Genetic Disease, Nonsense Mutation
Conditions
Keywords
Translational read through
Brief summary
Phase 1 Multiple Ascending Dose Study in Normal Healthy Volunteers
Detailed description
This is a study in humans of ELX-02, an advanced synthetic aminoglycoside optimized as a translational read-through drug (TRID) for the treatment of genetic conditions caused by nonsense mutations. This is a classical Phase 1b study designed as a randomized, double-blinded, placebo-controlled, multiple dose escalation to evaluate the safety, tolerability, and pharmacokinetics of ELX-02 in healthy adult volunteers.
Interventions
DRUGELX-02
ELX-02 is a synthetic, designer eukaryotic ribosomal specific glycoside (ERSG) optimized as a translational read-through drug
DRUGPlacebo
Placebo
Sponsors
SGS Life Sciences, a division of SGS Belgium NV
Eloxx Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
* Cohort 1: ELX-02 0.1 mg/kg or placebo SC twice a week for 9 doses; * Cohort 2: ELX-02 0.3 mg/kg or placebo SC twice a week for 9 doses; * Cohort 3: ELX-02 1.0 mg/kg or placebo SC twice a week for 9 doses; * Cohort 4: ELX-02 2.5 mg/kg or placebo SC twice a week for 9 doses; * Cohort 5: ELX-02 up to 2.5 mg/kg (50 mg/mL per injection) or placebo SC twice a week for 9 doses; * Cohort 6: ELX-02 2.5 to 5.0 mg/kg or placebo SC twice a week for 9 doses. Optional Cohort * Cohort 7: ELX-02 up to 5.0 mg/kg or placebo SC twice a week for 9 doses. Optional Cohort
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study: 1. Be able and willing to provide written Informed Consent indicating that the subject has been informed of all pertinent aspects of the study. 2. Healthy female subjects and male subjects who, at the time of screening, are between the ages of 18 and 55 years, inclusive. Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure (BP) and pulse rate measurement, 12-lead electrocardiogram (ECG), and clinical laboratory tests. 3. Female subjects of non-childbearing potential must meet at least one of the following criteria: * Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; post-menopausal status will be confirmed by a serum follicle-stimulating hormone level; * Have undergone a documented hysterectomy and/or bilateral oophorectomy; * Have medically confirmed ovarian failure. All other female subjects (including females with tubal ligations) will be considered to be of childbearing potential and may be enrolled if they have negative pregnancy tests at screening and admission day and agree to use a highly effective method of contraception for 14 days before first study drug administration and 28 days after last study drug administration. Female subjects of childbearing potential must agree to undergo repeated pregnancy tests. 4. Male subjects must be willing to use an effective method of contraception. They must agree to use a condom consistently and correctly, during the course of the study until 28 days after last study drug administration. 5. Not using any prescription medication and dietary supplements within 30 days or 5 half lives (whichever is longer) prior to the first study drug administration, except for contraceptives - nor be taking any over-the-counter (OTC) herbal or medicinal products. As an exception, acetaminophen/paracetamol may be used at doses of ≤2 g/day. 6. Non-smoking and no use of any tobacco or nicotine products (by declaration) for a period of at least 6 months prior to screening visit. 7. Be on no medication with potential to impair renal function (e.g., non steroidal anti inflammatory \[NSAID\]s) or with ototoxic potential (e.g., quinine, salicylates, aminoglycosides). 8. Normal renal function (glomular filtration rate \>60 mL/min) based on creatinine plasma concentration and the Modification of Diet in Renal Disease (MDRD) equation for estimated glomular filtration rate. Subjects with lower MDRD clearance can be included on the condition that they have a normal 24h creatinine clearance (determined by a 24h urine collection). 9. Negative human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) serology tests at screening. 10. No history of alcohol or DOA. Negative urine test for DOA and alcohol breath test at screening and Day -1. 11. No personal history (or current) or hereditary hearing loss, persistent tinnitus, persistent vertigo, persistent imbalance and persistent unsteadiness. 12. Body Mass Index (BMI) of 19.0 to 30.0 kg/m2 (inclusive); and a total body weight \>50.0 kg (110 lbs) and \<100.0 kg.
