On June 10, 2016 Amgen (NASDAQ:AMGN) reported new data from a prespecified interim analysis of the Phase 3 TOWER study, in which BLINCYTO (blinatumomab) demonstrated an almost two-fold increase in median overall survival (OS) compared to standard of care (SOC) (Press release, Amgen, JUN 10, 2016, View Source [SID:1234513177]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The randomized, open-label TOWER study evaluated the efficacy of BLINCYTO versus SOC chemotherapy in adult patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). Results from the analysis showed that median OS was 7.7 months (95 percent CI: 5.6, 9.6) for BLINCYTO versus 4 months (95 percent CI: 2.9, 5.3) for SOC (stratified log-rank test p=.012; hazard ratio=0.71). As per the recommendation of an independent data monitoring committee, Amgen ended the study early for efficacy based on these results. The data will be presented during The Presidential Symposium at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Copenhagen.

"Acute lymphoblastic leukaemia is the most aggressive type of B-cell malignancy," said Max S. Topp, M.D., professor and head of haematology, University Hospital of Wuerzburg, Germany. "The data presented today not only reinforce the potential of immunotherapy delivered by T cell engaging bispecific antibody constructs but also validate the efficacy of BLINCYTO in these heavily pretreated patients."

Improvement in OS was consistent across subgroups regardless of age, prior salvage therapy or prior allogeneic stem cell transplant (alloSCT). Serious adverse events included infection, blood and lymphatic system disorders, nervous system disorders and cytokine release syndrome. The BLINCYTO adverse events observed in the TOWER study were consistent with the known safety profile of BLINCYTO.

"This is the first study of an immunotherapy to demonstrate overall survival benefit in adult patients with Ph-negative B-cell precursor relapsed or refractory ALL, a very complex-to-treat disease with limited treatment options," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "BLINCYTO is currently approved for the treatment of Ph-negative B-cell precursor relapsed or refractory ALL under accelerated approval, and we look forward to working with regulatory authorities for a full approval for BLINCYTO in this patient population."

ALL is a rare and rapidly progressing cancer of the blood and bone marrow.1,2 Adult patients diagnosed with Ph- B-cell precursor ALL are often young, with a median age at diagnosis of 34-39.3,4 Currently, there is no broadly accepted standard treatment regimen for adult patients with relapsed or refractory ALL beyond chemotherapy.5 Adults with relapsed or refractory ALL typically have a very poor prognosis, with a median OS of three to five months.6

About the TOWER Study
The TOWER study was a Phase 3, randomized, open-label study investigating the efficacy of BLINCYTO versus SOC chemotherapy in adult patients with Ph-relapsed or refractory B-cell precursor ALL. Patients were randomized in a 2:1 ratio to receive BLINCYTO or treatment with investigator choice of one of four protocol defined SOC chemotherapy regimens. The primary endpoint was OS. Secondary endpoints included complete remission and the combined endpoint of complete remission plus complete remission with partial or incomplete hematologic recovery.

The TOWER study is the confirmatory trial for BLINCYTO, and Amgen plans to file for full approval of BLINCYTO based on results from the study. Click here to read about the trial on ClinicalTrials.gov.

About Adult ALL
The incidence of adult ALL in European countries is generally between 0.6 to 0.9 per 100,000 persons per year.7 In the United States (U.S.), the incidence of adult ALL is approximately 0.9 per 100,000 persons per year.7 In adult ALL, approximately 75 percent is B-cell precursor ALL, of which 75-80 percent is Ph- and roughly half will be refractory to treatment or experience relapse.7 Thus, with a population projection of 416 million adults in the European Union (EU),8 it is estimated that the incidence of adult Ph-relapsed or refractory B-cell precursor ALL in the EU is approximately 900 patients per year.9 In the U.S., the incidence was approximately 650 patients in 2015.7

About BLINCYTO (blinatumomab)
BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

BLINCYTO was granted breakthrough therapy and priority review designations by the U.S. Food and Drug Administration (FDA), and is now approved in the U.S. for the treatment of Ph- relapsed or refractory B-cell precursor ALL. This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

In November 2015 BLINCYTO was granted conditional marketing authorization in the EU for the treatment of adults with Ph- relapsed or refractory B-cell precursor ALL.

