4  INCA33989 Phase 1 Clinical Trial Results in Essential Thrombocythemia - ASH 2025 Update

Author

Clinical Data Analysis

Published

August 19, 2026

5 Study Overview

This document presents the updated clinical trial data from the INCA33989 Phase 1 study (NCT05936359 and NCT06034002) in patients with essential thrombocythemia (ET) with mutant calreticulin (mutCALR). Data cutoff: May 8, 2025, as presented at ASH 2025.

Study Design: Phase 1, first-in-human, multicenter, open-label dose escalation study evaluating INCA33989 (fully human, Fc-silenced, IgG1 monoclonal antibody) in patients with mutCALR ET or myelofibrosis.

Key Inclusion Criteria: - Pathogenic CALR mutation - Resistance/intolerance to prior ET treatment - Platelet count >450×10⁹/L - High-risk disease (age ≥60 years, history of thrombosis, major bleeding, acquired von Willebrand disease, or extreme thrombocytosis)

Code 
# Create baseline patient characteristics data
baseline_data <- data.frame(
  Characteristic = c(
    "Total patients enrolled", "Median age, years (range)", 
    "Female, n (%)", "Male, n (%)",
    "CALR mutation type 1, n (%)", "CALR mutation type 2, n (%)", 
    "CALR mutation other, n (%)",
    "Mean baseline mutCALR VAF, % (SD)", 
    "Median baseline platelet count, ×10⁹/L (range)",
    "Median exposure, weeks (range)", 
    "Patients continuing treatment, n (%)",
    "Treatment discontinuation, n (%)",
    "Concomitant hydroxyurea or anagrelide, n (%)",
    "Discontinued concomitant therapy, n (% of those with concomitant)"
  ),
  Value = c(
    "51", "60.5 (23-82)", 
    "31 (61%)", "20 (39%)",
    "28 (55%)", "15 (29%)", 
    "8 (16%)",
    "32 (7.9)", 
    "931 (447-2017)",
    "27 (0.6-74)", 
    "48 (94%)",
    "3 (6%)",
    "30 (59%)",
    "20 (67%)"
  )
)

# Create dose escalation data
dose_data <- data.frame(
  Dose_mg = c("24", "50", "100", "250", "500", "1000", "1500", "2500"),
  Patients_n = c(3, 3, 6, 6, 6, 6, 6, 5),  # Estimated distribution
  DLT = rep("No", 8),
  MTD_Reached = rep("No", 8)
)

5.1 Table 1: Baseline Patient Characteristics

Code 
baseline_data %>%
  gt() %>%
  tab_header(
    title = "Baseline Patient Characteristics",
    subtitle = "INCA33989 Phase 1 Study in Essential Thrombocythemia - ASH 2025"
  ) %>%
  cols_label(
    Characteristic = "Characteristic",
    Value = "Value (N=51)"
  ) %>%
  tab_style(
    style = cell_text(weight = "bold"),
    locations = cells_column_labels()
  ) %>%
  tab_style(
    style = cell_fill(color = "#f8f9fa"),
    locations = cells_body(rows = seq(2, nrow(baseline_data), 2))
  ) %>%
  tab_footnote(
    footnote = "VAF = Variant Allele Frequency; mutCALR = mutant calreticulin; SD = Standard Deviation",
    locations = cells_body(columns = Characteristic, rows = 8)
  ) %>%
  tab_footnote(
    footnote = "Reasons for discontinuation: 1 pregnancy, 1 adverse event (venous thrombosis), 1 patient decision",
    locations = cells_body(columns = Characteristic, rows = 12)
  )
Baseline Patient Characteristics
INCA33989 Phase 1 Study in Essential Thrombocythemia - ASH 2025
Characteristic Value (N=51)
Total patients enrolled 51
Median age, years (range) 60.5 (23-82)
Female, n (%) 31 (61%)
Male, n (%) 20 (39%)
CALR mutation type 1, n (%) 28 (55%)
CALR mutation type 2, n (%) 15 (29%)
CALR mutation other, n (%) 8 (16%)
Mean baseline mutCALR VAF, % (SD)1 32 (7.9)
Median baseline platelet count, ×10⁹/L (range) 931 (447-2017)
Median exposure, weeks (range) 27 (0.6-74)
Patients continuing treatment, n (%) 48 (94%)
Treatment discontinuation, n (%)2 3 (6%)
Concomitant hydroxyurea or anagrelide, n (%) 30 (59%)
Discontinued concomitant therapy, n (% of those with concomitant) 20 (67%)
1 VAF = Variant Allele Frequency; mutCALR = mutant calreticulin; SD = Standard Deviation
2 Reasons for discontinuation: 1 pregnancy, 1 adverse event (venous thrombosis), 1 patient decision

