Trial Outcomes & Findings for Safety, Tolerability, and Efficacy of Encaleret in Participants With Autosomal Dominant Hypocalcemia (ADH) Type 1 (NCT NCT04581629)

Last Updated: 2024-11-19

Results Overview

Adverse events (AEs) were defined as any untoward medical occurrence associated with the use of an intervention in humans, whether or not considered intervention-related. Treatment-emergence was defined as any AE(s) regardless of relationship to investigational medicinal product (IMP), that had an onset or worsened in severity on or after the first dose of IMP.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

13 participants

Primary outcome timeframe

Day 1 up to 16 months

Results posted on

2024-11-19

Participant Flow

A total of 13 participants were enrolled. Participants were enrolled in 3 periods sequentially to receive encaleret, Period 1(inpatient), Period 2(inpatient), and Period 3(outpatient). 6 participants were enrolled into Period 1. Participants who completed Period 1 enrolled into Period 2, and 7 additional participants enrolled into Period 2. 13 participants who completed Period 2 enrolled into Period 3. As pre-specified, data were collected and reported pooled for Period 1, 2 and 3 respectively.

Participant milestones

Participant milestones
Measure	Period 1: Encaleret In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Period 2: Encaleret In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID.	Period 3: Encaleret In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Period 1 (5 Days) STARTED	6	0	0
Period 1 (5 Days) Received at Least One Dose of Study Treatment	6	0	0
Period 1 (5 Days) COMPLETED	6	0	0
Period 1 (5 Days) NOT COMPLETED	0	0	0
Period 2 (5 Days) STARTED	0	13	0
Period 2 (5 Days) Received at Least One Dose of Study Treatment	0	13	0
Period 2 (5 Days) COMPLETED	0	13	0
Period 2 (5 Days) NOT COMPLETED	0	0	0
Period 3 (24 Weeks) STARTED	0	0	13
Period 3 (24 Weeks) Received at Least One Dose of Study Treatment	0	0	13
Period 3 (24 Weeks) COMPLETED	0	0	13
Period 3 (24 Weeks) NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Encaleret n=13 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID). In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Age, Continuous Period 1	40.0 years STANDARD_DEVIATION 17.65 • n=6 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Age, Continuous Periods 2 and 3	38.9 years STANDARD_DEVIATION 14.90 • n=13 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Sex: Female, Male Period 1 · Female	3 Participants n=6 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Sex: Female, Male Period 1 · Male	3 Participants n=6 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Sex: Female, Male Periods 2 and 3 · Female	8 Participants n=13 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Sex: Female, Male Periods 2 and 3 · Male	5 Participants n=13 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Ethnicity (NIH/OMB) Period 1 · Hispanic or Latino	0 Participants n=6 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Ethnicity (NIH/OMB) Period 1 · Not Hispanic or Latino	6 Participants n=6 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Ethnicity (NIH/OMB) Period 1 · Unknown or Not Reported	0 Participants n=6 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Ethnicity (NIH/OMB) Periods 2 and 3 · Hispanic or Latino	0 Participants n=13 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Ethnicity (NIH/OMB) Periods 2 and 3 · Not Hispanic or Latino	13 Participants n=13 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Ethnicity (NIH/OMB) Periods 2 and 3 · Unknown or Not Reported	0 Participants n=13 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Race (NIH/OMB) Period 1 · American Indian or Alaska Native	0 Participants n=6 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Race (NIH/OMB) Period 1 · Asian	0 Participants n=6 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Race (NIH/OMB) Period 1 · Native Hawaiian or Other Pacific Islander	0 Participants n=6 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Race (NIH/OMB) Period 1 · Black or African American	0 Participants n=6 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Race (NIH/OMB) Period 1 · White	6 Participants n=6 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Race (NIH/OMB) Period 1 · More than one race	0 Participants n=6 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Race (NIH/OMB) Period 1 · Unknown or Not Reported	0 Participants n=6 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Race (NIH/OMB) Periods 2 and 3 · American Indian or Alaska Native	0 Participants n=13 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Race (NIH/OMB) Periods 2 and 3 · Asian	0 Participants n=13 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Race (NIH/OMB) Periods 2 and 3 · Native Hawaiian or Other Pacific Islander	0 Participants n=13 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Race (NIH/OMB) Periods 2 and 3 · Black or African American	0 Participants n=13 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Race (NIH/OMB) Periods 2 and 3 · White	13 Participants n=13 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Race (NIH/OMB) Periods 2 and 3 · More than one race	0 Participants n=13 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.
Race (NIH/OMB) Periods 2 and 3 · Unknown or Not Reported	0 Participants n=13 Participants • Data are reported separately for each period of the study. As pre-specified, data for Periods 2 and 3 are combined as the same participants flowed from Period 2 to Period 3.

