Registered study purpose

“This Phase 2, Randomized, Double-Blind, Placebo-Controlled Study is intended to evaluate the Efficacy, Safety, and Tolerability and PK of INCB000928 administered to participants with a clinical diagnosis of fibrodysplasia ossificans progressiva (FOP).” (opens the source at this quote in a new tab)

Objective of the Cohort 1 interim analysis

“PROGRESS is a phase 2, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of zilurgisertib for FOP (Figure 1)” (opens the source at this quote in a new tab)
“Here, we present interim analysis of the phase 2 PROGRESS trial evaluating zilurgisertib in patients ≥12 years of age with FOP through 48 weeks of treatment (24 weeks of placebo-controlled treatment, then 24 weeks open-label zilurgisertib)” (opens the source at this quote in a new tab)

Objective stated in the congress abstract

“Assess efficacy and safety of ZGB vs placebo (PBO) in patients (pts) with FOP in the ongoing PROGRESS study (NCT05090891).” (opens the source at this quote in a new tab)

Study status and dates

Registry field	Quoted record
Sponsor	“Incyte Corporation”
Sponsor protocol number	“INCB 00928-201”
Overall status	“Recruiting”
Start date, actual	“2022-05-05”
Primary completion, estimated	“2027-07-30”
Completion, estimated	“2033-01-20”
Enrollment, estimated (all cohorts)	“98”

Registered study sites

Country	Quoted facility
United States	“Mayo Clinic Rochester”
United States	“Children'S Hospital of Philadelphia”
United States	“Penn Medicine - Perelman Center For Advanced Medicine”
Argentina	“Hospital Italiano de Buenos Aires”
Australia	“Royal North Shore Hospital”
Australia	“Murdoch Children'S Research Institute”
Brazil	“Albert Einstein Israelite Hospital”
Canada	“University Health Network Toronto General Hospital”
Chile	“Centro de Estudios Reumatologicos”
China	“Beijing Childrens Hospital Capital Medical University”
China	“Tongji Hospital of Tongji University”
China	“Shanghai Childrens Medical Center”
China	“Childrens Hospital of Fudan University”
France	“Ap-Hp Hopital Lariboisiere”
France	“Hopital Necker-Enfants Malades”
Germany	“Uniklinik Koln”
Italy	“Policlinico Universitario Agostino Gemelli Universita Cattolica Del Sacro Cuore”
Mexico	“Instituto Nacional de Rehabilitacion Luis Guillermo Ibarra”
Netherlands	“Amsterdam Umc - Vu Medisch Centrum (Vumc)”
New Zealand	“Starship Childrens Hospital”
South Africa	“Groote Schuur Hospital Radiation Oncology”
South Korea	“Seoul National University Hospital”
Spain	“Hospital Universitario Ramon Y Cajal”
United Kingdom	“Royal National Orthopaedic Hospital”

Sponsor and congress presentation of Cohort 1 results

“The PROGRESS study was sponsored by Incyte Corporation (Wilmington, DE, USA).” (opens the source at this quote in a new tab)
“ENDO 2026, Chicago, IL, USA; Presentation ORF37-04.” (opens the source at this quote in a new tab)
“Mirum Pharmaceuticals, Inc. has an exclusive license agreement with Incyte Corporation for worldwide rights to zilurgisertib for fibrodysplasia ossificans progressiva (FOP).” (opens the source at this quote in a new tab)

Enrollment status by cohort

“The PROGRESS development program also continues to advance, with enrollment completed in Cohort 2 of children aged 6 to <12 years, and enrollment underway in Cohort 3 of children aged 2 to <12 years.” (opens the source at this quote in a new tab)

Posted results

No evidence found.

Randomized, double-blind, placebo-controlled period followed by an open-label extension

“The effectiveness of ATEBRIOZ was evaluated in a randomized, double-blind, placebo-controlled trial (Study 1; NCT05090891).” (opens the prescribing information at this quote)
“Sixty-three patients (28 adults and 35 pediatric patients aged 12 years of age and older) with FOP were randomized 1:1 to treatment with ATEBRIOZ 100 mg or placebo once daily for 24 weeks followed by a 292-week open label extension (OLE) period of ATEBRIOZ 100 mg treatment.” (opens the prescribing information at this quote)

Stratified randomization

“Randomization was stratified by baseline CAJIS score (< 18 or 18-23).” (opens the prescribing information at this quote)

“were randomized 1:1 to ZGB 100 mg once daily (QD) or PBO for 24 weeks, stratified by joint function.” (opens the source at this quote in a new tab)

Duration of the open-label extension

“Pts who complete the double-blind (DB) period may enter an open-label extension, assessing longer-term efficacy and safety of ZGB 100 mg QD up to 316 weeks. Results are through Week 48.” (opens the source at this quote in a new tab)

Registry design fields

Design field	Quoted record
Phase	“Phase 2”
Allocation	“Randomized”
Intervention model	“Parallel”
Masking	“Double”
Primary purpose	“Treatment”

Three age cohorts

“Participants (≥ 12 years of age) will receive INCB000928 or placebo as defined in the protocol for 24 weeks (double-blind period). Participants who complete the double-blind period will continue into open-label extension period for an additional 292 weeks.” (opens the source at this quote in a new tab)
“Participants (6 to < 12 years of age) will receive INCB000928 or placebo as defined in the protocol for 24 weeks (double-blind period). Participants who complete the double-blind period will continue into open-label extension period for an additional 292 weeks.” (opens the source at this quote in a new tab)
“Participants (2 to < 12 years of age) will receive INCB000928 or placebo as defined in the protocol for 24 weeks (double-blind period). Participants who complete the double-blind period will continue into open-label extension period for an additional 292 weeks.” (opens the source at this quote in a new tab)

Blinding during the first 24 weeks and crossover to open-label treatment

“Neither patients nor doctors knew who was getting which treatment for the first 24 weeks” (opens the source at this quote in a new tab)
“After 24 weeks, everyone knowingly received zilurgisertib during the open-label extension period” (opens the source at this quote in a new tab)

Inclusion criteria stated in the prescribing information

“Inclusion criteria included clinical diagnosis of FOP, patient-reported FOP disease activity within 1 year of the screening visit (i.e., FOP flare-ups, worsening joint function, or radiographic progression of HO), and a baseline Cumulative Analogue Joint Involvement Scale (CAJIS) score ≤ 23.” (opens the prescribing information at this quote)

Registered inclusion criteria

“Cohort 1: ≥ 12 years of age.” (opens the source at this quote in a new tab)
“Clinical diagnosis of FOP.” (opens the source at this quote in a new tab)
“Willingness to avoid pregnancy or fathering children based on the criteria below.” (opens the source at this quote in a new tab)
“Willing and able to undergo low-dose WBCT (excluding the head) imaging without requiring intubation.” (opens the source at this quote in a new tab)

Registered exclusion criteria

“Pregnant or breast-feeding.” (opens the source at this quote in a new tab)
“CAJIS score ≥ 24.” (opens the source at this quote in a new tab)
“FOP disease severity that in the investigator's opinion precludes participation.” (opens the source at this quote in a new tab)
“Chronic or current active infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment.” (opens the source at this quote in a new tab)
“HIV, HBV, or HCV infection.” (opens the source at this quote in a new tab)

ACVR1 variants eligible for enrollment

“MUTATIONS: R206H and other mutations of the ACVR1 gene resulting in HO” (opens the source at this quote in a new tab)

Study drug, dose, and route

“INCBG000928 will be administered QD orally.” (opens the source at this quote in a new tab)
“Placebo will be administered QD orally.” (opens the source at this quote in a new tab)

“Cohort 1 of the PROGRESS study evaluated zilurgisertib 100 mg once-daily in 63 adolescents and adults (≥12 years of age) with FOP.” (opens the source at this quote in a new tab)

Concomitant and rescue medications for flare-ups

No evidence found.

Label efficacy endpoint: total new HO lesion volume on whole-body CT

“Efficacy was established based on the effect of ATEBRIOZ on total new HO lesion volume (assessed by whole-body computed tomography [WBCT], excluding the head) compared to placebo during the double-blind period.” (opens the prescribing information at this quote)

“Efficacy was established based on total new HO lesion volume. Total new HO lesion volume includes expansion of baseline HO lesion burden as well as any new discrete HO that developed during the 24-week double-blind period.” (opens the source at this quote in a new tab)

“Atebrioz’s efficacy was based on the change from baseline in volume of total new heterotopic ossification compared to placebo during the double-blind period, assessed by whole body CT scans.” (opens the source at this quote in a new tab)

Protocol-specified primary endpoint: occurrence of new HO lesions at Week 24

“Double Blind Period: Occurrence of new heterotopic ossification (HO) lesions from baseline” (opens the source at this quote in a new tab)
“HO will be assessed by low dose whole-body computed tomography (WBCT) (excluding the head) compared to baseline during the double-blind period.” (opens the source at this quote in a new tab)

“The primary endpoint of the study is the proportion of Cohort 1 patients with new heterotopic ossification (HO) lesions at Week 24 as assessed by whole-body CT scan data. Key secondary endpoints include the number and total volume of new HO lesions, changes in total HO lesion volume and flare activity through Week 24.” (opens the source at this quote in a new tab)

“The primary endpoint is proportion of pts with new HO lesions on whole-body CT scan at Week 24. Key secondary endpoints include number and total volume of new lesions, change in total volume of all lesions, and number of flares to Week 24.” (opens the source at this quote in a new tab)

Registered secondary endpoints of the double-blind period

“Double Blind Period: Number of new HO lesions from baseline” (opens the source at this quote in a new tab)
“Double Blind Period: Total volume of new HO lesions from baseline” (opens the source at this quote in a new tab)
“Double Blind Period: Change in the total volume of all HO lesions from baseline” (opens the source at this quote in a new tab)
“Double Blind Period: Number of new flares from baseline” (opens the source at this quote in a new tab)
“Number of Participants with Treatment Emergent Adverse Events (TEAE)” (opens the source at this quote in a new tab)

Registered open-label extension endpoints at Week 48

“Open-Label Extension: Occurrence of new HO lesions from Week 24” (opens the source at this quote in a new tab)
“HO will be assessed by low dose whole-body computed tomography (WBCT) (excluding the head) from Week 24 to Week 48 compared to baseline to Week 24 in participants randomized to placebo during the DB period.” (opens the source at this quote in a new tab)
“Open-Label Extension: Change in the total volume of all HO lesions from Week 24” (opens the source at this quote in a new tab)

Endpoints supporting the new drug application

“In addition, while the NDA for zilurgisertib is supported by secondary endpoints, the pivotal study did not reach statistical significance on the primary endpoint.” (opens the source at this quote in a new tab)

Expert recommendation for volumetric low-dose CT measurement of HO in FOP trials

“Volumetric measurements of ossification via total body (preferred) or site‐specific new HO by low‐dose computed tomography (CT) should be included. This will also allow quantitation of bone formation.” (opens the source at this quote in a new tab)

Natural history rate of new HO accrual on low-dose whole-body CT

“The mean annualized volume of new HO was 23.6 × 103 mm3/year; highest at 8 to <15 and 15 to <25 years (21.9 × 103 and 41.5 × 103 mm3/year, respectively) and lowest at 25 to 65 years (4.6 × 103 mm3/year).” (opens the source at this quote in a new tab)
“Results from individuals receiving standard care for up to 3 years in this natural history study show the debilitating effect and progressive nature of FOP cross-sectionally and longitudinally, with greatest progression during childhood and early adulthood.” (opens the source at this quote in a new tab)

Flare-up endpoint based on a patient-reported instrument

“Based on Fibrodysplasia Ossificans Progressiva - Patient RepOrted syMPtoms Tool (FOP-PROMPT).” (opens the source at this quote in a new tab)

Planned Cohort 1 enrollment

“Cohort 1: Oral zilurgisertib 100 mg QD (n=~60)” (opens the source at this quote in a new tab)

Participants randomized per arm

“Cohort 1 of the PROGRESS study evaluated zilurgisertib 100 mg once-daily in 63 adolescents and adults (≥12 years of age) with FOP. Patients were randomized 1:1 to receive zilurgisertib (n=32) or placebo (n=31) during a 24-week, placebo-controlled, double-blind period, followed by an open-label extension period.” (opens the source at this quote in a new tab)

Adults and pediatric participants

“Sixty-three patients (28 adults and 35 pediatric patients 12 years of age and older) with FOP were randomized to ATEBRIOZ 100 mg (n = 32) or placebo (n = 31) once daily for 24 weeks.” (opens the prescribing information at this quote)

Participants with Week 48 imaging

“A total of 61 patients had 48-week whole-body CT scan data available at the time of the open-label extension analysis.” (opens the source at this quote in a new tab)

Denominators reported for the Week 24 primary endpoint

“At Week 24, 1 of 32 patients in the zilurgisertib group had new lesions versus 5 of 30 patients in the placebo group (primary endpoint, P=0.0986; Figure 2)” (opens the source at this quote in a new tab)

Formal definitions of analysis populations

No evidence found.

