On June 16, 2018 Verastem, Inc. (Nasdaq: VSTM), the Company or Verastem Oncology, a biopharmaceutical company focused on developing and commercializing medicines to improve the survival and quality of life of cancer patients, reported one oral and three poster presentations at the 23rd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) being held June 14-17, 2018 in Stockholm, Sweden (Press release, Verastem, JUN 16, 2018, View Source;p=RssLanding&cat=news&id=2354840 [SID1234527361]).

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Data were presented on the Company’s lead product candidate, duvelisib, a first-in-class oral dual inhibitor of phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma. An oral presentation by Dr. Matthew Davids, Dana-Farber Cancer Institute, highlighted the latest data from a Phase Ib/II study evaluating duvelisib in combination with FCR (dFCR) as a frontline treatment in younger patients with chronic lymphocytic leukemia (CLL). Three poster presentations highlighted additional duvelisib data, including crossover extension results from the Phase 3 DUO study in patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL), and new biomarker analyses on the tumor microenvironment modulation from the DUOTM study and the Phase 2 DYNAMOTM study in patients with refractory indolent non-Hodgkin lymphoma (iNHL), and the dual PI3K-delta and PI3K-gamma activity of duvelisib in the CONTEMPOTM study in patients with untreated follicular lymphoma (FL) who are treated with duvelisib in combination with CD20 antibody immunotherapy.

"Dr. Matthew Davids gave an oral presentation of new clinical data from the ongoing Phase Ib/II study evaluating duvelisib in combination with FCR (chemo-immunotherapy) in younger, fit CLL patients," said Diep Le, MD, PhD, Chief Medical Officer of Verastem Oncology. "The combination regimen achieved an overall response rate (ORR) of 94%, including 26% of patients experiencing a complete response or complete response with incomplete blood count recovery (CR/CRi), and 68% achieving a partial response. In addition, patients also experienced a high rate of bone marrow MRD negativity of 76%, which is significantly higher than historical data with FCR. Importantly, the results from this study demonstrated that duvelisib can be combined with a triple chemo-immunotherapy in the front-line setting with an acceptable safety profile".

Dr. Le added, "In addition, the DUO crossover extension data presented build upon the previously reported positive Phase 3 DUO study results and further support duvelisib’s potential as an oral treatment option for patients with relapsed or refractory CLL/SLL. Post-crossover, oral duvelisib monotherapy demonstrated robust clinical activity with a 73% overall response rate (ORR) and a 15-month median PFS in the 89 patients that had previously received ofatumumab on DUO and subsequently progressed. Duvelisib monotherapy also demonstrated a manageable safety profile, with results from this study consistent with the well-characterized safety profile of duvelisib monotherapy in previous studies. It is encouraging to see such a robust response to duvelisib monotherapy, similar to response observed in the parent DUO study, in patients that had failed an additional line of therapy and needed a new treatment option. Collectively, the data presented at EHA (Free EHA Whitepaper) this year continue to provide important insights to guide the future clinical development of duvelisib across a wide range of hematologic malignancies, both as a monotherapy and in combination with other agents."

Jonathan Pachter, PhD, Chief Scientific Officer of Verastem Oncology, commented, "The results presented by Drs. Casulo and Weaver continue to provide important evidence that the dual inhibition of PI3K-δ and PI3K-γ by duvelisib potentially yields added clinical benefit for CLL/SLL and FL patients by targeting both malignant B cells and the supportive tumor microenvironment. For example, these data indicate that duvelisib significantly inhibits chemokines from both cancer cells and the tumor microenvironment, and specifically, PI3K-γ inhibition impairs function of cancer-supportive macrophages and T cells."

Details for the EHA (Free EHA Whitepaper) 2018 presentation and posters are as follows:

Oral Presentation

Title: A Phase IB/II Study of duvelisib in combination with FCR (dFCR) for Frontline Therapy of Younger CLL Patients
Lead author: Dr. Matthew Davids, Dana-Farber Cancer Institute
Final Abstract Code: S807
Summary: FCR is a common initial therapy for younger CLL patients; however, only about 20% will achieve a CR/CRi with minimum residual disease (MRD) negativity in the bone marrow (BM-MRD-). Oral duvelisib had previously shown promising efficacy in CLL, and therefore, the purpose of this study was to investigate the safety and rate of CR/CRi with BM-MRD- following treatment with dFCR. This Phase Ib/II study utilized a standard 3 + 3 design and included 2 dose levels of oral duvelisib (25mg once daily or 25mg twice daily). Duvelisib was given for 1 week with FCR added on Day 8. Up to 6 cycles of dFCR were administered, followed by up to 2 years of duvelisib maintenance.

