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TRC150094, a novel mitochondrial modulator, can restore metabolic flexibility by improving insulin resistance in preclinical studies. This study primarily aims to evaluate the safety, tolerability, and pharmacokinetics (PK) of oral TRC150094 after conducting two double-blind, randomized, Phase-I studies, single ascending dose (SAD) and multiple ascending dose (MAD), with
Type 2 diabetes mellitus (T2DM) is a chronic disease that presents a growing problem globally and that has reached alarming levels of severity (
Recently, this disease spectrum has been reclassified as dysglycemia-based chronic disease and cardiometabolic-based chronic disease (CMBCD) (
Traditional glucocentric approaches have failed to control disease progression across the spectrum, and only half of the individuals could achieve accepted treatment goals. In addition, an aggressive strategy, such as intensive glycemic control, has failed to reduce mortality and cardiovascular outcomes in those with T2DM. A previous study has reported the possible contribution of mitochondrial dysfunction to the pathological state (
TRC150094, a novel mitochondrial modulator, is developed, which demonstrates the ability to restore metabolic inflexibility caused by mitochondrial dysfunction. In preclinical studies, systemic administration of TRC150094 to high fat diet rats led to an increased activity of electron transport chain complex II and V and increased mitochondrial fatty acid import and oxidation, leading to increased energy expenditure (
The SAD study was conducted at Biotrial, Rennes, France (registered as EUDRA CT: 2009–014941–10). The MAD study was conducted at Lambda Therapeutic Research Ltd., Ahmedabad, India [registered in the Clinical Trial Registry–India (Identifier number: CTRI/2009/091/000601)]. The study protocols were reviewed and approved by the respective institutional review boards and concerned regulatory authorities before the conduct of the study.
The SAD study was approved by Comite de Protection des Personnes Ile de France VII (Hôpital de Bicêtre - 78, rue du Général Leclerc - 94270 Le Kremlin Bicêtre), and the MAD study was approved IEC-Aditya, Ahmedabad, India. Both clinical studies were conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki (
This study was conducted in two parts: Part A in adults (18–65 years) and elderly (>65 years) overweight/obese male and female and Part B (food effect study) in six healthy adult subjects (18–65 years). The key inclusion criteria for Part A were subjects with body mass index (BMI) of 25–40 kg/m2, non-smokers or smoker subjects smoking ≤10 cigarettes/day but willing to stop smoking during the study duration, and subjects without significant comorbidities. In Part B, subjects with BMI of 18–25 kg/m2 were enrolled, with the remaining inclusion criteria similar to Part A. The key exclusion criteria were Alanine transaminase (ALT) or Aspartate transaminase (AST) ≥ 2 times the upper limit of normal, with eGFR <40 ml/min/1.73 m2 (as evaluated by Modification of Diet in Renal disease (MDRD) method).
This study was a double-blind, randomized, placebo-controlled, sequential, single-dose, dose-escalation study to evaluate the safety, tolerability, and PK of TRC150094 administered orally to overweight/obese adults and elderly subjects. TRC150094 was administered as a tablet in strengths of 2.5, 12.5, 50, and 200 mg, which were manufactured as per Good Manufacturing Practice (GMP). Tablets were bulk supplied in high density polyethylene bottles (30’s count) containing desiccant and cotton, with an appropriate label as per GMP.
The subjects in Part A of the study were assigned to four cohorts. Adult subjects in cohorts 1–3 (
Dose escalation in the single ascending dose study.
Subjects ( |
Dose administered | |||||||
---|---|---|---|---|---|---|---|---|
Cohort 1 ( |
Dose 1 | Dose 4 | ||||||
5 mg | 100 mg | |||||||
Cohort 2 ( |
Dose 2 | Dose 5 | ||||||
25 mg | 200 mg | |||||||
Cohort 3 ( |
Dose 3 | Dose 6 | ||||||
50 mg | 400 mg | |||||||
Cohort 4 Elderly cohort ( |
Dose A | Dose B | ||||||
50 mg | 150 mg |
If a dosing regimen (beginning with the lowest dose) was found to be safe and well-tolerated by the Dose Review Committee (DRC), then the succeeding panel of eight subjects received the next higher dose of TRC150094 or placebo. The DRC was blinded when assessing the PK, safety, and tolerability data following each dosing occasion. The committee also confirmed dose modification and the highest dose level to be achieved. Considering no observed adverse effect levels (NOAEL) in rodents and dogs, the proposed starting dose level for SAD was 5 mg, which was administered to subjects with an approximate weight of 90 kg (1/260th and 1/750th of the NOAEL in rats and dogs, respectively). The maximum permitted dose level of TRC150094 of 400 mg (1/3rd and 1/9th of the NOAEL in rats and dogs, respectively) was considered appropriate by the DRC.
Part B was an open-label food effect study in which six subjects were randomized to receive 100 mg of TRC150094 in fasting and fed conditions in a 2-period crossover fashion.