Randomization and completion of the double-blind period

“A total of 63 patients were randomly assigned to zilurgisertib (n=32) or placebo (n=31)” (opens the source at this quote in a new tab)
“All patients in the zilurgisertib group completed treatment” (opens the source at this quote in a new tab)
“1 patient in the placebo group discontinued treatment due to patient withdrawal” (opens the source at this quote in a new tab)

Entry into the open-label extension

“62 enrolled in the extension.” (opens the source at this quote in a new tab)

Discontinuations due to adverse events

“No side effects led patients treated with zilurgisertib or placebo to leave the study or stop taking treatment” (opens the source at this quote in a new tab)

Enrolled population described in the prescribing information

“The median age of enrolled patients was 16 years (range: 12 to 64 years), 56% were 12 to 16 years of age, 51% were female, 56% were White, 5% were Black/African American, 29% were Asian, 2% were multiracial, and 10% were race not reported or missing; 19% identified as Hispanic or Latino ethnicity. All patients had a baseline CAJIS score of ≤ 23 and 84% of patients had a score < 18 (range: 2-22). At baseline, the mean (SD) total volume of all HO lesions was 333.3 (257.1) cm3 in the zilurgisertib group and 374.4 (376.5) cm3 in the placebo group.” (opens the prescribing information at this quote)

Demographics and baseline characteristics by arm

Characteristic	Zilurgisertib 100 mg (n=32)	Placebo (n=31)
Age, mean (SD), y	“20.5 (11.7)”	“22.0 (11.0)”
Male, n (%)	“17 (53.1)”	“14 (45.2)”
Race, White, n (%)	“17 (53.1)”	“18 (58.1)”
Race, Asian, n (%)	“8 (25.0)”	“10 (32.3)”
Race, Black, n (%)	“2 (6.3)”	“1 (3.2)”
Race, Multiracial, n (%)	“1 (3.1)”	“0”
Time since initial diagnosis, mean (SD), y	“12.6 (9.9)”	“13.2 (9.1)”
Baseline CAJIS score <18, n (%)	“27 (84.4)”	“26 (83.9)”
Baseline CAJIS score 18-23, n (%)	“5 (15.6)”	“5 (16.1)”
Time since last flare-up, mean (SD), y	“0.7 (0.6)”	“0.4 (0.2)”
Last flare-up location, upper back, n (%)	“4 (12.5)”	“5 (16.1)”
Last flare-up location, lower back, n (%)	“4 (12.5)”	“5 (16.1)”
Last flare-up location, right hip, n (%)	“4 (12.5)”	“4 (12.9)”
Last flare-up location, right leg, n (%)	“2 (6.3)”	“4 (12.9)”
Total volume of HO lesions at baseline, median (range), cm3	“270.0 (21.3–1140.1)”	“265.6 (5.7–1672.0)”

Missing race data

“Data were missing in 2 patients in the zilurgisertib group and 1 patient in the placebo group; data were not reported in 2 patients in the zilurgisertib group and 1 patient in the placebo group.” (opens the source at this quote in a new tab)
“Baseline characteristics and demographics were generally similar between groups (Table 1)” (opens the source at this quote in a new tab)

Summary: label endpoint and protocol primary endpoint

The protocol-specified primary endpoint, the proportion of participants with new HO lesions at Week 24, occurred in 1 of 32 participants (3.1%) receiving zilurgisertib and 5 of 30 participants (16.7%) receiving placebo (P=0.0986), a difference that did not reach statistical significance. The prescribing information establishes efficacy on a different measure, total new HO lesion volume on whole-body CT excluding the head, defined to include expansion of baseline lesions and new discrete HO: the mean change from baseline at Week 24 was −3.2 cm³ (SD 19.9) with zilurgisertib and +24.6 cm³ (SD 51.9) with placebo, a Hodges-Lehmann treatment difference of −15.8 cm³ (95% CI −32.1 to −6.0). The congress poster and the results press release report the volume of new lesions (mean 0.003 cm³ vs 6.57 cm³; nominal P<0.0001) and the change in total lesion volume (mean −3.24 cm³ vs 24.64 cm³; nominal P=0.004) as separate secondary endpoints. Through Week 48, no participant in either original arm had new HO lesions on whole-body CT (n=61).

Label endpoint: total new HO lesion volume at Week 24

“At Week 24, the mean change (SD) from baseline in total new HO volume was −3.2 cm³ (19.9) in the zilurgisertib group and +24.6 cm³ (51.9) in the placebo group, resulting in a Hodges-Lehmann treatment difference of −15.8 cm³ (95% CI: -32.1, -6.0).” (opens the prescribing information at this quote)

“At Week 24, mean total new HO lesion volume decreased by 3.2 cm3 in patients receiving zilurgisertib compared with an increase of 24.6 cm3 in placebo-treated patients. Treatment effects were maintained through Week 48 of the open-label extension.” (opens the source at this quote in a new tab)

Protocol primary endpoint: proportion of participants with new HO lesions at Week 24

“At Week 24, 1 of 32 patients in the zilurgisertib group had new lesions versus 5 of 30 patients in the placebo group (primary endpoint, P=0.0986; Figure 2)” (opens the source at this quote in a new tab)
“81% reduction in proportion of patients with new lesions at Week 24” (opens the source at this quote in a new tab)

“Fewer patients receiving zilurgisertib developed new HO lesions at Week 24, with an 81% reduction versus placebo (p=0.0986).” (opens the source at this quote in a new tab)

“At Week 24, there was an 81.2% reduction in pts with new lesions with ZGB (3.1% [1/32] vs PBO 16.7% [5/30]; P = 0.0986).” (opens the source at this quote in a new tab)

Statistical significance of the primary endpoint

“In addition, while the NDA for zilurgisertib is supported by secondary endpoints, the pivotal study did not reach statistical significance on the primary endpoint.” (opens the source at this quote in a new tab)

Secondary endpoint: number of new HO lesions at Week 24

“Fewer new lesions with ZGB vs PBO at Week 24 (mean [SD]: 0.06 [0.35] vs 0.23 [0.63])” (opens the source at this quote in a new tab)

Secondary endpoint: volume of new HO lesions at Week 24

“Smaller new lesion volume (cm3) with ZGB vs PBO at Week 24 (mean [SD]): 0.003 [0.02] vs 6.57 [20.70]); P<0.0001” (opens the source at this quote in a new tab)

“>99% reduction in total volume of new HO lesions in patients receiving zilurgisertib versus placebo at Week 24 (nominal p-value<0.0001).” (opens the source at this quote in a new tab)

“overall volume (cubic cm) of new lesions was 99.6% (95% CI; 93.6%, 100%) lower (mean [SD], 0.003 [0.02] vs 6.57 [20.71]).” (opens the source at this quote in a new tab)

Secondary endpoint: change in total volume of all HO lesions at Week 24

“From BL to Week 24, mean (SD) total lesion volume (cm3) change was greater with ZGB vs PBO (−3.24 [19.86] vs 24.64 [51.94]); P=0.004” (opens the source at this quote in a new tab)
“Nominal P value.” (opens the source at this quote in a new tab)

“Reduction in total HO lesion volume compared with an increase observed in placebo-treated patients at Week 24 (nominal p-value=0.004).” (opens the source at this quote in a new tab)

“Total lesion volume decreased with ZGB (mean [SD], -3.24 [19.86]), whereas PBO was associated with a marked increase (mean [SD], 24.64 [51.94]).” (opens the source at this quote in a new tab)

Secondary endpoint: annualized new flare-ups through Week 24

“Fewer mean (SD) annualized new flares by Week 24 with ZGB vs PBO (2.34 [6.06] vs 4.55 [7.71])” (opens the source at this quote in a new tab)

Open-label extension through Week 48: new HO lesions

“No patients had new lesions during the OLE period from Week 24 to 48” (opens the source at this quote in a new tab)
“Zilurgisertib had fewer new lesions and smaller new lesion volume compared to placebo at Week 24; at Week 48, both groups (zilurgisertib and placebo crossover to zilurgisertib) exhibited no new lesions” (opens the source at this quote in a new tab)

“During the open-label extension, no new HO lesions were observed among patients who continued to receive zilurgisertib or among placebo-treated patients who crossed over to active treatment at Week 24.” (opens the source at this quote in a new tab)

“In the open-label period, no new lesions were reported regardless of DB treatment assignment.” (opens the source at this quote in a new tab)

Open-label extension through Week 48: total HO lesion volume and flare-ups

“From baseline to Week 24, total lesion volume decreased in the zilurgisertib group but increased in the placebo group, while from Week 24 to 48, total lesion volume decreased from baseline in both groups” (opens the source at this quote in a new tab)

“From Week 24-48, mean [SD] decreases in total volume of all HO lesions were observed in both ZGB-randomized (-6.37 [19.43]) and crossover pts (-5.32 [20.91]). Mean [SD] number of annualized new flares was low for both ZGB-randomized (1.01 [3.26]) and crossover pts (1.22 [2.54]).” (opens the source at this quote in a new tab)

Investigator interpretation of the Week 24 and Week 48 results

“We observed fewer patients developing new HO lesions, a greater than 99% reduction in the volume of new HO lesions, reductions in total HO lesion volume and lower flare activity compared with placebo during the 24-week placebo-controlled period.” (opens the source at this quote in a new tab)

Patient-reported flare-up instrument

“Double Blind Period: Number of new flares from baseline” (opens the source at this quote in a new tab)
“Based on Fibrodysplasia Ossificans Progressiva - Patient RepOrted syMPtoms Tool (FOP-PROMPT).” (opens the source at this quote in a new tab)

Flare-up results in the plain language summary

“Number of yearly new FOP flares was lower with zilurgisertib than placebo (number estimated based on number of flares at Week 24)” (opens the source at this quote in a new tab)

Physical function and health-related quality of life

No evidence found.

Adverse reactions in at least 10% of participants through Week 24

Adverse reaction	Atebrioz (N = 32), n (%)	Placebo (N = 31), n (%)
Headache	“7 (22)”	“5 (16)”
Arthralgia	“7 (22)”	“3 (10)”
Upper respiratory tract infection	“7 (22)”	“3 (10)”
Epistaxis	“4 (13)”	“0”
Nausea	“4 (13)”	“1 (3)”

Adverse reactions in fewer than 10% of participants

“In patients receiving ATEBRIOZ 100 mg orally once daily through Week 24, adverse reactions occurring in < 10% of patients included gastroenteritis, gastroesophageal reflux disease, iron deficiency anemia, rash (3 patients each), and alopecia (2 patients). None of these events were reported in the placebo group.” (opens the prescribing information at this quote)

Iron parameters through Week 100

“Compared to placebo, ATEBRIOZ-treated patients experienced mean increases in serum iron, hemoglobin, and transferrin saturation levels; the mean values for all three measures remained within the normal range. No significant differences in mean ferritin change from baseline was observed between ATEBRIOZ- and placebo-treated patients, including patients who took iron supplements. Based on the data through Week 100, the increases in serum iron and transferrin saturation with ATEBRIOZ were not associated with signs or symptoms of iron overload.” (opens the prescribing information at this quote)

Treatment-emergent adverse events during the 24-week placebo-controlled period

Event	Zilurgisertib 100 mg (n=32), n (%)	Placebo (n=31), n (%)
Any TEAE	“29 (90.6)”	“30 (96.8)”
Treatment-related TEAE	“15 (46.9)”	“11 (35.5)”
Serious TEAE	“2 (6.3)”	“3 (9.7)”
Grade ≥3 TEAE	“2 (6.3)”	“4 (12.9)”
Fatal adverse event	“0”	“0”
Treatment-related serious TEAE	“1 (3.1)”	“0”
TEAE leading to dose interruption	“2 (6.3)”	“1 (3.2)”
TEAE leading to dose reduction or withdrawal	“0”	“0”
FOP flare-up or aching/pain due to FOP	“8 (25.0)”	“17 (54.8)”
Headache	“7 (21.9)”	“5 (16.1)”
Upper respiratory tract infection	“7 (21.9)”	“3 (9.7)”
Arthralgia	“6 (18.8)”	“1 (3.2)”
Epistaxis	“4 (12.5)”	“0”
Nausea	“4 (12.5)”	“1 (3.2)”

Grade 3 or higher events by participant

“No Grade ≥3 TEAEs occurred in more than one patient through Week 24. Zilurgisertib (n=2 patients; [dehydration, dyspnea, gastroesophageal reflux disease, hypotension, nausea, oxygen saturation decreased, pneumonia, urinary tract infection] and skull fracture base); placebo (n=4 patients; [arthralgia, shoulder fracture, back pain, traumatic pain], lipase increased, FOP flareup, and femoral neck fracture).” (opens the source at this quote in a new tab)

Severity, discontinuations, and consistency between adults and adolescents

“Most adverse events (AEs) were mild or moderate through Week 24, and no AEs led to dose reduction or discontinuation of zilurgisertib (Table 2)” (opens the source at this quote in a new tab)
“Safety was similar between adults and adolescents; this was also observed during the OLE” (opens the source at this quote in a new tab)

“Most AEs were mild or moderate. No AEs led to dose reduction or discontinuation with ZGB across both periods.” (opens the source at this quote in a new tab)

Summary: limitations of the PROGRESS Cohort 1 evidence

PROGRESS is a phase 2 trial in which 63 participants were randomized, with a placebo-controlled period of 24 weeks; data after Week 24 come from an open-label extension in which all participants received zilurgisertib, and the Week 48 analysis is reported as interim. The protocol-specified primary endpoint (new HO lesions in 1 of 32 vs 5 of 30 participants; P=0.0986) did not reach statistical significance, and approval rests on a secondary volumetric measure; the poster and results press release label the P values for secondary endpoints as nominal. Endpoint nomenclature differs across sources: the prescribing information reports "total new HO volume" (mean change −3.2 cm³ [SD 19.9] vs +24.6 cm³ [SD 51.9]), while the poster and results press release report "change in total lesion volume" with means and standard deviations (−3.24 [19.86] vs 24.64 [51.94]) that round to the label's values, and report a separate "new lesion volume" endpoint. The standard deviation for new lesion volume in the placebo arm is 20.70 in the poster and results press release and 20.71 in the congress abstract. The label's adverse reaction table and the poster's adverse event table report different arthralgia counts (7 [22%] vs 3 [10%] in the label; 6 [18.8%] vs 1 [3.2%] in the poster). No results are posted on ClinicalTrials.gov and no peer-reviewed publication of PROGRESS was identified; analysis-set definitions, the statistical analysis plan, and the multiplicity procedure are not public. Efficacy has not been established in participants younger than 12 years, and too few participants aged 65 years and older were enrolled to assess response in that group.

