On December 11, 2017 BeiGene, Ltd. (NASDAQ:BGNE), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly targeted and immuno-oncology drugs for the treatment of cancer, reported initial data from the ongoing Phase 1b trial of its investigational Bruton’s Tyrosine Kinase (BTK) inhibitor, zanubrutinib (BGB-3111), in combination with its investigational anti-PD-1 antibody, tislelizumab (BGB-A317), in patients with B-cell malignancies at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta, GA (Press release, BeiGene, DEC 11, 2017, View Source;p=RssLanding&cat=news&id=2322104 [SID1234522525]). The initial dose escalation data suggest that the combination of zanubrutinib and tislelizumab had a manageable toxicity profile and anti-tumor activity in patients with B-cell malignancies.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The initial data from this Phase 1b trial indicate that the combination of zanubrutinib and tislelizumab is tolerable with adverse events generally consistent with each therapeutic class. With only a short follow-up time, we have observed objective responses across different malignancy types in this heavily pre-treated population," commented Constantine Tam, MD, Disease Group Lead for Low Grade Lymphoma and Chronic Lymphocytic Leukemia at Peter MacCallum Cancer Centre, Director of Haematology at St. Vincent’s Hospital, Australia, and lead author of the presentation.

"Based on pre-clinical data suggesting the synergy of this combination, we are hopeful that this clinical trial will help to characterize the combination’s potential in treating patients with B-cell malignancies, particularly aggressive lymphomas," commented Jane Huang, MD, Chief Medical Officer, Hematology at BeiGene.

Summary of Results from the Ongoing Phase 1b Trial

The open-label, multi-center Phase 1b trial of zanubrutinib in combination with tislelizumab consists of a dose escalation portion to be followed by a dose expansion portion. Data presented at ASH (Free ASH Whitepaper) include patients enrolled at the first two dose levels of the dose escalation phase: dose 1 cohort of zanubrutinib at 320 mg once a day (QD) with tislelizumab at 2 mg/kg every three weeks (Q3W), and dose 2 cohort of zanubrutinib at 320 mg QD with tislelizumab at 5 mg/kg Q3W. Patients in the third dose cohort will receive zanubrutinib at 160 mg twice daily with tislelizumab at 200 mg Q3W.

As of September 15, 2017, the date of the most recent data cutoff, 25 patients, including 15 patients in the dose 1 cohort and 10 patients in the dose 2 cohort, had been enrolled. There were 13 patients with indolent lymphoma, including chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), marginal zone lymphoma (MZL), and Waldenström’s macroglobulinemia (WM), and 12 patients with aggressive lymphoma, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and transformed lymphoma. The median follow-up time was 5.1 months (0.4-14.1 months). Two cases of autoimmune hemolysis occurred in patients with WM in the dose 2 cohort, and one qualified as a dose-limiting toxicity (DLT). These events were not associated with a positive direct antiglobulin test and resolved with immunosuppressive therapy, but resulted in the decision to exclude further enrollment of WM patients in the trial. No further DLTs were observed after WM patients were excluded.

Among patients with indolent lymphoma, the most common adverse events (AEs) (occurring in ≥ 20% of patients) of any attribution were petechiae/purpura/contusion (31%) and thrombocytopenia (23%). Grade 3-4 AEs of any attribution reported in at least two patients included thrombocytopenia, anemia, and hemolysis (15% each). Besides the two cases of autoimmune hemolysis, there was one more immune-related event, a grade 4 autoimmune encephalitis. The patient was treated with aggressive immunosuppressive therapy and gradually improved over time.

Among patients with aggressive lymphoma, the most common AEs (occurring in ≥ 20% of patients) of any attribution were diarrhea, fatigue, pyrexia, upper respiratory tract infection (33% each), cough (25%), and nausea (25%). Grade 3-4 AEs of any attribution reported in at least two patients included pyrexia (17%). There was one patient with multiple occurrences of grade 2 and 3 pneumonitis.

At the time of data cutoff, the efficacy-evaluable population consisted of 25 patients. The median follow-up time was 5.1 months (0.4-14.1 months). Objective responses were observed in 10 patients (40%). By tumor type, two partial responses (PRs) were observed out of five patients with CLL, one complete response (CR) and one PR were observed out of five patients with FL, one very good partial response and one minor response were observed out of two patients with WM, one CR was observed out of five patients with DLBCL, and three PRs were observed out of five patients with transformed lymphoma.

