On December 11,2017 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that the phase III IMmotion151 study met its co-primary endpoint of investigator-assessed progression free survival (PFS), and demonstrated that the combination of atezolizumab and Avastin showed statistically significant improvement in PFS compared with sunitinib in patients whose disease expressed PD-L1 (programmed death-ligand 1: Expression ≧1%) for the first-line treatment of locally advanced or metastatic renal cell carcinoma (RCC)(Press release, Chugai, DEC 11, 2017, View Source [SID1234522503]).

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Observations of as pre-specified subgroup analysis of the atezolizumab and Avastin combination indicated that, in people whose disease expressed PD-L1, a numerical difference favoring atezolizumab and Avastin group was seen across all patient risk factor groups (favorable, intermediate and poor) compared to sunitinib; however, due to the study design these data could not be assessed for statistical significance and are descriptive only. As data is not fully matured, analysis for another co-primary endpoint of overall survival (OS) as well as the assessment of secondary endpoints is ongoing. Safety for the atezolizumab and Avastin combination appeared consistent with the known safety profile of the individual medicines and what was previously reported in the Phase II IMmotion150 study. No new safety signals were identified with the combination. The data of the IMmotion151 study will be presented at an upcoming oncology conference in 2018.

"Avastin is currently approved overseas for the treatment of RCC in combination with interferon. We are pleased that IMmotion151 study in which Japanese patients are participating showed the combination of atezolizumab and Avastin demonstrated an improvement in PFS," said Dr. Yasushi Ito, Senior Vice President and Head of Project & Lifecycle Management Unit. "We are committed to prepare the filing for approval in order to deliver both drugs to patients as a new treatment option as soon as possible."

About the IMmotion151 Study
A global phase III, multi-center, open label, randomized study designed to evaluate the efficacy and safety of atezolizumab plus Avastin compared to sunitinib in previously untreated patients with locally advanced or metastatic RCC.

The study’s co-primary endpoints include PFS in people whose tumors expressed PD-L1 (PD-L1 expression ≧1%) on immune cells (IC) and OS in intent to treat (ITT) population. PD-L1 expression was assessed using an immunohistochemistry (IHC) test, SP142 developed by Roche.

Depending on the presence of one or several of five risk factors, patients are classified in one of the three risk groups: "Favorable" with 0 risk factors, "Intermediate" with 1-2 risk factors and "Poor" with 3 or more factors.
Study design
915 patients were randomized into atezolizumab plus Avastin or sunitinib arm in a 1:1 ratio to receive treatment according to each group’s treatment regimen.
In Japan, Avastin is not approved for the treatment of RCC.

About atezolizumab
Atezolizumab is a monoclonal antibody designed to target a protein called PD-L1 (programmed death ligand-1), which is expressed on tumor cells and tumor-infiltrating immune cells. PD-L1 binds to PD-1 and B7.1, both found on the surface of T cells, causing inhibition of T cells. By blocking this coupling, atezolizumab may enable to release the suppression of T cells and promotes T cells to effectively attack tumor cells.
Atezolizumab (overseas brand name: TECENTRIQ) is an anti-PD-L1 immune checkpoint inhibitor. In US, atezolizumab was granted accelerated approval for the second line treatment of locally advanced or metastatic urothelial carcinoma (mUC) by the FDA in May, 2016. The FDA also approved atezolizumab as the treatment of metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy in October, 2016 and granted accelerated approval as the first line treatment of locally advanced or mUC who are ineligible for cisplatin chemotherapy in April, 2017. In EU, EMA approved atezolizumab for the second line treatment of locally advanced or mUC, the treatment of metastatic non-small cell lung cancer (NSCLC) who have disease progression during or following platinum-containing chemotherapy and the first line treatment of locally advanced or mUC who are ineligible for cisplatin chemotherapy in September, 2017. In Japan, the new drug application of atezolizumab for the treatment of unresectable advanced or recurrent NSCLC was filed in February, 2017.

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On December 11, 2017 bluebird bio, Inc. (Nasdaq: BLUE), a clinical-stage company committed to developing potentially transformative gene therapies for severe genetic diseases and T cell-based immunotherapies for cancer, reported data from the ongoing HGB-205 clinical study of its LentiGlobin gene therapy product candidate in patients with severe sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) (Press release, bluebird bio, DEC 11, 2017, View Source [SID1234522550]). The findings will be presented today in a poster session at the 59th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper).

