INCB 00928-101 single ascending dose and food effect study in healthy participants

36 evidence topics · 4 sources

Objective

Safety, pharmacokinetic, and food effect objectives

“The objectives of these studies were to evaluate zilurgisertib pharmacokinetics, safety, tolerability, and the effect of food in healthy participants from phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) studies.” (opens the source at this quote in a new tab)
“A further primary objective of the SAD study was determination of the effect of food on zilurgisertib pharmacokinetics.” (opens the source at this quote in a new tab)

Cardiac safety objective of the pooled concentration-QTc analysis

“The objective of this analysis was to evaluate the effect of zilurgisertib on QT intervals using a model based approach, as well as to assess other electrocardiogram (ECG) parameters, based on PK and ECG data collected during the phase 1 SAD and MAD studies in healthy adult participants.” (opens the source at this quote in a new tab)

Location and study date

Study sites and dosing period

“Ninety-one participants were enrolled into the SAD study at 2 sites in the United States and received ≥ 1 dose of zilurgisertib or placebo between November 24, 2019, and December 19, 2020.” (opens the source at this quote in a new tab)

Study design

Randomized, double-blind, placebo-controlled first-in-human design

“These were phase 1, randomized, double-blind (participants and investigators blinded, sponsor unblinded), placebo-controlled studies to determine safety, tolerability, and pharmacokinetics associated with single ascending doses (SAD) or multiple ascending doses (MAD) of oral zilurgisertib in healthy adults.” (opens the source at this quote in a new tab)
“The SAD was a multicenter study, and the MAD was a single-center study.” (opens the source at this quote in a new tab)

Two-part design with a crossover food effect cohort

“The SAD study (INCB 00928-101) was composed of 2 parts. In part 1, tolerability and pharmacokinetics of zilurgisertib were assessed under fasted conditions.” (opens the source at this quote in a new tab)
“Cohort 8 was to explore a single to-be-decided dose (e.g., if a dose level needed to be repeated, alternate dosing regimens explored, or further dose escalation allowed to proceed); this cohort was optional and not enrolled.” (opens the source at this quote in a new tab)
“A total of 12 healthy adult participants were enrolled into cohort 9 and randomized to receive a single oral dose of zilurgisertib 100 mg, after either an overnight fast or a high-fat meal, in a 2-way crossover manner with a 7-day washout period between drug administrations.” (opens the source at this quote in a new tab)

Continuous Holter electrocardiogram monitoring

“ECG was performed continuously from 4 hours pre dose to 24 hours post dose on day 1 (all cohorts) and day 8 (cohort 9 only) in the SAD study, and from 4 hours pre dose through 24 hours post dose on days 1 and 10 in the MAD study.” (opens the source at this quote in a new tab)

Eligibility criteria

Healthy adults aged 18 to 55 years

“Eligible participants were men and women, 18–55 years of age, with a body mass index between 18 and 30 kg/m2, assessed to be in good health based on their medical history and physical examinations, including vital signs, electrocardiogram (ECG), and clinical laboratory test results.” (opens the source at this quote in a new tab)
“Applicants with hemoglobin levels and white blood and platelet counts below the lower reference limit for the parameters were excluded.” (opens the source at this quote in a new tab)
“Use of any medications known to affect cytochrome P450 enzymes or P-glycoprotein activity was prohibited within 30 days or 5 half-lives (whichever was longer) before study start and throughout the study.” (opens the source at this quote in a new tab)

Treatment

Single oral doses of 10 to 500 mg or placebo

“Healthy adult participants were enrolled in 7 cohorts at dose levels of 10, 25, 50, 100, 175, 250, and 500 mg and were randomized to receive either a single dose of zilurgisertib or placebo, both in tablet form, in an approximately 3:1 ratio.” (opens the source at this quote in a new tab)
“Both studies used a tablet formulation of the study drug, with doses comprising 5-mg or 25-mg tablets.” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using adverse events and plasma pharmacokinetic parameters as the primary endpoints