Among the 31 patients evaluable for post-dFCR response, the ORR was 94%, with 26% achieving a CR (n=4) or CRi (n=4), and 68% achieving a partial response (PR). The best rate of MRD- in the BM in patients with at least one evaluation was 81% (25 of 31). All patients who achieved CR/CRi at primary endpoint were also BM-MRD- (26%). Among survivors, the median follow-up is 24.5 months (range 6.9-46). Two-year progression-free survival and overall survival are both 97%. Eight patients have now completed two years of duvelisib maintenance therapy. The most common all grade non-hematologic adverse events were nausea (72%, all Grade 1/2), fatigue (69%, 3% Grade 3), fever (53%, all Grade 1/2), diarrhea (47%, 3% Grade 3), transaminitis (34%, 28% Grade 3/4), anorexia (34%, all Grade 1/2), vomiting (28%, all Grade 1/2), pruritus (16%, 3% Grade 3), arthritis (9%, all Grade 2) and CMV reactivation (6%, both Grade 2). The most common all grade hematologic adverse events were thrombocytopenia (65%; 34% Grade 3-4), neutropenia (59%; 50% Grade 3-4), and anemia (38%, 16% Grade 3). Serious AEs included transaminitis (n=9, including 5 Grade 3, 4 Grade 4), febrile neutropenia (n=6, all Grade 3), pneumonia (n=6, including 3 cases of PJP despite planned prophylaxis), and colitis (n=2, including 1 Grade 2 and 1 Grade 3). Based on these results the recommended Phase 2 dose of duvelisib in combination with FCR was 25mg twice daily. These results support the thesis that dFCR is an effective regimen for the initial therapy of younger, fit CLL patients and results in a high 81% rate of BM-MRD negativity, significantly higher than historical data with FCR; however infectious and immune-mediated toxicities were observed.

A copy of the oral presentation is available here.

Poster Presentations

Title: The Efficacy of Duvelisib Monotherapy Following Disease Progression on Ofatumumab Monotherapy in Patients with Relapsed/Refractory CLL or SLL in a Phase 3 Crossover Extension Study
Lead author: Dr. Peter Hillman, St. James University Hospital, Leeds, UK
Final Abstract Code: PF354
Summary: In the previously reported Phase 3 DUO study oral duvelisib monotherapy achieved a statistically significant improvement in median progression-free survival (mPFS) compared to ofatumumab in patients with relapsed or refractory CLL/ SLL (13.3 months versus 9.9 months, respectively; HR=0.52; p<0.0001), along with a manageable safety profile (Flinn, ASH (Free ASH Whitepaper) 2017). The results reported here are from the open-label, DUO crossover extension study where patients with confirmed progressive disease (PD) following treatment with ofatumumab in DUO were given the option to receive treatment with duvelisib. Duvelisib 25mg BID was administered until PD, intolerance, death, or study withdrawal and responses were determined by investigators using modified IWCLL/IWG criteria.

Among the 89 evaluable patients (median three prior therapies (range 2-8), oral duvelisib monotherapy achieved a 73% overall response rate (ORR; 95% CI: 64, 82; 5% complete response with incomplete marrow recovery (CRis), 68% partial responses [PRs]) in the extension study. While on ofatumumab in the DUO study, these 89 patients had a 28% ORR (95% CI: 19, 37; 1% complete response (CR), 27% PRs). The mPFS for duvelisib in the extension study was 15 months (95% CI: 10, 17). While on ofatumumab in the DUO study, these 89 patients had a mPFS of 9 months (95% CI: 9, 11), per investigator’s assessment. Notably, 83% of patients in the duvelisib arm post-crossover had >50% reductions in the size of their target nodal lesions. These same 89 patients had 27% reductions in the size of their target nodal lesions in the DUO ofatumumab arm. Median exposure to duvelisib in the extension study was 32 weeks. The safety profile of duvelisib monotherapy was manageable and consistent with what was observed in the Phase 3 DUO study. The most common Grade ≥3 treatment-emergent adverse events were neutropenia (22%), diarrhea (17%), colitis (9%), pneumonia (9%), rash (5%) and pyrexia (4%). These data build upon the previously reported positive DUO results and further support oral duvelisib monotherapy as an effective oral treatment option for patients with relapsed or refractory CLL/SLL.