Exclusion criteria
Subjects with any of the following characteristics/conditions will not be included in the study: 1. Subjects who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or subjects who are the Sponsor employees directly involved in the conduct of the study. 2. Concurrent participation or participation in another clinical trial within at least 5 tissue half-lives prior to dosing (calculated from the previous study's last dosing day). If the previous trial involved agents with delayed effects or prolonged metabolism, a 12 months interval is required. 3. Evidence or history of clinically relevant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies). This includes any acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study. 4. Presence of mitochondrial mutations making subject susceptible to aminoglycoside toxicity. 5. Subjects with any history of ear disease or surgeries, persistent dizziness or persistent tinnitus. 6. Subjects with any abnormality at screening, that indicates the presence of a vestibular pathology, conductive hearing loss or balance problem (by an ENT). Subjects with abnormalities in audiometry results at screening as follows: any pure-tone threshold \>55 dB and/or inter-ear difference in any frequency of \>20 dB. Dizziness Handicap Inventory (DHI)-H score\>16. Tinnitus Handicap Inventory (THI)-H score \>14. 7. History of regular alcohol consumption exceeding 14 drinks/week for females or 21 drinks/week for males (1 drink = 150 mL of wine or 360 mL of beer or 45 mL of hard liquor) within 6 months of screening. 8. Screening supine BP ≥ 140 mm Hg (systolic) or ≥ 90 mm Hg (diastolic), following at least 5 min of supine rest. If BP is ≥ 140 mm Hg (systolic) or ≥ 90 mm Hg (diastolic), the BP should be repeated two more times and the average of the three BP values should be used to determine the subject's eligibility. 9. Screening supine 12-lead ECG demonstrating QTc \>450 msec for men and \>470 msec for women, or a QRS interval \>120 msec. If QTc or QRS exceed these limits, the ECG should be repeated two more times and the average of the three QTc or QRS values should be used to determine the subject's eligibility. 10. Subjects with ANY abnormalities in clinical laboratory tests at screening, considered by the study physician as clinically relevant. In particular, subjects with alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine and total bilirubin ≥ 1.5 upper limit of normal will be excluded. 11. Pregnant or breastfeeding female subjects. 12. Subjects who donated blood or received blood or plasma derivatives in the three months preceding study drug administration. 13. Unwilling or unable to comply with all scheduled visits, treatment plan, laboratory tests and other study procedures and the restrictions described in this protocol. 14. Known relevant allergy to any drug and/or aminoglycosides. 15. Subjects with an inability to communicate well with the Investigators and CPU staff (e.g., language problem, poor mental development). 16. Subjects with visual impairment or inability to read and comprehend the DHI and THI scales. 17. Subjects with any acute medical situation (e.g., acute infection) within 48 hours of study start, which is considered of significance by the Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Urine Pharmacokinetics Parameter - CLR24h | 24 h | Renal clearance on Day 29 (CLR=Ae24h/plasmaAUC24h) |
| Pharmacokinetic Parameters - Plasma AUC0-24 | Day 1: pre-dose, 15 min, 30 min, 45 min, 1h, 3h, 6h, 12h, 24h, post-dose | Day 1 Area under the curve (AUC0-24) of ELX-02 plasma concentration following the subcutaneous (SC) dose on Day 1 to 24 hours post-ose |
| Pharmacokinetic Parameters- Plasma AUC0-24 | Day 29: pre-dose, 15 min, 30 min, 45 min, 1h, 3h, 6h, 12h, 24h, post-dose | Day 29 Area under the curve (AUC0-24) of ELX-02 plasma concentration following the subcutaneous (SC) dose on Day 29 to 24 hours post-dose |
| Pharmacokinetic Parameters - Plasma Cmax | Day 1: pre-dose, 15 min, 30 min, 45 min, 1h, 3h, 6h, 12h, 24h, 36h, 48h, 72h, post-dose | Day 1 Peak Plasma Concentration (Cmax) of ELX-02 following the subcutaneous (SC) dose on Day 1 to 72 hours post-dose |
| Pharmacokinetic Parameter - Plasma AUC0-inf | Day 1: pre-dose, 15 min, 30 min, 45 min, 1h, 3h, 6h, 12h, 24h, 36h, 48h, 72h post dose | Day 1 Area under the curve (AUC0-inf) of ELX-02 plasma concentration following the subcutaneous (SC) dose on Day 1 extrapolated to infinity |
| Pharmacokinetic Parameter - Plasma Tmax | Day 1: pre-dose, 15 min, 30 min, 45 min, 1h, 3h, 6h, 12h, 24h, 36h, 48h, 72h post-dose | Day 1 Time to maximum concentration (Tmax) of ELX-02 plasma concentrations following the subcutaneous (SC) dose on Day 1 |
| Pharmacokinetic Parameter Plasma - Tmax | Day 29: pre-dose, 15 min, 30 min, 45 min, 1h, 3h, 6h, 12h, 24h, 36h, 48h, 72h post-dose | Day 29 Time to maximum concentration (Tmax) of ELX-02 plasma concentrations following the subcutaneous (SC) dose on Day 29 |
| Pharmacokinetic Parameter - Plasma Rac(AUC24h) | Day 1 and Day 24 hr | Accumulation ratio, calculated as AUC24h Day29/AUC24h Day 1 |
| Pharmacokinetic Parameter - Plasma RAC(Cmax) | Day 1 and Day 29 | Accumulation ratio, calculated as Cmax Day29/Cmax Day 1 |
| Urine Pharmacokinetics Parameter - Ae72h | Day 1: pre-dose and during 0-12h, 12-24h, 24-48h, and 48-72h post-dose | Day 1 Cumulative amount of unchanged drug excreted into urine (Ae72h) of ELX-02 following the subcutaneous (SC) dose on Day 1 |
| Urine Pharmacokinetic Parameter - Rmax | Day 1: pre-dose and during 0-12h, 12-24h, 24-48h, and 48-72h post-dose | Day 1 Maximum rate of urinary extraction (Rmax) of EXL-02 in each collection time interval following the subcutaneous (SC) dose on Day 1 |
| Urine Pharmacokinetics Parameter - Fe12h Day 1 | 12 hours | Percent of dose excreted (Fe) in urine on Day 1 |
| Urine Pharmacokinetics Parameter - Fe 12h on Day 29 | 12 h on Day 29 | Percent of dose excreted (Fe) in urine on Day 29 |
| Urine Pharmacokinetics Parameter - CLR24h on Day 1 | 24 hours | Renal clearance on Day 1 (CLR=Ae24h/plasmaAUC24h) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Experiencing at Least One Treatment-Emergent Adverse Events (TEAEs) | Day 1-29 | TEAEs are undesirable events not present prior to medical treatment, or an already present event that worsens either in intensity or frequency following the study treatment |
Countries
Belgium
Participant flow
Recruitment details
All subjects were treated at medical clinics. The first patient was enrolled on 22 November 2017 and the last subject visit occurred on 18 July 2019.