About Zanubrutinib

Zanubrutinib (BGB-3111) is an investigational small molecule inhibitor of BTK that has demonstrated higher selectivity against BTK than ibrutinib (a BTK inhibitor currently approved by the U.S. Food and Drug Administration and the European Medicines Agency) based on biochemical assays, higher exposure than ibrutinib based on their respective Phase 1 experience in separate studies, and sustained 24-hour BTK occupancy in both the peripheral blood and lymph node compartments.

About Tislelizumab

Tislelizumab (BGB-A317) is an investigational humanized monoclonal antibody that belongs to a class of immuno-oncology agents known as immune checkpoint inhibitors. It is designed to bind to PD-1, a cell surface receptor that plays an important role in downregulating the immune system by preventing the activation of T-cells. Tislelizumab has high affinity and specificity for PD-1. It is differentiated from the currently approved PD-1 antibodies in an engineered Fc region, which is believed to minimize potentially negative interactions with other immune cells. Tislelizumab is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers. BeiGene and Celgene Corporation have a global strategic collaboration for tislelizumab for solid tumors.

On December 11, 2017 Aura Biosciences, a biotechnology company developing a new class of therapies to target and selectively destroy cancer cells using viral nanoparticle conjugates, reported that Cadmus Rich, M.D., has joined the company’s leadership team as Chief Medical Officer (Press release, Aura Biosciences, DEC 11, 2017, View Source [SID1234522524]). In this role, he will oversee all clinical research and development activities.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We welcome Cadmus to our team during a pivotal time at Aura," said Elisabet de los Pinos, Ph.D., founder and CEO of Aura. "As Chief Medical Officer, Cadmus will play an instrumental role as we continue to advance our Phase 1b/2 clinical trial of light-activated AU-011, following release of positive interim safety data last month. We look forward to drawing on his extensive expertise leading product development and commercialization initiatives in ophthalmology."

Dr. Rich joins the company from Inotek Pharmaceuticals, where he was Vice President, Medical Affairs and Clinical Development, responsible for development of therapies to treat glaucoma and other serious eye diseases. Prior to Inotek, Dr. Rich held key leadership roles at Alcon, most recently as a Therapeutic Unit Head leading the intraocular lenses team and prior to this, as Global Head of Pharmaceutical Clinical Trial Management. At Alcon, he managed many development programs and clinical trials; therapeutic and device submissions; and approvals for six drugs and five devices in a number of international markets. Before that, he established a new center of excellence in ophthalmology at Quintiles Transnational (now IQVIA), the world’s largest contract research organization.

Dr. Rich earned a bachelor’s degree in psychology from Case Western Reserve University; a Doctor of Medicine from the University of North Carolina (UNC) School of Medicine, Chapel Hill; and a Master of Business Administration from Regis University. He completed his ophthalmology residency at the UNC Department of Ophthalmology, Chapel Hill and additionally, is a Certified Physician Executive. He serves on the national board of directors of Prevent Blindness, a volunteer eye health and safety organization dedicated to fighting blindness and saving sight.

"I’m pleased to help lead the important work that Aura is advancing in ocular melanoma, which has no FDA-approved, targeted therapies," said Dr. Rich. "In partnership with our global network of ocular oncology experts, we are striving to provide a novel option for early treatment intervention of this rare disease."

Aura also announced today that Alison Lawton has resigned from her role as Chief Operating Officer to pursue other opportunities. She will remain an advisor to Aura.

About ocular melanoma
Ocular melanoma, also known as uveal or choroidal melanoma, is a rare and aggressive eye cancer. Ocular melanoma is the most common primary ocular tumor and develops in the uveal tract of the eye. No targeted therapies are available at present, and current radiotherapy treatments can be associated with severe visual loss and other long-term sequelae such as dry eye, glaucoma, cataracts and radiation retinopathy. The most common current treatment is plaque radiotherapy, which involves surgical placement of a radiation device against the exterior of the eye over the tumor. This technique can control the melanoma but can also lead to radiation-related cataract, retinopathy, optic nerve damage and loss of vision. The alternative is enucleation, or removal of the eye. Ocular melanoma metastasizes to the liver in about 40 percent of cases in the long-term (source: OMF), and only 15 percent of patients whose melanoma has metastasized survive beyond five years after diagnosis (source: ACS).

