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Since the U.
S.
Food and Drug Administration (FDA) approved the JAK1/2 inhibitor Rucotinib in 2011 and the JAK2 inhibitor Fedratinib in 2019 for the treatment of myelofibrosis (MF; the most aggressive type of myeloproliferation) Sexual tumor [MPN]), the field of MPN treatment has entered a new era
.
The widespread application of approved JAK inhibitors has improved the quality of life of MF patients, and the exploration of new MF treatment strategies is still ongoing
.
Exploratory research focuses on the development of new monotherapy and combination therapy with rucotinib that can exhibit complementary or synergistic effects
.
New treatment modalities are designed to address unmet medical needs, such as anemia and thrombocytopenia, progression of MF to acute myeloid leukemia (AML), poor response or resistance to rucotinib treatment, and overall survival related to the above conditions Issues with a short period (OS)
.
The new exploration direction may target biological pathway targets other than JAK/STAT and/or enhance the efficacy of rucotinib
.
This article summarizes the promising drugs currently undergoing phase III clinical trials in the MF field
.
Treatment of MF patients with cytopenias Nearly half of MF patients have anemia within one year of diagnosis and require red blood cell (RBC) transfusion.
Thrombocytopenia (platelet count <50,000/mL) is the main feature of "bone marrow exhaustion" in MF patients , Can lead to a very poor prognosis
.
Clinical practice shows that anemia is one of the great challenges and poor prognostic factors of MF, and it is the main factor hindering the continued treatment of rucotinib
.
1MomelotinibMomelotinib is a JAK1/2 inhibitor with unique ability to inhibit activin receptor 1 (ACVR1; it can mediate the production of hepatic hepcidin), which is the basis for improving anemia in MF patients, and then maintaining RBC transfusion independence Sex
.
It was observed in two phase III trials (SIMPLIFY-1 and SIMPLIFY-2) that Momelotinib can benefit MF patients in improving anemia, splenomegaly, and systemic symptoms.
The pivotal phase III trial (MOMENTUM) will also further evaluate the previous treatment of Momelotinib The efficacy of JAK inhibitors in patients with anemia
.
2PacritinibPacritinib is a JAK2/FLT3 inhibitor.
Two phase III clinical trials (PERSIST-1 and PERSIST-2) have been carried out to evaluate the efficacy of Pacritinib in MF patients
.
It is worth noting that in the recent dose exploration PAC203 trial, 17% of patients with severe thrombocytopenia MF received 200 mg Pacritinib twice daily, and the spleen volume was reduced by ≥35% at 24 weeks (SVR35)
.
Currently, another phase III clinical trial (PACIFICA) evaluates Pacritinib and "doctor-chosen treatment" (low-dose rucotinib, hydroxyurea, danazol, or steroids) compared to patients with advanced MF and patients with severe thrombocytopenia The efficacy in
.
Currently there is a lack of such approved drugs on the market because the use of JAK inhibitors may accelerate the reduction of blood cells
.
3 In a phase II clinical trial of Luspatercept, a cohort of RBC transfusion-dependent and rucotinib-treated MF patients received Luspatercept (which can promote advanced erythropoiesis) combined with rucotinib treatment.
At 12 weeks, 46% Patients achieved a ≥50% reduction in RBC transfusion burden, and approximately 30% of patients achieved RBC transfusion independence for 12 weeks
.
Recently, a pivotal phase III trial (INDEPENDENCE) was launched to further evaluate the efficacy of Luspatercept in MF patients with MPN-related anemia who are also treated with rucotinib and are RBC infusion-dependent
.
Preclinical studies of the combination drug containing rucotinib 1 targeting BET protein and JAK2 against JAK2 mutant MPN mice have shown that the use of BET inhibitors as a single agent can reduce the production of inflammatory cytokines, and the combination of rucotinib can reduce the production of inflammatory cytokines.
Synergistically inhibit the production of inflammatory cytokines and megakaryocyte infiltration, and eliminate fibrosis
.
