Rapid and Sustained Response of Biochemically Uncontrolled Acromegaly to Once-daily Oral Paltusotine Treatment.

Background

To evaluate efficacy and safety of paltusotine in patients with biochemically uncontrolled acromegaly not currently receiving medical therapy.

评估在未接受药物治疗且生化指标未得到控制的肢端肥大症患者中，paltusotine的疗效和安全性。

Methods

In this phase 3, randomized, double-blind, placebo-controlledtrial, adults with medically untreated acromegaly at randomization (stratum 1: medication-naïve or off acromegaly medications ≥4 months [IGF-I ≥ 1.3 × upper limit of normal {ULN}]; stratum 2: controlled on a somatostatin receptor ligand and underwent washout [IGF-I increase ≥30% to ≥1.1 × ULN]) received paltusotine or placebo for 24 weeks.

在这项第三阶段、随机、双盲、安慰剂对照试验中，随机分组时未经医学治疗的肢端肥大症成人患者（第一层：未接受药物治疗或停用肢端肥大症药物≥4个月[IGF-I ≥ 1.3 ×正常上限{ULN}]；第二层：在生长抑素受体配体控制下并经过洗脱[IGF-I增加≥30%至≥1.1 × ULN]）接受了24周的paltusotine或安慰剂治疗。

Results

A total of 111 patients (stratum 1, n = 82; stratum 2, n = 29) enrolled (paltusotine, n = 54; placebo, n = 57).

共有111名患者（第一层，n = 82；第二层，n = 29）入组（paltusotine，n = 54；安慰剂，n = 57）。

The primary endpoint of IGF-I normalization at 24 weeks was met in 55.6% of paltusotine-treated patients vs 5.3% for placebo (odds ratio [OR]: 42.81; 95% CI, 8.44-455.82; P < .0001), with superiority to placebo in both strata.

在24周时IGF-I正常化的首要终点在55.6%接受paltusotine治疗的患者中实现，而安慰剂组为5.3%（比值比[OR]：42.81；95%置信区间，8.44-455.82；P < .0001），在两个层面上均优于安慰剂。

Paltusotine treatment decreased IGF-I in 92.6% of patients within the first 4 weeks.

在最初的4周内，92.6%的患者在接受paltusotine治疗后IGF-I有所下降。

All secondary endpoints were met: mean (±SE) change in IGF-I of -0.82 ± 0.08×ULN with paltusotine vs 0.09 ± 0.08×ULN with placebo (P < .0001); IGF-I < 1.3×ULN in 66.7% vs 14.0% of patients (OR: 18.32; 95% CI, 5.64-79.16; P < .0001); GH (5-sample mean) < 1.0 ng/mL in 57.4% vs 17.5% (OR: 7.59; 95% CI, 2.78-23.48; P < .0001); mean (±SE) change in Acromegaly Symptom Diary score of -2.7 ± 1.4 vs 2.8 ± 1.4 (P = .004).

所有次要终点均得到满足：与安慰剂相比，帕尔图索汀治疗组的IGF-I平均（±标准误）变化为-0.82 ± 0.08×ULN，安慰剂组为0.09 ± 0.08×ULN（P < .0001）；IGF-I < 1.3×ULN的患者比例为66.7% vs 14.0%（比值比OR: 18.32; 95% 置信区间CI, 5.64-79.16; P < .0001）；GH（5样本平均）< 1.0 ng/mL的患者比例为57.4% vs 17.5%（OR: 7.59; 95% CI, 2.78-23.48; P < .0001）；肢端肥大症症状日记评分平均（±标准误）变化为-2.7 ± 1.4 vs 2.8 ± 1.4（P = .004）。

Most adverse events were acromegaly symptoms or mild, transitory gastrointestinal effects characteristic of somatostatin receptor ligands (eg, diarrhea, abdominal pain).

大多数不良事件是肢端肥大症的症状或轻度、短暂的胃肠道效应，这是生长抑素受体配体的特征（例如，腹泻、腹痛）。

Pituitary tumor volume was stable or reduced in paltusotine-treated patients.

接受帕尔曲司汀治疗的患者的垂体瘤体积保持稳定或缩小。

Conclusions

IGF-I normalized in significantly more patients with uncontrolled acromegaly treated with paltusotine vs placebo.

与安慰剂相比，接受帕尔曲司汀治疗的未控制肢端肥大症患者的胰岛素样生长因子I（IGF-I）正常化的患者显著更多。

Paltusotine was associated with rapid, sustained IGF-I reduction, significant symptom improvement and stable or reduced pituitary tumor size and was well tolerated.

Paltusotine与快速持续的IGF-I降低、显著的症状改善以及垂体肿瘤大小稳定或缩小相关，并且耐受性良好。