Safety and pharmacokinetic primary objectives

“The primary objectives of both studies included determination of safety and tolerability of zilurgisertib, in either single (SAD study) or multiple (MAD study) ascending doses, as assessed by monitoring the frequency and severity of adverse events (AEs), physical examinations, vital signs, 12-lead ECGs, telemetry, and analysis of clinical laboratory data.” (opens the source at this quote in a new tab)
“Additional primary objectives were analysis of zilurgisertib pharmacokinetics following administration in the fasting state after either a single dose (SAD study) or multiple escalating doses (MAD study).” (opens the source at this quote in a new tab)

Secondary urine and exploratory saliva pharmacokinetic endpoints

“Secondary objectives of both studies were the characterization of additional plasma pharmacokinetic parameters, including apparent terminal half-life (t½), apparent oral dose clearance (CL/F), apparent oral dose volume of distribution (Vz/F), and apparent terminal elimination constant (ke), as well as urine pharmacokinetic parameters including amount of drug excreted in urine over 96 h (Ae0-96h; MAD study) or 144 h (SAD study) and renal clearance (CLR).” (opens the source at this quote in a new tab)
“Exploratory objectives of both studies included analysis of preliminary salivary pharmacokinetics, including salivary clearance after single or multiple doses of zilurgisertib in the SAD and MAD studies, respectively.” (opens the source at this quote in a new tab)

Saliva sampling as an alternative matrix for people with FOP

“Saliva is an attractive alternative to blood for drug monitoring and pharmacokinetic analysis, as it is non-invasive to retrieve. This is beneficial for patients, such as those with FOP, for whom blood draws can be challenging due to soft tissue damage susceptibility that can cause progressive heterotopic ossification, and for whom tourniquet time and blood draws must be minimized.” (opens the source at this quote in a new tab)

Saliva bioanalytical method for zilurgisertib

“Incurred sample reanalysis (ISR) using a successfully validated method failed in a healthy volunteer study because of inhomogeneous INCB000928 concentration across sample tube depths. Individual mixing of sample tubes followed by immediate aliquoting corrected the ISR failure, with 97.2% of repeats passing versus 41.7% for the same ISR samples.” (opens the source at this quote in a new tab)

Individualized QT correction as the primary cardiac endpoint

“As both studies indicated a dose‐dependent effect of zilurgisertib on heart rate, individualized QT correction (QTcI) was used as the primary endpoint for QTc analysis.” (opens the source at this quote in a new tab)
“Given the results of the present analysis, the waiver for thorough QT study has been approved by the FDA.” (opens the source at this quote in a new tab)

Food effect cohort as the ECG assay sensitivity control

“The effect of food on QTc was used to demonstrate ECG assay sensitivity, because administration of food shortens the QTc by 5‐10 ms, with the maximum effect occurring approximately 2‐4 hours after a meal.” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

Planned cohort size and its basis

“All cohorts were to have approximately 12 participants (9 participants in each cohort receiving zilurgisertib and 3 receiving matching placebo).” (opens the source at this quote in a new tab)
“Cohort sample sizes were determined empirically and not derived from statistical power calculations, per other initial safety and tolerability studies of a similar nature” (opens the source at this quote in a new tab)

Participants randomized and analyzed

“Overall, 91 participants (70 active, 21 placebo) were enrolled and randomized to the SAD study and 79 participants (59 active, 20 placebo) were enrolled and randomized to the MAD study.” (opens the source at this quote in a new tab)
“Ninety-one participants were included in the safety population and 70 participants were included in the pharmacokinetic population (58 in cohorts 1–7 and 12 in cohort 9).” (opens the source at this quote in a new tab)

Description of analysis sets

Safety and pharmacokinetic-evaluable populations

“The safety population included all randomized participants who received ≥ 1 dose of zilurgisertib or placebo. Treatment groups were determined per protocol. The pharmacokinetic-evaluable population included all participants who received ≥ 1 dose of zilurgisertib and provided ≥ 1 post-dose plasma pharmacokinetic sample.” (opens the source at this quote in a new tab)