Pre-assignment details
Nine (9) subjects were to be randomized to receive ELX-02 or placebo at the 2:1 ratio in each cohort. However, only 8 subjects were randomized in Cohort 2. Subjects who received placebo in any of the 7 cohorts were pooled in the All Placebo group.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 0.1 mg/kg Concentration 50 mg/mL | 6 |
| Cohort 2 0.3 mg/kg Concentration 50 mg/mL | 5 |
| Cohort 3 1.0 mg/kg Concentration 100 mg/mL | 6 |
| Cohort 4 2.5 mg/kg Concentration 100 mg/mL | 6 |
| Cohort 5 1.0 mg/kg Concentration 50 mg/mL | 6 |
| Cohort 6 2.5 mg/kg Concentration 50 mg/mL | 6 |
| Cohort 7 5.0 mg/kg Concentration 50 mg/mL | 6 |
| All Placebo 0 mg/kg | 21 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 | Cohort 5 | Cohort 6 | Cohort 7 | All Placebo |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 38.5 years STANDARD_DEVIATION 10.87 | 41.2 years STANDARD_DEVIATION 12.43 | 36.0 years STANDARD_DEVIATION 8.69 | 37.7 years STANDARD_DEVIATION 14.51 | 37.0 years STANDARD_DEVIATION 11.26 | 37.8 years STANDARD_DEVIATION 10.46 | 44.8 years STANDARD_DEVIATION 11.14 | 33.5 years STANDARD_DEVIATION 7.74 | 38.9 years STANDARD_DEVIATION 11.16 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 54 Participants | 6 Participants | 5 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 0 Participants | 19 Participants |
| Region of Enrollment Belgium | 53 participants | 6 participants | 5 participants | 6 participants | 6 participants | 6 participants | 6 participants | 0 participants | 18 participants |
| Region of Enrollment United States | 9 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 6 participants | 3 participants |
| Sex: Female, Male Female | 21 Participants | 5 Participants | 0 Participants | 3 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 41 Participants | 1 Participants | 5 Participants | 3 Participants | 4 Participants | 5 Participants | 6 Participants | 3 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 5 | 0 / 12 | 0 / 12 | 0 / 6 | 0 / 21 |
| other Total, other adverse events | 3 / 6 | 5 / 5 | 11 / 12 | 12 / 12 | 6 / 6 | 11 / 21 |
| serious Total, serious adverse events | 0 / 6 | 0 / 5 | 0 / 12 | 0 / 12 | 0 / 6 | 0 / 21 |
Outcome results
Primary
Pharmacokinetic Parameter - Plasma AUC0-inf
Day 1 Area under the curve (AUC0-inf) of ELX-02 plasma concentration following the subcutaneous (SC) dose on Day 1 extrapolated to infinity
Time frame: Day 1: pre-dose, 15 min, 30 min, 45 min, 1h, 3h, 6h, 12h, 24h, 36h, 48h, 72h post dose
Population: Plasma ELX-02 exposure was generally similar following SC administration of either a 50 or 100 mg/mL final diluted injection solution strength, indicating no formulation-related differences in PK, therefore the results from Cohorts 3 and 5, and Cohorts 4 and 6 were combined.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Pharmacokinetic Parameter - Plasma AUC0-inf | 1107.272 ng*hr/mL | Geometric Coefficient of Variation 15.345 |
| Cohort 2 | Pharmacokinetic Parameter - Plasma AUC0-inf | 3127.964 ng*hr/mL | Geometric Coefficient of Variation 13.898 |
| Cohort 3 and Cohort 5 | Pharmacokinetic Parameter - Plasma AUC0-inf | 11036.305 ng*hr/mL | Geometric Coefficient of Variation 12.631 |
| Cohort 4 and Cohort 6 | Pharmacokinetic Parameter - Plasma AUC0-inf | 28335.680 ng*hr/mL | Geometric Coefficient of Variation 16.468 |
| Cohort 7 | Pharmacokinetic Parameter - Plasma AUC0-inf | 62142.763 ng*hr/mL | Geometric Coefficient of Variation 20.712 |
Primary
Pharmacokinetic Parameter - Plasma AUC0-inf
Day 29 Area under the curve (AUC0-inf) of ELX-02 plasma concentration following the subcutaneous (SC) dose on Day 29 extrapolated to infinity
Time frame: Day 29: pre-dose, 15 min, 30 min, 45 min, 1h, 3h, 6h, 12h, 24h, 36h, 48h, 72h post dose
