INCB 00928-102 multiple ascending dose study in healthy participants

24 evidence topics · 2 sources

Objective

Safety, tolerability, and pharmacokinetics after repeated dosing

“The MAD study (INCB 00928-102) assessed tolerability and pharmacokinetics of zilurgisertib after multiple doses in healthy volunteers under fasted conditions.” (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 site and dosing period

“In the MAD study, 79 participants were enrolled at 1 site in the United States and received ≥ 1 dose of zilurgisertib or placebo between October 20, 2021, and January 3, 2022.” (opens the source at this quote in a new tab)

Study design

Randomized, double-blind, placebo-controlled, single-center 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)

Ten-day dosing with a twice-daily cohort

“BID dosing was used to reduce the total number of tablets required to be taken by participants at one time.” (opens the source at this quote in a new tab)
“Participants received study medication for 10 days.” (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)
“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

Once-daily doses of 50 to 400 mg or 300 mg twice daily

“Healthy adult participants were enrolled in 6 cohorts (cohorts 1–5 up to 12 participants, cohort 6 up to 20 participants) at dose levels of 50, 100, 150, 200, and 400 mg once daily (QD) or 300 mg twice daily (BID) approximately 12 h apart, and were randomized to receive either zilurgisertib tablets or placebo tablets in an approximately 3:1 ratio.” (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)
“Plasma pharmacokinetic parameters were assessed via evaluation of maximum plasma drug concentration (Cmax), time to Cmax (tmax), area under the plasma concentration–time curve (AUC) from time 0 to the last measurable concentration at time t (AUC0-t) analyzed after the first dose of the study drug (single dose, both studies) and at steady state (MAD study only), AUC over the dosing interval (AUC0-tau; MAD study only), and AUC extrapolated to infinity (AUC0-inf; SAD study only).” (opens the source at this quote in a new tab)

Accumulation analysis

“Accumulation of plasma exposure on day 10 versus day 1 in the MAD study was evaluated using ANOVA on log-transformed pharmacokinetic parameters [Cmax, AUC0-24h (QD regimens), or AUC0-12h (BID regimen) on day 1, and Cmax and AUC0-tau on day 10].” (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)

Statistical analysis description

Number of participants (Planned and analyzed)

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)
“Seventy-nine participants were included in the safety population; 59 of these received zilurgisertib and were included in the pharmacokinetic population.” (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)
“Only participants with pharmacokinetic data on both days 1 and 10 were included in the statistical analysis of accumulation.” (opens the source at this quote in a new tab)

Pooled concentration-QTc analysis set

“The final concentration‐ΔQTcI (C‐ΔQTcI) analysis was performed with pooled data from both studies (days 1 and 10).” (opens the source at this quote in a new tab)

Results

Participant disposition

Completion and withdrawals

“Seventy-seven participants completed the study. Two participants from cohort 6 (300 mg BID) were withdrawn from the study due to treatment-emergent AEs (TEAEs); 1 participant was withdrawn after 5 doses of zilurgisertib (2.5 days of 300 mg BID dosing) due to hypersensitivity and 1 participant was withdrawn after single doses of zilurgisertib 300 mg on days 1 and 3 due to tachycardia.” (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)

Efficacy results

Day 10 steady-state plasma pharmacokinetics

Dose	n	Cmax, geometric mean (geometric %CV), nM	AUC0-24h, geometric mean (geometric %CV), h·nM	t½, geometric mean (geometric %CV), h
50 mg QD	“9”	“375 (31%)”	“5430 (21%)”	“26.6 (11%)”
100 mg QD	“8”	“605 (36%)”	“8880 (36%)”	“27.5 (8%)”
150 mg QD	“9”	“1450 (18%)”	“19,500 (12%)”	“24.0 (11%)”
200 mg QD	“9”	“1840 (24%)”	“26,500 (25%)”	“25.6 (15%)”
400 mg QD	“9”	“4250 (22%)”	“67,100 (24%)”	“26.1 (11%)”
300 mg BID	“12”	“4690 (29%)”	“86,500 (28%)”	“22.8 (13%)”

Dose proportionality, half-life, and time to steady state

“Exponents (90% CIs) on dose from the power function regression were 1.1 (1.0–1.2) for both Cmax and AUC0-t following a single dose and 1.2 (1.1–1.3) and 1.2 (1.1–1.3) for Cmax and AUC0-24h, respectively, after multiple doses.” (opens the source at this quote in a new tab)
“Plasma t½ geometric mean (range) was 25.2 h (22.8–27.5) and values were similar across all dose levels. Steady state was achieved by day 5.” (opens the source at this quote in a new tab)

