Pseudoxanthoma Elasticum
Conditions
Keywords
Pseudoxanthoma Elasticum, DS-1211b
Brief summary
This study was designed to evaluate the safety, tolerability, pharmacodynamics (PD) of DS-1211b, and pharmacokinetics (PK) in individuals with Pseudoxanthoma elasticum (PXE). PXE is a rare disease that is associated with significant risks of visual impairments and comorbidity from peripheral and cardiovascular diseases, and adversely impacts the quality of life in afflicted individuals.
Detailed description
DS-1211b, a potent small-molecule inhibitor of tissue-nonspecific alkaline phosphatase, is being developed for the treatment ectopic calcification diseases such as PXE. This study will assess DS-1211b (low-, middle-, and high-dose tablets) administered once daily for 12 weeks in individuals with PXE.
Interventions
DRUGDS-1211b
DS-1211b tablet administered once daily in the morning either in the fasted state or with a meal
OTHERPlacebo
Placebo tablet administered once daily in the morning either in the fasted state or with a meal
Sponsors
PXE International
Daiichi Sankyo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Signed and dated informed consent * Male or female participants aged 18 to 75 years at screening * Have an established diagnosis of PXE * Fully vaccinated for coronavirus disease 2019 (COVID-19) per current Center for Disease Control and Prevention guidelines Key
Exclusion criteria
* Have a history of bone fracture in the past 6 months * Have a history of active metabolic bone disease, excluding osteopenia or osteoporosis without fragility fracture * Have a history of calcium pyrophosphate deposit disease * Have a history of hypophosphatasia * Have a history of untreated hyperparathyroidism * Participated in another interventional research study in the past 60 days. * Used bisphosphonate in the preceding 12 months or had plans to use bisphosphonate during the study. * Received Vitamin B6 supplementation \>5 mg/day in the month prior to screening and during the study * Initiated or changed dose of Vitamin D in the preceding month prior to screening * Have an alkaline phosphatase \<lower limit of normal (LLN) range * Have a QTcF interval duration \>450 ms at screening * Have moderate to severe renal insufficiency * Are pregnant or breast-feeding women * Are female participants unwilling to use contraceptive methods * Have any elective surgery planned during the study period * Have any other significant condition (medical, psychiatric, social, or medication) that, in the judgment of the Investigator, would prevent full participation or would be inappropriate for the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Pre-dose on Days 15, 43, 84; Day 86-88 and Day 98 of 12-week treatment period | PLP levels were assessed from collected plasma. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | From the date of signing informed consent form up to Day 98 (14 days after last dose of study drug) post-dose of 12-week treatment period | TEAEs are defined as events that start on or after the first dose of study drug or start prior to but then worsen after the first dose of study drug. Adverse events are coded using MedDRA version 26.1. |
| Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Pre-dose on Days 15, 43, 84; Day 86-88 and Day 98 of 12-week treatment period | ALP levels were assessed using the IFCC serum assay. |
| Percent Change From Baseline in Pharmacodynamic Parameter Inorganic Pyrophosphate (PPi) Levels | Pre-dose on Days 15, 43, and 84 of 12-week treatment period | PPi levels were assessed from collected plasma. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Parameter Time to Maximum Concentration (Tmax) | Day 1 and Day 84 post-dose of 12-week treatment period | Pharmacokinetic parameter Tmax was assessed using population PK modeling. |
| Pharmacokinetic Parameter Maximum Concentration (Cmax) | Day1 and Day 84 post-dose of 12-week treatment period | Pharmacokinetic parameter Cmax was estimated using population PK modeling. |
| Pharmacokinetic Parameter Trough Plasma Concentration (Ctrough) | Day 1 and Day 84 post-dose of 12-week treatment period | Pharmacokinetic parameter Ctrough was assessed using observed concentrations at 10 hours post-dose. |
| Pharmacokinetic Parameter Area Under the Plasma Concentration-time Curve (AUC) | Day 1 and Day 84 post-dose of 12-week treatment period | Pharmacokinetic parameter AUCtau was assessed using population PK modeling. |
Countries
Netherlands, United States
Participant flow
Recruitment details
A total of 65 participants who met all inclusion criteria and no exclusion criteria were enrolled in the study in the United States and in the Netherlands.