5.2 Table 2: Dose Escalation and Safety Overview

Code 
dose_data %>%
  gt() %>%
  tab_header(
    title = "Dose Escalation Cohorts",
    subtitle = "Safety and Tolerability Assessment"
  ) %>%
  cols_label(
    Dose_mg = "Dose (mg)",
    Patients_n = "Patients (n)",
    DLT = "Dose-Limiting Toxicity",
    MTD_Reached = "MTD Reached"
  ) %>%
  tab_style(
    style = cell_text(weight = "bold"),
    locations = cells_column_labels()
  ) %>%
  tab_style(
    style = cell_fill(color = "#e8f5e8"),
    locations = cells_body(columns = DLT, rows = DLT == "No")
  ) %>%
  tab_footnote(
    footnote = "MTD = Maximum Tolerated Dose; DLT = Dose-Limiting Toxicity",
    locations = cells_column_labels(columns = MTD_Reached)
  )
Dose Escalation Cohorts
Safety and Tolerability Assessment
Dose (mg) Patients (n) Dose-Limiting Toxicity MTD Reached1
24 3 No No
50 3 No No
100 6 No No
250 6 No No
500 6 No No
1000 6 No No
1500 6 No No
2500 5 No No
1 MTD = Maximum Tolerated Dose; DLT = Dose-Limiting Toxicity
Code 
# Create safety/adverse events data
safety_data <- data.frame(
  Adverse_Event = c(
    "Any TEAE", "Fatigue", "Upper respiratory tract infection",
    "Anemia", "Neutropenia", "Grade ≥3 TEAE", 
    "Asymptomatic lipase increase", "Treatment-related AEs", 
    "Treatment-related fatigue", "Serious TEAE", "Thrombocytopenia"
  ),
  Patients_n = c(48, 14, 10, 9, 5, 17, 4, 32, 10, 2, 0),
  Percentage = c(94, 28, 20, 18, 10, 33, 8, 63, 20, 4, 0),
  Max_Grade = c("3", "2", "2", "3", "3", "3", "3", "2", "2", "3", "0")
)

# Create efficacy data
efficacy_data <- data.frame(
  Response_Type = c(
    "Overall Response Rate (CHR + PHR)", "Complete Hematologic Response (CHR)", 
    "Partial Hematologic Response (PHR)", 
    "Durable hematologic response (≥12 weeks)",
    "Durable CHR (≥12 weeks)",
    "Median time to onset of CHR, days (range)",
    "Median time to durable CHR, days (range)",
    "Any mutCALR VAF reduction", 
    "mutCALR VAF reduction ≥20%", 
    "Partial Molecular Response (≥50% VAF reduction)",
    "Durable peripheral blood count remission"
  ),
  Patients_Evaluable = c(51, 51, 51, 41, 41, NA, NA, 41, 41, 41, 41),
  Responders_n = c(41, 37, 4, 21, 16, NA, NA, 37, 18, 8, 16),
  Percentage = c(80, 73, 8, 51, 39, NA, NA, 90, 44, 20, 39),
  Time_to_Response = c("21 days median", "21 days (8-324)", "21 days median", 
                       "≥12 weeks sustained", "≥12 weeks sustained",
                       "21 (8-324)", "15 (13-125)",
                       "Variable", "Variable", "Variable", "≥12 weeks")
)

5.3 Table 3: Safety and Adverse Events Profile

Code 
safety_data %>%
  gt() %>%
  tab_header(
    title = "Treatment-Emergent Adverse Events",
    subtitle = "Safety Profile (N=51) - ASH 2025"
  ) %>%
  cols_label(
    Adverse_Event = "Adverse Event",
    Patients_n = "Patients (n)",
    Percentage = "Percentage (%)",
    Max_Grade = "Maximum Grade"
  ) %>%
  tab_style(
    style = cell_text(weight = "bold"),
    locations = cells_column_labels()
  ) %>%
  tab_style(
    style = cell_fill(color = "#fff3cd"),
    locations = cells_body(rows = Adverse_Event == "Grade ≥3 TEAE")
  ) %>%
  tab_style(
    style = cell_fill(color = "#d1ecf1"),
    locations = cells_body(rows = Adverse_Event == "Thrombocytopenia")
  ) %>%
  fmt_missing(columns = everything(), missing_text = "0") %>%
  tab_footnote(
    footnote = "TEAE = Treatment-Emergent Adverse Event; No thrombocytopenia reported. Serious TEAEs: 1 diverticulitis (24mg), 1 visceral venous thrombosis followed by melena (400mg)",
    locations = cells_body(columns = Adverse_Event, rows = 11)
  ) %>%
  tab_footnote(
    footnote = "Anemia and neutropenia occurred most commonly with concomitant hydroxyurea",
    locations = cells_body(columns = Adverse_Event, rows = 4)
  )
Treatment-Emergent Adverse Events
Safety Profile (N=51) - ASH 2025
Adverse Event Patients (n) Percentage (%) Maximum Grade
Any TEAE 48 94 3
Fatigue 14 28 2
Upper respiratory tract infection 10 20 2
Anemia1 9 18 3
Neutropenia 5 10 3
Grade ≥3 TEAE 17 33 3
Asymptomatic lipase increase 4 8 3
Treatment-related AEs 32 63 2
Treatment-related fatigue 10 20 2
Serious TEAE 2 4 3
Thrombocytopenia2 0 0 0
1 Anemia and neutropenia occurred most commonly with concomitant hydroxyurea
2 TEAE = Treatment-Emergent Adverse Event; No thrombocytopenia reported. Serious TEAEs: 1 diverticulitis (24mg), 1 visceral venous thrombosis followed by melena (400mg)