PRIMARY outcome

Timeframe: Day 1 up to 16 months

Population: Safety Analysis Set included all participants who received at least one dose of study drug in the considered period. As pre-specified in the protocol, data were collected and are presented pooled for Periods 2 and 3.

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=6 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret n=13 Participants In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Periods 1, 2 and 3: Number of Participants With Treatment-emergent Adverse Events (TEAEs)	5 Participants	13 Participants	—

PRIMARY outcome

Timeframe: Baseline, Week 24

Population: Safety Analysis Set included all participants who received at least one dose of study drug in the considered period. As pre-specified in the protocol, data are presented for Period 3 only. As pre-specified, data were collected and are reported pooled for all dose levels in Period 3 and are presented at the specified timepoint.

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=13 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Period 3: Change From Baseline in Albumin-Corrected Blood Calcium Concentrations (cCa)	1.9 milligrams (mg)/deciliter (dL) Standard Deviation 0.48	—	—

PRIMARY outcome

Timeframe: Week 24

Population: Safety Analysis Set included all participants who received at least one dose of study drug in the considered period. As pre-specified in the protocol, data are presented for Period 3 only. Number analyzed = number of participants evaluable at the specified timepoint. As pre-specified, data were collected and are reported pooled for all dose levels in Period 3 and are presented at the specified timepoint.

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=13 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Period 3: Rate of Urinary Calcium Excretion	202 mg/24hour (hr) Standard Deviation 83	—	—

SECONDARY outcome

Timeframe: 15 minutes pre-dose on Day 5 of Periods 1 and 2 (Periods were 5 days)

Population: Safety Analysis Set, all participants who received at least 1 dose of study drug in the considered period. As pre-specified in the protocol, data are presented for Periods 1 and 2 only. Overall number of participants analyzed=those evaluable for this endpoint. Number analyzed=those evaluable at specified timepoints. As pre-specified, data were collected and reported pooled for all dose levels in Period 2 at the specified timepoint and per dose at the specified timepoint in Period 1.

Blood samples were taken for analysis of iPTH concentrations. iPTH concentrations were analyzed via an electrochemiluminescence immunoassay.

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=6 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret n=12 Participants In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Periods 1 and 2: Intact Parathyroid Hormone (iPTH) Concentrations in the Blood Period 1: Day 5 (180 mg)	43.8 Picograms (pg)/milliliter (mL) Standard Deviation 34.06	—	—
Periods 1 and 2: Intact Parathyroid Hormone (iPTH) Concentrations in the Blood Period 2: Day 5	—	20.6 Picograms (pg)/milliliter (mL) Standard Deviation 15.87	—

SECONDARY outcome

Timeframe: Periods 1 and 2: Day 5 (Periods were 5 days)

Population: Pharmacokinetic (PK) Analysis Set included all participants who received at least one dose of study drug and who had at least one non-missing PK concentration result. Overall number of participants analyzed = participants evaluable for this endpoint. Number analyzed = participants evaluable for this endpoint at the specified timepoints. As pre-specified in the protocol, data are presented for Periods 1 and 2 only.

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=6 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret n=1 Participants In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Periods 1 and 2: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Encaleret Period 1: Day 5 AM 180mg	11283.7 hour (hr)*nanogram (ng)/milliliter (mL) Standard Deviation 3556.12	—	—
Periods 1 and 2: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Encaleret Period 1: Day 5 PM 180 mg	13127.7 hour (hr)*nanogram (ng)/milliliter (mL) Standard Deviation 2992.61	—	—
Periods 1 and 2: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Encaleret Period 1: Day 5 PM 120 mg	12417.0 hour (hr)*nanogram (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.	—	—
Periods 1 and 2: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Encaleret Period 2: Day 5 PM 10mg	—	623.7 hour (hr)*nanogram (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.	—

SECONDARY outcome

Timeframe: Periods 1 and 2: Day 5, Period 3: Week 24 (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

Population: Pharmacokinetic (PK) Analysis Set included all participants who received at least one dose of study drug and who had at least one non-missing PK concentration result. Overall number of participants analyzed = participants evaluable for the endpoint. Number analyzed = participants evaluable for the endpoint at the specified timepoints. As pre-specified in the protocol, data for Periods 2 and 3 are reported per dose received.