Participants by arm
| Arm | Count |
|---|---|
| DS-1211b Low Dose Participants who were randomized to receive DS-1211 tablets once daily for 12 weeks. | 16 |
| DS-1211b Middle Dose Participants who were randomized to receive DS-1211b tablets once daily for 12 weeks. | 16 |
| DS-1211b High Dose Participants who were randomized to receive DS-1211b tablets once daily for 12 weeks. | 16 |
| Placebo Participants who were randomized to receive placebo tablets once daily for 12 weeks. | 17 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse event (central vision loss) | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | DS-1211b Low Dose | DS-1211b Middle Dose | DS-1211b High Dose | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 55.9 years STANDARD_DEVIATION 7.65 | 51.6 years STANDARD_DEVIATION 10.84 | 53.8 years STANDARD_DEVIATION 8.47 | 53.5 years STANDARD_DEVIATION 13.92 | 53.7 years STANDARD_DEVIATION 10.43 |
| Age, Customized <=18 years | 14 Participants | 14 Participants | 14 Participants | 12 Participants | 54 Participants |
| Age, Customized ≥64 years | 2 Participants | 2 Participants | 2 Participants | 5 Participants | 11 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 16 Participants | 15 Participants | 16 Participants | 16 Participants | 63 Participants |
| Sex: Female, Male Female | 7 Participants | 10 Participants | 10 Participants | 14 Participants | 41 Participants |
| Sex: Female, Male Male | 9 Participants | 6 Participants | 6 Participants | 3 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 17 |
| other Total, other adverse events | 8 / 16 | 7 / 16 | 6 / 16 | 6 / 17 |
| serious Total, serious adverse events | 1 / 16 | 0 / 16 | 0 / 16 | 0 / 17 |
Outcome results
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b
TEAEs are defined as events that start on or after the first dose of study drug or start prior to but then worsen after the first dose of study drug. Adverse events are coded using MedDRA version 26.1.
Time frame: From the date of signing informed consent form up to Day 98 (14 days after last dose of study drug) post-dose of 12-week treatment period
Population: Treatment-emergent adverse events were assessed in the Safety Analysis Set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DS-1211b Low Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE | 8 Participants |
| DS-1211b Low Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE related to study drug | 2 Participants |
| DS-1211b Low Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any serious TEAE related to study drug | 0 Participants |
| DS-1211b Low Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE by maximum severity, mild | 4 Participants |
| DS-1211b Low Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE leading to drug interruption | 1 Participants |
| DS-1211b Low Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE leading to drug discontinuation | 1 Participants |
| DS-1211b Low Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE by maximum severity, moderate | 3 Participants |
| DS-1211b Low Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE leading to death | 0 Participants |
| DS-1211b Low Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any related TEAE leading to drug discontinuation | 1 Participants |
| DS-1211b Low Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE by maximum severity, severe | 1 Participants |
| DS-1211b Low Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any serious TEAE | 1 Participants |
| DS-1211b Low Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any related TEAE leading to drug interruption | 1 Participants |
| DS-1211b Low Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any serious TEAE leading to drug interruption | 0 Participants |
| DS-1211b Low Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE related to COVID-19 | 0 Participants |
| DS-1211b Low Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any serious TEAE leading to drug discontinuation | 0 Participants |
| DS-1211b Middle Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any serious TEAE leading to drug discontinuation | 0 Participants |
| DS-1211b Middle Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE related to study drug | 2 Participants |
| DS-1211b Middle Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE by maximum severity, severe | 0 Participants |
| DS-1211b Middle Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any serious TEAE related to study drug | 0 Participants |
| DS-1211b Middle Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE leading to death | 0 Participants |
| DS-1211b Middle Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE leading to drug discontinuation | 0 Participants |
| DS-1211b Middle Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any related TEAE leading to drug interruption | 0 Participants |
| DS-1211b Middle Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE leading to drug interruption | 0 Participants |
| DS-1211b Middle Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE by maximum severity, mild | 6 Participants |
| DS-1211b Middle Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any serious TEAE leading to drug interruption | 0 Participants |
| DS-1211b Middle Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE related to COVID-19 | 0 Participants |
| DS-1211b Middle Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any related TEAE leading to drug discontinuation | 0 Participants |
| DS-1211b Middle Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any serious TEAE | 0 Participants |
| DS-1211b Middle Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE by maximum severity, moderate | 1 Participants |
| DS-1211b Middle Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE | 7 Participants |
| DS-1211b High Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any serious TEAE leading to drug discontinuation | 0 Participants |
| DS-1211b High Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE | 6 Participants |