Population: Plasma ELX-02 exposure was generally similar following SC administration of either a 50 or 100 mg/mL final diluted injection solution strength, indicating no formulation-related differences in PK, therefore the results from Cohorts 3 and 5, and Cohorts 4 and 6 were combined.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Pharmacokinetic Parameter - Plasma AUC0-inf | 1216.448 ng*h/mL | Geometric Coefficient of Variation 15.428 |
| Cohort 2 | Pharmacokinetic Parameter - Plasma AUC0-inf | 3114.486 ng*h/mL | Geometric Coefficient of Variation 16.704 |
| Cohort 3 and Cohort 5 | Pharmacokinetic Parameter - Plasma AUC0-inf | 10862.927 ng*h/mL | Geometric Coefficient of Variation 14.239 |
| Cohort 4 and Cohort 6 | Pharmacokinetic Parameter - Plasma AUC0-inf | 29778.143 ng*h/mL | Geometric Coefficient of Variation 23.469 |
| Cohort 7 | Pharmacokinetic Parameter - Plasma AUC0-inf | 54933.538 ng*h/mL | Geometric Coefficient of Variation 13.979 |
Primary
Pharmacokinetic Parameter - Plasma Rac(AUC24h)
Accumulation ratio, calculated as AUC24h Day29/AUC24h Day 1
Time frame: Day 1 and Day 24 hr
Population: Plasma ELX-02 exposure was generally similar following SC administration of either a 50 or 100 mg/mL final diluted injection solution strength, indicating no formulation-related differences in PK, therefore the results from Cohorts 3 and 5, and Cohorts 4 and 6 were combined.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Pharmacokinetic Parameter - Plasma Rac(AUC24h) | 1.093 Ratio | Geometric Coefficient of Variation 7.497 |
| Cohort 2 | Pharmacokinetic Parameter - Plasma Rac(AUC24h) | 0.995 Ratio | Geometric Coefficient of Variation 6.622 |
| Cohort 3 and Cohort 5 | Pharmacokinetic Parameter - Plasma Rac(AUC24h) | 0.984 Ratio | Geometric Coefficient of Variation 7.892 |
| Cohort 4 and Cohort 6 | Pharmacokinetic Parameter - Plasma Rac(AUC24h) | 1.056 Ratio | Geometric Coefficient of Variation 14.161 |
| Cohort 7 | Pharmacokinetic Parameter - Plasma Rac(AUC24h) | 0.911 Ratio | Geometric Coefficient of Variation 13.377 |
Primary
Pharmacokinetic Parameter - Plasma RAC(Cmax)
Accumulation ratio, calculated as Cmax Day29/Cmax Day 1
Time frame: Day 1 and Day 29
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Pharmacokinetic Parameter - Plasma RAC(Cmax) | 1.217 Ratio | Geometric Coefficient of Variation 15.278 |
| Cohort 2 | Pharmacokinetic Parameter - Plasma RAC(Cmax) | 0.958 Ratio | Geometric Coefficient of Variation 7.429 |
| Cohort 3 and Cohort 5 | Pharmacokinetic Parameter - Plasma RAC(Cmax) | 0.976 Ratio | Geometric Coefficient of Variation 12.401 |
| Cohort 4 and Cohort 6 | Pharmacokinetic Parameter - Plasma RAC(Cmax) | 1.018 Ratio | Geometric Coefficient of Variation 15.413 |
| Cohort 7 | Pharmacokinetic Parameter - Plasma RAC(Cmax) | 0.941 Ratio | Geometric Coefficient of Variation 1.262 |
Primary
Pharmacokinetic Parameter - Plasma Tmax
Day 1 Time to maximum concentration (Tmax) of ELX-02 plasma concentrations following the subcutaneous (SC) dose on Day 1
Time frame: Day 1: pre-dose, 15 min, 30 min, 45 min, 1h, 3h, 6h, 12h, 24h, 36h, 48h, 72h post-dose
Population: Plasma ELX-02 exposure was generally similar following SC administration of either a 50 or 100 mg/mL final diluted injection solution strength, indicating no formulation-related differences in PK, therefore the results from Cohorts 3 and 5, and Cohorts 4 and 6 were combined.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Pharmacokinetic Parameter - Plasma Tmax | 1.00 hour |
| Cohort 2 | Pharmacokinetic Parameter - Plasma Tmax | 0.75 hour |
| Cohort 3 and Cohort 5 | Pharmacokinetic Parameter - Plasma Tmax | 1.00 hour |
| Cohort 4 and Cohort 6 | Pharmacokinetic Parameter - Plasma Tmax | 1.00 hour |
| Cohort 7 | Pharmacokinetic Parameter - Plasma Tmax | 0.86 hour |
Primary
Pharmacokinetic Parameter Plasma - Tmax
Day 29 Time to maximum concentration (Tmax) of ELX-02 plasma concentrations following the subcutaneous (SC) dose on Day 29