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=6 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret n=3 Participants In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret n=2 Participants In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 2: Day 5PM 90 mg	—	822.3 nanograms (ng)/milliliter (mL) Standard Deviation 73.93	—
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 2: Day 5AM 150 mg	—	1560.0 nanograms (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.	—
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 2: Day 5AM 180 mg	—	1956.7 nanograms (ng)/milliliter (mL) Standard Deviation 748.09	—
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 2: Day 5PM 10 mg	—	134.3 nanograms (ng)/milliliter (mL) Standard Deviation 34.53	—
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 2: Day 5PM 30 mg	—	226.0 nanograms (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.	—
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 1: Day 5 AM 180mg	2593.3 nanograms (ng)/milliliter (mL) Standard Deviation 655.89	—	—
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 1: Day 5 PM 180 mg	1834.0 nanograms (ng)/milliliter (mL) Standard Deviation 470.46	—	—
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 1: Day 5 PM 120 mg	1890.0 nanograms (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.	—	—
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 2: Day 5AM 10 mg	—	102.0 nanograms (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.	—
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 2: Day 5AM 30 mg	—	223.6 nanograms (ng)/milliliter (mL) Standard Deviation 169.94	—
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 2: Day 5AM 60 mg	—	496.0 nanograms (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.	—
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 2: Day 5AM 90 mg	—	1041.0 nanograms (ng)/milliliter (mL) Standard Deviation 303.40	—
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 2: Day 5AM 120 mg	—	1720.0 nanograms (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.	—
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 2: Day 5PM 60 mg	—	373.0 nanograms (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.	—
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 2: Day 5PM 120 mg	—	1670.0 nanograms (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.	—
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 2: Day 5PM 150 mg	—	1590.0 nanograms (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.	—
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 2: Day 5PM 180 mg	—	2203.3 nanograms (ng)/milliliter (mL) Standard Deviation 254.23	—
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 3: Week 24 5 mg	—	—	44.4 nanograms (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 3: Week 24 10 mg	—	—	58.6 nanograms (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 3: Week 24 20 mg	—	—	200.5 nanograms (ng)/milliliter (mL) Standard Deviation 50.20
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 3: Week 24 30 mg	—	—	466.0 nanograms (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 3: Week 24 60 mg	—	—	403.0 nanograms (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 3: Week 24 70 mg	—	—	472.0 nanograms (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 3: Week 24 80 mg	—	—	872.0 nanograms (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 3: Week 24 120 mg	—	—	1090.0 nanograms (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 3: Week 24 150 mg	—	—	1110.0 nanograms (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 3: Week 24 180 mg	—	—	2125.0 nanograms (ng)/milliliter (mL) Standard Deviation 21.21
Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret Period 3: Week 24 190 mg	—	—	2080.0 nanograms (ng)/milliliter (mL) Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.

SECONDARY outcome

Timeframe: Periods 1 and 2: Day 5; Period 3: Week 24 (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

Population: Pharmacokinetic (PK) Analysis Set included all participants who received at least one dose of study drug and who had at least one non-missing PK concentration result. Overall number of participants analyzed = participants evaluable for the endpoint. Number analyzed = participants evaluable for the endpoint at the specified timepoints. As pre-specified in the protocol, data for Periods 2 and 3 are reported per dose received.

