Kowalski, Mark

7046 Background: Momelotinib (MMB) is a potent JAK1, JAK2 and ACVR1 inhibitor with clinical activity against the hallmark features of myelofibrosis (MF), namely anemia, constitutional symptoms and splenomegaly, across the continuum of JAKi naïve or previously JAKi treated intermediate/high risk MF patients as demonstrated in the previously conducted Phase 3 SIMPLIFY-1 & -2 clinical trials (S1, S2). S1 enrolled JAKi-naïve patients with MF (n = 432) double-blind randomized 1:1 to MMB or ruxolitinib (RUX). S2 enrolled patients with MF with hematological toxicity during prior RUX therapy (n = 156) randomized 2:1 to open-label MMB or best available therapy (BAT; consisting of RUX in 88% of patients). In both trials, following the 24-week randomized treatment (RT) period, patients could continue MMB (MMB→MMB) and those randomized to RUX/BAT could cross-over to MMB (RUX/BAT→MMB) for extended treatment (ET). Previously published data from the SIMPLIFY studies demonstrate robust overall survival (OS) for MMB-treated patients in S1 and S2 (median not reached and 34.3 months, respectively) with a maximum follow up of approximately 5 years and median of 2.9 years in S1 and 2.3 years in S2. Methods: OS data for patients receiving MMB in S1 and S2 are reported here for subgroups defined by Week 24 (W24) transfusion independence (TI) responders vs non-responders, and also other efficacy endpoints. Survival was estimated using KM analysis with descriptive log-rank tests for comparison applied (all p-values are descriptive). Results: As previously reported, W24 TI rates were higher in the MMB arms of S1 (67% vs 49%) and S2 (43% vs 21%). In S1, W24 TI responders in the MMB group show an OS advantage, with median OS not reached and 3-year survival of 80% (HR = 0.30; p = 0.0001) compared to MMB TI non-responders. Similarly in S2, W24 TI responders in the MMB group show a trend toward better OS compared to TI non-responders (HR = 0.57; p = 0.0652). The HRs in S1 for MMB responders vs non-responders for W24 SRR and TSS were 0.59 (p = 0.0904) and 0.65 (p = 0.1657), respectively. Alternative analyses using OS defined from W24 demonstrated consistent results. Conclusions: These new analyses suggest JAKi naïve patients receiving MMB who maintain or achieve TI at W24 have favorable OS compared to MMB TI non-responders, with a similar trend observed in S2. These findings are consistent with anemia and transfusion dependency being key predictors of shortened OS in MF and suggest that TI response at W24 may become a surrogate for clinical benefit, supporting the clinical relevance of MMB’s differentiated pro-erythropoietic ACVR1 inhibition. Clinical trial information: NCT01969838.

Abstract Momelotinib (MMB) is a JAK1/2 and ACVR1 inhibitor with demonstrated clinical activity in all 3 hallmarks of myelofibrosis (MF): anemia, constitutional symptoms, and splenomegaly. In this phase 2 open-label translational biology study (NCT02515630) of 41 transfusion-dependent patients with MF, we explored mechanisms underlying the favorable activity of MMB on MF-associated iron-restricted anemia, including its impact on serum hepcidin levels, and markers of iron storage and availability, erythropoiesis, and inflammation. A transfusion-independent response (TI-R), defined as red blood cell transfusion independence (TI) ≥12 weeks at any time on study, occurred in 17 patients (41%; 95% confidence interval [CI], 26%-58%), including 14 patients (34%; 95% CI, 20%-51%) who achieved TI-R by week 24. In addition, 78% of TI nonresponse (TI-NR) patients achieved a ≥50% decrease in transfusion requirement for ≥8 weeks. Adverse events (AEs) were consistent with previous studies of MMB in MF, with cough, diarrhea, and nausea as the most common. Twenty-one patients experienced grade ≥3 AEs, most commonly anemia and neutropenia. Consistent with preclinical data, daily MMB treatment led to an acute and persistent decrease in blood hepcidin associated with increased iron availability and markers of erythropoiesis. Baseline characteristics associated with TI-R were lower inflammation and hepcidin as well as increased markers of erythropoiesis and bone marrow function. Overall, the study demonstrates that MMB treatment decreases hepcidin in conjunction with improving iron metabolism and erythropoiesis, suggesting a mechanistic explanation for the reduced transfusion dependency observed in transfusion-dependent MF patients treated with MMB, thereby addressing the key unmet medical need in the MF population.