About BiTE Technology
Bispecific T cell engager (BiTE) antibody constructs are a type of immunotherapy being investigated for fighting cancer by helping the body’s immune system to detect and target malignant cells. The modified antibodies are designed to engage two different targets simultaneously, thereby juxtaposing T cells (a type of white blood cell capable of killing other cells perceived as threats) to cancer cells. BiTE antibody constructs help place the T cells within reach of the targeted cell, with the intent of allowing T cells to inject toxins and trigger the cancer cell to die (apoptosis). BiTE antibody constructs are currently being investigated for their potential to treat a wide variety of cancers. For more information, visit www.biteantibodies.com.

Important EU Product Safety Information

This product is subject to additional monitoring in the EU and EEA. All suspected adverse reactions should be reported in accordance with the national reporting system.

The adverse reactions described in this section were identified in the pivotal clinical study (N=189).The most serious adverse reactions that may occur during blinatumomab treatment include: infections (31.7%), neurologic events (16.4%), neutropenia/febrile neutropenia (15.3%) cytokine release syndrome (0.5%), and tumor lysis syndrome (0.5%). The most common adverse reactions were: infusion-related reactions (67.2%), infections (63.0%), pyrexia (59.8%), headache (34.4%), febrile neutropenia (28%), peripheral edema (25.9%), nausea (24.3%), hypokalaemia (23.8%), constipation (20.6%), anaemia (20.1%), cough (18.5%), diarrhea (18.0%), tremor (17.5%), neutropenia (17.5%), abdominal pain (16.9%), insomnia (15.3%), fatigue (15.3%), and chills (15.3%).

Please refer to the Summary of Product Characteristics for full European prescribing information.

BLINCYTO U.S. Product Safety Information
Important Safety Information Regarding BLINCYTO (blinatumomab) U.S. Indication

This safety information is specific to the current U.S. approved indication.

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.

Contraindications
BLINCYTO is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation.

Warnings and Precautions

Cytokine Release Syndrome (CRS): Life-threatening or fatal CRS occurred in patients receiving BLINCYTO. Infusion reactions have occurred and may be clinically indistinguishable from manifestations of CRS. Closely monitor patients for signs and symptoms of serious events such as pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Interrupt or discontinue BLINCYTO as outlined in the Prescribing Information (PI).

Neurological Toxicities: Approximately 50% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. Severe, life-threatening, or fatal neurological toxicities occurred in approximately 15% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The median time to onset of any neurological toxicity was 7 days. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO as outlined in the PI.

Infections: Approximately 25% of patients receiving BLINCYTO experienced serious infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO as needed.

Tumor Lysis Syndrome (TLS): Life-threatening or fatal TLS has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on treatment hydration, should be used during BLINCYTO treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO as needed to manage these events.

Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters during BLINCYTO infusion and interrupt BLINCYTO if prolonged neutropenia occurs.

Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.

Elevated Liver Enzymes: Transient elevations in liver enzymes have been associated with BLINCYTO treatment. The majority of these events were observed in the setting of CRS. The median time to onset was 15 days. Grade 3 or greater elevations in liver enzymes occurred in 6% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase (GGT), and TBILI prior to the start of and during BLINCYTO treatment. BLINCYTO treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN.

Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients previously treated with cranial irradiation and anti-leukemic chemotherapy. Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose).

Adverse Reactions
The most commonly reported adverse reactions (≥ 20%) in clinical trials were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), rash (21%), tremor (20%), diarrhea (20%) and constipation (20%).

Serious adverse reactions were reported in 65% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, infection, overdose, confusion, Staphylococcal bacteremia, and headache.

U.S. Dosage and Administration Guidelines
BLINCYTO is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm. It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose).

Please see full U.S. Prescribing Information and medication guide for BLINCYTO at www.BLINCYTO.com.

On June 10, 2016 Acceleron Pharma Inc. (NASDAQ:XLRN) and Celgene Corporation (NASDAQ: CELG), reported preliminary results from an ongoing long-term Phase 2 extension study with luspatercept in patients with lower risk myelodysplastic syndromes (MDS) at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Copenhagen, Denmark (Press release, Acceleron Pharma, JUN 10, 2016, View Source [SID:1234513176]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Results highlighted in an oral presentation showed that 51% of patients with lower risk MDS treated with luspatercept (n=49) achieved increased hemoglobin levels and 35% of patients achieved transfusion independence in the 3-month base study. In the ongoing extension study, 81% (26/32) of patients had increased hemoglobin levels and of the patients eligible for transfusion independence (TI), 50% achieved TI with luspatercept treatment. Luspatercept is being developed as part of the global collaboration between Acceleron and Celgene.