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=6 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret n=3 Participants In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret n=2 Participants In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 1: Day 5 AM 180mg	1.1 hour Interval 1.0 to 3.0	—	—
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 1: Day 5 PM 180 mg	1.5 hour Interval 1.5 to 3.0	—	—
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 1: Day 5 PM 120 mg	2.0 hour Interval 2.0 to 2.0	—	—
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 2: Day 5AM 10 mg	—	1.5 hour Interval 1.5 to 1.5	—
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 2: Day 5AM 30 mg	—	4.0 hour Interval 1.5 to 4.0	—
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 2: Day 5AM 60 mg	—	1.5 hour Interval 1.5 to 1.5	—
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 2: Day 5AM 90 mg	—	1.5 hour Interval 1.5 to 4.0	—
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 2: Day 5AM 120 mg	—	1.5 hour Interval 1.5 to 1.5	—
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 2: Day 5AM 150 mg	—	1.5 hour Interval 1.5 to 1.5	—
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 2: Day 5AM 180 mg	—	1.5 hour Interval 1.5 to 4.0	—
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 2: Day 5PM 10 mg	—	1.4 hour Interval 0.5 to 1.5	—
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 2: Day 5PM 30 mg	—	1.5 hour Interval 1.5 to 1.5	—
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 2: Day 5PM 60 mg	—	1.5 hour Interval 1.5 to 1.5	—
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 2: Day 5PM 90 mg	—	1.5 hour Interval 0.5 to 1.5	—
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 2: Day 5PM 120 mg	—	1.5 hour Interval 1.5 to 1.5	—
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 2: Day 5PM 150 mg	—	1.5 hour Interval 1.5 to 1.5	—
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 2: Day 5PM 180 mg	—	1.5 hour Interval 1.5 to 1.5	—
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 3: Week 24 5 mg	—	—	2.0 hour Interval 2.0 to 2.0
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 3: Week 24 10 mg	—	—	2.0 hour Interval 2.0 to 2.0
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 3: Week 24 20 mg	—	—	2.0 hour Interval 2.0 to 2.0
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 3: Week 24 30 mg	—	—	0.5 hour Interval 0.5 to 0.5
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 3: Week 24 60 mg	—	—	2.0 hour Interval 2.0 to 2.0
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 3: Week 24 70 mg	—	—	4.0 hour Interval 4.0 to 4.0
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 3: Week 24 80 mg	—	—	0.5 hour Interval 0.5 to 0.5
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 3: Week 24 120 mg	—	—	2.0 hour Interval 2.0 to 2.0
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 3: Week 24 150 mg	—	—	4.0 hour Interval 4.0 to 4.0
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 3: Week 24 180 mg	—	—	2.0 hour Interval 2.0 to 2.1
Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret Period 3: Week 24 190 mg	—	—	2.0 hour Interval 2.0 to 2.0

SECONDARY outcome

Timeframe: Period 2: Baseline, Day 5 (Period was 5 days), Period 3: Baseline, Week 24 (Period was 24 weeks)

Population: Safety Analysis Set included all participants who received at least one dose of study drug in the considered period. As pre-specified in the protocol, data are presented for Periods 2 and 3 only. Number analyzed = participants evaluable for the endpoint at the specified timepoints. As pre-specified, data were collected and are reported pooled for all dose levels in Period 2 and Period 3 and are presented at the specified timepoints.

Data values presented are for the change from baseline for the average values at the specified timepoints/visits.

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=13 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret n=13 Participants In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Periods 2 and 3: Change From Baseline in Blood Calcium Concentration (cCa) Period 2: Day 5	1.5 milligram (mg)/ deciliter (dL) Standard Deviation 0.60	—	—
Periods 2 and 3: Change From Baseline in Blood Calcium Concentration (cCa) Period 3: Week 24	—	1.9 milligram (mg)/ deciliter (dL) Standard Deviation 0.48	—

SECONDARY outcome

Timeframe: Period 3: Week 24, 15 minutes pre-dose (Period was 24 weeks)

Population: Safety Analysis Set included all participants who received at least one dose of study drug in the considered period. Number analyzed = participants evaluable for the endpoint at the specified timepoints. As pre-specified, data were collected and are reported pooled for all dose levels in Period 3 and are presented at the specified timepoint.

Fractional Excretion of Calcium was derived as (Urine Calcium at the interval considered \* Serum Creatinine at the end of the interval considered)/(Serum Calcium at the end of the interval considered \* Urine Creatinine at the interval considered) and is presented as percentage.

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=13 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Period 3: Urinary Calcium Clearance as Assessed by Fractional Excretion	0.016 percentage Standard Deviation 0.004	—	—

SECONDARY outcome

Timeframe: Periods 1 and 2: Day 5; Period 3, Week 24 (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

Population: Safety Analysis Set, which included all participants who received at least one dose of study drug in the considered period. Number analyzed = participants evaluable for the endpoint at the specified timepoints. As pre-specified, data were collected and are reported pooled for all dose levels in Period 2 and Period 3 at the specified timepoints. As pre-specified, data were collected and are presented per dose at the specified timepoint for Period 1.

