On December 6, 2016 Arvinas LLC, a private biotechnology company creating a new class of drugs known as PROTACs which function via targeted protein degradation reported that preclinical data were presented by three Arvinas collaborators at the 2016 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, CA (Press release, Arvinas, DEC 6, 2016, View Source [SID1234517044]). The data presented demonstrate superior efficacy of PROTACs targeting the BET (bromodomain and extraterminal domain) protein family when compared to BET inhibitors in preclinical models of lymphoma and leukemia.

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"The data further support our ongoing understanding of how the Arvinas BET PROTACs show pronounced efficacy improvements compared to BET inhibitors in in vitro and in vivo model systems. The advantages of BET degradation have now been demonstrated preclinically in a number of solid tumor and hematologic cancers including diffuse large B cell lymphoma, prostate cancer, ovarian cancer, mantle cell lymphoma and acute myeloid leukemia (AML)," said Manuel Litchman, M.D., President and CEO of Arvinas.

"These findings underscore the superior activity of BET PROTACs versus BET inhibitors against mantle cell lymphoma cells that are either sensitive or resistant to the drug ibrutinib, as well as against models of AML," said Kapil Bhalla, M.D., Professor of Leukemia at the University of Texas MD Anderson Cancer Center.

In a podium presentation titled "Novel BET PROTACs Exert Potent Single Agent and Synergistic Activity with Ibrutinib and Venetoclax Against Human Mantle Cell Lymphoma Cells" and presented by Dr. Bhalla, data show:
Compared to BET inhibitors, in primary mantle cell lymphoma (MCL) cells and MCL cell lines, BET PROTACs provide greater down-regulation of the expression of genes important to tumor growth and survival, greater killing of cells resistant to ibrutinib and greater inhibition of the growth of ibrutinib-resistant MCL xenografts alone and in combination with rationally selected targeted agents.

Dr. Sujan Piya of the University of Texas MD Anderson Cancer Center presented data on Arvinas BET PROTAC ARV-825 in a podium presentation titled "BRD4 PROTAC ARV-825 Causes Sustained Degradation of BRD4 and Modulation of Chemokine Receptors, Cell Adhesion and Metabolic Targets in Leukemia Resulting in Profound Anti-Leukemic Effects."

As a single agent, ARV-825 demonstrated substantial activity across multiple models of AML, including cell lines, primary AML blasts and a mouse model of human leukemia.

In all tested cell lines and primary cells, the BET PROTAC was significantly more potent than a BET inhibitor.
Importantly, in a co-culture model, ARV-825 was shown to modulate the tumor microenvironment and metabolism to overcome stroma-mediated drug resistance.

Dr. Warren Fiskus of the University of Texas MD Anderson Cancer Center delivered a podium presentation titled "Superior Lethal Activity of Novel BET PROTAC Versus BET Inhibitor Against Post-Myeloproliferative Neoplasm Secondary AML Cells (sAML)."
Arvinas BET PROTACs were significantly more potent than a BET inhibitor in inducing apoptosis-driven cell death of patient-derived and cultured secondary AML (sAML) cells and caused greater depletion of several key sAML signaling and survival proteins.
Co-treatment of BET PROTAC ARV-825 and JAK inhibitor ruxolitinib showed synergistic lethality against sAML cells.
Notably, BET PROTACs both alone and in combination with either an HSP90 inhibitor or a BCL2/BcL-xL antagonist were highly active against JAK inhibitor-resistant sAML cells.

Compared to a BET inhibitor, treatment with BET-PROTAC ARV-771 significantly reduced leukemia growth and improved survival of mice engrafted with sAML cell xenografts.

On December 6, 2016 Celgene Corporation (NASDAQ:CELG), reported results from two studies (Abstracts #1143, LBA-1) evaluating the investigational use of REVLIMID (lenalidomide) maintenance therapy in patients with multiple myeloma (Press release, Celgene, DEC 6, 2016, View Source [SID1234516959]). These studies were presented at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, Calif.

