On June 12, 2015 Acceleron Pharma reported that new preliminary results from the ongoing phase 2 clinical trials of luspatercept in patients with lower risk myelodysplastic syndromes (MDS) and in patients with beta-thalassemia were highlighted in oral presentations at the 20th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Vienna, Austria (Press release, Acceleron Pharma, JUN 12, 2015, View Source [SID:1234505408]). Acceleron and its collaboration partner, Celgene Corporation, are jointly developing luspatercept.

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"We have previously shown that with just 3 months of treatment, luspatercept can increase hemoglobin levels and achieve transfusion independence in lower risk MDS patients," said Matthew Sherman, Executive Vice President and Chief Medical Officer of Acceleron. "These new results show that longer-term treatment with luspatercept can produce sustained hemoglobin increases and transfusion independence in some patients now exceeding 6 months. Additionally, in our beta-thalassemia study, luspatercept has demonstrated positive effects on multiple complications of the disease by increasing hemoglobin levels, reducing transfusion burden and reducing iron overload in the majority of patients."

MDS Phase 2 Study:

For the first time, data from the 12-month extension study of low and intermediate-1 risk myelodysplastic syndromes patients were presented.

The preliminary results show encouraging longer-term, durable responses with luspatercept.

Patients who completed the initial 3-month study may have been eligible to enroll in the 12-month extension study.
Twenty-two patients were evaluable for efficacy analyses; 9 low transfusion burden patients and 13 high transfusion burden patients.
For the low transfusion burden patients, the mean hemoglobin increase at one month was approximately 2 g/dL, increased to between 2.5 and 3.0 g/dL and was maintained for the 6-month period for which data are available.
For transfused patients, 43% achieved transfusion independence with several patients maintaining this transfusion independence for more than 6 months with the longest ongoing transfusion independent patient at nearly 8 months. All of these patients remain on study.
Beta-Thalassemia Phase 2 Study:

Data were presented for both non-transfusion dependent (NTD) and transfusion dependent (TD) beta-thalassemia patients. The preliminary results demonstrate that luspatercept, by addressing the underlying ineffective erythropoiesis, can increase hemoglobin levels, reduce transfusion burden and reduce liver iron concentrations in iron overloaded patients.

Non-transfusion dependent patients

For patients who received luspatercept 0.8-1.25 mg/kg, 38% had a mean hemoglobin increase ≥ 1.5 g/dL maintained for at least 9 weeks.

For 8 of the 12 iron overloaded NTD patients, luspatercept reduced liver iron concentration by at least 1 and up to 4.6 mg/g dry weight over the 16 week period.

Transfusion dependent patients

All ten evaluable patients who received luspatercept 0.6-1.25 mg/kg had more than a 40% reduction in transfusion burden.

For 2 of the 3 iron overloaded TD patients, luspatercept reduced liver iron concentration by 1.96 and 4.7 mg/g dry weight, respectively.

The slides from these two oral presentations will be available on Acceleron’s website (www.acceleronpharma.com) under the Publications tab.

About Luspatercept

Luspatercept is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members in the Transforming Growth Factor-Beta (TGF-beta) superfamily involved in the late stages of erythropoiesis (red blood cell production). Luspatercept regulates late-stage erythrocyte (red blood cell) precursor cell differentiation and maturation. This mechanism of action is distinct from that of erythropoietin (EPO), which stimulates the proliferation of early-stage erythrocyte precursor cells. Acceleron and Celgene are jointly developing luspatercept as part of a global collaboration. Luspatercept is currently in phase 2 clinical trials in patients with beta-thalassemia and in patients with myelodysplastic syndromes. For more information, please visit www.clinicaltrials.gov.