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"People with SCD and TDT experience serious complications and organ damage as a result of their disease and complications from chronic blood transfusions. Addressing the underlying genetic causes of these diseases has the potential to dramatically improve patient outcomes," said Dave Davidson, M.D., chief medical officer, bluebird bio. "All three patients with severe SCD in the HGB-205 study showed a steady increase in HbAT87Q production in the first six months following LentiGlobin therapy, with the longest-treated patient showing stable hemoglobin levels over two and a half years. All four patients with TDT are transfusion-free following therapy, up to almost four years in the first patient treated. The durable treatment effects observed to date in this study are encouraging, particularly given the manufacturing process improvements that we implemented across our subsequent clinical studies of LentiGlobin, and additional changes to the HGB-206 study protocol that we hope will further improve outcomes for patients with SCD."

These data will be presented by Marina Cavazzana, M.D., Ph.D., Professor of Medicine at Paris Descartes University and Research Director at the Centre for Clinical Research in Biotherapy, Necker Hospital, and at the Institute of Genetic Diseases, Imagine, Paris, France. Professor Cavazzana is the primary investigator of the HGB-205 study.

"All seven patients in this study continue to experience notable clinical improvement. Since being treated with LentiGlobin therapy, the four patients with TDT have been free of chronic transfusions with near normal and stable levels of total hemoglobin," said Professor Cavazzana. "While progress has been made with medications to treat SCD and TDT, we are in need of better options for our patients. This study suggests that LentiGlobin has the potential to be a transformational one-time therapy for people with SCD and TDT."

Longer Term Follow-up on the First Patients with Severe Hemoglobinopathies Treated with LentiGlobin Gene Therapy (Poster Abstract #4609)

Presenter: Marina Cavazzana, M.D., Ph.D. Necker-Enfants Malades Hospital, Paris, France

Poster Session Date & Time:Monday, December 11 at 6:00 p.m.

Location: Building A, Level 1, Hall A2

HGB-205 is an ongoing, open-label, single-center Phase 1/2 study designed to evaluate the safety and efficacy of LentiGlobin drug product (DP) in the treatment of patients with severe SCD and TDT. The study enrolled three patients with severe SCD and four patients with TDT, who have undergone infusion with LentiGlobin DP. Results as of September 20, 2017 include:

SCD:

All three treated patients showed rising HbAT87Q levels in the first six months.
Patient 1204 was 13 years old at study enrollment. At last follow-up (35.2 months), this patient had a total hemoglobin of 12.4 g/dL, of which 6.1 g/dL was HbAT87Q (52 percent anti-sickling Hb). HbAT87Q concentration in this patient has remained stable since approximately nine months post-infusion. The patient continues to show marked clinical improvement.
Patient 1207 was 16 years old at study enrollment. At last follow-up (8.9 months), this patient had a total hemoglobin of 10.0 g/dl, of which 0.7 g/dl was HbAT87Q (14 percent anti-sickling Hb). This patient had a pre-treatment history of frequent episodes of vaso-occlusive crisis (VOC) and acute chest syndrome (ACS) despite hydroxyurea prior to beginning regular transfusions. Patient 1207 had episodes of ACS and hospitalization at six and eight months post-treatment, and received three transfusions.
Patient 1208 was 21 years old at study enrollment. At last follow-up (6.0 months), this patient had a total hemoglobin of 10.6 g/dL, of which 2.7 g/dL was HbAT87Q (46 percent total anti-sickling Hb). This patient had a pre-treatment history of frequent episodes of VOCs and ACS prior to beginning regular transfusions, and was still symptomatic while receiving regular transfusions. Following LentiGlobin treatment, Patient 1208 has had no episodes of VOCs or ACS (with six months follow-up).
TDT:

All four patients with TDT have remained free of chronic transfusions since shortly after receiving LentiGlobin DP.
Patient 1201 (β0/βE genotype) has been free of transfusions for 45.2 months with total hemoglobin of 10.1 g/dL, of which 6.7 g/dL was HbAT87Q.
Patient 1202 (β0/βE genotype) has been free of transfusions for 40.1 months with total hemoglobin of 12.9 g/dL, of which 10.1 g/dL was HbAT87Q.
Patient 1206 (β0/βE genotype) has been free of transfusions for 23.8 months with total hemoglobin of 11.1 g/dL, of which 8.0 g/dL was HbAT87Q.
Patient 1203, who is homozygous for the severe β+ mutation IVS1-110, has been free of transfusions for 20.9 months with total hemoglobin of 8.7 g/dL, of which 6.7 g/dL was HbAT87Q.
Three of four patients (1201, 1202 and 1206) were able to begin therapeutic phlebotomy. Patient 1202 subsequently discontinued iron chelation and phlebotomy.
The safety profile of LentiGlobin DP continues to be consistent with myeloablative conditioning with single-agent busulfan. No DP-related adverse events have been observed, and there is no evidence of clonal dominance.
About SCD
Sickle cell disease (SCD) is an inherited disease caused by a mutation in the beta-globin gene, that produces βS-globin. High levels of HbS in patients with SCD are responsible for the characteristic chronic anemia, vaso-occlusive crises, and other acute and chronic manifestations of SCD which lead to significant morbidity and early mortality.

Where adequate medical care is available, common treatments for patients with SCD largely revolve around prevention of infection and management and prevention of acute sickling episodes. Chronic management may include hydroxyurea and, in certain cases, chronic transfusions. Allogeneic hematopoietic stem cell transplant (HSCT) is currently the only available option to address the underlying genetic cause of SCD, though it carries significant risk. Complications of allogeneic HSCT include a risk of treatment-related mortality, graft failure, graft-versus-host disease (GvHD) and opportunistic infections, particularly in patients who undergo non-sibling-matched allogeneic HSCT.

About TDT
Transfusion-dependent β-thalassemia (TDT) is a severe genetic disease characterized by reduced or absent hemoglobin levels that results in severe anemia and ineffective red blood cell production. Supportive care for people with TDT consists of a lifelong regimen of chronic blood transfusions to enable survival and suppress symptoms of the disease, and iron chelation therapy to manage iron overload that results from the transfusions. Despite the availability of supportive care, many people with TDT experience serious complications and organ damage due to underlying disease and iron overload.

Allogeneic HSCT is currently the only available option to address the underlying genetic cause of TDT, though it carries significant risks. Complications of allogeneic HSCT include a risk of treatment-related mortality, graft failure, GvHD and opportunistic infections, particularly in patients who undergo non-sibling matched allogenic HSCT.

About the HGB-205 Study
HGB-205 is an ongoing, open-label Phase 1/2 study designed to evaluate the safety and efficacy of LentiGlobin in the treatment of subjects with TDT and SCD. The study enrolled seven subjects who will be followed to evaluate safety and transfusion requirements post-transplant. Among patients with sickle cell disease only, efficacy will also be measured based on the number of vaso-occlusive crises or acute chest syndrome events. For more information on the HGB-205 study, please visit clinicaltrials.gov using identifier NCT02151526.

On December 11, 2017 Juno Therapeutics, Inc. (NASDAQ: JUNO), a biopharmaceutical company developing innovative cellular immunotherapies for the treatment of cancer, and Celgene Corporation (NASDAQ: CELG) reported additional data from the TRANSCEND study of JCAR017 (lisocabtagene maraleucel; liso-cel) in patients with relapsed or refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (NHL) in a presentation at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Celgene, DEC 11, 2017, View Source [SID1234522552]).

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"We are highly encouraged by the latest efficacy and tolerability data, particularly at dose level two, as these are patients with a poor prognosis who need better treatment options," said Sunil Agarwal, M.D., Juno’s President of Research and Development. "These data support a potential best-in-class profile and further support the importance of a defined cell product. We continue to enroll our pivotal cohort in DLBCL patients and over the next twelve to eighteen months we intend to explore earlier lines of therapy, additional therapeutic areas, and combinations."

TRANSCEND is an open-label, multicenter Phase 1 study to determine the safety, pharmacokinetics, and antitumor activity of JCAR017 in adult patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, follicular lymphoma Grade 3B, and mantle cell lymphoma.

The data were based on a cutoff date of October 9, 2017 and presented by Jeremy Abramson, M.D., of Massachusetts General Hospital, who is a Principal Investigator for the TRANSCEND study. They add to those disclosed on November 1, 2017 in ASH (Free ASH Whitepaper) Abstract #581.