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=3 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret n=13 Participants In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret n=13 Participants In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Periods 1, 2 and 3: Urinary Calcium Clearance as Assessed by 24-Hour Total Excretion Period 1: Day 5 AM 180 mg; PM 180 mg	84 mg/24hr Standard Deviation 146	—	—
Periods 1, 2 and 3: Urinary Calcium Clearance as Assessed by 24-Hour Total Excretion Period 1: Day 5 AM 180 mg; PM 120 mg	0 mg/24hr Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.	—	—
Periods 1, 2 and 3: Urinary Calcium Clearance as Assessed by 24-Hour Total Excretion Period 2: Day 5	—	179 mg/24hr Standard Deviation 108	—
Periods 1, 2 and 3: Urinary Calcium Clearance as Assessed by 24-Hour Total Excretion Period 3: Week 24	—	—	202 mg/24hr Standard Deviation 83

SECONDARY outcome

Timeframe: Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3: Week 24 (15 minutes pre-dose) (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

eGFR was calculated using Chronic Kidney Disease - Epidemiology Collaboration (CKD-EPI) formula (mL/min/1.73m\^2) = 141 x min (SCr/K, 1)\^α x max(SCR /K,1)-1.209 x 0.993Age x 1.018 \[if female\] x 1.159 \[if Black\], where SCr is the serum creatinine (mg/dL), K = 0.7 for female and 0.9 for males, α is -0.329 for female and -0.411 for males.

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=6 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret n=13 Participants In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret n=13 Participants In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Periods 1, 2 and 3: Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR) Period 1: Day 5 AM (180 mg)	91.1 mL/min/1.73m^2 Standard Deviation 18.73	—	—
Periods 1, 2 and 3: Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR) Period 2: Day 5 AM	—	90.6 mL/min/1.73m^2 Standard Deviation 25.30	—
Periods 1, 2 and 3: Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR) Period 3: Week 24	—	—	82.0 mL/min/1.73m^2 Standard Deviation 21.10

SECONDARY outcome

Timeframe: Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3: Week 24 (15 minutes pre-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

Population: Safety Analysis Set, all participants who received at least 1 dose of study drug in the considered period. Overall number of participants analyzed=participants evaluable for the endpoint. Number analyzed=participants evaluable for the endpoint at specified timepoints. As pre-specified, data were collected and reported pooled for all dose levels in Period 2 and 3 at the specified timepoints. As pre-specified, data were collected and are reported per dose at the specified timepoint for Period 1.

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=6 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret n=13 Participants In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret n=13 Participants In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Periods 1, 2 and 3: Serum Levels of 1,25-(OH)2 Vitamin D Period 1: Day 5 AM (180 mg)	25.8 picograms per milliliter (pg/mL) Standard Deviation 12.24	—	—
Periods 1, 2 and 3: Serum Levels of 1,25-(OH)2 Vitamin D Period 2: Day 5 AM	—	30.5 picograms per milliliter (pg/mL) Standard Deviation 16.40	—
Periods 1, 2 and 3: Serum Levels of 1,25-(OH)2 Vitamin D Period 3: Week 24	—	—	31.2 picograms per milliliter (pg/mL) Standard Deviation 16.19

SECONDARY outcome

Timeframe: Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3: Week 24 (15 minutes pre-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

Population: Safety Analysis Set, all participants who received at least one dose of study drug in the considered period. Overall number of participants analyzed=participants evaluable for the endpoint. Number analyzed=participants evaluable for the endpoint at specified timepoints. As pre-specified, data were collected and reported pooled for all dose levels in Period 2 and 3 at specified timepoints. As pre-specified, data were collected and are presented per dose at the specified timepoint for Period 1.