Primary endpoint not statistically significant

“In addition, while the NDA for zilurgisertib is supported by secondary endpoints, the pivotal study did not reach statistical significance on the primary endpoint. The FDA may determine that the clinical data for zilurgisertib is not sufficient to approve the NDA for the program.” (opens the source at this quote in a new tab)

Interim analysis with an uncontrolled extension period

“Zilurgisertib in Patients With Fibrodysplasia Ossificans Progressiva: Interim Results From the PROGRESS Study” (opens the source at this quote in a new tab)
“The open-label period of PROGRESS for adolescents and adults is ongoing, and enrollment of younger age groups has begun” (opens the source at this quote in a new tab)

Age groups without established efficacy

“The safety and effectiveness of ATEBRIOZ have not been established in pediatric patients younger than 12 years of age.” (opens the prescribing information at this quote)
“Clinical studies of ATEBRIOZ did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.” (opens the prescribing information at this quote)

Registered objective: safety, pharmacokinetics, pharmacodynamics, and efficacy in anemia due to myelofibrosis

“This Phase 1/2, open-label, dose-finding study is intended to evaluate the safety and tolerability, PK, PD, and efficacy of INCB000928 administered as monotherapy or in combination with ruxolitinib in participants with MF who are transfusion-dependent or presenting with symptomatic anemia.” (opens the source at this quote in a new tab)
“A Phase 1/2 Open-Label, Multicenter Study of INCB000928 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Anemia Due to Myeloproliferative Disorders” (opens the source at this quote in a new tab)

Objective of the final analysis

“Here we present final results from a phase 1/2 study evaluating ALK2 inhibition as a treatment approach for management of MF-related anemia, including safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of the potent and selective oral ALK2 inhibitor zilurgisertib.” (opens the source at this quote in a new tab)

Study identifiers, dates, and status: registry record

Field	Registry record
Sponsor protocol number	“INCB 00928-104”
EudraCT number	“2020-004029-21”
Study start (actual)	“2021-03-19”
Primary completion (actual)	“2025-04-01”
Study completion (estimated)	“2027-11-26”
Enrollment (actual)	“84”
Overall status	“Active, not recruiting”
Results first posted	“2026-05-12”

Study centers and data cutoff for posted results

“This study was conducted in 25 study centers in Canada, France, Italy, Japan, the United Kingdom, and the United States. Data collected through a cut off date of 12 June 2025 have been reported.” (opens the source at this quote in a new tab)

Interim analysis data cutoff

“A total of 36 pts were enrolled at the time of analysis (data cutoff, February 15, 2023), with 20 in TGA and 16 in TGB.” (opens the source at this quote in a new tab)

Registered design details

Design feature	Registry record
Primary purpose	“Treatment”
Allocation	“Non-Randomized”
Interventional model	“Sequential Assignment”
Masking	“None (Open Label)”

Three treatment groups: monotherapy, add-on to ruxolitinib, and ruxolitinib-naive combination

“This open-label, phase 1/2, dose-escalation/expansion study (INCB00928-104/NCT04455841) evaluated zilurgisertib alone (treatment group A [TGA]), as an add-on to the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib (TGB), or with ruxolitinib in JAK inhibitor–naive pts (TGC).” (opens the source at this quote in a new tab)
“Zilurgisertib dose escalation was performed independently in each group, with ≤2-fold dose increases evaluated until identification of maximum tolerated dose (MTD) or recommended dose(s) for expansion.” (opens the source at this quote in a new tab)

Dose-escalation algorithm

“The INCB000928 dose will be escalated using an open-label BOIN design in each defined population, and a safe and tolerable dose(s) RDE(s) will be determined.” (opens the source at this quote in a new tab)
“One cycle will be defined as 28 consecutive days; treatment will consist of repeating 28-day cycles.” (opens the source at this quote in a new tab)

Planned dose-expansion stage not conducted

“Following a strategic decision (not based on safety concerns) to close study enrollment, the dose-expansion phase (Phase 2) was not conducted.” (opens the source at this quote in a new tab)

Anemia and transfusion-dependence definitions

“Anemia: An Hgb value < 10 g/dL demonstrated during screening recorded on 3 separate occasions with at least 7 days between measurements (Note: RBC transfusion must be at least 2 weeks before the Hgb measurement during screening).” (opens the source at this quote in a new tab)
“Transfusion-dependent: Participant has received at least 4 units of RBC transfusions during the 28 days immediately preceding Cycle 1 Day 1 OR has received an average of at least 4 units of RBC transfusions in the 8 weeks immediately preceding Cycle 1 Day 1, for an Hgb level of < 8.5 g/dL, in the absence of bleeding or treatment-induced anemia.” (opens the source at this quote in a new tab)
“Ineligible to receive or have not responded to available therapies for anemia such as ESAs.” (opens the source at this quote in a new tab)

Treatment group-specific criteria

“Participants previously treated with JAK inhibitors for at least 12 weeks.” (opens the source at this quote in a new tab)
“Participants must have been on a therapeutic and stable regimen of ruxolitinib for at least 12 consecutive weeks immediately preceding the first dose of study treatment.” (opens the source at this quote in a new tab)
“Participants must be JAK inhibitor treatment naive (no prior treatment with any JAK inhibitor) and have an indication for initiation of ruxolitinib treatment.” (opens the source at this quote in a new tab)

Age, risk category, and key exclusions

Criterion	Registry record
Ages eligible	“18 Years and older”
Life expectancy	“Life expectancy is greater than 6 months”
Transplant exclusion	“Undergone any prior allogenic or autologous stem cell transplantation or a candidate for such transplantation.”

“Eligible pts (≥18 years) had intermediate (Int)-1 (TGB, TGC) or Int-2/high-risk (all groups) MF and anemia, and they were transfusion-dependent (TD) or non–transfusion-dependent (NTD) with symptomatic anemia.” (opens the source at this quote in a new tab)

Starting doses and dose range

“In TGA, zilurgisertib monotherapy was evaluated at a 50-mg once-daily (qd) starting dose in escalation.” (opens the source at this quote in a new tab)
“In TGB, pts received a stable ruxolitinib regimen for ≥12 wk before initiating zilurgisertib at a 100-mg qd starting dose.” (opens the source at this quote in a new tab)
“In TGC, zilurgisertib and ruxolitinib were initiated concurrently at starting doses of 400 mg qd and 10 mg twice daily (bid), respectively.” (opens the source at this quote in a new tab)
“Ruxolitinib dose increases were permitted after the 28-day dose-limiting toxicity (DLT) period.” (opens the source at this quote in a new tab)
“The maximum zilurgisertib dose evaluated in each treatment group was 600 mg daily (administered as 600 mg qd or 300 mg bid); MTD was not reached.” (opens the source at this quote in a new tab)

Dose levels administered and treatment duration

Group as posted	Registry description of treatment
Monotherapy dose levels	“Zilurgisertib Monotherapy 50 mg QD”; “Zilurgisertib Monotherapy 100 mg QD”; “Zilurgisertib Monotherapy 200 mg QD”; “Zilurgisertib Monotherapy 400 mg QD”; “Zilurgisertib Monotherapy 600 mg QD”; “Zilurgisertib Monotherapy 300 mg BID”
Add-on to ruxolitinib dose levels	“Zilurgisertib 100 mg QD + Ruxolitinib, Add on to Ruxolitinib”; “Zilurgisertib 200 mg QD + Ruxolitinib, Add on to Ruxolitinib”; “Zilurgisertib 400 mg QD + Ruxolitinib, Add on to Ruxolitinib”; “Zilurgisertib 600 mg QD + Ruxolitinib, Add on to Ruxolitinib”; “Zilurgisertib 300 mg BID + Ruxolitinib, Add on to Ruxolitinib”
JAK inhibitor-naive combination dose levels	“Zilurgisertib 400 mg QD + Ruxolitinib, JAK naïve”; “Zilurgisertib 300 mg BID + Ruxolitinib, JAK naïve”
Treatment duration	“Zilurgisertib was administered to the study participants as long as they benefitted from study treatment and they did not present any study treatment discontinuation criterion as per investigator's assessment for up to 12 months of treatment.”

Interim description of dose-increase rules

“The zilurgisertib starting dose in TGA was 50 mg once daily (qd), with dose increases of ≤2-fold performed until a grade ≥2 toxicity with reasonable probability of being related to the treatment group was observed; subsequent dose increases were limited to ≤50% until the maximum tolerated dose (MTD) was reached or the recommended doses(s) for expansion were identified.” (opens the source at this quote in a new tab)

Registered primary outcome measures

Outcome measure	Time frame
“Number of Participants With Any Treatment-emergent Adverse Event (TEAE) and Any Treatment-emergent Serious Adverse Event (SAE)”	“up to approximately 4 years”
“Number of Participants With Any ≥Grade 3 TEAE and Any Treatment-emergent SAE”	“up to approximately 4 years”
“Number of Participants With Dose-limiting Toxicities (DLTs)”	“from Cycle 1 Day 1 to Cycle 1 Day 28”
“Maximum Tolerated Dose (MTD)”	“from Cycle 1 Day 1 to Cycle 1 Day 28”
“Recommended Dose for Expansion (RDE)”	“from Cycle 1 Day 1 to Cycle 1 Day 28”

Dose-limiting toxicity and maximum tolerated dose definitions

“A DLT was defined as the occurrence of any protocol-defined toxicity occurring during the first treatment cycle, from Cycle 1 Day 1 up to and including Cycle 1 Day 28 (per regimen cycle schedule), except those with a clear alternative explanation (e.g., disease progression) or transient (≤72 hours) abnormal laboratory values without associated clinically significant signs or symptoms based on investigator determination.” (opens the source at this quote in a new tab)
“The MTD was defined as the dose at which the observed DLT rate was closest to the target DLT rate of 28% using an isotonical method that took the assumption of a monotonic dose-toxicity relationship into account.” (opens the source at this quote in a new tab)

Rationale for dose-finding in three populations

“It is unclear which patient population may derive the greatest benefit from ALK2 inhibition and hepcidin reduction, when considering participants who are post-JAK inhibitor treatment (TGA) versus those on active ruxolitinib therapy (TGB) versus those who are JAK inhibitor naive and newly starting ruxolitinib (TGC).” (opens the source at this quote in a new tab)
“The dose-escalation stages will be performed in each treatment group to determine the MTD.” (opens the source at this quote in a new tab)

Mechanistic rationale: hepcidin as the pharmacodynamic target

“Activin receptor-like kinase-2 signaling through the SMAD pathway leads to transcriptional activation of hepatic hepcidin (HAMP gene), making ALK2 inhibition a potential therapeutic intervention point for hepcidin induced anemia.” (opens the source at this quote in a new tab)

“It has been proposed that activin receptor-like kinase-2 (ALK2 [ie, ACVR1]) contributes to MF-associated anemia via hepcidin upregulation and that ALK2 inhibition may improve anemia in patients (pts) with MF.” (opens the source at this quote in a new tab)

Secondary endpoints: anemia response, pharmacokinetics, and pharmacodynamics

“Primary endpoints were safety and tolerability, including DLTs and MTD.” (opens the source at this quote in a new tab)
“Secondary endpoints included PK, PD, and anemia response (defined as transfusion independence for any rolling 12-wk period for TD pts, and hemoglobin [Hb] increase ≥1.5 g/dL above baseline sustained for any rolling 12-wk period for NTD pts).” (opens the source at this quote in a new tab)

