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OPKO Announces Publication of ProtecT Study Using Kallikrein Biomarkers in 4Kscore Test

On April 21, 2015 OPKO Health, Inc. (NYSE:OPK) reported the online publication of a study entitled "Predicting High-Grade Cancer at Ten-Core Prostate Biopsy Using Four Kallikrein Markers Measured in Blood in the ProtecT Study" in the Journal of the National Cancer Institute (Press release, Opko Health, APR 21, 2015, View Source [SID:1234506587]). The study shows that the four kallikrein panel of biomarkers utilized in the OPKO 4Kscore Test (Total PSA, Free PSA, Intact PSA and hK2) accurately identifies risk for aggressive prostate cancer prior to prostate biopsy.

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The Prostate Testing for Cancer and Treatment (ProtecT) study is a prospective randomized controlled trial conducted in the United Kingdom for the purpose of evaluating the cost effectiveness of conventional treatments in PSA-detected, clinically localized prostate cancer. Of the 82,428 men recruited for the trial, a total of 6129 men with elevated PSA (≥3.0 ng/mL) who underwent prostate biopsy and provided an adequate blood sample were tested for the four kallikreins and their 4Kscore result was determined. The study showed that the four kallikrein panel enhanced aggressive prostate cancer detection compared with PSA and age alone. The area under the curve (AUC) for the 4K model was 0.820 (95% CI = 0.802 to 0.838) while the PSA model was 0.738 (95% CI = 0.716 to 0.761) for high-grade cancer.

"The ProtecT study is the latest in a series of peer-reviewed publications demonstrating the superior clinical value that testing with four kallikrein markers adds to risk prediction for aggressive prostate cancer compared to PSA alone," said Dr. Peter Scardino, Chair, Department of Surgery, Memorial Sloan Kettering Cancer Center. "The high level of discrimination for differentially detecting high-grade disease supports use of the four kallikrein panel as a reflex test prior to having a prostate biopsy for men with an elevated PSA."

"The 4Kscore biomarker algorithm has now been tested and published on over 20,000 men in 11 peer-reviewed publications covering multiple US and European cohorts," said David Okrongly, President of OPKO Diagnostics. "The results all demonstrated the high discrimination and favorable decision curve benefit of the 4Kscore algorithm for predicting the results of prostate biopsy pathology, as well as 20 year outcomes for risk of metastatic prostate cancer."

About Prostate Cancer

According to the World Health Organization, prostate cancer is the second most common cancer in men worldwide, with over 1.1 million men diagnosed with prostate cancer in 2012 and over 300,000 men dying from the disease. In countries like the U.S. where screening for prostate cancer with the PSA test began 20 years ago there has been a sharp increase in the number of prostate cancers detected. However, most of the prostate cancers detected are an indolent, non-life threatening form of the disease. The net result has been a decrease in prostate cancer mortality during the PSA era, but at a cost of over detection and over treatment of indolent prostate cancers.

About the 4Kscore Test

The 4Kscore is the only blood test that accurately identifies risk for aggressive prostate cancer. The 4Kscore measures the blood plasma levels of four different prostate-derived kallikrein proteins: Total PSA, Free PSA, Intact PSA and Human Kallikrein-2 (hK2). These biomarkers are combined with a patient’s age, Digital Rectal Exam (DRE) status (nodule / no nodule), and prior negative biopsy status (yes / no) using a proprietary algorithm to calculate the risk (probability) of finding a Gleason Score 7 or higher prostate cancer. The four kallikrein panel of biomarkers utilized in the 4Kscore Test is based on over a decade of research conducted by scientists at Memorial Sloan-Kettering Cancer Center and leading European institutions. The 4Kscore Test provides individualized risk for the presence of aggressive prostate cancer and adds new information to the shared decision making discussion between a Urologist and patient.

SignalRx Presents at 10th Annual Drug Discovery Chemistry Conference on its Dual Kinase-Epigenetic Inhibitors for Treating Cancer

On April 21, 2015 SignalRx Pharmaceuticals Inc., focused on developing more effective oncology drugs though molecular design imparting selected multiple target inhibition, reported the presentation of scientific data on the Company’s proprietary dual inhibitor program in oncology (Press release, SignalRx, APR 21, 2015, http://www.ireachcontent.com/news-releases/signalrx-presents-at-10th-annual-drug-discovery-chemistry-conference-on-its-dual-kinase-epigenetic-inhibitors-for-treating-cancer-500857951.html [SID1234527330]). The presentation by Dr. Donald L. Durden, MD, PhD, co-founder and science advisor to SignalRx was made at the Tenth Annual Drug Discovery Chemistry meeting at the Hilton San Diego Resort & Spa in San Diego, California.