"The results for luspatercept in lower risk MDS patients are increasingly encouraging as we gain longer term safety and efficacy experience with this agent," said Uwe Platzbecker, M.D., Professor of Hematology and Head of the MDS program at the University Hospital in Dresden, Germany. "There is a significant unmet need for new therapies that reduce the number of or eliminate the need for blood transfusions."

Highlights of the Luspatercept MDS Phase 2 Data Presented at EHA (Free EHA Whitepaper)

Study Design

Data from two Phase 2 studies were presented at the conference: the completed dose-escalation study in which patients received treatment with luspatercept for three months and the ongoing long-term extension study in which patients receive treatment with luspatercept for an additional 24 months. In both the 3-month base study and the long-term extension study, high transfusion burden patients (≥ 4 units RBC / 8 weeks) and low transfusion burden patients ( < 4 units RBC / 8 weeks) were enrolled and treated with open-label luspatercept, dosed subcutaneously once every 3 weeks. The primary outcome measure for the 3 month study was the proportion of patients who had an erythroid response. Erythroid response was defined as hemoglobin ≥ 1.5 g/dL from baseline for ≥ 14 days in non-transfusion dependent patients or a reduction of either ≥ 4 units or ≥ 50% of units of RBCs transfused compared to pretreatment in transfusion-dependent patients. The primary outcome for the long-term extension study is to evaluate the long-term safety and tolerability of luspatercept with low or intermediate-1 risk MDS who were previously enrolled in the 3-month study.

Efficacy


Response rate (% of patients)

3-month base study
(n=49, higher dose
levels)

Long-term extension
study
(n=32)
International Working Group Hematologic
Improvement-Erythroid (IWG HI-E)
Response Rate (reduction of ≥4 units RBC / 8
weeks or a hemoglobin increase ≥1.5 g/dL ≥ 8
weeks)
51% (25/49) 81% (26/32)
RBC Transfusion Independence (RBC-TI)
Response Rate (Transfusion free ≥ 8 weeks for
patients with ≥ 2 units RBC / 8 weeks prior to
treatment)
35% (14/40) 50% (11/22)
Duration of RBC-TI Range: 9-80+ weeks

For reference, results presented six months ago at the American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting in December 2015 were as follows:

IWG HI-E response rate was 69% (22/32)
RBC-TI response rate was 50% (11/22)
Duration of RBC-TI ranged from 9 to 50+ weeks
Safety

There were three grade 3 adverse events possibly/probably related to study drug (blast cell count increase, myalgia and worsening of general condition).
Adverse events at least possibly related to study drug that occurred in at least 2 patients during studies were fatigue, bone pain, diarrhea, myalgia, headache, hypertension and injection site erythema.
Luspatercept is an investigational product that is not approved for use in any country.

The MEDALIST Trial, a global Phase 3 study in patients with very low, low, or intermediate risk, MDS with ring sideroblasts who require red blood cell transfusions, is currently enrolling.

The slides from this oral presentation are available on Acceleron’s website (www.acceleronpharma.com) under the Science tab.

Acceleron EHA (Free EHA Whitepaper) Conference Call Information

Acceleron will host a conference call and live webcast from EHA (Free EHA Whitepaper) today at 8:00 a.m. EDT (2:00 p.m. CEST). To participate by teleconference, please dial 877-312-5848 (domestic) or 253-237-1155 (international) and refer to the Acceleron EHA (Free EHA Whitepaper) Congress Review.

To access the live webcast, please select "Events & Presentations" in the Investor section on Acceleron’s website (www.acceleronpharma.com) at least 10 minutes beforehand to ensure time for any downloads that may be required.

An archived webcast recording will be available on the Acceleron website beginning approximately two hours after the event.

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. Acceleron and Celgene are enrolling Phase 3 clinical trials that are designed to evaluate the safety and efficacy of luspatercept in patients with myelodysplastic syndromes (the "MEDALIST" study) and in patients with beta-thalassemia (the "BELIEVE" study). For more information, please visit www.clinicaltrials.gov.