A copy of the poster presentation will be available here.

Title: The effect of duvelisib, a dual inhibitor of PI3K-δ,γ, on components of the tumor microenvironment in previously untreated follicular lymphoma
Lead author: Dr. Carla Casulo, University of Rochester, Wilmot Cancer Center
Final Abstract Code: PF646
Summary: In previously reported data from the CONTEMPO trial, treatment-naive FL patients treated with duvelisib in combination with rituxumab had an ORR of 93% (36% CRR), and an ORR of 89% (41% CRR) was observed for patients treated with duvelisib in combination with obinutuzumab. In this study, blood samples from healthy volunteers and FL patients treated in the CONTEMPO study, both pre- and post-duvelisib treatment, were analyzed. Ex vivo and in vitro PI3K-γ assays and PI3K-δ assays, with PI3K-δ-selective (idelalisib, TGR-1202, IPI-3063) and PI3K-γ-selective (IPI-549) inhibitors were compared.

Duvelisib and idelalisib potently inhibited LPS-induced human monocytes via PI3K-δ, compared with the PI3K-γ selective IPI-549. For TGR-1202, the IC50 was below the recommended Phase 2 dose (RP2D) clinical exposure. Duvelisib and IPI-549 potently inhibited PI3K-γ dependent fMLP-stimulated human monocytes compared to idelalisib and TGR-1202. In FL patients treated with duvelisib, these PI3K-γ and PI3K-δ selective assays were inhibited 1-4 hours post treatment. Consistent with a PI3K-γ mechanism, both duvelisib and IPI-549 inhibited macrophage polarization to M2, reduced CXCL12-induced macrophage migration, and blocked CXCL12-induced T cell migration, which was not observed with PI3K-δ inhibitor IPI-3063. Collectively, these results support the thesis that duvelisib disrupts PI3K- δ,γ function in FL patients inhibiting the TME through cancer-supportive macrophages and T cells.

A copy of the poster presentation will be available here.

Title: Duvelisib inhibition of chemokines in patients with CLL (DUO study) and iNHL (DYNAMO study).
Lead author: Dr. David Weaver, Verastem Oncology
Final Abstract Code: PF649
Summary: PI3K-δ inhibition directly targets proliferation and survival of malignant leukemia and lymphoma cells, while PI3K-γ inhibition modulates the TME through key support cells, including tumor-associated macrophages, nurse-like stroma and T cells, and via soluble factors stimulating tumor growth, survival and migration. Serum samples from patients in the Phase 3 DUO study in relapsed/refractory CLL/SLL and the Phase 2 DYNAMO study in relapsed/refractory indolent NHL were collected at baseline and at C2D1 and used for correlative studies of 24 chemokines, cytokines and serum factors.

In serum samples from the DUO study, CCL1, CCL17, CXCL9, CXCL10, CXCL11, and IL-10 were reduced in patients treated with duvelisib (median 43.8%) but not in those treated with ofatumumab (p≤0.0009). Eight chemokines were reduced in both treatment arms, but the level of reduction was significantly greater for duvelisib-treated patients (median 64.6% for duvelisib versus 26.8% for ofatumumab [p≤0.001]). Many of the chemokines inhibited following duvelisib treatment are associated with the TME, including TNFα, IL-10, IL2Rα, IL12P40, CCL1, CCL17, CCL19, CXCL9, CXCL10, CXCL11, and CXCL13. In serum samples from the DYNAMO study, 13 corresponding chemokines were also inhibited (p≤0.008), including TME factors. Reductions occurred rapidly (by C2D1) in both studies. In DUO, there was a correlation between duration of response and reduction of the following chemokines: CCL17, CXCL11, IL-6, TRAIL, VEGF-D and TPO. These data support the hypothesis that treatment with duvelisib results in significant reduction of chemokines potentially derived from the tumor cells and TME and that further investigation of the effects of duvelisib on TME pharmacodynamic markers is warranted.

A copy of the poster presentation will be available here.

