FDA Approves INREBIC® for Myelofibrosis

SUMMARY: The FDA on August 16, 2019, approved INREBIC® (Fedratinib) for adults with Intermediate-2 or High-risk Primary or Secondary (post-Polycythemia Vera or post-Essential Thrombocythemia) Myelofibrosis (MF).

Myelofibrosis is a MyeloProliferative Neoplasm (MPN) characterized by ineffective hematopoiesis, progressive fibrosis of the bone marrow and potential for leukemic transformation. This stem cell disorder is Philadelphia Chromosome negative and manifestations include anemia, splenomegaly and related symptoms such as abdominal distension and discomfort with early satiety. Cytokine driven debilitating symptoms such as fatigue, fever, night sweats, weight loss, pruritus and bone or muscle pain can further impact an individual’s quality of life. Myelofibrosis can be Primary (PMF) or Secondary to Polycythemia Vera (PV) or Essential Thrombocythemia (ET).JAK-STAT-Signaling-Pathway The JAK-STAT signaling pathway has been implicated in the pathogenesis of Myelofibrosis. This pathway normally is responsible for passing information from outside the cell through the cell membrane to the DNA in the nucleus, for gene transcription. Janus Kinase (JAK) family of tyrosine kinases are cytoplasmic proteins and include JAK1, JAK2, JAK3 and TYK2. JAK1 helps propagate the signaling of inflammatory cytokines whereas JAK2 is essential for growth and differentiation of hematopoietic stem cells. These tyrosine kinases mediate cell signaling by recruiting STAT’s (Signal Transducer and Activator of Transcription), with resulting modulation of gene expression. In patients with MPN, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines associated with this abnormal signaling. These cytokines contribute to the symptoms often reported by patients with MF. JAK2 mutations such as JAK2 V617F are seen in approximately 60% of the patients with PMF and ET and 95% of patients with PV. Unlike CML where the BCR-ABL fusion gene triggers the disease, JAK2 mutations are not initiators of the disease and are not specific for MPN. Further, several other genetic events may contribute to the abnormal JAK2-STAT signaling. Currently, JAKAFI® (Ruxolitinib) is the only drug that has been approved by the FDA for Myelofibrosis.

INREBIC® is a highly selective JAK2 inhibitor and is active against a broader family of kinases and kinase mutants. This is unlike JAKAFI® which is a JAK1/2 inhibitor. The approval of INREBIC®was based on findings from the Phase III JAKARTA-2 study, which evaluated INREBIC® in patients with Primary or Secondary Myelofibrosis. In this double-blind, randomized, placebo-controlled trial, 289 patients with Intermediate-2 or High-risk MF, post-Polycythemia Vera MF, or post-Essential Thrombocythemia MF with splenomegaly, were randomized to receive either INREBIC® 500 mg (N=97), 400 mg (N=96) or placebo (N=96), once daily for at least 6 consecutive 4-week cycles. The Primary endpoint was the proportion of patients achieving 35% or more reduction in spleen volume from baseline at the end of cycle 6 measured by MRI or CT, with a follow up scan 4 weeks later. Secondary end point was symptom response (50% or more reduction in total symptom score, assessed using the modified Myelofibrosis Symptom Assessment Form).

The Primary end point was achieved by 37% of the patients receiving INREBIC® at the 400 mg dose compared with 1% of patients who were in the placebo group (P <0.0001). The median duration of spleen response was 18.2 months for the INREBIC® 400 mg group. Further, 40% of patients who received INREBIC® at the 400 mg dose, experienced a 50% or more reduction in Myelofibrosis-related symptoms, whereas only 9% of patients receiving placebo experienced a decrease in these symptoms (P<0.0001). The most common adverse reactions seen in 20% or more patients who received INREBIC® were diarrhea, nausea, anemia, and vomiting.

In conclusion, INREBIC® therapy significantly reduced splenomegaly and symptom burden in patients with Myelofibrosis. This FDA approval represents an important milestone for patients with Myelofibrosis and clinicians now have a new treatment option for these patients, including those previously treated with JAKAFI®. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fedratinib-myelofibrosis

INREBIC® (Fedratinib)

The FDA on August 16, 2019 approved INREBIC® for adults with intermediate-2 or high-risk Primary or Secondary (post-Polycythemia Vera or post-Essential Thrombocythemia) Myelofibrosis (MF). INREBIC® is a product of Impact Biomedicines, Inc.