Consistent with the results of preclinical studies, the results of the global phase II MANIFEST study showed that the selective BET inhibitor CPI-0610 (pelabresib) combined with rucotinib treats patients who have not previously been treated with rucotinib and has been treated with rucotinib However, MF patients with poor curative effect showed gratifying curative effect.
The SVR35 of CPI-0610 combined with Rucotinib in the treatment of patients who had not received JAK inhibitor treatment in the past was 63%, and 59% of the patients had symptom scores at week 24 ( TSS) improved >50%, which is better than the data on patients treated with rucotinib observed in the pivotal phase III trial
.
The potential synergy of CPI-0610 combined with Rucotinib prompted the development of the global Phase III MANIFEST-2 trial in MF patients who have not received JAK inhibitors
.
2 Targeting anti-apoptotic protein (BCL1-2/BCL-XL) and JAK2Navitoclax is a new oral anti-apoptotic protein BCL-XL and BCL-2 inhibitor
.
Preclinical studies have shown that ABT-737 (Navitoclax's non-clinical analogue) has a synergistic effect with rucotinib
.
A phase II clinical trial evaluated the efficacy of Navitoclax combined with Rucotinib in the treatment of Rucotinib-treated MF patients (platelet count ≥100×109/L).
The results showed that the clinical effect was significant, and 27% of the patients showed SUR35.
, 30% of patients get TSS improvement >50%, and myelofibrosis is reduced
.
Two randomized phase III studies are currently underway to evaluate the efficacy of Navitoclax combined with rucotinib for first-line therapy (TRANSFORM-1) and second-line therapy (TRANSFORM-2) for MF patients
.
3 Targeting phosphatidylinositol 3-kinase (PI3K) and JAK2Parsaclisib is a potent and highly selective PI3Kδ inhibitor.
In patients with MF who had a poor response to rucotinib treatment (stabilized dose), the investigator evaluated The efficacy of Parsaclisib (daily/weekly or daily, two dosages) combined with rucotinib was found, and it was found that daily administration of Parsaclisib had a better effect on reducing spleen volume and improving TSS
.
There will be two phase III trials to further evaluate Parsaclisib and rucotinib in MF patients who have not been treated with JAK-/PI3K inhibitors (LIMBER-313) or treated with rucotinib (LIMBER-304).
Efficacy of combination medication
.
Targeting the p53-HDM2 pathway, KRT-232 is the first HDM2 (a key negative regulator of p53) inhibitor.
In the phase II study (KRT-232-101), KRT-232 was treated with rucotinib in TP53 wild-type The failed MF patients showed good clinical efficacy and tolerability
.
A randomized phase III trial comparing KRT-232 (240mg, 1-7 days/28 days cycle) with Best Available Treatment (BAT) in JAK inhibitor refractory/resistant MF patients has been approved
.
Telomerase inhibitor: ImetelstatImetelstat is the first potent telomerase inhibitor.
In the phase II study IMbark, JAK inhibitor refractory/relapsed intermediate-risk-2 or high-risk MF patients received higher doses of Imetelstat ( (9.
4mg/kg) after treatment, the median overall survival was 29.
9 months
.
In view of this result, a key international phase III trial (IMpactMF) was launched to evaluate the possible survival advantage of Imetelstat for MF patients refractory to JAK inhibitors
.
Summary The application of JAK1/2 inhibitors in MF patients is a series of promising new drugs (such as BET inhibitors, HDM2 inhibitors, BCL-2/BCL-XL inhibitors and telomerase inhibitors, etc.
) The clinical development of the company has opened the way
.
Currently, phase III clinical trials of several promising drug candidates are being carried out in the first-line and second-line treatment of MF.
These studies may accelerate the approval of new drugs and are expected to change the current MF treatment landscape
.
Reference source: Helen T.
Chifotides, Srdan Verstovsek.
2021 SOHO.
EXABS-189-MPN.
Stamp "Read the original text", we make progress together
S.