As with previous readouts, the TRANSCEND data were presented for both the core and full groups. The core group (N=67) includes 29 patients who received dose level two (DL2 = 100 million cells), 34 patients who received dose level one (DL1 = 50 million cells), and 4 patients who received dose level one twice, approximately 14 days apart.

The core group includes patients with DLBCL (NOS and transformed from follicular lymphoma) who are ECOG Performance Status 0-1. These patients represent a high-risk patient population, with approximately 90% of treated patients having one or more predictors of poor survival, including double or triple hit lymphoma, being chemorefractory to front-line or subsequent therapies, never reaching a complete remission with prior treatments, or never having undergone an autologous transplant. Enrollment of the pivotal cohort is ongoing with the core group at DL2.

The full analysis group represents evaluable r/r patients in the DLBCL cohort (N=91), which includes an additional 24 patients with poor performance status (ECOG Performance Status 2) or with niche subtypes of aggressive NHL. In both analysis groups all efficacy data are based on at least one month of follow-up with a 28-day restaging scan and all safety evaluable data are based on having received JCAR017 (liso-cel) with at least one month of follow-up. Product was available for 98% (126/128) of patients apheresed in the DLBCL cohort.

"The results of this study continue to show the exciting potential of this CAR T therapy," said Jay Backstrom, Chief Medical Officer and Global Head of Regulatory Affairs for Celgene. "Our collaboration with Juno reflects our commitment to delivering transformational treatments to patients with blood cancers such as non-Hodgkin lymphoma."

Topline data from the presentation as of the October 9, 2017 data cutoff date included:

Responses in core group

At DL2, the data showed a 3 month overall response rate (ORR) of 74% (14/19) and a 3 month complete response (CR) rate of 68% (13/19). Of patients that have reached 6 months of follow-up, 50% (7/14) were in CR. Across doses, 80% (16/20) of patients with CR at 3 months stayed in CR at 6 months, and 92% (11/12) of patients in response at 6 months remain in response as of data cutoff.
Across doses, median duration of response (DOR) was 9.2 months and median durability of CR was not reached.
Tolerability in core group

1% (1/67) experienced severe cytokine release syndrome and 15% (10/67) experienced severe neurotoxicity.
36% (24/67) had any grade CRS and 21% (14/67) had any grade NT.
58% (39/67) had no CRS or NT of any grade.
At dose level 1, 3% (1/34) experienced severe CRS and 21% (7/34) experienced severe NT.
At dose level 2, 0% (0/29) experienced severe CRS and 7% (2/29) experienced severe NT.
13% (9/67) received tocilizumab and 18% (12/67) received corticosteroids.
Tolerability across doses in full group

1% (1/91) experienced severe CRS and 12% (11/91) experienced severe NT.
35% (32/91) had any grade CRS and 19% (17/91) had any grade NT.
60% (55/91) had no CRS or NT of any grade.
The most common treatment-emergent adverse events (TEAEs) other than CRS and NT that occurred at ≥25% included neutropenia (49%), anemia (38%), fatigue (37%), thrombocytopenia (29%), nausea (27%), and diarrhea (25%). The most common TEAEs were similar between core and full groups.
JCAR017 (liso-cel) is a defined composition CD19-directed CAR T cell product candidate using a 4-1BB costimulatory domain. Juno believes JCAR017’s clinical profile could enable outpatient administration. A biologics license application filing is expected to be completed in the second half of 2018, with approval as early as the end of 2018.

ASH Investor and Analyst Event and Webcast

The Juno ASH (Free ASH Whitepaper) Investor and Analyst Event and webcast will be held Monday, December 11, 2017 at 8:30 p.m. Eastern Time. The webcast can be accessed live on the Investor Relations page of Juno’s website, www.JunoTherapeutics.com, and will be available for replay for 30 days following the event.

On December 11, 2017 Fate Therapeutics, Inc. (NASDAQ:FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported Day 100 clinical data from the Phase 1 stage of its PROTECT clinical trial of ProTmune, the Company’s next-generation hematopoietic cell graft for patients with hematologic malignancies (Press release, Fate Therapeutics, DEC 11, 2017, View Source [SID1234522554]). All seven subjects receiving ProTmune remained alive and relapse-free during the first 100 days following hematopoietic cell transplantation (HCT). Three of the seven subjects experienced acute graft-versus-host disease (GvHD) during the first 100 days following HCT. Each of these three subjects responded to standard-of-care steroid treatment with a median time to resolution of the maximum GvHD grade of 7 days [range: 5-8 days].