Late Breaking Abstract – ASH 2016 Superior Efficacy Data with Pacritinib in Myelofibrosis

SUMMARY: Myelofibrosis is a MyeloProliferative Neoplasm (MPN) characterized by ineffective hematopoiesis, progressive fibrosis of the bone marrow and potential for leukemic transformation. This stem cell disorder is Philadelphia Chromosome negative and manifestations include anemia, splenomegaly and related symptoms such as abdominal distension and discomfort with early satiety. Cytokine driven debilitating symptoms such as fatigue, fever, night sweats, weight loss, pruritus and bone or muscle pain can further impact an individual’s quality of life. Myelofibrosis can be primary (PMF) or secondary to Polycythemia Vera (PV) or Essential Thrombocythemia (ET). The JAK-STAT signaling pathway has been implicated in the pathogenesis of Myelofibrosis. This pathway normally is responsible for passing information from outside the cell through the cell membrane to the DNA in the nucleus, for gene transcription. Janus Kinase (JAK) family of tyrosine kinases are cytoplasmic proteins and include JAK1, JAK2, JAK3 and TYK2. JAK1 helps propagate the signaling of inflammatory cytokines whereas JAK2 is essential for growth and differentiation of hematopoietic stem cells. These tyrosine kinases mediate cell signaling by recruiting STAT’s (Signal Transducer and Activator of Transcription), with resulting modulation of gene expression. In patients with MPN, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines associated with this abnormal signaling. These cytokines contribute to the symptoms often reported by patients with MF. JAK2 mutations such as JAK2 V617F are seen in approximately 60% of the patients with PMF and ET and 95% of patients with PV. Unlike CML where the BCR-ABL fusion gene triggers the disease, JAK2 mutations are not initiators of the disease and are not specific for MPN. Further, several other genetic events may contribute to the abnormal JAK2-STAT signaling.

Pacritinib is a potent JAK2 inhibitor, without significant JAK1 inhibition. It additionally targets FLT3, IRAK1, and CSF1R. Preliminary studies have shown minimal myelosuppression with Pacritinib. JAKAFI® (Ruxolitinib) is a potent JAK1 and JAK2 inhibitor approved by the FDA in 2011 to treat intermediate or high-risk Myelofibrosis. It is however not indicated for patients with platelet counts under 50,000/μl, and this group represents approximately one third of Myelofibrosis patients and have limited or no treatment options. Previously published PERSIST-1 trial showed that Pacritinib significantly reduced Spleen Volume and Myelofibrosis associated symptoms, in patients with low platelet count, when compared to Best Available Therapy (excluding JAKAFI®).

PERSIST-2 is an open label, phase III study in which the safety and efficacy of Pacritinib was compared with currently available therapies, including JAKAFI®, thus expanding the definition of Best Available Therapy (BAT). A total of 311 patients with platelet counts 100,000/μl or less were randomly assigned in a 1:1:1 ratio to receive Pacritinib 200 mg BID (N=107), 400 mg QD (N=104) or Best Available Therapy (N=100). The efficacy population in the Intent To Treat group included a total of 221 patients. Approximately half of the study population had platelet counts of less than 50,000/μl. Over 40% of the patients in both the treatment groups had prior therapy with JAKAFI®. About 60-70% of the patients had a diagnoses of Primary Myelofibrosis, and half of the patients fell in the International Prognostic Scoring System (IPSS) Intermediate-2 risk category. The two coprimary endpoints were the proportion of patients achieving 35% or greater reduction in Spleen Volume (SVR) as measured by MRI or CT scan and the proportion achieving a 50% or more improvement in symptoms such as fatigue, bone pain, itching, and abdominal pain after 24 weeks of follow up. The secondary objectives were to compare Pacritinib BID and Pacritinib QD, individually to BAT.

It was noted that 18% of patients who received Pacritinib achieved a 35% or greater reduction in Spleen Volume from baseline to week 24, compared to 3% of those in the BAT group (P=0.001). In the patient group who received Pacritinib twice daily, 32% reported a 50% or more reduction in symptoms compared with 14% in the BAT group (P=0.01). Further, patients treated with Pacritinib required fewer red blood cell transfusions and additionally, patients who received Pacritinib twice daily had substantially greater improvement in platelet count among those who had platelets counts 50,000/μl or less at enrollment. The most common adverse events related to Pacritinib included nausea, vomiting, diarrhea, anemia, and low platelets.