| DS-1211b High Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE leading to death | 0 Participants |
| DS-1211b High Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE by maximum severity, mild | 4 Participants |
| DS-1211b High Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE by maximum severity, moderate | 2 Participants |
| DS-1211b High Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE by maximum severity, severe | 0 Participants |
| DS-1211b High Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any serious TEAE | 0 Participants |
| DS-1211b High Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any serious TEAE leading to drug interruption | 0 Participants |
| DS-1211b High Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any serious TEAE related to study drug | 0 Participants |
| DS-1211b High Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE leading to drug interruption | 0 Participants |
| DS-1211b High Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE leading to drug discontinuation | 0 Participants |
| DS-1211b High Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE related to study drug | 1 Participants |
| DS-1211b High Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any related TEAE leading to drug interruption | 0 Participants |
| DS-1211b High Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any related TEAE leading to drug discontinuation | 0 Participants |
| DS-1211b High Dose | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE related to COVID-19 | 1 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any serious TEAE leading to drug interruption | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE leading to death | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE related to study drug | 1 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any serious TEAE | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE by maximum severity, severe | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE | 6 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any related TEAE leading to drug interruption | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE by maximum severity, moderate | 3 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE by maximum severity, mild | 3 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE related to COVID-19 | 1 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE leading to drug interruption | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any serious TEAE related to study drug | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any related TEAE leading to drug discontinuation | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any TEAE leading to drug discontinuation | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) in Participants Receiving DS-1211b | Any serious TEAE leading to drug discontinuation | 0 Participants |
Primary
Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels
ALP levels were assessed using the IFCC serum assay.
Time frame: Pre-dose on Days 15, 43, 84; Day 86-88 and Day 98 of 12-week treatment period
Population: ALP levels were assessed in participants with available data in the Biomarker Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DS-1211b Low Dose | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 86-88 | 16.60 percent change | Standard Deviation 18.39 |
| DS-1211b Low Dose | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 43 | 25.02 percent change | Standard Deviation 17.54 |
| DS-1211b Low Dose | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 98 | 7.65 percent change | Standard Deviation 15.34 |
| DS-1211b Low Dose | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 84 | 25.54 percent change | Standard Deviation 16.89 |
| DS-1211b Low Dose | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 15 | 17.93 percent change | Standard Deviation 10.6 |
| DS-1211b Middle Dose | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 84 | 39.81 percent change | Standard Deviation 20.19 |
| DS-1211b Middle Dose | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 86-88 | 29.93 percent change | Standard Deviation 14.61 |
| DS-1211b Middle Dose | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 98 | 9.48 percent change | Standard Deviation 14.99 |
| DS-1211b Middle Dose | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 43 | 42.89 percent change | Standard Deviation 30.26 |
| DS-1211b Middle Dose | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 15 | 24.39 percent change | Standard Deviation 14.45 |
| DS-1211b High Dose | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 84 | 61.90 percent change | Standard Deviation 37.86 |
| DS-1211b High Dose | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 15 | 39.40 percent change | Standard Deviation 11.52 |
| DS-1211b High Dose | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 43 | 63.48 percent change | Standard Deviation 35.68 |
| DS-1211b High Dose | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 86-88 | 49.67 percent change | Standard Deviation 26 |
| DS-1211b High Dose | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 98 | 22.95 percent change | Standard Deviation 22.42 |
| Placebo | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 86-88 | -3.20 percent change | Standard Deviation 9.46 |
| Placebo | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 43 | -2.54 percent change | Standard Deviation 10.38 |
| Placebo | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 15 | -0.48 percent change | Standard Deviation 6.14 |
| Placebo | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 84 | -4.31 percent change | Standard Deviation 9.58 |
| Placebo | Percent Change From Baseline in Pharmacodynamic Parameter Alkaline Phosphatase (ALP) Levels | Day 98 | -0.05 percent change | Standard Deviation 13.72 |
Primary
Percent Change From Baseline in Pharmacodynamic Parameter Inorganic Pyrophosphate (PPi) Levels
PPi levels were assessed from collected plasma.
