First in Man Study to Evaluate NST-1024 in Volunteers
Research type
Research Study
Full title
A Phase 1, First Time in Man Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of NST-1024 in Healthy Subjects and Otherwise Healthy Subjects with Elevated Triglycerides
IRAS ID
280596
Contact name
Firas Almazedi
Contact email
Sponsor organisation
NorthSea Therapeutics B.V.
Eudract number
2020-003195-41
Clinicaltrials.gov Identifier
REC ID, 20/NE/0084
Duration of Study in the UK
0 years, 7 months, 3 days
Research summary
Summary of Research
NST-1024 is a novel, orally administered, semi-synthetic fatty acid being developed for the treatment of severe hypertriglyceridemia (HTG), mixed dyslipidaemia, and hypercholesterolemia (increased blood levels of the most abundant fatty molecule in most organisms).
Elevated plasma triglycerides (TG) are associated with dual risks of acute pancreatitis (inflammation of the pancreas) and accelerated atherosclerosis (blocking of the arteries) leading to cardiovascular (CV) events. For patients with elevated TG who do not adequately respond to dietary and lifestyle restrictions, relatively few classes of drugs are available to treat HTG.
NST-1024 is a semi-synthetic, structurally engineered eicosapentaenoic acid (EPA) (a type of fatty acid found especially in fish oils). This helps reduce the amount of fats absorbed in the diet from the intestines. This study is a first-in-human study to evaluate the safety, tolerability, and pharmacokinetics (how the drug is used by the body) (PK) of NST-1024.
In Part A 48 healthy subjects will be studied in 6 planned groups (Groups A1 to A6), with each group consisting of 8 subjects. They will be provided with a single dose (except for group A4, who will receive one dose in the fasted state and one dose in the fed state). For each subsequent group the dose will increase after a safety meeting is conducted to ensure the drug was safe in the previous group.
In part B, 48 healthy subjects will receive NST-1024 for 14 consecutive days. They will be divided into 4 groups; each subsequent group will be dosed after a safety review of the previous group. Subjects in this group will have blood triglycerides above 150mg/dL.
Additional groups will only be added if the data from earlier cohorts and a rationale are submitted in a request to the Regulatory Agency for a substantial amendment to the protocol and the application is approved.
Summary of Results
Title of study: A Phase 1, First Time in Man Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of NST-1024 in Healthy Subjects and Otherwise Healthy Subjects with Elevated Triglycerides Investigational medicinal product: NST-1024
Sponsor: NorthSea Therapeutics B.V.
Investigator: Dr Firas Almazedi, MBChB, MSc, CPI, DipPharmMed. This study was conducted at 1 site in the United Kingdom.
Publications: None.
Period of study: 07 October 2020 (date of first informed consent) to 20 June 2022 (date of final poststudy observation).
Phase of development: Clinical Phase 1
Objectives:
The primary objective was:
• to evaluate the safety and tolerability of NST-1024 in healthy male and female subjects, and otherwise healthy subjects with elevated triglyceride (TG), aged 18 to 64 years.
The secondary objectives were:
• to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of NST-1024 following single and repeat dose administrations in healthy subjects and otherwise healthy subjects with elevated TG
• to evaluate the effects of food on the PK profile of NST-1024 following single dose administration.
Methodology:
This was a double-blind, randomised, placebo controlled, single and multiple oral dose study conducted in 2 parts. Part A evaluated single ascending doses and Part B evaluated multiple ascending doses in healthy subjects. Part A included a food-effect evaluation in healthy subjects in 1 group and Part B included an evaluation of multiple oral doses administered to otherwise healthy subjects with elevated TG.
Blood and urine samples were collected for the analysis of plasma and urinary concentrations of NST-1024 and were also collected from 1 group in Part B for the purpose of metabolite identification.
Blood samples were collected for the measurement of lipid and apolipoprotein (Apo) PD parameters (low density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL C], very low-density lipoprotein cholesterol [VLDL-C], total cholesterol, TG, ApoB, ApoA1, and ApoC3) and glycemic control PD parameters (C-reactive protein, fasting serum glucose, fasting insulin, and homeostatic model assessment for insulin resistance [HOMA IR]).