About light-activated AU-011
AU-011 is a first-in-class targeted therapy in development for the primary treatment of ocular melanoma. The therapy consists of viral nanoparticle conjugates that bind selectively to unique receptors on cancer cells in the eye and is derived from technology originally pioneered by Dr. John Schiller of the Center for Cancer Research at the National Cancer Institute (NCI), recipient of the 2017 Lasker-DeBakey Award. Upon activation with an ophthalmic laser, the drug rapidly and specifically destroys the membranes of tumor cells while sparing key eye structures, which may allow for the potential of preserving patients’ vision and reducing other long term complications of treatment. This therapy can be delivered in the ophthalmologist’s office and does not require a surgical procedure, enabling a less invasive, more convenient therapy for patients and physicians. AU-011 for ocular melanoma has been granted orphan drug and fast track designations by the U.S. Food and Drug Administration and is currently in clinical development.

On December 11, 2017 Alexion Pharmaceuticals, Inc. (NASDAQ:ALXN) reported the presentation of comprehensive dose-ranging data from two Phase 1b/2 studies of ALXN1210, the Company’s investigational long-acting C5 complement inhibitor, in patients with paroxysmal nocturnal hemoglobinuria (PNH), a chronic, progressive, debilitating and potentially life-threatening ultra-rare blood disorder characterized by complement-mediated hemolysis.1,2 Treatment with ALXN1210 for up to eight months resulted in rapid and sustained reduction of plasma lactate dehydrogenase (LDH) levels, a direct marker of hemolysis, with reductions in mean LDH levels from Baseline (BL) ranging from 73% to 88%. ALXN1210 was generally well tolerated with a safety profile that is consistent with that seen historically in patients with complement inhibition (Press release, Alexion, DEC 11, 2017, View Source [SID1234522523]). The data were presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in Atlanta. All patients from the Phase 1b study and from Cohorts 1, 2, and 3 of the Phase 2 study have been successfully transitioned to the Phase 3 dosing regimen, after which plasma LDH levels have remained suppressed.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"It is encouraging to see rapid and sustained reduction in plasma LDH levels in these dose optimization studies," said Alexander Röth, M.D. from the Department of Hematology, West German Cancer Center, University Hospital Essen, Essen, Germany and an investigator in the Phase 1b/2 studies. "These comprehensive results provide robust preliminary evidence for the efficacy and safety of ALXN1210 as a future treatment for patients with PNH."

"The strength of these data and exposure-response analyses, along with the totality of data for ALXN1210 and discussions with global regulators, allowed us to determine an eight-week, weight-based dosing regimen that targets complete C5 inhibition and rapid and sustained suppression of LDH," said John Orloff, M.D., Executive Vice President and Head of Research & Development at Alexion. "We have completed enrollment in our two multinational Phase 3 PNH studies, with nearly 450 patients enrolled, and expect data from these studies in the second quarter of 2018."

Optimization of Dose Regimen for ALXN1210, a Novel Complement C5 Inhibitor, in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH): Results of Two Phase 1b/2 Studies 3

The researchers presented results from two open-label Phase 1b/2 studies designed to provide dose ranging data to optimize the dosing regimen for the Phase 3 development of ALXN1210 as a treatment for patients with PNH based on exposure-response assessments. The studies included a total of 39 adult patients with PNH (Study 103, n=13; Study 201, n=26) who were naïve to complement inhibition. The primary efficacy endpoint was the change from BL in mean plasma LDH levels to day 169 in Study 103 and day 253 in Study 201. The secondary efficacy endpoints were changes from BL in free hemoglobin, haptoglobin, and reticulocytes. Post hoc efficacy analyses evaluated the proportion of patients achieving LDH levels within the normal range and the incidence of breakthrough hemolysis (days 29-253). LDH BL was defined as the average of values at screening, prior to the first ALXN1210 infusion. For other parameters, BL was defined as the most recent value prior to the first infusion. Study 103 evaluated two escalating intravenous (IV) dosing regimens of ALXN1210, and Study 201 evaluated four IV regimens with different doses and intervals. The results demonstrated exposure-response relationships, and further substantiate and extend previously presented results.4,5,6,7