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"The significant risk of GvHD limits broad application of allogeneic transplant due to uncertainty of its short- and long-term impact on the recipient. It occurs frequently with variable intensity and can be a devastating disease when unresponsive to treatment. The requisite extended use of immunosuppressive agents to treat GvHD compromises the anti-leukemia activity of the transplant procedure and can significantly increase the risk of cancer relapse and mortality while also placing patients at risk for opportunistic infection," said Richard Maziarz, M.D., Principal Investigator, Oregon Health Sciences University. "The administration of a hematopoietic cell graft that is optimized to attenuate T-cell alloreactivity and maintain the graft’s anti-leukemia activity is a novel and highly-attractive therapeutic approach to decrease the risk and enhance the curative potential of allogeneic transplantation."

PROTECT Phase 1 Day 100 Clinical Results

Clinical data from the Phase 1 stage of PROTECT were presented today by Dr. Maziarz during a poster session at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition. The Phase 1 stage included seven adult subjects with hematologic malignancies undergoing matched unrelated donor HCT following myeloablative conditioning. During the first 100 days following HCT, all seven subjects receiving ProTmune remained alive and relapse-free. Three of the seven subjects experienced acute GvHD during the first 100 days following HCT, all of whom responded to standard-of-care steroid treatment. The median time to resolution of the maximum GvHD grade was 7 days [range: 5-8 days]. There were no events of graft failure, and there were no ProTmune-related serious adverse events reported by investigators.

PROTECT Day 100 Clinical Data
Subject 1 2 3 4 5 6 7
Hematologic Malignancy MDS AML AML ALL ALL ALL AML
CD34+ cell dose (x106/kg) 10.3 4.6 10.9 4.8 3.2 3.0 9.4
CD3+ cell dose (x108/kg) 3.1 1.8 2.6 2.8 2.0 1.2 2.8
ProTmune-related SAEs None None None None None None None
Day of Neutrophil Engraftment 1 Day 14 Day 18 Day 22 Day 15 Day 16 Day 18 Day 19
Acute GvHD / Grade (CIBMTR) None None Grade 2 None Grade 2 Grade 3 None
Treatment Responsive — — Yes — Yes Yes —
Time to Resolution of Maximum Grade — — 7 days — 8 days 5 days —
Cancer Relapse-free Yes Yes Yes Yes Yes Yes Yes
Survival Yes Yes Yes Yes Yes Yes Yes
1 As measured from the day following HCT

"The Day 100 clinical results from our Phase 1 stage of PROTECT support the unique therapeutic potential of ProTmune to reduce graft-versus-host disease and promote relapse-free survival. We are very encouraged by these initial clinical findings and the potential of ProTmune to deliver transformative benefits to cancer patients," said Chris Storgard, M.D., Chief Medical Officer of Fate Therapeutics. "The randomized, controlled and double-blinded Phase 2 stage of PROTECT is enrolling subjects at 14 U.S. centers of excellence. Given the high rates of morbidity and mortality underlying hematopoietic cell transplantation, we have also engaged the FDA, under our Fast Track designation for ProTmune, to discuss the necessary activities for product registration."

All subjects receiving ProTmune in the PROTECT Phase 1 stage are being followed for a period of two years following HCT. As of a November 29, 2017 data cut-off, all subjects remained relapse-free, and there were no events of graft failure and no serious adverse events related to ProTmune reported by investigators. Non-relapse mortality was reported in two subjects (Subject 1 on Day 228; Subject 3 on Day 151). Five of seven subjects remained on study with median time on study of 154 days [Day 106 — 254].

PROTECT Phase 2 Design
The Phase 2 stage of PROTECT is a randomized, controlled and double-blinded clinical trial assessing the safety and efficacy of ProTmune in up to 60 adult subjects with hematologic malignancies undergoing matched unrelated donor HCT following myeloablative conditioning. Subjects are being randomized, in a 1:1 ratio, to receive either ProTmune or a conventional matched unrelated donor mobilized peripheral blood cell graft. The primary efficacy endpoint of PROTECT is cumulative incidence of Grades 2-4 acute GvHD by Day 100 following HCT, where prospective clinical studies have shown that 40% to 80% of patients undergoing matched unrelated donor transplant experience Grades 2-4 acute GvHD. Immunosuppressant treatments are effective in only about half of affected HCT patients and are associated with a marked increase in severe infections and cancer relapse. Additional endpoints, such as rates of cancer relapse, chronic GvHD, non-relapse mortality and overall survival, are also being assessed. Fourteen U.S. centers are currently open for enrollment in the Phase 2 stage of PROTECT.