Time frame: Pre-dose on Days 15, 43, and 84 of 12-week treatment period
Population: PPi levels were assessed in participants with available data in the Biomarker Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DS-1211b Low Dose | Percent Change From Baseline in Pharmacodynamic Parameter Inorganic Pyrophosphate (PPi) Levels | Day 15 | 118.97 percent change | Standard Deviation 362.42 |
| DS-1211b Low Dose | Percent Change From Baseline in Pharmacodynamic Parameter Inorganic Pyrophosphate (PPi) Levels | Day 84 | 23.48 percent change | Standard Deviation 78.04 |
| DS-1211b Low Dose | Percent Change From Baseline in Pharmacodynamic Parameter Inorganic Pyrophosphate (PPi) Levels | Day 43 | 17.75 percent change | Standard Deviation 50.05 |
| DS-1211b Middle Dose | Percent Change From Baseline in Pharmacodynamic Parameter Inorganic Pyrophosphate (PPi) Levels | Day 15 | 11.32 percent change | Standard Deviation 50.13 |
| DS-1211b Middle Dose | Percent Change From Baseline in Pharmacodynamic Parameter Inorganic Pyrophosphate (PPi) Levels | Day 84 | 81.77 percent change | Standard Deviation 313.08 |
| DS-1211b Middle Dose | Percent Change From Baseline in Pharmacodynamic Parameter Inorganic Pyrophosphate (PPi) Levels | Day 43 | -5.55 percent change | Standard Deviation 36.74 |
| DS-1211b High Dose | Percent Change From Baseline in Pharmacodynamic Parameter Inorganic Pyrophosphate (PPi) Levels | Day 43 | 4.59 percent change | Standard Deviation 19.47 |
| DS-1211b High Dose | Percent Change From Baseline in Pharmacodynamic Parameter Inorganic Pyrophosphate (PPi) Levels | Day 15 | 23.95 percent change | Standard Deviation 69.94 |
| DS-1211b High Dose | Percent Change From Baseline in Pharmacodynamic Parameter Inorganic Pyrophosphate (PPi) Levels | Day 84 | 24.27 percent change | Standard Deviation 97.87 |
| Placebo | Percent Change From Baseline in Pharmacodynamic Parameter Inorganic Pyrophosphate (PPi) Levels | Day 15 | 13.33 percent change | Standard Deviation 61 |
| Placebo | Percent Change From Baseline in Pharmacodynamic Parameter Inorganic Pyrophosphate (PPi) Levels | Day 84 | 4.28 percent change | Standard Deviation 41.45 |
| Placebo | Percent Change From Baseline in Pharmacodynamic Parameter Inorganic Pyrophosphate (PPi) Levels | Day 43 | 12.97 percent change | Standard Deviation 38.33 |
Primary
Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels
PLP levels were assessed from collected plasma.