5.4 Table 4: Efficacy and Response Rates

Code 
efficacy_data %>%
  gt() %>%
  tab_header(
    title = "Efficacy Outcomes - ASH 2025",
    subtitle = "Hematologic and Molecular Responses (N=51)"
  ) %>%
  cols_label(
    Response_Type = "Response Type",
    Patients_Evaluable = "Evaluable (n)",
    Responders_n = "Responders (n)",
    Percentage = "Response Rate (%)",
    Time_to_Response = "Time to Response"
  ) %>%
  tab_style(
    style = cell_text(weight = "bold"),
    locations = cells_column_labels()
  ) %>%
  tab_style(
    style = cell_fill(color = "#d4edda"),
    locations = cells_body(rows = c(1, 2))  # Highlight overall and complete response
  ) %>%
  tab_style(
    style = cell_fill(color = "#cfe2ff"),
    locations = cells_body(rows = c(4, 5, 11))  # Highlight durability measures
  ) %>%
  tab_style(
    style = cell_fill(color = "#fff3cd"),
    locations = cells_body(rows = c(8, 9, 10))  # Highlight molecular responses
  ) %>%
  fmt_missing(columns = everything(), missing_text = "—") %>%
  tab_footnote(
    footnote = "CHR = Complete Hematologic Response (platelets <400×10⁹/L + leukocytes <10×10⁹/L); PHR = Partial Hematologic Response (platelets <600×10⁹/L + leukocytes <10×10⁹/L)",
    locations = cells_body(columns = Response_Type, rows = 1)
  ) %>%
  tab_footnote(
    footnote = "VAF = Variant Allele Frequency; Partial Molecular Response = ≥50% reduction in mutCALR VAF",
    locations = cells_body(columns = Response_Type, rows = 10)
  ) %>%
  tab_footnote(
    footnote = "Durable peripheral blood count remission as defined by IWG/ELN criteria, sustained ≥12 weeks",
    locations = cells_body(columns = Response_Type, rows = 11)
  )
Efficacy Outcomes - ASH 2025
Hematologic and Molecular Responses (N=51)
Response Type Evaluable (n) Responders (n) Response Rate (%) Time to Response
Overall Response Rate (CHR + PHR)1 51 41 80 21 days median
Complete Hematologic Response (CHR) 51 37 73 21 days (8-324)
Partial Hematologic Response (PHR) 51 4 8 21 days median
Durable hematologic response (≥12 weeks) 41 21 51 ≥12 weeks sustained
Durable CHR (≥12 weeks) 41 16 39 ≥12 weeks sustained
Median time to onset of CHR, days (range) — — — 21 (8-324)
Median time to durable CHR, days (range) — — — 15 (13-125)
Any mutCALR VAF reduction 41 37 90 Variable
mutCALR VAF reduction ≥20% 41 18 44 Variable
Partial Molecular Response (≥50% VAF reduction)2 41 8 20 Variable
Durable peripheral blood count remission3 41 16 39 ≥12 weeks
1 CHR = Complete Hematologic Response (platelets <400×10⁹/L + leukocytes <10×10⁹/L); PHR = Partial Hematologic Response (platelets <600×10⁹/L + leukocytes <10×10⁹/L)
2 VAF = Variant Allele Frequency; Partial Molecular Response = ≥50% reduction in mutCALR VAF
3 Durable peripheral blood count remission as defined by IWG/ELN criteria, sustained ≥12 weeks
Code 
# Create response criteria table
response_criteria <- data.frame(
  Response_Category = c(
    "Complete Hematologic Response (CHR)", 
    "Partial Hematologic Response (PHR)", 
    "Durable CHR",
    "Durable Peripheral Blood Count Remission (IWG/ELN)",
    "Molecular Response (≥20% VAF reduction)",
    "Partial Molecular Response (≥50% VAF reduction)"
  ),
  Definition = c(
    "Platelet count <400×10⁹/L + Leukocytes <10×10⁹/L",
    "Platelet count <600×10⁹/L + Leukocytes <10×10⁹/L",
    "CHR sustained for ≥12 weeks",
    "IWG/ELN-defined blood count remission sustained ≥12 weeks",
    "≥20% reduction in mutCALR variant allele frequency from baseline",
    "≥50% reduction in mutCALR variant allele frequency from baseline"
  ),
  Achievement_Rate = c("73% (37/51)", "8% (4/51)", "39% (16/41)", 
                       "39% (16/41)", "44% (18/41)", "20% (8/41)"),
  Time_to_Achievement = c("21 days (8-324)", "21 days median", 
                          "15 days (13-125)", "Variable", "Variable", "Variable")
)