The authors concluded that this is the only randomized trial to date in patients with Myelofibrosis and thrombocytopenia that enrolled patients who had prior therapy with a JAK2 inhibitor. Regardless, Pacritinib was more effective at Spleen Volume Reduction than BAT and Pacritinib given BID was even more effective than QD dosing. Results of the Persist-2 Phase 3 Study of Pacritinib (PAC) Versus Best Available Therapy (BAT), Including Ruxolitinib (RUX), in Patients (pts) with Myelofibrosis (MF) and Platelet Counts <100,000/µl. Hoffman R, Talpaz M, Gerds AT, et al. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract LBA-5.

Long Term Data Confirms Durable Efficacy and Safety of JAKAFI® in Myelofibrosis

SUMMARY: MyeloFibrosis (MF) is a MyeloProliferative Neoplasm (MPN) characterized by a ineffective hematopoiesis, progressive fibrosis of the bone marrow and potential for leukemic transformation. This stem cell disorder is Philadelphia Chromosome negative and manifestations include anemia, splenomegaly and related symptoms such as abdominal distension and discomfort with early satiety. Cytokine driven debilitating symptoms such as fatigue, fever, night sweats, weight loss, pruritus and bone or muscle pain can further impact an individual’s quality of life. Myelofibrosis can be primary (PMF) or secondary to Polycythemia Vera (PV) or Essential Thrombocythemia (ET). The JAK-STAT signaling pathway has been implicated in the pathogenesis of Myelofibrosis. This pathway normally is responsible for passing information from outside the cell through the cell membrane to the DNA in the nucleus for gene transcription. Janus Kinase (JAK) family of tyrosine kinases are cytoplasmic proteins and include JAK1, JAK2, JAK3 and TYK2. JAK1 helps propagate the signaling of inflammatory cytokines whereas JAK2 is essential for growth and differentiation of hematopoietic stem cells. These tyrosine kinases mediate cell signaling by recruiting STAT’s (Signal Transducer and Activator of Transcription), with resulting modulation of gene expression. In patients with MPN, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines associated with this abnormal signaling. These cytokines contribute to the symptoms often reported by patients with MF. JAK2 mutations such as JAK2 V617F are seen in approximately 60% of the patients with PMF and ET and 95% of patients with PV. Unlike CML where the BCR-ABL fusion gene triggers the disease, JAK2 mutations are not initiators of the disease and are not specific for MPN. Further, several other genetic events may contribute to the abnormal JAK2-STAT signaling.

JAKAFI® (Ruxolitinib) is a potent JAK1 and JAK2 inhibitor and exerts its mechanism of action by targeting and inhibiting the dysregulated JAK2-STAT signaling pathway. The FDA approval of JAKAFI® for the treatment of Intermediate and high risk Myelofibrosis was based on two phase III trials – COMFORT (Controlled Myelofibrosis Study with Oral JAK1/JAK2 Inhibitor Treatment)-I and COMFORT-II studies. JAKAFI® in patients with Myelofibrosis, demonstrated rapid and durable improvements in splenomegaly and symptoms as well as improved survival in both phase III COMFORT studies. The authors now reported the final long term efficacy and safety results after 5 years of treatment with JAKAFI® in the COMFORT-I study. In COMFORT-I study, 309 intermediate or high risk patients were randomized to receive either JAKAFI® (N=155) or Placebo (N=154). The Primary end point was a 35% or more reduction in spleen size at 24 weeks. The preplanned 5- year analysis occurred when all patients reached the 5-year visit or discontinued treatment. Patients in the placebo group could crossover to the JAKAFI® group after the primary analysis (when all patients completed week 24) or at any time if they had pre-specified worsening of splenomegaly. Of the 154 patients randomized to placebo, 111 patients crossed over to the JAKAFI® group and the median time to crossover was 41 weeks.

It was noted that at week 24, patients in the JAKAFI® arm had a mean Spleen Volume reduction of 32% from baseline and this response was durable for patients who continued treatment, with a mean Spleen Volume reduction of 38% at week 264 (5 years). At 5 years, 18.5% of patients on JAKAFI® had a 35% or more, reduction in Spleen Volume from baseline. Median duration of this spleen response (35% or more reduction in Spleen Volume) in the JAKAFI® group was 168 weeks. Overall Survival was significantly better for patients originally randomized to JAKAFI® compared to placebo (HR=0.69; P=0.025). The mean hemoglobin and platelet count remained stable through 5 years, after week 24. Adverse events included anemia, thrombocytopenia, Herpes Zoster and Basal Cell Carcinomas

