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A multicenter, open-label study to determine the efficacy and safety of lucerastat oral therapy in Japanese subjects with Fabry disease

An open-label phase 3 study of lucerastat in Japanese subjects with Fabry disease

22

This study targeted Japanese patients with Fabry disease. The subjects had different baseline treatments, including those who had been receiving enzyme replacement therapy (ERT) at the time of consent and those who had not. Therefore, the study examined three treatment groups: the lucerastat monotherapy group (treatment-naïve group, switching from ERT group), and the add-on ERT group. The demographic characteristics of the 22 subjects analyzed were as follows: 13 males (4 in the treatment-naïve group, 1 in the switching from ERT group, and 8 in the add-on ERT group) and 9 females (3 in the treatment-naïve group, 4 in the switching from ERT group, and 2 in the add-on ERT group). The mean age ± standard deviation (SD) was 40.6 ± 15.6 years (treatment-naïve group: 28.4 ± 11.9 years, switching from ERT group: 46.2 ± 13.3 years, add-on ERT group: 46.4 ± 14.9 years). There were no marked differences among the groups in terms of mean values of body weight, height, BMI, and eGFR at screening. Almost all subjects enrolled in this clinical trial had normal or subnormal renal function. The mean value ± SD of the urinary albumin-to-creatinine ratio was higher in the add-on ERT group (194.8 ± 402.3 mg/g) compared to the treatment-naïve group (88.2 ± 188.7 mg/g) and the switching from ERT group (41.3 ± 46.8 mg/g).

All 23 subjects who signed informed consent form met the eligibility criteria. One subject withdrew consent and discontinued the study before the start of treatment. The remaining 22 eligible subjects took at least one dose of lucerastat and completed the 24-week study treatment period. 12 subjects received lucerastat monotherapy (7 treatment-naïve and 5 switching from ERT), and 10 subjects received lucerastat as an add-on ERT. All 22 treated subjects also completed the study, of which 21 subjects were enrolled in the extension study. The subject who did not enter the extension study completed the following-up period as per protocol.

The incidence (frequency) of treatment-emergent adverse events (TEAEs) was 20 out of 22 subjects (90.9%).At least one TEAEs occurred in 10 out of 12 subjects in the lucerastat monotherapy total group (5 out of 7 in the treatment-naïve group and 5 out of 5 in the switching from ERT group) and 10 out of 10 subjects in the add-on ERT group). The most frequently TEAE was nasopharyngitis [7 subjects (31.8%)], followed by headache [5 subjects (22.7%)], stomatitis [3 subjects (13.6%)], cough, feces soft, and oropharyngeal discomfort [each 2 subjects (9.1%)].

Primary Endpoint The primary objective of this study was to evaluate the efficacy of oral lucerastat in Japanese patients with Fabry disease by assessing the change in plasma globotriaosylceramide (Gb3) concentration from baseline to week 24. In the lucerastat total group (N=22), mean ± SD plasma concentration of Gb3 were 1528.3 ± 809.0 μg/L at baseline and 836.6 ± 765.2 μg/L at Week 24, resulting in a mean ± SD change from baselineof –691.6 ± 352.2 μg/L. Mean percentage change ± SD at Week 24 was –50.9 ± 20.1%. In the treatment-naïve group (n=7), the switching from ERT group (n=5), and the add-on ERT group (n=10), the mean plasma Gb3 concentration ± SD at baseline was 1949.1 ± 1091.8 μg/L, 1096.0 ± 282.4 μg/L, and 1449.8 ± 669.9 μg/L, respectively. The mean percentage change ± SD from baseline to week 24 was –38.7 ± 27.0%, –51.9 ± 17.4%, and –58.9 ± 11.7%, respectively. Mean percent change ± SD at Week 24 (V9/EOT) was lowest in the treatment-naïve group (−38.7 ± 27.0%) and similar in the switching from ERT group (−51.9 ± 17.4%) and the add-on ERT group (−58.9 ± 11.7%).

Secondary Endpoints Safety All TEAEs were mild or moderate in intensity. TEAEs assessed by the investigator or sub-investigator as related with the study treatment were reported in 9 out of 22 subjects (40.9%). No deaths, serious adverse events, or TEAEs leading to discontinuation of study treatment were reported during the study period. Pharmacokinetics At steady state, peak plasma lucerastat concentrations in the lucerastat total group were quickly reached with median Tmax (min, max) of 2.5 (1.0, 4.3) hours after administration.The geometric means (95% CI) AUCt and Cmax were 79426 (68582,91985) ngh/mL and 10753 (9214, 12547) ng/mL, respectively. After Cmax was reached, lucerastat was cleared from plasma. Geometric means t1/2 (95% CI) was 6.6 (5.4, 7.9) hours.