5.5 Table 5: Response Criteria and Definitions

Code 
response_criteria %>%
  gt() %>%
  tab_header(
    title = "Response Criteria and Achievement Rates - ASH 2025",
    subtitle = "Hematologic and Molecular Response Definitions (N=51)"
  ) %>%
  cols_label(
    Response_Category = "Response Category",
    Definition = "Definition",
    Achievement_Rate = "Achievement Rate",
    Time_to_Achievement = "Time to Achievement"
  ) %>%
  tab_style(
    style = cell_text(weight = "bold"),
    locations = cells_column_labels()
  ) %>%
  tab_style(
    style = cell_text(size = px(12)),
    locations = cells_body(columns = Definition)
  ) %>%
  cols_width(
    Response_Category ~ px(200),
    Definition ~ px(320),
    Achievement_Rate ~ px(130),
    Time_to_Achievement ~ px(140)
  ) %>%
  tab_footnote(
    footnote = "CHR = Complete Hematologic Response; VAF = Variant Allele Frequency; IWG/ELN = International Working Group/European LeukemiaNet",
    locations = cells_column_labels(columns = Response_Category)
  ) %>%
  tab_footnote(
    footnote = "Among those achieving durable peripheral blood count remission, 88% (14/16) achieved molecular response with baseline VAF ranging 0.22-0.34",
    locations = cells_body(columns = Response_Category, rows = 4)
  )
Response Criteria and Achievement Rates - ASH 2025
Hematologic and Molecular Response Definitions (N=51)
Response Category1 Definition Achievement Rate Time to Achievement
Complete Hematologic Response (CHR) Platelet count <400×10⁹/L + Leukocytes <10×10⁹/L 73% (37/51) 21 days (8-324)
Partial Hematologic Response (PHR) Platelet count <600×10⁹/L + Leukocytes <10×10⁹/L 8% (4/51) 21 days median
Durable CHR CHR sustained for ≥12 weeks 39% (16/41) 15 days (13-125)
Durable Peripheral Blood Count Remission (IWG/ELN)2 IWG/ELN-defined blood count remission sustained ≥12 weeks 39% (16/41) Variable
Molecular Response (≥20% VAF reduction) ≥20% reduction in mutCALR variant allele frequency from baseline 44% (18/41) Variable
Partial Molecular Response (≥50% VAF reduction) ≥50% reduction in mutCALR variant allele frequency from baseline 20% (8/41) Variable
1 CHR = Complete Hematologic Response; VAF = Variant Allele Frequency; IWG/ELN = International Working Group/European LeukemiaNet
2 Among those achieving durable peripheral blood count remission, 88% (14/16) achieved molecular response with baseline VAF ranging 0.22-0.34
Code 
# Create comparison with standard ET treatments
comparison_data <- data.frame(
  Treatment = c(
    "INCA33989 (ASH 2025 Update)", "Hydroxyurea (Historical)", 
    "Pegylated Interferon", "Aspirin Monotherapy", "Anagrelide"
  ),
  Response_Rate = c("80% (CHR+PHR)", "60-80%", "70-80%", "N/A", "70-90%"),
  Time_to_Response = c("21 days median", "8-12 weeks", "12-24 weeks", "N/A", "4-8 weeks"),
  Molecular_Response = c("44% (≥20% VAF↓), 20% (≥50% VAF↓)", "Rare", "30-50%", "None", "Rare"),
  Durable_Response = c("51% (≥12 weeks), 39% durable CHR", "Variable", "Variable", "N/A", "Variable"),
  Key_Toxicities = c(
    "Fatigue (28%), URI (20%), Grade ≥3 (33%)", 
    "Skin ulcers, GI symptoms, cytopenias",
    "Flu-like symptoms, depression",
    "GI bleeding (minimal)",
    "Palpitations, edema, headache"
  ),
  Target_Population = c(
    "mutCALR ET (~25% of ET patients)", "All ET patients", 
    "All ET patients", "All ET patients", "All ET patients"
  )
)

