治疗脊髓性肌萎缩药物ISIS-SMNRx的新进展

费城——Isis制药公司用于治疗1、2、3型脊髓型肌萎缩（SMA）的反义寡核苷酸药物ISIS-SMNRx仍在研究之中，开放研究的最新中期结果显示了其安全性，并将开始显示其潜在的疗效。

两项随访时间长达9个月的研究正在进行中，研究中2型或3型SMA患者使用ISIS-SMNRx总剂量达18mg而1型SMA患者使用ISIS-SMNRx总剂量达48mg，并未发生安全性或耐受性方面的问题。年龄在2~15岁的2型或3型SMA患儿显示出剂量、时间依赖性的亨墨斯密运动机能扩展量表（HFMSE）评分改善，这种改善与脑脊液中SMN蛋白水平的升高一致。患1型SMA的婴儿在亨墨斯密婴儿神经测试中（HINE）达到运动发展指标，运动技能检查评分也相应改善。

ISIS-SMNRx是一种可促进SMN2基因转录合成全长SMN蛋白的反义寡核苷酸。研究人员在3个月内对患者行腰穿后鞘内推注给药，之后随访6个月。8例患者接受每次3mg给药，总计9mg；8例患者接受每次6mg给药，总计18mg；9例患者接受每次9mg给药，总计18mg。之后研究人员又增加了单次12mg给药剂量组，但结果尚未公布。

2型和3型SMA患儿中包括10例2型SMA患者和15例3型SMA患者。他们病情稳定，年龄在2~15岁，平均年龄7.5岁。其中大多数（20例）有3个SMN2基因拷贝，4例有4个SMN2基因拷贝，1例有2个SMN2基因拷贝。大多数患者（16例）未截肢。

3mg治疗组患儿的HFMSE评分较基线水平平均提高1.5，6mg治疗组提高2.3，9mg治疗组显著提高3.7。85天时各组患儿脑脊液中SMN蛋白水平均较基线水平升高，但仅9mg治疗组显著性升高。

同样，在进行中的针对1型SMA患婴的开放研究中，分别在第1、15、83和253天对4例患儿以6mg剂量给药，对11例患儿以12mg剂量给药。患婴的年龄为7个月或更小，平均症状出现年龄为7周，平均年龄在18~21周时被纳入研究。除了1例患婴，其余患婴的SMN2拷贝数均为2。

没有患婴出现被认为与ISIS-SMNRx相关的不良反应。14起严重不良反应中，11起为呼吸道感染，并且所有严重不良反应都被认为与严重婴儿SMA有关。

6mg剂量组的4例患婴中1例意外死亡，1例接受长期机械通气。12mg剂量组的11例患儿中，2例死于肺部感染，1例需要长期机械通气（在没有急性可逆性疾病的情况下，每天持续16小时或更长时间，持续2周以上）。

11例患婴完成治疗和评估，其中8例的费城儿童医院婴儿神经肌肉性疾病测试（CHOP-INTEND）成绩改善，总体平均评分增加5.4，而12mg剂量组增加了8.3。11患婴中的9例、12mg剂量组7例患婴中的6例达到HINE增量指标。

大多数患婴尺神经支配的小指展肌和腓总神经支配的胫骨前肌部位的复合肌肉动作电位稳定或有升高。

这些结果令人振奋，Lsis已开始计划针对1~3型SMA患者的临床3期研究。

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By: JEFF EVANS, Clinical Neurology News Digital Network

PHILADELPHIA – The latest interim results from open-label studies of the investigational antisense oligonucleotide therapy ISIS-SMNRx for the treatment of patients with type 1, 2, or 3 spinal muscular atrophy support its safety and are starting to show its potential efficacy in treating the range of severity seen in the disease.

In two ongoing studies with up to 9 months of follow-up data, no safety or tolerability concerns arose with total doses of up to 18 mg in patients with type 2 or 3 spinal muscular atrophy (SMA) and in total doses of up to 48 mg in infants with type 1 SMA. Children aged 2-15 years with type 2 or 3 SMA had a dose- and time-dependent improvement in scores on the Hammersmith Functional Motor Scale-Expanded (HFMSE) that also correlated well with levels of SMN protein in cerebrospinal fluid. Infants with type 1 SMA achieved motor milestones on the Hammersmith Infant Neurological Exam that were consistent with increases in motor function test scores, according to investigators who presented the results at the annual meeting of the American Academy of Neurology.

"It’s very encouraging that we can do this safely and that the children tolerate the lumbar punctures, and there’s hope that the measures [used in the studies] are sensitive to change," said primary investigator Dr. Claudia Chiriboga, who presented the interim results of a study in patients with SMA types 2 or 3.