About Acute GvHD
Acute graft-versus-host disease (GvHD) is a severe immunological disease that commonly arises in patients during the first weeks following allogeneic HCT when newly-transplanted donor immune cells attack the patient’s tissues and organs, resulting in a potentially fatal immune system reaction. Prospective clinical studies have shown that 40% to 80% of patients undergoing matched unrelated donor transplant experience Grades 2-4 acute GvHD, with most incidents occurring by Day 60 following HCT despite the use of standard prophylaxis regimens. The disease is the leading cause of early morbidity and mortality in matched unrelated donor transplant, where death directly attributable to acute GvHD or its treatment occurs in 10% to 20% of patients. There are currently no FDA-approved preventive therapies and very few treatment options for acute GvHD.

About ProTmune
ProTmune is an investigational next-generation hematopoietic cell graft for the prevention of acute graft-versus-host disease (GvHD) in patients undergoing allogeneic hematopoietic cell transplantation. ProTmune is manufactured by pharmacologically modulating a donor-sourced, mobilized peripheral blood graft ex vivo with two small molecules (FT1050 and FT4145) to decrease the morbidity and mortality of acute GvHD while maintaining the anti-leukemia activity of the graft. ProTmune has been granted Orphan Drug and Fast Track Designations by the U.S. Food and Drug Administration, and Orphan Medicinal Product Designation by the European Commission.

On December 11, 2017 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that preliminary safety and efficacy data from a phase 1 study of DS-3201, an investigational and potential first-in-class EZH1/2 dual inhibitor, in patients with relapsed or refractory non-Hodgkin lymphomas (NHLs) were presented during a poster session at the 59th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Atlanta, Georgia (Press release, Daiichi Sankyo, DEC 11, 2017, View Source [SID1234522553]).

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Preliminary exploratory efficacy results from an ongoing phase 1 dose escalation study showed that an overall response rate of 58.8 percent (10 of 17 patients) was observed with single agent DS-3201 in 17 evaluable patients with NHLs, including B-cell and T-cell lymphomas, who were relapsed from or refractory to standard treatment or for whom no standard treatment was available. Among the 10 patients with response, there were one complete remission and nine partial remissions. Additionally, four patients experienced stable disease and three patients experienced progressive disease.

An overall response rate of 45.5 percent (5 of 11 patients) was observed with DS-3201 in 11 evaluable patients with B-cell lymphomas, including follicular lymphoma (5 patients), diffuse large B-cell lymphoma (3 patients), extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (2 patients) and lymphoplasmacytic lymphoma (1 patient). An overall response rate of 83.3 percent (5 of 6 patients) was observed with DS-3201 in six evaluable patients with T-cell lymphomas, including peripheral T-cell lymphoma not otherwise specified (2 patients), angioimmunoblastic T-cell lymphoma (2 patients) and adult T-cell leukemia-lymphoma (2 patients).

"Based on these preliminary safety and efficacy data on DS-3201 in a clinical setting, further evaluation of DS-3201 is warranted," said Dai Maruyama, MD, PhD, Department of Hematology, National Cancer Center Hospital, Tokyo, Japan. "As the first dual inhibitor of EZH1 and EZH2 in clinical development, DS-3201 may represent a new epigenetic approach to treating blood cancers. We look forward to reviewing additional data as it becomes available to evaluate the potential of this approach."

Following observation of dose-limiting toxicities (DLTs) in three of 18 evaluable patients, dose expansion is ongoing to determine a conclusive recommended phase 2 dose. Four DLTs were observed in three patients who received either the 200 mg or 300 mg dose: there were three cases of temporary grade 4 platelet count decreases (one patient in the 200 mg cohort and two patients in the 300 mg cohort) and one case of grade 3 anemia requiring transfusion in a patient in the 300 mg cohort. Preliminary safety data from 18 evaluable patients in the study also were reported. The most common treatment emergent hematologic adverse events of any grade seen in all patients included decreased platelet count (77.8 percent), anemia (55.6 percent), decreased lymphocyte count (50.0 percent) and decreased neutrophil count (44.4 percent). The most common treatment emergent non-hematologic adverse events were dysgeusia (50.0 percent), alopecia (33.3 percent), diarrhea (22.2 percent), decreased appetite (22.2 percent), nasopharyngitis (22.2 percent), alanine aminotransferase increased (22.2 percent), rash (16.7 percent), aspartate aminotransferase increased (16.7 percent) and dry skin (16.7 percent). One serious adverse event of grade 3 pneumocystis jirovecii pneumonia (PJP) led to discontinuation from the study.There was one additional non-serious case of PJP observed, leading to the institution of prophylactic treatment for all subsequent patients enrolled into the study.

