On December 05, 2015 Idera Pharmaceuticals, Inc. (NASDAQ:IDRA), a clinical-stage biopharmaceutical company developing toll-like receptor and RNA therapeutics for patients with cancer and rare diseases, reported initial clinical data from its ongoing Phase 1/2 clinical trial for IMO-8400, a Toll-like receptor 7, 8 and 9 antagonist, being evaluated for the treatment of patients with relapsed or refractory Waldenström’s Macroglobulinemia (WM) (Press release, Idera Pharmaceuticals, DEC 5, 2015, View Source [SID:1234508418]).

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These results provide evidence that IMO-8400 has clinical activity and is well tolerated. Today’s results were presented during a poster session (Abstract #1540) at the 57th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Orlando, FL.

"Our clinical trial in Waldenström’s Macroglobulinemia represents the first step in our understanding of the potential role that TLR antagonism could play in B-cell malignancies, specifically in those harboring the MYD88-L265P oncogenic mutation which is highly prevalent in Waldenström’s Macroglobulinemia," stated Vincent Milano, Idera’s Chief Executive Officer. "We are pleased that the initial results from this ongoing trial met our objectives in determining safety and tolerability, as well as clinical activity of IMO-8400 in this patient population. We are further encouraged that the safety profile seen to date will enable us to expand this study to evaluate higher dosing levels of IMO-8400.

The results being reported are from 15 evaluable patients with Waldenström’s Macroglobulinemia who had a history of relapse or failure to one or more prior therapies and who completed at least one cycle of therapy with IMO-8400. Patients enrolled in the multi-center, open-label, dose ranging clinical trial which evaluated 3 dose levels of IMO-8400 (06. mg/kg weekly, 1.2 mg/kg weekly, 1.2mg/kg twice a week) administration for a period of up to 24 weeks. The primary objectives of the study were to assess safety and tolerability. Secondary objectives were to assess clinical activity, PK and define the optimal dose for further clinical evaluation. In addition to clinical treatment parameters, cytokine levels were analyzed as an exploratory endpoint in the trial.

Top Line Results

Safety

IMO-8400 was generally well tolerated at all dose levels studied.
The Maximum Tolerated Dose of IMO-8400 has not yet been identified.

Clinical activity

Across all dose cohorts, 6 of 15 patients (40%) with relapsed or refractory WM had an objective response.
Three responders were refractory to their last treatment, including 1 patient who was refractory to ibrutinib.
In the highest dose cohort (1.2 mg/kg twice a week):
3 of 6 patients (50%) had an objective response and two had stable disease.
The median time to first response was ~10.5 weeks.

There was improvement in bone marrow findings, hemoglobin and disease symptoms.
An exploratory analysis showed a significant correlation between change in M-protein and a change in IL-10, with decreases in IL-10 being seen in responding patients.

Summary

These data in patients with WM provide the first clinical evidence supporting inhibition of the TLR pathway as a potential therapeutic approach for B-cell malignancies characterized by the MYD88 L265P oncogenic mutation.
Evaluation of higher IMO-8400 dose levels is planned.
The full poster presentation is currently available on the Investors Page of the Idera corporate website which can be found at www.iderapharma.com.

Investor Event and Webcast

Idera will host a conference call and live webcast on Monday, December 7 at 9:00 A.M. EST to review the data being presented at ASH (Free ASH Whitepaper) along with discussion of next steps for the IMO-8400 development program in B-cell Lymphomas. To participate in the conference call, please dial (866) 379-0841 (domestic) and (440) 996-5667 (international). The webcast can be accessed live or in archived form in the "Investors" section of the company’s website at www.iderapharma.com. The company has also posted a slide presentation to the Idera corporate website which will be referenced during the conference call.

About Waldenström’s macroglobulinemia (WM)

Waldenström’s macroglobulinemia is a rare and slow-growing form of B-cell lymphoma with approximately 1,000 to 1,500 new cases diagnosed in the United States each year.1 The median age at diagnosis is between 60 and 70 years of age. Symptoms include fatigue, night sweats, headaches, visual problems, pain and abnormal bleeding due to complications such as anemia, retinopathy and peripheral neuropathy.2 About 90 percent of WM patients harbor the MYD88 L265P oncogenic mutation.3

About Toll-Like Receptors (TLRs) and Idera’s Proprietary TLR Antagonism Technology Platform

TLRs are receptor proteins that play a central role in the innate immune system. In healthy people, TLRs recognize invading pathogens and endogenous molecules released from damaged or dysfunctional cells, and initiate signaling cascades that trigger an inflammatory response. Through these signaling cascades, TLRs are also involved in activating the adaptive immune system, in which B-cells play a critical role. Based on the company’s proprietary chemistry-based discovery platform, Idera discovered and is developing the synthetic oligonucleotide-based TLR antagonist, IMO-8400. This clinical-stage candidate has demonstrated activity in multiple preclinical models of cancer and autoimmune disease.

