BET Inhibitors Treatment of Myelofibrosis
by Dr. C.H. Weaver M.D. 1/2021
Updated MANIFEST clinical trial data were presented at the American Society of Hematology (ASH) 2020 meeting exploring the role of CPI-0610, a bromodomain and extra-terminal domain protein (BET) inhibitor in combination with Jakafi (ruxoltinib) in patients with myelofibrosis. Myelofibrosis (MF) is characterized by presence of bone marrow fibrosis, increased cytokine production and inflammation, over activation of JAK-STAT pathway, aberrant erythroid and megakaryocytic differentiation. BET inhibitors suppress cytokine production, promote erythroid differentiation and normalize megakaryocytic differentiation. (1)
BET proteins regulate key cancer causing pathways which are important drivers of pro-inflammatory cytokine expression and bone marrow fibrosis implicated in myelofibrosis. Preclinical studies suggest that a combination of BETi and Jakafi may result in synergistic reduction of splenomegaly and bone marrow fibrosis. (2)
CPI-0610 was evaluated alone and in combination with Jakafi in MF patients who were refractory/intolerant or had an inadequate initial response to Jakafi. Results of the first 48 patients enrolled in the Phase 2 MANIFEST clinical trial were released at ASH 2019.
- Spleen volume reduction was observed in 94% of patients.
- An increase in hemoglobin by 1.5 mg/dL post-baseline was observed with both CPI-0610 monotherapy and CPI-0610 + Jakafi.
- Improvement in bone marrow fibrosis was reported in 58% of evaluable patients.
Preliminary data indicate that CPI-0610 alone or combined with Jakafi is generally well-tolerated and provides clinical benefits in MF patients with inadequate responses or who are refractory to Jakafi. Improvement in bone marrow fibrosis and anemia responses indicate the potential for meaningful disease modification.
At ASH 2021 updates on the combination of CPI-0610 combined with Jakafi were presented.
Seventy-eight patients with intermediate or higher risk myelofibrosis with no prior JAK inhibitor (JAKi) treatment were treated with the Jakafi-CPI-0610 combination.
- The primary objective of spleen volume reduction by 35% (SVR35) at week 24 was achieved in 67% of patients.
- Total symptom score improved with a more than 50% reduction in symptoms (TSS50) reported in 57% of patients.
- Hemoglobin increase was noted among patients particularly those with baseline less than 10 g/dl.
- One third of the patients demonstrated at least one grade improvement in bone marrow fibrosis.
The MANIFEST-2 will be a global, double-blind, randomized Phase 3 clinical study with CPI-0610 with or without Jakafi in JAK-inhibitor-naïve patients with myelofibrosis who have splenomegaly and symptoms requiring therapy
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- MANIFEST, a Phase 2 Study of CPI-0610, a Bromodomain and Extraterminal Domain Inhibitor (BETi), As Monotherapy or "Add-on" to Ruxolitinib, in Patients with Refractory or Intolerant Advanced Myelofibrosis