Table 1.
Results of Select JAK Inhibitor Clinic Trials
| Agent | Target(s) | Clinical Trial | Patient Characteristics | Key Results | Toxicities |
|---|---|---|---|---|---|
| Ruxolitinib (RUX) | JAK 1/2 | COMFORT-1 Randomized phase 3 study of RUX vs placebo |
Intermediate-2 or high-risk MF RUX (n=155) Placebo (n=154) |
Primary endpoint: SVR ≥35% at 24 weeks - Reached in 41.9% of RUX cohort vs 0.7% in placebo cohort Reduction in TSS ≥50% at 24 weeks - 45.9% (RUX) vs 5.3% (placebo) Median spleen response duration 168.3 weeks (RUX) Median OS at 5 years not reached (RUX) vs 200 weeks (placebo) (HR 0.69; 95% CI 0.50-0.96, p=0.025) |
G3/4 anemia 45.2% G3/4 thrombocytopenia 12.9% G3/4 neutropenia 7.1% Rate of non-hematologic toxicities similar between RUX and placebo groups |
| COMFORT-II Randomized phase 3 study of RUX vs BAT |
Intermediate-2 or high-risk MF RUX (n=146) BAT (n=73) |
Primary endpoint: SVR ≥35% at 48 weeks - Reached in 28% (RUX) vs 0% (BAT) At 5 years, probability of maintaining spleen response 0.48 (95% CI, 0.35-0.60), median duration of spleen response 3.2 years Median OS at 5 years not reached (RUX) vs 4.1 years (BAT) |
Similar to COMFORT-I Any-grade diarrhea 23% |
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| Pacritinib | JAK2/FLT3 | PERSIST-I Randomized phase 3 study of pacritinib vs BAT (excluding JAK inhibitors) |
Intermediate-1, intermediate-2 or high-risk MF JAK inhibitor naïve No exclusions for cytopenias Pacritinib 400 mg daily (n=220) BAT (n=107) |
Primary endpoint: SVR ≥35% at 24 weeks - Reached in 19% (pacritinib) vs 5% (BAT) |
G3/4 anemia 17% G3/4 thrombocytopenia 12% G3/4 diarrhea 5% Heart failure 2% |
| PERSIST-II Randomized phase 3 study of pacritinib vs BAT (including RUX) |
Intermediate-1, intermediate-2, or high-risk MF with platelets <100×109/L Previously treated or JAK inhibitor naïve Pacritinib 400 mg daily (n=104) Pacritinib 200 mg BID (n=107) BAT (n=100) |
Primary endpoints: SVR ≥35% at 24 weeks -Reached in 18% (pacritinib) vs 3% (BAT) Reduction in TSS ≥50% at 24 weeks - Reached in 25% (pacritinib) vs 14% (BAT) |
Toxicities were less frequent in pacritinib BID dosing compared to daily dosing Cardiac AEs in 7% (pacritinib BID), 13% (pacritinib daily), and 9% (BAT) Intracranial hemorrhage 1% (pacritinib daily) *Pacritinib was on full clinical hold 2/2016-1/2017 for fatal toxicity concerns. Further dose finding studies are now planned. |
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| Momelotinib | JAK1/2 | SIMPLIFY-I Randomized phase 3 study of momelotinib vs RUX |
Intermediate-1 (symptomatic), intermediate-2, or high-risk MF, JAK inhibitor naïve Momelotonib (n=215) RUX (n=217) |
Primary endpoint: SVR ≥35% at 24 weeks - Momelotinib non-inferior to RUX for spleen reduction [26.9% (momelotinib) vs 29% (RUX)] Reduction in TSS ≥50% at 24 weeks - Momelotinib was inferior to RUX Transfusion requirements - Momelotinib was associated with decreased transfusion requirements |
G3/4 thrombocytopenia (7%) G3/4 anemia (6%) All grade peripheral neuropathy 10% (momelotinib) vs 5% (RUX) |
| SIMPLIFY-II Randomized phase 3 study of momelotinib vs BAT (including RUX) |
Intermediate-1 (symptomatic), intermediate-2, or high-risk MF previously treated with RUX Momelotinib (n=104) BAT (included RUX in 88%) (n=52) |
Primary endpoint: SVR ≥35% at 24 weeks - Momelotinib was not superior to BAT (including RUX) in improving spleen size in patients previously treated with RUX Reduction in TSS ≥50% at 24 weeks - Momelotinib superior to BAT [26.2% (momelotinib) vs 5.9% (BAT)] Transfusion requirements - Momelotinib was associated with decreased transfusion requirements |
G3/4 anemia (13%) G3/4 thrombocytopenia (7%) All grade peripheral neuropathy 11% (momelotinib) vs 0% (BAT) |
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| NS-018 | JAK2/Src | Phase 1/2 study of 2 dosing schedules of NS-018 (once daily or BID) | Intermediate-1, intermediate-2, or high-risk MF Previously treated or treatment naive Phase 1 n=48 Phase 2 n=29 (ongoing) |
20/36 (56%) evaluable patients with >50% reduction in spleen size by palpation - Includes 9/19 (47%) previously treated with a JAK inhibitor RP2D 300 mg BID. Phase 2 is ongoing. |
G3/4 anemia (21%) G3/4 thrombocytopenia (17%) |
MF, myelofibrosis; RUX, ruxolitinib; SVR, spleen volume reduction; TSS, total symptom score; OS, overall survival; HR, hazard ratio; CI, confidence interval; G3/4, grade 3/4; RP2D, recommended phase 2 dose