Study design and subject disposition in
The duration of study for each subject was approximately 37 days, including screening (14 days), treatment period (total of 6 days in two sequential study periods: period I and period II of 3 days each), washout period (at least 7 days), and follow-up (8–10 days after last study treatment administration). Blood samples (7 ml) were collected at 0 (pre-dose), 0.16, 0.33, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 h post-dose for all dose levels to measure the concentrations of TRC150094. Urine samples were collected in the intervals of pre-dose (bladder was emptied before dosing), 0–4, 4–8, 8–12, 12–24, 24–36, and at 36–48 h post-dose after dose 4 (100 mg) in adult and dose B (150 mg) in the elderly cohort in Part A.
Overweight/obese male and female subjects (18–65 years) with BMI 27–35 kg/m2; waist circumference ≥90 and ≥80 cm for men and women, respectively; nonalcoholic fatty liver grade 1–3 [based on Magnetic Resonance Spectroscopy (MRS)]; fasting serum insulin ≥10 mU/ml; fasting plasma glucose >100 mg/dl; systolic blood pressure ≥130 mmHg; and/or diastolic blood pressure ≥85 mmHg were enrolled. Furthermore, subjects on antihypertensive medications and fasting serum triglyceride (TG) ≥150 mg/dl, as well as non-smokers (or subjects smoking ≤10 cigarettes/day but willing to stop smoking during the study duration), were enrolled. Female subjects, with/without childbearing potential, using a highly effective method of contraception, except for oral contraceptive pills, at least 15 days prior to enrolment till 10 days after the last dose were included. The exclusion criteria were blood pressure ≥170/110 mmHg and ALT or AST ≥3 * ULN, and eGFR <60 ml/min/1.73 m2. All subjects provided written informed consent to participate in the study.
The study was a double-blind, single-center, placebo-controlled, multiple-dose, dose-ascending study to assess the safety, tolerability, and PK and to explore the early efficacy markers after multiple oral doses of TRC150094 in overweight/obese male and female subjects with nontraditional CV risk factors.
The subjects were randomly assigned to TRC150094 (50 mg or 150 mg) or placebo in a ratio of 3:1 for a treatment duration of 28 days. Each subject attended the clinical facility for a screening visit, one study period, and a post-study follow-up visit (Day 36–38). Subjects were admitted and housed in the clinical facility at least 2 days before administration of the first dose and continued to remain in the clinical facility for at least 48 h (Day 30) after receiving the last dose of the investigational medicinal product. All the subjects remained in the clinical facility for 31 consecutive nights. Subjects returned to the clinical facility for a follow-up visit 8–10 days after their last dose. Dosing was performed in the morning for 28 days (OD) in a fasting state of at least 8 h. For each subject, dosing time throughout the study period was based on the dosing time of Day 1. Blood samples (8 ml) were taken for PK analysis at Day 1: Pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 12, 18, and 24 h post-dose; Day 3–8, 15, 22: Pre-dose; and Day 28: Pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 12, 18, 24, 48 h, ambulatory 72 h, and 96 h post-dose. The urine samples were collected for analysis on Day 1: pre-dose collection (bladder was emptied before dosing), post-dose 0–4, 4–8, 8–12, 12–24 h; Day 28: pre-dose collection, 0–4, 4–8, 8–12, 12–24, 24–36, and post dose, 36–48 h (relative to the dose on Day 28).
Safety evaluations were similar in the two studies and were based on the medical review of adverse event (AE) reports. Clinical examination, vital signs, chest X-ray, electrocardiogram (12 lead ECG), clinical laboratory parameters (biochemistry and serum electrolytes, hematology, lipid parameters, urinalysis, and serology), and specific renal biomarkers (urinary alpha-glutathione S transferase for proximal tubular damage) were considered. Fecal occult blood test (FOBT) based on preclinical toxicity findings at highest dose and AE monitoring were performed as part of the safety and tolerability evaluations in both studies. Severity was graded as mild, moderate, and severe along the lines of Common Terminology Criteria for Adverse Events.
The PK parameters, namely the maximum concentration (Cmax), area under the plasma concentration-time curve (AUC) from time zero to the last measurable concentration (AUC o-last), time to Cmax (Tmax), AUC from time zero to infinity (AUC 0-∞), terminal rate constant (λz), and elimination half-life (t½), were analyzed for all doses in both studies. Concentrations of TRC150094 (50 and 150 mg doses) and its metabolites (150 mg dose), which are conjugated metabolite-1 (M1; acyl glucuronide), metabolite-2 (M2; hydroxy glucuronide), and metabolite-3 (M3; sulfate), were measured in the MAD study and were determined using sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) in plasma and urine at the bioanalytical laboratory, Torrent Research Centre, Gandhinagar, India. All the assays in plasma and urine analyses were validated according to the United States Food and Drug Administration (USFDA) guidance for bioanalysis (
TRC150094 and its metabolites were determined in plasma and urine via solid phase extraction (SPE; Waters Corporation, Milford, MA, United States), followed by reversed-phase chromatography using beta basic C8 column (Thermo Fisher Scientific, San Jose, CA, United States) and Zorbax SB-C18 column (Agilent Technologies Inc., Santa Clara, CA). In addition, Shimadzu HPLC, comprising SIL-HTc autosampler, LC-20AD Solvent Delivery Module, CTU-20A Column Oven, and DGU-20A5 Degasser (Shimadzu Corporation, Kyoto, Japan), coupled with an API4000 triple quadrupole mass spectrometer (AB SCIEX, Framingham, MA) or TSQ Vantage triple quadrupole mass spectrometer (Thermo Fisher Scientific, San Jose, CA, United States), was used. Detailed information on analytical methods are presented in the
The quantification ranges for TRC150094 were 0.5–200 (5/25 mg) and 5–2000 ng/ml (50/100/200/400 mg) for plasma, and 0.1–40 μg/ml for urine (all doses). For metabolites M1, M2, and M3, the quantification ranges were 5–2000 ng/ml, 5–1,000 ng/ml, and –1,500 ng/ml, respectively, for plasma and 0.1–40 μg/ml, 50–5,000 ng/ml, and 10–1,000 ng/ml, respectively, for urine.