Food and Drug Administration (FDA) approved the JAK1/2 inhibitor Rucotinib in 2011 and the JAK2 inhibitor Fedratinib in 2019 for the treatment of myelofibrosis (MF; the most aggressive type of myeloproliferation) Sexual tumor [MPN]), the field of MPN treatment has entered a new era
.
The widespread application of approved JAK inhibitors has improved the quality of life of MF patients, and the exploration of new MF treatment strategies is still ongoing
.
Exploratory research focuses on the development of new monotherapy and combination therapy with rucotinib that can exhibit complementary or synergistic effects
.
New treatment modalities are designed to address unmet medical needs, such as anemia and thrombocytopenia, progression of MF to acute myeloid leukemia (AML), poor response or resistance to rucotinib treatment, and overall survival related to the above conditions Issues with a short period (OS)
.
The new exploration direction may target biological pathway targets other than JAK/STAT and/or enhance the efficacy of rucotinib
.
This article summarizes the promising drugs currently undergoing phase III clinical trials in the MF field
.
Treatment of MF patients with cytopenias Nearly half of MF patients have anemia within one year of diagnosis and require red blood cell (RBC) transfusion.
Thrombocytopenia (platelet count <50,000/mL) is the main feature of "bone marrow exhaustion" in MF patients , Can lead to a very poor prognosis
.
Clinical practice shows that anemia is one of the great challenges and poor prognostic factors of MF, and it is the main factor hindering the continued treatment of rucotinib
.
1MomelotinibMomelotinib is a JAK1/2 inhibitor with unique ability to inhibit activin receptor 1 (ACVR1; it can mediate the production of hepatic hepcidin), which is the basis for improving anemia in MF patients, and then maintaining RBC transfusion independence Sex
.
It was observed in two phase III trials (SIMPLIFY-1 and SIMPLIFY-2) that Momelotinib can benefit MF patients in improving anemia, splenomegaly, and systemic symptoms.
The pivotal phase III trial (MOMENTUM) will also further evaluate the previous treatment of Momelotinib The efficacy of JAK inhibitors in patients with anemia
.
2PacritinibPacritinib is a JAK2/FLT3 inhibitor.
Two phase III clinical trials (PERSIST-1 and PERSIST-2) have been carried out to evaluate the efficacy of Pacritinib in MF patients
.
It is worth noting that in the recent dose exploration PAC203 trial, 17% of patients with severe thrombocytopenia MF received 200 mg Pacritinib twice daily, and the spleen volume was reduced by ≥35% at 24 weeks (SVR35)
.
Currently, another phase III clinical trial (PACIFICA) evaluates Pacritinib and "doctor-chosen treatment" (low-dose rucotinib, hydroxyurea, danazol, or steroids) compared to patients with advanced MF and patients with severe thrombocytopenia The efficacy in
.
Currently there is a lack of such approved drugs on the market because the use of JAK inhibitors may accelerate the reduction of blood cells
.
3 In a phase II clinical trial of Luspatercept, a cohort of RBC transfusion-dependent and rucotinib-treated MF patients received Luspatercept (which can promote advanced erythropoiesis) combined with rucotinib treatment.
At 12 weeks, 46% Patients achieved a ≥50% reduction in RBC transfusion burden, and approximately 30% of patients achieved RBC transfusion independence for 12 weeks
.
Recently, a pivotal phase III trial (INDEPENDENCE) was launched to further evaluate the efficacy of Luspatercept in MF patients with MPN-related anemia who are also treated with rucotinib and are RBC infusion-dependent
.
Preclinical studies of the combination drug containing rucotinib 1 targeting BET protein and JAK2 against JAK2 mutant MPN mice have shown that the use of BET inhibitors as a single agent can reduce the production of inflammatory cytokines, and the combination of rucotinib can reduce the production of inflammatory cytokines.
Synergistically inhibit the production of inflammatory cytokines and megakaryocyte infiltration, and eliminate fibrosis
.