Time frame: Day 29: pre-dose, 15 min, 30 min, 45 min, 1h, 3h, 6h, 12h, 24h, 36h, 48h, 72h post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Pharmacokinetic Parameter Plasma - Tmax | 1.00 hour |
| Cohort 2 | Pharmacokinetic Parameter Plasma - Tmax | 0.75 hour |
| Cohort 3 and Cohort 5 | Pharmacokinetic Parameter Plasma - Tmax | 1.00 hour |
| Cohort 4 and Cohort 6 | Pharmacokinetic Parameter Plasma - Tmax | 0.75 hour |
| Cohort 7 | Pharmacokinetic Parameter Plasma - Tmax | 0.98 hour |
Primary
Pharmacokinetic Parameters - Plasma AUC0-24
Day 1 Area under the curve (AUC0-24) of ELX-02 plasma concentration following the subcutaneous (SC) dose on Day 1 to 24 hours post-ose
Time frame: Day 1: pre-dose, 15 min, 30 min, 45 min, 1h, 3h, 6h, 12h, 24h, post-dose
Population: Plasma ELX-02 exposure was generally similar following SC administration of either a 50 or 100 mg/mL final diluted injection solution strength, indicating no formulation-related differences in PK, therefore the results from Cohorts 3 and 5, and Cohorts 4 and 6 were combined.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Pharmacokinetic Parameters - Plasma AUC0-24 | 1105.126 ng*h/mL | Geometric Coefficient of Variation 15.261 |
| Cohort 2 | Pharmacokinetic Parameters - Plasma AUC0-24 | 3125.484 ng*h/mL | Geometric Coefficient of Variation 13.836 |
| Cohort 3 and Cohort 5 | Pharmacokinetic Parameters - Plasma AUC0-24 | 11018.22 ng*h/mL | Geometric Coefficient of Variation 12.436 |
| Cohort 4 and Cohort 6 | Pharmacokinetic Parameters - Plasma AUC0-24 | 28235.823 ng*h/mL | Geometric Coefficient of Variation 16.255 |
| Cohort 7 | Pharmacokinetic Parameters - Plasma AUC0-24 | 61906.528 ng*h/mL | Geometric Coefficient of Variation 20.455 |
Primary
Pharmacokinetic Parameters- Plasma AUC0-24
Day 29 Area under the curve (AUC0-24) of ELX-02 plasma concentration following the subcutaneous (SC) dose on Day 29 to 24 hours post-dose
Time frame: Day 29: pre-dose, 15 min, 30 min, 45 min, 1h, 3h, 6h, 12h, 24h, post-dose
Population: Plasma ELX-02 exposure was generally similar following SC administration of either a 50 or 100 mg/mL final diluted injection solution strength, indicating no formulation-related differences in PK, therefore the results from Cohorts 3 and 5, and Cohorts 4 and 6 were combined.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Pharmacokinetic Parameters- Plasma AUC0-24 | 1215.098 ng*h/mL | Geometric Coefficient of Variation 15.431 |
| Cohort 2 | Pharmacokinetic Parameters- Plasma AUC0-24 | 3109.978 ng*h/mL | Geometric Coefficient of Variation 16.601 |
| Cohort 3 and Cohort 5 | Pharmacokinetic Parameters- Plasma AUC0-24 | 10847.306 ng*h/mL | Geometric Coefficient of Variation 14.098 |
| Cohort 4 and Cohort 6 | Pharmacokinetic Parameters- Plasma AUC0-24 | 29651.700 ng*h/mL | Geometric Coefficient of Variation 23.223 |
| Cohort 7 | Pharmacokinetic Parameters- Plasma AUC0-24 | 54749.370 ng*h/mL | Geometric Coefficient of Variation 13.77 |
Primary
Pharmacokinetic Parameters - Plasma Cmax
Day 29 Peak Plasma Concentration (Cmax) of ELX-02 following the subcutaneous (SC) dose on Day 29 to 72 hours post-dose
Time frame: Day 29: pre-dose, 15 min, 30 min, 45 min, 1h, 3h, 6h, 12h, 24h, 36h, 48h, 72h post-dose
Population: Plasma ELX-02 exposure was generally similar following SC administration of either a 50 or 100 mg/mL final diluted injection solution strength, indicating no formulation-related differences in PK, therefore the results from Cohorts 3 and 5, and Cohorts 4 and 6 were combined.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Pharmacokinetic Parameters - Plasma Cmax | 342.779 ng/mL | Geometric Coefficient of Variation 12.021 |
| Cohort 2 | Pharmacokinetic Parameters - Plasma Cmax | 961.448 ng/mL | Geometric Coefficient of Variation 7.46 |
| Cohort 3 and Cohort 5 | Pharmacokinetic Parameters - Plasma Cmax | 2806.966 ng/mL | Geometric Coefficient of Variation 16.403 |