About Duvelisib

Duvelisib is a first-in-class investigational oral, dual inhibitor of phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells and T-cells. PI3K signaling may lead to the proliferation of malignant B- and T-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.1,2,3 Duvelisib was evaluated in late- and mid-stage extension trials, including DUO, a randomized, Phase 3 monotherapy study in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL),4 and DYNAMO, a single-arm, Phase 2 monotherapy study in patients with refractory indolent non-Hodgkin lymphoma (iNHL).5 Both DUO and DYNAMO achieved their primary endpoints. Verastem Oncology’s New Drug Application (NDA) requesting the full approval of duvelisib for the treatment of patients with relapsed or refractory CLL/SLL, and accelerated approval for the treatment of patients with relapsed or refractory follicular lymphoma (FL) was accepted for filing by the U.S. Food and Drug Administration (FDA), granted Priority Review and assigned a target action date of October 5, 2018. Duvelisib is also being developed by Verastem Oncology for the treatment of peripheral T-cell lymphoma (PTCL), and is being investigated in combination with other agents through investigator-sponsored studies.6 Information about duvelisib clinical trials can be found on www.clinicaltrials.gov.

On June 16, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that positive results from the pivotal QuANTUM-R phase 3 study of single agent quizartinib were presented today as a late-breaking oral presentation in the plenary program at the 23rd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Stockholm, Sweden (Press release, Daiichi Sankyo, JUN 16, 2018, View Source [SID1234527368]).

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QuANTUM-R study results showed that patients with relapsed/refractory acute myeloid leukemia (AML) with FLT3-ITD mutations who received single agent quizartinib had a 24 percent reduction in the risk of death compared to patients who received salvage chemotherapy (hazard ratio [HR] = 0.76, P=0.0177, 95 percent CI 0.58-0.98). The median overall survival was 6.2 months (two-sided 95 percent CI 5.3-7.2) for patients treated with quizartinib and 4.7 months (two-sided 95 percent CI 4.0-5.5) for patients treated with salvage chemotherapy. The estimated survival probability at 1 year was 27 percent for patients who received quizartinib and 20 percent for patients who received salvage chemotherapy.

"FLT3-ITD mutated AML represents a high unmet need entity as patients with this aggressive form of the disease have an overall dismal prognosis as evidenced by low response rates to current available therapies, high risk of relapse and a shorter overall survival than those without this mutation," said Jorge E. Cortes, MD, Deputy Chair of the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. "In relapsed/refractory AML with FLT3-ITD mutations, these findings represent the first reported clinical data demonstrating that a single agent can significantly improve overall survival, suggesting that quizartinib could potentially help these patients live longer. Additionally, in the study, a higher proportion of patients received a stem cell transplant in the quizartinib arm compared to the chemotherapy arm."

Secondary and key exploratory analyses including composite complete remission (CRc) are consistent and supportive of the primary analysis.

"Results of this study are consistent with previous phase 2 studies of quizartinib and demonstrate the value of targeting the FLT3-ITD driver mutation. We are encouraged by these data, which will form the basis of regulatory submissions to health authorities. If approved, quizartinib has the potential to redefine the treatment of patients with relapsed/refractory AML with FLT3-ITD mutations," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "These results also build on our understanding of this difficult-to-treat type of AML as we continue to explore the potential role of quizartinib in combination with chemotherapy and other novel mechanisms to further advance the treatment of patients with relapsed/refractory and newly-diagnosed AML with FLT3-ITD mutations."

The safety profile observed in QuANTUM-R appears consistent with that observed at similar doses in the quizartinib clinical development program. The median treatment duration with quizartinib was 4 cycles of 28 days (97 days; range: 1-1,182 days) versus 1 cycle (range: 1-2) in the salvage chemotherapy arm. The median relative dose intensity for quizartinib was 89 percent. Incidence of treatment-emergent adverse events were comparable between patients who received single agent quizartinib (n=241) and those who received salvage chemotherapy (n=94). The most common adverse events (>30 percent, any Grade) in patients treated with quizartinib versus chemotherapy, respectively, included nausea (48 vs 42 percent), thrombocytopenia (39 vs 34 percent), fatigue (39 vs 29 percent), musculoskeletal pain (37 vs 28 percent), pyrexia (38 vs 45 percent), anemia (37 vs 32 percent), neutropenia (34 vs 26 percent), febrile neutropenia (34 vs 28 percent), vomiting (33 vs 21 percent) and hypokalemia (32 vs 28 percent). The most common adverse events Grade ≥3 (>10 percent of patients) were thrombocytopenia (35 vs 34 percent), anemia (30 vs 29 percent), neutropenia (32 vs 25 percent), febrile neutropenia (31 vs 21 percent), leukopenia (17 vs 16 percent), sepsis/septic shock (16 vs 18 percent), hypokalemia (12 vs 9 percent) and pneumonia (12 vs 9 percent). QTcF >500 msec occurred in 8 patients (3.3 percent) and 2 out of 241 patients discontinued quizartinib due to QTcF prolongation. There were no reported events of Grade 4 QTcF prolongation (Torsade de Pointe, sudden death or cardiac arrest) in the quizartinib arm.