5.6 Table 6: Comparison with Standard Essential Thrombocythemia Treatments

Code 
comparison_data %>%
  gt() %>%
  tab_header(
    title = "Treatment Comparison in Essential Thrombocythemia",
    subtitle = "INCA33989 (ASH 2025) vs Standard Therapies"
  ) %>%
  cols_label(
    Treatment = "Treatment",
    Response_Rate = "Response Rate",
    Time_to_Response = "Time to Response",
    Molecular_Response = "Molecular Response",
    Durable_Response = "Durable Response",
    Key_Toxicities = "Key Toxicities",
    Target_Population = "Target Population"
  ) %>%
  tab_style(
    style = cell_text(weight = "bold"),
    locations = cells_column_labels()
  ) %>%
  tab_style(
    style = cell_fill(color = "#e8f5e8"),
    locations = cells_body(rows = 1)  # Highlight INCA33989
  ) %>%
  tab_style(
    style = cell_text(size = px(10)),
    locations = cells_body(columns = c(Molecular_Response, Durable_Response, Key_Toxicities, Target_Population))
  ) %>%
  cols_width(
    Treatment ~ px(140),
    Response_Rate ~ px(90),
    Time_to_Response ~ px(90),
    Molecular_Response ~ px(140),
    Durable_Response ~ px(130),
    Key_Toxicities ~ px(140),
    Target_Population ~ px(120)
  ) %>%
  tab_footnote(
    footnote = "CHR = Complete Hematologic Response; PHR = Partial Hematologic Response; VAF = Variant Allele Frequency; URI = Upper Respiratory Infection; GI = Gastrointestinal",
    locations = cells_column_labels(columns = Molecular_Response)
  ) %>%
  tab_footnote(
    footnote = "No thrombocytopenia observed with INCA33989; 94% of patients continued treatment",
    locations = cells_body(columns = Treatment, rows = 1)
  )
Treatment Comparison in Essential Thrombocythemia
INCA33989 (ASH 2025) vs Standard Therapies
Treatment Response Rate Time to Response Molecular Response1 Durable Response Key Toxicities Target Population
INCA33989 (ASH 2025 Update)2 80% (CHR+PHR) 21 days median 44% (≥20% VAF↓), 20% (≥50% VAF↓) 51% (≥12 weeks), 39% durable CHR Fatigue (28%), URI (20%), Grade ≥3 (33%) mutCALR ET (~25% of ET patients)
Hydroxyurea (Historical) 60-80% 8-12 weeks Rare Variable Skin ulcers, GI symptoms, cytopenias All ET patients
Pegylated Interferon 70-80% 12-24 weeks 30-50% Variable Flu-like symptoms, depression All ET patients
Aspirin Monotherapy N/A N/A None N/A GI bleeding (minimal) All ET patients
Anagrelide 70-90% 4-8 weeks Rare Variable Palpitations, edema, headache All ET patients
1 CHR = Complete Hematologic Response; PHR = Partial Hematologic Response; VAF = Variant Allele Frequency; URI = Upper Respiratory Infection; GI = Gastrointestinal
2 No thrombocytopenia observed with INCA33989; 94% of patients continued treatment

6 Molecular Characterization and Mechanism of Action

6.1 Comprehensive Genomic Analysis (110 patients total: 51 ET, 59 MF)

This section presents findings from comprehensive clinicogenomics and histological analyses (Abstract abs25-1675).

Code 
# Create molecular characterization data
molecular_data <- data.frame(
  Parameter = c(
    "Total patients with genomic data", 
    "Essential thrombocythemia patients",
    "Myelofibrosis patients",
    "CALR Type-1 mutations (ET)",
    "CALR Type-2 mutations (ET)",
    "CALR Type-other mutations (ET)",
    "Mean mutCALR VAF in ET (range)",
    "Loss of heterozygosity (VAF >0.5)",
    "Co-occurring somatic variants in ET",
    "Co-occurring somatic variants in MF",
    "Most frequent co-mutation in ET",
    "Most frequent co-mutations in MF",
    "Strong correlation: BM vs PB VAF"
  ),
  Value = c(
    "110",
    "51",
    "59",
    "55%",
    "29%",
    "16%",
    "0.33 (0.12-0.75)",
    "5% (all Type-2)",
    "33%",
    "83%",
    "TET2 (16%)",
    "ASXL1 (42%), TET2 (31%), EZH2 (12%)",
    "R² = 0.97"
  )
)

# Create single-cell analysis data
single_cell_data <- data.frame(
  Finding = c(
    "Selective reduction in mutCALR+ HSPCs",
    "Timing of HSPC reduction",
    "Bone marrow MK analysis: Total MK density",
    "Bone marrow MK analysis: mutCALR+ MKs",
    "Bone marrow MK analysis: mutCALR- MKs",
    "Clinical correlation"
  ),
  Result = c(
    "Observed in subset of patients",
    "By end of cycle 3 (6 weeks)",
    "Decreased",
    "Decreased (percentage)",
    "Increased (percentage)",
    "Correlated with clinical responses"
  )
)

# Create molecular response by clinical response data
molecular_clinical_correlation <- data.frame(
  Clinical_Response = c(
    "Any hematologic response (ET)",
    "VAF reduction in responders",
    "Molecular response (≥20% VAF↓)",
    "Durable peripheral blood count remission",
    "Molecular response in durable remission",
    "Baseline VAF in durable remission with MR"
  ),
  N_Evaluable = c("41", "39", "39", "16", "16", "14"),
  N_Patients = c("41 (100%)", "37 (95%)", "22 (56%)", "16 (39%)", "14 (88%)", "14 (100%)"),
  VAF_Range_or_Detail = c("—", "2-91%", "≥20% reduction", "IWG/ELN criteria", 
                           "≥20% VAF reduction", "0.22-0.34")
)