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The oral presentation entitled "Discovery of Dual PI3K/BRD4 (kinase/epigenetic) Inhibitors" was given during the Second Annual Epigenetic Inhibitor Discovery track of the meeting at the "Advances in BET Bromodomain Inhibitor Development" session. The presentation highlighted a novel thienopyranone molecular scaffold that selectively inhibits both PI3 kinase (PI3K) and the bromodomain protein BRD4. The presentation described how molecular modeling studies were used to identify and design SignalRx’s single small molecules that can bind and inhibit simultaneously PI3K and BRD4. While the small molecule SF2523 inhibits PI3K via ATP competitive binding at the catalytic site, BRD4 inhibition appears to take place by binding in the acetyl-lysine recognition moiety of BRD4 thus blocking BRD4’s ability to alter chromatin structure and induce transcription. Blocking the binding of BRD4 to acetylated histones within chromatin can then block the transcription of various genes that are promoting cancer cell survival and growth. Recent reports suggest that BRD4 inhibition may block cancer cell resistance arising from widespread epigenetic kinome adaptation following exposure to targeted kinase inhibitor drugs which in turn may lead to more durable anticancer effects.

The presentation also included a specific rationale for the dual PI3K/BRD4 inhibition approach in cancers driven by the key cancer promoting transcription factor MYC. MYC (both cMYC and MYCN) acts downstream of many cell receptor complexes and signal transduction pathways to activate genes that drive cancer cell growth and proliferation. To date, small molecule inhibitors of MYC have been elusive. Inhibition of PI3K enhances the degradation of the cancer promoting transcription factor MYC. Inhibition of BRD4 blocks the production of MYC; thus, a dual PI3K/BRD4 inhibitor can lead to maximal MYC extinction by inhibiting these two different mechanisms. Our approach enables us to go after cancers expected to be susceptible to maximal MYC extinction as a beneficial treatment, such as CLL, medulloblastoma, multiple myeloma, and certain ovarian cancers exhibiting elevated MYCN expression. In vivo data also showed that SF2523 (50 mg/kg 3X per week) exhibited potent antitumor efficacy and anti-metastatic effects without toxicity in renal cell carcinoma xenograft models, neuroblastoma mouse models, orthotopic pancreatic cancer model and Lewis lung cancer models. Lastly, pre-clinical in vivo proof-of-concept with SF2523 was presented showing the pharmacodynamic knockdown of both the PI3K pathway and MYC in mouse neuroblastoma tumor samples four hours after administration, confirming the dual PI3K/BRD4 inhibitory profile of lead compound SF2523. Further preclinical studies of several PI3K/BRD4 dual inhibitor thienopyranones are underway to identify and select a clinical candidate.

Pfizer Phase 3 Study Of Inotuzumab Ozogamicin Meets Primary Endpoint In Adult Patients With Relapsed Or Refractory Acute Lymphoblastic Leukemia

On April 21, 2015 Pfizer reported that the Phase 3 study investigating the treatment of inotuzumab ozogamicin met its first primary endpoint of demonstrating a higher complete hematologic remission rate in adult patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL) compared to that achieved with standard of care chemotherapy(Press release, Pfizer, APR 21, 2015, View Source [SID:1234503105]).

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The Phase 3 study has two primary endpoints, complete hematologic remission rate and overall survival. Pfizer is continuing the study to allow for the data on overall survival to mature.

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"We are excited about the results of the INO-VATE ALL study especially since relapsed and refractory acute lymphoblastic leukemia is a particularly difficult disease to treat in adults. The top-line results show that inotuzumab ozogamicin has the potential to be an important new treatment option for patients with relapsed or refractory disease," said Dr. Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology. "We look forward to discussing these data with the FDA and other regulatory authorities."

No new or unexpected safety issues were identified. Efficacy and safety data from this study will be submitted for presentation at an upcoming medical meeting.

About the INO-VATE ALL Study

The INO-VATE ALL Study, also known as Study 1022, is an open-label, randomized, Phase 3 study evaluating the safety and efficacy of the investigational compound inotuzumab ozogamicin as compared with a defined set of chemotherapy choices in adult patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL).

