Mucopolysaccharidosis I
Conditions
Brief summary
Phase I/II, open-label, multicenter, multinational (Japan, Brazil and US),designed to evaluate the safety, pharmacokinetics and explore the efficacy for the treatment of mucopolysaccharidosis type I (MPS I).
Detailed description
In the JR-171-102 study, subjects will receive either 2.0 or 4.0 mg/kg/week of JR-171 intravenously at the same dosages received at Week 12 of the JR-171-101 study.
Interventions
DRUGJR-171 (lepunafusp alfa)
IV infusion
Sponsors
JCR Pharmaceuticals Co., Ltd.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
0 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A patient aged 18 years or older in Part 1 or any age in Part 2, at the time of informed consent * A patient from whom written informed consent can be obtained. If the patient is aged under 18 years (20 years in case of Japan) at the time of assent or willingness to participate in the study cannot be confirmed due to MPS I-related intellectual disability, informed permission from the patient's legally acceptable representative (e.g. his/her parents or guardians) need to be obtained instead of his/her consent. Even in this case, written informed consent or assent should be obtained from the patient, wherever possible * A patient diagnosed with MPS I based on any one of the following criteria: * Activity of IDUA enzyme below 10% of lower reference level in leucocytes or cultured skin fibroblasts, AND increased age-related urinary levels of GAGs (before enzyme replacement therapy) * Activity of IDUA enzyme below 10% of lower reference level in leucocytes or cultured skin fibroblasts, AND presence of one pathogenic mutation in each of the alleles of the IDUA gene * Increased age-related urinary levels of GAGs (before enzyme replacement therapy), AND presence of one pathogenic mutation in each of the alleles of the IDUA gene * A patient diagnosed as having no or mild MPS I-related intellectual disability (able to report their own subjective symptoms) by the principal investigator or subinvestigator (Part 1 only) * A patient who has received laronidase continuously for at least 12 weeks and has received laronidase on a stable dosage for 2 weeks immediately before the initial administration of JR-171, except for a laronidase naïve patient or a patient who has previously been treated by HSCT) * Female patient or male patient whose co-partner is of child-bearing potential agrees to use a medically accepted, highly effective method of contraception, such as spermatocidal gel plus condom, an intrauterine device or oral contraceptives until one month after the final administration
Exclusion criteria
* A patient who received gene therapy treatment * A patient who, in the opinion of the principal investigator or subinvestigator, cannot undergo lumbar puncture, including those who have a difficulty in taking a position for lumbar puncture due to joint contracture and those who are likely to develop dyspnea during lumbar puncture * A patient who is pregnant or lactating * A patient who has developed serious drug allergy or hypersensitivity to any drugs, in the opinion of the principal investigator or subinvestigator, is inappropriate for participation in the study * A patient who has received another investigational product within 12 months before enrollment in the study * A patient who, in the opinion of the principal investigator or subinvestigator, is ineligible to participate in the study out of consideration for the participant safety.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants With Adverse Events | Time of the first dose of JR-171 until the last visit (Week 5 for Part 1/ Week 13 for Part 2). |
Secondary
| Measure | Time frame |
|---|---|
| Pharmacokinetics of Each Dose in Part 1 (Cmax) | Week 1 to Week 4 |
| Pharmacokinetics of Each Dose in Part 2 (AUC0-t) | Week 1 to Week 12 |
| Pharmacokinetics of Each Dose in Part 2 (Cmax) | Week 1 to Week 12 |
| Heparan Sulfate Concentrations in Cerebrospinal Fluid in Part 1 | Baseline to Week 4 |
| Dermatan Sulfate Concentrations in Cerebrospinal Fluid in Part 1 | Baseline to Week 4 |
| Heparan Sulfate Concentrations in Cerebrospinal Fluid in Part 2 | Baseline to Week 12 |
| Dermatan Sulfate Concentrations in Cerebrospinal Fluid in Part 2 | Baseline to Week 12 |