Planned dose-escalation sample size

“In each treatment group, up to approximately 40 evaluable participants will be treated in the dose-escalation stage, and the dose-escalation procedure may be stopped if the number of evaluable participants treated at any dose level is greater than 9.” (opens the source at this quote in a new tab)

Planned expansion sample size, withdrawn by amendment

“Upon implementation of Amendment 9, expansion cohorts will not be enrolled.” (opens the source at this quote in a new tab)
“In the expansion stage for TGB and TGC, assuming an unacceptable anemia response rate of 0.07 (H0: p ≤ 0.07 vs Ha: p > 0.07) and a target response rate of 0.25, twenty-five participants per cohort will provide an actual Type I error of 0.0936 and a power of 0.904 using the exact binomial test (null hypothesis will be rejected if at least 4 out of 25 responses are observed).” (opens the source at this quote in a new tab)
“Rationale for change: Sponsor decision to close overall study enrollment and discontinue development of INCB000928 in this indication.” (opens the source at this quote in a new tab)

Participants enrolled and analyzed

“84 pts were enrolled in dose escalation to TGA (n=32), TGB (n=38), or TGC (n=14).” (opens the source at this quote in a new tab)

Statistical testing

“All statistical analyses are exploratory in nature; for the other endpoints, CIs will be reported at a 95% confidence level.” (opens the source at this quote in a new tab)

Full analysis set and safety population

“The FAS will include all participants who received at least 1 dose of INCB000928 or ruxolitinib, as applicable. Participants will be analyzed according to the treatment to which they have been initially assigned.” (opens the source at this quote in a new tab)
“The safety population will include all participants who received at least 1 dose of INCB000928 or ruxolitinib, as applicable. Treatment groups for this population will be determined according to the actual treatment the participant received regardless of assigned study drug treatment.” (opens the source at this quote in a new tab)

DLT-evaluable population as posted

“DLT-Evaluable Population: all participants who were observed for at least the first treatment cycle (Day 1 to Day 28), who received ≥75% of doses of study treatment at the level assigned to that cohort (i.e., 21 days of treatment) or who had a DLT during the first study treatment cycle, and who did not receive any strong or potent cytochrome P450 3A4/5 inhibitor/inducer and who did not have a ruxolitinib dose reduction during the first study treatment cycle (DLT assessment period)” (opens the source at this quote in a new tab)

Participant flow by dose group, posted results

Group	Started	Completed	Death	Sponsor decision	Physician decision	Withdrawal by subject	Ongoing
Monotherapy 50 mg once daily	“4”	“0”	“2”	“0”	“1”	“0”	“1”
Monotherapy 100 mg once daily	“4”	“2”	“0”	“0”	“0”	“1”	“0”
Monotherapy 200 mg once daily	“6”	“0”	“2”	“1”	“1”	“1”	“0”
Monotherapy 400 mg once daily	“11”	“4”	“2”	“2”	“0”	“1”	“2”
Monotherapy 600 mg once daily	“4”	“3”	“0”	“0”	“0”	“1”	“0”
Monotherapy 300 mg twice daily	“3”	“1”	“1”	“0”	“1”	“0”	“0”
Add-on 100 mg once daily + ruxolitinib	“4”	“1”	“2”	“0”	“1”	“0”	“0”
Add-on 200 mg once daily + ruxolitinib	“8”	“1”	“1”	“1”	“1”	“2”	“2”
Add-on 400 mg once daily + ruxolitinib	“12”	“3”	“4”	“3”	“0”	“2”	“0”
Add-on 600 mg once daily + ruxolitinib	“7”	“0”	“1”	“4”	“1”	“1”	“0”
Add-on 300 mg twice daily + ruxolitinib	“6”	“0”	“1”	“3”	“1”	“0”	“0”
JAK inhibitor-naive 400 mg once daily + ruxolitinib	“7”	“1”	“0”	“4”	“1”	“0”	“0”
JAK inhibitor-naive 300 mg twice daily + ruxolitinib	“8”	“0”	“0”	“5”	“2”	“1”	“0”

Demographics of all 84 participants, posted results

Characteristic	Total
Age, mean (years)	“72.0”
Age, standard deviation (years)	“7.15”
Female	“38”
Male	“46”
White/Caucasian	“61”
Asian	“14”
Black/African-American	“3”

Age and baseline hemoglobin by treatment group, final analysis

“Median (range) age was 73.5 (53‒84) years for TGA, 74.5 (54‒85) for TGB, and 70.0 (60–82) for TGC.” (opens the source at this quote in a new tab)
“Baseline median (range) Hb (g/dL) was 7.9 (6.5–9.7), 8.1 (5.1–9.9), and 8.0 (6.1–9.4) for TGA, TGB, and TGC, respectively.” (opens the source at this quote in a new tab)

Transfusion dependence and baseline hepcidin, interim analysis

“Median (range) age was 73 (53–84) years for TGA and 75.5 (54–85) years for TGB; 65% of TGA pts had received prior RUX therapy.” (opens the source at this quote in a new tab)
“In total, 55% of pts in TGA and 25% in TGB were transfusion dependent at time of enrollment.” (opens the source at this quote in a new tab)
“Baseline median (range) hepcidin was high in both cohorts (TGA, 171 [18–535] ng/mL; TGB, 126 [7–421] ng/mL; normal range, 0–50 ng/mL).” (opens the source at this quote in a new tab)

Anemia response at Weeks 24 and 48

“Among NTD pts included in the Wk 24 and 48 anemia response analysis (TGA, n=16; TGB, n=22; TGC, n=5), response occurred in 2 pts in TGA, 1 in TGB, and none in TGC at Wk 24 and 3 pts in TGA, 4 in TGB, and 1 in TGC at Wk 48.” (opens the source at this quote in a new tab)
“Among anemia response–evaluable TD pts (TGA, n=9; TGB, n=4; TGC, n=4), anemia response at Wk 24 was not achieved by any pt; 2 pts achieved response by Wk 48 (1 in TGB; 1 in TGC).” (opens the source at this quote in a new tab)
“Median values for the largest increase (g/dL) from baseline in mean Hb values over any rolling 12-wk treatment period through Wk 24 were 0.3, 0.4, and –0.03 for TGA, TGB, and TGC, respectively.” (opens the source at this quote in a new tab)
“Dose expansion was not initiated in any treatment group following analysis of anemia response rates in dose escalation.” (opens the source at this quote in a new tab)

Duration of anemia response, posted results

Group	Participants analyzed	Median duration (days)
Monotherapy 200 mg once daily, non-transfusion dependent at baseline	“1 participants”	“429”
Monotherapy 400 mg once daily, non-transfusion dependent at baseline	“1 participants”	“182”
Add-on 100 mg once daily + ruxolitinib, non-transfusion dependent at baseline	“1 participants”	“691”

Hepcidin suppression

“Hepcidin suppression following zilurgisertib dosing was observed in all 3 treatment groups, indicating target engagement; longitudinal PD hepcidin suppression was also observed.” (opens the source at this quote in a new tab)

Percentage change in hepcidin from Cycle 1 Day 15 to Cycle 7 Day 1, posted results

Group	Participants analyzed	Mean percent change	Standard deviation
Monotherapy 50 mg once daily	“4”	“-38.50”	“32.98”
Monotherapy 100 mg once daily	“4”	“-30.46”	“28.81”
Monotherapy 200 mg once daily	“6”	“-10.13”	“62.13”
Monotherapy 400 mg once daily	“8”	“-30.57”	“50.8”
Monotherapy 600 mg once daily	“4”	“-39.36”	“34.4”
Monotherapy 300 mg twice daily	“3”	“-54.89”	“40.6”
Add-on 100 mg once daily + ruxolitinib	“4”	“6.08”	“69.09”
Add-on 200 mg once daily + ruxolitinib	“8”	“-44.31”	“33.37”
Add-on 400 mg once daily + ruxolitinib	“11”	“-42.44”	“48.87”
Add-on 600 mg once daily + ruxolitinib	“7”	“-54.71”	“35.36”
Add-on 300 mg twice daily + ruxolitinib	“5”	“-45.43”	“54.41”
JAK inhibitor-naive 400 mg once daily + ruxolitinib	“7”	“56.26”	“116.2”
JAK inhibitor-naive 300 mg twice daily + ruxolitinib	“7”	“-58.00”	“39.01”

Spleen, response, and survival endpoints not analyzed

“This endpoint was intended to be analyzed in Part 2, which did not enroll participants.” (opens the source at this quote in a new tab)

Pharmacokinetics at steady state, interim analysis

“The PK profile for zilurgisertib at steady state was consistent with that observed with previous healthy volunteer studies, with observed time of maximum concentration at 2–4 hours after administration and predicted half-life of approximately 24 hours.” (opens the source at this quote in a new tab)

Dose-limiting toxicities and maximum tolerated dose, final analysis

“No pts in TGA or TGC experienced a DLT; 3 pts in TGB had DLTs (grade 1 gastrointestinal hemorrhage and epistaxis, n=1; grade 3 alveolar hemorrhage, n=1; grade 3 diarrhea, n=1).” (opens the source at this quote in a new tab)
“Treatment-emergent adverse events (TEAEs) occurred without apparent dose dependence” (opens the source at this quote in a new tab)
“serious TEAEs (TGA, n=11 [34.4%]; TGB, n=17 [44.7%]; TGC, n=5 [35.7%])” (opens the source at this quote in a new tab)
“Fatal TEAEs occurred in 2 pts in TGA (death, n=1; sepsis, n=1) and 1 pt in TGB (sepsis, n=1).” (opens the source at this quote in a new tab)
“Zilurgisertib monotherapy or in combination with ruxolitinib had a favorable tolerability profile, with few DLTs and no apparent correlation between dose and TEAE frequency.” (opens the source at this quote in a new tab)

Maximum tolerated dose not determined, posted results

“MTD could not be declared based on DLTs. Per protocol, MTD was determined separately for each group. Prior to enrollment stop, 0 DLTs were observed in the monotherapy or the zilurgisertib+ruxolitinib in JAK-naive groups. In the zilurgisertib as add-on group, 1 DLT was observed at the 300 BID dose, which falls within the decision boundaries that require additional dose-level enrollment. Additional enrollment was not completed, so dose escalation was not completed/MTD was not reached.” (opens the source at this quote in a new tab)
“The RDE was not established because, at the time of enrollment stop, dose escalation was ongoing and the dose that had evidence of the best pharmacologic activity while being below the MTD had not yet been identified.” (opens the source at this quote in a new tab)

Primary safety outcomes by dose group, posted results

Group	Any TEAE	Any grade 3 or higher TEAE and any treatment-emergent SAE	DLT-evaluable participants	Participants with DLTs
Monotherapy 50 mg once daily	“4”	“1”	“4”	“0”
Monotherapy 100 mg once daily	“4”	“0”	“3”	“0”
Monotherapy 200 mg once daily	“6”	“5”	“3”	“0”
Monotherapy 400 mg once daily	“11”	“3”	“3”	“0”
Monotherapy 600 mg once daily	“4”	“2”	“4”	“0”
Monotherapy 300 mg twice daily	“3”	“2”	“2”	“0”
Add-on 100 mg once daily + ruxolitinib	“4”	“3”	“4”	“0”
Add-on 200 mg once daily + ruxolitinib	“8”	“5”	“4”	“0”
Add-on 400 mg once daily + ruxolitinib	“12”	“6”	“3”	“0”
Add-on 600 mg once daily + ruxolitinib	“7”	“6”	“7”	“0”
Add-on 300 mg twice daily + ruxolitinib	“6”	“3”	“4”	“1”
JAK inhibitor-naive 400 mg once daily + ruxolitinib	“7”	“6”	“7”	“0”
JAK inhibitor-naive 300 mg twice daily + ruxolitinib	“8”	“6”	“3”	“0”

Serious adverse events and all-cause mortality by dose group, posted results

Group	Serious adverse events, affected/at risk (%)	All-cause mortality, affected/at risk (%)
Monotherapy 50 mg once daily	“1/4 (25.00%)”	“2/4 (50.00%)”
Monotherapy 100 mg once daily	“0/4 (0.00%)”	“0/4 (0.00%)”
Monotherapy 200 mg once daily	“4/6 (66.67%)”	“2/6 (33.33%)”
Monotherapy 400 mg once daily	“3/11 (27.27%)”	“2/11 (18.18%)”
Monotherapy 600 mg once daily	“1/4 (25.00%)”	“0/4 (0.00%)”
Monotherapy 300 mg twice daily	“2/3 (66.67%)”	“1/3 (33.33%)”
Add-on 100 mg once daily + ruxolitinib	“3/4 (75.00%)”	“2/4 (50.00%)”
Add-on 200 mg once daily + ruxolitinib	“3/8 (37.50%)”	“1/8 (12.50%)”
Add-on 400 mg once daily + ruxolitinib	“6/12 (50.00%)”	“4/12 (33.33%)”
Add-on 600 mg once daily + ruxolitinib	“4/7 (57.14%)”	“1/7 (14.29%)”
Add-on 300 mg twice daily + ruxolitinib	“1/6 (16.67%)”	“1/6 (16.67%)”
JAK inhibitor-naive 400 mg once daily + ruxolitinib	“3/7 (42.86%)”	“0/7 (0.00%)”
JAK inhibitor-naive 300 mg twice daily + ruxolitinib	“2/8 (25.00%)”	“0/8 (0.00%)”
Total	“33/84 (39.29%)”	“16/84 (19.05%)”

