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)