The authors concluded that after a median follow up of over 5 years, patients with Myelofibrosis randomized to receive JAKAFI® in the COMFORT-I study, had a superior Overall Survival compared to placebo, as well as durable spleen response, while on long term therapy with JAKAFI®. Long-Term Outcomes of Ruxolitinib(RUX) Therapy in Patients(PTS) with Myelofibrosis(MF): 5-Year Final Efficacy and Safety Analysis from COMFORT-I. Verstovsek S, Mesa RA, Gotlib JR, et al. Presented at 2016 European Hematology Association Congress; June 9-12, 2016; Copenhagen, Denmark. Abstract:S452

Pacritinib for Myelofibrosis – A New JAK-2 Inhibitor with a Better Toxicity Profile

SUMMARY: Myelofibrosis is a MyeloProliferative Neoplasm (MPN) characterized by a ineffective hematopoiesis, progressive fibrosis of the bone marrow and potential for leukemic transformation. This stem cell disorder is Philadelphia Chromosome negative and manifestations include anemia, splenomegaly and related symptoms such as abdominal distension and discomfort with early satiety. Cytokine driven debilitating symptoms such as fatigue, fever, night sweats, weight loss, pruritus and bone or muscle pain can further impact an individual’s quality of life. Myelofibrosis can be primary (PMF) or secondary to Polycythemia Vera (PV) or Essential Thrombocythemia (ET). The JAK-STAT signaling pathway has been implicated in the pathogenesis of Myelofibrosis. This pathway normally is responsible for passing information from outside the cell through the cell membrane to the DNA in the nucleus, for gene transcription. Janus Kinase (JAK) family of tyrosine kinases are cytoplasmic proteins and include JAK1, JAK2, JAK3 and TYK2. JAK1 helps propagate the signaling of inflammatory cytokines whereas JAK2 is essential for growth and differentiation of hematopoietic stem cells. These tyrosine kinases mediate cell signaling by recruiting STAT’s (Signal Transducer and Activator of Transcription), with resulting modulation of gene expression. In patients with MPN, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines associated with this abnormal signaling. These cytokines contribute to the symptoms often reported by patients with MF. JAK2 mutations such as JAK2 V617F are seen in approximately 60% of the patients with PMF and ET and 95% of patients with PV. Unlike CML where the BCR-ABL fusion gene triggers the disease, JAK2 mutations are not initiators of the disease and are not specific for MPN. Further, several other genetic events may contribute to the abnormal JAK2-STAT signaling.

Pacritinib is a potent JAK2 inhibitor, without significant JAK1 inhibition. Preliminary studies have shown minimal myelosuppression with Pacritinib. JAKAFI® (Ruxolitinib) is a potent JAK1 and JAK2 inhibitor and is not safe for patients with low platelet counts. PERSIST-1 is a phase III study in which 327 patients with intermediate or high-risk Primary MyeloFibrosis (PMF), Post–Polycythemia Vera MF or Post–Essential Thrombocythemia MF were enrolled. Patients were randomized in a 2:1 ratio to receive Pacritinib 400 mg once daily (N=220) or Best Available Therapy (BAT) excluding JAKAFI® (N=107). Patients in the BAT group received Erythropoietin Stimulating Agents, Immunomodulatory drugs such as THALOMID® (Thalidomide), REVLIMID® (Lenalidomide) and Hydroxyurea. Because patients with very low platelet counts were enrolled in this study, JAKAFI® therapy was excluded, as JAKAFI® is not considered safe for patients with low platelet count. Approximately 32% of the patients had a platelet count of less than 100,000/µL and 15% had a platelet count of less than 50,000/ µL. About 75% of the patients were JAK2V617F positive. The median duration of treatment was 16.2 months in the Pacritinib group and 5.9 months in the BAT group. The primary endpoint was the proportion of patients achieving 35% or more reduction in the spleen volume at 24 weeks. Secondary endpoints included the proportion achieving 50% or more reduction in MyeloProliferative Neoplasm symptom score at 24 weeks.

At 24 weeks of treatment, 19.1% of patients in the Pacritinib group experienced 35% or more reduction in spleen volume compared to 4.7% in the Best Available Therapy (BAT) group (P=0.0003). This benefit was even more so in the subgroup of patients with the lowest platelet counts (less than 50,000/ µL), with 33.3% in the Pacritinib group demonstrating spleen volume reduction, compared to none in the BAT group. Patients in the Pacritinib arm were much more likely to experience more than a 50% reduction in symptoms, compared to BAT group at 24 weeks (24.5% vs 6.5%; P<0.0001), with significant improvements in fatigue, early satiety, abdominal discomfort, pruritus, night sweats and bone pain. This symptom improvement was noted by 4-8 weeks. Approximately 25% of the patients in the Pacritinib group achieved transfusion independence compared with none in the control group (P=0.043). The most common adverse events associated with Pacritinib were diarrhea, nausea and vomiting.