Abstract Abstract 3849 Background: CYT387 is a potent JAK-1/2 inhibitor. The maximum tolerated dose (MTD) and preliminary safety and efficacy of once daily dosing of CYT387 were determined in a single center Phase I/II study. Previously reported results from the first 60 subjects enrolled in this study determined a MTD of 300 mg QD and demonstrated improvements in splenomegaly and constitutional symptoms as well as in RBC transfusion requirements. The study was expanded into a multicenter study with planned accrual of 165 subjects at 6 study sites and a twice daily dosing arm was added. The preliminary safety and efficacy results from this expanded multicenter study will be presented. Methods: Subjects with high or intermediate-risk primary myelofibrosis (PMF) and post-polycythemia vera (post-PV) or post-essential thrombocythemia (ET) myelofibrosis were enrolled. In the core expansion study, oral CYT387 was administered either once daily at 150 mg or 300 mg or twice daily at 150 mg for 9 months. Patients who maintained at least stable disease were permitted to continue CYT387 treatment beyond 9 months in an extension phase of the study. Responses were assessed by International Working Group (IWG) Criteria. Results: At present, 163 subjects have been enrolled across the 6 study sites. The diagnoses of enrolled subjects include 64% PMF, 14% post-ET MF and 22% post-PV MF; 67% of the patients were JAK2V617F positive. Starting doses of CYT387 in the dose escalation, confirmation and expansion phases of the study are shown in Table 1. The median duration (range) of treatment was 6.6 months (0.25 to 20.4 months). Patient characteristics were as follows: median age 68 years, 58% male, 87% were spleen evaluable at baseline per IWG criteria (median spleen length was 18 cm by palpation). Sixty three percent (63%) of subjects were anemia evaluable at baseline per IWG criteria; 46% were transfusion dependent. Previous JAK inhibitor and IMiD therapy was reported for 11% and 8% of enrolled subjects, respectively. Reductions in spleen size, improvements in constitutional symptoms and the achievement of transfusion independence were observed in subjects in the expanded multicenter study. CYT387 was well tolerated. Based on currently available data, 73% of subjects reported treatment-related adverse events, with the majority reported as Grade 1. The most common Grade 3–4 treatment related adverse events included thrombocytopenia (16%), and hyperlipasemia (3%). New onset treatment-related Grade 3–4 anemia remains rare (<1%). Grade 1 toxicities included peripheral sensory neuropathy whose incidence and natural history is currently being studied. Twenty-five of 163 subjects (15%) have discontinued from the 9 month core study giving a retention rate of 85%. Conclusions: When examined in an expanded, multicenter study, CYT387 continues to show substantial clinical activity in myelofibrosis, with improvements in splenomegaly, constitutional symptoms and anemia. It appears to be well tolerated when administered in either a once or twice daily dosing regimen. CYT387 continues to demonstrate an ability to induce durable anemia responses in a subset of subjects. Detailed analyses of safety and efficacy will be available at the time of the meeting. Disclosures: Gupta: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Smith:YM Biosciences: Employment, Equity Ownership. Bavisotto:YM Biosciences: Consultancy. Kowalski:YM Biosciences: Employment, Equity Ownership.