Number of subjects (planned and analysed):
In Part A, up to 48 healthy subjects were planned to be studied in 6 groups (Groups A1 to A6), with each group consisting of 8 subjects (randomised to 6 active and 2 placebo). Following review of safety, tolerability, and PK data in earlier groups, 1 additional group of 8 subjects (randomised to 6 active and 2 placebo) was subsequently included in the study (Group A7).
Fifty-five subjects were randomised, dosed, and completed the single ascending dose portion of the study (Part A) in 7 dose groups in accordance with the protocol. One subject who received placebo did not complete the study as the subject was lost to follow-up.
In Part B, up to 48 otherwise healthy subjects with elevated TG were planned to be studied in 4 groups (Groups B1 to B4), with the first 3 groups consisting of 10 subjects (randomised to 8 active and 2 placebo), and 1 group consisting of 18 subjects (randomised to 12 active and 6 placebo). Subsequently, the option of expanding the number of subjects in Group B3 if Group B4 was not conducted was allowed, and the requirement for elevated TG was revised to Groups B3 and B4 only. Following review of safety, tolerability, and PK data in earlier groups, 1 additional group of 10 subjects (randomised to 8 active and 2 placebo) was subsequently included in the study (Group B5).
Forty-seven subjects were randomised, dosed, and completed the multiple ascending dose portion of the study (Part B) in 5 dose groups in accordance with the protocol. One subject who received 200 mg once daily (QD) was withdrawn from the study due to a positive coronavirus disease-2019 test.
All subjects were included in the safety populations for both the single and multiple ascending dose portions of the study. For the single ascending dose portion of the study, 42 (75.0%) of 56 subjects were included in the PK population and for the multiple ascending dose portion of the study, 38 (79.2%) of 48 subjects were included in the PK population.
Diagnosis and main criteria for inclusion:
Healthy male and female subjects aged between 18 and 64 years with a body mass index (BMI) between 18.0 and 32.0 kg/m2, inclusive, at screening were selected according to the inclusion and exclusion criteria listed in the protocol. Healthy subjects with fasting TG levels >150 mg/dL were included in the study in a portion of Part B.
Test product, dose and mode of administration, batch/lot number:
The investigational medicinal products (IMPs), 10 mg NST-1024 capsules (lot number QB140949/1) and 100 mg NST-1024 capsules (lot number QB140950/1) were supplied by the sponsor (or designee). NST-1024 was supplied as liquid in soft gelatin capsules.
In the single ascending dose portion of the study, oral NST-1024 doses of 10, 50, 60, 200, and 400 mg were administered in the fasted state; a dose of 30 mg was administered in fasted and fed states (food effect evaluation); and a dose of 100 mg was administered in the fed state.
In the multiple ascending dose portion of the study, oral NST-1024 doses of 10, 30, 60, and 200 mg were administered QD in the fed state and 300 mg was administered twice daily (BID) in the fasted state.
Reference therapy, dose and mode of administration, batch/lot number:
The placebo capsules (lot number QB141055/1) were supplied by the sponsor (or designee). Placebo was supplied as medium chain TG in matching soft gelatin capsules.
For both the single and multiple ascending dose portions of the study, the same number of placebo capsules as active drug capsules were administered orally in each group to maintain the study blind. The same dose regimen and dietary conditions were used for the placebo as for active drug in each group.Duration of treatment:
Single doses were administered in each group in Part A.
In the multiple ascending dose portion of the study (Part B), NST-1024 doses of 10, 30, 60, and 200 mg were administered QD over 14 consecutive days and 300 mg was administered BID over 13 consecutive days with a single dose administered on Day 14.
Endpoints:
The primary safety endpoints for this study were incidence and severity of adverse events (AEs); incidence of laboratory abnormalities, based on clinical laboratory evaluations (chemistry, haematology, urinalysis, and coagulation); 12 lead electrocardiogram (ECG) parameters; vital sign measurements; and physical examinations.