Study 201 Study 103
LDH at Protocol-Specified Endpointa Cohort 1
1000 mg q4w
n=6
Cohort 2
1600 mg q6w
n=6
Cohort 3
2400 mg q8w
n=7
Cohort 4
5400 mg q12w
n=7
Cohort 1
900 mg q4w
n=6
Cohort 2
1800 mg q4w
n=7
% LDH reduction from BL, mean (SD)b 72.9 (12.1) 77.8 (6.5) 85.0 (4.4) 87.6 (6.9) 86.0 (3.2) 84.7 (3.8)
LDH levels, U/L, mean (SD) 230.0 (44.0) 266.0 (54.3) 306.1 (130.7) 276.4 (196.9) 232.0 (82.3) 227.9 (50.6)
LDH normalization (D29-D253)c
LDH normalized, n/N (%) 5/6 (83) 3/6 (50) 4/7 (57) 5/7 (71) 4/6 (67) 6/7 (86)
LDH >1.5 x ULN, n/N (%) 4/6 (67) 3/6 (50) 2/7 (29) 3/7(43) 2/6 (33) 1/7 (14)
LDH >2 x ULN, n/N (%) 2/6 (33) 1/6 (17) 2/7 (29) 1/7 (14) 1/6 (17) 0/7 (0)
Breakthrough hemolysis (D29-253)d
Incidence of breakthrough hemolysis through day 253, n/N (%) 2/6 (33.3) 1/6 (16.7) 2/7 (28.6) 1/7 (14.3) 1/6 (16.7) 0/7 (0)
BL: baseline; SD: standard deviation; D: day; LDH: lactate dehydrogenase; ULN: upper limit of normal
q4w: every 4 weeks; q6w: every 6 weeks; q8w: every 8 weeks; q12w: every 12 weeks
a LDH parameters at protocol-specified endpoint: Study 103, day 169/24 weeks; Study 201, day 253/36 weeks.
b Primary efficacy endpoint.
c Patients meeting each parameter at least once after day 29 through day 253.
d Defined as at least 1 symptom or sign of intravascular hemolysis (fatigue, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 g/dL and hemoglobin< baseline hemoglobin], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) within ±7 days of an elevated LDH ≥2 x ULN after prior LDH reduction to <1.5 x ULN on therapy.

The most frequent related treatment-emergent adverse event (TEAE) was headache. No patient stopped treatment or withdrew from the studies, and there were no deaths. Two patients in Study 201 experienced meningococcal infections but recovered completely and continued receiving ALXN1210. Meningococcal infections are a known risk with terminal complement inhibition, and specific risk-management plans have been in place for ten years for Soliris (eculizumab) to minimize the risk for patients.

About Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, progressive, debilitating and potentially life-threatening ultra-rare blood disorder that can strike men and women of all races, backgrounds, and ages without warning, with an average age of onset in the early 30s.1,2,8 PNH often goes unrecognized, with delays in diagnosis ranging from one to more than 10 years.2 In patients with PNH, chronic, uncontrolled activation of the complement system, a component of the body’s immune system, results in hemolysis (the destruction of red blood cells)9, which in turn can result in progressive anemia, fatigue, dark urine and shortness of breath.10,11,12 The most devastating consequence of chronic hemolysis is thrombosis (the formation of blood clots), which can damage vital organs and cause premature death.13 Historically, it had been estimated that one in three patients with PNH did not survive more than five years from the time of diagnosis.2 PNH is more common among patients with disorders of the bone marrow, including aplastic anemia (AA) and myelodysplastic syndromes (MDS).14,15,16 In certain patients with thrombosis of unknown origin, PNH may be an underlying cause.9

About ALXN1210

ALXN1210 is an innovative, long-acting C5 inhibitor discovered and developed by Alexion that works by inhibiting the C5 protein in the terminal complement cascade, a part of the body’s immune system that, when activated in an uncontrolled manner, plays a role in severe ultra-rare disorders like paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and anti-acetylcholine receptor (AchR) antibody-positive myasthenia gravis (MG). In early studies, ALXN1210 demonstrated rapid, complete, and sustained reduction of free C5 levels, as well as rapid and sustained reduction of plasma lactate dehydrogenase (LDH) levels, a direct marker of hemolysis (the destruction of red blood cells).4,5,6,7 ALXN1210 is currently being evaluated in Phase 3 clinical studies as a potential treatment for patients PNH and aHUS, administered intravenously every eight weeks. In addition, Alexion plans to initiate a single, pharmacokinetics (PK)-based Phase 3 clinical study of ALXN1210 delivered subcutaneously once per week as a potential treatment for patients with PNH and aHUS.