Adverse event collection period

“From Informed Consent Form signature to ≥30 days after the last study treatment or start of a new anticancer treatment (up to 1560 days)” (opens the source at this quote in a new tab)

Most frequent serious adverse events, all 84 participants

Serious adverse event	Affected/at risk (%)
Pneumonia	“7/84 (8.33%)”
Sepsis	“3/84 (3.57%)”
Atrial fibrillation	“3/84 (3.57%)”
Acute kidney injury	“3/84 (3.57%)”
Squamous cell carcinoma of skin	“3/84 (3.57%)”

Nonserious adverse events in 10% or more of all 84 participants, and events listed in the FOP label

Adverse event	Affected/at risk (%)
Diarrhoea	“24/84 (28.57%)”
Nausea	“18/84 (21.43%)”
Alopecia	“17/84 (20.24%)”
Oedema peripheral	“15/84 (17.86%)”
Thrombocytopenia	“14/84 (16.67%)”
Fatigue	“14/84 (16.67%)”
Dyspnoea	“14/84 (16.67%)”
Epistaxis	“13/84 (15.48%)”
Hyperuricaemia	“12/84 (14.29%)”
Cough	“12/84 (14.29%)”
Blood creatinine increased	“11/84 (13.10%)”
Anaemia	“11/84 (13.10%)”
Urinary tract infection	“10/84 (11.90%)”
Pruritus	“10/84 (11.90%)”
Hyperkalaemia	“10/84 (11.90%)”
Neutropenia	“9/84 (10.71%)”
Headache	“7/84 (8.33%)”
Rash	“6/84 (7.14%)”
Arthralgia	“4/84 (4.76%)”
Upper respiratory tract infection	“4/84 (4.76%)”
Iron overload	“1/84 (1.19%)”

Grade 3 or higher adverse events, interim analysis

“Grade ≥3 TEAEs occurred in 11 pts, with thrombocytopenia the most common (n=4).” (opens the source at this quote in a new tab)

Summary: limitations for a formulary review of zilurgisertib in fibrodysplasia ossificans progressiva

LIMBER-104 is an open-label, nonrandomized dose-escalation study without a control group, so adverse events cannot be attributed to zilurgisertib apart from myelofibrosis, ruxolitinib, and age-related comorbidity. The population differs from the FOP population in the label: the mean age of the 84 participants was 72.0 years, and all had myelofibrosis with anemia. Daily zilurgisertib doses ranged from 50 mg to 600 mg, and 52 of 84 participants (62%) received ruxolitinib concurrently. The planned expansion stage (Phase 2) was not conducted after enrollment was closed by sponsor decision, so the maximum tolerated dose and the recommended dose for expansion were not established, and spleen, response, and survival endpoints were not analyzed.

The two public sources differ on several counts. The final congress abstract reports 3 participants with dose-limiting toxicities in the add-on group, while the posted registry results report 1 dose-limiting toxicity among DLT-evaluable participants. Group sizes also differ (32, 38, and 14 participants in the abstract; 32, 37, and 15 in the registry safety population, which assigns participants by the treatment actually received). The abstract reports fatal treatment-emergent adverse events in 3 participants, while the registry reports all-cause mortality of 16 of 84 participants (19.05%) over a collection period of up to 1,560 days. No full peer-reviewed publication was identified, and no health-related quality of life or patient-reported outcome results were reported.

Registry statement on enrollment closure

“Enrollment in this study was closed following a strategic decision, not based on safety concerns, to discontinue the development of zilurgisertib for the treatment of anemia in myeloproliferative disorders.” (opens the source at this quote in a new tab)

Investigator conclusion on anemia efficacy

“However, despite evidence of on-target hepcidin suppression, zilurgisertib provided minimal improvements for anemia.” (opens the source at this quote in a new tab)

Registered objective: safety, pharmacokinetics, pharmacodynamics, and efficacy in anemia due to MDS or multiple myeloma

“This Phase 1/2, open-label, dose-finding study is intended to evaluate the safety and tolerability, PK, PD, and efficacy of INCB000928 administered as monotherapy in participants with MDS or MM who are transfusion-dependent or present with symptomatic anemia.” (opens the source at this quote in a new tab)
“A Phase 1/2, Open-Label, Multicenter Study of INCB000928 Administered as a Monotherapy in Participants With Anemia Due to Myelodysplastic Syndromes or Multiple Myeloma” (opens the source at this quote in a new tab)

Study identifiers, dates, and status: registry record

Field	Registry record
Acronym	“LIMBER”
Sponsor protocol number	“INCB 00928-105”
EudraCT number	“2020-002771-35”
Study start (actual)	“2021-08-19”
Primary completion (actual)	“2024-08-15”
Study completion (actual)	“2024-08-15”
Enrollment (actual)	“22”
Overall status	“Terminated”
Reason stopped	“Strategic Business Decision”
Results first posted	“2025-10-22”

Study centers

“This study was conducted at 8 study centers in the United States, France, and Italy.” (opens the source at this quote in a new tab)

Registered design details

Design feature	Registry record
Primary purpose	“Treatment”
Allocation	“N/A”
Interventional model	“Sequential Assignment”
Masking	“None (Open Label)”

Planned dose-escalation and expansion stages

“In the dose-escalation stage, a BOIN design will be used to determine the MTD. In each dose-escalation cohort, data from both participants with MDS and participants with MM will be evaluated together.” (opens the source at this quote in a new tab)
“The study has 2 disease groups:” (opens the source at this quote in a new tab)
“Participants with MDS or MDS/MPN overlap syndromes, collectively referred to as MDS participants.” (opens the source at this quote in a new tab)
“Participants with relapsed/refractory MM.” (opens the source at this quote in a new tab)

Inclusion criteria

“Participants who are transfusion-dependent or present with symptomatic anemia” (opens the source at this quote in a new tab)
“Ineligible to receive or have not responded to available therapies for anemia such as ESAs or lenalidomide.” (opens the source at this quote in a new tab)
“Histologically confirmed diagnosis of the MDS, CMML and unclassifiable MDS/MPN overlap syndromes.” (opens the source at this quote in a new tab)
“After failure of available standard treatments such as alkylating agents, glucocorticoids, immunomodulatory drugs (lenalidomide,pomalidomide, or thalidomide), proteasome inhibitors (bortezomib or carfilzomib), and daratumumab.” (opens the source at this quote in a new tab)

Exclusion criteria relevant to safety interpretation

“Undergoing treatment with a strong or potent inhibitor or inducer of CYP3A4/5 within 28 days or 5 half-lives (whichever is longer) before the first dose of study drug or expected to receive such treatment during the study.” (opens the source at this quote in a new tab)
“History of clinically significant or uncontrolled cardiac disease.” (opens the source at this quote in a new tab)
“Diagnosis of chronic liver disease.” (opens the source at this quote in a new tab)

Age

“18 Years and older” (opens the source at this quote in a new tab)

Dose levels and treatment duration, posted results

“Participants with myelodysplastic syndromes (MDS) or multiple myeloma (MM) who were transfusion dependent or presented with symptomatic anemia received oral zilurgisertib 50 milligrams (mg) once daily (QD) administered as a monotherapy for up to 6 months.” (opens the source at this quote in a new tab)

Group as posted	Registry record
Dose levels	“Zilurgisertib 50 mg QD”; “Zilurgisertib 100 mg QD”; “Zilurgisertib 200 mg QD”; “Zilurgisertib 400 mg QD”; “Zilurgisertib 600 mg QD”

Registered primary outcome measures

Outcome measure	Time frame
“Number of Participants With Any Treatment-emergent Adverse Event (TEAE)”	“up to 950 days”
“Number of Participants With Any ≥Grade 3 TEAE”	“up to 950 days”
“Number of Participants With Dose-limiting Toxicities (DLTs)”	“up to Day 28”
“Maximum Tolerated Dose (MTD)”	“up to Day 28”
“Recommended Dose for Expansion (RDE)”	“up to Day 28”

Dose-limiting toxicity and maximum tolerated dose definitions

“A DLT was defined as the occurrence of any protocol-defined toxicities occurring during the first study drug treatment cycle, from C1D1 up to and including Cycle 1 Day 28 (per regimen cycle schedule), except those with a clear alternative explanation (e.g., disease progression) or transient (≤72 hours) abnormal laboratory values without associated clinically significant signs or symptoms based on investigator determination.” (opens the source at this quote in a new tab)
“Bayesian optimal interval (BOIN) design was used to determine the MTD for this study.” (opens the source at this quote in a new tab)
“RDE doses were defined as pharmacodynamically active. RDE doses were not to have exceeded the MTD defined in each treatment group.” (opens the source at this quote in a new tab)

Secondary endpoints: anemia response and transfusion independence

“Participants with anemia response were those with a hemoglobin (Hgb) increase of ≥1.5 grams per deciliter (g/dL) relative to baseline for any 8-week period (with each assessment meeting this requirement) during the first 24 weeks of treatment if transfusion independent at baseline.” (opens the source at this quote in a new tab)
“Participants with RBC-transfusion independence were defined as those who did not require any RBC transfusion for at least 8 consecutive weeks during the first 24 weeks of treatment.” (opens the source at this quote in a new tab)

Planned sample size

“The cohort size will be 3. In each disease group, up to approximately 24 evaluable participants may be treated in the dose-escalation stages, and the dose-escalation procedure may be stopped if the number of evaluable participants treated at any dose level is > 9.” (opens the source at this quote in a new tab)
“Fifteen participants per cohort will provide a > 75% chance of identifying a toxicity with a true event rate of 9%.” (opens the source at this quote in a new tab)
“All statistical analyses are exploratory in nature.” (opens the source at this quote in a new tab)

Participants enrolled and analyzed

Measure	Registry record
Enrollment (actual)	“22”
Overall number of baseline participants	“21”
Participants with multiple myeloma	“No participants with MM were enrolled.”

Full analysis set and DLT-evaluable population

“The FAS includes all participants who received at least 1 dose of INCB000928. The FAS will be used for the summary of demographics, baseline characteristics, participant disposition, and analyses of all safety and efficacy data.” (opens the source at this quote in a new tab)

“Full Analysis Set-MDS: all participants with myelodysplastic syndromes (MDS) or MDS/myeloproliferative neoplasm (MPN) overlap syndromes who received at least 1 dose of zilurgisertib” (opens the source at this quote in a new tab)
“DLT Evaluable Population: all participants in the FAS Population who met the following criteria: observed for at least the first treatment cycle (i.e., 28 days); received ≥75% of doses of study treatment at the level assigned to that cohort (i.e., 21 days of treatment) or had a DLT during the first study treatment cycle; did not receive any strong or potent CYP3A4/5 inhibitor or inducer during the first study drug treatment cycle (DLT assessment period); was not part of a backfill cohort” (opens the source at this quote in a new tab)

Participant flow by dose group, posted results

Group	Started	Completed	Death	Lost to follow-up	Study terminated by sponsor	Physician decision	Withdrawal by subject	Started new therapy
50 mg once daily	“4”	“0”	“1”	“1”	“1”	“0”	“1”	“0”
100 mg once daily	“5”	“0”	“1”	“0”	“3”	“1”	“0”	“0”
200 mg once daily	“4”	“0”	“0”	“0”	“2”	“0”	“2”	“0”
400 mg once daily	“5”	“0”	“1”	“0”	“2”	“0”	“1”	“1”
600 mg once daily	“3”	“0”	“0”	“0”	“3”	“0”	“0”	“0”

Demographics of all 21 treated participants, posted results

Characteristic	Total
Age, mean (years)	“74.4”
Age, standard deviation (years)	“5.55”
Female	“10”
Male	“11”
White	“15”
Asian	“2”
Black or African American	“1”
Race unknown or not reported	“3”

Anemia response and transfusion independence, posted results

Group	Anemia response: participants analyzed	Anemia response (%)	Anemia response 95% CI	Transfusion independence: participants analyzed	Transfusion independence (%)	Transfusion independence 95% CI
50 mg once daily	“2”	“0.0”	“(0.0 to 84.2)”	“2”	“0.0”	“(0.0 to 84.2)”
100 mg once daily	“4”	“0.0”	“(0.0 to 60.2)”	“1”	“100.0”	“(2.5 to 100.0)”
200 mg once daily	“2”	“0.0”	“(0.0 to 84.2)”	“2”	“0.0”	“(0.0 to 84.2)”
400 mg once daily	“4”	“0.0”	“(0.0 to 60.2)”	“1”	“0.0”	“(0.0 to 97.5)”
600 mg once daily	“2”	“0.0”	“(0.0 to 84.2)”	“1”	“0.0”	“(0.0 to 97.5)”