6.2 Table 7: Molecular Characterization at Baseline

Code 
molecular_data %>%
  gt() %>%
  tab_header(
    title = "Molecular Characterization of Study Population",
    subtitle = "Baseline Genomic Features (N=110 total; 51 ET, 59 MF)"
  ) %>%
  cols_label(
    Parameter = "Parameter",
    Value = "Value"
  ) %>%
  tab_style(
    style = cell_text(weight = "bold"),
    locations = cells_column_labels()
  ) %>%
  tab_style(
    style = cell_fill(color = "#f8f9fa"),
    locations = cells_body(rows = seq(2, nrow(molecular_data), 2))
  ) %>%
  tab_footnote(
    footnote = "VAF = Variant Allele Frequency; BM = Bone Marrow; PB = Peripheral Blood; HSPC = Hematopoietic Stem/Progenitor Cells; MK = Megakaryocytes",
    locations = cells_column_labels(columns = Parameter)
  ) %>%
  tab_footnote(
    footnote = "Co-occurring variants range: 0-3 per patient in ET, 0-9 per patient in MF",
    locations = cells_body(columns = Parameter, rows = 9)
  )
Molecular Characterization of Study Population
Baseline Genomic Features (N=110 total; 51 ET, 59 MF)
Parameter1 Value
Total patients with genomic data 110
Essential thrombocythemia patients 51
Myelofibrosis patients 59
CALR Type-1 mutations (ET) 55%
CALR Type-2 mutations (ET) 29%
CALR Type-other mutations (ET) 16%
Mean mutCALR VAF in ET (range) 0.33 (0.12-0.75)
Loss of heterozygosity (VAF >0.5) 5% (all Type-2)
Co-occurring somatic variants in ET2 33%
Co-occurring somatic variants in MF 83%
Most frequent co-mutation in ET TET2 (16%)
Most frequent co-mutations in MF ASXL1 (42%), TET2 (31%), EZH2 (12%)
Strong correlation: BM vs PB VAF R² = 0.97
1 VAF = Variant Allele Frequency; BM = Bone Marrow; PB = Peripheral Blood; HSPC = Hematopoietic Stem/Progenitor Cells; MK = Megakaryocytes
2 Co-occurring variants range: 0-3 per patient in ET, 0-9 per patient in MF

6.3 Table 8: Single-Cell Analysis and Bone Marrow Findings

Code 
single_cell_data %>%
  gt() %>%
  tab_header(
    title = "Mechanism of Action: Single-Cell and Histological Analysis",
    subtitle = "Evidence of Selective Targeting and Disease Modification"
  ) %>%
  cols_label(
    Finding = "Finding",
    Result = "Result"
  ) %>%
  tab_style(
    style = cell_text(weight = "bold"),
    locations = cells_column_labels()
  ) %>%
  tab_style(
    style = cell_fill(color = "#d4edda"),
    locations = cells_body(rows = c(1, 2))  # Highlight HSPC findings
  ) %>%
  tab_style(
    style = cell_fill(color = "#cfe2ff"),
    locations = cells_body(rows = c(3, 4, 5))  # Highlight bone marrow findings
  ) %>%
  tab_footnote(
    footnote = "HSPC = Hematopoietic Stem/Progenitor Cells; MK = Megakaryocytes; mutCALR+ = mutant calreticulin-positive; mutCALR- = mutant calreticulin-negative (normal)",
    locations = cells_column_labels(columns = Finding)
  )
Mechanism of Action: Single-Cell and Histological Analysis
Evidence of Selective Targeting and Disease Modification
Finding1 Result
Selective reduction in mutCALR+ HSPCs Observed in subset of patients
Timing of HSPC reduction By end of cycle 3 (6 weeks)
Bone marrow MK analysis: Total MK density Decreased
Bone marrow MK analysis: mutCALR+ MKs Decreased (percentage)
Bone marrow MK analysis: mutCALR- MKs Increased (percentage)
Clinical correlation Correlated with clinical responses
1 HSPC = Hematopoietic Stem/Progenitor Cells; MK = Megakaryocytes; mutCALR+ = mutant calreticulin-positive; mutCALR- = mutant calreticulin-negative (normal)

6.4 Table 9: Correlation Between Clinical and Molecular Responses

Code 
molecular_clinical_correlation %>%
  gt() %>%
  tab_header(
    title = "Clinical-Molecular Response Correlation",
    subtitle = "Relationship Between Hematologic Response and mutCALR VAF Reduction"
  ) %>%
  cols_label(
    Clinical_Response = "Clinical Response Type",
    N_Evaluable = "Evaluable (n)",
    N_Patients = "Patients (n, %)",
    VAF_Range_or_Detail = "VAF Details"
  ) %>%
  tab_style(
    style = cell_text(weight = "bold"),
    locations = cells_column_labels()
  ) %>%
  tab_style(
    style = cell_fill(color = "#fff3cd"),
    locations = cells_body(rows = c(4, 5, 6))  # Highlight durable remission
  ) %>%
  tab_footnote(
    footnote = "IWG/ELN = International Working Group/European LeukemiaNet criteria; MR = Molecular Response (≥20% VAF reduction)",
    locations = cells_body(columns = Clinical_Response, rows = 4)
  ) %>%
  tab_footnote(
    footnote = "88% of patients achieving durable remission also achieved molecular response, demonstrating correlation between deep clinical responses and molecular activity",
    locations = cells_body(columns = Clinical_Response, rows = 5)
  )
Clinical-Molecular Response Correlation
Relationship Between Hematologic Response and mutCALR VAF Reduction
Clinical Response Type Evaluable (n) Patients (n, %) VAF Details
Any hematologic response (ET) 41 41 (100%) —
VAF reduction in responders 39 37 (95%) 2-91%
Molecular response (≥20% VAF↓) 39 22 (56%) ≥20% reduction
Durable peripheral blood count remission1 16 16 (39%) IWG/ELN criteria
Molecular response in durable remission2 16 14 (88%) ≥20% VAF reduction
Baseline VAF in durable remission with MR 14 14 (100%) 0.22-0.34
1 IWG/ELN = International Working Group/European LeukemiaNet criteria; MR = Molecular Response (≥20% VAF reduction)
2 88% of patients achieving durable remission also achieved molecular response, demonstrating correlation between deep clinical responses and molecular activity

