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An multicenter open-label long-term continuous administration study to investigate the safety and tolerability of lucerastat in Japanese Fabry disease patients

An multicenter open-label long-term continuous administration study to investigate the safety and tolerability of lucerastat in Japanese Fabry disease patients

21

Among the 22 subjects who completed preceding study (jRCT2080224659), 21 signed the consent and fulfilled the eligibility criteria. The subject population comprised 13 males (4, 1, and 8 subjects in the treatment-naive, switching from ERT, and add-on to ERT groups, respectively) and 8 females (3, 4, and 1 subject, respectively). Overall, the mean age +/- standard deviation (SD) was 40.0 +/- 15.68 years. And the mean +/- SD age in the treatment-naive group was 28.4 +/- 11.89 years, which was lower than the mean age in the other treatment groups (46.2 +/- 13.31 and 45.7 +/- 15.57 years in the switching from ERT and add-on to ERT groups, respectively). The mean weight, height, body mass index (BMI), and eGFR at screening in preceding study (jRCT2080224659) did not differ substantially across the 3 groups. The mean +/- SD of eGFR was 101.9 +/- 35.54 and it was within the normal range in most of subjects. The mean +/- SD of UACR was 121.90 +/- 297.010 mg/g overall. The UACR was higher in the add-on to ERT group (192.87 +/- 426.620 mg/g) than in the treatment-naive (88.24 +/- 188.742 mg/g) and switching from ERT (41.26 +/- 46.783 mg/g) groups, but there was no significant difference in the median values.

All 21 subjects fulfilled the eligibility criteria received at least 1 dose of lucerastat. Among them, 12 received lucerastat monotherapy (treatment-naive, 7; switching from ERT, 5) and 9 received lucerastat in combination with ERT. Of these 9 subjects on combination therapy, 4 subjects who satisfied the protocol criteria discontinued ERT and were changed to lucerastat monotherapy. The study was discontinued prematurely by sponsor decision, with 12 subjects (57.1%) completing the end-of-study visit. Other reasons for discontinuation included subjects withdrawal of consent (3 subjects, 4.8%), withdrawal from the change protocol to end the ERT coadministration. (3 subjects, 4.8%), disease progression (2 subjects, 9.5%), and pregnancy (1 subject, 4.8%).

All subjects (21 subjects, 100%) in the study developed at least 1 TEAE. The most common TEAE was headache (8 subjects, 38.1%), followed by pyrexia (7 subjects, 33.3%), COVID-19 (6 subjects, 28.6%), and nasopharyngitis (5 subjects, 23.8%).Regarding most common TEAEs above, no TEAEs were observed to occur more frequently in any particular treatment group.

Primary endpoint The primary endpoint of this study is to evaluate the safety and tolerability of long-term administration of lucerastat in Japanese subjects with Fabry disease. The mean +/- SD exposure to study treatment including preceding study (jRCT2080224659) in the total subjects was 164.32 +/- 61.08 weeks (approximately 3 years). All subjects (21 subjects, 100%) in this study developed at least 1 TEAE. Except for 2 severe TEAEs (sepsis, gastric ulcer haemorrhage) reported in 1 (4.8%) of the total 21 subjects, all TEAEs were mild or moderate. TEAEs assessed as related to study treatment by the principal investigator or subinvestigator were reported in 5 (23.8%) of the 21 subjects. Of the five subjects, nausea occurred in two subjects (9.5%), headache and increased alanine aminotransferase occurred in one subject (4.8%), each of which occurred in different subjects, and headache, diarrhea, dizziness, and hypoesthesia occurred in one subject (4.8%). No subjects died during the study. Serious TEAEs were reported in 2 treatment groups, with a total of 8 events occurring in 6 (28.6%) of the total 21 subjects. The serious TEAEs were reported in 1 subject (4.8% each) as dental caries, dental cyst, gastric ulcer haemorrhage, infectious mononucleosis, large intestine polyp, sepsis, suicide attempt, and visual field defect. There were no serious TEAEs reported in 2 or more subjects nor were any assessed as related to study treatment. TEAEs leading to discontinuation were reported 2 events in 2 subjects (9.5%), with being exposure during pregnancy (not related to study treatment) and nausea (related).

Secondary endpoint The improvements from baseline in biomarkers such as plasma Gb3 concentration, and renal function (UACR), which were observed by the Week 24in preceding study (start of this long term study), were generally maintained until the end of administration of lucerastat in this study (an average of 3 years after the start of administration).

In this study, 21 Japanese subjects with Fabry disease were treated with lucerastat at a dose of 1000 mg (it decreased based on eGFR value) twice daily over an extended period, with a mean exposure of more than 3 years. The study results indicate that prolonged exposure to lucerastat posed no relevant safety concerns and was well tolerated overall. Regarding efficacy, the improvements from baseline in plasma Gb3 and UACR, which were observed by the 24th week, were generally maintained.

Nov. 26, 2024

No

Yokoyama Yoshinari

Nxera Pharma Japan ltd

9-7-2 Akasaka, Minato-ku, Tokyo,Japa

JP-MB-chiken.info@nxera.life

Yokoyama Yoshinari

Nxera Pharma Japan ltd

9-7-2 Akasaka, Minato-ku, Tokyo,Japan

+81-3-5962-5600

JP-MB-chiken.info@nxera.life

completed

Oct. 01, 2019

Interventional

Multicenter, long-term continuous administration study

treatment purpose

3

Patients who complete the preceding study and continue its eligibility

Patients with a risk of worsening of clinical symptoms due to an organ lesion during the study period at the discretion of the investigator

Both

Fabry disease

investigational material(s)
Generic name etc : Lucerastat (ACT-434964)
INN of investigational material : lucerastat
Therapeutic category code : 399 Agents affecting metabolism, n.e.c.
Dosage and Administration for Investigational material : 1000 mg twice daily

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

safety
TEAEs and SAEs

efficacy
change of biomarkers

Mar. 28, 2019