For Part A, the single ascending dose and food-effect evaluation PK outcome endpoints of NST-1024 were as follows:
• area under the plasma concentration time curve (AUC) from time zero to infinity (AUC0 ∞)
• AUC from time zero to infinity normalised by dose (AUC0 ∞/dose)
• AUC from time zero to the time of the last quantifiable concentration (AUC0 tlast)
• AUC from time zero to the time of the last quantifiable concentration normalised by dose (AUC0 tlast/dose)
• maximum observed plasma concentration (Cmax)
• Cmax normalised by dose (Cmax/dose)
• time of the maximum observed plasma concentration (tmax)
• apparent plasma terminal elimination half life (t1/2)
• apparent total plasma clearance (CL/F)
• apparent volume of distribution (Vz/F)
• renal clearance (CLR)
• amount of drug excreted in the urine (Ae)
• percentage of dose excreted unchanged in the urine (fe).
For Part B, the multiple ascending dose PK outcome endpoints of NST-1024 were as follows:
• AUC over a dosing interval (AUC0 τ)
• AUC from time zero to 24 hours postdose (AUC0-24, for BID regimen at steady state, where not redundant with AUC0 τ)
• AUC over a dosing interval normalised by dose (AUC0 τ/dose)
• AUC0 ∞ (Day 1 only)
• AUC0 ∞/dose (Day 1 only)
• Cmax
• Cmax/dose
• minimum observed plasma concentration (Cmin)
• tmax
• t1/2
• CL/F
• Vz/F
• observed accumulation ratio based on AUC0-τ (RAAUC0-τ)
• observed accumulation ratio based on Cmax (RACmax).
For Parts A and B of the study, the PD outcome endpoints were as follows:
• full lipid profile including LDL-C, HDL-C, total cholesterol, VLDL-C, TG, ApoB, ApoA1, and ApoC3
• C-reactive protein
• fasting serum glucose
• fasting insulin
• HOMA-IR.
For 1 group in Part B, additional blood and urine samples were taken for the purpose of identification of metabolites of NST-1024.
Statistical methods:
Analysis populations:
Analysis populations applied to the study included the all subjects population (all subjects who signed the informed consent form and had any study assessment recorded in the database per the protocol), safety population (all subjects who received at least 1 dose of study treatment [NST-1024 or placebo]), PK population (all subjects who received at least 1 dose of active study treatment [NST-1024] and had at least 1 valid PK concentration), and PD population (all subjects who received at least 1 dose of study treatment [NST-1024 or placebo]) and had at least 1 valid postdose PD assessment.
Statistical methodology - safety:
For safety statistical methodology, all safety data for the safety population were listed.
Treatment emergent AEs (TEAEs) were summarized by treatment, severity, and relationship to the IMP. The frequency of TEAEs was summarized by treatment and Medical Dictionary for Regulatory Activities system organ class and preferred term. Summary and frequency TEAE tables were presented for all causalities and for those considered related to the IMP.
All clinical laboratory parameters were listed; any value outside the clinical reference range was flagged. Separate listings were provided for any parameter for which there was any individual subject value outside the respective clinical reference range. Summary tables and boxplots by treatment and timepoint were provided for clinical chemistry, haematology, and coagulation parameters.
All vital sign and 12-lead ECG parameters and their changes from baseline were listed, as applicable; any value outside the clinical reference range was flagged. Summary tables and boxplots by treatment and timepoint were provided for all vital sign and 12-lead ECG parameters and their changes from baseline, as applicable.
An outlier analysis was performed for QT interval corrected for heart rate using Bazett’s formula and QT interval corrected for heart rate using Fridericia’s method. The analysis included all individual original, repeat, and unscheduled postdose values. The maximum postdose values were summarised by treatment according to the following categories:
• ≤450 ms
• >450 and ≤480 ms (all instances flagged in the listing)
• >480 and ≤500 ms (all instances flagged in the listing)
• >500 ms (all instances flagged in the listing).
The maximum increases from baseline were summarised by treatment according to the following categories:
• ≤30 ms
• >30 and ≤60 ms (all instances flagged in the listing)
• >60 ms (all instances flagged in the listing).
No inferential statistical analyses were planned for safety data.
Statistical methodology – pharmacokinetics:
For PK statistical methodology, all PK concentrations and parameters were listed. Summary tables, arithmetic mean (+ standard deviation) figures, overlaying individual figures, and individual figures by treatment and time postdose were provided for plasma PK concentrations. Summary tables by treatment were provided for all PK parameters, with the exception of diagnostic regression-related PK parameters. Separate summary tables by treatment and time interval were to be provided for excretion parameters and cumulative excretion parameters.
