9 JAK inhibitor combination therapies

9.1 Pelabresib plus Ruxolitinib

9.1.1 MANIFEST-2

9.1.2 MANIFEST-3

9.2 Selinexor plus Ruxolitinib

9.2.1 SENTRY clinical trial

9.3 Navtemadlin

9.3.1 BOREAS Study

SVR35 at week 25 - 15%
Reduction in circulating CD34 positive cells. It correlates with SVR
Reduction in inflammatory markers

9.3.2 POIESIS Study

N=600

9.4 Imetelstat

9.4.1 IMbark

Phase 2 trial

9.4.2 IMpactMF

Phase 3 trial

9.5 INCB057632

Incyte BETi

9.6 Nuvisertib combination therapy

highly selective PIM1 kinase inhibitor
PIM1 is overexpressed in hematologic malignancies, including myelofibrosis (MF), contributing to disease progression by modulating cytokine-driven pathways such as PI3K/AKT and JAK/STAT.
PIM1 knockout was shown to prevent MF progression without affecting platelet (PLT) counts, whereas pan-PIM knockout caused decreased PLT counts.

9.6.1 Nuvisertib monotherapy (Arm 1)

ASH 2025 abstract

n= 77 r/r MF
5 dose levels from 480 mg QD to 720 mg BID
No DLT occurred
Treatment-related adverse events (TRAEs) occurring in ≥20% of pts were primarily grade 1/2 diarrhea, nausea, and vomiting.
In pts treated with 720 mg BID dose for ≥12 weeks, ≥25% SVR was observed in 4 of 20 pts (20% SVR25 response) and ≥50% reduction in TSS in 9 of 20 pts (44% TSS50 response) at any time.
A strong correlation (p<0.001) between cytokine modulation (e.g. ↓ ENRAGE, ↓ MIP1β, ↓ PAI-1, ↓ IL-1ra and ↑adiponectin) and SVR25, TSS50, and individual symptom improvement were observed.
Anemia Benefit: In pts with baseline Hgb <10 g/dL, 6 of 26 (23%) pts showed Hgb response [≥1.0 g/dL Hgb increase sustained for ≥12 weeks without transfusion, including 3 pts with ≥1.5 g/dL Hgb increase]. Hgb responses were also observed in pts with baseline Hgb >10 g/dL.
Hepcidin reduction
Platelet Response: In pts with baseline PLT <100 × 109/L, 8 of 30 (26.7%) pts showed PLT response [≥30×109/L increase maintained ≥4 weeks] and PLT recovered to ≥100 × 109/L in all responders. Increased levels of cytokines (e.g. TN-C) were observed in PLT responder pts, suggesting a potential link between TN-C modulation and platelet recovery
BM Fibrosis: 13 of 34 (38.2%) evaluable pts (assessments at baseline and ≥Week 24) showed ≥1 grade reduction in BM fibrosis; 11 of 13 pts also showed at least one of SVR25, TSS50, Hgb or PLT responses (5 pts showed dual Hgb and PLT response).
Survival: The 1-year survival rate following nuvisertib treatment was 82% which also correlated with cytokine modulation.

9.6.2 Nuiversitib plus Rux

9.6.3 Nuvisertib plus Momelotinib

--- title: "JAK inhibitor combination therapies" number-sections: true css: style.css code-tools: true --- ## Pelabresib plus Ruxolitinib ### MANIFEST-2 ### MANIFEST-3 ## Selinexor plus Ruxolitinib ### SENTRY clinical trial ## Navtemadlin ### BOREAS Study - SVR35 at week 25 - 15% - *Reduction in circulating CD34 positive cells. It correlates with SVR* - Reduction in inflammatory markers ### POIESIS Study - N=600 ## Imetelstat ### IMbark - Phase 2 trial ### IMpactMF - Phase 3 trial ## INCB057632 - Incyte BETi ------------------------------------------------------------------------ ## Nuvisertib combination therapy - highly selective `PIM1 kinase inhibitor` - PIM1 is overexpressed in hematologic malignancies, including myelofibrosis (MF), contributing to disease progression by modulating cytokine-driven pathways such as PI3K/AKT and JAK/STAT. - PIM1 knockout was shown to prevent MF progression without affecting platelet (PLT) counts, whereas pan-PIM knockout caused decreased PLT counts. ### Nuvisertib monotherapy (Arm 1) ------------------------------------------------------------------------ ASH 2025 abstract - n= 77 r/r MF - 5 dose levels from 480 mg QD to 720 mg BID - No DLT occurred - Treatment-related adverse events (TRAEs) occurring in ≥20% of pts were primarily `grade 1/2 diarrhea`, `nausea`, and `vomiting`. - In pts treated with `720 mg BID` dose for ≥12 weeks, ≥25% SVR was observed in 4 of 20 pts (20% SVR25 response) and ≥50% reduction in TSS in 9 of 20 pts (44% TSS50 response) at any time. - A strong correlation (p\<0.001) between cytokine modulation (e.g. ↓ ENRAGE, ↓ MIP1β, ↓ PAI-1, ↓ IL-1ra and ↑adiponectin) and SVR25, TSS50, and individual symptom improvement were observed. - **Anemia Benefit**: In pts with baseline Hgb \<10 g/dL, 6 of 26 (23%) pts showed Hgb response \[≥1.0 g/dL Hgb increase sustained for ≥12 weeks without transfusion, including 3 pts with ≥1.5 g/dL Hgb increase\]. Hgb responses were also observed in pts with baseline Hgb \>10 g/dL. - Hepcidin reduction - **Platelet Response**: In pts with baseline PLT \<100 × 109/L, 8 of 30 (26.7%) pts showed PLT response \[≥30×109/L increase maintained ≥4 weeks\] and PLT recovered to ≥100 × 109/L in all responders. Increased levels of cytokines (e.g. TN-C) were observed in PLT responder pts, suggesting a potential link between `TN-C` modulation and platelet recovery - **BM Fibrosis**: 13 of 34 (38.2%) evaluable pts (assessments at baseline and ≥Week 24) showed ≥1 grade reduction in BM fibrosis; 11 of 13 pts also showed at least one of SVR25, TSS50, Hgb or PLT responses (5 pts showed dual Hgb and PLT response). - **Survival**: The 1-year survival rate following nuvisertib treatment was 82% which also correlated with cytokine modulation. ------------------------------------------------------------------------ ### Nuiversitib plus Rux ------------------------------------------------------------------------ ### Nuvisertib plus Momelotinib ------------------------------------------------------------------------