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Myeloma XI Study

The Myeloma XI trial is a UK-based, large, randomized, open-label phase III study that included a comparison of investigational lenalidomide maintenance treatment versus no maintenance for patients with newly diagnosed multiple myeloma. The study included both transplant-eligible (TE) and transplant non-eligible (TNE) patients. Patients received induction treatment in both segments with lenalidomide or thalidomide plus cyclophosphamide and dexamethasone. TE patients proceeded to a standard melphalan 200mg/m2 autologous stem cell transplant (ASCT). Patients were then randomized to either maintenance lenalidomide or observation after achieving maximum response (TNE) or at 100 days after transplant (TE). Lenalidomide maintenance was administered at a dose of 10mg daily in 21/28 day cycles until disease progression.

Overall, the primary endpoint of progression-free survival (PFS) was 36 months for patients receiving lenalidomide (n=857) and 18 months for observation (n=694) (HR:0.45 95% CI [0.39, 0.52] P < 0.0001) in the maintenance phase of the study.

For TE patients, median PFS was 50 months for lenalidomide (n=451) and 28 months for observation (n=377) (HR:0.48 95% CI [0.38, 0.60] P < 0.0001).
For TNE patients, median PFS was 24 months for lenalidomide (n=406) and 11 months for observation (n=317) (HR:0.42 95% CI [0.35, 0.60] P < 0.0001).
Grade 3-4 adverse events for patients receiving lenalidomide (n=864) included neutropenia (34%), thrombocytopenia (7%) and anemia (4%). The incidence of deep-vein thrombosis/pulmonary embolism was 1% in all grades. Second primary malignancies (SPM) were observed in 72 patients in the study (24 in the observation arm and 48 in the lenalidomide arm (HR 1.78 95% CI [1.02, 3.10]))
"The Myeloma XI study provides important insights for the continued investigation of lenalidomide as a maintenance treatment for people living with multiple myeloma," said Gareth Morgan, M.D., Ph.D., Director of the Myeloma Institute at the University of Arkansas for Medical Sciences. "Building on previous studies, lenalidomide maintenance in this study delayed relapse in patients compared to no maintenance."

StaMINA Study

In the phase III BMT CTN 0702 StaMINA trial, TE patients were randomized following transplant between three arms to receive either 4 cycles of lenalidomide-bortezomib-dexamethasone (RVD) consolidation (ACM) (n=254), tandem melphalan 200mg/m2 autologous stem cell transplant (TAM) consolidation (n=247), or no consolidation (AM) (n=257). All arms included lenalidomide maintenance (at a starting dose of 10 mg daily in 28/28 day cycles until disease progression.

At a median follow-up of 38 months, all three arms demonstrated comparable PFS and OS. The addition of RVD consolidation or a second ASCT was not superior to a single ASCT followed by lenalidomide maintenance. The estimated PFS rates were 57% (95% CI: 50-63%), 56% (95% CI: 49-63%) and 52% (95% CI: 45-59%) for ACM, TAM and AM arms, respectively (ACM vs TAM p=0.75, ACM vs AM p=0.21, TAM vs AM p=0.37). The estimated overall survival (OS) rates were 86% (95% CI: 80-90%), 82% (95% CI: 76-87%) and 83% (95% CI: 78-88%). Median OS had not been reached.

There were 39 cases of SPM reported in 36 patients and the cumulative incidences for first SPM were 6.0% (95% CI: 3.4-9.6%), 5.9% (95% CI: 3.3-9.6%) and 4.0% (95% CI: 1.9-7.2%) for the ACM, TAM and AM arms, respectively.

"The StaMINA trial demonstrated that the addition of RVD consolidation or a second autologous stem cell transplant did not provide a superior outcome, on average, to a single autologous stem cell transplant followed immediately by lenalidomide maintenance," said Edward Stadtmauer, M.D., Section Chief, Hematologic Malignancies at the University of Pennsylvania School of Medicine. "As transplants continue to be an option for many myeloma patients, these are important insights for determining the path to subsequent maintenance therapy."

Health-Related Quality of Life Analysis

An additional analysis presented at ASH (Free ASH Whitepaper) (Abstract #537) examined health related quality of life in post-transplant maintenance in patients from Celgene’s CONNECT MM registry.

The analysis evaluated data from patients newly-diagnosed with multiple myeloma (n=1493) registered between September 2009 and December 2011.