| Cohort 4 and Cohort 6 | Pharmacokinetic Parameters - Plasma Cmax | 7852.172 ng/mL | Geometric Coefficient of Variation 12.342 |
| Cohort 7 | Pharmacokinetic Parameters - Plasma Cmax | 15435.789 ng/mL | Geometric Coefficient of Variation 13.872 |
Primary
Pharmacokinetic Parameters - Plasma Cmax
Day 1 Peak Plasma Concentration (Cmax) of ELX-02 following the subcutaneous (SC) dose on Day 1 to 72 hours post-dose
Time frame: Day 1: pre-dose, 15 min, 30 min, 45 min, 1h, 3h, 6h, 12h, 24h, 36h, 48h, 72h, post-dose
Population: Plasma ELX-02 exposure was generally similar following SC administration of either a 50 or 100 mg/mL final diluted injection solution strength, indicating no formulation-related differences in PK, therefore the results from Cohorts 3 and 5, and Cohorts 4 and 6 were combined.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Pharmacokinetic Parameters - Plasma Cmax | 284.710 ng/mL | Geometric Coefficient of Variation 21.06 |
| Cohort 2 | Pharmacokinetic Parameters - Plasma Cmax | 1003.266 ng/mL | Geometric Coefficient of Variation 5.766 |
| Cohort 3 and Cohort 5 | Pharmacokinetic Parameters - Plasma Cmax | 2880.233 ng/mL | Geometric Coefficient of Variation 11.647 |
| Cohort 4 and Cohort 6 | Pharmacokinetic Parameters - Plasma Cmax | 7721.256 ng/mL | Geometric Coefficient of Variation 6.387 |
| Cohort 7 | Pharmacokinetic Parameters - Plasma Cmax | 15912.090 ng/mL | Geometric Coefficient of Variation 17.265 |
Primary
Urine Pharmacokinetic Parameter - Rmax
Day 29 Maximum rate of urinary extraction (Rmax) of ELX-02 in each collection time interval following the subcutaneous (SC) dose on Day 29
Time frame: Day 29: pre-dose and during 0-12h, 12-24h, 24-48h, and 48-72h post-dose
Population: Plasma ELX-02 exposure was generally similar following SC administration of either a 50 or 100 mg/mL final diluted injection solution strength, indicating no formulation-related differences in PK, therefore the results from Cohorts 3 and 5, and Cohorts 4 and 6 were combined.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Urine Pharmacokinetic Parameter - Rmax | 1.950 mg/h | Geometric Coefficient of Variation 37.938 |
| Cohort 2 | Urine Pharmacokinetic Parameter - Rmax | 5.028 mg/h | Geometric Coefficient of Variation 15.875 |
| Cohort 3 and Cohort 5 | Urine Pharmacokinetic Parameter - Rmax | 18.327 mg/h | Geometric Coefficient of Variation 23.862 |
| Cohort 4 and Cohort 6 | Urine Pharmacokinetic Parameter - Rmax | 40.607 mg/h | Geometric Coefficient of Variation 18.389 |
| Cohort 7 | Urine Pharmacokinetic Parameter - Rmax | 89.796 mg/h | Geometric Coefficient of Variation 14.725 |
Primary
Urine Pharmacokinetic Parameter - Rmax
Day 1 Maximum rate of urinary extraction (Rmax) of EXL-02 in each collection time interval following the subcutaneous (SC) dose on Day 1
Time frame: Day 1: pre-dose and during 0-12h, 12-24h, 24-48h, and 48-72h post-dose
Population: Plasma ELX-02 exposure was generally similar following SC administration of either a 50 or 100 mg/mL final diluted injection solution strength, indicating no formulation-related differences in PK, therefore the results from Cohorts 3 and 5, and Cohorts 4 and 6 were combined.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Urine Pharmacokinetic Parameter - Rmax | 1.846 mg/h | Geometric Coefficient of Variation 30.561 |
| Cohort 2 | Urine Pharmacokinetic Parameter - Rmax | 4.759 mg/h | Geometric Coefficient of Variation 6.706 |
| Cohort 3 and Cohort 5 | Urine Pharmacokinetic Parameter - Rmax | 16.132 mg/h | Geometric Coefficient of Variation 15.54 |
| Cohort 4 and Cohort 6 | Urine Pharmacokinetic Parameter - Rmax | 41.587 mg/h | Geometric Coefficient of Variation 21.2 |
| Cohort 7 | Urine Pharmacokinetic Parameter - Rmax | 69.304 mg/h | Geometric Coefficient of Variation 13.495 |
Primary
Urine Pharmacokinetics Parameter - Ae72h