On December 5, 2015 Bristol-Myers Squibb Company (NYSE:BMY) reported extended follow-up data and a pre-specified interim overall survival (OS) analysis of Empliciti in combination with Revlimid (lenalidomide) and dexamethasone (ERd) in patients with relapsed or refractory multiple myeloma from ELOQUENT-2 (Press release, Bristol-Myers Squibb, DEC 5, 2015, View Source [SID:1234508413]).

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The follow-up data demonstrated that Empliciti in combination with Rd had an improvement in progression-free survival (PFS) with a hazard ratio (HR) of 0.73 (95% CI: 0.60, 0.89; p=0.0014) versus Rd alone. This result was consistent with the improvement in PFS that was observed at the time of the primary analysis (HR 0.70 [95% CI: 0.57, 0.85; p = 0.0004]).

The Empliciti combination delayed the need for subsequent myeloma therapy by a median of one year compared to Rd alone. A pre-specified interim analysis of OS found a positive trend favoring the Empliciti combination versus Rd alone (HR 0.77; [{95% CI: 0.61, 0.97; 98.6% CI: 0.58, 1.03}; p=0.0257]), though at the time of the interim analysis the OS endpoint had not reached the pre-determined threshold for statistical significance. Patients will continue to be followed for survival. Updated safety and tolerability data were consistent with previous findings. Common Grade 3 or 4 adverse events included neutropenia (26%), anemia (15%), fatigue (9%), and diarrhea (5%).

These data from ELOQUENT-2, a randomized, open-label, Phase 3 study (Abstract #28) were presented at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in Orlando, FL.

"The Empliciti extended follow-up results provide physicians with additional insight into the potential benefit this new treatment may offer patients with relapsed or refractory multiple myeloma," said Paul G. Richardson, M.D., Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute. "Empliciti represents a new approach in multiple myeloma treatment of directly activating the body’s immune system, and it is very encouraging to see these data demonstrate the efficacy benefit persisted in some patients up to three years, allowing patients to live longer without experiencing disease progression."

Empliciti as combination therapy with lenalidomide and dexamethasone was approved by the U.S. Food and Drug Administration on November 30, 2015, for the treatment of patients with multiple myeloma who have received one to three prior therapies.

"The extended follow-up and overall survival data presented at ASH (Free ASH Whitepaper) for our immunostimulatory antibody, Empliciti, reinforce our commitment to helping improve outcomes for patients with multiple myeloma," said Michael Giordano, M.D., senior vice president, head of Development, Oncology, Bristol-Myers Squibb. "These data further demonstrate Empliciti as combination therapy provides improved efficacy compared to lenalidomide and dexamethasone alone."

About ELOQUENT-2

ELOQUENT-2 (CA204-004) is a randomized, open-label, Phase 3 study evaluating Empliciti in combination with lenalidomide and dexamethasone (ERd) versus lenalidomide and dexamethasone (Rd) alone in patients with relapsed or refractory multiple myeloma. The trial enrolled 646 patients who had received one to three prior therapies. Patients were randomized 1:1 to receive either Empliciti 10 mg/kg in combination with Rd or Rd alone in 4-week cycles until disease progression or unacceptable toxicity. Baseline patient demographics and disease characteristics were well balanced between treatment arms and included a meaningful portion of patients who were ≥ 65 years old, had high-risk cytogenetics, and/or were refractory to the most recent line of therapy. The co-primary endpoints were PFS, as assessed by HR, and overall response rate. Results of the primary analysis of the ELOQUENT-2 study were published in The New England Journal of Medicine on June 2, 2015.

In the exploratory, extended follow-up analysis, the ERd regimen resulted in a 27% reduction in the risk of disease progression or death (HR 0.73 [95% CI: 0.6, 0.89]) and a 44% relative improvement in the PFS rate at three years compared to Rd alone. The benefit observed was consistent with the pivotal two year analysis which showed ERd resulted in a 30% reduction in the risk of disease progression or death compared to Rd alone (HR 0.70 [95% CI: 0.57, 0.85; p = 0.0004]) and a 52% relative improvement in PFS rate at two years. The extended follow-up analysis also showed ERd had a median delay of one year in the time to next treatment compared to Rd alone 33.35 months (95% CI: 26.15, 40.21) vs. 21.22 months (95% CI: 18.07, 23.20) (HR=0.62 [95% CI: 0.50, 0.77]). An interim analysis of OS found a positive trend favoring the Empliciti combination compared to Rd alone (HR 0.77; [{95% CI: 0.61, 0.97; 98.6% CI 0.58; 1.03}; p=0.0257]), though at the time of the interim analysis the OS endpoint had not reached the pre-determined threshold for statistical significance. Patients will continue to be followed for survival.