Largest increase in hemoglobin over any rolling 8-week period and transfusion rate, posted results

Group	Hemoglobin: participants analyzed	Largest mean hemoglobin increase (g/L)	Standard deviation	Transfusion rate, Weeks 12 to 24 (RBC units per participant-month)	Standard deviation
50 mg once daily	“3”	“2.19”	“2.782”	“2.53”	“1.955”
100 mg once daily	“4”	“9.73”	“2.842”	“1.34”	“0.948”
200 mg once daily	“3”	“2.51”	“3.681”	“3.01”	“2.955”
400 mg once daily	“5”	“4.92”	“10.240”	“2.71”	“2.232”
600 mg once daily	“3”	“6.59”	“4.229”	“1.19”	“2.067”

Disease response, progression, and leukemic transformation in MDS, posted results

Group	Overall response rate in MDS (%)	MDS participants with progression or death (%)	Participants with leukemia or death (%)
50 mg once daily	“0.0”	“25.0”	“25.0”
100 mg once daily	“0.0”	“0.0”	“20.0”
200 mg once daily	“0.0”	“0.0”	“0.0”
400 mg once daily	“0.0”	“20.0”	“20.0”
600 mg once daily	“0.0”	“0.0”	“0.0”

Percentage change in hepcidin and trough concentration, posted results

Group	Hepcidin: participants analyzed	Mean percent change in hepcidin, Cycle 1 Day 15 to Cycle 7 Day 1	Standard deviation	Mean Ctrough (nanomolar)	Standard deviation
50 mg once daily	“4”	“-24.53”	“41.69”	“214”	“91.8”
100 mg once daily	“4”	“-16.25”	“47.06”	“304”	“175”
200 mg once daily	“4”	“-11.25”	“39.97”	“619”	“241”
400 mg once daily	“5”	“-59.02”	“32.35”	“981”	“3130”
600 mg once daily	“3”	“-63.79”	“44.23”	“NA”	“NA”

Pharmacokinetic values not determined at 600 mg

“Two participants had values above the upper limit of quantification, meaning data for PK parameters could not be determined.” (opens the source at this quote in a new tab)

Primary safety outcomes by dose group, posted results

Group	Participants analyzed	Any TEAE	Any grade 3 or higher TEAE	DLT-evaluable participants	Participants with DLTs
50 mg once daily	“4”	“4”	“2”	“4”	“0”
100 mg once daily	“5”	“5”	“3”	“3”	“0”
200 mg once daily	“4”	“4”	“2”	“4”	“0”
400 mg once daily	“5”	“5”	“2”	“3”	“0”
600 mg once daily	“3”	“2”	“2”	“2”	“1”

Maximum tolerated dose and recommended dose for expansion not determined

“The maximum sample size for each dose level was 9. Given that there were 2 DLT-evaluable participants at the 600 mg QD dose level and 1 DLT was observed, the dose should have been de-escalated. As a result, the dose escalation was incomplete at the time of study termination, and the MTD could not be determined since the stopping rule had not been met.” (opens the source at this quote in a new tab)
“The RDE was not established because, at the time of early study termination, dose escalation was ongoing and the dose that had evidence of the best pharmacologic activity while being below the MTD had not yet been identified.” (opens the source at this quote in a new tab)

Serious adverse events and all-cause mortality by dose group, posted results

Group	Serious adverse events, affected/at risk (%)	All-cause mortality, affected/at risk (%)
50 mg once daily	“2/4 (50.00%)”	“1/4 (25.00%)”
100 mg once daily	“1/5 (20.00%)”	“1/5 (20.00%)”
200 mg once daily	“2/4 (50.00%)”	“0/4 (0.00%)”
400 mg once daily	“2/5 (40.00%)”	“1/5 (20.00%)”
600 mg once daily	“0/3 (0.00%)”	“0/3 (0.00%)”
Total	“7/21 (33.33%)”	“3/21 (14.29%)”

Serious adverse events in more than 1 participant

Serious adverse event	Affected/at risk (%)
Anaemia	“2/21 (9.52%)”
COVID-19	“2/21 (9.52%)”

Nonserious adverse events in 3 or more of 21 participants, and events listed in the FOP label

Adverse event	Affected/at risk (%)
Oedema peripheral	“6/21 (28.57%)”
Fatigue	“4/21 (19.05%)”
Nausea	“4/21 (19.05%)”
Urinary tract infection	“4/21 (19.05%)”
Abdominal pain	“3/21 (14.29%)”
Alopecia	“3/21 (14.29%)”
Amylase increased	“3/21 (14.29%)”
Constipation	“3/21 (14.29%)”
Diarrhoea	“3/21 (14.29%)”
Dizziness	“3/21 (14.29%)”
Dyspnoea	“3/21 (14.29%)”
Electrocardiogram QT prolonged	“3/21 (14.29%)”
Hyperphosphataemia	“3/21 (14.29%)”
Pruritus	“3/21 (14.29%)”
Epistaxis	“1/21 (4.76%)”
Arthralgia	“1/21 (4.76%)”
Serum ferritin increased	“1/21 (4.76%)”

Adverse event collection period and population

“Analysis was conducted in the Full Analysis Set-MDS, comprised of all participants with myelodysplastic syndromes (MDS) or MDS/myeloproliferative neoplasm (MPN) overlap syndromes who received at least 1 dose of zilurgisertib.” (opens the source at this quote in a new tab)

Summary: limitations for a formulary review of zilurgisertib in fibrodysplasia ossificans progressiva

LIMBER-105 was terminated for a strategic business decision after enrolling 22 participants, of whom 21 were treated and analyzed. No participants with multiple myeloma were enrolled, so all results come from participants with MDS or MDS/MPN overlap syndromes, with a mean age of 74.4 years. The study was open-label, single-arm, and without a control group, with 2 to 5 participants per dose level (50 mg to 600 mg once daily for up to 6 months). The expansion stage enrolled no participants, the maximum tolerated dose could not be determined because the stopping rule was not met, and the recommended dose for expansion was not established. The SAP defines all analyses as exploratory. No peer-reviewed publication or congress abstract of the results was identified, and no health-related quality of life or patient-reported outcome results were reported.

Registry statement on termination

“The sponsor terminated study enrollment as a strategic decision. Due to early study termination, no participants were enrolled in the expansion stage of the study.” (opens the source at this quote in a new tab)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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.

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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.

Effect of a strong CYP3A inhibitor and a strong CYP3A4 inducer on zilurgisertib

“A drug-drug interaction study was conducted to evaluate the impact of the strong CYP3A inhibitor itraconazole and the strong CYP3A4 inducer rifampin on the pharmacokinetics of zilurgisertib in healthy participants.” (opens the source at this quote in a new tab)

Study dates, site, and ethics approval

“This open-label, fixed-sequence, drug-drug interaction study was conducted between March 25, 2021, and May 18, 2021, at Altasciences (Cypress, CA, USA).” (opens the source at this quote in a new tab)
“The protocol was approved by the Salus Institutional Review Board (Austin, TX, USA).” (opens the source at this quote in a new tab)

Two fixed-sequence cohorts in healthy participants

“Participants in Cohort 1 (n = 18) received zilurgisertib 100 mg on Days 1 and 10 and itraconazole 200 mg once daily on Days 6-13. Participants in Cohort 2 (n = 18) received zilurgisertib 100 mg on Days 1 and 13 and rifampin 600 mg once daily on Days 6-15.” (opens the source at this quote in a new tab)

Rationale for the zilurgisertib dose and fixed-sequence design

“Participants in both cohorts received zilurgisertib 100 mg, a dose 5 times lower than the maximum dose assessed in a previous Phase 1 study (INCB 009280-101), where no dose-limiting toxicities were observed and the maximum tolerated dose was not reached.” (opens the source at this quote in a new tab)
“In the current study, a dose of zilurgisertib 100 mg was selected to allow for the anticipated increase in exposure following coadministration with the strong CYP3A inhibitor itraconazole, and a reduction in exposure when coadministered with the potent CYP3A4 inducer rifampin.” (opens the source at this quote in a new tab)

Inclusion and exclusion criteria

“Eligible participants were healthy adults aged 18-55 years” (opens the source at this quote in a new tab)
“no significant findings on clinical, laboratory, and electrocardiogram (ECG) screening evaluations.” (opens the source at this quote in a new tab)
“Participants were excluded if they had a history or clinical manifestations of significant metabolic, hepatic, renal, hematologic, pulmonary, cardiovascular, gastrointestinal, urologic, neurologic, or psychiatric disorders or any current or recent history of a clinically significant bacterial, fungal, parasitic, or mycobacterial infection or were currently receiving systemic antibiotics.” (opens the source at this quote in a new tab)

Zilurgisertib 100 mg alone and with itraconazole or rifampin

“Participants in Cohort 1 (n = 18) received zilurgisertib 100 mg on Days 1 and 10 and itraconazole 200 mg once daily on Days 6-13. Participants in Cohort 2 (n = 18) received zilurgisertib 100 mg on Days 1 and 13 and rifampin 600 mg once daily on Days 6-15.” (opens the source at this quote in a new tab)

CYP3A4/5 as the primary elimination pathway

“In vitro metabolism studies suggest zilurgisertib is primarily eliminated via cytochrome P450 (CYP) 3A4/5-mediated metabolism, with an additional contribution from renal excretion.” (opens the source at this quote in a new tab)

Fraction metabolized by CYP3A4/5 and CYP2D6

“In vitro, zilurgisertib is metabolized primarily by CYP3A4/5 (fraction metabolized [fm], 0.77), and to a lesser extent by CYP2D6 (fm, 0.23).” (opens the source at this quote in a new tab)

Participants per cohort

“Participants in Cohort 1 (n = 18) received zilurgisertib 100 mg on Days 1 and 10 and itraconazole 200 mg once daily on Days 6-13. Participants in Cohort 2 (n = 18) received zilurgisertib 100 mg on Days 1 and 13 and rifampin 600 mg once daily on Days 6-15.” (opens the source at this quote in a new tab)

Sample size set empirically, not by a power calculation

“The sample size for each cohort was based on the precedent set by similar initial safety and tolerability studies and was empirical and not based on statistical power calculations.” (opens the source at this quote in a new tab)

Pharmacokinetic-evaluable and safety populations

“The PK-evaluable population included all participants who received at least 1 dose of the study drug and provided at least 1 measurable postdose PK blood sample.” (opens the source at this quote in a new tab)
“The safety population included all participants who received at least 1 dose of study drug.” (opens the source at this quote in a new tab)

Enrollment, completion, and withdrawals by cohort

“A total of 38 participants were enrolled in the study (18 in Cohort 1 and 20 in Cohort 2). Thirty-five participants completed the study.” (opens the source at this quote in a new tab)
“One participant in Cohort 1 withdrew on Day 19 (participant withdrew consent).” (opens the source at this quote in a new tab)
“Two participants in Cohort 2 withdrew; 1 withdrew on Day 11 (participant met a withdrawal criterion [noncompliance]) and 1 withdrew on Day 18 (due to treatment-related treatment-emergent AEs [TEAEs; abdominal pain and 2 episodes of vomiting]; participant discontinued treatment on Day 8).” (opens the source at this quote in a new tab)
“Both these participants were replaced.” (opens the source at this quote in a new tab)

Age, sex, and body weight by cohort

“There were no apparent differences between the 2 cohorts with regard to age, sex, and race. The mean age was 37.2 years in Cohort 1 and 32.4 years in Cohort 2. Mean body weight was 80.4 kg in Cohort 1 and 78.0 kg in Cohort 2.” (opens the source at this quote in a new tab)
“Sixteen participants (89%) in Cohort 1 and 17 (85%) in Cohort 2 were men.” (opens the source at this quote in a new tab)

Change in zilurgisertib exposure with itraconazole and rifampin

“With the concomitant administration of itraconazole, the geometric mean maximum plasma drug concentration (Cmax) and area under the concentration-time curve from time 0 to infinity (AUC0-inf) of zilurgisertib increased by 1.28- and 2.13-fold, respectively. With the concomitant administration of rifampin, there was a 2.27- and 4.76-fold reduction in the geometric mean Cmax and AUC0-inf of zilurgisertib, respectively.” (opens the source at this quote in a new tab)
“Zilurgisertib dose adjustment may be necessary with concomitant administration of strong CYP3A4 inhibitors, and coadministration of zilurgisertib with strong CYP3A4 inducers is not recommended.” (opens the source at this quote in a new tab)

Additional exposure parameters: AUC0-t, clearance, and half-life

“Coadministration of zilurgisertib with itraconazole significantly increased geometric mean Cmax, AUC0-t, and AUC0-inf by 1.28-, 2.17-, and 2.13-fold, respectively.” (opens the source at this quote in a new tab)
“Coadministration with itraconazole decreased geometric mean CL/F by 2.13-fold” (opens the source at this quote in a new tab)
“a 2.27-fold decrease in geometric mean Cmax and a 4.76-fold decrease in both AUC0-t and AUC0-inf were observed.” (opens the source at this quote in a new tab)
“Coadministration with rifampin increased geometric mean CL/F by 4.88-fold” (opens the source at this quote in a new tab)