Quality of life was measured for those who received ASCT (n=540) using the EQ-5D quality of life index, Fact-MM total score and brief pain inventory (BPI), assessed at a median follow-up of 39.5 months. Patients who received any maintenance therapy (n=238) were compared with those receiving no maintenance therapy (n=138). Another analysis compared those receiving any maintenance therapy versus those who received lenalidomide maintenance (n=167).

In the analysis, patients on average did not report a decrease in quality of life measures with the use of maintenance therapy. The EQ-5D overall index score was 0.79 (0.14) across all patient groups. The Fact-MM total score was 117.7 for any maintenance, compared with 118.9 for lenalidomide maintenance and 114.8 for no maintenance. BPI was 4.0 for any maintenance and 3.9 for both lenalidomide maintenance and no maintenance.

REVLIMID is not approved as a maintenance treatment for post ASCT patients with multiple myeloma.

Celgene filed a supplemental New Drug Application (sNDA) with the U.S. Food and Drug Administration (FDA) for the expanded indication of REVLIMID as maintenance treatment in newly diagnosed multiple myeloma patients after receiving an ASCT based on separate studies. The sNDA was granted Priority Review and the Prescription Drug User Fee Act date of February 24, 2017.

In June, an application was submitted to the European Medicines Agency (EMA) for the review of REVLIMID as maintenance treatment in NDMM patients after receiving an ASCT. A decision on the European Union (EU) application is expected in the first half of 2017.

About REVLIMID

REVLIMID (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM)

REVLIMID is indicated for the treatment of patients with transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities

REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib

REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Important Safety Information

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity

Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS program (formerly known as the "RevAssist" program).

Information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)

REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.

Venous and Arterial Thromboembolism

REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

CONTRAINDICATIONS

Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus

Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: See Boxed WARNINGS

Females of Reproductive Potential: See Boxed WARNINGS
Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm
Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID
REVLIMID REMS Program: See Boxed WARNINGS: Prescribers and pharmacies must be certified with the REVLIMID REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive REVLIMID. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements

Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. MM: Patients taking REVLIMID/dex should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter. MDS: Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or dose reduction. Please see the Black Box WARNINGS for further information. MCL: Patients taking REVLIMID for MCL should have their CBCs monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction

Venous and Arterial Thromboembolism: See Boxed WARNINGS: Venous thromboembolic events (DVT and PE) and arterial thromboses (MI and CVA) are increased in patients treated with REVLIMID. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended and regimen is based on patients underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision

Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials

Second Primary Malignancies (SPM): In clinical trials in patients with MM receiving REVLIMID, an increase of invasive SPM notably AML and MDS have been observed. Monitor patients for the development of SPMs. Take into account both the potential benefit of REVLIMID and risk of SPMs when considering treatment

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID/dex. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered

Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose; risk-benefit of treatment should be evaluated in patients with lactose intolerance

Tumor Lysis Syndrome (TLS): Fatal instances of TLS have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken

Tumor Flare Reaction (TFR): TFR has occurred during investigational use of lenalidomide for CLL and lymphoma. Monitoring and evaluation of TFR is recommended in patients with MCL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with REVLIMID until TFR resolves to ≤ Grade 1. REVLIMID may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment ( > 4 cycles) with REVLIMID has been reported. Consider early referral to transplant center to optimize timing of the stem cell collection

ADVERSE REACTIONS

Multiple Myeloma

In newly diagnosed: The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or RD18
The most common adverse reactions reported in ≥20% (Arm Rd Continuous): diarrhea (46%), anemia (44%), neutropenia (35%), fatigue (33%), back pain (32%), asthenia (28%), insomnia (28%), rash, (26%), decreased appetite (23%), cough (23%), dyspnea (22%), pyrexia (21%), abdominal pain (21%), muscle spasms (20%), and thrombocytopenia (20%)
After at least one prior therapy the most common adverse reactions reported in ≥20% (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), and weight decreased (20% vs 15%)
Myelodysplastic Syndromes