ALXN1210 has received Orphan Drug Designation (ODD) for the intravenous treatment of patients with PNH in the U.S. and EU, and for the subcutaneous treatment of patients with aHUS in the U.S.

About Soliris (eculizumab)

Soliris is a first-in-class complement inhibitor that works by inhibiting the C5 protein in the terminal part of the complement cascade, a part of the immune system that, when activated in an uncontrolled manner, plays a role in severe rare and ultra-rare disorders like paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and anti-acetylcholine receptor (AchR) antibody-positive myasthenia gravis (MG). Soliris is approved in the U.S., EU, Japan, and other countries as the first and only treatment for patients with PNH and aHUS, in the EU as the first and only treatment of refractory generalized MG (gMG) in adults who are anti-AchR antibody-positive, and in the U.S. for the treatment of adult patients with gMG who are anti-AchR antibody-positive. Alexion’s new drug application in Japan for Soliris as a treatment for patients with anti-AchR antibody-positive refractory gMG has been accepted for review by the Japanese Ministry of Health, Labour, and Welfare (MHLW). Soliris is not indicated for the treatment of patients with Shiga-toxin E. coli-related hemolytic uremic syndrome (STEC-HUS).

Soliris has received Orphan Drug Designation (ODD) for the treatment of patients with PNH in the U.S., EU, Japan, and many other countries, for the treatment of patients with aHUS in the U.S., EU, and many other countries, for the treatment of patients with MG in the U.S. and EU, and for the treatment of patients with refractory gMG in Japan. Alexion and Soliris have received some of the pharmaceutical industry’s highest honors for the medical innovation in complement inhibition: the Prix Galien USA (2008, Best Biotechnology Product) and France (2009, Rare Disease Treatment).

For more information on Soliris, please see full prescribing information for Soliris, including BOXED WARNING regarding risk of serious meningococcal infection, available at www.soliris.net

Important Soliris Safety Information

The U.S. prescribing information for Soliris includes the following warnings and precautions: Life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Comply with the most current Centers for Disease Control (CDC)’s Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies. Immunize patients with meningococcal vaccines at least two weeks prior to administering the first dose of Soliris, unless the risks of delaying Soliris therapy outweigh the risk of developing a meningococcal infection. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected. Soliris is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the Soliris REMS, prescribers must enroll in the program. Enrollment in the Soliris REMS program and additional information are available by telephone: 1-888-SOLIRIS (1-888-765-4747) or at www.solirisrems.com.

Patients may have increased susceptibility to infections, especially with encapsulated bacteria. Aspergillus infections have occurred in immunocompromised and neutropenic patients. Children treated with Soliris may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenza type b (Hib). Soliris treatment of patients with PNH should not alter anticoagulant management because the effect of withdrawal of anticoagulant therapy during Soliris treatment has not been established. Administration of Soliris may result in infusion reactions, including anaphylaxis or other hypersensitivity reactions.

In patients with PNH, the most frequently reported adverse events observed with Soliris treatment in clinical studies were headache, nasopharyngitis, back pain and nausea. In patients with aHUS, the most frequently reported adverse events observed with Soliris treatment in clinical studies were headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary tract infections, and pyrexia. In patients with gMG who are anti-AchR antibody-positive, the most frequently reported adverse reaction observed with Soliris treatment in the placebo-controlled clinical study (≥10%) was musculoskeletal pain.