Infusion reactions occurred in 10% of patients treated with ERd; these adverse events were Grade 3 or lower and occurred during the first treatment cycle. The most common adverse reactions in ERd and Rd, respectively (≥30%) were infections (83%, 75%), fatigue (48%, 40%), diarrhea (48%, 37%), anemia (41%, 37%), pyrexia (38%, 25%), constipation (36%, 28%), cough (33%, 19%), muscle spasms (30%, 27%), and neutropenia (34%, 43%). Adverse events of special interest in ERd and Rd, respectively, included gastrointestinal disorders (81%, 68%), respiratory disorders (63%, 53%), renal/urinary disorders (25%, 18%), peripheral neuropathy (15%, 9%), hypertension (10%, 7%), deep vein thrombosis (8%, 4%) and cardiac failure (1%, 2%). Updated safety and tolerability data were consistent with previous findings.

About Empliciti

Empliciti is an immunostimulatory antibody that specifically targets Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7), a cell-surface glycoprotein. SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities. SLAMF7 is also expressed on Natural Killer cells, plasma cells, and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage.

Empliciti has a dual mechanism-of-action. It directly activates the immune system through Natural Killer cells via the SLAMF7 pathway. Empliciti also targets SLAMF7 on myeloma cells, tagging these malignant cells for Natural Killer cell-mediated destruction via antibody-dependent cellular toxicity.

Bristol-Myers Squibb and AbbVie are co-developing Empliciti, with Bristol-Myers Squibb solely responsible for commercial activities. Prior to approval, Empliciti was granted Breakthrough Therapy Designation by the FDA for use in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in patients who have received one to three prior therapies. According to the FDA, Breakthrough Therapy Designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for Breakthrough Therapy Designation requires preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy.

About Multiple Myeloma

Multiple myeloma is a hematologic, or blood, cancer that develops in the bone marrow. It occurs when a plasma cell, a type of cell in the soft center of bone marrow, becomes cancerous and multiplies uncontrollably. Common symptoms of multiple myeloma include bone pain, fatigue, kidney impairment, and infections.

Despite advances in multiple myeloma treatment over the last decade, less than half of patients survive for five or more years after diagnosis. A common characteristic for many patients is that they experience a cycle of remission and relapse, in which they stop treatment for a short time, but eventually return to a treatment shortly after. It is estimated that annually, more than 114,200 new cases of multiple myeloma are diagnosed and more than 80,000 people die from the disease globally.

EMPLICITI (elotuzumab) INDICATIONS & IMPORTANT SAFETY INFORMATION

INDICATION

EMPLICITI (elotuzumab) is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies.

IMPORTANT SAFETY INFORMATION

Infusion Reactions

EMPLICITI can cause infusion reactions. Common symptoms include fever, chills, and hypertension. Bradycardia and hypotension also developed during infusions. In the trial, 5% of patients required interruption of the administration of EMPLICITI for a median of 25 minutes due to infusion reactions, and 1% of patients discontinued due to infusion reactions. Of the patients who experienced an infusion reaction, 70% (23/33) had them during the first dose. If a Grade 2 or higher infusion reaction occurs, interrupt the EMPLICITI infusion and institute appropriate medical and supportive measures. If the infusion reaction recurs, stop the EMPLICITI infusion and do not restart it on that day. Severe infusion reactions may require permanent discontinuation of EMPLICITI therapy and emergency treatment.

Premedicate with dexamethasone, H1 Blocker, H2 Blocker, and acetaminophen prior to infusing with EMPLICITI.

Infections

In a clinical trial of patients with multiple myeloma (N=635), infections were reported in 81.4% of patients in the EMPLICITI with lenalidomide/dexamethasone arm (ERd) and 74.4% in the lenalidomide/dexamethasone arm (Rd). Grade 3-4 infections were 28% (ERd) and 24.3% (Rd). Opportunistic infections were reported in 22% (ERd) and 12.9% (Rd). Fungal infections were 9.7% (ERd) and 5.4% (Rd). Herpes zoster was 13.5% (ERd) and 6.9% (Rd). Discontinuations due to infections were 3.5% (ERd) and 4.1% (Rd). Fatal infections were 2.5% (ERd) and 2.2% (Rd). Monitor patients for development of infections and treat promptly.

Second Primary Malignancies

In a clinical trial of patients with multiple myeloma (N=635), invasive second primary malignancies (SPM) were 9.1% (ERd) and 5.7% (Rd). The rate of hematologic malignancies were the same between ERd and Rd treatment arms (1.6%). Solid tumors were reported in 3.5% (ERd) and 2.2% (Rd). Skin cancer was reported in 4.4% (ERd) and 2.8% (Rd). Monitor patients for the development of SPMs.

Hepatotoxicity

Elevations in liver enzymes (AST/ALT greater than 3 times the upper limit, total bilirubin greater than 2 times the upper limit, and alkaline phosphatase less than 2 times the upper limit) consistent with hepatotoxicity were 2.5% (ERd) and 0.6% (Rd). Two patients experiencing hepatotoxicity discontinued treatment; however, 6 out of 8 patients had resolution and continued treatment. Monitor liver enzymes periodically. Stop EMPLICITI upon Grade 3 or higher elevation of liver enzymes. After return to baseline values, continuation of treatment may be considered.