Grade 3 and 4 adverse events reported in ≥ 5% of patients with del 5q MDS were neutropenia (53%), thrombocytopenia (50%), pneumonia (7%), rash (7%), anemia (6%), leukopenia (5%), fatigue (5%), dyspnea (5%), and back pain (5%)
Adverse events reported in ≥15% of del 5q MDS patients (REVLIMID): thrombocytopenia (61.5%), neutropenia (58.8%), diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral edema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%), asthenia (15%), upper respiratory tract infection (15%)
Mantle Cell Lymphoma

Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%)
Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%)
DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels is recommended due to increased Cmax and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as erythropoietin stimulating agents or estrogen containing therapies may have an increased risk of thrombosis. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin

NURSING MOTHERS

Discontinue drug or nursing taking into consideration the importance of the drug to the mother

PEDIATRIC USE

Safety and effectiveness in patients below the age of 18 have not been established

RENAL IMPAIRMENT

REVLIMID is primarily excreted unchanged by the kidneys; adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis

Please see full Prescribing Information, including Boxed WARNINGS.

On December 6, 2016 Geron Corporation (Nasdaq:GERN) reported four presentations of exploratory preclinical and clinical data related to the imetelstat program at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition held in San Diego, California from December 3-6, 2016 (Press release, Geron, DEC 6, 2016, View Source;p=RssLanding&cat=news&id=2228012 [SID1234516976]). The presentations are available on Geron’s website at www.geron.com/presentations.

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"The imetelstat data presented at ASH (Free ASH Whitepaper) this year indicate the potential application of imetelstat in multiple myeloid malignancies," said John A. Scarlett, M.D., Geron’s President and Chief Executive Officer. "These presentations reflect the ongoing work by academic scientists, clinical investigators and our colleagues at Janssen to advance the imetelstat program, and support the clinical trials being conducted by Janssen in patients with myelofibrosis and myelodysplastic syndromes, who are in need of new treatment options."

Oral Presentation

Title: The preclinical efficacy of a novel telomerase inhibitor, imetelstat, in AML – a randomized trial in patient-derived xenografts (Abstract #578)

Academic scientists presented data of imetelstat’s activity in human acute myeloid leukemia (AML) xenograft models. The preclinical data demonstrated that imetelstat prolonged overall survival of AML xenografts derived from nine out of 15 individual patient samples compared to saline-treated controls, with robust responses associated with favorable cytogenetic risk groups and mutations in molecular pathways controlling DNA damage. The effects on normal human hematopoiesis were modest and predominantly seen in the B-lymphocyte lineage with relative preservation of myeloid and stem cell populations. These data build on previously published preclinical work conducted in patient-derived models of AML and suggest potential application of imetelstat in the treatment of AML.

Poster Presentations

Title: Characterization of Disease, Treatment Patterns, and Outcomes of Patients with Myelofibrosis: Analysis of 2 United States Commercial Claims Databases (Abstract #4769)

Janssen presented an analysis of treatment patterns and outcomes of patients with myelofibrosis (MF) diagnosed between 2006 and 2015 from two United States medical health insurance claims databases. The analysis suggests that many MF patients (43%) received no treatment or supportive care, and only a fraction received ruxolitinib in spite of a favorable median overall survival associated with frontline treatment (30 months compared with 22 months for patients receiving other treatments). Among patients who failed or discontinued frontline ruxolitinib, the median overall survival was seven months, which underscores the need for new treatment options for this disease.

Title: Dynamics of Telomere Length Reflect the Clonal Suppression Seen with the Telomerase Inhibitor Imetelstat in Patients with Essential Thrombocythemia (Abstract #1938)

Academic scientists and clinical investigators from the prior Geron-sponsored proof-of-concept study in patients with essential thrombocythemia (ET) presented new clinical data on telomere length dynamics following treatment with imetelstat. The data showed that in 10 out of 13 ET patients, telomere length in granulocytes was higher after nine months of treatment with imetelstat, and the change correlated with the reduction of JAK2V617F mutational burden. These observations suggest that imetelstat may suppress neoplastic clones and favor recovery of normal hematopoiesis in these patients providing further evidence of the potential disease-modifying activity of imetelstat in hematologic myeloid malignancies.