A statistical analysis was conducted to investigate the dose proportionality of AUC0-tlast, AUC0-∞, and Cmax on profile Day 1 for dose levels administered in the fasted state in Part A; AUC0-∞ and Cmax on profile Day 1 and AUC0-τ and Cmax on profile Day 14 for QD doses administered in the fed state in Part B (only for plasma NST-1024). The hypothesis testing was 2-sided and carried out on 0.05 significance level. The PK parameters were analysed using a power model.
A statistical analysis was conducted to investigate the food effect on the treatment by comparing NST-1024 (fed) treatment to NST-1024 (fasted) at the same dose level. The hypothesis testing was 2-sided and carried out on both 0.05 and 0.1 significance levels. The natural log transformed AUC0-tlast, AUC0-∞, and Cmax on profile Day 1 for the food effect group in Part A (only for plasma NST-1024) were analysed using a mixed model. The model included actual treatment as fixed effect and subject as a random effect.
Statistical methodology – pharmacodynamics:
For both parts of the study, all lipid, apolipoprotein, and glycemic control PD parameters, their changes from baseline, and their percentage changes from baseline were listed. For Part B only, summary tables, mean figures, and overlaying individual figures by treatment and timepoint were provided for all lipid, apolipoprotein, and glycemic control PD parameters, their changes from baseline, and their percentage changes from baseline.
A statistical analysis was conducted to investigate the effect of the treatment on the PD by comparing each dose of NST-1024 (test treatment) to placebo (reference treatment).
For Part B only, the changes from baseline and percentage changes from baseline in lipid, Apo, and glycemic control PD parameters were analysed separately using a mixed model. The model included baseline, actual treatment, timepoint, and treatment by timepoint interaction as fixed effects, and subject as a random effect. For each PD parameter and timepoint combination separately, the least-squares mean (LSM) for each treatment, difference in LSMs between the test and reference treatments, and corresponding 95% confidence interval (CI) were calculated; 2 sided p value was also calculated.
Additionally, the residual plots were produced to assess the adequacy of the model(s) fitted.
The appropriateness of the parametric model assumptions (eg, normality and equal variance) was checked by examining diagnostic plots.
Determination of sample size:
No formal statistical assessment, in terms of sample size, was conducted as this is the first time NST-1024 is being administered to humans. However, the number of subjects in each part of the study is common in early clinical pharmacology studies and was considered sufficient to achieve the objectives of the study.
Summary - Conclusions:
Subject demographics and protocol deviations:
For the single ascending dose portion of the study (Part A), 42 (75.0%) of 56 subjects were male and 14 (25.0%) were female; mean age of all subjects was 39.8 years (range: 19 to 64 years), with a mean BMI of 25.21 kg/m2 (range: 18.9 to 31.8 kg/m2). The majority of subjects were White (89.3%) and no subjects were Hispanic or Latino.
For the multiple ascending dose portion of the study (Part B), 41 (85.4%) of 48 subjects were male and 7 (14.6%) were female; mean age of all subjects was 42.1 years (range: 18 to 63 years), with a mean BMI of 25.90 kg/m2 (range: 19.0 to 31.9 kg/m2). The majority of subjects were White (85.4%) and no subjects were Hispanic or Latino.
Subjects in the 60 mg NST-1024 QD fed group had elevated TGs at screening (ranging from 1.71 to 3.41 mmol/L [151 to 302 mg/dL]) as required by the protocol.
There were no protocol deviations in the single or multiple ascending dose portions of the study that were considered to have any implications on the conduct of the study or the integrity of the study results.
Safety results:
After single oral administration of NST-1024 under fasted condition over a dose range of 10 to 400 mg, 4 treatment-related TEAEs were reported by 7.1% (4/56) of subjects. Mild headache was reported by 1 subject who received 50 mg NST-1024, 1 subject who received 200 mg NST-1024, and 1 subject who received placebo. Mild diarrhoea was reported by 1 subject who received 60 mg NST-1024. No treatment-related TEAEs were reported by any subjects administered 10, 30, or 400 mg NST-1024 under fasted conditions.
After single oral administration of NST-1024 under fed condition at dose levels of 30 and 100 mg, no treatment-related TEAEs were reported by any subjects.