About the QuANTUM-R Study

QuANTUM-R is a pivotal, global, phase 3, open-label randomized study that enrolled 367 patients with FLT3-ITD-mutated AML who were refractory to or in relapse following (with duration of remission of six months or less) standard first-line AML therapy with or without hematopoietic stem cell transplantation (HSCT). Patients were randomized in a 2:1 ratio to receive either single agent oral quizartinib (60 mg, with 30 mg lead-in) or salvage chemotherapy. The primary objective of the study was to determine whether single agent quizartinib prolonged overall survival compared to salvage chemotherapy.

About Quizartinib

Quizartinib, the lead investigational agent in the AML Franchise of the Daiichi Sankyo Cancer Enterprise, is an oral selective FLT3 inhibitor currently in global phase 3 development for relapsed/refractory (QuANTUM-R) and newly-diagnosed (QuANTUM-First) AML with FLT3-ITD mutations, and phase 2 development for relapsed/refractory AML with FLT3-ITD mutations in Japan.

Quizartinib has been granted Fast Track designation by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed/refractory AML. Quizartinib also has been granted Orphan Drug designation by the FDA and European Medicines Agency (EMA) for the treatment of AML. Quizartinib is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

About Acute Myeloid Leukemia with FLT3-ITD Mutations

AML is an aggressive blood and bone marrow cancer that causes uncontrolled growth and accumulation of malignant white blood cells that fail to function normally and interfere with the production of normal blood cells.1 The five-year survival rate of AML reported from 2005 to 2011 was approximately 26 percent, which was the lowest of all leukemias.1

FLT3 gene mutations are one of the most common genetic abnormalities in AML.2 The FLT3-ITD mutation is the most common FLT3 mutation, affecting approximately one in four patients with AML.3,4,5,6 Patients with FLT3-ITD-mutated AML have a worse overall prognosis, including an increased incidence of relapse, an increased risk of death following relapseand a higher likelihood of relapse following HSCT as compared to those without this mutation.7,8

On June 15, 2018 Novartis reported results from a new comparison study showing that Jakavi(ruxolitinib)-treated patients with polycythemia vera (PV), who were resistant or intolerant to hydroxyurea (HU), had a significantly reduced risk of thrombosis (blood clots) and death compared to PV patients who received best available therapy[1] (Press release, Novartis, JUN 15, 2018, View Source [SID1234527352]). The study findings are based on a comparison of patients in the Phase III RESPONSE Jakavi clinical trial and the real-world Spanish GEMFIN patient registry. PV is a rare and incurable blood cancer associated with an overproduction of blood cells that can cause serious cardiovascular complications, such as blood clots, stroke and heart attack[4].

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The new findings were presented at the 23rd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Stockholm, Sweden.

"When you can complement clinical trial data with real-world experiences, it can provide valuable insight into how treatments affect patients in their day-to-day lives," said lead study investigator, Alberto Alvarez-Larran, MD, Hematology Department, Hospital Clinic, Barcelona, Spain. "This latest research supports the use of Jakavi to help people with polycythemia vera gain better control of their disease when hydroxyurea is not an option."

Additional Jakavi data presented at the EHA (Free EHA Whitepaper) Annual Congress includes efficacy and safety analyses of the largest expanded access trial of myelofibrosis (MF) patients treated with Jakavi to date (JUMP). An efficacy analysis showed that patients with lower-risk MF achieved spleen size reductions when treated with Jakavi, with most patients (82.1%) achieving a >=50% reduction at any time[2],[3]. A separate analysis identified factors that may lead to a greater spleen response in patients with MF treated with Jakavi, including treating earlier in the course of the disease and at a higher dose (>=10 mg BID)[5].

"With limited treatment options, patients with myeloproliferative neoplasms (MPNs) often struggle to keep their disease under control," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "The research conducted by Novartis teams and our physician partners in both PV and MF is helping to clarify how Jakavi can help relieve disease burden for patients."

