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)