Abstract Background Momelotinib (MMB, GS-0387, CYT387) is a JAK1 and JAK2 inhibitor under investigation for the treatment of myelofibrosis. Preliminary results of a phase I/II core study (n=166) were previously reported. Subjects who achieved at least stable disease in the core study could continue MMB treatment in an extension study (n=120). Final data from the phase I/II core study and updated data from the extension study are presented. Methods Subjects with myelofibrosis categorized as IPSS intermediate-2 or high risk, or intermediate-1 risk with symptomatic splenomegaly or hepatomegaly and/or unresponsive to available therapy, were enrolled. Following a dose escalation phase, subjects were treated on a dose expansion phase in the core study with MMB at either 150 mg or 300 mg once-daily, or 150 mg twice-daily for 9 months. In the extension study, MMB was at the same dose the subject tolerated and derived clinical benefit from in the core study. Clinical responses were adjudicated according to IWG-MRT criteria. Spleen Response was defined as ≥ 50% reduction in palpable splenomegaly that lasted ≥ 8 weeks (wks) for baseline splenomegaly ≥ 10 cm, plus resolution of palpable splenomegaly that lasted ≥ 8 wks for baseline splenomegaly > 5 to < 10 cm. Anemia Response was defined as transfusion-free interval of ≥ 12 wks for baseline transfusion dependence, plus ≥ 2 g/dL rise in hemoglobin (Hb) for baseline transfusion independence and Hb < 10 g/dL. Baseline transfusion dependence was defined as ≥ 2U RBC transfusion in the 30 days prior to first dose of MMB or identified as transfusion dependent in medical history. Results As of April 2013, 58 of 120 subjects remained on treatment in the open-label extension study, with median treatment duration of 507 days (range 23-1036) for both core and extension studies. Based on interim analysis, the most common reasons for discontinuation from the extension study were disease progression (n=13), investigator's decision (n=12), and consent withdrawal (n=10), with 2 drug-related adverse events (both peripheral neuropathy) that led to study discontinuation. Efficacy data for the core and extension studies are depicted in table below. Median time to onset of Spleen Response was not yet reached (range 6-693 days), median duration of Spleen Response was 324 days (range 56-936). Median duration of 12-week transfusion independence was not yet reached (91-987 days), median duration of Anemia Response was not yet reached (57-987). Constitutional symptoms assessment at 3 months for the core study showed ≥ 50% improvement in 72%, 46%, 77%, 100%, and 74% of subjects with pruritis, cough, bone pain, fever, and night sweats respectively. Most common Grade 3 or 4 treatment-related events were thrombocytopenia (29%), neutropenia (5%), and elevated lipase (4%) without clinical pancreatitis. Peripheral neuropathy was reported by 38% of subjects, all ≤ Grade 2, with 17 subjects experiencing neuropathy at baseline. Four subjects transformed into acute leukemia (1 in core study, 3 in extension study). There was no treatment-related death. Conclusion Prolonged administration of MMB for treatment of myelofibrosis is well tolerated and has an acceptable safety profile. MMB is efficacious in durably reducing myelofibrosis-related splenomegaly as well as improving transfusion requirement and disease-related symptoms. These data form the basis for the phase 3 randomized study of MMB in myelofibrosis. Disclosures: Gupta: Novartis: Lecture fee, Lecture fee Other; Novartis: Consultancy; Incyte: Consultancy; Novartis: Research Funding; Incyte: Research Funding. Bavisotto:YM Biosciences: Consultancy. Kawashima:Gilead Sciences: Employment. Lee:Gilead Sciences: Employment. Kowalski:Gilead Sciences: Employment. Deng:Gilead Sciences: Employment. Niforos:Gilead Sciences: Employment.

