有六人[18%]），腹泻（在33人中有九人[27%]；在34人中有六人[18%]），以及呕吐（在33人中有十人[30%]；在34人中有四人[12%]）。

Treatment-emergent adverse events led to treatment discontinuation in four (12%) of 33 participants in the DD01 group and one (3%) of 34 participants in the placebo group.

治疗后不良事件导致DD01组的33名参与者中有四人（12%）停止治疗，而安慰剂组的34名参与者中有一人（3%）停止治疗。

Two (6%) treatment-emergent serious adverse events occurred in the DD01 group (abdominal pain and acute cholecystitis) and zero in the placebo group.

DD01组出现了两例（6%）治疗后严重不良事件（腹痛和急性胆囊炎），而安慰剂组没有出现。

No deaths occurred.

没有发生死亡事件。

interpretation

In this prespecified 12-week primary analysis, DD01 produced rapid reductions in liver fat compared with placebo, supporting further evaluation in long-term studies.

在这项预先设定的为期12周的主要分析中，与安慰剂相比，DD01能够迅速减少肝脏脂肪，支持在长期研究中进一步评估。

funding

D&D Pharmatech, Neuraly.

D&D Pharmatech, Neuraly.