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=6 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret n=13 Participants In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret n=13 Participants In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations ⦁ Magnesium - Period 1: Day 5 AM (180 mg)	2.2 mg/dL Standard Deviation 0.36	—	—
Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations Magnesium - Period 2: Day 5 AM	—	1.9 mg/dL Standard Deviation 0.28	—
Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations Magnesium - Period 3: Week 24	—	—	2.0 mg/dL Standard Deviation 0.20
Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations ⦁ Phosphorus - Period 1: Day 5 AM (180 mg)	2.9 mg/dL Standard Deviation 0.39	—	—
Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations Phosphorus - Period 2: Day 5 AM	—	3.1 mg/dL Standard Deviation 0.75	—
Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations Phosphorus - Period 3: Week 24	—	—	3.7 mg/dL Standard Deviation 0.52
Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations ⦁ Creatinine - Period 1: Day 5 AM (180 mg)	0.93 mg/dL Standard Deviation 0.188	—	—
Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations Creatinine - Period 2: Day 5 AM	—	0.94 mg/dL Standard Deviation 0.229	—
Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations Creatinine - Period 3: Week 24	—	—	1.01 mg/dL Standard Deviation 0.212

SECONDARY outcome

Timeframe: Periods 1 and 2: Day 5 (0-24h post-dose), Period 3: Week 24 (0-24h post-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

Population: Safety Analysis Set, all participants who received at least one dose of study drug in the considered period. Overall number of participants analyzed=participants evaluable for the endpoint. Number analyzed=participants evaluable for the endpoint at the specified timepoints. As pre-specified, data were collected and reported pooled for all dose levels in Period 2 and 3 at specified timepoints. As pre-specified, data were collected and are reported per dose at the specified timepoint for Period 1.

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=3 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret n=13 Participants In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret n=13 Participants In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations Creatinine - Period 1: Day 5 AM 180 mg, PM 180 mg	1454 mg/24hr Standard Deviation 248	—	—
Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations Creatinine - Period 1: Day 5 AM 180 mg, PM 120 mg	1190 mg/24hr Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.	—	—
Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations Creatinine - Period 2: Day 5	—	1408 mg/24hr Standard Deviation 367	—
Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations Creatinine - Period 3: Week 24	—	—	1345 mg/24hr Standard Deviation 373
Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations Phosphorus - Period 1: Day 5 AM 180 mg, PM 180 mg	877 mg/24hr Standard Deviation 353	—	—
Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations Phosphorus - Period 1: Day 5 AM 180 mg, PM 120 mg	1100 mg/24hr Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.	—	—
Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations Phosphorus - Period 2: Day 5	—	962 mg/24hr Standard Deviation 226	—
Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations Phosphorus - Period 3: Week 24	—	—	754 mg/24hr Standard Deviation 240
Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations Magnesium - Period 1: Day 5 AM 180 mg, PM 180 mg	104 mg/24hr Standard Deviation 5	—	—
Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations Magnesium - Period 1: Day 5 AM 180 mg, PM 120 mg	110 mg/24hr Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.	—	—
Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations Magnesium - Period 2: Day 5	—	161 mg/24hr Standard Deviation 66	—
Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations Magnesium - Period 3: Week 24	—	—	121 mg/24hr Standard Deviation 38
Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations Citrate - Period 1: Day 5 AM 180 mg, PM 180 mg	662 mg/24hr Standard Deviation 77	—	—
Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations Citrate - Period 1: Day 5 AM 180 mg, PM 120 mg	778 mg/24hr Standard Deviation NA Standard deviation could not be calculated as there was only 1 participant with evaluable data.	—	—
Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations Citrate - Period 2: Day 5	—	381 mg/24hr Standard Deviation 203	—
Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations Citrate - Period 3: Week 24	—	—	439 mg/24hr Standard Deviation 224

SECONDARY outcome

Timeframe: Periods 1 and 2: Day 5 (0-24 hours post-dose), Period 3: Week 24: (0-24 hours post-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

Population: Safety Analysis Set, all participants who received at least one dose of study drug in the considered period. Overall number of participants analyzed=participants evaluable for the endpoint. Number analyzed=participants evaluable for the endpoint at the specified timepoints. As pre-specified, data were collected and reported pooled for all dose levels in Period 2 and 3 at specified timepoints. As pre-specified, data were collected and are reported per dose at the specified timepoint for Period 1.