About Myelodysplastic Syndromes

MDS comprise a heterogeneous group of hematologic malignancies of the bone marrow commonly leading to severe and chronic anemia due to ineffective erythropoiesis. The National Cancer Institute estimates that more than 10,000 people are diagnosed with MDS in the United States each year. Patients with MDS often have a hypercellular bone marrow with various dysplastic changes of the cells that are also seen in peripheral blood, resulting in cytopenias (low blood cell counts) and an increased risk of progression to acute myeloid leukemia. Nearly all MDS patients suffer from anemia. The anemia in MDS is often characterized by high endogenous levels of EPO driving an abundance of early stage red blood cell precursors and an inability of these precursor cells to properly differentiate into healthy, functional red blood cells. Many patients are therefore unresponsive to the administration of erythropoietin to correct the resulting anemia and instead require red blood cell transfusions, which can increase the risk of infection and iron-overload related toxicities.

About Beta-thalassemia

Beta-thalassemia is an inherited disease involving mutations in the beta globin gene leading to deficient hemoglobin levels and defective red blood cell production in the bone marrow known as ineffective erythropoiesis. Beyond the severe anemia, many patients also suffer from multiple organ dysfunction, largely due to excess iron deposits, known as "iron overload," resulting from the ineffective erythropoiesis as well as the repeated red blood cell (RBC) transfusions to address the anemia. Iron overload can lead to heart failure, liver fibrosis, and diabetes, among other consequences. Current clinical management for beta-thalassemia includes RBC transfusions and iron chelation therapy, which is associated with toxicities. There are no drugs approved to treat beta-thalassemia, leaving healthcare providers with few options for patients.

On June 12, 2015 CTI BioPharma and Baxter International reported new patient-reported outcome (PRO) data for pacritinib – an investigational oral multikinase inhibitor with specificity for JAK2 and FLT3 – from the Phase 3 PERSIST-1 study (Press release, CTI BioPharma, JUN 12, 2015, View Source;p=RssLanding&cat=news&id=2058786 [SID:1234505405]). As recently reported at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting, results show a significant reduction in the Total Symptom Score (TSS) (the proportion of patients with a 50 percent or greater reduction in TSS from baseline to Week 24), and in each individual common disease-related symptom, from baseline to Week 24, in patients treated with pacritinib compared to best available therapy (exclusive of a JAK inhibitor) (BAT). These PROs, as well as other quality of life measures, will be presented at the 20th Congress of European Hematology Association (EHA) (Free EHA Whitepaper) by Adam Mead, M.D., Guy’s and St. Thomas’ NHS Foundation Trust, Guy’s Hospital, London, United Kingdom in an oral presentation on Sunday, June 14, 2015 at 12:15 CEST (abstract #LB2072). These data were also selected for inclusion in the official EHA (Free EHA Whitepaper) Press Briefing which occurred today (Friday, June 12, 2015) at 08:30 CEST. As previously reported, the PERSIST-1 trial met its primary endpoint of spleen volume reduction of 35 percent or greater from baseline to Week 24 as measured by MRI/CT scan.

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Myelofibrosis is a rare blood cancer associated with significantly reduced quality of life and shortened survival. As the disease progresses, the body slows production of important blood cells and within one year of diagnosis the incidence of disease-related thrombocytopenia (very low blood platelet counts), severe anemia, and red blood cell transfusion requirements increases significantly. Among other complications, most patients with myelofibrosis present with enlarged spleens (splenomegaly), as well as many other potentially devastating physical symptoms such as abdominal discomfort, bone pain, feeling full after eating little, severe itching, night sweats, and extreme fatigue.

"Patient-reported outcomes are an important measure for understanding the potential benefit of a therapy on patients’ lives – particularly for a disease such as myelofibrosis where the symptoms have such a tremendous impact on the quality of patients’ daily lives," stated James A. Bianco, M.D., President and CEO of CTI BioPharma. "These new data from the PERSIST-1 study further support our belief, not only in the activity of pacritinib, but also the potential to positively impact patients’ daily lives by relieving the symptoms that accompany myelofibrosis."

"The PERSIST-1 trial has continued to generate positive and important findings for the hematology community," said David Meek, Head of Oncology at Baxter BioScience. "We look forward to advancing the clinical trial program of pacritinib as we work to realize the full potential of this investigational compound to help patients with serious blood cancers, such as myelofibrosis."