DS-3201 targets epigenetic regulation by inhibiting both the EZH1 (enhancer of zeste homolog 1) and EZH2 (enhancer of zeste homolog 2) enzymes, which may reactivate various genes that have been silenced by the protein H3K27me3.1 Reactivation of the silenced genes has been shown to result in decreased proliferation of EZH2-expressing cancer cells. Preclinical research has shown that DS-3201 suppressed trimethylation of H3K27 in cells (IC50: 0.55 nM) more potently than EZH2 selective inhibitors.1

"Targeting epigenetic regulation is an approach to treating cancer that aims to reverse aberrant epigenetic changes that contribute to cancer cell growth and to maintain normal gene expression. The dual inhibition of EZH1/2 is theoretically able to provide a different spectrum of activity compared to EZH2-specific inhibitors already in the clinic. Our phase 1 program is designed to address the question of the potential benefit for this dual mode of action," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "In addition to the phase 1 study in non-Hodgkin lymphomas, we also are evaluating targeting epigenetic regulation with DS-3201 in patients with acute myeloid leukemia and acute lymphocytic leukemia."

About Non-Hodgkin Lymphoma
Non-Hodgkin lymphoma (NHL) is a form of cancer that originates in lymphocytes, a type of white blood cell.2 The two main types of NHL are B-cell lymphomas and T-cell lymphomas, which are classified into subtypes based on the origin and stage of the cancer.2 There were an estimated 386,000 new cases and about 200,000 deaths globally from NHL in 2012.3 In Japan, there were nearly 21,000 new cases of NHL in 2012, accounting for around five percent of cases worldwide.3 While recent treatment advances have led to improved outcomes for patients with certain types of NHL, patients with aggressive NHL subtypes or relapsed or refractory disease still face a poor prognosis.2,4

About the DS-3201 Phase 1 Study
A multicenter, non-randomized, open-label phase 1 dose escalation trial in Japan is enrolling adult patients with non-Hodgkin lymphomas (NHL) who have relapsed from or are refractory to standard treatment or for whom no standard treatment is available. The primary objectives are to evaluate the safety and pharmacokinetics of multiple-dose monotherapy of DS-3201 and to determine the recommended phase 2 dose. Secondary objectives are to determine the maximum tolerated dose of DS-3201 and to conduct exploratory evaluations of DS-3201-related biomarkers and the efficacy of DS-3201. For more information about the clinical trial, visit ClinicalTrials.gov.

About DS-3201
Part of the AML Franchise of the Daiichi Sankyo Cancer Enterprise, DS-3201 is an investigational and potential first-in-class EZH1/2 dual inhibitor in phase 1 clinical development for hematologic cancers including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma (NHL). DS-3201 is an investigational agent that has not been approved by the FDA or any other regulatory agency worldwide as a treatment for any indication. Safety and efficacy have not been established.

About Daiichi Sankyo Cancer Enterprise
The vision of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking in order to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by our Antibody Drug Conjugate (ADC) and Acute Myeloid Leukemia (AML) Franchises, our cancer pipeline includes more than 20 small molecules, monoclonal antibodies and ADCs stemming from our powerful research engines: our two laboratories for biologic/immuno-oncology and small molecules in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. Compounds in development include: quizartinib, an oral FLT3 inhibitor, for newly-diagnosed and relapsed or refractory AML with FLT3-ITD mutations; DS-8201, an ADC for HER2-expressing breast and gastric cancer, and other HER2-expressing solid tumors; and pexidartinib, an oral CSF-1R inhibitor, for tenosynovial giant cell tumor (TGCT), which is also being explored in a range of solid tumors in combination with the anti-PD1 immunotherapy pembrolizumab.