Interference with Determination of Complete Response

EMPLICITI is a humanized IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis and immunofixation assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein.

Pregnancy/Females and Males of Reproductive Potential

There are no studies with EMPLICITI with pregnant women to inform any drug associated risks.
There is a risk of fetal harm, including severe life-threatening human birth defects associated with lenalidomide and it is contraindicated for use in pregnancy. Refer to the lenalidomide full prescribing information for requirements regarding contraception and the prohibitions against blood and/or sperm donation due to presence and transmission in blood and/or semen and for additional information.

Adverse Reactions

Infusion reactions were reported in approximately 10% of patients treated with EMPLICITI with lenalidomide and dexamethasone. All reports of infusion reaction were Grade 3 or lower. Grade 3 infusion reactions occurred in 1% of patients.
Serious adverse reactions were 65.4% (ERd) and 56.5% (Rd). The most frequent serious adverse reactions in the ERd arm compared to the Rd arm were: pneumonia (15.4%, 11%), pyrexia (6.9%, 4.7%), respiratory tract infection (3.1%, 1.3%), anemia (2.8%, 1.9%), pulmonary embolism (3.1%, 2.5%), and acute renal failure (2.5%, 1.9%).
The most common adverse reactions in ERd and Rd, respectively (>20%) were fatigue (61.6%, 51.7%), diarrhea (46.9%, 36.0%), pyrexia (37.4%, 24.6%), constipation (35.5%, 27.1%), cough (34.3%, 18.9%), peripheral neuropathy (26.7%, 20.8%), nasopharyngitis (24.5%, 19.2%), upper respiratory tract infection (22.6%, 17.4%), decreased appetite (20.8%, 12.6%), and pneumonia (20.1%, 14.2%).

On December 5, 2015 Bellicum Pharmaceuticals, Inc. (Nasdaq:BLCM), a clinical stage biopharmaceutical company focused on discovering and developing novel cellular immunotherapies for cancers and orphan inherited blood disorders, reported the presentation of interim data from the lead site in the ongoing BP-004 Phase 1/2 clinical trial during the 57th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Orlando, Florida (Press release, Bellicum Pharmaceuticals, DEC 5, 2015, View Source [SID:1234508412]). Pediatric patients in the study with a variety of genetic diseases achieved disease-free outcomes following a haploidentical, T cell-depleted hematopoietic stem cell transplant (HSCT) followed by an add-back of BPX-501 donor T cells. The study is designed to evaluate whether this regimen is safe and improves immune reconstitution, infection control and overall outcomes.

Initial outcomes were reported from the 39 pediatric patients who have received the BPX-501 product (of a total of 49 enrolled) at the European trial site as of November 30. Twenty of these children had non-malignant genetic diseases including Fanconi anemia (5), beta thalassemia (4), severe combined immunodeficiency (SCID or “bubble boy” disease) (5), Wiskott-Aldrich Syndrome (3) and others. Nineteen additional patients had blood cancers, with acute lymphoblastic leukemia being the most common. (The cohort with blood cancers requires longer-term endpoints and will be reported on in more detail at a later date.)

“These interim results present strong evidence that the addition of BPX-501 modified donor T cells provides important immune support and improves outcomes in patients undergoing a T-depleted haploidentical stem cell transplant,” said lead investigator Dr. Franco Locatelli, Director, Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù.

“Historically, haplo-transplants had to be given without T cells to avoid Graft versus Host Disease, increasing the risk of deadly infections and delayed immune recovery, and relapse in patients with malignant disease. An approach that addresses these risks without elevating the GvHD risk could shift the standard of care, making haplo-sourced transplants—almost always available from a family member—an attractive option for patients. I am very happy for the patients and the families who have benefited from participation in this BPX-501 clinical trial.”

The presented data show that treatment with BPX-501 is safe and well tolerated for patients with non-malignant and malignant diseases, and provides several important immune benefits compared to the clinical site’s historical controls. Highlights include:

Safety: No adverse events associated with infusion of BPX-501 were reported. The occurrence and severity of GvHD in study subjects was generally consistent with the historical control group. There were seven instances of Grade 1 or 2 GvHD which all resolved without requiring activation of the CaspaCIDe safety switch with rimiducid.

Survival: There was no transplant-related mortality (TRM) in the 37 study patients with a minimum of 30 days follow-up. In particular, for non-malignant patients, this lack of TRM (0/18) compares favorably with 9% TRM in the historical non-malignant control patients (3/33). TRM, when it occurs, typically happens early in the post-transplant period in non-malignant transplant patients, primarily due to infection.

Immune Reconstitution: Non-malignant patients in the trial achieved a mean improvement of approximately 40 fewer days to reach a T-cell count of 500 cells/ul, showing immune recovery was significantly faster than historical controls.