After multiple oral administrations of NST-1024 QD under fed condition for 14 consecutive days over a dose range of 10 to 200 mg and BID under fasted condition for 14 consecutive days at a dose level of 300 mg, 4 treatment-related TEAEs were reported by 6.3% (3/48) of subjects. Mild abdominal pain lower and mild diarrhoea were reported by 1 subject who received 60 mg QD NST-1024 and mild nausea was reported by 1 subject who received 10 mg QD NST-1024. Mild dysgeusia was reported by 1 subject who received 300 mg BID NST-1024. No treatment-related TEAEs were reported by any subjects administered 30 mg QD or 200 mg QD under fed conditions.
There were no serious AEs or deaths after single or multiple oral dose administrations in this study. No subjects were discontinued due to a treatment-related TEAE. All treatment-related TEAEs resolved without intervention by the end of the study.
There were no treatment related trends identified or clinically significant findings in the clinical laboratory evaluations, vital signs data, safety 12 lead ECG data, or physical examinations after single or multiple dose administrations during the study.
The follow-up visit for 1 subject in the single dose portion of the study who received placebo was delayed due to positive SARS-CoV-2 test and the subject was ultimately lost to follow up. One subject who received 200 mg QD in the multiple dose portion of the study was discontinued from the study after 9 of 14 days of planned dose administration due to positive SARS-CoV-2 test.
Overall, single oral doses of NST-1024 over a dose range of 10 to 400 mg under fasted condition and at dose levels of 30 and 100 mg under fed condition and multiple doses of NST 1024 for 14 consecutive days over a dose range of 10 to 200 mg QD under fed condition and at a dose level of 300 mg BID under fasted condition were safe and well tolerated. Maximum tolerated dose was not determined.
Pharmacokinetic results:
Single doses of 10 to 400 mg NST-1024 under fasted condition exhibited approximately dose-proportional (or slightly less than proportional) PK; single and multiple doses of 10 to 200 mg NST-1024 QD under fed condition exhibited increases in exposure that were somewhat greater than dose-proportional. Following administration of single doses of 10 to 400 mg NST-1024 (fasted), median tmax occurred between 1.0 and 3.0 hours postdose; on Day 14 following administration of multiple doses of 10 to 200 mg NST-1024 QD (fed), median tmax occurred between 1.5 and 4.0 hours postdose. Geometric mean t1/2 ranged from approximately 3.6 to 9.8 hours following administration of single doses of 10 to 400 mg NST 1024 (fasted) and from approximately 4.5 to 11.8 hours on Day 14 following multiple doses of 10 to 200 mg NST-1024 QD. Unchanged NST-1024 was not excreted at a measurable level in urine, as concentrations for all samples collected following both single and multiple dose administrations were below the limit of quantification (BLQ). There was no notable evidence for accumulation of NST-1024 in plasma following multiple doses of 10 and 200 mg NST-1024 QD for 14 days, with mean accumulation ratios ranging between 1.05 and 1.17 at the 10 mg QD dose level and 0.933 and 1.01 at the 200 mg QD dose level. Predose samples collected throughout 2 weeks of daily dosing were relatively stable at all doses, suggesting Day 14 PK results are representative of steady state.
Following administration of 300 mg BID under fasted conditions, absorption was similar to repeat administration in the fed state, with median tmax of 2.0 and 2.5 hours postdose on Days 1 and 14, respectively. Following the trend of increasing t1/2 with increasing dose, geometric mean t1/2 was 15.3 hours on Day 14 (measured through 72 hours). Mean accumulation ratios based on AUC0-τ and Cmax were 0.891 and 0.822, respectively, lower than would be expected for the dosing interval and t1/2 estimate.
When a single dose of 30 mg NST-1024 was administered in the fed state, tmax was delayed by approximately 1.75 hours and there was a decrease in Cmax of approximately 42% when compared to administration of a single dose of 30 mg NST-1024 in the fasted state. The AUC0-∞ and AUC0-tlast in the fed state were comparable to that found in the fasted state, and the 95% CI spanned unity for these PK parameters. Food effect results at 30 mg may not extend reliably to higher single or repeat doses, specifically with regard to trends in Cmax.
Generally, there was low to moderate between-subject variability in AUCs and Cmax observed across all single and multiple ascending dose groups in this study.