In the MAD study, non-traditional cardiovascular risk factors, including hepatic fat, ApoB, and insulin sensitivity, were evaluated as early efficacy PD markers after TRC150094 administration.
The insulin sensitivity was assessed by oral glucose tolerance test (OGTT). A 75 gm oral glucose load was administered, and the blood samples were collected at 0, 30, 60, 90, 120, 180 min for glucose and insulin measurements. HOMA-IR and MATSUDA Index were derived using the following formulas: ○ HOMA-IR (mg/dl = fasting Glucose (mg/dl) ○ MATSUDA Insulin Sensitivity Index =
(where FPG = fasting plasma glucose, FPI = fasting plasma insulin)
Hepatic fat was measured at screening, baseline, and at the end of the study. MRS was performed by a 3.0 T MRI using SENSE XL Torso coil (Philips) and single-voxel MRS, with the torso coil as the transmitter and phased surface coils as the receiver. MRS measurements were acquired during breath-hold using single-voxel stimulated acquisition mode (TE/TR 20/3.000 ms, six acquisitions) at a voxel size of 27 mm3. Data analysis and interpretation were conducted using jMRUI software version 3. x (proprietary software package for advanced analysis of MRS data) at the Academic Medical Center, Amsterdam, the Netherlands.
These were measured by cardiopulmonary exercise testing (CPET) using a metabolic cart (Innocor). The CPET parameter oxygen uptake efficiency slope (OUES) was obtained at screening, baseline, and at the end of the study from the data obtained during the properly identified exercise phase. OUES was calculated as the slope derived from the equation: VO2 = a log10 VE + b, where a represents OUES, and VE represents minute ventilation. The VO2 and VE data obtained from the exercise phase was used for this calculation. Peak VO2 (VO2 max) was estimated as maximal VO2 observed during the end of the exercise phase and the first 30 s of the recovery phase. Other markers measured were serum TG, apolipoprotein B (Apo B).
For TRC150094 and its three metabolites, the WinNonlin® Version 5.0.1 and 5.3 (Certara L.P., Princeton, NJ, United States) was used to estimate PK parameters in plasma (Cmax, Tmax, AUC0-t, AUC0-24, AUC0-∞, Kel, and t1/2) and urine (AURC0-24 and AURC0-48, with 24 and 48 h renal clearance, respectively) were estimated, and to prepare the dataset. SAS® Version 9.2 (SAS Institute Inc., United States) was used to generate the randomization code and perform statistical analysis. A formal sample size calculation was not conducted for the SAD and MAD studies.
Descriptive statistics were calculated for plasma concentration and PK parameters of TRC150094 and its three phase II metabolites. The effect of food on PK was evaluated based on logarithmically transformed PK parameters (Cmax and AUC0-∞) using an analysis of variance (ANOVA) model.
Dose proportionality of PK parameter estimates was evaluated based on the derived PK parameters, Cmax and AUC0-24, separately for days 1 and 28, along with AUC0-∞ for Day 28, in the MAD study. The PK parameters and doses were logarithmically transformed before conducting statistical analysis using the power model (
The accumulation of TRC150094 was evaluated based on the AUC0-12 and AUC0-24 after their logarithmic transformation. The analysis was performed using an ANOVA mixed-effects model, comprising fixed effects for sex, day, dose, and dose-by-day interaction, with subject-within-dose as a random effect. A 95% CI for mean between-day difference (Day 28 AUC minus Day 1 AUC) was calculated by dose using the ANOVA model for Cmax, AUC0-12, and AUC0-24.
A 95% CI for least-square means (LSM) for days 1 and 28 was calculated for each dose using the ANOVA model, with fixed effects for log (dose), sex, log (dose)*sex for ln transformed Cmax, AUC0-12, AUC0-24, and AUC0-∞. These CIs were exponentiated to obtain the confidence interval for each dose.
The time to achieve a steady-state plasma concentration of TRC150094 for each dose and metabolite(s) was evaluated in trough predose plasma concentration (CPD) collected during multiple-dose administrations at each dose level in the MAD study. The evaluation was performed after logarithmic transformation at each dosing level using a repeated measure ANOVA model.
For PD efficacy markers, % change observed after 28 days to baseline in each group for MATSUDA Index, HOMA-IR, OUES, Peak VO2, Hepatic Fat, Apo B, and Triglycerides were subjected to ANOVA with fixed effect as ‘dose’ adjusted for ‘Change in body weight’ (multiple comparisons using Dunnett test).
Changes observed at baseline and after 28 days in each group for MATSUDA Index, HOMA-IR, OUES, Peak VO2, Hepatic Fat, Apo B, and Triglycerides were subjected to paired
A total of 46 subjects (part A:
Demography and baseline characteristics.