On December 11, 2017 Syros Pharmaceuticals (NASDAQ: SYRS), a biopharmaceutical company pioneering the discovery and development of medicines to control the expression of disease-driving genes, reported initial clinical data from its ongoing Phase 2 trial of SY-1425, its first-in-class oral, selective retinoic acid receptor alpha (RARα) agonist, in genomically defined subsets of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) (Press release, Syros Pharmaceuticals, DEC 11, 2017, View Source [SID1234522519]). The data are being presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"I’m encouraged with the single-agent activity and tolerability of SY-1425 in difficult-to-treat leukemia and MDS patients who have few treatment options," said Joseph G. Jurcic, Professor of Medicine at Columbia University Medical Center and Director of the Hematologic Malignancies Section of the Division of Hematology/Oncology. "We saw improved blood counts and reduced blast counts in conjunction with differentiation of cancer cells in genomically defined patients. These data, along with the mechanistic and preclinical data supporting combinations with azacitidine and with daratumumab, suggest SY-1425 could be a meaningful combination agent with the potential to address a substantial unmet need for patients with AML and MDS."

"The biologic and clinical activity seen in patients selected by our proprietary RARA and IRF8 biomarkers provide validation of our platform’s ability to enrich for patients most likely to respond to gene control therapies," said Nancy Simonian, M.D., Chief Executive Officer of Syros. "These data support continued development of SY-1425 in combination,

which will be our focus going forward. Our preclinical data showing the tumor-killing activity of SY-1425 in combination with azacitidine and with daratumumab support the ongoing development of SY-1425 in combination with these therapies, and we plan to present initial clinical data on these two combinations in 2018."

Data from the Ongoing Phase 2 Clinical Trial

The ongoing Phase 2 clinical trial of SY-1425 is assessing the safety and efficacy as both a single agent and a combination agent in AML and MDS patients who are positive for either the RARA or IRF8 biomarkers, or both. The data being presented at ASH (Free ASH Whitepaper) are from two of the five cohorts in the ongoing trial. As of the data cutoff at the end of October 2017, 58 patients had been treated with SY-1425 in two single-agent cohorts, consisting of 29 patients in the relapsed or refractory AML and higher-risk MDS cohort and 29 patients in the lower-risk transfusion-dependent MDS cohort.

The relapsed or refractory AML and higher-risk MDS cohort had a median age of 72 years with more than half the patients having poor risk cytogenetics and 45% having two or more prior therapies, and the lower-risk MDS cohort had a median age of 76 years. Target enrollment has been reached in both cohorts.

Initial Safety Data

· Chronic daily dosing of SY-1425 administered at 6 mg/m2 orally divided in two doses was generally well-tolerated, with a median treatment duration of 80 days, and patients treated up to eight months and remaining on study.
· The majority of adverse events (AEs) were Grade 1 or Grade 2.
· Across all grades and causality, the most commonly reported AEs included hypertriglyceridemia (36%), fatigue (31%), and dermatologic effects (28%).
· The most common Grade 3 or 4 AE was hypertriglyceridemia (16%).

Initial Clinical Activity Data

As of the data cutoff, 48 patients were evaluable for response assessment, including 23 patients in the relapsed or refractory AML and higher-risk MDS cohort and 25 patients in the lower-risk transfusion-dependent MDS cohort.

· Ten of the 23 (43%) evaluable relapsed or refractory AML and higher-risk MDS patients and two of the 25 (8%) evaluable transfusion-dependent lower-risk MDS patients had evidence of clinical activity, including:.

· Nine with improvements in hematological parameters. Of those, four achieved hematological improvement lasting at least eight weeks, as defined by Revised International Working Group (IWG) criteria.
· Five with reductions in bone marrow blasts. Of those, one relapsed or refractory higher-risk MDS patient achieved a marrow complete response as defined by IWG criteria. The patient had been on treatment 238 days and remained on treatment as of the data cutoff.

· 13 of the 23 (57%) evaluable relapsed or refractory AML and higher-risk MDS patients had stable disease.
· 11 of 13 (85%) of patients with pre- and post-treatment immunophenotyping samples showed increased expression of CD38, a marker of cell differentiation, on bone marrow blasts after one 28-day cycle of treatment.
· No patients with lower-risk MDS achieved transfusion independence.

Additionally, myeloid cell differentiation in the bone marrow, as measured by morphologic evaluation, FISH analysis and immunophenotyping, was observed, consistent with the underlying mechanism of action of SY-1425 as a differentiating agent. The induction of CD38 observed in bone marrow blasts from patients treated with SY-1425 supports the combination cohort with daratumumab recently added to the Phase 2 trial.