Study Details and Findings Presented at EHA (Free EHA Whitepaper)
PERSIST-1 is a randomized (2:1), controlled Phase 3 registration-directed trial comparing the efficacy and safety of pacritinib to BAT – which included a range of currently utilized off-label treatments – in 327 patients with myelofibrosis, regardless of the patients’ platelet counts. As previously reported at ASCO (Free ASCO Whitepaper), the trial met its primary endpoint of spleen volume reduction (35 percent or greater reduction from baseline to Week 24 by MRI/CT scan) in the intent-to-treat (ITT) population; these results included patients with severe or life-threatening thrombocytopenia. The study also measured patient-reported outcomes (PROs), the proportion of patients with a 50 percent or greater reduction in TSS from baseline to Week 24, which have become important for approval of new therapies and was one of the secondary endpoints of the study. As previously reported, patients treated with pacritinib experienced greater improvement in their disease-related symptoms (ITT patient population: 24.5 percent of pacritinib-treated patients vs 6.5 percent of BAT-treated patients, p<0.0001; evaluable patient population: 40.9 percent of pacritinib-treated patients vs 9.9 percent of BAT-treated patients, p<0.0001).

New data presented at EHA (Free EHA Whitepaper), which included results from multiple PROs measurement tools, showed:

Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS and MPN-SAF TSS 2.0)

When using the MPN-SAF TSS and MPN-SAF TSS 2.0, each of the six common disease-related symptoms from the TSS results showed improvements in abdominal discomfort (46 percent improvement with pacritinib vs no improvement with BAT); bone pain (32 percent improvement with pacritinib vs 8 percent improvement with BAT); feeling of early fullness (45 percent improvement with pacritinib vs 1 percent worsening with BAT); itching (48.5 percent improvement with pacritinib vs 10 percent improvement with BAT); night sweats (69.5 percent improvement with pacritinib vs no improvement with BAT); and fatigue (27.5 percent improvement with pacritinib vs 4 percent worsening with BAT). MPN-SAF TSS and MPN-SAF TSS 2.0 are specific sets of questions patients answer daily (via electronic diary) and which are based on a questionnaire originally developed by Ruben A. Mesa, M.D., Deputy Director of the Mayo Clinic Cancer Center in Scottsdale, Arizona, USA.

Patient Global Impression of Change (PGIC)
Based on the PGIC assessment – which measures a patient’s assessment of overall health on a 7-point scale ranging from "very much worse" to "very much improved" – approximately 80 percent of evaluable patients treated with pacritinib rated their condition as improved compared to approximately 20 percent with BAT.

European Organization for Research and Treatment of Cancer Quality-of-Life 30 Questionnaire (EORTC QLQ-C30)
A greater improvement was also reported by evaluable patients treated with pacritinib vs BAT across all components of the EORTC QLQ-C30 questionnaire, a well-validated measure of quality of life in cancer patients.

The most common adverse events occurring with pacritinib within 24 weeks, of any grade, were mild to moderate diarrhea (53.2 percent vs 12.3 percent with BAT), nausea (26.8 percent vs 6.6 percent with BAT), anemia (22.3 percent vs 19.8 percent with BAT), thrombocytopenia (16.8 percent vs 13.2 percent with BAT), and vomiting (15.9 percent vs 5.7 percent with BAT). Of the patients treated with pacritinib, 3 discontinued therapy and 13 patients required dose interruption (average one week) for diarrhea. Patients received a daily full dose of pacritinib over the duration of treatment. Gastrointestinal symptoms typically lasted for approximately one week and few patients discontinued treatment due to side effects. There were no Grade 4 gastrointestinal events reported.

About Pacritinib
Pacritinib is an investigational oral multikinase inhibitor with specificity for JAK2 and FLT3. The JAK family of enzymes is a central component in signal transduction pathways, which are critical to normal blood cell growth and development, as well as inflammatory cytokine expression and immune responses. Mutations in these kinases have been shown to be directly related to the development of a variety of blood-related cancers, including myeloproliferative neoplasms, leukemia, and lymphoma.