The two primary endpoints are hematologic remission, defined as a complete response with or without platelet and/or neutrophil recovery (CR/CRi), and overall survival. Secondary endpoints include progression-free survival, volume of distribution and systemic clearance for inotuzumab ozogamicin in serum, duration of response, rate of stem-cell transplantation, minimal residual disease, cytogenetics, safety and quality of life (European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire, Core-30 and EuroQual-5D Health Questionnaire).1

Inotuzumab ozogamicin was administered intravenously once weekly for three weeks for a three to four week cycle up to six cycles. Chemotherapy options included fludarabine, cytarabine and G-CSF (FLAG); high dose cytarabine (HIDAC); or cytarabine and mitoxantrone.2

There were 326 patients enrolled in the trial. Enrollment is now complete.

About Acute Lymphoblastic Leukemia (ALL)

Acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia with a poor prognosis in adults.3 The current foundational treatment is intensive, long-term chemotherapy.4 Approximately 20 to 40 percent of newly diagnosed adults with ALL are cured with current treatment regimens.5 For patients with relapsed or refractory adult ALL, the five-year overall survival rate is less than 10 percent.6

About Inotuzumab Ozogamicin

Inotuzumab ozogamicin is an investigational antibody-drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22,7 a cell surface antigen expressed on approximately 90 percent of B-cell malignancies,8 linked to a cytotoxic agent. When inotuzumab ozogamicin binds to the CD22 antigen on malignant B-cells, it is internalized into the cell, where the cytotoxic agent calicheamicin is released to destroy the cell.9

Inotuzumab ozogamicin originates from a collaboration between Pfizer and Celltech, now UCB. Pfizer has sole responsibility for all manufacturing and clinical development activities for this molecule.

Pfizer Receives U.S. FDA Breakthrough Therapy Designation For XALKORI® (crizotinib) For The Treatment Of Patients With ROS1-Positive Non-Small Cell Lung Cancer

On April 21, 2015 Pfizer reported that XALKORI (crizotinib) received Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) for the potential treatment of patients with ROS1-positive non-small cell lung cancer (NSCLC) (Press release, Pfizer, APR 21, 2015, View Source [SID:1234503104]). Occurring in approximately one percent of NSCLC cases1, ROS1-positive NSCLC represents a particular molecular subgroup of NSCLC.2 XALKORI currently is approved in the U.S. for the treatment of patients with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

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Enacted as part of the 2012 FDA Safety and Innovation Act (FDASIA), Breakthrough Therapy designation is intended to expedite the development and review of a potential new medicine if it is "intended to treat a serious or life-threatening disease and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies."3The Breakthrough Therapy designation is distinct from the FDA’s other mechanisms to expedite drug development and review.4

"We are excited that the FDA has granted Breakthrough Therapy designation for XALKORI as a potential treatment for patients with ROS1-positive NSCLC," said Dr. Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology. "XALKORI pioneered precision medicine for ALK-positive metastatic NSCLC, and ROS1 represents a second molecular subgroup of NSCLC in which XALKORI has demonstrated a level of anti-tumor activity that can potentially make a real difference for patients."

Pfizer will work closely with the FDA on the development of XALKORI for ROS1-positive NSCLC and provide the information needed to support a potential regulatory submission.

The Breakthrough Therapy designation was based on a data analysis from an expansion cohort of a global Phase 1 study (Study 1001), which evaluated XALKORI in 50 patients with ROS1-positive advanced NSCLC. These data published in the November 20, 2014 issue of the New England Journal of Medicine demonstrated that XALKORI exhibited marked anti-tumor activity in patients with ROS1-positive advanced NSCLC.5 The safety profile of XALKORI in ROS1-rearranged advanced NSCLC was similar to that observed in patients with ALK-positive advanced NSCLC.5

About Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer death worldwide.6 NSCLC accounts for about 85 percent of lung cancer cases and remains difficult to treat, particularly in the metastatic setting.7 Approximately 75 percent of NSCLC patients are diagnosed late with metastatic, or advanced, disease where the five-year survival rate is only 5 percent.7,8,9

About XALKORI (crizotinib)

XALKORI is a kinase inhibitor indicated in the U.S. for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. XALKORI has received approval in more than 80 countries10 including Australia, Canada, China, Japan, South Korea and the European Union.

XALKORI Important Safety Information

Hepatotoxicity: Across three main clinical trials fatal hepatotoxicity occurred in 0.2% of patients. Monitor with periodic liver testing. Temporarily suspend, dose reduce, or permanently discontinue XALKORI.

Pneumonitis: Across three main clinical trials interstitial lung disease (ILD)/pneumonitis occurred in 2% of patients. Permanently discontinue in patients with ILD/pneumonitis.