Variable | Categories | SAD | MAD | ||||||
---|---|---|---|---|---|---|---|---|---|
Adult (Part A) | Elderly (Part A) | Food effect (Part B) | |||||||
TRC150094 | Placebo | TRC150094 | Placebo | 100 mg | TRC150094 | TRC150094 | Placebo | ||
5–400 mg | ( |
50/150 mg | ( |
( |
50 mg | 150 mg | ( |
||
( |
( |
( |
( |
||||||
|
Female | 12 (66.7) | 4 (66.7) | 5 (41.7) | 2 (50.0) | 3 (50.0) | 3 (33.3) | 4 (44.4) | 2 (22.2) |
Male | 6 (33.3) | 2 (33.3) | 7 (58.3) | 2 (50.0) | 3 (50.0) | 9 (47.4) | 5 (26.3) | 5 (26.3) | |
|
Black/African | 1 (5.6) | 3 (50.0) | 0 | 0 | 1 (16.7) | 0 | 0 | 0 |
Other (African/White) Mixed | 1 (5.6) | 0 | 0 | 0 | 1 (16.7) | 0 | 0 | 0 | |
Other: Metis | 0 | 0 | 1 (8.3) | 0 | 0 | 0 | 0 | 0 | |
Other: West Indies | 1 (5.6) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
White | 15 (83.3) | 3 (50.0) | 11 (91.7) | 4 (100.0) | 4 (66.7) | 0 | 0 | 0 | |
Indian | 0 | 0 | 0 | 0 | 0 | 12 (100) | 9 (100) | 7 (100) | |
|
All Subjects | 46.1 (15.3) | 42.3 (19.1) | 70.4 (4.8) | 69.5 (0.5) | 50.0 (7.7) | 39.7 (11.8) | 46.0 (5.7) | 45.1 (10.5) |
|
All Subjects | 167.9 (6.5) | 165.3 (6.2) | 164.8 (10.3) | 161.5 (7.1) | 165.7 (7.9) | 164.9 (7.8) | 161.2 (6.7) | 161.3 (7.8) |
|
All Subjects | 86.5 (15.0) | 79.0 (8.2) | 77.8 (12.0) | 72.5 (4.4) | 63.8 (10.0) | 84.3 (10.0) | 77.3 (6.7) | 82.6 (12.3) |
|
All Subjects | 30.6 (3.9) | 28.9 (2.6) | 28.5 (1.6) | 27.8 (0.8) | 23.2 (2.1) | 30.9 (2.4) | 29.8 (2.6) | 31.6 (2.4) |
|
|
2 (11.1) | 2 (33.3) | 2 (16.7) | 0 (0.0) | - | 0 (0.0) | 0 (0.0) | 1 (14.3) |
|
6 (33.3) | 2 (33.3) | 5 (41.7) | 1 (25.0) | - | 3 (25.0) | 1 (11.1) | 0 (0.0) |
Abbreviations: BMI, body mass index; SAD, single ascending dose; MAD, multiple ascending doses.
TRC150094 was found to be well-tolerated in single and multiple doses. There were no deaths, serious AEs (SAEs), or discontinuation due to AEs observed in the study. All the AEs reported were mild to moderate in severity, and none of the AEs were considered definitely or probably related to treatment. In both SAD and MAD studies, the treatment-emergent AEs reported included decreased appetite, back pain, myalgia, pain in extremity, dizziness, headache, pyrexia, and cough (
Summary of adverse events.
Adverse event | SAD/Adult | SAD elderly (Part A) | MAD | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
System organ class (SOC) | Preferred term (PT) | TRC150094 5-400 mg n (%) | Placebo | TRC150094 | Placebo | TRC150094 | Placebo ( |
||||||||
5 |
25 |
50 |
100 |
200 |
400 |
All ( |
( |
50 mg ( |
150 mg ( |
( |
50 mg ( |
150 mg ( |
|||
No. of subjects reporting at least one AEs post-treatment | 0 | 1 (16.7) | 2 (33.3) | 1 (16.7) | 2 (33.3) | 1 (16.7) | 7 (19.4) | 1 (8.3) | 3 (25.0) | 0 | 0 | 0 | 1 (11.1) | 1 (14.3) | |
Metabolism and Nutrition | Decreased Appetite | 0 | 0 | 0 | 0 | 1 (16.7) | 1 (16.7) | 2 (5.6) | 1 (8.3) | 0 | 0 | 0 | 0 | 0 | 0 |
Musculoskeletal and Connective Tissue Disorders | Back Pain | 0 | 0 | 0 | 0 | 0 | 1 (16.7) | 1 (2.8) | 1 (8.3) | 1 (8.3) | 0 | 0 | 0 | 0 | 0 |
Myalgia | 0 | 0 | 1 (16.7) | 0 | 0 | 0 | 1 (2.8) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
Pain in Extremity | 0 | 0 | 0 | 0 | 1 (16.7) | 1 (16.7) | 2 (5.6) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
Nervous System Disorders | Dizziness Postural | 0 | 1 (16.7) | 0 | 1 (16.7) | 0 | 0 | 2 (5.6) | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Headache | 0 | 0 | 1 (16.7) | 0 | 1 (16.7) | 1 (16.7) | 3 (8.3) | 0 | 1 (8.3) | 0 | 0 | 0 | 0 | 0 | |
General disorders and administration site conditions | Pyrexia | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (11.1) | 0 |
Respiratory, thoracic, and mediastinal disorders | Cough | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (14.3) |
N=Number of subjects with non-missing values; n/% = Number/percentage of subjects with the given characteristics.