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=3 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret n=13 Participants In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret n=11 Participants In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Periods 1, 2 and 3: pH as Assessed by Urine Sample Examinations Period 1: Day 5 AM 180 mg; PM 180 mg 0-24 hours post-dose	6.2 pH Standard Deviation 2.02	—	—
Periods 1, 2 and 3: pH as Assessed by Urine Sample Examinations Period 1: Day 5 AM 180 mg; PM 120 mg 0-24 hours post-dose	5.0 pH Standard Deviation NA Standard deviation could not be calculated as there was only one participant with evaluable data.	—	—
Periods 1, 2 and 3: pH as Assessed by Urine Sample Examinations Period 2: Day 5 0-24 hours post-dose	—	6.1 pH Standard Deviation 0.68	—
Periods 1, 2 and 3: pH as Assessed by Urine Sample Examinations Period 3: Week 24 0-24 hours post-dose	—	—	6.5 pH Standard Deviation 0.69

SECONDARY outcome

Timeframe: Periods 1 and 2: Day 5 (0-24h post-dose), Period 3: Week 24 (0-24h post-dose); (Period was 5 days for periods 1 and 2; 24 weeks for period 3)

Population: Safety Analysis Set, all participants who received at least one dose of study drug in the considered period. Overall number of participants analyzed=participants evaluable for the endpoint. Number analyzed=participants evaluable for the endpoint at specified timepoints. As pre-specified, data were collected and reported pooled for all dose levels in Period 2 and 3 at specified timepoints. As pre-specified, data were collected and are reported per dose at the specified timepoint for Period 1.

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=3 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret n=13 Participants In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret n=13 Participants In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations Sodium Period 2: Day 5	—	184.77 Milliequivalents (meq)/24hr Standard Deviation 51.038	—
Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations Potassium Period 1: Day 5 AM 180 mg, PM 180 mg	79.00 Milliequivalents (meq)/24hr Standard Deviation 48.662	—	—
Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations Potassium Period 1: Day 5 AM 180 mg, PM 120 mg	82.00 Milliequivalents (meq)/24hr Standard Deviation NA Standard deviation could not be calculated as there was only one participant with evaluable data.	—	—
Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations Potassium Period 2: Day 5	—	69.38 Milliequivalents (meq)/24hr Standard Deviation 24.476	—
Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations Potassium Period 3: Week 24	—	—	61.46 Milliequivalents (meq)/24hr Standard Deviation 32.196
Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations Sodium Period 1: Day 5 AM 180 mg, PM 180 mg	186.33 Milliequivalents (meq)/24hr Standard Deviation 84.831	—	—
Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations Sodium Period 1: Day 5 AM 180 mg, PM 120 mg	192.00 Milliequivalents (meq)/24hr Standard Deviation NA Standard deviation could not be calculated as there was only one participant with evaluable data.	—	—
Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations Sodium Period 3: Week 24	—	—	182.23 Milliequivalents (meq)/24hr Standard Deviation 95.407

SECONDARY outcome

Timeframe: Periods 1 and 2: Day 5 (0-4h post-dose), Period 3: Week 24 (0-4h post dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

Population: Safety Analysis Set, all participants who received at least one dose of study drug in the considered period. Overall number of participants analyzed=participants evaluable for the endpoint. Number analyzed=participants evaluable for the endpoint at the specified timepoints. As pre-specified, data were collected and reported pooled for all dose levels in Period 2 and 3 at specified timepoints. As pre-specified, data were collected and are reported per dose at the specified timepoint for Period 1.

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=5 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret n=13 Participants In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret n=11 Participants In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Periods 1, 2 and 3: Cyclic Adenosine Monophosphate (cAMP) Total Excretion Levels as Assessed by Urine Sample Examinations Period 1: Day 5 AM, 180 mg, PM 180 mg, 0-4 hours post-dose	2.98 nanomoles per deciliter (nmol/dL) Standard Deviation 0.795	—	—
Periods 1, 2 and 3: Cyclic Adenosine Monophosphate (cAMP) Total Excretion Levels as Assessed by Urine Sample Examinations Period 1: Day 5, AM 180 mg, PM 120 mg 0-4 hours post-dose	2.90 nanomoles per deciliter (nmol/dL) Standard Deviation NA Standard deviation could not be calculated as there was only one participant with evaluable data.	—	—
Periods 1, 2 and 3: Cyclic Adenosine Monophosphate (cAMP) Total Excretion Levels as Assessed by Urine Sample Examinations Period 2: Day 5 0-4 hours post-dose	—	2.79 nanomoles per deciliter (nmol/dL) Standard Deviation 0.762	—
Periods 1, 2 and 3: Cyclic Adenosine Monophosphate (cAMP) Total Excretion Levels as Assessed by Urine Sample Examinations Period 3: Week 24 0-4 hours post-dose	—	—	2.68 nanomoles per deciliter (nmol/dL) Standard Deviation 0.704