Dose proportionality and food effect analyses

“Dose proportionality of zilurgisertib was assessed by a power model that regresses the natural log-transformed pharmacokinetic parameters (Cmax, AUC0-t, AUC0-inf, and AUC0-tau, as deemed appropriate) against the natural log-transformed doses.” (opens the source at this quote in a new tab)
“Food effect on plasma pharmacokinetics after a single dose of zilurgisertib 100 mg was evaluated by ANOVA using a mixed-effects model with fast/fed status, sequence, and period as fixed effects and participant as a random effect fitted to the log-transformation of plasma exposures (Cmax, AUC0-t, and AUC0-inf).” (opens the source at this quote in a new tab)

QT/QTc and PK/QTc populations

“Categorical and central tendency analyses were conducted in the QT/QTc population, comprising all participants in the safety population with continuous ECG measurements at baseline and on treatment. The C‐QTc analysis was conducted in the PK/QTc population, which comprised all participants who were in the QT/QTc population and the PK‐evaluable population plus participants treated with placebo with at least one pair of time‐matched post‐baseline PK and QTc data.” (opens the source at this quote in a new tab)
“The PK/QTc data from cohort 9 of the SAD study (12 participants fed with high‐fat meals) were excluded from the ECG central tendency analysis and the primary C‐QTc analysis but were analyzed in the sensitivity analysis of food effects on QTc shortening.” (opens the source at this quote in a new tab)

Results

Participant disposition

Allocation by cohort and completion

“Nine participants each were allocated to the 10-, 25-, 50- (cohorts 1–3), 175-, and 250-mg (cohorts 5, 6) fasted groups; 7 to the 100-mg (cohort 4) fasted group; and 6- to the 500-mg (cohort 7) fasted group. Twelve participants were allocated to the 100-mg fasted and fed group (cohort 9) and 21 patients in total received placebo. Ninety participants completed the study. One participant from the 100-mg fasting cohort completed treatment but was lost to follow-up on day 7.” (opens the source at this quote in a new tab)

Baseline characteristics

Sex, age, and body mass index

“Overall, 64% of participants in the SAD study and 67% in the MAD study were male. Mean [standard deviation (SD)] age of participants was 36.1 (9.2) years and 35.3 (8.4) years and mean (SD) body mass index was 25.8 (2.8) kg/m2 and 26.4 (2.5) kg/m2 in the SAD and MAD studies, respectively.” (opens the source at this quote in a new tab)

Sex distribution reported in the cardiac safety analysis

“Overall, 91 participants in the SAD study and 79 participants in the MAD study provided at least one pair of zilurgisertib PK and ECG data. In the SAD study, most participants (63.7%) were female, whereas in the MAD study, the majority (67.1%) were male” (opens the source at this quote in a new tab)

Efficacy results

Single-dose plasma pharmacokinetics under fasting conditions

Dose	n	Cmax, geometric mean (geometric %CV), nM	AUC0-inf, geometric mean (geometric %CV), h·nM	t½, geometric mean (geometric %CV), h
10 mg	“9”	“32.0 (23%)”	“779 (24%)”	“23.1 (23%)”
25 mg	“9”	“87.4 (40%)”	“2040 (29%)”	“25.9 (14%)”
50 mg	“9”	“179 (25%)”	“3790 (21%)”	“30.2 (21%)”
100 mg	“7”	“416 (28%)”	“8670 (24%)”	“29.1 (25%)”
175 mg	“9”	“892 (26%)”	“18,800 (15%)”	“31.4 (13%)”
250 mg	“9”	“1320 (40%)”	“25,600 (29%)”	“30.3 (14%)”
500 mg	“6”	“2460 (28%)”	“50,500 (18%)”	“25.3 (13%)”