| Heparan Sulfate Concentrations in Serum in Part 1 | Baseline to Week 5 |
| Dermatan Sulfate Concentrations in Serum in Part 1 | Baseline to Week 5 |
| Pharmacokinetics of Each Dose in Part 1 (AUC0-t) | Week 1 to Week 4 |
| Dermatan Sulfate Concentrations in Serum in Part 2 | Baseline to Week 13 |
| Heparan Sulfate Concentrations in Urine in Part 1 | Baseline to Week 5 |
| Dermatan Sulfate Concentrations in Urine in Part 1 | Baseline to Week 5 |
| Heparan Sulfate Concentrations in Urine in Part 2 | Baseline to Week 13 |
| Dermatan Sulfate Concentrations in Urine in Part 2 | Baseline to Week 13 |
| Liver Volumes (Body Weight Adjusted) in Part 1 | Baseline to Week 5 |
| Spleen Volumes (Body Weight Adjusted) in Part 1 | Baseline to Week 5 |
| Liver Volumes (Body Weight Adjusted) in Part 2 | Baseline to Week 13 |
| Spleen Volumes (Body Weight Adjusted) in Part 2 | Baseline to Week 13 |
| Heparan Sulfate Concentrations in Serum in Part 2 | Baseline to Week 13 |
Countries
Brazil, Japan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part1, Dose-escalation JR-171, Dose-escalation:
* Initial dose, 0.1 mg/kg/week
* Second dose, 1.0 mg/kg/week
* Third dose, 2.0 mg/kg/week
* Fourth dose, 4.0 mg/kg/week | 4 |
| Part 2, Dose-escalation JR-171, Dose-escalation:
* Initial dose, 1.0 mg/kg/week
* Second dose, 2.0 mg/kg/week
* Third dose, 4.0 mg/kg/week
* Subsequent doses, 4.0 mg/kg/week
Participants are included as 4.0 mg/kg/week group. | 2 |
| Part2, 2.0 mg JR-171, 2.0 mg/kg/week group | 6 |
| Part 2, 4.0 mg JR-171, 4.0 mg/kg/week group | 6 |
| Total | 18 |
Baseline characteristics
| Characteristic | Part1, Dose-escalation | Total | Part 2, 4.0 mg | Part2, 2.0 mg | Part 2, Dose-escalation |
|---|---|---|---|---|---|
| Age, Continuous | 46.8 years STANDARD_DEVIATION 13.6 | 19.2 years STANDARD_DEVIATION 17.8 | 12.3 years STANDARD_DEVIATION 11.4 | 11.0 years STANDARD_DEVIATION 6 | NA years |
| HSCT treatment No | 4 Participants | 17 Participants | 6 Participants | 5 Participants | 2 Participants |
| HSCT treatment Yes | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Intellectual disabilities No | 4 Participants | 8 Participants | 2 Participants | 1 Participants | 1 Participants |
| Intellectual disabilities Yes | 0 Participants | 10 Participants | 4 Participants | 5 Participants | 1 Participants |
| Phenotype Hurler | 0 Participants | 7 Participants | 2 Participants | 5 Participants | 0 Participants |
| Phenotype Hurler-Scheie | 0 Participants | 5 Participants | 3 Participants | 0 Participants | 2 Participants |
| Phenotype Scheie | 4 Participants | 6 Participants | 1 Participants | 1 Participants | 0 Participants |
| Prior laronidase-related IAR No | 3 Participants | 15 Participants | 5 Participants | 5 Participants | 2 Participants |
| Prior laronidase-related IAR Yes | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants |
| Prior use of laronidase No | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Prior use of laronidase Yes | 4 Participants | 17 Participants | 5 Participants | 6 Participants | 2 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian (Except for Japanese) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian (Japanese) | 2 Participants | 4 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian (Total) | 2 Participants | 4 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 2 Participants | 11 Participants | 3 Participants | 6 Participants | 0 Participants |
| Region of Enrollment Brazil | 2 participants | 12 participants | 5 participants | 5 participants | 0 participants |
| Region of Enrollment Japan | 2 participants | 4 participants | 0 participants | 0 participants | 2 participants |
| Region of Enrollment United States | 0 participants | 2 participants | 1 participants | 1 participants | 0 participants |
| Sex: Female, Male Female | 4 Participants | 9 Participants | 1 Participants | 3 Participants | 1 Participants |
| Sex: Female, Male Male | 0 Participants | 9 Participants | 5 Participants | 3 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 1 / 6 | 0 / 8 |
| other Total, other adverse events | 3 / 4 | 6 / 6 | 7 / 8 |
| serious Total, serious adverse events | 0 / 4 | 1 / 6 | 1 / 8 |
Outcome results
Primary
Number of Participants With Adverse Events
Time frame: Time of the first dose of JR-171 until the last visit (Week 5 for Part 1/ Week 13 for Part 2).
