A 24-week course of bardoxolone methyl, an experimental antioxidant inflammation modulator, improved glomerular filtration rates in chronic kidney disease patients with type II diabetes, according to a randomized phase IIb study funded by the drug’s sponsor, Reata Pharmaceuticals Inc.
A phase III study slated to start next year will test whether the mean improvement of 10.1 mL/minute per 1.73 m2 leads to better patient outcomes, according to nephrologist Dr. Pablo Pergola of the University of Texas Health Science Center, San Antonio, who presented the findings.
“You want to make sure this drug will be associated with a clinical outcome,” said Dr. Pergola, the lead investigator of the phase IIb study.
Patients in the randomized, double-blind, placebo-controlled trial were assigned to 25-mg, 75-mg, or 150-mg daily doses of bardoxolone or to placebo. Each group had 57 subjects, except the 150-mg group, which had 56.
In addition to type II diabetes, subjects had stage 3b or 4 chronic kidney disease (CKD), with an estimated glomerular filtration rate (eGFR) of 20-45 mL/min per 1.73m2.
Their median age was 67 years, and all were on standard-of-care therapy – 98% of patients took ACE inhibitors or angiotensin-receptor blockers.
At the end of 24 weeks, bardoxolone patients had a mean eGFR gain of 10.1 mL/minute per 1.73 m2, with gains noted in each group ranging from 8.3 to 11.5 mL/minute per 1.73 m2. There was a 0.1 mL/minute per 1.73 m2 eGFR gain in the placebo group. The treatment effect of bardoxolone relative to placebo was significant.
About 73% (124) of patients in each bardoxolone group had at least a 10% eGFR increase; approximately 25% (43) had more than a 50% increase.
Increased eGFRs also correlated with decreased blood-urea-nitrogen levels, decreased serum phosphorous and uric acid levels, and improved CKD stage.
“The maximal effect seems to be at 75 mg,” Dr. Pergola said, with smaller eGFR gains at 25 mg and no greater gains at 150 mg.
Adverse events were more common in the bardoxolone groups; 49% of bardoxolone patients reported muscle spasms, compared with 12% in the placebo group. The spasms were thought to be treatment related, as were nausea, hypomagnesemia, and diminished appetite.
The muscle cramps led to slightly higher discontinuation rates in bardoxolone subjects, Dr. Pergola said. But “the [spasms] seem to be transient and, importantly, there is no increase in biochemical markers of muscle damage.”
Reata plans to release 52-week outcomes early next year.
Dr. Pergola said he has no disclosures.
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一项由Reata制药公司资助的IIb期随机、双盲、安慰剂对照试验表明，合并II型糖尿病的慢性肾脏病患者使用试验药抗氧化炎症调节剂甲基bardoxolone治疗24周可提高其肾小球滤过率。
这项研究是由圣安东尼奥德克萨斯大学健康科学中心的肾病学家Pablo Pergola博士带领完成。在该研究中，受试者被随机分配至日剂量为25 mg、75 mg或150 mg的bardoxolone治疗组或安慰剂对照组。150 mg治疗组中有56名受试者，其余各组中均有57名受试者，他们均患有II型糖尿病同时合并3b期或4期慢性肾脏病(CKD)，肾小球滤过率估计值(eGFR)为20~45 ml/(min•1.73 m2)不等，中位年龄为67岁，均在接受标准治疗——98%的患者服用了血管紧张素转换酶抑制剂或血管紧张素II受体拮抗剂。
研究发现，在第24周末时，bardoxolone治疗组患者的平均eGFR增幅为10.1ml/(min•1.73 m2)，各剂量治疗组患者的eGFR增幅均介于8.3~ 11.5ml/(min•1.73 m2)之间；而安慰剂对照组的eGFR增幅为0.1ml/(min•1.73 m2)。与安慰剂相比，Bardoxolone的疗效显著。各bardoxolone治疗组约有73%(124例)的患者eGFR增加10%以上；近25% (43例)的患者eGFR增加50%以上。eGFR增加与血尿素氮水平下降、血磷和血清尿酸水平下降以及CKD分期改善相关。在各治疗组中，75 mg治疗组的疗效最大，25 mg治疗组的eGFR增幅较小，150 mg治疗组的eGFR几无增幅。
Bardoxolone治疗组的不良事件发生率较高，有49%的患者报告发生肌痉挛，而安慰剂对照组中则有12%。据推测，痉挛、恶心、低镁血症和食欲减退与治疗有关。另外，bardoxolone治疗组因肌肉抽搐导致的停药率略高，但似乎呈暂时性且不伴有肌肉损伤的生化标志物增加。
Reata公司计划于明年年初期发布52周的研究结论。
Pergola博士无披露内容。
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