Pharmacodynamic results:
Based on the percentage changes from baseline in lipid and apolipoprotein parameters analysed using a mixed model, there were no notable differences between NST 1024 and placebo for the majority of the results following repeat dose administrations, with some exceptions where the difference was found to be statistically significant (eg, total cholesterol and TG at 1 or 2 timepoints for subjects administered 10 mg QD under fed condition; VLDL C for subjects administered 30 mg QD under fed condition; ApoB for subjects administered 200 mg QD under fed condition; or for ApoA1 and ApoC3 at 1 timepoint for subjects administered 200 mg QD under fed condition).
Based on the percentage changes from baseline in glycemic control parameters analysed using a mixed model, there were no notable differences between NST 1024 and placebo for majority of the results following repeat dose administrations, with exception of C-reactive protein at 1 timepoint for subjects administered 10 mg QD under fed condition where the difference was found to be statistically significant.Conclusions:
• Single oral doses of 10 to 400 mg under fed and fasted condition were safe and well tolerated by healthy male and female subjects.
• Multiple oral doses of 10 to 200 mg QD under fed condition and 300 mg BID under fasted condition over 14 consecutive days were safe and well tolerated by healthy male and female subjects.
• All treatment-related TEAEs were mild and resolved without treatment. None of the subjects had a severe TEAE or serious adverse event during the study and no subjects were discontinued due to a treatment-related TEAE.
• There were no treatment-related trends identified and no clinically significant findings in the clinical laboratory evaluations, vital signs data, safety 12 lead ECG data, or physical examinations during the study.
• Single doses of 10 to 400 mg NST-1024 under fasted conditions exhibited approximately dose proportional (or slightly less than proportional) PK, while single and multiple doses of 10 to 200 mg NST 1024 QD under fed conditions exhibited increases in exposure that were somewhat more than dose proportional.
• Following administration of single doses of 10 to 400 mg NST-1024 under fasted condition, median tmax occurred between 1 and 3 hours postdose. On Days 1 and 14 following administration of single or multiple doses of 10 to 200 mg NST-1024 QD under fed conditions and 300 mg NST-1024 BID under fasted conditions, median tmax occurred between approximately 2 and 4 hours postdose.
• Geometric mean t1/2 ranged from approximately 4 to 10 hours following administration of single doses of 10 to 400 mg NST-1024 under fasted condition and from approximately 5 to 15 hours on Day 14 following multiple doses of 10 to 200 mg NST-1024 QD under fed condition and 300 mg NST-1024 BID under fasted condition. Estimates of t1/2 increased with increasing dose.
• Administration of a single dose of 30 mg NST-1024 in the fed state resulted in tmax being delayed by approximately 1.75 hours and a decrease in Cmax of approximately 42%. Exposure based on AUCs was comparable between fed and fasted condition, indicating an absence of significant effect of food on NST-1024.
• Unchanged NST-1024 was not excreted at a measurable level in urine, as concentrations for all samples collected following both single and multiple dose administrations were BLQ.
• NST-1024 exhibited no notable accumulation in plasma following multiple doses of 10 to 200 mg QD under fed condition and 300 mg NST-1024 BID under fasted condition for 14 days, with mean accumulation ratios of approximately 0.82 to 1.2. The lowest accumulation ratios were observed for the highest dose level.
• Predose samples were relatively stable throughout 2 weeks of daily (or BID) administration; Day 14 PK assessments appear representative of steady state levels of NST-1024 at all doses evaluated.
• Low to moderate between-subject variability in AUCs and Cmax was observed across all single and multiple dose groups, with geometric coefficient of variation ≤30% for the majority of values.
• In the multiple-ascending dose part of this first-in-human study, NST 1024 had limited effect on lipid and apolipoprotein parameters following 14-day repeat dose administrations in healthy subjects and healthy subjects with elevated TG.
• In the multiple-ascending dose part of this first-in-human study, NST 1024 had limited effect on glycemic control parameters following 14-day repeat dose administrations in healthy subjects and healthy subjects with elevated TG.REC name
North East - York Research Ethics Committee
REC reference
20/NE/0084
Date of REC Opinion
21 Aug 2020
REC opinion
Further Information Favourable Opinion