Population: Since participants with dose-escalation treatment continued treatment with 4.0 mg/kg/week after the first three weeks, they were analyzed as 4.0 mg/kg/week group participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part1, Dose-escalation | Number of Participants With Adverse Events | Adverse events | 3 participants |
| Part1, Dose-escalation | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| Part1, Dose-escalation | Number of Participants With Adverse Events | Adverse events of special interests | 1 participants |
| Part1, Dose-escalation | Number of Participants With Adverse Events | Adverse events leading to death | 0 participants |
| Part1, Dose-escalation | Number of Participants With Adverse Events | IARs (Adverse events) | 1 participants |
| Part1, Dose-escalation | Number of Participants With Adverse Events | Adverse drug reactions | 1 participants |
| Part1, Dose-escalation | Number of Participants With Adverse Events | Serious adverse drug reactions | 0 participants |
| Part1, Dose-escalation | Number of Participants With Adverse Events | Adverse drug reactions of special interests | 1 participants |
| Part1, Dose-escalation | Number of Participants With Adverse Events | Adverse drug reactions leading to death | 0 participants |
| Part1, Dose-escalation | Number of Participants With Adverse Events | IARs (Adverse drug reactions) | 1 participants |
| Part2, 2.0 mg | Number of Participants With Adverse Events | Adverse drug reactions leading to death | 0 participants |
| Part2, 2.0 mg | Number of Participants With Adverse Events | Adverse events | 6 participants |
| Part2, 2.0 mg | Number of Participants With Adverse Events | Adverse drug reactions | 1 participants |
| Part2, 2.0 mg | Number of Participants With Adverse Events | IARs (Adverse events) | 1 participants |
| Part2, 2.0 mg | Number of Participants With Adverse Events | Serious adverse events | 1 participants |
| Part2, 2.0 mg | Number of Participants With Adverse Events | IARs (Adverse drug reactions) | 1 participants |
| Part2, 2.0 mg | Number of Participants With Adverse Events | Adverse drug reactions of special interests | 1 participants |
| Part2, 2.0 mg | Number of Participants With Adverse Events | Adverse events of special interests | 3 participants |
| Part2, 2.0 mg | Number of Participants With Adverse Events | Serious adverse drug reactions | 0 participants |
| Part2, 2.0 mg | Number of Participants With Adverse Events | Adverse events leading to death | 1 participants |
| Part 2, 4.0 mg | Number of Participants With Adverse Events | Adverse drug reactions of special interests | 3 participants |
| Part 2, 4.0 mg | Number of Participants With Adverse Events | Adverse events leading to death | 0 participants |
| Part 2, 4.0 mg | Number of Participants With Adverse Events | IARs (Adverse events) | 3 participants |
| Part 2, 4.0 mg | Number of Participants With Adverse Events | Adverse drug reactions | 3 participants |
| Part 2, 4.0 mg | Number of Participants With Adverse Events | Adverse drug reactions leading to death | 0 participants |
| Part 2, 4.0 mg | Number of Participants With Adverse Events | Serious adverse drug reactions | 0 participants |
| Part 2, 4.0 mg | Number of Participants With Adverse Events | Adverse events | 7 participants |
| Part 2, 4.0 mg | Number of Participants With Adverse Events | IARs (Adverse drug reactions) | 3 participants |
| Part 2, 4.0 mg | Number of Participants With Adverse Events | Serious adverse events | 1 participants |
| Part 2, 4.0 mg | Number of Participants With Adverse Events | Adverse events of special interests | 3 participants |
Secondary
Dermatan Sulfate Concentrations in Cerebrospinal Fluid in Part 1
Time frame: Baseline to Week 4
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Cerebrospinal Fluid in Part 1 | Baseline | 264.0 ng/mL | Standard Deviation 72.6 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Cerebrospinal Fluid in Part 1 | Week 4 | 213.0 ng/mL | Standard Deviation 135.4 |
Secondary
Dermatan Sulfate Concentrations in Cerebrospinal Fluid in Part 2
Time frame: Baseline to Week 12
Population: Since participants with dose-escalation treatment continued treatment with 4.0mg/kg/week after the first three weeks, they were analyzed as 4.0 mg/kg/group participants.~Protocol visit was not performed at Week 12 by one participant in 4.0 mg group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Cerebrospinal Fluid in Part 2 | Baseline | 2241.17 ng/mL | Standard Deviation 2994.88 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Cerebrospinal Fluid in Part 2 | Week 12 | 896.80 ng/mL | Standard Deviation 814.82 |
| Part2, 2.0 mg | Dermatan Sulfate Concentrations in Cerebrospinal Fluid in Part 2 | Baseline | 679.38 ng/mL | Standard Deviation 451.16 |