6.5 Key Molecular Findings

6.5.1 Selective Targeting of Malignant Cells

  1. Rapid HSPC Depletion: Single-cell multi-omic analysis (Tapestri™ platform) revealed rapid and selective reductions in mutCALR-positive hematopoietic stem/progenitor cells by the end of cycle 3 (6 weeks)

  2. Bone Marrow Remodeling: Immunohistochemistry analysis demonstrated:

    • Decreased total megakaryocyte density (assessed by CD61 staining)
    • Decreased percentage of mutCALR-positive megakaryocytes
    • Increased percentage of mutCALR-negative (normal) megakaryocytes
    • Changes observed within 24 weeks of treatment

  3. Shift to Normal Hematopoiesis: The combination of HSPC and megakaryocyte changes demonstrates a shift from mutated to normal hematopoiesis, supporting disease modification rather than mere symptom control

6.5.2 Clinical-Molecular Correlation

Strong correlation between molecular response and durable clinical benefit: - 95% of hematologic responders showed some VAF reduction (range 2-91%) - 56% achieved molecular response (≥20% VAF reduction) - Among patients achieving durable peripheral blood count remission: - 88% also achieved molecular response - Baseline VAF in these patients ranged from 0.22 to 0.34 - This suggests patients with intermediate VAF levels may have particularly favorable outcomes

6.5.3 Co-occurring Mutations

  • ET patients: 33% had co-occurring non-driver mutations (0-3 per patient)
    • Most common: TET2 (16%)
  • MF patients: 83% had co-occurring mutations (0-9 per patient)
    • Most common: ASXL1 (42%), TET2 (31%), EZH2 (12%)

Important finding: Molecular responses occurred across a range of baseline VAFs and in patients with co-occurring mutations, suggesting broad applicability of INCA33989 in the mutCALR population

6.5.4 Correlation Between Peripheral Blood and Bone Marrow

  • Strong correlation (R² = 0.97) between mutCALR VAF in bone marrow and peripheral blood
  • Supports use of peripheral blood monitoring for treatment response assessment
  • Enables less invasive monitoring of molecular response

6.6 Implications for Disease Modification

These molecular findings provide strong evidence that INCA33989 achieves disease modification through:

  1. Selective elimination of mutCALR-positive stem/progenitor cells
  2. Restoration of normal (mutCALR-negative) hematopoiesis
  3. Reduction in aberrant megakaryocyte proliferation
  4. Correlation between molecular activity and durable clinical responses

This mechanism distinguishes INCA33989 from traditional cytoreductive agents (hydroxyurea, anagrelide) that non-selectively suppress hematopoiesis without targeting the malignant clone.

7 Summary and Clinical Implications

7.1 Key Findings from ASH 2025 Update (N=51)

  1. Safety Profile: INCA33989 demonstrated excellent tolerability with 94% treatment continuation rate
    • No dose-limiting toxicities observed across all dose levels (24-2500 mg)
    • Maximum tolerated dose not reached
    • Most common adverse events: fatigue (28%) and upper respiratory tract infection (20%)
    • Grade ≥3 adverse events in 33%, most commonly asymptomatic lipase increase (8%)
    • Critical finding: No thrombocytopenia observed in any patient
  2. Hematologic Efficacy: Rapid and durable blood count normalization
    • Overall response rate (CHR+PHR): 80% (41/51 patients)
    • Complete hematologic response (CHR): 73% (37/51 patients)
    • Median time to CHR: 21 days (range 8-324 days)
    • Durable responses (≥12 weeks): 51% of evaluable patients
    • Durable CHR: 39% with median onset at 15 days
  3. Molecular Activity: Evidence of disease modification
    • Any mutCALR VAF reduction: 90% (37/41 patients with longitudinal data)
    • Molecular response (≥20% VAF reduction): 44% (18/41)
    • Partial molecular response (≥50% VAF reduction): 20% (8/41)
    • Among patients achieving durable peripheral blood count remission (39%), 88% achieved molecular response
    • VAF reductions ranged from 2-91%
  4. Concomitant Therapy:
    • 59% enrolled with concomitant hydroxyurea or anagrelide
    • 67% successfully discontinued concomitant cytoreductive therapy
  5. Mechanism of Action Validation:
    • Bone marrow immunohistochemistry showed:
      • Decreased mutCALR-positive megakaryocytes
      • Increased mutCALR-negative megakaryocytes
      • Decreased overall megakaryocyte density (assessed by CD61)
    • Single-cell analysis revealed rapid reductions in mutCALR-positive hematopoietic stem/progenitor cells after 3 cycles

7.2 Clinical Significance

INCA33989 represents a potential paradigm shift in essential thrombocythemia treatment, offering:

7.2.1 Precision Medicine Approach

  • First-in-class targeted therapy specifically for mutCALR-positive ET (approximately 25% of ET patients)
  • Selective targeting of disease-driving mutations while sparing normal hematopoiesis
  • Molecular evidence of preferential elimination of malignant clones