Cohort 1 received 2 dose levels, 5 and 100 mg, separated by a washout period of 7 days.
Cohort 2 received 2 dose levels, 25 and 200 mg, separated by a washout period of 7 days.
Cohort 3 received 2 dose levels, 50 and 400 mg, separated by a washout period of 7 days.
Abbreviation: SAD, single ascending dose; MAD, multiple ascending doses.
The most commonly occurring AE was headache in both the elderly and adult cohorts and was experienced by 2 (8.3%) and 3 (8.3%) subjects, respectively, and was considered to be possibly related. Decreased appetite, pain in extremity, and postural dizziness were observed in 2 (5.6%) subjects, each respectively; back pain and myalgia were experienced by 1 (2.8%) subject each, respectively. At least one AE was experienced by 7 (19.4%) and 1 (8.3%) subjects receiving TRC150094 and placebo, respectively. Decreased appetite and myalgia were considered as possibly related to the TRC150094. There were no AEs reported for the 5 mg dose. Two AEs were reported for the 50 and 200 mg doses. One subject each reported AEs for doses of 25, 100, and 400 mg in the adult cohort. As compared to one AE of dizziness in fasting state, there were no AEs in the fed state. AEs were mild in severity, except back pain (moderate severity was experienced by one subject taking dose 400 mg and pain in the extremity in one subject each taking 200 and 400 mg doses).
In the elderly cohort, 3 (12.5%) subjects on TRC150094 experienced AEs with 50 mg dose, while none was observed with 150 mg dose. In subjects receiving TRC150094, headache was experienced by 2 (8.3%) subjects and was considered as possibly related. There were no AE/SAEs reported in Part B (food effect) of the study. Fecal occult blood test was negative in all subjects, and renal biomarker, alpha-GST, was below limit of detection in all subjects. No clinically significant abnormalities were found in hematological and biochemical laboratory parameters during the course of the study. In addition, there were no abnormal clinically significant findings in 12-lead ECG (including QTc interval) (
Two AEs were experienced by two subjects (one each in the placebo and test group, respectively) in the MAD study. Pyrexia and cough were experienced by one subject each (11.1 and 14.3%) receiving TRC150094 150 mg and placebo, respectively. Both AEs were mild and were unlikely related to the study drug. No clinically relevant differences were observed for ECG (including QTc interval) (
Plasma Cmax and AUC increased dose-proportionally across the full dose range tested from dose level 5–400 mg (
Mean plasma concentration of TRC150094 in single ascending dose study (adults, elderly subjects, and food effect study) and multiple ascending dose study.
Summary of PK parameters of single dose study (SAD).
Variable (unit) | SAD (adult) | SAD (elderly) | SAD (food effect) | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Dose (mg) N (M/F) | 5 |
25 |
50 |
100 |
200 |
400 |
50 12 (7/5) | 150 12 (7/5) | Fasted, 100 6 (3/3) | Fed, 100 6 (3/3) | |
|
Mean ± SD | 55.36 ± 22.65 | 266.489 ± 125.21 | 491.17 ± 172.51 | 1,602.98 ± 913.84 | 4,708.14 ± 2,960.82 | 7,153.41 ± 2052.63 | 557.06 ± 154.42 | 2,299.11 ± 868.25 | 1,619.58 ± 794.82 | 770.43 ± 129.05 |
GM (95%CI) | 50.67 (31.62, 79.15) | 245.20 (135.10, 397.90) | 467.22 (310.10, 672.20) | 1,413.29 (644.10, 2,562.00) | 3,928.92 (1,601.00, 7,815.00) | 6,884.85 (4,999.00, 9,308.00) | 537.41 (458.90, 655.20) | 2,166.79 (1748.00, 2,851.00) | 1,483.00 (785.30, 2,454.00) | 761.20 (635.00, 905.90) | |
|