About Myelofibrosis
Myelofibrosis is a serious and life-threatening chronic blood cancer caused by the accumulation of malignant bone marrow cells that triggers an inflammatory response and scars the bone marrow. The replacement of bone marrow with scar tissue limits its ability to produce red blood cells, prompting the spleen and liver to take over this function. Symptoms that arise from this disease include enlargement of the spleen, anemia, extreme fatigue, and pain. Myelofibrosis is a one of three main types of myeloproliferative neoplasms (MPN), which are a closely related group of hematological blood cancers.1 The estimated prevalence of MPNs suggest there are approximately 300,000 people living with the disease in the U.S. of which myelofibrosis accounts for approximately 18,000 patients.2 In Europe, there is a wide variation of prevalence observed across data sources. Myelofibrosis has a median age of 64 at the time of diagnosis2 and is a progressive disease with approximately 20 percent of patients eventually developing acute myeloid leukemia.3 The median survival for high-risk patients is less than one and a half years; median survival for myelofibrosis patients overall is approximately six years.4

About the PERSIST Phase 3 Development Program of Pacritinib
Pacritinib is currently being evaluated in two Phase 3 clinical trials, known as the PERSIST program, for patients with myelofibrosis. PERSIST-1 is a randomized (2:1), open-label, multinational Phase 3 clinical trial comparing the efficacy and safety of pacritinib with that of BAT, in 327 enrolled patients with primary and secondary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia myelofibrosis (PET-MF), without exclusion for low platelet counts. PERSIST-2 is a randomized (2:1), open-label, multinational Phase 3 clinical trial evaluating pacritinib compared to BAT, including the approved JAK1/JAK2 inhibitor dosed according to product label for patients with myelofibrosis whose platelet counts are less than or equal to 100,000 per microliter. The trial is designed to enroll up to 300 patients in North America, Europe, Australia, New Zealand, and Russia.

Additional details are available at www.clinicaltrials.gov or www.PERSISTprogram.com.

CTI BioPharma and Baxter BioScience, which is expected to become Baxalta Incorporated in mid-2015, entered into a worldwide license agreement in November 2013 to develop and commercialize pacritinib. CTI BioPharma and Baxter will jointly commercialize pacritinib in the U.S. while Baxter has exclusive commercialization rights for all indications outside the U.S.

On June 12, 2015 Agios Pharmaceuticals reported new data from the dose-escalation phase and expansion cohorts from the ongoing Phase 1 study evaluating single agent AG-221, a first-in-class, oral, selective, potent inhibitor of mutant isocitrate dehydrogenase-2 (IDH2), in advanced hematologic malignancies (Press release, Agios Pharmaceuticals, JUN 12, 2015, View Source;p=RssLanding&cat=news&id=2058805 [SID:1234505404]). The data will be presented at the 20th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) taking place June 11-14, 2015 in Vienna.

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Data as of May 1, 2015 from 177 patients (104 in dose escalation and 73 from the first four expansion cohorts) with advanced hematologic malignancies treated with single agent AG-221 showed durable clinical activity and a favorable safety profile. More than half of the 177 patients remain on treatment. The study had an overall response rate of 40 percent (63 of 158 response-evaluable patients, using the criteria below) and a complete remission rate of 16 percent (26 of 158 response-evaluable patients). Patients responding to AG-221 continue to show durable clinical activity on treatment for more than 15 months, with an estimated 76 percent of responders staying on treatment for six months or longer. The overall safety profile observed was consistent with previously reported data with more than 100 additional patients treated as of the last analysis.

This new data reflects responses in the evaluable population, which includes all patients with a pre-AG-221 screening assessment and day 28 or later response assessment or an earlier discontinuation for any reason. Patients with a screening assessment who were still on treatment, but had not reached the day 28 disease assessment, were excluded.

"The clinical profile of AG-221 continues to be impressive from the perspectives of response rate, durability, safety and unique mechanism of action," said Courtney DiNardo, M.D., lead investigator and assistant professor, leukemia at University of Texas MD Anderson Cancer Center. "Additionally, it is encouraging to see early proof-of-concept in myelodysplastic syndrome (MDS) and untreated acute myeloid leukemia (AML) given the need for more effective therapies for these patients."