| Part2, 2.0 mg | Dermatan Sulfate Concentrations in Cerebrospinal Fluid in Part 2 | Week 12 | 320.31 ng/mL | Standard Deviation 228.3 |
Secondary
Dermatan Sulfate Concentrations in Serum in Part 1
Time frame: Baseline to Week 5
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Serum in Part 1 | Baseline | 965.0 ng/mL | Standard Deviation 224.4 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Serum in Part 1 | Week 2 | 929.8 ng/mL | Standard Deviation 204.4 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Serum in Part 1 | Week 3 | 1000.5 ng/mL | Standard Deviation 200.1 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Serum in Part 1 | Week 4 | 958.0 ng/mL | Standard Deviation 207.1 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Serum in Part 1 | Week 5 | 867.3 ng/mL | Standard Deviation 241.3 |
Secondary
Dermatan Sulfate Concentrations in Serum in Part 2
Time frame: Baseline to Week 13
Population: Participants are separate to S/H and Naive in this table, since these two will show a different trend of changes.~DS data were NA for one participant at W6 (Not assessed), and for another participant at Week 8, 10, 12, and 13 (due to hospitalization) in 4.0 mg Switched/HSCT group. DS data were NA at Week 4 due to difficult venous access in participant in 4.0 mg Naïve group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Serum in Part 2 | Baseline | 1664.5 ng/mL | Standard Deviation 670.8 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 2 | 1847.5 ng/mL | Standard Deviation 991.8 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 4 | 1639.3 ng/mL | Standard Deviation 792.1 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 6 | 1585.5 ng/mL | Standard Deviation 686.8 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 8 | 1553.7 ng/mL | Standard Deviation 811.9 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 10 | 1510.2 ng/mL | Standard Deviation 704.1 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 12 | 1362.2 ng/mL | Standard Deviation 642.8 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 13 | 1510.8 ng/mL | Standard Deviation 699.1 |
| Part2, 2.0 mg | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 4 | 1321.6 ng/mL | Standard Deviation 687.2 |
| Part2, 2.0 mg | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 6 | 1234.0 ng/mL | Standard Deviation 807.1 |
| Part2, 2.0 mg | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 8 | 1191.5 ng/mL | Standard Deviation 681.7 |
| Part2, 2.0 mg | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 10 | 1206.7 ng/mL | Standard Deviation 719.3 |
| Part2, 2.0 mg | Dermatan Sulfate Concentrations in Serum in Part 2 | Baseline | 1442.4 ng/mL | Standard Deviation 756.6 |
| Part2, 2.0 mg | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 2 | 1571.6 ng/mL | Standard Deviation 916.6 |
| Part2, 2.0 mg | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 13 | 1197.2 ng/mL | Standard Deviation 811.1 |
| Part2, 2.0 mg | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 12 | 1208.8 ng/mL | Standard Deviation 763.4 |
| Part 2, 4.0 mg | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 2 | 1740 ng/mL | — |
| Part 2, 4.0 mg | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 6 | 788 ng/mL | — |
| Part 2, 4.0 mg | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 12 | 899 ng/mL | — |
| Part 2, 4.0 mg | Dermatan Sulfate Concentrations in Serum in Part 2 | Baseline | 4110 ng/mL | — |
| Part 2, 4.0 mg | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 8 | 679 ng/mL | — |
| Part 2, 4.0 mg | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 13 | 762 ng/mL | — |
| Part 2, 4.0 mg | Dermatan Sulfate Concentrations in Serum in Part 2 | Week 10 | 702 ng/mL | — |
Secondary
Dermatan Sulfate Concentrations in Urine in Part 1
Time frame: Baseline to Week 5
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Urine in Part 1 | Baseline | 22.704 µg/mgCr | Standard Deviation 13.815 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Urine in Part 1 | Week 2 | 29.317 µg/mgCr | Standard Deviation 8.615 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Urine in Part 1 | Week 3 | 24.366 µg/mgCr | Standard Deviation 16.614 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Urine in Part 1 | Week 4 | 20.400 µg/mgCr | Standard Deviation 16.88 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Urine in Part 1 | Week 5 | 17.112 µg/mgCr | Standard Deviation 17.026 |
Secondary
Dermatan Sulfate Concentrations in Urine in Part 2
Time frame: Baseline to Week 13