Additionally, 48-week data from the EXPAND study support Jakavi 10 mg BID as a starting dose in patients with MF with low platelet counts, providing important information in a patient population at an increased risk of bleeding and serious complications[5]. Nearly one-third of patients in the study treated with Jakavi achieved a >=50% reduction in spleen size at week 48 (31.8% of patients [7/22] with a platelet count of 75 to 99 x 109/L and 35.7% [5/14] of patients with a platelet count of 50 to 74 x 109/L)[5].

About the PV Real-World Comparison Study
The new data presented at EHA (Free EHA Whitepaper) compares overall survival and thrombosis (blood clots) rates using data from patients treated in the Jakavi arm of the RESPONSE trial and patients treated in a real-world setting with best available therapy (BAT) from the Grupo Español de Enfermedades Mieloproliferativas Crónicas Filadelfia Negativas (GEMFIN) registry[1].

In the previously reported Phase III RESPONSE trial, the high rate of crossover from BAT to Jakavi precluded the comparison of overall survival and thrombosis rates. RESPONSE was a global, open-label study that included patients with PV resistant to or intolerant of hydroxyurea, who were randomized 1:1 to receive either Jakavi (starting dose of 10 mg twice daily) or BAT, which was defined as investigator-selected monotherapy or observation only. The GEMFIN registry patients in the real-world BAT group had resistance or intolerance to hydroxyurea according to the modified European Leukemia Net criteria and received hydroxyurea (44%), busulfan (10%), radioactive phosphorus (2%), interferon (6%), anagrelide (12%), other therapy (11%) or no cytoreductive therapy (26%). Some patients were also treated with multiple therapies[1].

In the GEMFIN study, patients treated with Jakavi had a significantly prolonged overall survival (HR=0.28 [0.11-0.72]) and a lower risk of blood clots (HR=0.21 [0.06-0.76]) when compared to real-world patients treated with BAT[1].

About the JUMP Study
JUMP is an expanded access Phase IIIb study designed to further evaluate the safety and efficacy of Jakavi in MF. It includes the largest cohort of patients with MF treated with Jakavi, 2,233, to date. The study provided access to Jakavi for patients who had no access to the treatment outside of a clinical trial and included 60 patients who were determined to have DIPSS low-risk disease[2],[3].

About the EXPAND Study
EXPAND is an open-label, Phase Ib, dose-finding study in patients with MF with baseline platelet counts of 50 to 99 x 109/L. Results presented at EHA (Free EHA Whitepaper) are from the 48-week follow- period[5].

The study evaluated 10 mg BID as a safe starting dose of Jakavi. The key secondary endpoints are safety and efficacy, including proportion of patients achieving >=50% of reduction in spleen size. Safety findings were also consistent with previous studies of Jakavi[5].

About Myelofibrosis and Polycythemia Vera
Myelofibrosis (MF) and polycythemia vera (PV) are part of a group of related and rare blood cancers called myeloproliferative neoplasms (MPNs) in which bone marrow cells responsible for the body’s blood cells develop and function abnormally[4],[6].

In patients with MF, the bone marrow can no longer produce enough normal blood cells, causing the spleen to enlarge. MF affects approximately one in every 100,000 people[6].

PV is associated with an overproduction of blood cells that can cause serious cardiovascular complications if left inadequately controlled, such as blood clots, stroke and heart attack. PV affects up to three per 100,000 people globally each year[4].

About Jakavi
Jakavi (ruxolitinib) is an oral inhibitor of the JAK 1 and JAK 2 tyrosine kinases. Jakavi is approved by the European Commission for the treatment of adult patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea and for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (MF) (also known as chronic idiopathic MF), post-polycythemia vera MF or post-essential thrombocythemia MF. Jakavi is approved in 101 countries for patients with MF, including EU countries, Switzerland, Canada, Japan and in more than 75 countries for patients with PV, including EU countries, Switzerland, Japan and Canada. The exact indication for Jakavi varies by country. Additional worldwide regulatory filings are underway in MF and PV.

Novartis licensed ruxolitinib from Incyte Corporation for development and commercialization outside the United States. Jakavi is marketed in the United States by Incyte Corporation as Jakafi for the treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea and for the treatment of patients with intermediate or high-risk MF.