"As the data from the AG-221 study continue to mature, we are compiling a robust dataset to quickly move this program into global registration studies later this year in collaboration with Celgene," said Chris Bowden, M.D., chief medical officer of Agios. "We are excited about the speed of enrollment we’ve seen to date in our four expansion cohorts and are on track to enroll our recently announced fifth expansion cohort of 125 patients with relapsed and/or refractory AML. With this progress, we are executing on our strategy to combine speed and breadth to reach people with hematologic malignancies in urgent need of better treatments."

About the Ongoing Phase 1 Trial for AG-221 in Advanced Hematologic Malignancies

AG-221 is currently being evaluated in an ongoing Phase 1 trial that includes a dose-escalation phase and four expansion cohorts of 25 patients each, evaluating patients with relapsed or refractory AML who are 60 years of age and older and transplant ineligible; relapsed or refractory AML patients under age 60; untreated AML patients who decline standard of care chemotherapy; and patients with other IDH2-mutant positive hematologic malignancies. Data reported here are from patients receiving AG-221 administered from 60 mg to 450 mg total daily doses in the dose escalation arm and 100 mg once daily in the first four expansion arms, as of May 1, 2015. The median age of these patients is 69 (ranging from 22-90). Treatment with AG-221 showed substantial reduction in the plasma levels of the oncometabolite 2-hydroxglutarate (2HG) to the level observed in healthy volunteers.

Safety Data

A safety analysis was conducted for all 177 treated patients as of May 1, 2015.

The majority of adverse events reported by investigators were mild to moderate, with the most common being nausea, fatigue, increased blood bilirubin and diarrhea.

The majority of serious adverse events (SAE) were disease related; SAEs possibly related to study drug were reported in 27 patients.
A maximum tolerated dose (MTD) has not been reached.
The all-cause 30-day mortality rate was 4.5 percent.

Efficacy Data

Sixty-three out of 158 response-evaluable patients achieved investigator-assessed objective responses for an overall response rate of 40 percent as of May 1, 2015.

Of the 63 patients who achieved an objective response, there were 26 (16 percent) complete remissions (CR), three CRs with incomplete platelet recovery (CRp), 14 marrow CRs (mCR), two CRs with incomplete hematologic recovery (CRi) and 18 partial remissions (PR).
Of the 111 patients with relapsed or refractory AML, 46 (41 percent) achieved an objective response, including 20 (18 percent) CRs, one CRp, 16 PRs, eight mCRs and one CRi.

Of the 22 patients with AML that had not been treated, seven achieved an objective response, including three CRs, two PRs, one mCR and one CRi.

Of the 14 patients with myelodysplastic syndrome (MDS), seven achieved an objective response, including two CRs, one CRp and four mCRs.

Responses were durable, with duration on study drug more than 15 months and ongoing. As of the analysis date, an estimated 88 percent of responses lasted three months or longer, and 76 percent of responses lasted six months or longer.

Upcoming Milestones for AG-221

Agios studies in IDH2-mutated solid and hematologic tumors are ongoing or planned for 2015 to further support development of AG-221.

Continue to enroll patients in the fifth expansion cohort of 125 patients with IDH2 mutant-positive AML who are in second or later relapse, refractory to second-line induction or re-induction treatment, or have relapsed after allogeneic transplantation.

Initiate combination trials to evaluate AG-221 as a potential frontline treatment for patients with AML and a broad range of hematologic malignancies in the second half of 2015.

Initiate a global Phase 3 registration-enabling study in relapsed/refractory AML patients that harbor an IDH2 mutation in the second half of 2015.

Continue dose escalation in the Phase 1/2 trial in patients with advanced solid tumors, including glioma and angioimmunoblastic T-cell lymphoma (AITL) that carry an IDH2 mutation in 2015.

On June 12, 2015 Agios Pharmaceuticals reported new data from the ongoing Phase 1 study evaluating single agent AG-120, a first-in-class, oral, selective, potent inhibitor of mutant isocitrate dehydrogenase-1 (IDH1), in advanced hematologic malignancies presented at the 20th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) taking place June 11-14, 2015 in Vienna (Press release, Agios Pharmaceuticals, JUN 12, 2015, View Source;p=RssLanding&cat=news&id=2058807 [SID:1234505403]).