As presented at the European School of Haematology’s 4th International Conference on Acute Myeloid Leukemia in October 2017, approximately 40% of 201 patients screened for the clinical trial as of the end of August 2017 were biomarker-positive, including approximately one-third of relapsed or refractory AML and higher-risk MDS patients. In blood samples taken from patients upon screening and treated ex vivo with SY-1425, a positive biomarker status was significantly correlated with SY-1425 induced myeloid cell differentiation, supporting the predictive value of the biomarker test for patient selection.

Preclinical Combination Data for SY-1425

SY-1425 has shown synergistic tumor-killing activity in combination with azacitidine, a standard-of-care therapy in AML and MDS, as well as with daratumumab, an anti-CD38 antibody approved to treat multiple myeloma, in preclinical models of RARA biomarker-positive AML. In combination with azacitidine, SY-1425 demonstrated greater clearance of tumor cells in bone marrow and other tissues and greater depth and duration of tumor response, compared to either azacitidine or SY-1425 alone. In combination with daratumumab, SY-1425 triggered robust immune cell-mediated tumor death. Notably, AML cells do not normally express high levels of CD38. Syros has shown that by inducing CD38 expression, SY-1425 sensitizes biomarker-positive AML models to the tumor-killing effects of daratumumab.

Clinical Development Plans for SY-1425

Syros plans to focus its ongoing Phase 2 clinical trial on assessing the safety and efficacy of SY-1425 in combination with other therapies. Syros is continuing to enroll patients in a cohort evaluating SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy. Syros recently added a cohort in relapsed or refractory AML and higher-risk MDS patients to evaluate SY-1425 in combination with daratumumab and expects to begin enrolling patients in that cohort in early 2018. All patients enrolled or to be enrolled in the trial are prospectively selected using the Company’s RARA or IRF8 biomarkers. Syros expects to report initial clinical data from each combination cohort in 2018. Syros does not plan to pursue further development of SY-1425 as a single agent and is stopping enrollment in the single-agent cohort in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.

Additional details about the trial can be found using the identifier NCT02807558 at www.clinicaltrials.gov.

Investor Event and Webcast Information

Syros will host an investor event on Monday, December 11 beginning at 12:00 p.m. ET in Atlanta to discuss the initial SY-1425 clinical data presented at ASH (Free ASH Whitepaper). The event can be accessed by dialing 866-595-4538 (domestic) or 636-812-6496 (international) and providing the passcode 8887999. A live webcast will also be available and can be accessed under "Events & Presentations" in the Investors section of the Company’s website at View Source A replay of the webcast will be available approximately two hours after the event and will be available for 30 days following the event.

On December 11, 2017 MorphoSys AG (FSE: MOR; Prime Standard Segment; TecDAX, OTC: MPSYY) reported clinical data from the ongoing phase 2 clinical trial (L-MIND) evaluating MOR208 in combination with lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL). DLBCL is the most frequent type of malignant lymphoma worldwide and accounts for approximately 30% of all non-Hodgkin lymphomas. Data will be reported in a poster presentation (available for download) at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta, Georgia/USA. MOR208 is an investigational Fc-engineered monoclonal antibody directed against CD19 (Press release, MorphoSys, DEC 11, 2017, View Source [SID1234522518]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The data presented at ASH (Free ASH Whitepaper) formed the basis for the Breakthrough Therapy designation recently awarded by the FDA for MOR208, in combination with lenalidomide, for the treatment of non-transplant eligible patients with R/R DLBCL.

At data cut-off (June 13, 2017), 51 patients had been enrolled in the study, of whom 44 were evaluable for efficacy assessments. Preliminary data show an objective response in 23 out of 44 patients (ORR: 52%), 19 (83%) of whom show ongoing responses. Complete remission was seen in 14 out of 44 patients (CR: 32%). The median time to response was 1.8 months, the median time to complete response was 2.3 months. The preliminary median progression-free survival (PFS) based on Kaplan Meier calculation was 11.3 months.