Population: Participants are separated into S/H and Naive since it shows a different trend of changes.~4 participants data were excluded from analysis due to incorrect procedure of assessment (2 each for 2.0 and 4.0 mg S/H) Data were NA for 3 participants (1 at W12 (2.0 mg)\[missing creatinine data\] and 1 at W6 \[No assessment\], 1 at W8, 10, 12, 13 (4.0 mg S/H) \[due to hospitalization\]). DS data were not available at W2, 4, and 6 (due to creatinine BLD)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Urine in Part 2 | Week 13 | 97.508 µg/mgCr | Standard Deviation 116.753 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Urine in Part 2 | Week 8 | 117.417 µg/mgCr | Standard Deviation 158.567 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Urine in Part 2 | Baseline | 130.164 µg/mgCr | Standard Deviation 131.983 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Urine in Part 2 | Week 12 | 95.576 µg/mgCr | Standard Deviation 131.815 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Urine in Part 2 | Week 10 | 103.365 µg/mgCr | Standard Deviation 124.166 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Urine in Part 2 | Week 4 | 103.212 µg/mgCr | Standard Deviation 117.351 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Urine in Part 2 | Week 2 | 114.215 µg/mgCr | Standard Deviation 128.204 |
| Part1, Dose-escalation | Dermatan Sulfate Concentrations in Urine in Part 2 | Week 6 | 117.873 µg/mgCr | Standard Deviation 145.111 |
| Part2, 2.0 mg | Dermatan Sulfate Concentrations in Urine in Part 2 | Week 8 | 13.330 µg/mgCr | Standard Deviation 7.224 |
| Part2, 2.0 mg | Dermatan Sulfate Concentrations in Urine in Part 2 | Baseline | 39.750 µg/mgCr | Standard Deviation 16.704 |
| Part2, 2.0 mg | Dermatan Sulfate Concentrations in Urine in Part 2 | Week 2 | 30.817 µg/mgCr | Standard Deviation 12.606 |
| Part2, 2.0 mg | Dermatan Sulfate Concentrations in Urine in Part 2 | Week 4 | 20.873 µg/mgCr | Standard Deviation 9.749 |
| Part2, 2.0 mg | Dermatan Sulfate Concentrations in Urine in Part 2 | Week 6 | 20.127 µg/mgCr | Standard Deviation 10.079 |
| Part2, 2.0 mg | Dermatan Sulfate Concentrations in Urine in Part 2 | Week 10 | 13.171 µg/mgCr | Standard Deviation 3.257 |
| Part2, 2.0 mg | Dermatan Sulfate Concentrations in Urine in Part 2 | Week 12 | 15.406 µg/mgCr | Standard Deviation 3.826 |
| Part2, 2.0 mg | Dermatan Sulfate Concentrations in Urine in Part 2 | Week 13 | 18.432 µg/mgCr | Standard Deviation 6.375 |
| Part 2, 4.0 mg | Dermatan Sulfate Concentrations in Urine in Part 2 | Week 13 | 85.04 µg/mgCr | — |
| Part 2, 4.0 mg | Dermatan Sulfate Concentrations in Urine in Part 2 | Week 12 | 80.21 µg/mgCr | — |
| Part 2, 4.0 mg | Dermatan Sulfate Concentrations in Urine in Part 2 | Baseline | 630.43 µg/mgCr | — |
| Part 2, 4.0 mg | Dermatan Sulfate Concentrations in Urine in Part 2 | Week 10 | 78.61 µg/mgCr | — |
| Part 2, 4.0 mg | Dermatan Sulfate Concentrations in Urine in Part 2 | Week 8 | 60.61 µg/mgCr | — |
Secondary
Heparan Sulfate Concentrations in Cerebrospinal Fluid in Part 1
Time frame: Baseline to Week 4
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Cerebrospinal Fluid in Part 1 | Baseline | 1131.8 ng/mL | Standard Deviation 532.9 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Cerebrospinal Fluid in Part 1 | Week 4 | 467.0 ng/mL | Standard Deviation 500.7 |
Secondary
Heparan Sulfate Concentrations in Cerebrospinal Fluid in Part 2
Time frame: Baseline to Week 12
Population: Since participants with dose-escalation treatment continued treatment with 4.0mg/kg/week after the first three weeks, they were analyzed as 4.0 mg/kg/group participants.~Protocol visit was not performed at Week 12 by one participant in 4.0 mg group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Cerebrospinal Fluid in Part 2 | Baseline | 3239.8 ng/mL | Standard Deviation 2726.1 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Cerebrospinal Fluid in Part 2 | Week 12 | 917.5 ng/mL | Standard Deviation 1216.2 |
| Part2, 2.0 mg | Heparan Sulfate Concentrations in Cerebrospinal Fluid in Part 2 | Baseline | 2054.0 ng/mL | Standard Deviation 1542.7 |
| Part2, 2.0 mg | Heparan Sulfate Concentrations in Cerebrospinal Fluid in Part 2 | Week 12 | 407.6 ng/mL | Standard Deviation 372.1 |
Secondary
Heparan Sulfate Concentrations in Serum in Part 1
Time frame: Baseline to Week 5
Population: Contamination happened with Heparin or Heparin-like compounds in one participant at Week 5.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Serum in Part 1 | Baseline | 358.5 ng/mL | Standard Deviation 52.7 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Serum in Part 1 | Week 2 | 385.8 ng/mL | Standard Deviation 62.5 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Serum in Part 1 | Week 3 | 339.8 ng/mL | Standard Deviation 59.7 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Serum in Part 1 | Week 4 | 311.3 ng/mL | Standard Deviation 86.3 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Serum in Part 1 | Week 5 | 255.7 ng/mL | Standard Deviation 67.3 |