Abstract Abstract 178 Background: CYT387 is a potent and selective small molecule inhibitor of JAK 1 and JAK 2 which is in clinical development for the treatment of myelofibrosis. Previously reported preliminary results from a phase I/II multicenter study demonstrated improvements in splenomegaly and constitutional symptoms as well as in RBC transfusion requirements. Enrollment has been completed and all subjects have now reached a minimum of 9 months on study. Updated safety and efficacy results are presented. Methods: Subjects with high or intermediate-risk primary myelofibrosis (PMF) and post-polycythemia vera (post-PV) or post-essential thrombocythemia (ET) myelofibrosis were enrolled. Following an initial dose expansion phase, subjects were treated in a 9 month core study at an initial dose of 150 mg QD, 300 mg QD or 150 mg BID. Continued treatment with CYT387 was permitted in an extension phase for subjects who maintained at least stable disease. Responses were assessed by International Working Group (IWG) criteria with transfusion independence response defined as achieving a minimum 12 week transfusion-free period. Results: Enrollment of 166 subjects was completed at 6 study sites. Initial doses included 52 subjects at 150 mg QD, 60 subjects at 300 mg QD and 42 subjects at 150 mg BID. An additional 12 subjects were enrolled in other dose groups (100 mg QD, 200 mg QD, 400 mg QD) during the initial dose escalation phase. The median duration (range) of follow-up is 16.1 months (0.7 to 31.0 months). Durable transfusion independence responses were observed in more than half of the RBC transfusion dependent subjects with a maximal transfusion-free period exceeding 2 years and ongoing. In addition, the percentage of all subjects requiring RBC transfusions substantially decreased over the treatment period. Treatment with CYT387 resulted in rapid and sustained reductions in splenomegaly with a maximal response duration approaching 2 years. The majority of subjects reporting constitutional symptoms at baseline experienced complete resolution or marked improvement by 6 months with measurable improvement within the first month of therapy. Higher transfusion independence and spleen response rates were seen in the 300 mg dose group compared to the 150 mg QD or 150 mg BID dose groups. For the first 60 consecutively enrolled subjects for whom the most mature data is available, the median follow-up period (range) is 21.5 months (2.9–31.0 months). The anemia and spleen response rates in these subjects, per IWG-MRT, were 59% and 48%, respectively; among 33 of these subjects who were RBC transfusion dependent by IWG-MRT criteria, 70% achieved a minimum 12-week period without transfusions with a maximal transfusion-free period of greater than 2 years and ongoing. While 90% of subjects reported at least one treatment-related AE, the majority were reported as Grade 1. The most common treatment-related AEs were thrombocytopenia, peripheral neuropathy, dizziness, diarrhea, nausea, and headache. Treatment-related peripheral neuropathy was sensory, with almost all events reported as Grade 1. The most common Grade 3–4 treatment-related AEs included thrombocytopenia and hyperlipasemia. Only 5% of subjects reported treatment-related AEs resulting in study drug discontinuation. There were no treatment-related deaths. Conclusions: CYT387 has proven safe and well tolerated even with prolonged administration for over 2.5 years. Treatment with CYT387 results in clinical improvement by effecting a rapid, meaningful and durable reduction of splenomegaly and the achievement of sustained RBC transfusion independence in a substantial number of subjects. CYT387 is also effective in improving constitutional symptoms. These results support the development of CYT387 at a dose of 300 mg QD for the treatment of myelofibrosis. Final analyses of safety and efficacy will be available at the time of the meeting. Disclosures: Pardanani: Bristol-Myers Squibb: Clinical trial support, Clinical trial support Other; YM BioSciences: Clinical trial support, Clinical trial support Other; Sanofi-Aventis: Clinical trial support Other. Off Label Use: Data from the ongoing Phase-1/2 study of CYT387 use in myelofibrosis treatment will be described. Gotlib:YM Biosciences: Research Funding. Gupta:Celgene: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; YM Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Roberts:YM BioSciences: clinical trial support Other. Wadleigh:Incyte: Membership on an entity's Board of Directors or advisory committees. Sirhan:Novartis: Consultancy, Honoraria. Bavisotto:YM BioSciences: Consultancy. Kawashima:YM BioSciences: Employment. Kowalski:YM BioSciences: Employment.