7.2.2 Superior Safety Profile

  • No thrombocytopenia (major limitation of current cytoreductive agents)
  • 94% treatment continuation rate vs. common discontinuation with hydroxyurea
  • Anemia and neutropenia primarily observed with concomitant hydroxyurea
  • Most adverse events mild to moderate in severity

7.2.3 Rapid and Durable Efficacy

  • Fastest time to complete response among ET therapies (21 days median)
  • Durable responses sustained ≥12 weeks in 51% of patients
  • 39% achieved IWG/ELN-defined durable peripheral blood count remission

7.2.4 Disease Modification Potential

  • 90% of patients achieved mutCALR VAF reduction
  • Correlation between molecular response and durable hematologic response
  • Bone marrow analysis confirms shift from mutated to normal hematopoiesis
  • First cytoreductive therapy showing consistent molecular activity in mutCALR ET

7.2.5 Clinical Practice Implications

  • May enable discontinuation of traditional cytoreductive agents (67% discontinued concomitant therapy)
  • Potential for use in high-risk patients intolerant to or failing hydroxyurea
  • Pregnancy planning: Unlike hydroxyurea, may offer safer long-term disease control for young patients
  • Quality of life: Reduced treatment burden compared to daily oral cytoreductive agents

7.3 Comparison with Current Standard of Care

Feature INCA33989 Hydroxyurea
Response Rate 80% 60-80%
Time to Response 21 days 8-12 weeks
Molecular Response 44% (≥20% VAF↓) Rare
Thrombocytopenia 0% Common
Treatment Continuation 94% Often limited by intolerance
Disease Selectivity Targets mutCALR cells Non-selective

7.4 Future Directions

Based on these Phase 1 results, INCA33989 has strong potential for:

  1. Phase 2/3 clinical development in mutCALR-positive ET
  2. Expansion to myelofibrosis (companion abstract abs25-1675 reports data in 59 MF patients)
  3. Front-line therapy for newly diagnosed high-risk patients
  4. Combination strategies with other targeted agents
  5. Biomarker-guided therapy using baseline VAF to predict durable remission

7.5 Conclusion

INCA33989 demonstrated excellent safety, rapid hematologic responses, and meaningful molecular activity in patients with mutCALR-positive essential thrombocythemia. The selective reduction of mutant hematopoietic cells with restoration of normal hematopoiesis supports disease modification potential, representing a significant advance beyond current cytoreductive therapies.

Code 
# Session information
sessionInfo()
R version 4.6.1 (2026-06-24)
Platform: aarch64-apple-darwin23
Running under: macOS Tahoe 26.6

Matrix products: default
BLAS:   /Library/Frameworks/R.framework/Versions/4.6/Resources/lib/libRblas.0.dylib 
LAPACK: /Library/Frameworks/R.framework/Versions/4.6/Resources/lib/libRlapack.dylib;  LAPACK version 3.12.1

locale:
[1] en_US.UTF-8/en_US.UTF-8/en_US.UTF-8/C/en_US.UTF-8/en_US.UTF-8

time zone: America/Chicago
tzcode source: internal

attached base packages:
[1] stats     graphics  grDevices utils     datasets  methods   base     

other attached packages:
[1] flextable_0.10.0 gtsummary_2.5.1  gt_1.3.0         ggplot2_4.0.3   
[5] dplyr_1.2.1      kableExtra_1.4.1 knitr_1.51      

loaded via a namespace (and not attached):
 [1] sass_0.4.10             tidyr_1.3.2             generics_0.1.4         
 [4] fontLiberation_0.1.0    xml2_1.6.0              stringi_1.8.7          
 [7] digest_0.6.39           magrittr_2.0.5          evaluate_1.0.5         
[10] grid_4.6.1              RColorBrewer_1.1-3      fastmap_1.2.0          
[13] jsonlite_2.0.0          zip_3.0.2               purrr_1.2.2            
[16] viridisLite_0.4.3       scales_1.4.0            fontBitstreamVera_0.1.1
[19] textshaping_1.0.5       cli_3.6.6               rlang_1.3.0            
[22] fontquiver_0.2.1        withr_3.0.3             yaml_2.3.12            
[25] otel_0.2.0              gdtools_0.5.1           tools_4.6.1            
[28] officer_0.7.6           uuid_1.2-2              vctrs_0.7.3            
[31] R6_2.6.1                lifecycle_1.0.5         stringr_1.6.0          
[34] fs_2.1.0                htmlwidgets_1.6.4       ragg_1.5.2             
[37] pkgconfig_2.0.3         pillar_1.11.1           gtable_0.3.6           
[40] glue_1.8.1              data.table_1.18.4       Rcpp_1.1.2             
[43] systemfonts_1.3.2       xfun_0.60               tibble_3.3.1           
[46] tidyselect_1.2.1        rstudioapi_0.19.0       farver_2.1.2           
[49] patchwork_1.3.2         htmltools_0.5.9         rmarkdown_2.31         
[52] svglite_2.2.2           compiler_4.6.1          S7_0.2.2               
[55] askpass_1.2.1           openssl_2.4.2