The authors concluded that Pacritinib significantly reduces spleen volume and Myelofibrosis associated symptoms, and fulfills an unmet need for Myelofibrosis patients with low platelet count, in addition to achieving RBC transfusion independence. Results of the PERSIST-1 phase III study of pacritinib (PAC) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia-myelofibrosis (PET-MF). Mesa RA, Egyed M, Szoke A, et al. J Clin Oncol 33, 2015 (suppl; abstr LBA7006)

Ruxolitinib for Myelofibrosis – An Update of Its Clinical Effects

SUMMARY: MyeloFibrosis (MF) is a MyeloProliferative Neoplasm (MPN) characterized by a ineffective hematopoiesis, progressive fibrosis of the bone marrow and potential for leukemic transformation. This stem cell disorder is Philadelphia Chromosome negative and manifestations include anemia, splenomegaly and related symptoms such as abdominal distension and discomfort with early satiety. Cytokine driven debilitating symptoms such as fatigue, fever, night sweats, weight loss, pruritus and bone or muscle pain can further impact an individual’s quality of life. Myelofibrosis can be primary (PMF) or secondary to Polycythemia Vera (PV) or Essential Thrombocythemia (ET). The JAK-STAT signaling pathway has been implicated in the pathogenesis of Myelofibrosis. This pathway normally is responsible for passing information from outside the cell through the cell membrane to the DNA in the nucleus for gene transcription. Janus Kinase (JAK) family of tyrosine kinases are cytoplasmic proteins and include JAK1, JAK2, JAK3 and TYK2. JAK1 helps propagate the signaling of inflammatory cytokines whereas JAK2 is essential for growth and differentiation of hematopoietic stem cells. These tyrosine kinases mediate cell signaling by recruiting STAT’s (Signal Transducer and Activator of Transcription), with resulting modulation of gene expression. In patients with MPN, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines associated with this abnormal signaling. These cytokines contribute to the symptoms often reported by patients with MF. JAK2 mutations such as JAK2 V617F are seen in approximately 60% of the patients with PMF and ET and 95% of patients with PV. Unlike CML where the BCR-ABL fusion gene triggers the disease, JAK2 mutations are not initiators of the disease and are not specific for MPN. Further, several other genetic events may contribute to the abnormal JAK2-STAT signaling. JAKAFI® is a potent JAK1 and JAK2 inhibitor and exerts its mechanism of action by targeting and inhibiting the dysregulated JAK2-STAT signaling pathway. The FDA approval of JAKAFI® for the treatment of Intermediate and high risk Myelofibrosis was based on 2 phase III trials – COMFORT (Controlled Myelofibrosis Study with Oral JAK1/JAK2 Inhibitor Treatment) – I and COMFORT-II studies. In COMFORT-I study, 309 intermediate or high risk patients were randomized to receive either JAKAFI® (N=155) or Placebo (N=154). The primary end point of a 35% or more reduction in spleen size at 24 weeks was noted in 42% of those who received JAKAFI® vs 0.7% in the placebo group (P<0.0001). Most patients in the JAKAFI® group had some reduction in the spleen volume whereas majority of those in the placebo arm had increase in splenomegaly. There was a 46% reduction in the TSS (Total Symptom Score) at week 24 in the JAKAFI® group compared to 5% in the placebo group and majority of patients in the later group had worsening of symptoms (P<0.0001). When JAKAFI® was compared to Best Available Therapy (BAT) in the COMFORT-II study, 28% of the patients in the JAKAFI® group met the primary endpoint of a 35% or more reduction in the spleen volume at 48 weeks compared to none in the BAT group (P<0.0001). Over 55% had a mean decrease in spleen size in the JAKAFI® compared to a 4% mean increase in the BAT group. The 2 year follow up analyses from both these trials showed improved overall survival and a reduction in the risk of death for patients randomized to JAKAFI®, compared to those in the control groups. There was weight gain with alleviation of cachexia and improvements in splenomegaly and symptoms were durable. This benefit was seen in patients regardless of JAK mutations. It remains to be seen if JAKAFI® will benefit patients with Polycythemia Vera and Essential Thrombocythemia. Kantarjian HM, Silver RT, Komrokji RS, et al. Clinical Lymphoma Myeloma and Leukemia 2013; 13:638-645