Label statement of the interaction results and resulting dosing instructions

“Coadministration of itraconazole (a strong CYP3A4 inhibitor) increased the geometric mean Cmax and AUC of zilurgisertib 1.28-fold and 2.13-fold, respectively” (opens the prescribing information at this quote)
“Coadministration of rifampin (a strong CYP3A4 inducer) decreased zilurgisertib Cmax and AUC by 56% and 79%, respectively” (opens the prescribing information at this quote)
“Reduce the ATEBRIOZ dosage to 50 mg once daily when used concomitantly with a strong CYP3A4 inhibitor” (opens the prescribing information at this quote)
“Avoid concomitant use of ATEBRIOZ with strong or moderate CYP3A4 inducers.” (opens the prescribing information at this quote)

Adverse events with coadministration

“No dose-limiting toxicities occurred in either cohort, and all treatment-emergent adverse events were Grade 1 in severity.” (opens the source at this quote in a new tab)

Adverse event incidence, discontinuations, and clinical monitoring

“Nine participants (24%) reported at least 1 TEAE during the study (Cohort 1, 4 participants [22%] reported a total of 5 TEAEs [salivary gland mucocele, corneal abrasion, psoriasis, headache, n = 1 participant each; 1 participant experienced 2 incidences of headache]; Cohort 2, 5 participants [25%] reported a total of 8 TEAEs [vomiting, urticaria, skin abrasion, allergic rhinitis, n = 1 participant each; mild abdominal pain, n = 2 participants; 1 participant experienced 3 TEAEs (mild abdominal pain and 2 incidences of vomiting), 1 participant experienced 2 TEAEs (2 incidences of urticaria)]).” (opens the source at this quote in a new tab)
“Although 1 participant discontinued rifampin due to a TEAE of vomiting, no TEAEs led to the discontinuation of zilurgisertib.” (opens the source at this quote in a new tab)
“There were no safety concerns based on clinical laboratory results, vital signs, or 12-lead ECGs.” (opens the source at this quote in a new tab)
“There were no serious TEAEs or deaths reported in the study.” (opens the source at this quote in a new tab)

Summary: limitations of the drug interaction study

Each cohort enrolled 18 healthy adults and used an open-label, fixed-sequence design in which zilurgisertib 100 mg was given alone and then with itraconazole or rifampin, so each participant served as their own control rather than being randomized to a comparator arm. The study tested a single zilurgisertib dose of 100 mg, one-fifth of the highest dose evaluated in earlier phase 1 studies, together with a single regimen of one strong CYP3A4 inhibitor (itraconazole 200 mg once daily) and one strong CYP3A4 inducer (rifampin 600 mg once daily); the label's statements on moderate CYP3A4 inhibitors, moderate CYP3A4 inducers, and CYP2D6 inhibitors remain model predictions rather than results of a clinical study, and the full-text discussion notes that more potent strong CYP3A4 inhibitors than itraconazole could produce a larger increase in zilurgisertib exposure than observed here. Sample size for each cohort was set empirically, following precedent from similar studies, rather than by a statistical power calculation, and two participants in the rifampin cohort discontinued before the second treatment period and were replaced. The study enrolled healthy adults rather than participants with fibrodysplasia ossificans progressiva, and the reason for the variability in interaction magnitude observed across participants was not determined. The cardiac safety publication cites a 2.5-fold increase in AUC under strong CYP3A inhibition, which differs from the 2.13-fold increase in AUC0-inf reported by this study and by the label.

Effect of renal impairment and hemodialysis on zilurgisertib pharmacokinetics

“A Phase 1 Study to Evaluate the Pharmacokinetics, Safety, and Pharmacodynamics of INCB000928 in Participants With Impaired Renal Function and Hemodialysis” (opens the source at this quote in a new tab)

“Here are the results of two separate Phase I, open‐label, parallel‐group studies (INCB 00928‐108; INCB 00928‐109) assessing the effect of renal and hepatic impairment, respectively, on zilurgisertib exposure.” (opens the source at this quote in a new tab)

Registry status and dates

Registry field	Quoted record
Sponsor protocol number	“INCB 00928-108”
Overall status	“Completed”
Start date, actual	“2021-12-14”
Primary completion, actual	“2023-02-19”
Study completion, actual	“2023-02-27”
Enrollment, actual	“48”

Study sites

“These studies were undertaken at seven overlapping study sites in the United States (renal impairment study four sites, hepatic impairment study five sites).” (opens the source at this quote in a new tab)

Open-label, parallel-group design with matched controls

“This is a multicenter, open-label parallel-group to evaluate single oral doses of INCB000928 in participants with varying level of renal function or impairment.” (opens the source at this quote in a new tab)

“Participants with normal renal or hepatic function, were enrolled and matched on a 1:1 basis with participants with impaired renal/hepatic function respectively, according to age (±10 years), sex and body mass index (±20%).” (opens the source at this quote in a new tab)

Renal function groups assigned by estimated glomerular filtration rate

“Renal function was assessed at screening (2–28 days before administration of zilurgisertib) based on estimated glomerular filtration rate (eGFR) score, calculated via the isotope dilution mass spectrometry (IDMS)‐traceable 4‐variable Modification of Diet in Renal Disease (MDRD‐4‐IDMS) formula, and on the requirement for haemodialysis.” (opens the source at this quote in a new tab)

Dosing before and after hemodialysis in end-stage renal disease

“Group 5 participants were admitted on two separate occasions. During their first visit, zilurgisertib was administered per Groups 1–4 and 3 h before the start of haemodialysis. Blood and dialysate samples were collected during the 4‐day stay in the unit following dosing. On visit 2 (5–7 days after the end of their first visit), zilurgisertib was administered 1 h after the end of haemodialysis.” (opens the source at this quote in a new tab)

Inclusion criteria

“Age 18 to 82 years (inclusive) at the time of signing the ICF.” (opens the source at this quote in a new tab)
“Participants eligible for Group 5 with ESRD have received HD for at least 3 months prior to screening.” (opens the source at this quote in a new tab)
“Body mass index within the range 18.0 to 40.0 kg/m2 (inclusive) at screening.” (opens the source at this quote in a new tab)

Exclusion criteria

“Evidence of rapidly deteriorating renal function.” (opens the source at this quote in a new tab)
“Participants who have a current, functioning organ transplant or have a scheduled organ transplant within 6 weeks after check-in.” (opens the source at this quote in a new tab)
“Current treatment or treatment within 30 days or 5 half-lives (whichever is longer) of study drug administration with strong or moderate inducer or inhibitor of CYP3A4 or P-gp” (opens the source at this quote in a new tab)

Single 200 mg oral dose

“INCB000928 200 mg will be administered on Day 1 of each treatment period.” (opens the source at this quote in a new tab)

“Zilurgisertib was administered as a single 200‐mg dose (8 × 25 mg tablets) in both studies.” (opens the source at this quote in a new tab)
“Following an 8‐h fast, Groups 1–4 participants received a single 200 mg oral dose in the morning of Day 1 and were confined to the unit for 4 days.” (opens the source at this quote in a new tab)

Registered primary outcome measures

“PK for plasma of INCB000928: Cmax” (opens the source at this quote in a new tab)
“PK for plasma of INCB000928: AUC0-t” (opens the source at this quote in a new tab)
“Defined as area under the single-dose plasma or serum concentration-time curve extrapolated to time of infinity, this test will assess the effect of renal impairment and hemodialysis on the exposure of single oral doses of INCB00928.” (opens the source at this quote in a new tab)

Renal impairment can alter exposure to drugs cleared by non-renal pathways

“The potential impact of renal impairment on the PK of drugs cleared by non‐renal pathways (including intestinal and hepatic drug metabolism and transport) is well established.” (opens the source at this quote in a new tab)
“As such, drugs with minimal renal clearance may still need dose adjustments in individuals with renal impairment, as reflected in current US Food and Drug Administration (FDA) guidance.” (opens the source at this quote in a new tab)

Choice of the MDRD equation for group assignment

“was selected because, of the three standard methods available (MDRD‐4‐IDMS, Cockroft‐Gault and Chronic Kidney Disease Epidemiology Collaboration [CKD‐EPI]), it shows the greatest accuracy in estimation of renal clearance across difference stages of renal impairment.” (opens the source at this quote in a new tab)

Truncated AUC as a supporting exposure measure

“Recent guidance from the US Food & Drug Administration supports the use of truncated AUCs (e.g., AUC0–72) as the primary exposure metrics for IR drugs with long half‐lives.” (opens the source at this quote in a new tab)
“Therefore, AUC0–72 represents a robust and interpretable measure of systemic exposure across renal function groups; AUC0–∞ should be interpreted with caution in this population.” (opens the source at this quote in a new tab)

Hemodialysate bioanalytical method

“INCB000928 in hemodialysate exhibited strong nonspecific binding to polypropylene containers. In the presence of 10% isopropyl alcohol, the loss of INCB000928 was fully recovered, regardless of pre- or post-addition of the solvent.” (opens the source at this quote in a new tab)

Planned group sizes and their basis

“Up to eight participants could be enrolled into each renal/hepatic impairment group, to allow six or more participants per group to complete the study. The normal renal/hepatic function groups could consist of ≤ 16 participants. The sample size for these respective cohorts was based upon other PK studies of a similar nature and was not based on power calculations.” (opens the source at this quote in a new tab)

Participants enrolled by renal function group

“Forty‐eight participants were enrolled in the renal impairment study: normal renal function n = 16; mild impairment n = 7; moderate impairment n = 8; severe impairment n = 8; end‐stage renal disease (ESRD) n = 9.” (opens the source at this quote in a new tab)

Safety and pharmacokinetic populations

“All participants who received zilurgisertib were included in the safety population; those with at least one measurable PK sample collected were included in the PK population.” (opens the source at this quote in a new tab)

Matched comparison by analysis of variance

“To evaluate the effect of renal/hepatic impairment on zilurgisertib PK, log‐transformed PK parameters (Cmax, AUC0–t, AUC0–∞) were compared between participants with renal/hepatic impairment and matched participants with normal renal/hepatic function using a one‐way analysis of variance (ANOVA) with a fixed factor for renal/hepatic function group and a random factor for participant.” (opens the source at this quote in a new tab)
“Summary statistics are presented for both excluding (n = 6) and including (n = 7) one participant with mild renal impairment who lacked a healthy‐matched participant with normal renal function. This participant was excluded from the ANOVA test.” (opens the source at this quote in a new tab)

Completion and exclusion from the pharmacokinetic population

“All participants completed the study and were included in the safety population; one participant with ESRD was excluded from the PK population because zilurgisertib was mistakenly administered before haemodialysis during their second visit.” (opens the source at this quote in a new tab)

Demographics and renal function by group

Characteristic	Normal function (n = 16)	Mild impairment (n = 7)	Moderate impairment (n = 8)	Severe impairment (n = 8)	ESRD (n = 9)
Age, median (range), years	“58.5 (34–75)”	“65.0 (63–79)”	“71.0 (48–76)”	“72.5 (38–80)”	“54.0 (44–67)”
Male, n (%)	“11 (69)”	“4 (57)”	“5 (63)”	“5 (63)”	“9 (100)”
White/Caucasian, n (%)	“15 (94)”	“5 (71)”	“5 (63)”	“8 (100)”	“5 (56)”
BMI, median (range), kg/m2	“29.0 (22.2–35.6)”	“27.1 (21.1–33.1)”	“30.0 (26.4–36.5)”	“32.0 (25.4–39.4)”	“28.0 (22.5–39.4)”
eGFR, median (range), mL/min/1.73 m2	“99.2 (76.5–114.0)”	“63.9 (53.3–82.0)”	“48.3 (33.0–65.0)”	“19.5 (15.5–28.0)”	“6.7 (2.9–11.0)”

Geometric mean ratios versus matched participants with normal renal function

Renal function group	Cmax GMR (90% CI)	AUC0-inf GMR (90% CI)
Mild impairment	“0.92 (0.64–1.34)”	“0.98 (0.77–1.24)”
Moderate impairment	“1.22 (0.92–1.63)”	“1.64 (1.28–2.10)”
Severe impairment	“1.00 (0.74–1.35)”	“1.70 (1.33–2.16)”
ESRD, dosed before hemodialysis	“1.17 (0.91–1.49)”	“1.47 (1.15–1.88)”
ESRD, dosed after hemodialysis	“1.32 (1.00–1.75)”	“1.68 (1.29–2.19)”