QT Interval Prolongation: Across three main clinical trials QT interval prolongation occurred in 2.7% of patients. Monitor with electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong QT. Temporarily suspend, dose reduce, or permanently discontinue XALKORI.

Bradycardia: XALKORI can cause bradycardia. Across three main clinical trials 11% of patients experienced a heart rate of less than 50 beats per minute. Monitor heart rate and blood pressure regularly. Temporarily suspend, dose reduce, or permanently discontinue XALKORI.

Embryofetal Toxicity: XALKORI can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving XALKORI.

Adverse Reactions: Across three main clinical trials the most common adverse reactions (≥25%) were vision disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue.

In a phase 3 study in patients with previously treated ALK-positive metastatic NSCLC randomized to XALKORI (n=172) or chemotherapy (n=171), serious adverse reactions were reported in 37.2% of patients treated with XALKORI. The most frequent serious adverse reactions reported in patients treated with XALKORI were pneumonia (4.1%), pulmonary embolism (3.5%), dyspnea (2.3%), and ILD (2.9%). Fatal adverse reactions in XALKORI-treated patients occurred in 9 (5%) patients, consisting of: acute respiratory distress syndrome, arrhythmia, dyspnea, ILD, pneumonia, pneumonitis, pulmonary embolism, respiratory failure, and sepsis. Grade 3 or 4 events occurring at a higher incidence with XALKORI than with chemotherapy and at greater than 2%, were syncope (3%), QT prolongation (3%), and pulmonary embolism (5%). Elevation of ALT of any grade occurred in 76% of patients and grade 3 or 4 in 17% of patients. Neutropenia of any grade occurred in 49% of patients and grade 3 or 4 in 12% of patients. Lymphopenia of any grade occurred in 51% of patients and grade 3 or 4 in 9% of patients. Renal cysts occurred in 4% and neuropathy occurred in 19% of patients treated with XALKORI.

Drug Interactions: Exercise caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Dose reduction may be needed for co-administered drugs that are predominantly metabolized by CYP3A.

Nursing Mothers: Given the potential for serious adverse reactions in nursing infants, consider whether to discontinue nursing or discontinue XALKORI.

Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Use caution in patients with hepatic impairment.

Renal Impairment: Administer XALKORI at a starting dose of 250 mg taken orally once daily in patients with severe renal impairment (CLcr<30 mL/min) not requiring dialysis. No starting dose adjustment is needed for patients with mild and moderate renal impairment.

For more information and full prescribing information, please visit www.XALKORI.comExternal Links icon.

Juno Therapeutics’ CAR T Cell Product Candidate JCAR017 Continues to Demonstrate Encouraging Outcomes in Pediatric Patients With Relapsed/Refractory CD19 Positive Acute Lymphoblastic Leukemia

On April 21, 2015 Juno Therapeutics reported encouraging clinical responses in a Phase 1 study evaluating JCAR017 in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL) (Press release, Juno, APR 21, 2015, View Source [SID:1234503099]). The results of this trial to date demonstrated that 91% of patients achieved a complete remission as documented by flow cytometry. Adverse events were consistent with what has been previously reported. JCAR017 is a chimeric antigen receptor (CAR) T cell product candidate subject to a licensing arrangement with Seattle Children’s Research Institute. The results were presented in an oral presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2015 in Philadelphia, Pennsylvania.

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"The 91% remission rate in this Phase 1 study of JCAR017 is highly encouraging, particularly when considering these pediatric patients failed to respond to standard treatments," said Michael Jensen, M.D., Scientific Co-Founder, Juno Therapeutics, and Director of the Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute. "Based on these results we are eager to advance this study, and to continue advancing the use of cell therapies to change how we treat cancer and provide patients the opportunity for better treatment options."

Data from the ongoing, open-label, Phase 1 dose escalation study were presented by Dr. Jensen at AACR (Free AACR Whitepaper) today. The study is evaluating escalating doses of JCAR017 in pediatric patients with relapsed/refractory CD19 positive ALL. JCAR017, a defined cell product candidate, was successfully manufactured for all enrolled patients. The study was designed and conducted by Seattle Children’s Research Institute with patients from Seattle Children’s Research Institute.

In an intent-to-treat analysis, a complete remission documented by flow cytometry in 20 of 22 patients (91%) was measured. The complete remissions were observed at all doses evaluated in patients with prior CD19-directed therapy as well as in patients with infantile ALL. Severe cytokine release syndrome and/or severe neurotoxicity was observed in 8 patients. Four relapses have been observed to date, only one of which had CD19 positive disease.