臨床研究等提出・公開システム

Phase I/II Study of DS-5141b: Open-label study of DS-5141b in patients with Duchenne muscular dystrophy

Phase I/II Study of DS-5141b

8

No significant differences in demographics and baseline characteristics were found between treatment groups. Subjects in the safety analysis population had a mean (SD) age of 6.9 (1.73) years, mean (SD) height of 114.53 (8.583) cm, and mean (SD) weight of 23.80 (8.068) kg, all male and Asian. Exon deletion regions were 44, 46-47, and 46-49 in two subjects each, and 46-48 and 46-51 in one subject each. mean (SD) walking distance in the 6-minute walk test was 374.0 (41.15) m, and mean (SD) left ventricular ejection fraction was 65.39 (4.123) %. Seven subjects (87.5%) had no prior history of complications, and five subjects (62.5%) had complications.

Informed consent was obtained for 12 subjects, of whom 1 subject was not enrolled due to "subject's request to discontinue" and 3 subjects were not enrolled due to "selection criteria deviation/exclusion criteria violation". All 8 enrolled subjects completed the study.

Adverse events occurred in all 8 subjects. Common adverse events were injection site reaction (8 subjects), nasopharyngitis (6 subjects), alpha 1 microglobulin increased (5 subjects), beta 2 microglobulin urine increased (5 subjects), upper respiratory tract inflammation (4 subjects), influenza (4 subjects), and contusion (4 subjects). No death or adverse events leading to discontinuation were reported. One serious adverse event (appendicitis) occurred in one subject, but was mild and resolved with treatment.

Safety: Adverse events were reported in all 8 subjects. Pharmacokinetics: - Following single subcutaneous doses of DS-5141b 0.1 mg/kg, 0.5 mg/kg, 2.0 mg/kg, and 6.0 mg/kg, Tmax of plasma DS-5141a (free form of DS-5141b) ranged from 1.98 h to 6.08 h. The dose-normalized Cmax and AUC168h of plasma DS-5141a were generally consistent, and Cmax and AUC168h generally increased dose-proportionally within the DS-5141b dose range of 0.1 to 6.0 mg/kg. - After repeated subcutaneous doses of DS-5141b 2.0 mg/kg or 6.0 mg/kg once a week, plasma DS-5141a concentrations at pre-dose increased with the number of doses and reached at steady state from 24 to 48 weeks. The arithmetic mean of accumulation ratio of AUCtau at the 48th dose to AUC168h at the 1st dose was 1.92 for the 2.0 mg/kg dose and 2.07 for the 6.0 mg/kg dose. Efficacy: The expression rate of dystrophin protein in muscle tissue was calculated against standard muscle by the Western blot and compared before and after administration. The arithmetic mean (SD) of the change from before the first dose to the end of Part 2-Extension-2 was 0.783 (1.1564) % overall.

Dystrophin mRNA production skipping exon 45 in muscle tissue was evaluated. RT-PCR results showed that no exon 45-skipped bands were detected in the samples before the first dose, but all subjects were positive for exon 45-skipping at the end of Part 2-Extension-2.

The safety, tolerability, efficacy, and pharmacokinetics of DS-5141b in 8 subjects with DMD were evaluated. No safety concerns were found at either the DS-5141b 2.0 mg/kg or 6.0 mg/kg dose, indicating that the drug was well tolerated. Plasma DS-5141a concentrations generally increased dose-proportionally within the assessed DS-5141b dose range, with only minor cumulative Cmax and AUC168h at steady state. A certain level of efficacy was found in subjects with DMD.

July. 18, 2023

No

-

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

completed

Jan. 05, 2016

Interventional

Multicenter, uncontrolled, open-label

treatment purpose

1-2

1) Confirmation of out-of-frame deletion(s) that could be corrected by dystrophin gene exon 45 skipping.
2) Intact muscles of adequate quality for biopsy to allow evaluation of the efficacy of the study drug.
3) Boys aged from 5 years to <11 years.
4) Patients able to walk at least 325 meters in the 6-minutes walk test.
5) Glucocorticoid-naive patients, or patients who have used glucocorticoids for at least 6 months prior to enrollment in this study with no dose changes for at least 3 months prior to enrollment.

1) A genetic mutation that can not be expected the expression of dystrophin protein by dystrophin gene exon 45 skipping.
2) A concurrent illness other than DMD that can cause muscle weakness and/or impairment of motor function.
3) Current or history of severe disorder.
4) Left ventricular ejection fraction (LEVF) <55%.
5) Corrected QT interval (QTc) >0.45 sec.

Male

Duchenne muscular dystrophy

investigational material(s)
Generic name etc : DS-5141b
INN of investigational material : -
Therapeutic category code : 49- Other agents affecting cellular function
Dosage and Administration for Investigational material : subcutaneous administration

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material : -

safety
efficacy
pharmacokinetics
Exploratory evaluation of the safety, tolerability, efficacy, and PK profile.
Safety: Adverse events, Labolatory tests, etc.
Efficacy: Dystrophin protein expression in muscle tissue
PK profile: PK parameters (Cmax, AUC, Tmax, T1/2, etc.)

efficacy
Efficacy: Production of exon 45-skipped dystrophin mRNA in muscle tissue

-

Nov. 18, 2015