Half-life and apparent clearance in moderate and severe renal impairment

“Zilurgisertib plasma exposure was 45% higher in participants with moderate renal impairment versus normal renal function when determined by AUC0–t (GMR: 1.45, p = 0.0073) and 64% higher based on AUC0–∞ (GMR: 1.64, p = 0.0031); geometric mean terminal t½ (35.6 vs. 25.1 h, p = 0.0031; Table 2) was longer and geometric mean CL/F (12.3 vs. 20.2 L/h, p = 0.0031) was lower in participants with moderate renal impairment.” (opens the source at this quote in a new tab)
“Geometric mean terminal t½ (39.0 vs. 26.4 h, p = 0.0376; Table 2) was longer and geometric mean CL/F (11.0 vs. 18.7 L/h, p = 0.0017) was lower in participants with severe renal impairment, compared with those with normal renal function.” (opens the source at this quote in a new tab)

End-stage renal disease and timing of hemodialysis

“Overall, changes in zilurgisertib exposure in participants with ESRD were similar to those seen in participants with moderate and severe renal impairment.” (opens the source at this quote in a new tab)
“Exposure was also increased by 30%–68% in participants with ESRD; notably, comparison of data obtained before and after haemodialysis demonstrate that zilurgisertib PK was not affected by the timing of dosing relative to this procedure.” (opens the source at this quote in a new tab)

Renal and dialysate clearance

“In participants with normal renal function, the GMR of renal clearance of zilurgisertib was 4.4 L/h, dropping to 3.9, 2.1 and 1.4 L/h in participants with mild, moderate and severe renal impairment, respectively. Similarly, the fraction of dose eliminated in urine as unchanged drug dropped from 19% in participants with normal renal function to 18%, 12% and 9% in participants with mild, moderate and severe renal impairment, respectively” (opens the source at this quote in a new tab)
“The geometric mean dialysate clearance among participants with ESRD was 1.3 L/h and the geometric mean fraction excreted in dialysate was 1.0%.” (opens the source at this quote in a new tab)

Plasma protein binding across renal function groups

“Average fraction unbound was 32%, 36%, 30%, 30% and 30% in participants with normal renal function, mild, moderate and severe renal impairment, and ESRD, respectively” (opens the source at this quote in a new tab)

Label statement of renal impairment results

“No significant difference in the exposure of zilurgisertib was observed in patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m2, MDRD) compared to healthy subjects with normal renal function.” (opens the prescribing information at this quote)
“Zilurgisertib exposure (AUC0-∞) was approximately 64% higher in patients with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2), approximately 70% higher in” (opens the prescribing information at this quote)
“patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), and approximately 47% and 68% higher in patients with end-stage renal disease before and after hemodialysis (eGFR <15 mL/min/1.73 m2), respectively, than in healthy subjects with normal renal function.” (opens the prescribing information at this quote)

Treatment-emergent adverse events in the renal impairment study

“Overall, all TEAEs were of Grade 1 or 2 severity and resolved before the end of the studies; no serious or fatal TEAEs were observed. In the renal impairment study, five TEAEs occurred in three of 48 participants (6%), with four TEAEs in two participants with normal renal function considered treatment‐related by the study investigators.” (opens the source at this quote in a new tab)
“The second participant reported a treatment‐related TEAE of alopecia (Grade 1) on Day 5, which resolved by Day 7 without treatment. One participant with severe renal impairment experienced skin abrasion (Grade 1) that was not considered treatment‐related.” (opens the source at this quote in a new tab)

Summary: limitations of the renal impairment study

The study gave one 200 mg dose to 48 adults with a median age of 54.0 to 72.5 years across groups, with 7 to 16 participants per group; group sizes were not based on power calculations, and it does not describe steady-state exposure at the 100 mg daily dose or exposure in adolescents. One participant with mild impairment had no matched control and was excluded from the comparison, and one participant with end-stage renal disease was excluded from the pharmacokinetic population after a dosing error. In moderate or worse impairment, sampling to 72 hours covered less than two half-lives, and the authors state that AUC0-inf should be interpreted with caution in this population. The label reports the 64% to 70% increases in AUC0-inf in its pharmacokinetics section and gives no dose adjustment for renal or hepatic impairment; the authors note that dosing recommendations were to be informed by the therapeutic index from the pivotal trial. The publication reports four renal study sites, while the registry record lists five locations.

Effect of hepatic impairment on zilurgisertib pharmacokinetics

“Here are the results of two separate Phase I, open‐label, parallel‐group studies (INCB 00928‐108; INCB 00928‐109) assessing the effect of renal and hepatic impairment, respectively, on zilurgisertib exposure.” (opens the source at this quote in a new tab)

Study sites

“These studies were undertaken at seven overlapping study sites in the United States (renal impairment study four sites, hepatic impairment study five sites).” (opens the source at this quote in a new tab)

Open-label, parallel-group design with matched controls

“Participants with normal renal or hepatic function, were enrolled and matched on a 1:1 basis with participants with impaired renal/hepatic function respectively, according to age (±10 years), sex and body mass index (±20%).” (opens the source at this quote in a new tab)

Child-Pugh groups and the omitted mild impairment cohort

“Hepatic function was assessed at screening (2–28 days before zilurgisertib administration) based on Child–Pugh score, then reassessed for consistency on the day of admission before dosing. Participants with normal hepatic function were assigned to Group 4, those with severe hepatic impairment (Child–Pugh score of 10–14 points) to Group 1, and those with moderate impairment (7–9 points) to Group 2” (opens the source at this quote in a new tab)
“Following a pre‐specified interim analysis of PK results, it was determined that an additional cohort with mild hepatic impairment (Group 3; 4–6 points) was unnecessary as zilurgisertib exposure was similar between participants with normal and moderate hepatic impairment.” (opens the source at this quote in a new tab)

Age, body mass index, and excluded conditions and medications

“Eligible participants were adults (18–82 years, renal impairment study, 18–80 years, hepatic impairment study), with body mass index of 18–40 and 18–44 kg/m2 in the renal and hepatic impairment studies, respectively.” (opens the source at this quote in a new tab)
“In both studies, participants with unstable or clinically significant comorbidities were excluded” (opens the source at this quote in a new tab)
“Use of medications known to be potent inhibitors or potent/moderate inducers of CYP3A4 (hepatic study) and medications known to affect CYP3A4 or P‐glycoprotein (renal study) for the longer of 30 days or five half‐lives prior to dosing was prohibited.” (opens the source at this quote in a new tab)

Single 200 mg oral dose

“Zilurgisertib was administered as a single 200‐mg dose (8 × 25 mg tablets) in both studies.” (opens the source at this quote in a new tab)
“Participants refrained from food for 8 h before and 4 h after dosing.” (opens the source at this quote in a new tab)

Pharmacokinetic parameters derived in both studies

“For both studies, the following PK parameters were calculated: maximum plasma drug concentration (Cmax); area under the plasma or serum concentration–time curve from time 0 to the last measurable concentration at time t (AUC0–t); total AUC extrapolated to infinity (AUC0–∞)” (opens the source at this quote in a new tab)

Hepatic clearance as the basis for a hepatic impairment study

“Similarly, plasma exposure can be influenced by liver diseases via altered hepatic metabolism/biliary excretion.” (opens the source at this quote in a new tab)
“PK studies should also be performed in patients with hepatic impairment where the condition is likely to significantly alter the PK of the drug and/or its metabolites, e.g., where hepatic metabolism/excretion accounts for >20% of the elimination of the parent/metabolite absorbed drug, and for drugs that may have a narrow therapeutic index.” (opens the source at this quote in a new tab)

Planned group sizes and their basis

“Up to eight participants could be enrolled into each renal/hepatic impairment group, to allow six or more participants per group to complete the study. The normal renal/hepatic function groups could consist of ≤ 16 participants. The sample size for these respective cohorts was based upon other PK studies of a similar nature and was not based on power calculations.” (opens the source at this quote in a new tab)

Participants enrolled by hepatic function group

“Twenty‐eight participants were enrolled in the hepatic impairment study: normal hepatic function n = 12; moderate impairment n = 9; severe impairment n = 7.” (opens the source at this quote in a new tab)

Safety and pharmacokinetic populations

“All participants who received zilurgisertib were included in the safety population; those with at least one measurable PK sample collected were included in the PK population.” (opens the source at this quote in a new tab)
“To evaluate the effect of renal/hepatic impairment on zilurgisertib PK, log‐transformed PK parameters (Cmax, AUC0–t, AUC0–∞) were compared between participants with renal/hepatic impairment and matched participants with normal renal/hepatic function using a one‐way analysis of variance (ANOVA) with a fixed factor for renal/hepatic function group and a random factor for participant.” (opens the source at this quote in a new tab)

Completion

“All participants completed the study and were included in the safety and PK populations.” (opens the source at this quote in a new tab)

Demographics and liver function by group

Characteristic	Normal function (n = 12)	Moderate impairment (n = 9)	Severe impairment (n = 7)
Age, median (range), years	“57.5 (40–64)”	“59.0 (40–69)”	“54.0 (48–61)”
Male, n (%)	“7 (58)”	“7 (78)”	“3 (43)”
White/Caucasian, n (%)	“7 (58)”	“8 (89)”	“6 (86)”
BMI, median (range), kg/m2	“32.1 (27.2–37.8)”	“32.8 (24.4–35.7)”	“32.1 (25.8–42.8)”
Albumin, median (range), g/dL	“4.2 (3.5–4.4)”	“3.9 (3.2–4.5)”	“2.4 (1.3–3.1)”
Bilirubin, median (range), mg/dL	“0.5 (0.15–0.8)”	“1.0 (0.3–9.0)”	“3.0 (0.6–6.3)”

Geometric mean ratios versus matched participants with normal hepatic function

“Among participants with hepatic impairment, values were as follows: moderate, 1.06 (0.80–1.42) and 1.13 (0.93–1.38); severe: 1.36 (1.05–1.76) and 1.25 (1.06–1.48), respectively.” (opens the source at this quote in a new tab)

Moderate hepatic impairment

“GMRs for zilurgisertib exposure among participants with normal hepatic function versus those with moderate hepatic impairment were 1.06, 1.09 and 1.13 for Cmax, AUC0–t and AUC0–∞, respectively, with 90% CIs including unity for all parameters.” (opens the source at this quote in a new tab)

Severe hepatic impairment

“Zilurgisertib plasma AUC0–t and AUC0–∞ were 22% and 25% higher in participants with severe hepatic impairment, respectively, than in participants with normal hepatic function. Cmax was similar in participants with severe hepatic impairment and those with normal hepatic function (GMR: 1.36, p = 0.0585). Lower geometric mean CL/F (16.0 vs. 20.1 L/h, p = 0.0347) and earlier median tmax (1.0 vs. 2.0 h, p = 0.0208) were observed in participants with severe hepatic impairment versus normal hepatic function.” (opens the source at this quote in a new tab)

Plasma protein binding across hepatic function groups

“Plasma protein binding was independent of both renal and hepatic function; hence, PK analysis was not performed on the unbound fraction.” (opens the source at this quote in a new tab)

Label statement of hepatic impairment results

“The zilurgisertib Cmax and AUC in patients with moderate hepatic impairment was comparable to healthy subjects with normal hepatic function. In patients with severe hepatic impairment, zilurgisertib AUC was 25% higher and Cmax was similar to that in subjects with normal hepatic function.” (opens the prescribing information at this quote)

Treatment-emergent adverse events in the hepatic impairment study

“In the hepatic impairment study, four TEAEs occurred in two of 28 participants (7.1%) none of which were considered treatment‐related. One participant with severe hepatic impairment experienced TEAEs of vomiting (Grade 1) and nausea (Grade 2), and one participant with moderate hepatic impairment reported TEAEs of diarrhoea and headache (both Grade 1); all TEAEs resolved on the day of onset.” (opens the source at this quote in a new tab)

Summary: limitations of the hepatic impairment study

The study gave one 200 mg dose to 28 adults (12 with normal hepatic function, 9 with moderate impairment, and 7 with severe impairment), with group sizes not based on power calculations. The mild impairment group was not enrolled after an interim analysis found similar exposure with moderate impairment, so no exposure data exist for mild hepatic impairment. The study describes neither steady-state exposure at the 100 mg daily dose nor exposure in adolescents. No registry record or study dates were located for this study.

Single oral 400 mg dose of radiolabeled zilurgisertib

“Following a single oral 400 mg dose of radiolabeled zilurgisertib, 49% of the dose was recovered in feces (10% unchanged) and 38.5% in urine (28% unchanged).” (opens the prescribing information at this quote)

Recovery of the dose in feces and urine

“Following a single oral 400 mg dose of radiolabeled zilurgisertib, 49% of the dose was recovered in feces (10% unchanged) and 38.5% in urine (28% unchanged).” (opens the prescribing information at this quote)
“Zilurgisertib is predominantly metabolized by CYP3A4 and to a minor extent by CYP2D6.” (opens the prescribing information at this quote)

Summary: limitations of the mass balance evidence

The only public evidence of this study is one sentence of the prescribing information, which reports recovery of 49% of a single 400 mg radiolabeled dose in feces and 38.5% in urine, for a total of 87.5%. No publication or registry record was located, so the population, number of participants, dates, and safety results are unknown. The label's 28% of the dose excreted unchanged in urine is close to the 27% fraction excreted unchanged in urine after multiple doses in the multiple ascending dose study.