Time in Hospital: Non-malignant patients in the trial were discharged significantly faster from the hospital, 21 days sooner on average following HSCT, compared to historical controls. The number of patients re-hospitalized was also substantially reduced.

“It’s exciting to see the progress and outcomes from this BPX-501 study that we initiated just a year ago,” said Annemarie Moseley, Ph.D., M.D. Chief Operating Officer and Executive Vice President of Clinical Development at Bellicum. “We are making preparations for dialogue with the regulators in Europe and the U.S. in the first half of 2016, with the goal of defining the path to regulatory approval initially for non-malignant pediatric diseases. We look forward to the further evaluation of BPX-501 in different transplant settings, and in accumulating longer-term data to assess relevant clinical outcomes in the malignant setting.”

Investor/Analyst Luncheon

Bellicum will also host an investor and analyst luncheon on Monday, December 7, 2015 from 12:15 – 1:15 p.m. EST at the Hyatt Regency Orlando. Management and select key opinion leaders, including lead Principal Investigator Professor Franco Locatelli, M.D., will review the BPX-501 Phase 1/2 clinical study data from the above-mentioned poster and additional data from the BP-004 study. The luncheon will be webcast live and may be accessed from the News & Events section of the Bellicum website. An archived version of the webcast will be available for replay for at least two weeks following the event.

About BPX-501

BPX-501 is an adjunct T cell therapy of genetically modified donor T cells incorporating Bellicum’s proprietary CaspaCIDe safety switch. The product candidate is designed to provide a safety net to eliminate the BPX-501 alloreactive T cells should severe GvHD occur, enabling physicians to more safely perform haploidentical stem cell transplants by adding back the BPX-501 genetically engineered T cells to speed immune reconstitution and provide control over viral infections.

BP-004 Clinical Trial Design

In December 2014, Bellicum initiated BP-004, a Phase 1/2 clinical trial in children with leukemias, lymphomas, or orphan inherited blood disorders, such as severe combined immunodeficiency (SCID), Wiskott-Aldrich Syndrome, beta thalassemia and sickle cell disease, all chronic life-long disorders for which HSCT is curative. The trial is being conducted in both European and U.S. pediatric transplant centers and will enroll up to 90 patients. The open label dose escalation trial is evaluating whether BPX-501 T cells from a haploidentical donor, typically the child’s mother or father, administered following a T-depleted HSCT, are safe and can enhance immune reconstitution.

On December 5, 2015 CTI BioPharma Corp. (CTI BioPharma) (NASDAQ and MTA: CTIC) and Baxalta Incorporated (Baxalta) (NYSE: BXLT) reported results from a new analysis of the pivotal Phase 3 trial, PERSIST-1, evaluating pacritinib versus best available therapy, excluding treatment with JAK2 inhibitors (BAT), in patients with myelofibrosis (Press release, Baxalta, DEC 5, 2015, View Source [SID:1234508410]). Data examining patient outcomes across baseline demographic factors that are associated with prognosis – including age, baseline hemoglobin, baseline platelet count, ECOG status, JAK2 mutation status and red blood cell transfusion dependency – showed that treatment with pacritinib resulted in consistent rates of spleen volume reduction and control of disease-related symptoms across all intermediate or high-risk myelofibrosis subgroups. These findings were presented by Alessandro M. Vannucchi, M.D., associate professor of Hematology, University of Florence, Italy, during an oral presentation at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) (ASH 2015) Annual Meeting & Exposition in Orlando (Abstract #58).

Pacritinib is an investigational oral multikinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R, which are kinases found to be involved in the growth and spread of myelofibrosis and other blood-related cancers such as acute myeloid leukemia (AML).

“Reducing the burden of myelofibrosis-related symptoms is an important goal of treatment. However, for patients diagnosed with this rare blood cancer, there are limited therapeutic options – a gap that is even more significant for patients with low platelet counts,” said Prof. Vannucchi. “These data presented at ASH (Free ASH Whitepaper) 2015 are important and clinically meaningful as they demonstrate pacritinib’s potential to achieve treatment goals across intermediate or high-risk patients with myelofibrosis, regardless of baseline characteristics including starting platelet count.”

Myelofibrosis is a rare blood cancer associated with significantly reduced quality of life and shortened survival. Most patients with the disease 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.

“The results from this analysis add to the growing body of data for pacritinib suggesting it is a unique JAK inhibitor with a differentiated efficacy and safety profile that is not limited by the baseline characteristics of patients with myelofibrosis,” said James Bianco, M.D., President and Chief Executive Officer, CTI BioPharma. “We believe pacritinib has the potential to fill a gap that exists for many patients whose lives are profoundly impacted by myelofibrosis, particularly those patients with low platelet counts.”