Consistent with the results of preclinical studies, the results of the global phase II MANIFEST study showed that the selective BET inhibitor CPI-0610 (pelabresib) combined with rucotinib treats patients who have not previously been treated with rucotinib and has been treated with rucotinib However, MF patients with poor curative effect showed gratifying curative effect.
The SVR35 of CPI-0610 combined with Rucotinib in the treatment of patients who had not received JAK inhibitor treatment in the past was 63%, and 59% of the patients had symptom scores at week 24 ( TSS) improved >50%, which is better than the data on patients treated with rucotinib observed in the pivotal phase III trial
.
The potential synergy of CPI-0610 combined with Rucotinib prompted the development of the global Phase III MANIFEST-2 trial in MF patients who have not received JAK inhibitors
.
2 Targeting anti-apoptotic protein (BCL1-2/BCL-XL) and JAK2Navitoclax is a new oral anti-apoptotic protein BCL-XL and BCL-2 inhibitor
.
Preclinical studies have shown that ABT-737 (Navitoclax's non-clinical analogue) has a synergistic effect with rucotinib
.
A phase II clinical trial evaluated the efficacy of Navitoclax combined with Rucotinib in the treatment of Rucotinib-treated MF patients (platelet count ≥100×109/L).
The results showed that the clinical effect was significant, and 27% of the patients showed SUR35.
, 30% of patients get TSS improvement >50%, and myelofibrosis is reduced
.
Two randomized phase III studies are currently underway to evaluate the efficacy of Navitoclax combined with rucotinib for first-line therapy (TRANSFORM-1) and second-line therapy (TRANSFORM-2) for MF patients
.
3 Targeting phosphatidylinositol 3-kinase (PI3K) and JAK2Parsaclisib is a potent and highly selective PI3Kδ inhibitor.
In patients with MF who had a poor response to rucotinib treatment (stabilized dose), the investigator evaluated The efficacy of Parsaclisib (daily/weekly or daily, two dosages) combined with rucotinib was found, and it was found that daily administration of Parsaclisib had a better effect on reducing spleen volume and improving TSS
.
There will be two phase III trials to further evaluate Parsaclisib and rucotinib in MF patients who have not been treated with JAK-/PI3K inhibitors (LIMBER-313) or treated with rucotinib (LIMBER-304).
Efficacy of combination medication
.
Targeting the p53-HDM2 pathway, KRT-232 is the first HDM2 (a key negative regulator of p53) inhibitor.
In the phase II study (KRT-232-101), KRT-232 was treated with rucotinib in TP53 wild-type The failed MF patients showed good clinical efficacy and tolerability
.
A randomized phase III trial comparing KRT-232 (240mg, 1-7 days/28 days cycle) with Best Available Treatment (BAT) in JAK inhibitor refractory/resistant MF patients has been approved
.
Telomerase inhibitor: ImetelstatImetelstat is the first potent telomerase inhibitor.
In the phase II study IMbark, JAK inhibitor refractory/relapsed intermediate-risk-2 or high-risk MF patients received higher doses of Imetelstat ( (9.
4mg/kg) after treatment, the median overall survival was 29.
9 months
.
In view of this result, a key international phase III trial (IMpactMF) was launched to evaluate the possible survival advantage of Imetelstat for MF patients refractory to JAK inhibitors
.
Summary The application of JAK1/2 inhibitors in MF patients is a series of promising new drugs (such as BET inhibitors, HDM2 inhibitors, BCL-2/BCL-XL inhibitors and telomerase inhibitors, etc.
) The clinical development of the company has opened the way
.
Currently, phase III clinical trials of several promising drug candidates are being carried out in the first-line and second-line treatment of MF.
These studies may accelerate the approval of new drugs and are expected to change the current MF treatment landscape
.
Reference source: Helen T.
Chifotides, Srdan Verstovsek.
2021 SOHO.
EXABS-189-MPN.
Stamp "Read the original text", we make progress together