Secondary
Heparan Sulfate Concentrations in Serum in Part 2
Time frame: Baseline to Week 13
Population: Participants are separated to S/H and Naive since these two will show a different trend of changes.~Contamination happened with Heparin or Heparin-like compounds in 1 participant in 2.0 mg S/H group at W8 HS data were NA for 1 participant at W6(Not assessed), and another participant at W8, 10, 12, and 13(due to hospitalization) in 4.0 mg S/H group. Contamination happened in participant in 4.0 mg Naïve group at BL and W8, and HS data were not available at W4(due to difficult venous access).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Serum in Part 2 | Baseline | 668.5 ng/mL | Standard Deviation 341.9 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Serum in Part 2 | Week 2 | 613.3 ng/mL | Standard Deviation 353.9 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Serum in Part 2 | Week 4 | 549.8 ng/mL | Standard Deviation 315.9 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Serum in Part 2 | Week 6 | 509.7 ng/mL | Standard Deviation 331.2 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Serum in Part 2 | Week 8 | 545.2 ng/mL | Standard Deviation 368.2 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Serum in Part 2 | Week 10 | 538.5 ng/mL | Standard Deviation 357.7 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Serum in Part 2 | Week 12 | 454.8 ng/mL | Standard Deviation 341.2 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Serum in Part 2 | Week 13 | 487.5 ng/mL | Standard Deviation 306.7 |
| Part2, 2.0 mg | Heparan Sulfate Concentrations in Serum in Part 2 | Week 12 | 274.0 ng/mL | Standard Deviation 100.3 |
| Part2, 2.0 mg | Heparan Sulfate Concentrations in Serum in Part 2 | Baseline | 465.0 ng/mL | Standard Deviation 314.2 |
| Part2, 2.0 mg | Heparan Sulfate Concentrations in Serum in Part 2 | Week 2 | 417.9 ng/mL | Standard Deviation 201 |
| Part2, 2.0 mg | Heparan Sulfate Concentrations in Serum in Part 2 | Week 13 | 312.8 ng/mL | Standard Deviation 202.6 |
| Part2, 2.0 mg | Heparan Sulfate Concentrations in Serum in Part 2 | Week 4 | 368.9 ng/mL | Standard Deviation 184.8 |
| Part2, 2.0 mg | Heparan Sulfate Concentrations in Serum in Part 2 | Week 6 | 268.3 ng/mL | Standard Deviation 135.4 |
| Part2, 2.0 mg | Heparan Sulfate Concentrations in Serum in Part 2 | Week 8 | 265.5 ng/mL | Standard Deviation 109.6 |
| Part2, 2.0 mg | Heparan Sulfate Concentrations in Serum in Part 2 | Week 10 | 281.3 ng/mL | Standard Deviation 131.6 |
| Part 2, 4.0 mg | Heparan Sulfate Concentrations in Serum in Part 2 | Week 6 | 549 ng/mL | — |
| Part 2, 4.0 mg | Heparan Sulfate Concentrations in Serum in Part 2 | Week 12 | 594 ng/mL | — |
| Part 2, 4.0 mg | Heparan Sulfate Concentrations in Serum in Part 2 | Week 2 | 1410 ng/mL | — |
| Part 2, 4.0 mg | Heparan Sulfate Concentrations in Serum in Part 2 | Week 13 | 491 ng/mL | — |
| Part 2, 4.0 mg | Heparan Sulfate Concentrations in Serum in Part 2 | Week 10 | 522 ng/mL | — |
Secondary
Heparan Sulfate Concentrations in Urine in Part 1
Time frame: Baseline to Week 5
Population: Contamination happened with Heparin or Heparin-like compounds in one participant at Week 5.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Urine in Part 1 | Baseline | 31.050 µg/mgCr | Standard Deviation 14.339 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Urine in Part 1 | Week 2 | 34.835 µg/mgCr | Standard Deviation 11.885 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Urine in Part 1 | Week 3 | 27.314 µg/mgCr | Standard Deviation 20.634 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Urine in Part 1 | Week 4 | 21.773 µg/mgCr | Standard Deviation 19.901 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Urine in Part 1 | Week 5 | 20.321 µg/mgCr | Standard Deviation 20.612 |
Secondary
Heparan Sulfate Concentrations in Urine in Part 2
Time frame: Baseline to Week 13
Population: Participants are separated into S/H and Naive since it shows a different trend of changes.~4 participants data were excluded from analysis due to incorrect procedure of assessment (2 each for 2.0 and 4.0 mg S/H) Data were NA for 3 participants (1 at W12 (2.0 mg)\[missing creatinine data\] and 1 at W6 \[No assessment\], 1 at W8, 10, 12, 13 (4.0 mg S/H) \[due to hospitalization\]) Contamination happened in participant in 4.0 mg Naïve group at BL, and HS data were NA at W2, 4, 6 (due to creatinine BLD)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Urine in Part 2 | Week 8 | 90.174 µg/mgCr | Standard Deviation 137.086 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Urine in Part 2 | Week 4 | 73.752 µg/mgCr | Standard Deviation 99.221 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Urine in Part 2 | Week 13 | 79.425 µg/mgCr | Standard Deviation 110.272 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Urine in Part 2 | Week 10 | 79.363 µg/mgCr | Standard Deviation 112.278 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Urine in Part 2 | Week 6 | 89.412 µg/mgCr | Standard Deviation 122.895 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Urine in Part 2 | Week 2 | 82.487 µg/mgCr | Standard Deviation 103.439 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Urine in Part 2 | Week 12 | 84.446 µg/mgCr | Standard Deviation 128.037 |