Time frame: Pre-dose on Days 15, 43, 84; Day 86-88 and Day 98 of 12-week treatment period
Population: PLP levels were assessed using Biomarker Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DS-1211b Low Dose | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 86-88 | -5.96 percent change | Standard Deviation 27.93 |
| DS-1211b Low Dose | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 43 | 8.56 percent change | Standard Deviation 42.26 |
| DS-1211b Low Dose | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 98 | 6.10 percent change | Standard Deviation 47.54 |
| DS-1211b Low Dose | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 84 | 12.03 percent change | Standard Deviation 46.95 |
| DS-1211b Low Dose | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 15 | 11.01 percent change | Standard Deviation 53.93 |
| DS-1211b Middle Dose | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 84 | 53.07 percent change | Standard Deviation 110.74 |
| DS-1211b Middle Dose | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 86-88 | -6.52 percent change | Standard Deviation 41.25 |
| DS-1211b Middle Dose | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 98 | -10.96 percent change | Standard Deviation 45.58 |
| DS-1211b Middle Dose | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 43 | 36.73 percent change | Standard Deviation 79.89 |
| DS-1211b Middle Dose | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 15 | 45.42 percent change | Standard Deviation 92.18 |
| DS-1211b High Dose | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 84 | 6.04 percent change | Standard Deviation 38.72 |
| DS-1211b High Dose | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 15 | 50.97 percent change | Standard Deviation 56.78 |
| DS-1211b High Dose | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 43 | 25.00 percent change | Standard Deviation 48.51 |
| DS-1211b High Dose | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 86-88 | -28.76 percent change | Standard Deviation 31.72 |
| DS-1211b High Dose | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 98 | -8.41 percent change | Standard Deviation 35.1 |
| Placebo | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 86-88 | -10.77 percent change | Standard Deviation 45.53 |
| Placebo | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 43 | 16.25 percent change | Standard Deviation 35.09 |
| Placebo | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 15 | 3.42 percent change | Standard Deviation 36.86 |
| Placebo | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 84 | -8.44 percent change | Standard Deviation 41.44 |
| Placebo | Percent Change From Baseline in Pharmacodynamic Parameter Pyridoxal 5'-Phosphate (PLP) Levels | Day 98 | 17.07 percent change | Standard Deviation 98.34 |
Secondary
Pharmacokinetic Parameter Area Under the Plasma Concentration-time Curve (AUC)
Pharmacokinetic parameter AUCtau was assessed using population PK modeling.
Time frame: Day 1 and Day 84 post-dose of 12-week treatment period
Population: Pharmacokinetic parameters were assessed using the PK Analysis Set.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| DS-1211b Low Dose | Pharmacokinetic Parameter Area Under the Plasma Concentration-time Curve (AUC) | Day 1, AUCtau | 978 ng*h/mL | Geometric Coefficient of Variation 28.3 |
| DS-1211b Low Dose | Pharmacokinetic Parameter Area Under the Plasma Concentration-time Curve (AUC) | Day 84, AUCtau | 1020 ng*h/mL | Geometric Coefficient of Variation 29.3 |
| DS-1211b Middle Dose | Pharmacokinetic Parameter Area Under the Plasma Concentration-time Curve (AUC) | Day 84, AUCtau | 2210 ng*h/mL | Geometric Coefficient of Variation 29 |
| DS-1211b Middle Dose | Pharmacokinetic Parameter Area Under the Plasma Concentration-time Curve (AUC) | Day 1, AUCtau | 2090 ng*h/mL | Geometric Coefficient of Variation 28 |
| DS-1211b High Dose | Pharmacokinetic Parameter Area Under the Plasma Concentration-time Curve (AUC) | Day 1, AUCtau | 2780 ng*h/mL | Geometric Coefficient of Variation 32.1 |
| DS-1211b High Dose | Pharmacokinetic Parameter Area Under the Plasma Concentration-time Curve (AUC) | Day 84, AUCtau | 3000 ng*h/mL | Geometric Coefficient of Variation 33.7 |
Secondary
Pharmacokinetic Parameter Maximum Concentration (Cmax)
Pharmacokinetic parameter Cmax was estimated using population PK modeling.