Accumulation after repeated dosing

“Following multiple QD zilurgisertib dose administrations, geometric mean accumulation ratios (based on ANOVA) ranged from 1.7 to 2.1 and from 1.9 to 2.6, respectively, for Cmax and AUC with zilurgisertib QD, and were approximately 3.1 and 3.8, respectively, for plasma Cmax and AUC with zilurgisertib 300 mg BID.” (opens the source at this quote in a new tab)

Urinary excretion of unchanged drug

“Overall, geometric mean fraction of the total dose excreted in urine was 16% and 27% with single and multiple doses, respectively, showing that renal elimination of the parent molecule was not the predominant route.” (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 and treatment-related adverse events

“32 participants (41%) during the MAD study [zilurgisertib, n = 27 (46%); placebo, n = 5 (25%)]” (opens the source at this quote in a new tab)
“In the MAD study, there was no clear dose-related trend in incidence or type of TEAEs reported across dose levels.” (opens the source at this quote in a new tab)
“14 participants (18%) reported TRAEs in the MAD study; [all n = 1, except palpitation [n = 2 (3%)], headache [n = 6 (8%)], nausea [n = 2 (3%)], and dizziness postural [n = 2 (3%)].” (opens the source at this quote in a new tab)
“No dose-related trends were seen in incidence or types of TEAEs across doses, although incidence of TRAEs was slightly higher with the 300 mg BID dose versus the 50–400 mg QD doses in the MAD study.” (opens the source at this quote in a new tab)

Dose interruptions and withdrawals

“In the MAD study, 1 participant experienced grade 1 TEAEs on days 1 and 2, leading to study drug being withheld on days 2 and 3. TEAEs were considered unrelated to the study drug by the investigator.” (opens the source at this quote in a new tab)
“Two participants withdrew from the MAD study due to TEAEs (tachycardia, n = 1; hypersensitivity, n = 1).” (opens the source at this quote in a new tab)

Heart rate and QTcI central tendency after repeated doses

“higher than ±5 (3.56, 9.36) bpm at 4 hours after administration on day 1 of the MAD study for the 300‐mg BID dose group; and at 4 and 6 hours after administration on day 10 of the MAD study for 300 mg BID dose group.” (opens the source at this quote in a new tab)
“On day 1 of the MAD study, the highest upper limit of 90% CIs of the LSM ∆∆QTcI was 17.4 ms in the dose group of 50 mg QD at the 16 hour post‐dosing timepoint; on day 10, the highest upper limit of 90% CIs of the LSM ∆∆QTcI was 16.4 ms in the dose group of 50 mg QD at the 16 hour post‐dosing timepoint.” (opens the source at this quote in a new tab)

Predicted QT effect at the highest exposure studied

“−0.71 ms (90% CI, −2.99, 1.57) at 4690 nm (or 2359 ng/mL), the highest observed geometric mean of peak zilurgisertib plasma concentrations after 300 mg BID” (opens the source at this quote in a new tab)
“The mean observed zilurgisertib plasma concentrations at 100 mg QD (0.61 µm [or 0.3 µg/mL]) are expected to be approximately 12‐fold lower than the highest concentration (7.4 µm [or 3.7 µg/mL]) studied in this analysis and thus no cardiac safety concerns are anticipated.” (opens the source at this quote in a new tab)
“A QT effect exceeding the threshold of concern (10 ms) can be excluded for zilurgisertib plasma concentrations up to 7.4 µm (or 3.7 µg/mL).” (opens the source at this quote in a new tab)

Study limitations

Summary: limitations of the multiple ascending dose study

The study enrolled 79 healthy adults aged 18 to 55 years at a single United States site and dosed them for 10 days, so it does not describe exposure or safety over the long-term daily use intended in fibrodysplasia ossificans progressiva, or in participants younger than 18 years. Cohorts held 9 to 12 participants receiving zilurgisertib. Exposure rose more than dose-proportionally, with power-model exponents of 1.2 for Cmax and AUC0-24h after multiple doses. Two of the 79 participants, both in the 300 mg twice-daily cohort, withdrew for adverse events (tachycardia and hypersensitivity), and heart rate increased at that dose, so the cardiac analysis used an individualized QT correction. The concentration-QTc conclusions rest on pooled data from this study and the single ascending dose study.