Mean ± SD | 219.00 ± 58.50 | 1,434.47 ± 465.24 | 2,124.69 ± 485.22 | 4,590.58 ± 1,191.41 | 12,896.34 ± 5,806.48 | 25,108.27 ± 4,945.19 | 2,671.15 ± 654.60 | 8,405.46 ± 2,135.12 | 3,976.99 ± 394.03 | 3,929.60 ± 653.63 |
GM (95%CI) | 212.58 (157.80, 280.60) | 1,379.28 (948.10, 1923.35) | 2078.61 (1,616.00, 2,634.00) | 4,470.21 (3,352.00, 5,839.00) | 11,932.98 (6,837.00, 19,011.00) | 24,684.91 (19,918.00, 30,298.00) | 2,597.77 (2,257.00, 3,087.00) | 8,167.36 (7,049.00, 9,762.00) | 4,064.00 (3,587.00, 4,590.00) | 3,789.00 (3,227.00, 4,431.00) | |
|
Mean ± SD | 267.92 ± 83.15 | 1,673.31 ± 518.50 | 2,491.36 ± 661.03 | 5,281.86 ± 1,383.74 | 14,436.62 ± 6,422.69 | 27,814.48 ± 5,621.42 | 3,104.88 ± 707.61 | 9,576.71 ± 2,279.08 | 4,677.88 ± 580.03 | 4,526.18 ± 782.75 |
GM (95%CI) | 257.46 (180.90, 355.10) | 1,613.98 (1,131.75, 2,217.08) | 2,419.32 (1798.00, 3,185.00) | 5,147.24 (3,841.00, 6,733.00) | 13,365.46 (7,732.00, 21,196.00) | 27,320.52 (21,915.00, 33,713.00) | 3,029.85 (2,657.00, 3,554.00) | 9,335.31 8,129.00, 11,025.00 | 4,656.00 (4,070.00, 5,307.00) | 4,501.00 (3,740.00, 5,384.00) | |
|
Mean ± SD | 300.66 ± 101.79 | 1834.28 ± 542.31 | 2,744.43 ± 847.92 | 5,756.48 ± 1,467.45 | 15,436.31 ± 6,666.12 | 29,305.01 ± 6,377.20 | 3,415.58 ± 678.57 | 10,218.60 ± 2,389.89 | 5,119.05 ± 766.96 | 5,141.52 ± 1,079.02 |
GM (95%CI) | 287.20 (193.90, 407.40) | 1772.81 (1,267.68, 2,403.95) | 2,640.27 (1855.00, 3,634.00) | 5,622.68 (4,225.00, 7,298.00) | 14,338.23 (8,478.00, 22,450.00) | 28,695.55 (22,613.00, 35,998.00) | 3,351.98 (2,986.00, 3,846.00) | 9,964.42 (8,700.00, 11,737.00) | 5,077.00 (4,318.00, 5,942.00) | 5,040.00 (4,008.00, 6,274.00) | |
|
Mean ± SD | 0.04 ± 0.01 | 0.04 ± 0.01 | 0.05 ± 0.01 | 0.05 ± 0.01 | 0.04 ± 0.01 | 0.05 ± 0.02 | 0.04 ± 0.01 | 0.05 ± 0.01 | 0.04 ± 0.01 | 0.04 ± 0.01 |
GM (95%CI) | 0.04 (0.03,0.05) | 0.04 (0.03,0.05) | 0.05 (0.03,0.06) | 0.05 (0.03,0.06) | 0.04 (0.03,0.05) | 0.0482 (0.03,0.07) | 0.04 (0.03,0.05) | 0.0466 (0.03,0.04) | 0.04 (0.03,0.06) | 0.04 (0.03,0.05) | |
|
Mean ± SD | 16.64 ± 3.13 | 18.67 ± 3.99 | 15.63 ± 4.27 | 16.08 ± 5.75 | 17.43 ± 4.20 | 14.85 ± 3.95 | 19.10 ± 8.02 | 15.19 ± 3.21 | 17.46 ± 4.40 | 18.71 ± 4.07 |
GM (95%CI) | 16.40 (13.37, 19.92) | 18.31 (14.48, 22.86) | 15.16 (11.14, 20.11 | 15.40 (10.05, 22.11 | 17.01 (13.02, 21.83) | 14.37 (10.71, 19.00) | 17.84 (14.01, 24.19) | 14.88 (13.15, 17.23 | 16.91 (12.84, 22.08 | 18.36 (14.43, 22.98) | |
|
Median (range) | 0.80 (0.33–3.00) | 1.01 (0.75–−3.00) | 1.12 (0.33–−4.00) | 1.37 (0.75–−3.00) | 1.40 (0.50–−4.00) | 1.75 (1.00–−3.00) | 1.12 (0.50–−3.00) | 0.87 (0.50–−2.00) | 0.94 (0.33–−2.02) | 2.01 (2.00–−3.00) |
Cohort 1 received 2 dose levels, 5 and 100 mg, separated by a washout period of 7 days.
Cohort 2 received 2 dose levels, 25 and 200 mg, separated by a washout period of 7 days.
Cohort 3 received 2 dose levels, 50 and 400 mg, separated by a washout period of 7 days.
Abbreviation: AUC, Area under curve; Kel, elimination rate constant; SAD, single ascending dose; SD, standard deviation; Tmax, time to reach Cmax.
Compared to the fasting state, the Cmax of TRC150094 in the fed state was reduced by approximately 50% in the food effect study. However, there was no effect of food on AUC (
The amount of drug recovered in urine at the end of the collection period (48 h) was approximately 20% of the dose administered (100 mg), and more than 80% of this amount was recovered in 24 h. The renal clearance was approximately 4.22 L/h and 2.07 L/h in adults and the elderly, respectively.
TRC150094 was absorbed with the Tmax similar to single-dose and eliminated with a median half-life of approximately 6–7 h (
Summary of PK parameters of multiple dose study (MAD).