Absorption, half-life, and dose proportionality

“Zilurgisertib was absorbed rapidly at all dose levels. Median plasma tmax ranged from 2.0 to 4.1 h and was 2 h with doses ≥ 100 mg, the proposed clinically relevant dose.” (opens the source at this quote in a new tab)
“Geometric mean t½ was consistent across all 7 dose levels [range, 23.1 (10-mg cohort) to 31.4 h (175-mg cohort)] and overall geometric mean t½ was 27.8 h.” (opens the source at this quote in a new tab)
“The exponents on dose from the power function regression were 1.1 for Cmax, AUC0-t, and AUC0-inf, and 90% CIs excluded unity in all cases” (opens the source at this quote in a new tab)

Food effect: single 100 mg dose, fasted and after a high-fat meal

Condition	n	Cmax, geometric mean (geometric %CV), nM	tmax, median (range), h	AUC0-inf, geometric mean (geometric %CV), h·nM
100 mg fasted	“12”	“392 (27%)”	“3.0 (2.0–5.0)”	“9090 (22%)”
100 mg fed	“12”	“383 (19%)”	“4.0 (1.0–5.0)”	“9370 (20%)”

Geometric mean ratios for fed versus fasted administration

“Median tmax was not significantly different with and without food (4 h versus 3 h; p = 0.2788). ANOVA analysis of Cmax, AUC0-t, and AUC0-inf also showed no significant impact of food, sequence, or period on the pharmacokinetics of single dose administration of zilurgisertib. GMRs (90% CI) for Cmax, AUC0-t, and AUC0-inf were 0.98 (0.91–1.06), 1.03 (0.97–1.10), and 1.03 (0.97–1.10), respectively” (opens the source at this quote in a new tab)

Label statement on absorption and food effect

“Following a single dose of 100 mg zilurgisertib in healthy subjects, the median (minimum to maximum) time to peak zilurgisertib plasma concentration (Tmax) was 2.1 hours (2.0 to 4.0 hours).” (opens the prescribing information at this quote)
“Administration of a single dose of 100 mg zilurgisertib with a high-fat, high-calorie meal (50% calories from fat) had no clinically meaningful effect on zilurgisertib pharmacokinetics.” (opens the prescribing information at this quote)

Renal clearance after a single dose

“Renal clearance was similar across all dose levels in both studies. Geometric mean CLR was 3.6 L/h with single doses, and 4.3 L/h with multiple doses. In the SAD study, CLR accounted for 18% of the total CL/F.” (opens the source at this quote in a new tab)

Saliva and plasma concentration correlation

“Strong correlation was seen between plasma and saliva zilurgisertib concentrations and exposure with both single (Supplementary Fig. S2) and multiple doses (Fig. 5); r2 values ranged from 0.9 to 1.0 in the SAD study and from 0.7 to 0.9 in the MAD study (Table 5).” (opens the source at this quote in a new tab)
“Saliva zilurgisertib Cmax and AUC values were approximately 2.1- and 2.5-fold higher, respectively, with single doses and 3.1- and 2.7-fold higher with multiple doses than in plasma” (opens the source at this quote in a new tab)

Health-related quality of life and patient-reported outcomes

Not applicable.

Safety results

Treatment-emergent adverse events

“In total, TEAEs were reported for 28 participants (31%) during the SAD study [zilurgisertib, n = 23 (33%); placebo, n = 5 (24%)]” (opens the source at this quote in a new tab)
“TEAEs reported in the SAD study were similar across cohorts 1, 3, 4, 5, and 7 (range, 17–29%) and were possibly elevated in cohorts 2 (25 mg) and 6 (250 mg) (range, 44–67%). These differences should be interpreted with caution due to the small cohort sizes. TEAEs were similar between the fasted and fed participants in cohort 9 (1 participant, 8% vs. 3 participants, 25%).” (opens the source at this quote in a new tab)
“Ten participants (11%) reported 14 treatment-related TEAEs (TRAEs) in the SAD study (all n = 1)” (opens the source at this quote in a new tab)