The recommended starting dose of Jakavi in PV is 10 mg given orally twice daily. The recommended starting dose of Jakavi in MF is 15 mg given orally twice daily for patients with a platelet count between 100,000 cubic millimeters (mm[3]) and 200,000 mm[3], and 20 mg twice daily for patients with a platelet count of >200,000 mm[3]. Doses may be titrated based on safety and efficacy. There is limited information to recommend a starting dose for MF and PV patients with platelet counts between 50,000/mm[3] and <100,000/mm[3]. The maximum recommended starting dose in these patients is 5 mg twice daily, and patients should be titrated cautiously[7].

Jakavi is a registered trademark of Novartis AG in countries outside the United States. Jakafi is a registered trademark of Incyte Corporation. The safety and efficacy profile of Jakavi has not yet been established outside the approved indications.

Jakavi Important Safety Information for Treatment of Myelofibrosis (MF) and Polycythemia Vera (PV)
Jakavi can cause serious side effects, including a decrease in blood cell count and infections. Complete blood count monitoring is recommended. Dose reduction or interruption may be required in patients with any hepatic impairment or severe renal impairment or in patients developing hematologic adverse reactions such as thrombocytopenia, anemia and neutropenia. Dose reductions are also recommended when Jakavi is co-administered with strong CYP3A4 inhibitors or fluconazole. Use of Jakavi during pregnancy is not recommended, and women should avoid becoming pregnant during Jakavi therapy. Women taking Jakavi should not breast feed. Progressive multifocal leukoencephalopathy (PML) has been reported. Physicians should be alert for neuropsychiatric symptoms suggestive of PML. Hepatitis B viral load (HBV-DNA titer) increases have been reported in patients with chronic HBV infections. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines. Non-melanoma skin cancer (NMSC) has been reported in Jakavi treated patients. Periodic skin examination is recommended. Very common adverse reactions in MF (>10%) include urinary tract infections, anemia, thrombocytopenia, neutropenia, hypercholesterolemia, dizziness, headache, alanine aminotransferase increased, aspartate aminotransferase increased, bruising and weight gain. Common adverse reactions in MF (1 to 10%) include herpes zoster and flatulence. Uncommon adverse reactions in MF include tuberculosis. Very common adverse reactions in PV (>10%) include anemia, thrombocytopenia, hypercholesterolemia, hypertriglyceridemia, dizziness, alanine aminotransferase increased and aspartate aminotransferase increased. Common adverse reactions in PV (1 to 10%) include urinary tract infections, herpes zoster, weight gain, constipation and hypertension.

Please see full Prescribing Information available at www.jakavi.com.

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Dr Reddy’s has filed a 20-F – Annual and transition report of foreign private issuers [Sections 13 or 15(d)] with the U.S. Securities and Exchange Commission (Filing, 20-F, Dr Reddy’s, 2018, JUN 15, 2018, View Source [SID1234527343]).

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On June 15, 2018 Atara Biotherapeutics, Inc. (Nasdaq:ATRA), a leading off-the-shelf, allogeneic T-cell immunotherapy company developing novel treatments for patients with cancer, autoimmune and viral diseases, reported positive long-term outcomes including durable remissions and encouraging safety findings from two Phase 2 studies of tab-cel (tabelecleucel), Atara’s most advanced off-the-shelf T-cell immunotherapy (Press release, Atara Biotherapeutics, JUN 15, 2018, View Source [SID1234527345]). These single center, open-label studies enrolled patients with Epstein-Barr virus associated post-transplant lymphoproliferative disorder (EBV+ PTLD) following allogeneic hematopoietic cell transplant (HCT) or solid organ transplant (SOT) who failed first-line therapy. Atara and its collaborating investigators at Memorial Sloan Kettering Cancer Center (MSK) reported the Phase 2 results in a poster presentation at the 23rd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper), being held in Stockholm, Sweden, June 14-17, 2018.

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"Tab-cel demonstrated durable remissions and an encouraging safety profile after substantial follow-up time for patients with EBV-associated lymphomas who have limited treatment options and often experience poor outcomes," said Dietmar Berger, M.D., Ph.D., Global Head of Research and Development of Atara Biotherapeutics. "No patient who responded to tab‑cel in these studies died of EBV+ PTLD after treatment with this off-the-shelf, allogeneic T-cell immunotherapy. We are progressing two tab-cel Phase 3 clinical studies to confirm the Phase 2 findings in patients with EBV+ PTLD following HCT and SOT who have failed first line therapy."