Variable (unit) | 50 mg ( |
150 mg ( |
|||
---|---|---|---|---|---|
Day 1 | Day 28 | Day 1 | Day 28 | ||
|
Median (Range) | 1.38 (0.25–4.00) | 1.13 (0.25–3.00) | 1.50 (0.50–3.00) | 1.00 (0.75–1.50) |
|
Mean ± SD | 869.32 ± 350.29 | 1,048.58 ± 381.02 | 2,583.06 ± 790.49 | 3,311.59 ± 699.20 |
GM (95%CI) | 800.27 (646.76, 1,091.88) | 992.82 (806.50, 1,290.66) | 2,462.57 (1975.44, 3,190.68) | 3,244.59 (2,774.14, 3,849.04) | |
|
Mean ± SD | 3,388.92 ± 884.45 |
6,288.65 ± 1955.92 | 9,644.49 ± 2,730.91 |
14,217.39 ± 2,524.40 |
GM (95%CI) | 3,292.26 (2,826.98, 3,950.87) | 5,996.61 (5,045.94, 7,531.37) | 9,319.60 (7,545.33, 11,743.7) | 14,034.9 (12,277.0, 16,157.8) | |
|
Mean ± SD | 3,683.53 ± 936.03 |
6,463.85 ± 1961.86 | 10,413.09 ± 3,037.68 |
14,410.00 ± 2,568.95 |
GM (95%CI) | 3,582.61 (3,088.82, 4,278.25) | 6,178.82 (5,217.36, 7,710.34) | 10,047.6 (8,078.13, 12,748.1) | 14,223.90 (12,435.30, 16,384.70) | |
|
Mean ± SD | 3,388.92 ± 884.45 | 5,307.37 ± 1,474.97 | 9,644.49 ± 2,730.91 | 12,088.55 ± 2,265.08 |
GM (95%CI) | 3,292.26 (2,826.98, 3,950.87) | 5,105.96 (4,370.24, 6,244.51) | 9,319.60 (7,545.33, 11,743.7) | 11,915.6 (10,347.5, 13,829.6) | |
|
Mean ± SD | - | 6,089.80 ± 1727.59 | - | 13,594.22 ± 2,406.65 |
GM (95%CI) | - | 5,853.08 (4,992.16, 7,187.44) | - | 13,420.8 (11,744.3, 15,444.1) | |
|
Mean ± SD | - | 6,382.18 ± 1901.64 | - | 14,249.44 ± 2,502.39 |
GM (95%CI) | - | 6,110.85 (5,173.95, 7,590.42) | 14,070.6 (12,325.9, 16,172.9) | ||
|
Mean ± SD | 0.10 ± 0.02 | 0.11 ± 0.01 | 0.10 ± 0.02 | 0.11 ± 0.02 |
GM (90%CI) | 0.10 (0.09, 0.12) | 0.11 (0.10, 0.12) | 0.10 (0.09, 0.11) | 0.10 (0.09, 0.12) | |
|
Mean ± SD | - | 0.06 ± 0.02 | - | 0.04 ± 0.01 |
GM (95%CI) | - | 0.05 (0.04, 0.07) | - | 0.04 (0.03, 0.05) | |
|
Mean ± SD | - | 14.063 ± 4.49 | - | 17.629 ± 4.13 |
GM (95%CI) | - | 13.31 (11.05, 17.08) | - | 17.23 (14.46, 20.80) | |
|
Mean ± SD | 1.54 ± 0.27 | 1.27 ± 0.17 | ||
GM (95%CI) | 1.57 (1.42, 1.75) | 1.27 (1.14, 1.41) | |||
|
Mean ± SD | 1.57 ± 0.27 | 1.29 ± 0.18 | ||
GM (95%CI) | 1.60 (1.46, 1.77) | 1.28 (1.15, 1.43) |
For day 1, AUClast and AUC0-inf from 0 to 24 plasma concentration-time profile.
GM: Geometric mean. 95% CI: 95% confidence interval.
TRC150094 showed a dose-proportional increase in the rate of absorption (Cmax) and the extent of absorption (AUC0-24) upon a single dose. On Day 28, the t1/2 was 13.61 and 16.4 h for 50 and 150 mg doses, respectively (
The mean accumulation ratio between Day 1 and Day 28 as a measure of AUC0-12 and AUC0-24 were 1.54 and 1.57 at 50 mg dose level and 1.27 and 1.29 at 150 mg dose levels, respectively (
Upon administration of single and multiple oral doses of TRC150094 150 mg, the parent compound was rapidly and extensively converted to its metabolites. Refer to the structure of the TRC150094 and its metabolites is shown in
Comparison of TRC150094 50 and 150 mg with placebo for percentage change of pharmacodynamic markers using Dunnett’s test while adjusting for the change in body weight.
Comparison | Apo B | Triglycerides | MATSUDA index | HOMA-IR | Hepatic fat by MRS |
---|---|---|---|---|---|
Difference between means 95% CI (LL-UL), |
Difference between means 95% CI (LL-UL), |
Difference between means 95% CI (LL-UL), |
Difference between means 95% CI (LL-UL), |
Difference between means 95% CI (LL-UL), |
|
TRC150094 50 mg–Placebo | −22.49 |
−43.01 (−89.54, 3.51), 0.07 | −17.66 (−163.45, 128.12), 0.93 | −89.00 (−324.63, 146.62), 0.56 | −4.57 (−26.58, 17.44), 0.84 |
TRC150094 150 mg–Placebo | −12.33 (−31.02, 6.35), 0.21 | −19.83 (−69.13, 29.47), 0.49 | 94.34 (−60.14, 248.81), 0.24 | −29.19 (278.87–220.48), 0.83 | −0.27 (−23.59, 23.06), 0.99 |
Comparisons significant at the 0.05 level. 95% CI (LL-UL):95% Confidence Interval (CI) (Lower limit, Upper limit).