“We are developing pacritinib with particular focus on targeting the underlying biology of myelofibrosis to improve the treatment landscape for patients with this underserved, progressive disease, including those in intermediate and high-risk subgroups,” said David Meek, Executive Vice President and President, Oncology at Baxalta. “We look forward to working with worldwide regulatory authorities to advance treatment options for all patients with myelofibrosis as we begin our registration submissions for pacritinib in the coming months.”

About the Subgroup Analysis
Findings presented at ASH (Free ASH Whitepaper) 2015 were based on the analysis of baseline patients’ characteristics from PERSIST-1, a randomized Phase 3 registration-directed trial comparing the efficacy and safety of pacritinib to BAT that included a broad range of currently utilized treatments. As previously reported, the trial met its primary endpoint of spleen volume reduction (35 percent or greater from baseline to Week 24 by MRI/CT scan) in the intent-to-treat population.

The subgroup analysis discussed above assessed results observed in patients achieving 35 percent or greater spleen volume reduction from baseline or a decrease of 50 percent or more in Total Symptom Score (TSS) by baseline characteristics or risk factors, including initial platelet count, JAK2V617F mutation status, red blood cell transfusions and bone pain. Findings showed that results (from the primary analysis) were consistent across all subgroups evaluated. Achievement of 35 percent or greater spleen volume reduction was independent of most risk factors assessed and a 50 percent or more decrease in TSS was independent of characteristics evaluated, except bone pain score greater than three at baseline.

The most common adverse events in the pacritinib arm vs. BAT that showed more than 5 percent difference were diarrhea (57 percent vs. 12 percent), nausea (29 percent vs. 6 percent) and vomiting (19 percent vs. 5 percent). No Grade 4 gastrointestinal events were reported.

Additional Pacritinib Data Presented at ASH (Free ASH Whitepaper)
Also presented today were patient-reported outcome data that examined the relationship between myelofibrosis-associated symptoms (based on the TSS) and changes in splenomegaly and health-related quality of life (HRQoL) outcomes in the PERSIST-1 overall patient population and in patients with baseline thrombocytopenia. The analysis showed TSS response was associated with improvements in spleen volume response and perceived Overall Health State; this trend was also observed in patients with low baseline platelet counts (<50,000/µL and <100,000/ µL). In all patient populations analyzed, TSS response was significantly associated with improvements in fatigue, a major contributor to poor HRQoL in patients with myelofibrosis. Significant improvements in social functioning, appetite loss and insomnia were also observed in patients with baseline thrombocytopenia. These data were presented in a poster presentation by Ruben Mesa, M.D., Chair, Hematology and Medical Oncology Division, Mayo Clinic, Scottsdale, AZ (Abstract #1609). About PERSIST-1 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 broad range of currently utilized treatments – in 327 patients with myelofibrosis (primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis), regardless of the patients' platelet counts. At study entry, 46 percent of patients were thrombocytopenic; 32 percent of patients had platelet counts less than 100,000 per microliter (<100,000/µL); and 16 percent of patients had platelet counts less than 50,000 per microliter (<50,000/µL); normal platelet counts range from 150,000 to 450,000 per microliter. The median duration of treatment was 16.2 months in patients treated with pacritinib, compared to 5.9 months in patients treated with BAT. The majority (79 percent) of patients on the BAT arm eventually crossed over to receive pacritinib therapy. About Pacritinib Pacritinib is an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R. In August 2014, pacritinib was granted Fast Track designation by the U.S. Food and Drug Administration (FDA) for the treatment of intermediate and high-risk myelofibrosis, including but not limited to patients with disease-related thrombocytopenia, patients experiencing treatment-emergent thrombocytopenia on other JAK2 inhibitor therapy or patients who are intolerant of, or whose symptoms are sub-optimally managed on other JAK2 inhibitor therapy. CTI BioPharma and Baxalta are parties to a worldwide license agreement to develop and commercialize pacritinib. CTI BioPharma and Baxalta will jointly commercialize pacritinib in the U.S. while Baxalta has exclusive commercialization rights for all indications outside the U.S. The companies recently announced the initiation of a rolling new drug application (NDA) to the FDA for pacritinib. The companies are seeking accelerated approval and priority review of pacritinib for the treatment of patients with intermediate and high-risk myelofibrosis with low platelet counts of less than 50,000 per microliter (<50,000/µL). About Myelofibrosis and Myeloproliferative Neoplasms Myelofibrosis is one of three main types of myeloproliferative neoplasms (MPN), which are a closely related group of hematological blood cancers. The three main types of MPNs are myelofibrosis, polycethemia vera and essential thrombocythemia.1 Myelofibrosis is a serious and life-threatening chronic bone marrow disorder 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. 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), anemia and red blood cell transfusion requirements increase significantly. 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 AML.3 The median survival for high-risk myelofibrosis patients is less than one and a half years, while the median survival for myelofibrosis patients overall is approximately six years.4

On December 5, 2015 Amgen (NASDAQ:AMGN) reported the submission to the European Medicines Agency (EMA) of a Variation to the Marketing Authorization Application (MAA) to expand the indication for Kyprolis (carfilzomib) in combination with dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy (Press release, Amgen, DEC 5, 2015, View Source [SID:1234508409]).