Day 1 Cumulative amount of unchanged drug excreted into urine (Ae72h) of ELX-02 following the subcutaneous (SC) dose on Day 1
Time frame: Day 1: pre-dose and during 0-12h, 12-24h, 24-48h, and 48-72h post-dose
Population: Plasma ELX-02 exposure was generally similar following SC administration of either a 50 or 100 mg/mL final diluted injection solution strength, indicating no formulation-related differences in PK, therefore the results from Cohorts 3 and 5, and Cohorts 4 and 6 were combined.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Urine Pharmacokinetics Parameter - Ae72h | 6.702 mg | Geometric Coefficient of Variation 16.721 |
| Cohort 2 | Urine Pharmacokinetics Parameter - Ae72h | 15.177 mg | Geometric Coefficient of Variation 8.524 |
| Cohort 3 and Cohort 5 | Urine Pharmacokinetics Parameter - Ae72h | 58.270 mg | Geometric Coefficient of Variation 20.046 |
| Cohort 4 and Cohort 6 | Urine Pharmacokinetics Parameter - Ae72h | 160.665 mg | Geometric Coefficient of Variation 11.622 |
| Cohort 7 | Urine Pharmacokinetics Parameter - Ae72h | 332.467 mg | Geometric Coefficient of Variation 18.102 |
Primary
Urine Pharmacokinetics Parameter - Ae72h
Day 29 Cumulative amount of unchanged drug excreted into urine (Ae72h) of ELX-02 following the subcutaneous (SC) dose on Day 29
Time frame: Day 29: pre-dose and during 0-12h, 12-24h, 24-48h, and 48-72h post-dose
Population: Plasma ELX-02 exposure was generally similar following SC administration of either a 50 or 100 mg/mL final diluted injection solution strength, indicating no formulation-related differences in PK, therefore the results from Cohorts 3 and 5, and Cohorts 4 and 6 were combined.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Urine Pharmacokinetics Parameter - Ae72h | 6.331 mg | Geometric Coefficient of Variation 28.505 |
| Cohort 2 | Urine Pharmacokinetics Parameter - Ae72h | 15.021 mg | Geometric Coefficient of Variation 9.189 |
| Cohort 3 and Cohort 5 | Urine Pharmacokinetics Parameter - Ae72h | 66.354 mg | Geometric Coefficient of Variation 15.505 |
| Cohort 4 and Cohort 6 | Urine Pharmacokinetics Parameter - Ae72h | 162.609 mg | Geometric Coefficient of Variation 12.742 |
| Cohort 7 | Urine Pharmacokinetics Parameter - Ae72h | 399.302 mg | Geometric Coefficient of Variation 14.863 |
Primary
Urine Pharmacokinetics Parameter - CLR24h
Renal clearance on Day 29 (CLR=Ae24h/plasmaAUC24h)
Time frame: 24 h
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Urine Pharmacokinetics Parameter - CLR24h | 5.152 L/h | Geometric Coefficient of Variation 29.234 |
| Cohort 2 | Urine Pharmacokinetics Parameter - CLR24h | 4.784 L/h | Geometric Coefficient of Variation 10.828 |
| Cohort 3 and Cohort 5 | Urine Pharmacokinetics Parameter - CLR24h | 6.068 L/h | Geometric Coefficient of Variation 17.2 |
| Cohort 4 and Cohort 6 | Urine Pharmacokinetics Parameter - CLR24h | 5.435 L/h | Geometric Coefficient of Variation 28.521 |
| Cohort 7 | Urine Pharmacokinetics Parameter - CLR24h | 7.239 L/h | Geometric Coefficient of Variation 7.903 |
Primary
Urine Pharmacokinetics Parameter - CLR24h on Day 1
Renal clearance on Day 1 (CLR=Ae24h/plasmaAUC24h)
Time frame: 24 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Urine Pharmacokinetics Parameter - CLR24h on Day 1 | 5.871 L/h | Geometric Coefficient of Variation 22.645 |
| Cohort 2 | Urine Pharmacokinetics Parameter - CLR24h on Day 1 | 4.823 L/h | Geometric Coefficient of Variation 9.834 |
| Cohort 3 and Cohort 5 | Urine Pharmacokinetics Parameter - CLR24h on Day 1 | 5.251 L/h | Geometric Coefficient of Variation 19.135 |
| Cohort 4 and Cohort 6 | Urine Pharmacokinetics Parameter - CLR24h on Day 1 | 5.653 L/h | Geometric Coefficient of Variation 22.959 |
| Cohort 7 | Urine Pharmacokinetics Parameter - CLR24h on Day 1 | 5.331 L/h | Geometric Coefficient of Variation 16.66 |
Primary