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Data as of May 1, 2015 from 57 patients with advanced hematologic malignancies showed durable clinical activity and a favorable safety profile, with 25 patients on study as of the analysis. The study had an overall response rate of 31 percent (16 of 52 response-evaluable patients) and a complete remission rate of 15 percent (8 of 52 response-evaluable patients). Data continue to show durable clinical activity for AG-120, with responding patients on treatment for up to 11 months, and an estimated 79 percent of responders on treatment at three months. The overall safety profile remains consistent with 40 additional patients treated as of the last analysis.

"The durable clinical activity observed with AG-120 in such a refractory patient population is impressive," said Stéphane de Botton, M.D., the principal investigator at the Institut de Cancérologie Gustave Roussy, Villejuif, France. "These findings provide additional evidence that AG-120 can inhibit the IDH1-mutant protein allowing for cancer cells to appropriately mature. AG-120 has the potential to improve outcomes in patients with IDH1 mutant cancers."

"These encouraging data represent the tremendous progress to date in our AG-120 program, as this therapy is proving to be well tolerated and effective, with an objective response rate of 31 percent of treated patients and duration on study up to 11 months," said Chris Bowden, M.D., chief medical officer of Agios. "Along with the insight gained from the AG-221 program, we are excited to move the AG-120 program forward rapidly with our partner Celgene. Our goal is to reach patients in need quickly, as evidenced by the recent announcement of our plans to initiate three expansion cohorts as part of the Phase 1 study."

About the Ongoing Phase 1 Trial for AG-120 in Advanced Hematologic Malignancies

AG-120 is being evaluated in an ongoing Phase 1 trial in patients with AML and other IDH1-mutant positive advanced hematologic malignancies. Data reported are from patients receiving AG-120 administered from 100 mg to 1,200 mg total daily doses as of May 1, 2015. The median age of these patients is 68 (ranging from 38-89). Treatment with AG-120 showed substantial reduction in the plasma levels of the oncometabolite 2-hydroxglutarate (2HG) to the level observed in healthy volunteers.

This new data reflects responses in the evaluable population, which includes all patients with a pre-AG-120 screening assessment and day 28 or later response assessment or an earlier discontinuation for any reason. Patients with a screening assessment who were still on treatment, but had not reached the day 28 disease assessment, were excluded.

Safety Data

A safety analysis was conducted for all 57 treated patients as of May 1, 2015.

The majority of adverse events reported by investigators were mild to moderate, with the most common being fatigue, diarrhea, pyrexia and nausea.

35 serious adverse events (SAEs) were reported, the majority being disease related, with four cases of leukocytosis potentially related to AG-120.

A maximum tolerated dose (MTD) has not been reached.

13 deaths were reported, and all were considered unrelated to AG-120.

Efficacy Data

Sixteen out of 52 response-evaluable patients achieved investigator-assessed objective responses for an overall response rate of 31 percent as of May 1, 2015.

Of the 16 patients who achieved an objective response, there were eight complete remissions (CR), one complete remission with incomplete platelet recovery (CRp), three marrow complete remissions (mCR) and four partial remissions (PR).

Responses were durable, with duration on study drug as long as 11 months and ongoing. As of the analysis date, an estimated 79 percent of responders were on treatment for three months or longer, and 50 percent of responders were on treatment for six months or longer.

Upcoming Milestones for AG-120

Agios studies in IDH1-mutated solid and hematological tumors are ongoing or planned for 2015/2016 to further support the speed and breadth of development of AG-120.

Initiate three expansion cohorts to evaluate AG-120 in 175 patients with IDH1-mutated advanced hematologic malignancies (125 in relapsed and/or refractory AML, 25 in untreated AML and 25 in basket IDH1-mutant positive cancers).

Present first data from the Phase 1 trial in advanced solid tumors at a medical conference in the second half of 2015.

Begin combination trials to evaluate AG-120 as a potential frontline treatment of IDH1-mutated AML and a broad range of hematologic malignancies in the second half of 2015.

Intend to initiate a global registration-enabling Phase 3 study in AML patients that harbor an IDH1 mutation in the first half of 2016.