The results of this study, a marked decrease in plasma concentrations of the Fabry disease marker Gb3 was observed in the lucerastat total group, as well as in all three individual groups (treatment-naïve group, switching from ERT group. Additionally, this study showed that lucerastat administered at 1000 mg b.i.d. (adjusted based on eGFR value) for 24 weeks was safe and well tolerated in Japanese subjects in all three groups.

Nov. 26, 2024

No

Yokoyama Yoshinari

Nxera Pharma Japan ltd

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

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

April. 30, 2019

Interventional

Multicenter, open-label 3 study

treatment purpose

3

(1)Patients who have given consent to participate in this study.
(2)Male and female Japanese patients of at least 16 years of age
(3)Patients who have received a final diagnosis of Fabry disease confirmed by a genetic test (patients found to have at least 1 genetic abnormality in the GLA gene coding alpha-galactosidase A [alpha-GalA])
(4)Patients with history of treatment for Fabry disease that meets the following:
a)Lucerastat monotherapy group (One of the following conditions has to apply)
-Patient has not received ERT for at least 6 months at the time of the consent
-Patients receiving treatment with ERT at the time of consent who wishes to be treated with the study drug and agrees to discontinue the current treatment with existing drugs before the start of study drug administration
b)ERT-lucerastat combination therapy group
-Patients treated with ERT for at least 12 months at the time of consent
(5)In case of women who have a potential of childbearing, meeting all the following conditions:
-Patients with negative results from serum pregnancy test during the screening period (V1).
-Patients who consent to undertake monthly urine pregnancy tests during the period up to EOS.
-Patients who consent to comply with a method of contraception scheme in the protocol during the period up to EOS.
(6)Male patients with reproductive potential (in the opinion of the principal investigator or subinvestigator) meeting the two following conditions:
-Patients who agree to using a condom during the period up to EOS (84 days (+7 days) after EOT).
-Patients who agree to refrain from attempting to father a child during the period up to EOS (84 days (+7 days) after EOT)
(7)Patients who agree to record patient diary during the period from informed consent until EOT.

(1)Patients who become pregnant, plan to become pregnant or breastfeed, during the period up to EOS.
(2)Patients with severe renal impairment with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 calculated based on the laboratory test results performed during the screening period.
(3)Patients receiving renal dialysis
(4)Patients with a transplanted kidney or other organ
(5)Patients with a history of transient ischemic attack, stroke, unstable angina pectoris or myocardial infarction within 6 months before the consent.
(6)Patients with unstable heart disease as judged by the principal investigator or subinvestigator (e.g., uncontrolled arrhythmia or NYHA class III or IV heart failure).
(7)Patients with a risk of worsening of clinical symptoms due to an organ lesion during the study period in the opinion of the principal investigator or subinvestigator
(8)Patients with the following causal factors or disease causing difficulty complying with the study drug regimen, or difficulty conducting the study or interpreting results
(a)Patients with disease conditions hindering evaluation of neuropathic pain (for example: diabetic neuropathy, peripheral neuropathy due to chemotherapy or radiotherapy, chronic inflammatory demyelinating neuropathy, etc.)
(b)Patients with other diseases hindering the evaluation of gastrointestinal symptoms due to Fabry disease
(c)Patients with uncontrollable diabetes mellitus (for example: patients with HbA1c > 8.0% measured during the screening period)
(d)patients with obvious nervous disease
(e)Patients with obvious psychiatric disease (including suicidal ideation during the screening period or suicide attempt/suicidal behavior within 6 months before consent is obtained in the opinion of the principal investigator or subinvestigator)
(f)Patients with a history of drug dependence (including opioids) or alcohol dependence
(g)Patients with difficulty recording patient diaries every day
(9)Patients with a fatal disease with life expectancy < 18 months
(10)Patients with hypersensitivity to the study drug or any drugs in the same class of imino sugars (for example: miglitol, miglustat or migalastat) or their excipients
(11)Patients who have started any of the following drugs, or had the dosage of any of the following drugs changed, within 4 weeks before consent was obtained
(a)Angiotensin converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs)
(b)adjuvant analgesics (Antiepileptics, TCA and SNRI/SSRI) and/or other antidepressants)
(12)Patients currently receiving other study drugs, or who have received other study drug within 3 months before consent was obtained (for example, lucerastat, ibiglustat, venglustat)
(13)Patients who have received treatment with glucosylceramide synthase (GCS) inhibitors (e.g., miglustat, eliglustat) or an alpha-GalA chaperone (migalastat) within the last 6 months before the consent.
(14)Other patients who are considered ineligible for the study subject in the opinion of the principal investigator or subinvestigator (expected difficulty of study visit or drug compliance etc.)

Both

Fabry disease

investigational material(s)
Generic name etc : ACT-434964
INN of investigational material : Lucerastat
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : 1000mg twice a day, oral administration

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

efficacy
Change in plasma Gb3 from baseline to end of treatment

safety
pharmacokinetics
Safety: Treatment emergent adverse event and serious adverse event
Pharmacokinetics: blood drug concentration

April. 05, 2019