No unexpected toxicities were observed for the treatment combination and no infusion-related reactions were reported for MOR208. The most frequent adverse events with a toxicity grading of 3 or higher were neutropenia, thrombocytopenia, and leukopenia, observed in 35%, 10%, and 8% of patients, respectively. Pneumonia and hypokalemia were reported for 10% and 8% of the patients. To date, 45% of patients required a reduction of their lenalidomide dose, from a starting dose of 25mg daily.

The trial has recently completed patient recruitment as required by the study protocol. To date, 81 patients have been enrolled.

"We are very encouraged by the updated clinical trial results from the ongoing L-MIND trial, especially the complete responses and the duration of responses we have seen so far. DLBCL is a very aggressive lymphoma. In particular, those patients with relapsed or refractory DLBCL who are not eligible for high-dose chemotherapy and autologous stem cell transplantation are in need of more therapeutic options. Based on the FDA Breakthrough Therapy designation we recently obtained, we intend to develop MOR208 together with lenalidomide as a potential new treatment option for this patient group as quickly as possible," commented Dr. Malte Peters, Chief Development Officer of MorphoSys AG.

The L-MIND trial (Lenalidomide plus MOR208 in DLBCL) is a single-arm, open-label, multicenter study of MOR208 in combination with lenalidomide. The trial is enrolling patients with relapsed or refractory DLBCL after up to three prior lines of therapy, with at least one prior therapy including an anti-CD20 targeting therapy (e.g. rituximab). Patients could not be candidates for high-dose chemotherapy and autologous stem cell transplantation. Patients enrolled had a median age of 74 years.

Details of the MOR208 presentation at ASH (Free ASH Whitepaper) 2017:

Abstract #4123; Poster III

Single-Arm Phase II Study of MOR208 Combined with Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: L-Mind

The poster will be presented during the session #626 "Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)-Results from Prospective Clinical Trials" on Monday, December 11, 2017, 6:00pm-8:00pm EST (Dec. 12, 2017, 0:00am-2:00am CET), in the Georgia World Congress Center, Bldg A, Lvl 1, Hall A2.

In addition to the presentation, the abstract has been published online in the December 8, 2017 supplemental volume of Blood. Additional information can be found at www.hematology.org, including the abstract.

MorphoSys will hold an investor & analyst conference call after the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting 2017 on December 12, 2017, 11:00am EST(5:00pm CET).

Dial in:
Germany: +49 89 2444 32975
United Kingdom: +44 20 3003 2666
USA: +1 202 204 1514
The presentation slides and webcast link will be available at www.morphosys.com/conference-calls. A slide-synchronized audio replay of the conference will also be available at the corporate website following the live event.

About CD19 and MOR208
CD19 is broadly and homogeneously expressed across different B cell malignancies including DLBCL and CLL. CD19 has been reported to enhance B cell receptor (BCR) signaling, which is assumed important for B cell survival, making CD19 a potential target in B cell malignancies.
MOR208 (previously Xmab(R)5574) is an investigational Fc-enhanced monoclonal antibody directed against CD19, a prominent marker present on the surface of B-cells. Fc-modification of MOR208 is intended to lead to a significant potentiation of antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), thus aiming to improve a key mechanism of tumor cell killing. Furthermore, MOR208 has been observed in preclinical models to induce direct apoptosis by binding to CD19, which is assumed to be a crucial component for B cell receptor (BCR) signaling.
MorphoSys AG is clinically investigating MOR208 as a therapeutic option in B cell malignancies in a number of ongoing combination trials. An open-label phase 2 combination trial (L-MIND study) was started in March 2016 and is designed to investigate the safety and efficacy of MOR208 in combination with lenalidomide in patients with relapsed/refractory DLBCL. The phase 2/3 B-MIND study was started in August 2016 and transitioned into its phase 3 pivotal part in June 2017 following a recommendation of the IDMC based on the available data from the phase 2 initial safety evaluation. The B-MIND study is designed to investigate MOR208 in combination with the chemotherapeutic agent bendamustine in comparison to the combination of the anti-CD20 antibody rituximab plus bendamustine in patients with relapsed/refractory DLBCL who are not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). Furthermore, MOR208 is currently being clinically investigated in combination with idelalisib or venetoclax in patients with relapsed/refractory CLL after discontinuation of a prior Bruton tyrosine kinase (BTK) inhibitor therapy (e.g. ibrutinib).