SECONDARY outcome

Timeframe: Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3 Week 24 (15 minutes pre-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

Population: Safety Analysis Set, all participants who received at least one dose of study drug in the considered period. Overall number of participants analyzed=participants evaluable for the endpoint. Number analyzed=participants evaluable for the endpoint at the specified timepoints. As pre-specified, data were collected and reported pooled for all dose levels in Period 2 and 3 at specified timepoints. As pre-specified, data were collected and are reported per dose at the specified timepoint for Period 1.

Blood samples were taken for analysis of bone resorption markers (CTx).

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=6 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret n=13 Participants In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret n=13 Participants In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Periods 1, 2 and 3: Bone Resorption Markers as Assessed by Collagen Cross-Linked C-Telopeptide (CTx) Period 1: Day 5 AM 180 mg	386 Picograms per milliliter (pg/mL) Standard Deviation 165	—	—
Periods 1, 2 and 3: Bone Resorption Markers as Assessed by Collagen Cross-Linked C-Telopeptide (CTx) Period 2: Day 5 AM	—	266 Picograms per milliliter (pg/mL) Standard Deviation 161	—
Periods 1, 2 and 3: Bone Resorption Markers as Assessed by Collagen Cross-Linked C-Telopeptide (CTx) Period 3: Week 24	—	—	744 Picograms per milliliter (pg/mL) Standard Deviation 565

SECONDARY outcome

Timeframe: Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3 Week 24 (15 minutes pre-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)

Population: Safety Analysis Set, all participants who received at least one dose of study drug in the considered period. Overall number of participants analyzed=participants evaluable for the endpoint. Number analyzed=participants evaluable for the endpoint at the specified timepoints. As pre-specified, data were collected and reported pooled for all dose levels in Period 2 and 3 at specified timepoints. As pre-specified, data were collected and are reported per dose at the specified timepoint for Period 1.

Blood samples were taken for analysis of bone formation markers (P1NP).

Outcome measures

Outcome measures
Measure	Period 1: Encaleret n=6 Participants In Period 1 (5 days), participants received an ascending dose of oral encaleret once daily (QD) for the first 3 days (Day 1: 30 mg QD, Day 2: 10, 60 or 90 mg QD, Day 3: 20, 40, 60, 90, 120 or 180 mg QD). Participants then received an individualized dose of oral encaleret twice daily (BID) for 2 days (Day 4 and Day 5: 10 to 180 mg BID).	Periods 2 and 3: Encaleret n=13 Participants In Period 2 (5 days), participants received encaleret BID for 5 days at dose levels based on responses from Period 1. On Day 1 and Day 2, participants received 10 to 240 mg BID. On Day 3 to Day 5, participants received 10 to 360 mg BID. In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.	Period 3: Encaleret n=13 Participants In Period 3 (24 weeks), participants received encaleret for an additional 24 weeks. Participants received encaleret at an initial dose based on tolerance and response to the encaleret dose at the end of Period 2.
Periods 1, 2 and 3: Bone Formation Markers as Assessed by Blood Procollagen Type 1 N-Propeptide (P1NP) Period 1: Day 5 AM 180 mg	27.33 Micrograms per liter (mcg/L) Standard Deviation 5.007	—	—
Periods 1, 2 and 3: Bone Formation Markers as Assessed by Blood Procollagen Type 1 N-Propeptide (P1NP) Period 2: Day 5 AM	—	26.8 Micrograms per liter (mcg/L) Standard Deviation 12.25	—
Periods 1, 2 and 3: Bone Formation Markers as Assessed by Blood Procollagen Type 1 N-Propeptide (P1NP) Period 3: Week 24	—	—	103.7 Micrograms per liter (mcg/L) Standard Deviation 87.20

Adverse Events

Period 1: Encaleret

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Periods 2 and 3: Encaleret

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Medical Information

Calcilytix Therapeutics, Inc., a BridgeBio company

Phone: 650.600.3610

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place