| Part1, Dose-escalation | Heparan Sulfate Concentrations in Urine in Part 2 | Baseline | 120.572 µg/mgCr | Standard Deviation 152.114 |
| Part2, 2.0 mg | Heparan Sulfate Concentrations in Urine in Part 2 | Week 12 | 10.412 µg/mgCr | Standard Deviation 4.905 |
| Part2, 2.0 mg | Heparan Sulfate Concentrations in Urine in Part 2 | Week 13 | 15.642 µg/mgCr | Standard Deviation 5.705 |
| Part2, 2.0 mg | Heparan Sulfate Concentrations in Urine in Part 2 | Week 4 | 10.927 µg/mgCr | Standard Deviation 5.751 |
| Part2, 2.0 mg | Heparan Sulfate Concentrations in Urine in Part 2 | Week 6 | 11.662 µg/mgCr | Standard Deviation 5.623 |
| Part2, 2.0 mg | Heparan Sulfate Concentrations in Urine in Part 2 | Week 8 | 6.963 µg/mgCr | Standard Deviation 3.027 |
| Part2, 2.0 mg | Heparan Sulfate Concentrations in Urine in Part 2 | Baseline | 35.387 µg/mgCr | Standard Deviation 24.919 |
| Part2, 2.0 mg | Heparan Sulfate Concentrations in Urine in Part 2 | Week 10 | 9.211 µg/mgCr | Standard Deviation 2.844 |
| Part2, 2.0 mg | Heparan Sulfate Concentrations in Urine in Part 2 | Week 2 | 17.962 µg/mgCr | Standard Deviation 10.584 |
| Part 2, 4.0 mg | Heparan Sulfate Concentrations in Urine in Part 2 | Week 13 | 124.41 µg/mgCr | — |
| Part 2, 4.0 mg | Heparan Sulfate Concentrations in Urine in Part 2 | Week 8 | 93.24 µg/mgCr | — |
| Part 2, 4.0 mg | Heparan Sulfate Concentrations in Urine in Part 2 | Week 10 | 120.98 µg/mgCr | — |
| Part 2, 4.0 mg | Heparan Sulfate Concentrations in Urine in Part 2 | Week 12 | 131.33 µg/mgCr | — |
Secondary
Liver Volumes (Body Weight Adjusted) in Part 1
Time frame: Baseline to Week 5
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Liver Volumes (Body Weight Adjusted) in Part 1 | Baseline | 21.912 cm3/kg | Standard Deviation 3.607 |
| Part1, Dose-escalation | Liver Volumes (Body Weight Adjusted) in Part 1 | Week 5 | 22.332 cm3/kg | Standard Deviation 3.916 |
Secondary
Liver Volumes (Body Weight Adjusted) in Part 2
Time frame: Baseline to Week 13
Population: Participants are separated to Switched/HSCT and Naive in this table, since these two will show a different trend of changes.~Liver volume data were not available for one participant each in 2.0 mg and 4.0 mg Switched/HSCT group (One couldn't arrive at the site because of the weather and another was hospitalized).~Another participant data in 4.0 mg Switched/HSCT group was excluded from analysis since assessment was performed out of the acceptable time frame.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Liver Volumes (Body Weight Adjusted) in Part 2 | Baseline | 25.027 cm3/kg | Standard Deviation 6.129 |
| Part1, Dose-escalation | Liver Volumes (Body Weight Adjusted) in Part 2 | Week 13 | 23.795 cm3/kg | Standard Deviation 6.602 |
| Part2, 2.0 mg | Liver Volumes (Body Weight Adjusted) in Part 2 | Baseline | 25.510 cm3/kg | Standard Deviation 12.295 |
| Part2, 2.0 mg | Liver Volumes (Body Weight Adjusted) in Part 2 | Week 13 | 20.014 cm3/kg | Standard Deviation 3.778 |
| Part 2, 4.0 mg | Liver Volumes (Body Weight Adjusted) in Part 2 | Baseline | 35.95 cm3/kg | — |
| Part 2, 4.0 mg | Liver Volumes (Body Weight Adjusted) in Part 2 | Week 13 | 29.08 cm3/kg | — |
Secondary
Pharmacokinetics of Each Dose in Part 1 (AUC0-t)
Time frame: Week 1 to Week 4
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Pharmacokinetics of Each Dose in Part 1 (AUC0-t) | 0.1 mg/kg | 475.141 h*ng/mL | Standard Deviation 494.371 |
| Part1, Dose-escalation | Pharmacokinetics of Each Dose in Part 1 (AUC0-t) | 1.0 mg/kg | 10293.474 h*ng/mL | Standard Deviation 8199.941 |
| Part1, Dose-escalation | Pharmacokinetics of Each Dose in Part 1 (AUC0-t) | 2.0 mg/kg | 30776.649 h*ng/mL | Standard Deviation 28504.162 |
| Part1, Dose-escalation | Pharmacokinetics of Each Dose in Part 1 (AUC0-t) | 4.0 mg/kg | 107077.423 h*ng/mL | Standard Deviation 89015.623 |
Secondary
Pharmacokinetics of Each Dose in Part 1 (Cmax)
Time frame: Week 1 to Week 4
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Pharmacokinetics of Each Dose in Part 1 (Cmax) | 0.1 mg/kg | 94.875 ng/mL | Standard Deviation 93.331 |