Overall Survival (OS)

One- and three-year OS for tab-cel treated patients with EBV+ PTLD following HCT who failed rituximab (n=35) was 68% and 55%, respectively. Median OS was not reached after 23.3 months of follow-up in this patient group. The expected median survival for patients with EBV+ PTLD following HCT who have failed rituximab first line therapy is 16 to 56 days.1,2
In patients with EBV+ PTLD following SOT who failed rituximab, the one- and three-year OS after treatment with tab-cel (n=14) was 64% and 43%, respectively. Median survival in this patient group was 21.3 months, which compares favorably to the expected 12- to 13-month median survival in patients with EBV+ PTLD following SOT who fail to achieve a complete response to first-line therapy with single-agent rituximab.3
None of the EBV+ PTLD patients who had complete or partial responses (CR or PR) after treatment with tab-cel died of EBV+ PTLD. Two-year OS for these responding patients was 83% and 86% following HCT (n=24) and SOT (n=7), respectively.
Overall response rates (ORR)

Tab-cel was associated with durable ORR (CR plus PR) of 69% and 50% in patients with EBV+ PTLD following HCT and SOT, respectively, who have failed rituximab.
Safety

Tab-cel was generally well-tolerated. Safety findings were consistent with previous reports of these studies with no new signals noted with additional follow up.
Atara anticipates results from the first tab-cel Phase 3 study and submission of an EU conditional marketing authorization application in the first half of 2019.

Details for the poster presentation at the EHA (Free EHA Whitepaper) Congress are as follows:

Abstract PF401: Long Term Outcomes of Tabelecleucel (Allogeneic Third-Party EBV-Targeted Cytotoxic T Lymphocytes) for Rituximab-Refractory Post-Transplant EBV+ Lymphomas: A Single Center Experience
Session Title: Gene therapy, cellular immunotherapy and vaccination – Clinical
Presentation Date & Time: Friday, June 15; 5:30 p.m. to 7:00 p.m. CEST
Authors:Susan Prockop, Ekaterina Doubrovina, Amy Feng, Guenther Koehne, Parastoo Dahi, Esperanza Papadopoulos, Craig Sauter, Stephanie Suser, Willis Navarro, Akshay Sudhindra, Richard O’Reilly
Location: Poster area, Älvsjö building, Stockholm International Fairs and Congress Centre (Stockholmsmässan)

About EBV+ PTLD
Since its discovery as the first human oncovirus, Epstein-Barr virus (EBV) has been implicated in the development of a wide range of lymphoproliferative disorders, including lymphomas, and other cancers. EBV is widespread in all human populations and persists as a lifelong, asymptomatic infection. In immunocompromised patients, such as those undergoing allogeneic hematopoietic cell transplants (HCT) or solid organ transplants (SOT), EBV-associated post-transplant lymphoproliferative disorder (EBV+ PTLD) represents a life-threatening condition. Median overall survival in patients with EBV+ PTLD following HCT who have failed rituximab-based first line therapy is 16-56 days. In EBV+ PTLD following SOT, patients failing rituximab experience increased chemotherapy-induced treatment-related mortality compared to other lymphoma patients. One- and two-year survival in patients with high-risk EBV+ PTLD following SOT is 36% and 0%, respectively.

About tab-cel (tabelecleucel; formerly known as ATA129)
Atara’s most advanced T-cell immunotherapy in development, tab-cel, is a potential treatment for patients with Epstein-Barr virus (EBV) associated post-transplant lymphoproliferative disorder (EBV+ PTLD) who have failed rituximab, as well as other EBV-associated hematologic and solid tumors, including nasopharyngeal carcinoma (NPC). In February 2015, FDA granted tab-cel Breakthrough Therapy Designation for EBV+ PTLD following allogeneic hematopoietic cell transplant (HCT), and in October 2016, tab-cel was accepted into the EMA Priority Medicines (PRIME) regulatory pathway for the same indication, providing enhanced regulatory support. Atara also received positive regulatory feedback from Health Canada in September 2017 supporting the submission of tab-cel for an expedited approval pathway. In addition, tab-cel has orphan status in the U.S. and EU. Tab-cel is in Phase 3 clinical development for the treatment of EBV+ PTLD following an allogeneic hematopoietic cell transplant (MATCH study) or solid organ transplant (ALLELE study), and Atara is planning a Phase 1/2 study in NPC. Tab-cel is also available to eligible patients with EBV-associated hematologic and solid tumors through an ongoing multicenter expanded access protocol clinical study, positive interim results of which were presented in December 2017 at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.