Time frame: Day1 and Day 84 post-dose of 12-week treatment period
Population: Pharmacokinetic parameters were assessed using PK Analysis Set.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| DS-1211b Low Dose | Pharmacokinetic Parameter Maximum Concentration (Cmax) | Day 1 | 252 ng/mL | Geometric Coefficient of Variation 20.5 |
| DS-1211b Low Dose | Pharmacokinetic Parameter Maximum Concentration (Cmax) | Day 84 | 255 ng/mL | Geometric Coefficient of Variation 20.6 |
| DS-1211b Middle Dose | Pharmacokinetic Parameter Maximum Concentration (Cmax) | Day 1 | 540 ng/mL | Geometric Coefficient of Variation 34.8 |
| DS-1211b Middle Dose | Pharmacokinetic Parameter Maximum Concentration (Cmax) | Day 84 | 547 ng/mL | Geometric Coefficient of Variation 34.9 |
| DS-1211b High Dose | Pharmacokinetic Parameter Maximum Concentration (Cmax) | Day 1 | 713 ng/mL | Geometric Coefficient of Variation 26.9 |
| DS-1211b High Dose | Pharmacokinetic Parameter Maximum Concentration (Cmax) | Day 84 | 726 ng/mL | Geometric Coefficient of Variation 27 |
Secondary
Pharmacokinetic Parameter Time to Maximum Concentration (Tmax)
Pharmacokinetic parameter Tmax was assessed using population PK modeling.
Time frame: Day 1 and Day 84 post-dose of 12-week treatment period
Population: Pharmacokinetic parameters were assessed using PK Analysis Set.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| DS-1211b Low Dose | Pharmacokinetic Parameter Time to Maximum Concentration (Tmax) | Day 1 | 1.25 hours |
| DS-1211b Low Dose | Pharmacokinetic Parameter Time to Maximum Concentration (Tmax) | Day 84 | 1.25 hours |
| DS-1211b Middle Dose | Pharmacokinetic Parameter Time to Maximum Concentration (Tmax) | Day 1 | 1.13 hours |
| DS-1211b Middle Dose | Pharmacokinetic Parameter Time to Maximum Concentration (Tmax) | Day 84 | 1.13 hours |
| DS-1211b High Dose | Pharmacokinetic Parameter Time to Maximum Concentration (Tmax) | Day 1 | 1.25 hours |
| DS-1211b High Dose | Pharmacokinetic Parameter Time to Maximum Concentration (Tmax) | Day 84 | 1.25 hours |
Secondary
Pharmacokinetic Parameter Trough Plasma Concentration (Ctrough)
Pharmacokinetic parameter Ctrough was assessed using observed concentrations at 10 hours post-dose.
Time frame: Day 1 and Day 84 post-dose of 12-week treatment period
Population: Pharmacokinetic parameters were assessed in participants with available data in the PK Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DS-1211b Low Dose | Pharmacokinetic Parameter Trough Plasma Concentration (Ctrough) | Day 1 (10 hour) | 17.15 ng/mL | Standard Deviation 11.58 |
| DS-1211b Low Dose | Pharmacokinetic Parameter Trough Plasma Concentration (Ctrough) | Day 84 (10 hour) | 15.19 ng/mL | Standard Deviation 9 |
| DS-1211b Middle Dose | Pharmacokinetic Parameter Trough Plasma Concentration (Ctrough) | Day 1 (10 hour) | 26.30 ng/mL | Standard Deviation 13.71 |
| DS-1211b Middle Dose | Pharmacokinetic Parameter Trough Plasma Concentration (Ctrough) | Day 84 (10 hour) | 38.53 ng/mL | Standard Deviation 30.45 |
| DS-1211b High Dose | Pharmacokinetic Parameter Trough Plasma Concentration (Ctrough) | Day 1 (10 hour) | 48.43 ng/mL | Standard Deviation 46.5 |
| DS-1211b High Dose | Pharmacokinetic Parameter Trough Plasma Concentration (Ctrough) | Day 84 (10 hour) | 54.48 ng/mL | Standard Deviation 40.79 |