Title: Telomerase Inhibition with Imetelstat Eradicates β-catenin Activated Blast Crisis Chronic Myeloid Leukemia Stem Cells (Abstract #3065)

Academic scientists presented a preliminary investigation into the potential impact of imetelstat on leukemia stem cells in non-clinical models of chronic myeloid leukemia (CML) in blast crisis. The preclinical data suggest that imetelstat plus dasatinib, a standard treatment for CML, may inhibit self-renewal of blast crisis cells in vitro compared with normal bone marrow progenitors. In mouse xenograft models of blast crisis CML, imetelstat treatment reduced the number of leukemia progenitor cells detected in bone marrow and decreased expression of β-catenin, which is believed to be required for the self-renewal of leukemic stem cells in CML. This is the first report of data to suggest that imetelstat might inhibit proliferation of malignant progenitors in CML.

About Imetelstat

Imetelstat (GRN163L; JNJ-63935937) is a potent and specific inhibitor of telomerase that is administered by intravenous infusion. This first-in-class compound, discovered by Geron, is a specially designed and modified short oligonucleotide, which targets and binds directly with high affinity to the active site of telomerase. Preliminary clinical data suggest imetelstat has disease-modifying activity by inhibiting malignant progenitor cell clones associated with hematologic malignancies in a relatively select manner. Most commonly reported adverse events in imetelstat clinical studies include fatigue, gastrointestinal symptoms and cytopenias. Patients in these studies also experienced elevated liver enzymes, which resolved to normal or baseline in the majority of patients followed after imetelstat treatment was withdrawn. Imetelstat has not been approved for marketing by any regulatory authority.

On December 6, 2016 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a Phase 3 clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer and Cellworks, a customized therapy design company that improves clinical outcomes and creates value for pharma, payers and physicians, reported the presentation of their collaborative effort to identify higher-risk MDS (HR-MDS) patients that are likely to respond to rigosertib at the 2016 ASH (Free ASH Whitepaper) Annual Meeting in San Diego California, taking place December 3-6, 2016 (Press release, Onconova, DEC 6, 2016, View Source [SID1234516960]).

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The presentation by Dr. Guillermo Garcia-Manero from the MD Anderson Cancer Center, lead investigator from the ONTME trial, used Cellworks’ proprietary bio-simulation platform to retrospectively correlate clinical benefit to IV rigosertib treatment in the Phase 3 ONTIME study in HR-MDS patients with molecular and cytogenetic data. This computer simulation led to the characterization of certain biological pathways that predict response to IV rigosertib in HR-MDS patients. Notably, patients with these predictive biological pathways also shared common cytogenetic abnormalities — trisomy of chromosomes 8 and 21 — that correlated with positive clinical outcome in ONTIME.

"This retrospective analysis of ONTIME has helped identify biological factors related to clinical outcomes to treatment with IV rigosertib," stated Guillermo Garcia-Manero, MD, Chief of the Section of Myelodysplastic Syndromes at The University of Texas MD Anderson Cancer Center, and lead author of the study. "These results confirm prior studies where patients with certain cytogenetic abnormalities were sensitive to IV rigosertib. These data also reinforce the clinical strategy of the ongoing Phase 3 INSPIRE trial to target only the highest-risk MDS patients with rigosertib."

"We are excited by this use of our proprietary bio-simulation platform to predict response to novel therapeutics in a heterogeneous disease like HR-MDS," commented Yatin Mundkur, CEO of Cellworks. "Among other applications, the Cellworks platform is intended to inform the design of Phase 2 and 3 clinical trials by establishing and validating inclusion criteria. In this case, we are pleased that this analysis has validated enrollment criteria for Onconova’s Phase 3 INSPIRE trial."

The poster entitled "Computational Analysis of Genomic Abnormalities from a Phase 3 Trial of Rigosertib in Higher-Risk MDS: Simulation of a Predictive Signature for Clinical Response," was presented on December 5, 2016 at the ASH (Free ASH Whitepaper) Annual Meeting in San Diego, California. A copy of the poster is available by visiting the Scientific Presentations section under the Investors & Media tab of Onconova’s website.

About Onconova Therapeutics, Inc.