Abbreviation: ApoB, apolipoprotein B, HOMA-IR, Homeostatic model assessment-insulin resistance; MRS, magnetic resonance spectroscopy.
For ApoB, there was a significant reduction from baseline observed at the lower dose of TRC150094 50 mg (−2.34%) vs. placebo (13.24%) (
TRC150094, a novel mitochondrial modulator, was evaluated primarily for its safety and PK properties in this study. The safety, tolerability, and PK profile of single and multiple ascending doses of TRC150094 (5–400 mg) administered to healthy overweight/obese subjects was studied for up to 28 days.
Analysis of safety data showed that TRC150094 was well-tolerated when administered in fed or fasted conditions. All the AEs reported were mild to moderate in nature, and none was considered definitely or probably related to treatment. The most frequently occurring AE, considered to be possibly related to the treatment, was headache in both the elderly and adult cohorts. Most of the AEs resolved on their own without the need for rescue medications. There were no abnormal clinical or laboratory findings for cardiac or renal parameters. Additionally, there were no SAEs or withdrawals due to AEs in both studies.
The PK data demonstrated that oral doses of TRC150094 were rapidly absorbed. The Tmax ranged from 0.25 to 4 h, and the elimination half-life ranged from 15 to 18 h, making it suitable for once-daily dosing. The half-life is similar to commonly used antidiabetic drugs with once-daily dosing recommendations with comparable terminal half-life, such as canagliflizin (10.6–13.1 h), Dapagliflozin (12.9 h), empagliflozin (11.7–19 h), and sitagliptin (8–14 h). The PK of TRC150094 was similar irrespective of age and sex. The consumption of food delayed the absorption of TRC150094; however, the extent of absorption remained unchanged. Therefore, food does not interfere with the overall absorption of the drug. The metabolites of TRC150094 are glucuronide and sulfate conjugates, and 20% of the drug is excreted unchanged in the urine. TRC150094 is primarily metabolized by the Phase-II conjugation reactions, which are not catalyzed by the cytochrome P450 system. As evaluated in isolated human hepatocytes (non-clinical study), TRC150094 does not have a positive inductive effect on CYP3A and CYP1A isozymes and thus have a lesser likelihood of CYP-mediated drug-drug interactions.
The American College of Cardiology/American Heart Association guidelines acknowledge that ApoB and non-HDL-C are more accurate markers of cardiovascular risk than LDL-C (
A limitation of our study is the relatively small sample size, which needs to be considered when interpreting the PD markers. The preclinical models, which showed improvement in PD parameters, had overt diabetes associated with marked obesity, dyslipidemia, and hypertension, and the duration of treatment was 24 weeks. The subjects in this study had baselines that were mildly deranged at best, and the duration of treatment was limited to 28 days. These observations are similar to those reported in an exploratory study by Fleur van der Valk et al., wherein TRC150094 was administered for 28 days to obese insulin-resistant males (
Overall, TRC150094 has shown a promising safety profile in line with preclinical studies. The current Phase-I SAD and MAD studies reconfirm the safety of the investigational product. TRC150094 is a mitochondrial modulator that restored metabolic flexibility and improved insulin resistance in preclinical models. Translation of the benefit observed in animal models to the clinical situation needs to be evaluated further in those with distinctly deranged glycemic and lipid profiles, i.e., CMBCD with concurrent diabetes, dyslipidemia, and hypertension.
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
The studies involving human participants were reviewed and approved by The single ascending dose (SAD) study was conducted at Biotrial, Renne, France (registered as EUDRA CT: 2009–014941–10). The multiple ascending dose (MAD) study was conducted at Lambda Therapeutic Research Ltd., Ahmedabad, India (registered in the Clinical Trial Registry–India (Identifier number: CTRI/2009/091/000601). The study protocols were reviewed and approved by the respective institutional review boards and concerned regulatory authorities before the conduct of the study. MAD study was approved by Independent Ethics Committee-Aditya (IEC-Aditya). The patients/participants provided their written informed consent to participate in this study.
DJ, SK, PJ, ASI, DB, and JK wrote the manuscript; DJ, CD, and JK designed the research; DJ, CD, and ASH analyzed the data. AM and JK contributed new reagents/analytical tools.
This study was funded by Torrent Pharmaceuticals Ltd., Ahmedabad, Gujarat, India.
DJ, PJ, SK, ASI, JK, DB, ASH, AM, and CD were employed by Torrent Pharmaceuticals Ltd.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
The authors would like to acknowledge Lambda Therapeutic Research Ltd. (CRO), Biotrial Research (CRO), Chetankumar Gandhi, and Sudarshan Deshmukh (Torrent Pharmaceuticals) for bioanalysis; Binita Shah (Torrent Pharmaceuticals) for review of the manuscript; and Tech Observer (India) Private Limited for editorial assistance.
The Supplementary Material for this article can be found online at: