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Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone receptor-β agonist
Atherosclerosis 230 (2013) 373e380
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Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone receptor-b agonist Rebecca Taub a, *, Edward Chiang a, Malorie Chabot-Blanchet b, Martha J. Kelly a, Richard A. Reeves c, Marie-Claude Guertin b, Jean-Claude Tardif d a
Madrigal Pharmaceuticals, Fort Washington, PA, USA Montreal Heart Institute Coordinating Center, Montreal, Canada RAR Consulting LLC, Pennington, NJ, USA d Montreal Heart Institute, Université de Montréal, Montreal, Canada b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 May 2013 Received in revised form 16 July 2013 Accepted 31 July 2013 Available online 21 August 2013
MGL-3196 is an oral, liver-targeted selective agonist for the thyroid hormone receptor-b (THR-b) that is being developed for the treatment of dyslipidemia. The safety profile and tolerability of THR-b agonist MGL-3196 was assessed in first-in humans studies, including a single ascending dose study (NCT01367873) in which MGL-3196 appeared safe at all doses tested. A two-week multiple dose study was conducted at doses of 5, 20, 50, 80, 100, and 200 mg per day in healthy subjects with mildly elevated low density lipoprotein (LDL) cholesterol (>110 mg/dL) (NCT01519531). MGL-3196 was well-tolerated at all doses with no dose-related adverse events or liver enzyme, ECG or vital-sign changes. At the highest dose, there was a reversible reduction of w20% in the level of pro-hormone, free thyroxine (free T4) that was significantly different from placebo (p < 0.0001) that may be explained by increased hepatic metabolism of T4. There was no change in thyrotropin (TSH) or triiodothyronine (free T3) or other evidence of central thyroid axis dysfunction at any dose. Doses ranging from 50 to 200 mg demonstrated highly statistically significant reductions relative to placebo of up to: 30% for LDL cholesterol (range, p ¼ 0.05e<0.0001); 28% for non- high density lipoprotein (HDL) cholesterol (range, p ¼ 0.027e0.0001); 24% for Apolipoprotein B (range, p ¼ 0.008e0.0004), and statistical trends of up to 60% reduction in triglycerides (TG) (range, p ¼ 0.13e0.016). The near maximal lipid effects were observed at a dose of 80 mg daily. In summary, in a two-week study in healthy volunteers with mild LDL cholesterol elevation, MGL-3196 appeared safe, was well-tolerated and showed a beneficial effect on lipid parameters. Ó 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Thyroid hormone receptor agonist Cholesterol Triglycerides
1. Background Despite advances in treatment, approximately 70% of high risk cardiovascular patients do not achieve LDL cholesterol (LDL-C) goals, and as many as 10% of hypercholesterolemic patients do not tolerate statins [1,2]. Elevated LDL-C levels are associated with cardiovascular (CV) disease including myocardial infarctions and strokes, and drugs such as statins that lower LDL-C also reduce cardiovascular morbidity and mortality. Insulin resistant type 2 diabetics have a high incidence of atherosclerosis, and 65e80% of diabetics die of macrovascular CV disease [3]. Diabetes is associated with a dyslipidemia characterized by fatty liver, elevated * Corresponding author. Madrigal Pharmaceuticals, 500 Office Center Blvd, Fort Washington, PA 19034, USA. Tel.: þ1 610 220 7260. E-mail addresses: [email protected], [email protected] (R. Taub). 0021-9150/$ e see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2013.07.056
triglycerides (TGs), atherogenic LDL particles and low HDL-C that is not well-treated by existing therapies [4,5]. Thyroxine (T4) via its active derivative, triiodothyronine (T3), provides beneficial metabolic effects on cholesterol and triglyceride levels, primarily through action at the thyroid hormone receptor beta isoform (THR-b), the predominant liver TH receptor [6e10]. Specifically, thyroid hormone increases cholesterol metabolism and excretion through the bile. In part because of accompanying hypercholesterolemia, hypothyroidism is associated with increased rates of atherosclerosis. However, excessive levels of TH can lead to adverse effects, particularly in heart and bone, that are primarily mediated by the THR-a receptor which is the major systemic thyroid hormone receptor [11,12]. THR analogs demonstrating an improved therapeutic window between beneficial lipid effects and adverse systemic effects have been developed and tested in clinical trials and demonstrated validation of cholesterol and triglyceride lowering [10,13]. In
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human clinical studies, eprotirome (KB2115), when administered at oral doses of up to 200 ug daily for 2 weeks, lowered LDL-C by up to 40% [14]. Similarly, 25e100 mg daily doses of eprotirome for 12 weeks lowered LDL-C by up to 32%, with no change in TSH or T3 reported [15]. In a 2-week dose-ascending Phase 1 study, MB07811 at doses of 2.5 and 5 mg reduced TG and LDL-C levels by 30% and 15e41%, respectively (M. Erion, personal communication). However, eprotirome and other analogs also demonstrated safety issues that resulted in discontinuation of clinical development. These include low margins relative to doses that suppress the central thyroid axis, elevated liver enzymes in Phase 1 and 2 studies, and other safety issues such as formation of a nitrated mutagenic impurity at gastric pH and collagen damage in a preclinical toxicology study [16]. The THR-b agonist MGL-3196 was selected for clinical development based on its enhanced THR-b selectivity in functional THR assays and its greatly improved safety in preclinical animal models relative to other THR analogs and T3 ([17,18], manuscripts in preparation). Unlike previous clinical analogs including eprotirome and MB07811, MGL-3196 is highly THR-b selective in a functional assay with virtually no THR-a activity. Liver uptake is mediated by hepatic transporters. In preclinical animal studies, MGL-3196 showed rapid and robust lowering of non-HDL-C, TGs and liver TGs (18, manuscript in preparation), differentiating MGL-3196 from statins and other lipid-lowering agents. 2. Methods 2.1. Materials MGL-3196 ([17], manuscript in preparation) was administered in orange, hard gelatin capsules consisting of the MGL-3196 active ingredient (except placebo), pregelatinized starch, colloidal silicon dioxide, and magnesium stearate. Available strengths were 0.25 mg, 2.5 mg, 10 mg, 50 mg, and placebo. All excipients used in the formulation meet United States Pharmacopeia/National Formulary (USP/NF) requirements. 2.2. Single dose study This first-in-human single ascending dose study was conducted as a randomized, double-blind, placebo-controlled clinical trial in healthy male subjects and female subjects not of child-bearing potential. The objectives were to assess primarily the safety and tolerability of MGL-3196 after single oral dosing and secondarily the pharmacokinetics (PK) of MGL-3196, its safety biomarkers and pharmacodynamic parameters, and the effect of food on a single oral dose of MGL-3196. The study was sponsored by Madrigal Pharmaceuticals, designed by Madrigal Pharmaceuticals and RAR, and conducted at a single study site PRACS Institute, formerly Cetero Research, Fargo, ND with review and approval by the PRACS Institute, Ltd Institutional Review Board. All subjects participating in the study provided written informed consent prior to any study-related activities. Study dosing was organized into cohorts corresponding to escalating doses of MGL-3196 or matching placebo. In the single ascending dose study, 72 subjects including nine cohorts of 8 subjects (blinded, 2 placebo, 6 MGL-3196) received doses ranging from 0.25 to 200 mg of MGL-3196 (54 subjects) or placebo (18 subjects) (Table 1, Supplementary data). Study drug was administered in capsule form in the morning. In the first cohort, 1 subject received active drug and 1 other subject received placebo. Once their adverse event profiles were reviewed by the investigator for any unexpected events, the remaining 6 subjects in the cohort were dosed on the following day. Escalation to the next cohort
commenced following a safety evaluation of the prior cohort. The dose escalation scheme was 0.25, 1, 2.5, 5, 10, 20, 50, 100 and 200 mg MGL-3196. During dosing, the subjects, the investigator, study site personnel, and sponsor were blinded to which subjects received active drug and which received placebo. Site personnel were not unblinded until the safety database was finalized after the conclusion of the study. For each cohort, written informed consent followed by screen procedures occurred within 14 days prior to admission to the clinical facility on Day -1. In each cohort, subjects were randomized on the morning of Day 1 to receive MGL-3196 or matching placebo. Subjects fasted for 10 h predose and until 4 h postdose. Subjects were evaluated for safety through monitoring of adverse events, vital signs, clinical laboratory parameters and 12-lead ECGs. Vital signs (temperature, respiratory rate, pulse rate, and blood pressure) were measured starting predose and continued to be measured periodically postdose. In addition, 24-h Holter ECG monitoring started predose and continued for 24 h postdose. Pharmacokinetic and pharmacodynamic samples were collected starting predose and periodically postdose through Day 2. After completion of the Day 3 procedures, subjects were furloughed from the clinical facility to return approximately 1 week later for final evaluations and study discharge. To assess the effect of food on pharmacokinetics, all 8 subjects of Cohort 5 (10 mg MGL-3196 or matching placebo) returned 1 week after initial dosing for a second, single dose administration (designated Period 2). During Period 2, within 30 min subjects first ate a standard high-fat breakfast, followed by administration of second single dose of study drug. For each subject, the second dose administered was the same (either MGL-3196 or placebo) as their first dose (to preserve the blind) and dosing was at approximately the same time. 2.3. Multiple dose study The multiple dose study was also a randomized, double-blind, placebo-controlled clinical trial in healthy subjects. The objectives of the study were to assess primarily the safety and tolerability of MGL-3196 after multiple oral dosing and secondarily the pharmacokinetics of MGL-3196, its safety biomarkers including the thyroid axis hormones and pharmacodynamic parameters including LDL-C lowering. The study was sponsored by Madrigal Pharmaceuticals, designed by Madrigal Pharmaceuticals and RAR, and conducted at a single study site PRACS Institute, formerly Cetero Research, Fargo, ND with review and approval by the PRACS Institute, Ltd Institutional Review Board. All subjects participating in the study provided written informed consent prior to any study-related activities. A total of 48 subjects were dosed in 6 cohorts. Each cohort again consisted of 8 subjects, 6 subjects randomized to receive MGL-3196 at doses of 5, 20, 50, 80, 100, or 200 mg and 2 subjects receiving matching placebo. The average age of the cohorts ranged from 27.7 to 44 years, with the average BMI ranging from 24.9 to 27.6 kg/m2 across cohorts. Most subjects were white males (Table 1, Supplementary data). Study drug was administered in capsule form for 14 days in the morning at approximately same time for each subject. The subjects, the investigator, study site personnel, and sponsor were blinded to which subjects received active drug and which received placebo. Escalation to the next cohort commenced following a safety evaluation of the prior cohort. For each cohort, written informed consent followed by screen procedures occurred within 14 days prior to admission to the clinical facility on Day -1. Following completion of predose safety assessments, study drug was administered in the morning of Days 1e14. On Days 1 and 14 subject fasted starting at least 12 h pre dose and continued to fast until 4 h postdose (water was permitted 1 h
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after dosing). On other days, subjects were allowed to eat after dosing and any blood collection. Subjects were evaluated for safety through monitoring of adverse events, and periodic assessment of vital signs (temperature, respiratory rate, pulse rate, and blood pressure), 12-lead ECGs, clinical laboratory parameters and cardiac biomarkers. On Days 1 and 14, except for the 80-mg cohort, continuous ECG Holter recordings were performed beginning at least 30 min before and for 24 h after dosing. Holters were read blinded by a Core ECG laboratory. For Cohort 6 (80-mg dosing), additional 12-Lead ECGs were obtained instead of Holter ECG monitoring. Plasma samples for pharmacokinetic and pharmacodynamic assessments were collected periodically during the 14 days of dosing in the morning prior to dosing. After medical review of clinical safety parameters including physical examination, vital signs, clinical laboratory results and 12lead ECGs, subjects were released from the clinical facility on the morning of Day 16, to return 5 days later for post-treatment, endof-study evaluations. Subjects were monitored for adverse events throughout the study. 2.4. Statistical analyses Data are reported using descriptive statistics. Mean standard deviation are presented for continuous variables; count and frequency are presented for categorical variables. Changes from baseline to Post-Dose 14 in lipids, TSH and sex hormone binding globulin (SHBG) were analyzed using analysis of covariance (ANCOVA) models adjusting for the baseline value. Within the ANCOVA models, changes were compared between the active treatment groups and placebo. When appropriate, changes were also tested against zero within group. The Post-Dose 14 values of free T3, free T4, total T3 and total T4 were analyzed using analysis of variance (ANOVA) models and again, means at Post-Dose 14 were compared between the active treatment groups and placebo. The last observation carried forward approach was used in the few cases (2 subjects) where data were missing at Post-Dose 14. All tests were twosided and conducted at the 0.05 significance level. Statistical analyses were performed using SAS statistical software version 9.3. 3. Results 3.1. Single dose study MGL-3196 appeared safe and was well-tolerated at all doses and no maximal tolerated dose was reached. Adverse events were mild, not dose-related or considered related to study drug. There were no effects on 24-h Holter heart rate, ECG intervals including QTcF (Fridericia’s correction), or blood pressure. Drug exposure was dose-dependent (Fig. 1A) and the area under the curve (AUC) was unaffected by food; Cmax was somewhat reduced and Tmax delayed after food. No treatment related effect on lipids, TSH or thyroid hormones was observed after the single doses. 3.2. Multiple dose study, pharmacokinetics The first day pharmacokinetics were consistent with what was observed in the single ascending dose study with the exception of the 100 mg cohort which showed on average a higher Cmax and AUC exposure than in the first study (Fig. 1B,C). The only apparent difference in demographics was that the multiple ascending dose cohort included 3/6 women and single ascending dose study 0/6 women. The exposure was dose-dependent and fairly linear through 80 mg. Variability in exposure was greater at 14 days relative to day 1 particularly at higher doses. A Day 14 AUC ratio of 1.5e2.5 fold was observed for doses 50 mg and was greater than
Fig. 1. Geometric mean MGL-3196 plasma concentration (ng/ml) at indicated times after single dose (Doses 5 mg) (A) and multiple doses on Day 1 (B) and Day 14 (C).
predicted by the plasma terminal half-life. Drug levels appeared to reach steady-state by day 3e6. 3.3. Multiple dose study, safety MGL-3196 appeared safe and was well-tolerated at all doses tested. Adverse events were generally mild and not dose-related or
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attributed to study drug (Table 2, Supplementary data). There was no effect of MGL-3196 on vital signs, heart rate (Fig. 1, Supplementary data) or QTcF (not shown) as assessed by Holter monitor or blood pressure. The expected diurnal pattern in heart rate was observed that was similar in placebo and all groups. There was no effect on standard safety laboratory tests including liver enzymes or troponin levels.
3.4. Multiple dose study, thyroid hormones There were decreases in free T4 of w20% at the highest dose (200 mg) (Fig. 2B, Table 3, Supplementary data) and the level after day 14 was significantly different from placebo at 100 mg (p ¼ 0.037) and 200 mg (p < 0.0001). The changes in free T4 attributed to dose appeared to plateau at approximately 8e11 days after dosing and were reversible (not shown). Statistically
significant dose-related decreases relative to placebo in mean total T4 were observed at the 100 and 200 mg doses (Table 3, Supplementary data). There were no dose-dependent differences or meaningful changes in the level of free T3 or total T3 (Fig. 2A). TSH was mildly elevated within the normal reference range after 14 days relative to baseline in the pooled placebo and MGL-3196 groups. There was maintenance of diurnal variation of TSH (assessed at days 1 and 14) in all groups and no meaningful doserelated difference in the within-day TSH pattern between placebo and MGL-3196 groups (Fig. 2C). Thyroid hormones showed biological variability in some individuals during the study that was not related to dose of drug. Other statistically significant differences from placebo in thyroid hormones (e.g. free T4 at 5 mg; TSH at 20 mg) were isolated findings, not dose-related or meaningful (Table 3, Supplementary data). There was no significant effect on levels of thyroid binding globulin at any dose (not shown). 3.5. Multiple dose study, lipids and sex hormone binding globulin (SHBG) At doses of MGL-3196 ranging from 50 to 200 mg highly statistically significant and dose-related reductions relative to placebo were observed of up to 30% for LDL-cholesterol (range, p ¼ 0.05e <0.0001) (Fig. 3, Table 1). Parallel reductions were seen of up to 28% for non-HDL-C (range, p ¼ 0.027e0.0001), and up to 24% for Apolipoprotein B (ApoB) (range, p ¼ 0.008e0.0004). A strong trend with dose, and up to a 60% reduction in triglycerides was seen as well (range, p ¼ 0.13e0.016). There was also a significant reduction relative to placebo in the ApoB/ApoA-1 ratio (Table 1). In general, the maximal or near-maximal effect on these lipid parameters was observed at the 80 mg dose. The lipid effects were observed as early as after 2 doses (2 days) and had not fully renormalized at the time of the return visit (6 days off study drug) (Fig. 4). The possible effects of MGL-3196 on apolipoprotein A-A1 (ApoA-1) and HDL-C could not be fairly evaluated in this study, because a significant decrease in levels occurred between baseline and day 14 in the placebo as well as in all the other study groups (Table 1) that may be attributed to confinement in the study unit, and lack of exercise. The reduction in HDL was relatively less at the higher dose groups than in placebo suggesting that MGL-3196 is neutral or may slightly improve HDL. Although thyroid agonists have been shown to lower Lp(a) in larger studies [15], small sample size, high inter-subject variability, few subjects in each cohort with detectable Lp(a) and
Fig. 2. Thyroid hormone levels after 14 doses. Daily doses of MGL-3196 were given for fourteen days, after which no additional doses were given. Thyroid hormones were assessed 24 h after dose 14. Mean free T3 (A), mean free T4 levels (B); dotted line, lower range of normal. Multiple measurements of TSH (C) were assessed on the first and last day of dosing to demonstrate diurnal variation.
Fig. 3. Changes in lipids after fourteen doses. The percent change from baseline (CFB) for each subject was determined, averaged by dose and corrected to placebo. The baseline determination was fasting, just prior to the first dose and the determination was made fasting 24 h after the 14th dose. ApoB, apolipoprotein B; Chol, total cholesterol; LDL-C, LDL cholesterol directly measured; Non-HDL-C, non-HDL cholesterol, TG, triglycerides (median % CFB). The standard deviations for the assessments are shown in Table 1.
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Table 1 Changes in lipids, multiple dose study. Placebo
5 mg
20 mg
50 mg
80 mg
100 mg
200 mg
(N ¼ 12)
(N ¼ 6)
(N ¼ 6)
(N ¼ 6)
(N ¼ 6)
(N ¼ 6)
(N ¼ 6)
227.8 30.9 230.9 40.2 3.1 21.0
240.3 41.4 242.7 41.8 2.3 33.6 0.96 0.7 13.4
212.7 30.3 218.2 47.3 5.5 21.4 0.95 0.7 10
217.8 39.4 193.8 35.7 24.0 28.9 0.021 11.3 15.3
197.7 11.7 154.7 16.3 43.0 18.3 0.0002 22.8 8.7
216.3 40.7 183.2 30.2 33.2 16.3 0.0027 16.0 6.5
220.2 23.2 182.0 33.6 38.2 21.6 0.0009 18.7 10.3
153.1 23.0 156.1 31.5 3.1 17.2
160.0 27.1 165.1 33.9 5.1 23.8 0.78 2.0 14.3
143.6 24.2 156.3 43.7 12.8 24.6 0.4 6.1 15.3
148.6 39.6 131.8 33.9 16.8 26.8 0.05 10.9 22
136.213.8 101.6 18.2 34.5 14.2 0.0005 27.2 9.9
143.8 28.6 113.8 19.9 30.0 17.6 0.0018 21.8 10.4
150.1 22.1 107.2 23.3 42.9 17.6 <0.0001 30.3 10.8
122.0 15.5 126.1 23.4 4.2 16.4
131.3 19.4 128.4 20.3 2.9 16.7 0.49 4.9 11.7
123.0 18.7 119.4 27.9 3.6 15.3 0.32 6.6 12.8
116.5 20.1 100.5 16.2 16.0 19.7 0.008 15.4 18.6
98.2 12.0 79.4 13.0 18.7 12.2 0.002 22.0 11.1
107.9 16.1 90.1 12.7 17.8 8.5 0.003 19.5 6.5
117.3 11.1 93.0 17.4 24.3 13.4 0.0004 24.1 11.7
181 29.4 189.9 37.1 8.9 19.2
186.3 30.1 198.3 37.2 12.0 29.8 0.75 3.3 15.8
174.5 31.3 185.3 44.3 10.8 19.8 0.9 1.7 11.6
170.5 35.2 154.8 33.7 15.7 26.1 0.027 12.2 17.4
154.0 18.7 116.2 19.3 37.8 19.0 0.0001 28.3 10.7
162.2 28.7 133.5 20.0 28.7 17.1 0.0012 21.0 8.9
172.5 16.4 137.0 32.2 35.5 21.9 0.0002 25.1 13.6
0.87 0.18 1.03 0.23 0.16 0.12
0.83 0.21 1.01 0.29 0.18 0.10 0.7752
1.13 0.22 1.16 0.21 0.02 0.14 0.045
0.82 0.2 0.88 0.19 0.06 0.09 0.0875
0.78 0.18 0.75 0.18 0.03 0.14 0.0025
0.72 0.17 0.70 0.18 0.02 0.08 0.0044
0.81 0.09 0.78 0.13 0.04 0.09 0.0015
125.4 43.6 135.4 58.0 10.0 53.7
107.8 21.8 139.5 31.7 31.7 18.6 0.52 16.7 17
169.7 90.2 158.7 76.0 11.0 67.7 0.9 4.7 47.2
116.0 49.0 95.3 49.9 20.7 54.5 0.13 30.6 39.9
91.3 19.5 58.2 15.67 33.2 13.2 0.016 59.8 11.7
99.2 27.2 80.7 39.9 18.5 23.1 0.089 44.4 21.1
135.5 48.3 104.2 61.6 31.3 63.3 0.1 54.8 44.8
HDL-C (mg/dL) Baseline Post-Dose 14 Difference Within group change from baseline (P value)
46.810.2 41 9.2 5.8 4.1 <0.0001
54.0 19.9 44.3 15.8 9.7 6.6 <0.0001
38.2 4.1 32.8 3.4 5.3 4.8 0.0002
47.3 10.2 39.0 8.9 8.3 4.0 <0.0001
43.7 9.5 38.5 6.7 5.2 6.9 0.0015
54.2 19.7 49.7 18.5 4.5 4.9 0.089
47.7 9.2 45.0 7.3 2.7 2.8 0.14
Apolipoprotein A (mg/dL) Baseline Post-Dose 14 Difference Within group change from baseline (P value)
143.4 21.1 124.8 17.4 18.6 18.6 <0.0001
165.0 42.1 135.1 37.2 29.8 19.4 0.0002
109.7 11.6 102.8 7.9 7.0 13.5 0.0044
145.7 23.9 116.9 16.4 28.8 17.3 <0.0001
129.2 16.9 107.4 11.9 21.8 12.5 <0.0001
156 35.8 133.5 30.2 22.5 10.0 0.0018
145.0 18.1 120.2 17.4 24.8 5.0 <0.0001
37.1 12.6 32.5 12.0 4.6 5.3
35.7 9.1 30.8 6.2 4.8 4.7 0.80 0.04 10.9
23.0 11.1 24.3 8.6 1.3 6.9 0.37 25.531.2
35.5 9.3 38.2 8.7 2.7 6.8 0.046 22.3 21.0
37.0 63.8 26.8 0.038 77.5
44.7 72.8 28.2 0.003 84.4
34.0 10.3 54.0 26.0 20.0 23.8 0.058 85 68.5
71.0 74.0 62.5 62.1 8.5 13.9
59.8 110.9 62.5 112.2 2.7 4.5
57.8 84.3 59.7 95.7 1.8 12.4
44.5 45.0 43.5 51.3 1.0 12.8
Total Cholesterol (mg/dL) Baseline Post-dose 14 Difference P value vs. placebo Difference in %CFB vs. Placebo (%) LDL-C (mg/dL) Baseline Post-dose 14 Difference P value vs. placebo Difference in %CFB vs. Placebo (%) Apolipoprotein B (mg/dL) Baseline Post-dose 14 Difference P value vs. placebo Difference in %CFB vs. Placebo (%) Non-HDL-C (mg/dL) Baseline Post-dose 14 Difference P value vs. placebo Difference in %CFB vs. Placebo (%) ApoB/ApoA-1 ratio Baseline Post-Dose 14 Difference P value vs. placebo Triglycerides (mg/dL) Baseline Post-Dose 14 Difference P value vs. placebo Difference in %CFB vs. Placebo (%)
SHBG (nmol/L) Baseline Post-Dose 14 Difference P value vs. placebo Difference in %CFB vs. Placebo (%CFB) Lp(a) (nmol/L) Baseline Post-Dose 14 Difference
118.1 119.0 122.6 121.1 4.5 13.4
13.9 37.5 24.9 34.9
20.8 28.7 13.6 55.2
80.2 153.1 75.7 142.1 4.5 11.3
117.0 119.2 97.0 91.3 20.0 40.5
P-values obtained from an ANCOVA model on change from baseline to a determination 24 h after the 14th dose (Post-dose 14). Placebo corrected mean percent change from baseline was obtained by subtracting the average percent change in the placebo group from individual’s % change from baseline and averaging the change in each dose group. CFB ¼ change from baseline. Values are mean standard deviation.
short study duration precluded determining the effect of MGL-3196 on Lp(a) in this study (Table 1). Sex hormone binding globulin (SHBG) has been noted to be a THR-b regulated gene that is responsible for binding to and stabilizing the levels of sex hormones such as testosterone. Significant increases relative to placebo in SHBG of up to w85% were
observed at doses from 50 to 200 mg [range, p ¼ 0.057e0.003] (Table 1). There were apparent trends to increased total testosterone in males at 100 and 200 mg (not shown) that would be expected given the increases in SHBG. No effects on follicle stimulating hormone (FSH) or luteinizing hormone (LH) were seen (not shown).
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4. Discussion
Fig. 4. Time course of lipids. Levels of LDL-C (A), Apolipoprotein B (B), Non-HDL-C (C) (% CFB) at indicated times (days). Fourteen daily doses of MGL-3196 or placebo were given from 0 to day 13, after which no additional doses were given.
Presented here are the first-in human data for the liver-selective THR-b agonist MGL-3196. Given in daily doses from 0.25 to 200 mg, MGL-3196 was well-tolerated and appeared safe at all doses tested in the single and multiple dose Phase 1 studies in healthy volunteers. Up to w30% lowering of LDL-C, non-HDL-C and ApoB and up to 60% lowering of TGs were observed after 14 days of daily doses of MGL-3196 with a near maximal effect observed at the 80 mg dose. A drug with the potential for lowering LDL-C and plasma triglycerides has a unique profile and potential to treat patients with dyslipidemia alone or in combination with other lipid modifying drugs such as statins. A high percentage of patients with CV disease do not achieve optimal LDL-C levels, and diabetics in particular have high triglycerides and fatty liver that are not treated by existing therapies. Hepatic steatosis is a cause of liver insulin resistance (IR) and non-alcoholic steatohepatitis (NASH) and is associated with increased CV disease [19]. At the lower doses, drug exposure was consistent between day 1 and 14 whereas at higher doses a Day 14/Day 1 ratio of 1.5e2.5 was observed, suggesting that MGL-3196 has a longer residence than predicted by plasma exposure half-life after the first dose. There were no changes in vital signs, and adverse events were generally mild, unrelated to study drug and not dose-dependent. There were no apparent effects on heart rate or QTc (not shown) as assessed by Holter monitor. Unlike previous thyroid analogs, no increases in liver enzymes were observed at any dose in the Phase 1 multiple dose study. The levels of prohormone free T4, active hormone free T3 and TSH are generally viewed as most accurately reflecting thyroid hormone status [20]. Factors that affect thyroid binding globulin (TBG) levels and therefore, the levels of total T4 may not affect the free T4 levels or euthyroid status. In euthyroid individuals small changes in thyroid hormones of 20% whilst values remain within reference ranges are not considered clinically meaningful [20]. Reversible dose-related reductions in free T4 of w20% and w10% were observed only at the highest doses of 200 and 100 mg, respectively. At all doses free T3 and TSH showed no meaningful or dose-dependent change compared with placebo indicating that there were no effects on the central thyroid axis at any dose. The reduction of free T4 may be attributed to the role of the liver where prohormone T4 by the action of deiodinase 1 is converted to either active hormone, T3 or reverse T3 and then may be further metabolized and excreted [21]. It is known that increased hepatic THR-b agonism increases the level of hepatic diodinase 1 [21,22]. Increase in THR-b agonism in the liver is consistent with lowering of free T4 without changes in T3 or TSH or any central effect [23]. Regulation of TSH is complex [24], and primarily reflects T3 homeostasis. Proof-of-concept for LDL-C, ApoB and non-HDL-C lowering was achieved in the Phase 1 multiple dose study. Lipid lowering was robust, rapid and significant at doses 50 mg, with a near-maximal effect observed at 80 mg. Although the lipid lowering effects at 50 mg were substantially less than at 80 mg, there was a single nonresponder at 50 mg who skewed the overall mean effect. It is also possible that lower clinical doses given over a long time period will show improved effects relative to placebo and relative to what was observed in a Phase 1 study. The design of the Phase 1 study was not optimized to assess the impact of MGL-3196 on triglycerides because of highly variable baseline TGs and few subjects with baseline TGs> 150 mg/dL. Nonetheless there were strong dose-dependent effects and trends to reduced TGs. Reduced triglycerides may be a reflection of reduced hepatic triglycerides that were consistently observed in preclinical animal models treated with MGL-3196 (18, manuscript in preparation). In addition as has been demonstrated with thyroid
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hormone [25], MGL-3196 may directly lower ApoB, both mechanisms resulting in reduced VLDL production. The effect of MGL3196 on liver or plasma triglycerides must be tested in subsequent clinical studies. Likewise the study was not appropriately designed to assess the effect of MGL-3196 on HDL-C or ApoA-1; however, significant improvement in the ApoB to ApoA-1 ratio was observed with MGL-3196. Additionally, MGL-3196 increased SHBG, a liver specific protein that has been inversely correlated with the incidence of type 2 diabetes [26]. Although SHBG may be regulated by several factors, the level is well correlated with the level of THR-b activity in the liver [27]. In addition to its effects on cholesterol and triglycerides, MGL-3196 reduced hepatic triglycerides and glucose in diet induced obese mice, and demonstrated insulin sensitizing actions [18, in preparation]. Studies have shown that clearance of liver lipids by thyroid hormone agonists results from accelerated hepatic fatty acid oxidation [28]. Diabetics have a specific dyslipidemia characterized by fatty liver, elevated TGs, atherogenic LDL and low HDL-cholesterol [4,5]. Diabetics have also been noted to have low free T3 and reduced free T3/free T4, suggesting low hepatic diodinase 1 and reduced production of T3 [29]. The combined effects of MGL-3196 in reducing hepatic TGs, plasma TGs, LDL-C, raising SHBG and testosterone, as well as having potential other insulin sensitizing effects could make MGL-3196 a particularly appropriate therapy for type 2 diabetics. MGL-3196 showed similar lipid lowering effects and improved safety in the Phase 1 multiple dose study relative to other clinical thyroid analogs. MGL-3196 is differentiated from previous analogs by several features: 1- novel chemical scaffold 2- lack of central thyroid axis suppression 3- selectivity for THR-b in a functional assay 4- absence of ALT elevations and 5-lack of potency at THR-a. In particular MGL-3196 did not increase liver enzymes in the Phase 1 studies. Such elevations were readily observed with other analogs such as eprotirome [14,15]. The effects on ALT were attributed to a pharmacologic action of thyroid hormonedhowever thyroid hormone treatment and thyrotoxicosis are not known to be associated with liver enzyme elevations except in unusual cases of thyroid storm. Moreover whereas eprotirome and MB78011 reduced both free T3 and TSH at doses just above the clinically relevant dose in the Phase 1 study, MGL-3196 did not affect the central thyroid axis or lower T3 at any dose tested suggesting that MGL-3196 may have a significantly better therapeutic window. Eprotirome was discontinued because a cartilage abnormality was found in long term dog toxicology studies [16]. Although the specific mechanism is not known, THR-a is the primary TH receptor present in cartilage [11] and eprotirome is equipotent to T3 at THR-a. Recently, eprotirome was also found to cause increased insulin resistance in a rat model because of a postulated off-target action in muscle [30]. No bone or cartilage abnormalities have been observed in MGL-3196 dog toxicology studies conducted for up to three months. The major limitation of the study is that small numbers of subjects with only mildly elevated LDL-C were treated for a relatively short duration. However within this group of subjects, some fulfilled criteria for dyslipidemia, particularly as regards the LDL-C pathway. There is currently insufficient data to properly assess the variability of the lipid response to MGL-3196 that will be resolved by treating larger numbers of dyslipidemic patients. In subsequent MGL-3196 Phase 2 studies in patients with mixed dyslipidemias, the ability of MGL-3196 to lower triglycerides and LDL-C alone and in combination with a statin will be determined. In conclusion, in first-in-human studies, MGL-3196, a livertargeted THR-b agonist, given orally once-daily appeared safe and was well-tolerated at all doses tested up to 200 mg for up to 14 days in healthy human volunteers. There was no evidence of any effects on vital signs, or standard laboratory assessments including liver
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enzymes and Holter ECGs. Reversible reductions in prohormone free T4 levels at the highest doses can be explained by a hepatic effect on T4 metabolism, and there was no evidence of central thyroid axis suppression at any dose. The improved safety profile differentiates MGL-31196 from previous thyroid analogues tested in similar Phase 1 studies. Doses from 50 to 200 mg of MGL-3196 per day, with a near-maximal effect at 80 mg, demonstrated robust and rapid reductions in lipids, including LDL-C, non-HDL-C and apolipoprotein B up to 30%, with statistical trends to reduce triglycerides up to 60%. Disclosures RT, EC, MK are employees of Madrigal Pharmaceuticals which sponsored this study. RAR is a consultant to Madrigal Pharmaceuticals, and J-C T received honoraria from Madrigal Pharmaceuticals. Appendix A. Supplementary data Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.atherosclerosis.2013.07.056. References [1] Waters DD, Brotons C, Chiang CW, et al., Lipid Treatment Assessment Project. Lipid treatment assessment project 2: a multinational survey to evaluate the proportion of patients achieving low-density lipoprotein cholesterol goals. Circulation 2009;120(1):28e34. [2] Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med 2009;150(12):858e68. [3] DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14(3):173e94. [4] Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab 2009;5(3):150e9. [5] Toledo FG, Sniderman AD, Kelley DE. Influence of hepatic steatosis (fatty liver) on severity and composition of dyslipidemia in type 2 diabetes. Diabetes Care 2006;29(8):1845e50. [6] Grover GJ, Egan DM, Sleph PG, et al. Effects of the thyroid hormone receptor agonist GC-1 on metabolic rate and cholesterol in rats and primates: selective actions relative to 3,5,3’-triiodo-L-thyronine. Endocrinology 2004;145(4): 1656e61. [7] Grover GJ, Mellstrom K, Ye L, et al. Selective thyroid hormone receptor-beta activation: a strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability. Proc Natl Acad Sci U S A 2003;100(17):10067e72. [8] Johansson L, Rudling M, Scanlan TS, et al. Selective thyroid receptor modulation by GC-1 reduces serum lipids and stimulates steps of reverse cholesterol transport in euthyroid mice. Proc Natl Acad Sci U S A 2005;102(29): 10297e302. [9] Morkin E, Pennock GD, Spooner PH, Bahl JJ, Goldman S. Clinical and experimental studies on the use of 3,5-diiodothyropropionic acid, a thyroid hormone analogue, in heart failure. Thyroid 2002;12(6):527e33. [10] Baxter JD, Webb P. Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes. Nat Rev Drug Discov 2009;8(4): 308e20. [11] Gogakos AI, Duncan Bassett JH, Williams GR. Thyroid and bone. Arch Biochem Biophys 2010;503(1):129e36. [12] Klein I, Danzi S. Thyroid disease and the heart. Circulation 2007;116(15): 1725e35. [13] Erion MD, Cable EE, Ito BR, et al. Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index. Proc Natl Acad Sci U S A 2007;104(39):15490e5. [14] Berkenstam A, Kristensen J, Mellstrom K, et al. The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans. Proc Natl Acad Sci U S A 2008;105(2):663e7. [15] Ladenson PW, Kristensen JD, Ridgway EC, et al. Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med 2010;362(10):906e16. [16] Bengsston P. “Karo Bio terminates the eprotirome Program” Karo Bio February 14. http://www.karobio.com/investormedia/pressreleaser/pressrelease? pid¼639535; 2012. [17] Kelly MJ, Larigan JD, Pietranico-Cole S, et al. Discovery and development of MGL-3196, a liver-directed thyroid hormone beta agonist for the treatment of hypercholesterolemia/dyslipidemia and hypertriglyceridemia; 2013.
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R. Taub et al. / Atherosclerosis 230 (2013) 373e380 Abstracts of Papers, 245th ACS National meeting & Exposition, New Orleans, LA, United States MEDI-280. Taub R, Grimsby J, Larigan JD, Pietranico S, Dvorozniak M, Conde-Knape K. VIA-3196, a liver-directed thyroid beta agonist for treating cardiometabolic disease. Circulation 2009;120:S1095. Cazanave SC, Gores GJ. Mechanisms and clinical implications of hepatocyte lipoapoptosis. Clin Lipidol 2010;5(1):71e85. Dong BJ. How medications affect thyroid function. West J Med 2000;172(2):102e6. Kelly GS. Peripheral metabolism of thyroid hormones: a review. Altern Med Rev 2000;5(4):306e33. Bianco AC, Kim BW. Deiodinases: implications of the local control of thyroid hormone action. J Clin Invest 2006;116(10):2571e9. Bochukova E, Schoenmakers N, Agostini M, et al. A mutation in the thyroid hormone receptor alpha gene. N Engl J Med 2012;366(3):243e9. Spencer CA, LoPresti JS, Nicoloff JT, Dlott R, Schwarzbein D. Multiphasic thyrotropin responses to thyroid hormone administration in man. J Clin Endocrinol Metab 1995;80(3):854e9.
[25] Goldberg IJ, Huang LS, Huggins LA, et al. Thyroid hormone reduces cholesterol via a non-LDL receptor-mediated pathway. Endocrinology 2012;153(11): 5143e9. [26] Semple R, Savage DB, O’Rahilly S. Sex hormone-binding globulin and risk of type 2 diabetes. N Engl J Med 2009;361(27):2677 author reply 2677e2678. [27] Mitchell CS, Savage DB, Dufour S, et al. Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia. J Clin Invest 2010;120(4):1345e54. [28] Cable EE, Finn PD, Stebbins JW, et al. Reduction of hepatic steatosis in rats and mice after treatment with a liver-targeted thyroid hormone receptor agonist. Hepatology 2009;49(2):407e17. [29] Islam S, Yesmine S, Khan SA, Alam NH, Islam S. A comparative study of thyroid hormone levels in diabetic and non-diabetic patients. Southeast Asian J Trop Med Public Health 2008;39(5):913e6. [30] Vatner DF, Weismann D, Beddow SA, et al. Thyroid hormone receptor-beta agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways. Am J Physiol Endocrinol Metab 2013;305:89e100.
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Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone receptor-b agonist Rebecca Taub a, *, Edward Chiang a, Malorie Chabot-Blanchet b, Martha J. Kelly a, Richard A. Reeves c, Marie-Claude Guertin b, Jean-Claude Tardif d a
Madrigal Pharmaceuticals, Fort Washington, PA, USA Montreal Heart Institute Coordinating Center, Montreal, Canada RAR Consulting LLC, Pennington, NJ, USA d Montreal Heart Institute, Université de Montréal, Montreal, Canada b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 May 2013 Received in revised form 16 July 2013 Accepted 31 July 2013 Available online 21 August 2013
MGL-3196 is an oral, liver-targeted selective agonist for the thyroid hormone receptor-b (THR-b) that is being developed for the treatment of dyslipidemia. The safety profile and tolerability of THR-b agonist MGL-3196 was assessed in first-in humans studies, including a single ascending dose study (NCT01367873) in which MGL-3196 appeared safe at all doses tested. A two-week multiple dose study was conducted at doses of 5, 20, 50, 80, 100, and 200 mg per day in healthy subjects with mildly elevated low density lipoprotein (LDL) cholesterol (>110 mg/dL) (NCT01519531). MGL-3196 was well-tolerated at all doses with no dose-related adverse events or liver enzyme, ECG or vital-sign changes. At the highest dose, there was a reversible reduction of w20% in the level of pro-hormone, free thyroxine (free T4) that was significantly different from placebo (p < 0.0001) that may be explained by increased hepatic metabolism of T4. There was no change in thyrotropin (TSH) or triiodothyronine (free T3) or other evidence of central thyroid axis dysfunction at any dose. Doses ranging from 50 to 200 mg demonstrated highly statistically significant reductions relative to placebo of up to: 30% for LDL cholesterol (range, p ¼ 0.05e<0.0001); 28% for non- high density lipoprotein (HDL) cholesterol (range, p ¼ 0.027e0.0001); 24% for Apolipoprotein B (range, p ¼ 0.008e0.0004), and statistical trends of up to 60% reduction in triglycerides (TG) (range, p ¼ 0.13e0.016). The near maximal lipid effects were observed at a dose of 80 mg daily. In summary, in a two-week study in healthy volunteers with mild LDL cholesterol elevation, MGL-3196 appeared safe, was well-tolerated and showed a beneficial effect on lipid parameters. Ó 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Thyroid hormone receptor agonist Cholesterol Triglycerides
1. Background Despite advances in treatment, approximately 70% of high risk cardiovascular patients do not achieve LDL cholesterol (LDL-C) goals, and as many as 10% of hypercholesterolemic patients do not tolerate statins [1,2]. Elevated LDL-C levels are associated with cardiovascular (CV) disease including myocardial infarctions and strokes, and drugs such as statins that lower LDL-C also reduce cardiovascular morbidity and mortality. Insulin resistant type 2 diabetics have a high incidence of atherosclerosis, and 65e80% of diabetics die of macrovascular CV disease [3]. Diabetes is associated with a dyslipidemia characterized by fatty liver, elevated * Corresponding author. Madrigal Pharmaceuticals, 500 Office Center Blvd, Fort Washington, PA 19034, USA. Tel.: þ1 610 220 7260. E-mail addresses: [email protected], [email protected] (R. Taub). 0021-9150/$ e see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2013.07.056
triglycerides (TGs), atherogenic LDL particles and low HDL-C that is not well-treated by existing therapies [4,5]. Thyroxine (T4) via its active derivative, triiodothyronine (T3), provides beneficial metabolic effects on cholesterol and triglyceride levels, primarily through action at the thyroid hormone receptor beta isoform (THR-b), the predominant liver TH receptor [6e10]. Specifically, thyroid hormone increases cholesterol metabolism and excretion through the bile. In part because of accompanying hypercholesterolemia, hypothyroidism is associated with increased rates of atherosclerosis. However, excessive levels of TH can lead to adverse effects, particularly in heart and bone, that are primarily mediated by the THR-a receptor which is the major systemic thyroid hormone receptor [11,12]. THR analogs demonstrating an improved therapeutic window between beneficial lipid effects and adverse systemic effects have been developed and tested in clinical trials and demonstrated validation of cholesterol and triglyceride lowering [10,13]. In
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human clinical studies, eprotirome (KB2115), when administered at oral doses of up to 200 ug daily for 2 weeks, lowered LDL-C by up to 40% [14]. Similarly, 25e100 mg daily doses of eprotirome for 12 weeks lowered LDL-C by up to 32%, with no change in TSH or T3 reported [15]. In a 2-week dose-ascending Phase 1 study, MB07811 at doses of 2.5 and 5 mg reduced TG and LDL-C levels by 30% and 15e41%, respectively (M. Erion, personal communication). However, eprotirome and other analogs also demonstrated safety issues that resulted in discontinuation of clinical development. These include low margins relative to doses that suppress the central thyroid axis, elevated liver enzymes in Phase 1 and 2 studies, and other safety issues such as formation of a nitrated mutagenic impurity at gastric pH and collagen damage in a preclinical toxicology study [16]. The THR-b agonist MGL-3196 was selected for clinical development based on its enhanced THR-b selectivity in functional THR assays and its greatly improved safety in preclinical animal models relative to other THR analogs and T3 ([17,18], manuscripts in preparation). Unlike previous clinical analogs including eprotirome and MB07811, MGL-3196 is highly THR-b selective in a functional assay with virtually no THR-a activity. Liver uptake is mediated by hepatic transporters. In preclinical animal studies, MGL-3196 showed rapid and robust lowering of non-HDL-C, TGs and liver TGs (18, manuscript in preparation), differentiating MGL-3196 from statins and other lipid-lowering agents. 2. Methods 2.1. Materials MGL-3196 ([17], manuscript in preparation) was administered in orange, hard gelatin capsules consisting of the MGL-3196 active ingredient (except placebo), pregelatinized starch, colloidal silicon dioxide, and magnesium stearate. Available strengths were 0.25 mg, 2.5 mg, 10 mg, 50 mg, and placebo. All excipients used in the formulation meet United States Pharmacopeia/National Formulary (USP/NF) requirements. 2.2. Single dose study This first-in-human single ascending dose study was conducted as a randomized, double-blind, placebo-controlled clinical trial in healthy male subjects and female subjects not of child-bearing potential. The objectives were to assess primarily the safety and tolerability of MGL-3196 after single oral dosing and secondarily the pharmacokinetics (PK) of MGL-3196, its safety biomarkers and pharmacodynamic parameters, and the effect of food on a single oral dose of MGL-3196. The study was sponsored by Madrigal Pharmaceuticals, designed by Madrigal Pharmaceuticals and RAR, and conducted at a single study site PRACS Institute, formerly Cetero Research, Fargo, ND with review and approval by the PRACS Institute, Ltd Institutional Review Board. All subjects participating in the study provided written informed consent prior to any study-related activities. Study dosing was organized into cohorts corresponding to escalating doses of MGL-3196 or matching placebo. In the single ascending dose study, 72 subjects including nine cohorts of 8 subjects (blinded, 2 placebo, 6 MGL-3196) received doses ranging from 0.25 to 200 mg of MGL-3196 (54 subjects) or placebo (18 subjects) (Table 1, Supplementary data). Study drug was administered in capsule form in the morning. In the first cohort, 1 subject received active drug and 1 other subject received placebo. Once their adverse event profiles were reviewed by the investigator for any unexpected events, the remaining 6 subjects in the cohort were dosed on the following day. Escalation to the next cohort
commenced following a safety evaluation of the prior cohort. The dose escalation scheme was 0.25, 1, 2.5, 5, 10, 20, 50, 100 and 200 mg MGL-3196. During dosing, the subjects, the investigator, study site personnel, and sponsor were blinded to which subjects received active drug and which received placebo. Site personnel were not unblinded until the safety database was finalized after the conclusion of the study. For each cohort, written informed consent followed by screen procedures occurred within 14 days prior to admission to the clinical facility on Day -1. In each cohort, subjects were randomized on the morning of Day 1 to receive MGL-3196 or matching placebo. Subjects fasted for 10 h predose and until 4 h postdose. Subjects were evaluated for safety through monitoring of adverse events, vital signs, clinical laboratory parameters and 12-lead ECGs. Vital signs (temperature, respiratory rate, pulse rate, and blood pressure) were measured starting predose and continued to be measured periodically postdose. In addition, 24-h Holter ECG monitoring started predose and continued for 24 h postdose. Pharmacokinetic and pharmacodynamic samples were collected starting predose and periodically postdose through Day 2. After completion of the Day 3 procedures, subjects were furloughed from the clinical facility to return approximately 1 week later for final evaluations and study discharge. To assess the effect of food on pharmacokinetics, all 8 subjects of Cohort 5 (10 mg MGL-3196 or matching placebo) returned 1 week after initial dosing for a second, single dose administration (designated Period 2). During Period 2, within 30 min subjects first ate a standard high-fat breakfast, followed by administration of second single dose of study drug. For each subject, the second dose administered was the same (either MGL-3196 or placebo) as their first dose (to preserve the blind) and dosing was at approximately the same time. 2.3. Multiple dose study The multiple dose study was also a randomized, double-blind, placebo-controlled clinical trial in healthy subjects. The objectives of the study were to assess primarily the safety and tolerability of MGL-3196 after multiple oral dosing and secondarily the pharmacokinetics of MGL-3196, its safety biomarkers including the thyroid axis hormones and pharmacodynamic parameters including LDL-C lowering. The study was sponsored by Madrigal Pharmaceuticals, designed by Madrigal Pharmaceuticals and RAR, and conducted at a single study site PRACS Institute, formerly Cetero Research, Fargo, ND with review and approval by the PRACS Institute, Ltd Institutional Review Board. All subjects participating in the study provided written informed consent prior to any study-related activities. A total of 48 subjects were dosed in 6 cohorts. Each cohort again consisted of 8 subjects, 6 subjects randomized to receive MGL-3196 at doses of 5, 20, 50, 80, 100, or 200 mg and 2 subjects receiving matching placebo. The average age of the cohorts ranged from 27.7 to 44 years, with the average BMI ranging from 24.9 to 27.6 kg/m2 across cohorts. Most subjects were white males (Table 1, Supplementary data). Study drug was administered in capsule form for 14 days in the morning at approximately same time for each subject. The subjects, the investigator, study site personnel, and sponsor were blinded to which subjects received active drug and which received placebo. Escalation to the next cohort commenced following a safety evaluation of the prior cohort. For each cohort, written informed consent followed by screen procedures occurred within 14 days prior to admission to the clinical facility on Day -1. Following completion of predose safety assessments, study drug was administered in the morning of Days 1e14. On Days 1 and 14 subject fasted starting at least 12 h pre dose and continued to fast until 4 h postdose (water was permitted 1 h
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after dosing). On other days, subjects were allowed to eat after dosing and any blood collection. Subjects were evaluated for safety through monitoring of adverse events, and periodic assessment of vital signs (temperature, respiratory rate, pulse rate, and blood pressure), 12-lead ECGs, clinical laboratory parameters and cardiac biomarkers. On Days 1 and 14, except for the 80-mg cohort, continuous ECG Holter recordings were performed beginning at least 30 min before and for 24 h after dosing. Holters were read blinded by a Core ECG laboratory. For Cohort 6 (80-mg dosing), additional 12-Lead ECGs were obtained instead of Holter ECG monitoring. Plasma samples for pharmacokinetic and pharmacodynamic assessments were collected periodically during the 14 days of dosing in the morning prior to dosing. After medical review of clinical safety parameters including physical examination, vital signs, clinical laboratory results and 12lead ECGs, subjects were released from the clinical facility on the morning of Day 16, to return 5 days later for post-treatment, endof-study evaluations. Subjects were monitored for adverse events throughout the study. 2.4. Statistical analyses Data are reported using descriptive statistics. Mean standard deviation are presented for continuous variables; count and frequency are presented for categorical variables. Changes from baseline to Post-Dose 14 in lipids, TSH and sex hormone binding globulin (SHBG) were analyzed using analysis of covariance (ANCOVA) models adjusting for the baseline value. Within the ANCOVA models, changes were compared between the active treatment groups and placebo. When appropriate, changes were also tested against zero within group. The Post-Dose 14 values of free T3, free T4, total T3 and total T4 were analyzed using analysis of variance (ANOVA) models and again, means at Post-Dose 14 were compared between the active treatment groups and placebo. The last observation carried forward approach was used in the few cases (2 subjects) where data were missing at Post-Dose 14. All tests were twosided and conducted at the 0.05 significance level. Statistical analyses were performed using SAS statistical software version 9.3. 3. Results 3.1. Single dose study MGL-3196 appeared safe and was well-tolerated at all doses and no maximal tolerated dose was reached. Adverse events were mild, not dose-related or considered related to study drug. There were no effects on 24-h Holter heart rate, ECG intervals including QTcF (Fridericia’s correction), or blood pressure. Drug exposure was dose-dependent (Fig. 1A) and the area under the curve (AUC) was unaffected by food; Cmax was somewhat reduced and Tmax delayed after food. No treatment related effect on lipids, TSH or thyroid hormones was observed after the single doses. 3.2. Multiple dose study, pharmacokinetics The first day pharmacokinetics were consistent with what was observed in the single ascending dose study with the exception of the 100 mg cohort which showed on average a higher Cmax and AUC exposure than in the first study (Fig. 1B,C). The only apparent difference in demographics was that the multiple ascending dose cohort included 3/6 women and single ascending dose study 0/6 women. The exposure was dose-dependent and fairly linear through 80 mg. Variability in exposure was greater at 14 days relative to day 1 particularly at higher doses. A Day 14 AUC ratio of 1.5e2.5 fold was observed for doses 50 mg and was greater than
Fig. 1. Geometric mean MGL-3196 plasma concentration (ng/ml) at indicated times after single dose (Doses 5 mg) (A) and multiple doses on Day 1 (B) and Day 14 (C).
predicted by the plasma terminal half-life. Drug levels appeared to reach steady-state by day 3e6. 3.3. Multiple dose study, safety MGL-3196 appeared safe and was well-tolerated at all doses tested. Adverse events were generally mild and not dose-related or
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attributed to study drug (Table 2, Supplementary data). There was no effect of MGL-3196 on vital signs, heart rate (Fig. 1, Supplementary data) or QTcF (not shown) as assessed by Holter monitor or blood pressure. The expected diurnal pattern in heart rate was observed that was similar in placebo and all groups. There was no effect on standard safety laboratory tests including liver enzymes or troponin levels.
3.4. Multiple dose study, thyroid hormones There were decreases in free T4 of w20% at the highest dose (200 mg) (Fig. 2B, Table 3, Supplementary data) and the level after day 14 was significantly different from placebo at 100 mg (p ¼ 0.037) and 200 mg (p < 0.0001). The changes in free T4 attributed to dose appeared to plateau at approximately 8e11 days after dosing and were reversible (not shown). Statistically
significant dose-related decreases relative to placebo in mean total T4 were observed at the 100 and 200 mg doses (Table 3, Supplementary data). There were no dose-dependent differences or meaningful changes in the level of free T3 or total T3 (Fig. 2A). TSH was mildly elevated within the normal reference range after 14 days relative to baseline in the pooled placebo and MGL-3196 groups. There was maintenance of diurnal variation of TSH (assessed at days 1 and 14) in all groups and no meaningful doserelated difference in the within-day TSH pattern between placebo and MGL-3196 groups (Fig. 2C). Thyroid hormones showed biological variability in some individuals during the study that was not related to dose of drug. Other statistically significant differences from placebo in thyroid hormones (e.g. free T4 at 5 mg; TSH at 20 mg) were isolated findings, not dose-related or meaningful (Table 3, Supplementary data). There was no significant effect on levels of thyroid binding globulin at any dose (not shown). 3.5. Multiple dose study, lipids and sex hormone binding globulin (SHBG) At doses of MGL-3196 ranging from 50 to 200 mg highly statistically significant and dose-related reductions relative to placebo were observed of up to 30% for LDL-cholesterol (range, p ¼ 0.05e <0.0001) (Fig. 3, Table 1). Parallel reductions were seen of up to 28% for non-HDL-C (range, p ¼ 0.027e0.0001), and up to 24% for Apolipoprotein B (ApoB) (range, p ¼ 0.008e0.0004). A strong trend with dose, and up to a 60% reduction in triglycerides was seen as well (range, p ¼ 0.13e0.016). There was also a significant reduction relative to placebo in the ApoB/ApoA-1 ratio (Table 1). In general, the maximal or near-maximal effect on these lipid parameters was observed at the 80 mg dose. The lipid effects were observed as early as after 2 doses (2 days) and had not fully renormalized at the time of the return visit (6 days off study drug) (Fig. 4). The possible effects of MGL-3196 on apolipoprotein A-A1 (ApoA-1) and HDL-C could not be fairly evaluated in this study, because a significant decrease in levels occurred between baseline and day 14 in the placebo as well as in all the other study groups (Table 1) that may be attributed to confinement in the study unit, and lack of exercise. The reduction in HDL was relatively less at the higher dose groups than in placebo suggesting that MGL-3196 is neutral or may slightly improve HDL. Although thyroid agonists have been shown to lower Lp(a) in larger studies [15], small sample size, high inter-subject variability, few subjects in each cohort with detectable Lp(a) and
Fig. 2. Thyroid hormone levels after 14 doses. Daily doses of MGL-3196 were given for fourteen days, after which no additional doses were given. Thyroid hormones were assessed 24 h after dose 14. Mean free T3 (A), mean free T4 levels (B); dotted line, lower range of normal. Multiple measurements of TSH (C) were assessed on the first and last day of dosing to demonstrate diurnal variation.
Fig. 3. Changes in lipids after fourteen doses. The percent change from baseline (CFB) for each subject was determined, averaged by dose and corrected to placebo. The baseline determination was fasting, just prior to the first dose and the determination was made fasting 24 h after the 14th dose. ApoB, apolipoprotein B; Chol, total cholesterol; LDL-C, LDL cholesterol directly measured; Non-HDL-C, non-HDL cholesterol, TG, triglycerides (median % CFB). The standard deviations for the assessments are shown in Table 1.
R. Taub et al. / Atherosclerosis 230 (2013) 373e380
377
Table 1 Changes in lipids, multiple dose study. Placebo
5 mg
20 mg
50 mg
80 mg
100 mg
200 mg
(N ¼ 12)
(N ¼ 6)
(N ¼ 6)
(N ¼ 6)
(N ¼ 6)
(N ¼ 6)
(N ¼ 6)
227.8 30.9 230.9 40.2 3.1 21.0
240.3 41.4 242.7 41.8 2.3 33.6 0.96 0.7 13.4
212.7 30.3 218.2 47.3 5.5 21.4 0.95 0.7 10
217.8 39.4 193.8 35.7 24.0 28.9 0.021 11.3 15.3
197.7 11.7 154.7 16.3 43.0 18.3 0.0002 22.8 8.7
216.3 40.7 183.2 30.2 33.2 16.3 0.0027 16.0 6.5
220.2 23.2 182.0 33.6 38.2 21.6 0.0009 18.7 10.3
153.1 23.0 156.1 31.5 3.1 17.2
160.0 27.1 165.1 33.9 5.1 23.8 0.78 2.0 14.3
143.6 24.2 156.3 43.7 12.8 24.6 0.4 6.1 15.3
148.6 39.6 131.8 33.9 16.8 26.8 0.05 10.9 22
136.213.8 101.6 18.2 34.5 14.2 0.0005 27.2 9.9
143.8 28.6 113.8 19.9 30.0 17.6 0.0018 21.8 10.4
150.1 22.1 107.2 23.3 42.9 17.6 <0.0001 30.3 10.8
122.0 15.5 126.1 23.4 4.2 16.4
131.3 19.4 128.4 20.3 2.9 16.7 0.49 4.9 11.7
123.0 18.7 119.4 27.9 3.6 15.3 0.32 6.6 12.8
116.5 20.1 100.5 16.2 16.0 19.7 0.008 15.4 18.6
98.2 12.0 79.4 13.0 18.7 12.2 0.002 22.0 11.1
107.9 16.1 90.1 12.7 17.8 8.5 0.003 19.5 6.5
117.3 11.1 93.0 17.4 24.3 13.4 0.0004 24.1 11.7
181 29.4 189.9 37.1 8.9 19.2
186.3 30.1 198.3 37.2 12.0 29.8 0.75 3.3 15.8
174.5 31.3 185.3 44.3 10.8 19.8 0.9 1.7 11.6
170.5 35.2 154.8 33.7 15.7 26.1 0.027 12.2 17.4
154.0 18.7 116.2 19.3 37.8 19.0 0.0001 28.3 10.7
162.2 28.7 133.5 20.0 28.7 17.1 0.0012 21.0 8.9
172.5 16.4 137.0 32.2 35.5 21.9 0.0002 25.1 13.6
0.87 0.18 1.03 0.23 0.16 0.12
0.83 0.21 1.01 0.29 0.18 0.10 0.7752
1.13 0.22 1.16 0.21 0.02 0.14 0.045
0.82 0.2 0.88 0.19 0.06 0.09 0.0875
0.78 0.18 0.75 0.18 0.03 0.14 0.0025
0.72 0.17 0.70 0.18 0.02 0.08 0.0044
0.81 0.09 0.78 0.13 0.04 0.09 0.0015
125.4 43.6 135.4 58.0 10.0 53.7
107.8 21.8 139.5 31.7 31.7 18.6 0.52 16.7 17
169.7 90.2 158.7 76.0 11.0 67.7 0.9 4.7 47.2
116.0 49.0 95.3 49.9 20.7 54.5 0.13 30.6 39.9
91.3 19.5 58.2 15.67 33.2 13.2 0.016 59.8 11.7
99.2 27.2 80.7 39.9 18.5 23.1 0.089 44.4 21.1
135.5 48.3 104.2 61.6 31.3 63.3 0.1 54.8 44.8
HDL-C (mg/dL) Baseline Post-Dose 14 Difference Within group change from baseline (P value)
46.810.2 41 9.2 5.8 4.1 <0.0001
54.0 19.9 44.3 15.8 9.7 6.6 <0.0001
38.2 4.1 32.8 3.4 5.3 4.8 0.0002
47.3 10.2 39.0 8.9 8.3 4.0 <0.0001
43.7 9.5 38.5 6.7 5.2 6.9 0.0015
54.2 19.7 49.7 18.5 4.5 4.9 0.089
47.7 9.2 45.0 7.3 2.7 2.8 0.14
Apolipoprotein A (mg/dL) Baseline Post-Dose 14 Difference Within group change from baseline (P value)
143.4 21.1 124.8 17.4 18.6 18.6 <0.0001
165.0 42.1 135.1 37.2 29.8 19.4 0.0002
109.7 11.6 102.8 7.9 7.0 13.5 0.0044
145.7 23.9 116.9 16.4 28.8 17.3 <0.0001
129.2 16.9 107.4 11.9 21.8 12.5 <0.0001
156 35.8 133.5 30.2 22.5 10.0 0.0018
145.0 18.1 120.2 17.4 24.8 5.0 <0.0001
37.1 12.6 32.5 12.0 4.6 5.3
35.7 9.1 30.8 6.2 4.8 4.7 0.80 0.04 10.9
23.0 11.1 24.3 8.6 1.3 6.9 0.37 25.531.2
35.5 9.3 38.2 8.7 2.7 6.8 0.046 22.3 21.0
37.0 63.8 26.8 0.038 77.5
44.7 72.8 28.2 0.003 84.4
34.0 10.3 54.0 26.0 20.0 23.8 0.058 85 68.5
71.0 74.0 62.5 62.1 8.5 13.9
59.8 110.9 62.5 112.2 2.7 4.5
57.8 84.3 59.7 95.7 1.8 12.4
44.5 45.0 43.5 51.3 1.0 12.8
Total Cholesterol (mg/dL) Baseline Post-dose 14 Difference P value vs. placebo Difference in %CFB vs. Placebo (%) LDL-C (mg/dL) Baseline Post-dose 14 Difference P value vs. placebo Difference in %CFB vs. Placebo (%) Apolipoprotein B (mg/dL) Baseline Post-dose 14 Difference P value vs. placebo Difference in %CFB vs. Placebo (%) Non-HDL-C (mg/dL) Baseline Post-dose 14 Difference P value vs. placebo Difference in %CFB vs. Placebo (%) ApoB/ApoA-1 ratio Baseline Post-Dose 14 Difference P value vs. placebo Triglycerides (mg/dL) Baseline Post-Dose 14 Difference P value vs. placebo Difference in %CFB vs. Placebo (%)
SHBG (nmol/L) Baseline Post-Dose 14 Difference P value vs. placebo Difference in %CFB vs. Placebo (%CFB) Lp(a) (nmol/L) Baseline Post-Dose 14 Difference
118.1 119.0 122.6 121.1 4.5 13.4
13.9 37.5 24.9 34.9
20.8 28.7 13.6 55.2
80.2 153.1 75.7 142.1 4.5 11.3
117.0 119.2 97.0 91.3 20.0 40.5
P-values obtained from an ANCOVA model on change from baseline to a determination 24 h after the 14th dose (Post-dose 14). Placebo corrected mean percent change from baseline was obtained by subtracting the average percent change in the placebo group from individual’s % change from baseline and averaging the change in each dose group. CFB ¼ change from baseline. Values are mean standard deviation.
short study duration precluded determining the effect of MGL-3196 on Lp(a) in this study (Table 1). Sex hormone binding globulin (SHBG) has been noted to be a THR-b regulated gene that is responsible for binding to and stabilizing the levels of sex hormones such as testosterone. Significant increases relative to placebo in SHBG of up to w85% were
observed at doses from 50 to 200 mg [range, p ¼ 0.057e0.003] (Table 1). There were apparent trends to increased total testosterone in males at 100 and 200 mg (not shown) that would be expected given the increases in SHBG. No effects on follicle stimulating hormone (FSH) or luteinizing hormone (LH) were seen (not shown).
378
R. Taub et al. / Atherosclerosis 230 (2013) 373e380
4. Discussion
Fig. 4. Time course of lipids. Levels of LDL-C (A), Apolipoprotein B (B), Non-HDL-C (C) (% CFB) at indicated times (days). Fourteen daily doses of MGL-3196 or placebo were given from 0 to day 13, after which no additional doses were given.
Presented here are the first-in human data for the liver-selective THR-b agonist MGL-3196. Given in daily doses from 0.25 to 200 mg, MGL-3196 was well-tolerated and appeared safe at all doses tested in the single and multiple dose Phase 1 studies in healthy volunteers. Up to w30% lowering of LDL-C, non-HDL-C and ApoB and up to 60% lowering of TGs were observed after 14 days of daily doses of MGL-3196 with a near maximal effect observed at the 80 mg dose. A drug with the potential for lowering LDL-C and plasma triglycerides has a unique profile and potential to treat patients with dyslipidemia alone or in combination with other lipid modifying drugs such as statins. A high percentage of patients with CV disease do not achieve optimal LDL-C levels, and diabetics in particular have high triglycerides and fatty liver that are not treated by existing therapies. Hepatic steatosis is a cause of liver insulin resistance (IR) and non-alcoholic steatohepatitis (NASH) and is associated with increased CV disease [19]. At the lower doses, drug exposure was consistent between day 1 and 14 whereas at higher doses a Day 14/Day 1 ratio of 1.5e2.5 was observed, suggesting that MGL-3196 has a longer residence than predicted by plasma exposure half-life after the first dose. There were no changes in vital signs, and adverse events were generally mild, unrelated to study drug and not dose-dependent. There were no apparent effects on heart rate or QTc (not shown) as assessed by Holter monitor. Unlike previous thyroid analogs, no increases in liver enzymes were observed at any dose in the Phase 1 multiple dose study. The levels of prohormone free T4, active hormone free T3 and TSH are generally viewed as most accurately reflecting thyroid hormone status [20]. Factors that affect thyroid binding globulin (TBG) levels and therefore, the levels of total T4 may not affect the free T4 levels or euthyroid status. In euthyroid individuals small changes in thyroid hormones of 20% whilst values remain within reference ranges are not considered clinically meaningful [20]. Reversible dose-related reductions in free T4 of w20% and w10% were observed only at the highest doses of 200 and 100 mg, respectively. At all doses free T3 and TSH showed no meaningful or dose-dependent change compared with placebo indicating that there were no effects on the central thyroid axis at any dose. The reduction of free T4 may be attributed to the role of the liver where prohormone T4 by the action of deiodinase 1 is converted to either active hormone, T3 or reverse T3 and then may be further metabolized and excreted [21]. It is known that increased hepatic THR-b agonism increases the level of hepatic diodinase 1 [21,22]. Increase in THR-b agonism in the liver is consistent with lowering of free T4 without changes in T3 or TSH or any central effect [23]. Regulation of TSH is complex [24], and primarily reflects T3 homeostasis. Proof-of-concept for LDL-C, ApoB and non-HDL-C lowering was achieved in the Phase 1 multiple dose study. Lipid lowering was robust, rapid and significant at doses 50 mg, with a near-maximal effect observed at 80 mg. Although the lipid lowering effects at 50 mg were substantially less than at 80 mg, there was a single nonresponder at 50 mg who skewed the overall mean effect. It is also possible that lower clinical doses given over a long time period will show improved effects relative to placebo and relative to what was observed in a Phase 1 study. The design of the Phase 1 study was not optimized to assess the impact of MGL-3196 on triglycerides because of highly variable baseline TGs and few subjects with baseline TGs> 150 mg/dL. Nonetheless there were strong dose-dependent effects and trends to reduced TGs. Reduced triglycerides may be a reflection of reduced hepatic triglycerides that were consistently observed in preclinical animal models treated with MGL-3196 (18, manuscript in preparation). In addition as has been demonstrated with thyroid
R. Taub et al. / Atherosclerosis 230 (2013) 373e380
hormone [25], MGL-3196 may directly lower ApoB, both mechanisms resulting in reduced VLDL production. The effect of MGL3196 on liver or plasma triglycerides must be tested in subsequent clinical studies. Likewise the study was not appropriately designed to assess the effect of MGL-3196 on HDL-C or ApoA-1; however, significant improvement in the ApoB to ApoA-1 ratio was observed with MGL-3196. Additionally, MGL-3196 increased SHBG, a liver specific protein that has been inversely correlated with the incidence of type 2 diabetes [26]. Although SHBG may be regulated by several factors, the level is well correlated with the level of THR-b activity in the liver [27]. In addition to its effects on cholesterol and triglycerides, MGL-3196 reduced hepatic triglycerides and glucose in diet induced obese mice, and demonstrated insulin sensitizing actions [18, in preparation]. Studies have shown that clearance of liver lipids by thyroid hormone agonists results from accelerated hepatic fatty acid oxidation [28]. Diabetics have a specific dyslipidemia characterized by fatty liver, elevated TGs, atherogenic LDL and low HDL-cholesterol [4,5]. Diabetics have also been noted to have low free T3 and reduced free T3/free T4, suggesting low hepatic diodinase 1 and reduced production of T3 [29]. The combined effects of MGL-3196 in reducing hepatic TGs, plasma TGs, LDL-C, raising SHBG and testosterone, as well as having potential other insulin sensitizing effects could make MGL-3196 a particularly appropriate therapy for type 2 diabetics. MGL-3196 showed similar lipid lowering effects and improved safety in the Phase 1 multiple dose study relative to other clinical thyroid analogs. MGL-3196 is differentiated from previous analogs by several features: 1- novel chemical scaffold 2- lack of central thyroid axis suppression 3- selectivity for THR-b in a functional assay 4- absence of ALT elevations and 5-lack of potency at THR-a. In particular MGL-3196 did not increase liver enzymes in the Phase 1 studies. Such elevations were readily observed with other analogs such as eprotirome [14,15]. The effects on ALT were attributed to a pharmacologic action of thyroid hormonedhowever thyroid hormone treatment and thyrotoxicosis are not known to be associated with liver enzyme elevations except in unusual cases of thyroid storm. Moreover whereas eprotirome and MB78011 reduced both free T3 and TSH at doses just above the clinically relevant dose in the Phase 1 study, MGL-3196 did not affect the central thyroid axis or lower T3 at any dose tested suggesting that MGL-3196 may have a significantly better therapeutic window. Eprotirome was discontinued because a cartilage abnormality was found in long term dog toxicology studies [16]. Although the specific mechanism is not known, THR-a is the primary TH receptor present in cartilage [11] and eprotirome is equipotent to T3 at THR-a. Recently, eprotirome was also found to cause increased insulin resistance in a rat model because of a postulated off-target action in muscle [30]. No bone or cartilage abnormalities have been observed in MGL-3196 dog toxicology studies conducted for up to three months. The major limitation of the study is that small numbers of subjects with only mildly elevated LDL-C were treated for a relatively short duration. However within this group of subjects, some fulfilled criteria for dyslipidemia, particularly as regards the LDL-C pathway. There is currently insufficient data to properly assess the variability of the lipid response to MGL-3196 that will be resolved by treating larger numbers of dyslipidemic patients. In subsequent MGL-3196 Phase 2 studies in patients with mixed dyslipidemias, the ability of MGL-3196 to lower triglycerides and LDL-C alone and in combination with a statin will be determined. In conclusion, in first-in-human studies, MGL-3196, a livertargeted THR-b agonist, given orally once-daily appeared safe and was well-tolerated at all doses tested up to 200 mg for up to 14 days in healthy human volunteers. There was no evidence of any effects on vital signs, or standard laboratory assessments including liver
379
enzymes and Holter ECGs. Reversible reductions in prohormone free T4 levels at the highest doses can be explained by a hepatic effect on T4 metabolism, and there was no evidence of central thyroid axis suppression at any dose. The improved safety profile differentiates MGL-31196 from previous thyroid analogues tested in similar Phase 1 studies. Doses from 50 to 200 mg of MGL-3196 per day, with a near-maximal effect at 80 mg, demonstrated robust and rapid reductions in lipids, including LDL-C, non-HDL-C and apolipoprotein B up to 30%, with statistical trends to reduce triglycerides up to 60%. Disclosures RT, EC, MK are employees of Madrigal Pharmaceuticals which sponsored this study. RAR is a consultant to Madrigal Pharmaceuticals, and J-C T received honoraria from Madrigal Pharmaceuticals. Appendix A. Supplementary data Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.atherosclerosis.2013.07.056. References [1] Waters DD, Brotons C, Chiang CW, et al., Lipid Treatment Assessment Project. Lipid treatment assessment project 2: a multinational survey to evaluate the proportion of patients achieving low-density lipoprotein cholesterol goals. Circulation 2009;120(1):28e34. [2] Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med 2009;150(12):858e68. [3] DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14(3):173e94. [4] Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab 2009;5(3):150e9. [5] Toledo FG, Sniderman AD, Kelley DE. Influence of hepatic steatosis (fatty liver) on severity and composition of dyslipidemia in type 2 diabetes. Diabetes Care 2006;29(8):1845e50. [6] Grover GJ, Egan DM, Sleph PG, et al. Effects of the thyroid hormone receptor agonist GC-1 on metabolic rate and cholesterol in rats and primates: selective actions relative to 3,5,3’-triiodo-L-thyronine. Endocrinology 2004;145(4): 1656e61. [7] Grover GJ, Mellstrom K, Ye L, et al. Selective thyroid hormone receptor-beta activation: a strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability. Proc Natl Acad Sci U S A 2003;100(17):10067e72. [8] Johansson L, Rudling M, Scanlan TS, et al. Selective thyroid receptor modulation by GC-1 reduces serum lipids and stimulates steps of reverse cholesterol transport in euthyroid mice. Proc Natl Acad Sci U S A 2005;102(29): 10297e302. [9] Morkin E, Pennock GD, Spooner PH, Bahl JJ, Goldman S. Clinical and experimental studies on the use of 3,5-diiodothyropropionic acid, a thyroid hormone analogue, in heart failure. Thyroid 2002;12(6):527e33. [10] Baxter JD, Webb P. Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes. Nat Rev Drug Discov 2009;8(4): 308e20. [11] Gogakos AI, Duncan Bassett JH, Williams GR. Thyroid and bone. Arch Biochem Biophys 2010;503(1):129e36. [12] Klein I, Danzi S. Thyroid disease and the heart. Circulation 2007;116(15): 1725e35. [13] Erion MD, Cable EE, Ito BR, et al. Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index. Proc Natl Acad Sci U S A 2007;104(39):15490e5. [14] Berkenstam A, Kristensen J, Mellstrom K, et al. The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans. Proc Natl Acad Sci U S A 2008;105(2):663e7. [15] Ladenson PW, Kristensen JD, Ridgway EC, et al. Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med 2010;362(10):906e16. [16] Bengsston P. “Karo Bio terminates the eprotirome Program” Karo Bio February 14. http://www.karobio.com/investormedia/pressreleaser/pressrelease? pid¼639535; 2012. [17] Kelly MJ, Larigan JD, Pietranico-Cole S, et al. Discovery and development of MGL-3196, a liver-directed thyroid hormone beta agonist for the treatment of hypercholesterolemia/dyslipidemia and hypertriglyceridemia; 2013.
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