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The application is based on results from the Phase 3 head-to-head ENDEAVOR study in which patients with multiple myeloma treated with Kyprolis plus dexamethasone achieved superior progression-free survival (PFS) compared to those receiving Velcade (bortezomib) plus dexamethasone (18.7 versus 9.4 months, respectively) (p<0.0001). The most common adverse events (greater than 25 percent) in the Kyprolis arm were diarrhea, anemia, fatigue, dyspnea, pyrexia and insomnia.

"Physicians need options to personalize treatment for complicated diseases like multiple myeloma," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "We look forward to continued discussions with health authorities with the goal of bringing new Kyprolis-based regimens to patients in Europe."

The European Commission (EC) recently granted marketing authorization following accelerated assessment for Kyprolis in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse.1 It is a rare and very aggressive orphan disease that accounts for approximately one percent of all cancers.2-4 In Europe, approximately 39,000 patients are diagnosed with multiple myeloma each year and 24,000 patient deaths are reported on an annual basis.2

About ENDEAVOR
The randomized ENDEAVOR (RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma) trial of 929 patients evaluated Kyprolis in combination with low-dose dexamethasone, versus bortezomib with low-dose dexamethasone in patients whose multiple myeloma has relapsed after at least one, but not more than three prior therapeutic regimens. The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. In a clinical trial, measuring the PFS is one way to demonstrate how well a treatment works.

The superiority of the Kyprolis combination compared to the bortezomib combination with respect to PFS was seen across key pre-specified subgroups, including bortezomib-naïve patients, those with high- or standard-risk cytogenetics and with or without prior transplantation. The Kyprolis combination also demonstrated superiority over the bortezomib combination for secondary endpoints, achieving a higher overall response rate (76.9 percent versus 62.6 percent; p<0.0001) and lower rate of grade 2 or higher neuropathy events (6 percent versus 32 percent; p<0.0001). Treatment with the Kyprolis combination resulted in a two-fold increase in the median duration of response (21.3 months) compared to the bortezomib combination (10.4 months).

In the Kyprolis and bortezomib groups, 54.3 percent and 28.6 percent of patients achieved a very good partial response or better (p<0.0001), and 12.5 percent and 6.2 percent of patients achieved a complete response or better (p<0.0001), respectively. Overall survival data are not yet mature and continue to be monitored.

Treatment discontinuation due to adverse events and on-study deaths were comparable between the two arms. A number of known adverse drug reactions were reported at a higher rate in the Kyprolis group compared with the bortezomib group, including any-grade dyspnea, hypertension, pyrexia, and cough (preferred terms) as were any-grade cardiac failure (grouped term; 8.2 percent versus 2.9 percent) and acute renal failure (grouped term; 8.2 percent versus 4.8 percent). The rates of cardiac and renal failure for Kyprolis were comparable to those observed in previous Phase 3 ASPIRE study.

Rates of grade 3 or higher adverse events were 73.2 percent in the Kyprolis group and 66.9 percent in the bortezomib group. Grade 3 or higher adverse events of interest in the Kyprolis and bortezomib groups included hypertension (preferred term; 8.9 percent versus 2.6 percent), dyspnea (preferred term; 5.4 percent versus 2.2 percent), cardiac failure (grouped term; 4.7 percent versus 1.8 percent), acute renal failure (grouped term; 4.0 percent versus 2.6 percent), ischemic heart disease (grouped term; 1.7 percent versus 1.6 percent) and pulmonary hypertension (grouped term; 0.6 percent versus 0.2 percent).

Patients received treatment until progression with Kyprolis as a 30-minute infusion on days 1, 2, 8, 9, 15 and 16 of 28 day treatment cycles, along with low-dose dexamethasone (20 mg). For Cycle 1 only, Kyprolis was administered at 20 mg/m2 on days 1 and 2, followed by escalation to 56 mg/m2 from day 8. Patients who tolerated 56 mg/m2 in Cycle 1 were kept at this dose for subsequent cycles. Patients who received bortezomib (1.3 mg/m2) with low-dose dexamethasone (20 mg) were administered bortezomib subcutaneously or intravenously at the discretion of the investigator and in accordance with regulatory approval of bortezomib. More than 75 percent of the patients in the control arm received bortezomib subcutaneously. This study was conducted at 235 sites worldwide. For information about this trial, please visit www.clinicaltrials.gov under trial identification number NCT01568866.

About Kyprolis (carfilzomib)
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.5 Kyprolis has been shown to block proteasomes, leading to an excessive build-up of proteins within cells.6 In some cells, Kyprolis can cause cell death, especially in myeloma cells because they are more likely to contain a higher amount of abnormal proteins.6 The irreversibility of Kyprolis’ binding has also been shown to offer a more sustained inhibition of the targeted enzymes.7

Kyprolis is currently approved in the United States (U.S.), European Union, Argentina, Israel, Kuwait, Mexico, Thailand and Colombia. Additional regulatory applications for Kyprolis are underway and have been submitted to health authorities worldwide.