Urine Pharmacokinetics Parameter - Fe12h Day 1
Percent of dose excreted (Fe) in urine on Day 1
Time frame: 12 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Urine Pharmacokinetics Parameter - Fe12h Day 1 | 79.572 percentage of drug excreted | Geometric Coefficient of Variation 10.03 |
| Cohort 2 | Urine Pharmacokinetics Parameter - Fe12h Day 1 | 79.440 percentage of drug excreted | Geometric Coefficient of Variation 6.178 |
| Cohort 3 and Cohort 5 | Urine Pharmacokinetics Parameter - Fe12h Day 1 | 76.028 percentage of drug excreted | Geometric Coefficient of Variation 17.403 |
| Cohort 4 and Cohort 6 | Urine Pharmacokinetics Parameter - Fe12h Day 1 | 89.639 percentage of drug excreted | Geometric Coefficient of Variation 9.227 |
| Cohort 7 | Urine Pharmacokinetics Parameter - Fe12h Day 1 | 83.362 percentage of drug excreted | Geometric Coefficient of Variation 5.495 |
Primary
Urine Pharmacokinetics Parameter - Fe 12h on Day 29
Percent of dose excreted (Fe) in urine on Day 29
Time frame: 12 h on Day 29
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Urine Pharmacokinetics Parameter - Fe 12h on Day 29 | 76.095 percentage of drug excreted | Geometric Coefficient of Variation 14.874 |
| Cohort 2 | Urine Pharmacokinetics Parameter - Fe 12h on Day 29 | 78.398 percentage of drug excreted | Geometric Coefficient of Variation 3.615 |
| Cohort 3 and Cohort 5 | Urine Pharmacokinetics Parameter - Fe 12h on Day 29 | 88.130 percentage of drug excreted | Geometric Coefficient of Variation 15.218 |
| Cohort 4 and Cohort 6 | Urine Pharmacokinetics Parameter - Fe 12h on Day 29 | 88.914 percentage of drug excreted | Geometric Coefficient of Variation 4.157 |
| Cohort 7 | Urine Pharmacokinetics Parameter - Fe 12h on Day 29 | 94.219 percentage of drug excreted | Geometric Coefficient of Variation 7.407 |
Secondary
Number of Patients Experiencing at Least One Treatment-Emergent Adverse Events (TEAEs)
TEAEs are undesirable events not present prior to medical treatment, or an already present event that worsens either in intensity or frequency following the study treatment
Time frame: Day 1-29
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | Number of Patients Experiencing at Least One Treatment-Emergent Adverse Events (TEAEs) | Related to study drug | 1 Participants |
| Cohort 1 | Number of Patients Experiencing at Least One Treatment-Emergent Adverse Events (TEAEs) | At least 1 TEAE | 3 Participants |
| Cohort 2 | Number of Patients Experiencing at Least One Treatment-Emergent Adverse Events (TEAEs) | Related to study drug | 5 Participants |
| Cohort 2 | Number of Patients Experiencing at Least One Treatment-Emergent Adverse Events (TEAEs) | At least 1 TEAE | 5 Participants |
| Cohort 3 and Cohort 5 | Number of Patients Experiencing at Least One Treatment-Emergent Adverse Events (TEAEs) | Related to study drug | 10 Participants |
| Cohort 3 and Cohort 5 | Number of Patients Experiencing at Least One Treatment-Emergent Adverse Events (TEAEs) | At least 1 TEAE | 11 Participants |
| Cohort 4 and Cohort 6 | Number of Patients Experiencing at Least One Treatment-Emergent Adverse Events (TEAEs) | At least 1 TEAE | 12 Participants |
| Cohort 4 and Cohort 6 | Number of Patients Experiencing at Least One Treatment-Emergent Adverse Events (TEAEs) | Related to study drug | 12 Participants |
| Cohort 7 | Number of Patients Experiencing at Least One Treatment-Emergent Adverse Events (TEAEs) | At least 1 TEAE | 6 Participants |
| Cohort 7 | Number of Patients Experiencing at Least One Treatment-Emergent Adverse Events (TEAEs) | Related to study drug | 6 Participants |
| All Placebo | Number of Patients Experiencing at Least One Treatment-Emergent Adverse Events (TEAEs) | Related to study drug | 9 Participants |
| All Placebo | Number of Patients Experiencing at Least One Treatment-Emergent Adverse Events (TEAEs) | At least 1 TEAE | 14 Participants |