Serious adverse events, dose-limiting toxicities, and discontinuations

“No dose-limiting toxicities were observed and no deaths occurred during either study. No TEAEs led to study drug discontinuation, interruption, or reduction in the SAD study.” (opens the source at this quote in a new tab)
“One serious TEAE was reported in the SAD study (pneumonia, grade 3, beginning on study day 15 and considered unrelated to zilurgisertib); the participant required hospitalization before the pneumonia resolved on day 24. All other TEAEs across both studies were grade 1 or 2. No notable trends or treatment-emergent safety concerns emerged from clinical laboratory tests or monitoring of vital signs and 12-lead ECGs in either study.” (opens the source at this quote in a new tab)

Heart rate and QTcI central tendency after single doses

“LSMs (90% CI) of ΔΔHR were higher than ±5 (1.84, 12.50) bpm at 6, 8, and 12 hours after study drug administration for the 500‐mg dose group in the SAD study” (opens the source at this quote in a new tab)
“In the SAD study, the highest upper limit of 90% CIs of the LSM ∆∆QTcI was 12.3 ms in the dose group of 250 mg at the 8 hours post treatment timepoint.” (opens the source at this quote in a new tab)
“All participants except for 2 in the SAD study had baseline and post‐treatment PR ≤200 ms. There was no dose dependence in incidence of QRS >100 ms.” (opens the source at this quote in a new tab)

Concentration-QTc model pooled with the multiple ascending dose study

“The estimated population slope of the C‐ΔQTcI relationship was shallow at 0.02 ms per µm (standard error [SE], 0.319; 90% CI, −0.60, 0.65), which was not statistically significantly different from 0, and treatment effect–specific intercept was also small and non‐significant (−0.83 ms [SE, 0.728]; 90% CI, −2.26, 0.61).” (opens the source at this quote in a new tab)
“At no dose level did the upper limit of the two‐sided 90% confidence band of the predicted QT effect exceed 5 ms across the observed range of zilurgisertib concentrations in this study (i.e. up to 7420 nm [or 3732 ng/mL]).” (opens the source at this quote in a new tab)

ECG assay sensitivity in the food effect cohort

“In the assay sensitivity analysis by food effect (cohort 9 of the SAD study), estimated effects of a high‐fat breakfast on LSM (90% CI) of ΔQTcI were −11.7 (−15.59, −7.81) ms and −8.6 (−12.46, −4.76) ms at 2 and 4 hours post dose. Estimated 90% CIs for these effects were <0, and thus ECG assay sensitivity was considered to have been established.” (opens the source at this quote in a new tab)

Label statement on cardiac electrophysiology

“Clinically significant QT interval prolongation was not observed at concentrations up to 6.7 times the mean maximum concentrations achieved with the recommended daily dose of ATEBRIOZ.” (opens the prescribing information at this quote)

Study limitations

Summary: limitations of the single ascending dose study

The study enrolled 91 healthy adults aged 18 to 55 years with a body mass index of 18 to 30 kg/m2, so it provides no pharmacokinetic or safety data in people with fibrodysplasia ossificans progressiva or in participants younger than 18 years, although the labeled population begins at 12 years of age. Dose cohorts held 6 to 12 participants each, and cohort sizes were set empirically without power calculations; the authors state that the higher adverse event rates in the 25 mg and 250 mg cohorts should be interpreted with caution because of the small cohort sizes. The food effect was tested at one dose (100 mg) in 12 participants. Zilurgisertib increased heart rate in a dose-dependent manner, so the cardiac analysis replaced the planned Fridericia correction with an individualized correction; the concentration-QTc analysis pooled this study with the multiple ascending dose study and served in place of a thorough QT study. The two publications from this study report different sex distributions for the same 91 participants: 64% male in the pharmacokinetic report and 63.7% female in the cardiac safety report.