| Part1, Dose-escalation | Pharmacokinetics of Each Dose in Part 1 (Cmax) | 1.0 mg/kg | 2825.750 ng/mL | Standard Deviation 2132.838 |
| Part1, Dose-escalation | Pharmacokinetics of Each Dose in Part 1 (Cmax) | 2.0 mg/kg | 6889.000 ng/mL | Standard Deviation 5195.335 |
| Part1, Dose-escalation | Pharmacokinetics of Each Dose in Part 1 (Cmax) | 4.0 mg/kg | 19040.000 ng/mL | Standard Deviation 13064.037 |
Secondary
Pharmacokinetics of Each Dose in Part 2 (AUC0-t)
Time frame: Week 1 to Week 12
Population: There is no data for participants in dose-escalation group for plasma drug concentration after administration of JR-171.~Though number of participants for PK set is 6 for each group, two participants from the 2.0 mg group and three participants from the 4.0 mg group was excluded from the data set since PK sample was collected by the same route as JR-171 administration and potential contamination could not be ruled out.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Pharmacokinetics of Each Dose in Part 2 (AUC0-t) | Week 1 | 18232.756 h*ng/mL | Standard Deviation 9950.396 |
| Part1, Dose-escalation | Pharmacokinetics of Each Dose in Part 2 (AUC0-t) | Week 4 | 19466.227 h*ng/mL | Standard Deviation 7542.104 |
| Part1, Dose-escalation | Pharmacokinetics of Each Dose in Part 2 (AUC0-t) | Week 12 | 22203.369 h*ng/mL | Standard Deviation 7851.121 |
| Part2, 2.0 mg | Pharmacokinetics of Each Dose in Part 2 (AUC0-t) | Week 1 | 53691.447 h*ng/mL | Standard Deviation 25202.412 |
| Part2, 2.0 mg | Pharmacokinetics of Each Dose in Part 2 (AUC0-t) | Week 4 | 33209.686 h*ng/mL | Standard Deviation 18465.369 |
| Part2, 2.0 mg | Pharmacokinetics of Each Dose in Part 2 (AUC0-t) | Week 12 | 35128.134 h*ng/mL | Standard Deviation 8312.799 |
Secondary
Pharmacokinetics of Each Dose in Part 2 (Cmax)
Time frame: Week 1 to Week 12
Population: There is no data for participants in dose-escalation group for plasma drug concentration after administration of JR-171.~Though number of participants for PK set is 6 for each group, two participants from the 2.0 mg group and three participants from the 4.0 mg group was excluded from the data set since PK sample was collected by the same route as JR-171 administration and potential contamination could not be ruled out.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Pharmacokinetics of Each Dose in Part 2 (Cmax) | Week 1 | 5032.500 ng/mL | Standard Deviation 2755.085 |
| Part1, Dose-escalation | Pharmacokinetics of Each Dose in Part 2 (Cmax) | Week 4 | 5421.200 ng/mL | Standard Deviation 2094.819 |
| Part1, Dose-escalation | Pharmacokinetics of Each Dose in Part 2 (Cmax) | Week 12 | 6059.747 ng/mL | Standard Deviation 1889.616 |
| Part2, 2.0 mg | Pharmacokinetics of Each Dose in Part 2 (Cmax) | Week 1 | 11526.667 ng/mL | Standard Deviation 3082.229 |
| Part2, 2.0 mg | Pharmacokinetics of Each Dose in Part 2 (Cmax) | Week 4 | 8116.667 ng/mL | Standard Deviation 3459.947 |
| Part2, 2.0 mg | Pharmacokinetics of Each Dose in Part 2 (Cmax) | Week 12 | 8983.333 ng/mL | Standard Deviation 938.74 |
Secondary
Spleen Volumes (Body Weight Adjusted) in Part 1
Time frame: Baseline to Week 5
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Spleen Volumes (Body Weight Adjusted) in Part 1 | Baseline | 4.342 cm3/kg | Standard Deviation 2.978 |
| Part1, Dose-escalation | Spleen Volumes (Body Weight Adjusted) in Part 1 | Week 5 | 4.914 cm3/kg | Standard Deviation 4.011 |
Secondary
Spleen Volumes (Body Weight Adjusted) in Part 2
Time frame: Baseline to Week 13
Population: Participants are separated to Switched/HSCT and Naive in this table, since these two will show a different trend of changes.~Spleen volume data were not available for one participant each in 2.0 mg and 4.0 mg Switched/HSCT group (One couldn't arrive at the site because of the weather and another was hospitalized).~Another participant data in 4.0 mg Switched/HSCT group was excluded from analysis since assessment was performed out of the acceptable time frame.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part1, Dose-escalation | Spleen Volumes (Body Weight Adjusted) in Part 2 | Baseline | 3.924 cm3/kg | Standard Deviation 0.766 |
| Part1, Dose-escalation | Spleen Volumes (Body Weight Adjusted) in Part 2 | Week 13 | 3.629 cm3/kg | Standard Deviation 0.492 |
| Part2, 2.0 mg | Spleen Volumes (Body Weight Adjusted) in Part 2 | Baseline | 4.416 cm3/kg | Standard Deviation 2.084 |
| Part2, 2.0 mg | Spleen Volumes (Body Weight Adjusted) in Part 2 | Week 13 | 4.408 cm3/kg | Standard Deviation 1.486 |
| Part 2, 4.0 mg | Spleen Volumes (Body Weight Adjusted) in Part 2 | Baseline | 4.30 cm3/kg | — |
| Part 2, 4.0 mg | Spleen Volumes (Body Weight Adjusted) in Part 2 | Week 13 | 3.10 cm3/kg | — |