In that study, ISIS-SMNRx, an antisense oligonucleotide that promotes transcription of the full-length SMN protein from the SMN2 gene, was administered in an intrathecal bolus via lumbar puncture at points during a 3-month period; patients were then followed for 6 months. A total of eight patients received 3 mg at each dose (total dose, 9 mg); eight received 6 mg at each dose (total dose, 18 mg); and nine received 9 mg at each dose (18 mg total). Later, investigators added a 12-mg dose cohort that currently has eight patients enrolled, but results in that cohort are not yet available, said Dr. Chiriboga of the division of child neurology at Columbia University, New York.

 

The SMA type 2 and 3 patients included 10 patients with type 2 and 15 with type 3. They were medically stable and 2-15 years old, with a mean age of 7.5 years. Most (20) had three copies of the SMN2 gene; 4 had four copies and 1 had two copies. A majority of the patients (16) were nonambulatory.

None of the adverse events reported were considered related to the study drug, and most of the 143 adverse events were mild or moderate, the investigators found. Two severe adverse events were back pain and myalgia. Most of the adverse events were related to the lumbar punctures.

Scores on the HFMSE improved from baseline by a mean of 1.5 points in the 3-mg group, 2.3 points in the 6-mg group, and a statistically significant 3.7 points in the 9-mg group. SMN levels in cerebrospinal fluid at day 85 increased from baseline in all groups but were significantly increased in the 9-mg group only.

Additional secondary endpoints showed nonsignificant improvement of 22.7 m at 9 months on the 6-minute walk test in those who could walk, and an improvement of 2.3 points on an 18-point scale measuring upper limb function in weaker nonambulatory patients, but the open-label nature of the study and small numbers of patients make it difficult to interpret such findings, Dr. Chiriboga said.

"The feeling is that when there’s chronicity, like end-stage type of changes – severe scoliosis, for example – that those individuals don’t do as well. ... It’s not so much the age," Dr. Chiriboga said in an interview. Patients with type 3 disease also do better because they have more SMN2 to begin with, she said.

Similarly, in the ongoing open-label studyof infants with type 1 SMA, ISIS-SMNRx was administered to 4 patients in 6-mg doses at days 1, 15, 85, and 253, and in 12-mg doses to 11 patients at the same time points. These infants were all aged 7 months or younger. Their mean age at symptom onset was 7 weeks, and they were enrolled in the study at a mean age of 18-21 weeks. All but one patient had two copies of the SMN2 gene, reported primary investigator Dr. Richard S. Finkel.

None of the adverse events in the infants were deemed to be related to ISIS-SMNRx. Of 14 severe adverse events, 11 were respiratory infections, and all were considered to be consistent with severe infant SMA, said Dr. Finkel, chief of the division of neurology at Nemours Children’s Hospital and professor of neurology at the University of Central Florida, both in Orlando.

One patient in the 6-mg group died accidentally, and another underwent permanent ventilation. Two of 11 patients in the 12-mg group died of pulmonary infection, and 1 required permanent ventilation (16 or more hours per day continuously for more than 2 weeks in the absence of an acute reversible illness), although 4 of the patients in this group have not yet received all their doses. At the last follow-up, or at the time of death or permanent ventilation, the median age was 14 months in the 6-mg group and 9.6 months in the 12-mg group (which has not been followed as long).

Scores on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) showed increases in 8 of 11 infants who had completed treatment and evaluation. The scores increased by a mean of 5.4 points overall and by 8.3 points in those in the 12-mg group. Incremental milestones on the Hammersmith Infant Neurological Exam were achieved by 9 of 11 infants, including 6 of 7 in the 12-mg group.

The median age at death or need for permanent ventilation is 10.5 months in infants with two SMN2 gene copies, and 85% reach this endpoint at 18 months. Scores on the CHOP-INTEND also declined by 1.27 points per year, according to a study of the natural history of type 1 SMA in 34 patients by Dr. Finkel and his colleagues that is under review for publication.

Compound muscle action potentials measured in the ulnar nerve–innervated abductor digitiminimi and peroneal nerve–innervated anterior tibialis were stable or increased in most infants, he said.

These encouraging results with ISIS-SMNRx have led Isis to begin plans for phase III trials in patients with SMA types 1-3, the investigators said.

The studies are funded by Isis Pharmaceuticals, the Department of Defense, and the National Institute of Neurological Disorders and Stroke. Neither Dr. Finkel nor Dr. Chiriboga had conflicts of interest. Some of the coauthors in each study were employees of Isis.