Onconova Therapeutics is a Phase 3 clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer. Onconova’s clinical and pre-clinical stage drug development candidates are derived from its extensive chemical library and are designed to work against specific cellular pathways that are important in cancer cells, while causing minimal damage to normal cells. The Company’s most advanced product candidate, rigosertib, is a small molecule inhibitor of cellular signaling and acts as a RAS mimetic. These effects of rigosertib appear to be mediated by direct binding of the compound to the RAS-binding domain (RBD) found in many RAS effector proteins, including the Raf and PI3 kinases. Rigosertib is protected by issued patents (earliest expiry in 2026) and has been awarded Orphan Designation for MDS in the United States, Europe and Japan. In addition to rigosertib, two other candidates are in the clinical stage, and several candidates are in pre-clinical stages. For more information, please visit View Source

About IV Rigosertib

The intravenous form of rigosertib has been employed in Phase 1, 2, and 3 clinical trial involving more than 800 patients, and is currently being evaluated in the randomized Phase 3 global INSPIRE trial as 2nd-line treatment for patients with higher-risk MDS, after failure of hypomethylating agent, or HMA, therapy. This formulation is suited for patients with advanced disease and provides long duration of exposure and ensures adequate dosing under a controlled setting.

About INSPIRE

The INternational Study of Phase III IV RigosErtib, or INSPIRE, is based on guidance received from the U.S. Food and Drug Administration and European Medicines Agency and derives from the findings of the ONTIME Phase 3 trial. INSPIRE is a multi-center, randomized controlled study to assess the efficacy and safety of IV rigosertib in HR-MDS patients who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first nine months of initiation of HMA treatment. This time frame optimizes the opportunity to respond to treatment with an HMA prior to declaring treatment failure, as per NCCN Guidelines. The trial will enroll approximately 225 patients randomized at a 2:1 ratio into two treatment arms: IV rigosertib plus Best Supportive Care versus Physician’s Choice plus Best Supportive Care. The primary endpoint of INSPIRE is overall survival and an interim analysis is anticipated. Full details of the INSPIRE trial, such as inclusion and exclusion criteria, as well as secondary endpoints, can be found on clinicaltrials.gov (NCT02562443).

On December 6, 2016 Juno Therapeutics, Inc. (NASDAQ: JUNO), a biopharmaceutical company developing innovative cellular immunotherapies for the treatment of cancer, reported an update of key data from studies of its investigational chimeric antigen receptor (CAR) T cell product candidates, presented at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, December 3-6, 2016 (Press release, Juno, DEC 6, 2016, View Source;p=RssLanding&cat=news&id=2228009 [SID1234516977]).

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"We are encouraged by the safety and efficacy results we are seeing with JCAR017 and JCAR014 in several B-cell malignancy settings, including in non-Hodgkin lymphoma, chronic lymphocytic leukemia, and pediatric acute lymphoblastic leukemia, and the possibilities suggested by early data in treating patients with CD19-negative disease," said Hans Bishop, Juno’s President and CEO. "We are also learning more about factors that contribute to efficacy and managing the toxicities associated with CAR T therapy and will apply what we learn to our broader development pipeline."

Pediatric Acute Lymphoblastic Leukemia (ALL): JCAR017
Final results from the Phase I Pediatric Leukemia Adoptive Therapy-02 (PLAT-02) study with JCAR017 in children and young adults with relapsed or refractory (r/r) CD19-positive ALL were presented in an oral session by Rebecca Gardner, M.D., of Seattle Children’s Research Institute (Abstract #219), on Saturday, December 4. JCAR017 uses a defined CD4:CD8 cell composition and 4-1BB as the costimulatory domain, which differentiates it from other CD19-directed CAR T product candidates in clinical development.

The presentation updated data previously presented at ASCO (Free ASCO Whitepaper) in June 2016. It included 43 pediatric and young adult patients treated with JCAR017 who were evaluable for response.

Key results:
40/43 (93%) patients experienced a minimal residual disease (MRD)-negative complete remission (CR).
In patients who received preconditioning with fludarabine/cyclophosphamide (flu/cy) lymphodepletion, the overall response (OR) rate was 14/14 (100%) patients. The estimated 12-month event-free survival is 50.8% (95%CI 36.9, 69.9) and overall survival (OS) is 69.5% (95%CI 55.8, 86.5).
Severe cytokine release syndrome (sCRS) was observed in 10/43 (23%) patients.
A second study presented by Dr. Gardner examined toxicity management in the PLAT-02 trial (Abstract #586). In the study, two cohorts were given either anti-IL6 (tocilizumab) alone or the combination of tocilizumab and the steroid dexamethasone, with the goal of preventing sCRS. Results showed:
Both cohorts experienced similar overall rates of Grade 1-2 CRS following treatment: 21/23 (91%) in cohort 1 and 19/20 (95%) on in the early intervention cohort. In the tocilizumab arm, 7 of 23 (30%) patients experienced sCRS, versus 3/20 (15%) in the tocilizumab / dexamethasone arm.
Early intervention with immunomodulation appeared to decrease the rates of sCRS, while preserving the previously observed high rates of MRD-negative CR.
Long-term persistence of CD19 CAR-T cells is protective against relapse.
Pediatric ALL: JCAR018
Nirali N. Shah, M.D., of the National Cancer Institute, presented data from a Phase I study of JCAR018, a CAR T cell product candidate targeting CD22, in 16 pediatric patients with r/r CD19-negative ALL (Abstract #650) on Monday, December 5. The study is the first to evaluate CAR T cell therapy in patients expressing CD22. All of the patients had been previously treated with anti-CD19 CAR T cell therapy and had previously undergone at least one allogeneic stem cell transplant.
Key results:
The primary adverse event was grade 1-2 cytokine release syndrome, with no severe or irreversible neurotoxicity. There was one death due to sepsis in a patient after resolution of CRS.
3/9 (33%) patients are in ongoing remission ranging 3-12+ months.
Results showed 7/8 (88%) patients achieved an MRD-negative CR with flu/cy lymphodepletion followed by JCAR018 at dose level 2 (1 x 106 transduced CAR T cells/kg).
The study continues to enroll patients. Juno is currently testing pre-clinical constructs to better understand the optimal way to target these two antigens in the same product.
Diffuse Large B-Cell Lymphoma (DLBCL): JCAR017
In a poster presentation on Monday, December 5, Jeremy Abramson, M.D., of Massachusetts General Hospital Cancer Center, presented results from the Phase I TRANSCEND study in patients with r/r DLBCL, follicular lymphoma grade 3B or mantle cell lymphoma (MCL) who were treated with flu/cy lymphodepletion and JCAR017.
Topline results included a 12/20 (60%) complete response in patients with r/r DLBCL (N=19) and follicular lymphoma grade 3B (N=1) treated with a single dose of JCAR017 at dose level 1 (5×107 cells). No sCRS was observed; grade 3-4 neurotoxicity was observed in 3/22 (14%) patients, all of whom received the steroid dexamethasone for neurotoxicity. In addition, the side effect profile plus cell persistence suggests the potential for combination therapy.
The Phase I TRANSCEND trial continues, enrolling more patients at dose levels 1 and 2. Juno intends to initiate a pivotal trial in the U.S. in patients with r/r DLBCL in 2017.
Chronic Lymphocytic Leukemia (CLL): JCAR014
In an oral presentation on Saturday, December 4, Cameron Turtle, M.B.B.S., Ph.D., of the Fred Hutchinson Cancer Research Center, reported on results from a Phase I study of heavily pre-treated patients with CLL who failed treatment with ibrutinib, the standard-of-care treatment for CLL. Fifteen of 17 (88%) efficacy-evaluable patients who had bone marrow disease at the start of the trial and treated with flu/cy and the two lowest doses of JCAR014 had a complete marrow response by flow cytometry. Fourteen of the complete bone marrow response patients had a response assessment by the more sensitive method of IgH deep sequencing, with 7/14 (50%) having no detectable disease. All seven of these patients are alive and progression free with follow-up ranging from 3 to 26 months.
Two of 24 (8%) patients developed grade 3-5 sCRS and 6/24 (25%) patients developed grade 3-5 severe neurotoxicity. There was one treatment-related mortality (4%) in the trial in a patient who received flu/cy lymphodepletion, with both grade 5 CRS and cerebral edema.
Plans to study JCAR014 in combination with ibrutinib in CLL are underway, with a cohort expected to begin enrollment in early 2017. Juno is evaluating the use of this data with JCAR014 as a monotherapy and in combination with ibrutinib in support of a potential Juno-sponsored trial with JCAR017 in CLL.