Kyprolis is approved in the U.S. in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior lines of therapy.

Kyprolis is also indicated under FDA accelerated approval as a single agent for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Kyprolis is a product of Onyx Pharmaceuticals, Inc. Onyx Pharmaceuticals is a subsidiary of Amgen and holds development and commercialization rights to Kyprolis globally, excluding Japan.

Important EU Product Safety Information

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Kyprolis treatment should be supervised by a physician experienced in the use of anti-cancer therapy. The most serious side effects that may occur during Kyprolis treatment include: Cardiac toxicity, pulmonary toxicities, pulmonary hypertension, dyspnea, hypertension including hypertensive crises, acute renal failure, tumor lysis syndrome, infusion reactions, thrombocytopenia, hepatic toxicity, posterior reversible encephalopathy syndrome (PRES) and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). The most common side effects are anemia, fatigue, diarrhea, thrombocytopenia, nausea, pyrexia, dyspnea, respiratory tract infection, cough and peripheral edema.

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

Important U.S. Product Safety Information

Cardiac Toxicities
New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of Kyprolis. Death due to cardiac arrest has occurred within a day of Kyprolis administration.

Withhold Kyprolis for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart Kyprolis based on a benefit/risk assessment.

Adequate hydration is required prior to each dose in Cycle 1. Monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure.

Patients > 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, and conduction abnormalities may be at greater risk for cardiac complications.

Acute Renal Failure
Cases of acute renal failure and renal insufficiency adverse events (renal impairment, acute renal failure, renal failure) have occurred in patients receiving Kyprolis. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received Kyprolis monotherapy. This risk was greater in patients with a baseline reduced estimated creatinine clearance. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.

Tumor Lysis Syndrome
Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred in patients receiving Kyprolis. Patients with multiple myeloma and a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly. Withhold Kyprolis until TLS is resolved.

Pulmonary Toxicity
Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving Kyprolis. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue Kyprolis.

Pulmonary Hypertension
Pulmonary arterial hypertension (PAH) was reported in patients treated with Kyprolis. Evaluate with cardiac imaging and/or other tests as indicated. Withhold Kyprolis for PAH until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment.

Dyspnea
Dyspnea was reported in patients treated with Kyprolis. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop Kyprolis for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart Kyprolis based on a benefit/risk assessment.

Hypertension
Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. Some of these events have been fatal. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on a benefit/risk assessment.

Venous Thrombosis
Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. Thromboprophylaxis is recommended and should be based on an assessment of the patient’s underlying risks, treatment regimen, and clinical status.

Infusion Reactions
Infusion reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms of an infusion reaction and to contact a physician immediately if they occur.

Thrombocytopenia
Kyprolis causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was reported in patients receiving Kyprolis. Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate.

Hepatic Toxicity and Hepatic Failure
Cases of hepatic failure, including fatal cases, have been reported during treatment with Kyprolis. Kyprolis can cause increased serum transaminases. Monitor liver enzymes regularly. Reduce or withhold dose as appropriate.

Thrombotic Thrombocytopenic Purpura /Hemolytic Uremic Syndrome (TTP/HUS)
Cases of TTP/HUS including fatal outcome have occurred in patients receiving Kyprolis. Monitor for signs and symptoms of TTP/HUS. Discontinue Kyprolis if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. The safety of reinitiating Kyprolis therapy in patients previously experiencing TTP/HUS is not known.

Posterior Reversible Encephalopathy Syndrome (PRES)
Cases of PRES have occurred in patients receiving Kyprolis. PRES was formerly known as Reversible Posterior Leukoencephalopathy Syndrome. Consider a neuro-radiological imaging (MRI) for onset of visual or neurological symptoms. Discontinue Kyprolis if PRES is suspected and evaluate. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known.

Embryo-fetal Toxicity
Kyprolis can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals.

Females of reproductive potential should be advised to avoid becoming pregnant while being treated with Kyprolis and the potential hazard to the fetus if Kyprolis is used during pregnancy.

ADVERSE REACTIONS
The most common adverse events occurring in at least 20% of patients treated with Kyprolis in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, decreased platelets, dyspnea, diarrhea, decreased lymphocyte, headache, decreased hemoglobin, cough, edema peripheral.

The most common adverse events occurring in at least 20% of patients treated with Kyprolis in the combination therapy trial: decreased lymphocytes, decreased absolute neutrophil count, decreased phosphorus, anemia, neutropenia, decreased total white blood cell count, decreased platelets, diarrhea, fatigue, thrombocytopenia, pyrexia, muscle spasm, cough, upper respiratory tract infection, decreased hemoglobin, hypokalemia.

Full prescribing information for the U.S. is available at www.kyprolis.com.