On December 12, 2017 Servier, Pfizer Inc. (NYSE: PFE) and Cellectis (Euronext Growth: ALCLS – Nasdaq: CLLS) presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in Atlanta preliminary results from two phase 1 studies of UCART19, an investigational allogeneic anti-CD19 CAR T-cell product, in adult and pediatric patients with relapsed or refractory (R/R) CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) (Press release, Cellectis, DEC 12, 2017, View Source;utm_medium=feed&utm_campaign=Feed%3A+cellectis+%28Cellectis+RSS+Feed%29#When:23:42:00Z [SID1234522594]). These first-in-human data demonstrated the safety and tolerability of UCART19, resulting in an 83% complete remission rate across the adult and pediatric patient population.

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Results from the CALM (UCART19 in Advanced Lymphoid Malignancies) Trial

The CALM study (UCART19 in Advanced Lymphoid Malignancies) is an open label, dose-escalation study designed to evaluate the safety, tolerability and anti-leukemic activity of UCART19 in adult patients with R/R B-ALL. Five out seven patients treated achieved molecular remission at Day 28 post UCAR19. Molecular remission is defined by negative minimal residual disease (MRD). MRD is a measurement of the number of residual leukemic cells that remain after treatment.

"These early results for UCART19 are very encouraging both in terms of manageable safety and the impressive complete molecular remission rate in these hard-to-treat adult patients with R/R B-ALL," said Reuben Benjamin, Principal Investigator of the CALM Study and Consultant Hematologist at King’s College Hospital, United Kingdom. "This first cohort explored a lower dose of UCART19 that is approximately one tenth of that used in most autologous CAR-T trials. These results support additional evaluation of UCART19 at varying doses."

Only one Grade 1 cutaneous acute graft versus host disease (GvHD) occurred. No severe neurotoxicity was observed. Cytokine release syndromes (CRS) were mild and manageable except in one patient treated with UCART19 at the first dose level, who developed CRS Grade 4 and neutropenic sepsis leading to death at Day 15.

Results from the PALL (Pediatric Acute Lymphoblastic Leukemia) Trial

The PALL (Pediatric Acute Lymphoblastic Leukemia) study is a phase 1, open label study designed to evaluate the safety and ability of UCART19 to induce molecular remission defined by MRD negativity at Day 28 to enable allogeneic stem cell transplantation in pediatric patients with high-risk R/R B-ALL. Results showed all five children achieved MRD negativity, enabling them to proceed to allogeneic stem cell transplant. Only one Grade 1 cutaneous acute GvHD occurred. No severe neurotoxicity was observed. Cytokine release syndromes were mild in the majority of cases and were all manageable.

Servier is the sponsor of both studies that are active in Europe and the United States.

"We are proud to present the first clinical trial data with UCART19 in patients with heavily pretreated R/R ALL," said Patrick Therasse, MD, PhD, Head of Research and Development-Oncology for Servier. "We believe this innovative, allogeneic CAR T-cell approach could be disruptive to the patient community."

About UCART19

UCART19 is an allogeneic CAR T-cell product candidate being developed for treatment of CD19-expressing hematological malignancies, gene edited with TALEN. UCART19 is initially being developed in adult and pediatric ALL and is currently in Phase I. UCART19 has the potential to overcome the limitation of the current autologous approach by providing an allogeneic, frozen, "off-the-shelf" T cell based medicinal product.

In November 2015, Servier acquired the exclusive rights to UCART19 from Cellectis. Following further agreements, Servier and Pfizer began collaborating on a joint clinical development program for this cancer immunotherapy. Pfizer has been granted exclusive rights by Servier to develop and commercialize UCART19 in the United States, while Servier retains exclusive rights for all other countries.

On December 12, 2017 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and Puma Biotechnology, Inc. (Nasdaq: PBYI) reported a preclinical research collaboration with Memorial Sloan Kettering Cancer Center (MSK) to explore the combination of Daiichi Sankyo’s investigational antibody drug conjugate DS-8201 and Puma Biotechnology’s irreversible pan-HER tyrosine kinase inhibitor neratinib (NERLYNX) in HER2-mutated or HER2-positive solid tumors (Press release, Daiichi Sankyo, DEC 12, 2017, View Source [SID1234522606]).

A team of scientists led by Maurizio Scaltriti, PhD, and in collaboration with a team of clinical investigators led by Bob Li, MD, will use isogenic models and established patient-derived xenograft models to assess the susceptibility of HER2-mutated or HER2-positive cancers to DS-8201, neratinib and other HER2-targeting therapies, elucidate mechanisms of action and resistance of these various tumor types, and evaluate the potential for synergistic combinations. Daiichi Sankyo and Puma Biotechnology will co-sponsor the research.

"Since early clinical data suggest that DS-8201 may have activity beyond breast and gastric cancers, the archetype HER2-driven tumors, we are interested in studying this asset on a molecular level as well as in combination with other HER2-targeting agents," said Tom Held, Vice President, Global Head, Antibody Drug Conjugate Task Force, Daiichi Sankyo. "In this collaboration, we are examining whether combining DS-8201 and neratinib, with its specific covalent binding to the HER2 receptor and associated increased internalization, is a rational combination therapy strategy to pursue. We are excited to join forces with Memorial Sloan Kettering and Puma to advance the understanding of combining HER2-targeted therapies to potentially treat various forms of HER2-mutated cancer."

"We are pleased to enter into this research collaboration with Memorial Sloan Kettering and Daiichi Sankyo to explore the combination of neratinib and DS-8201," said Alan Auerbach, Puma’s Chief Executive Officer and President. "Combination therapy with agents that address different and complementary pathways, with neratinib targeting the HER2 kinase and DS-8201 providing an innovative targeted delivery of a potent cytotoxic, represents an intriguing approach to the treatment of HER2 mutated tumors and helps to maximize the potential for both agents in treating cancers with a HER2 mutation."

About DS-8201

DS-8201 is the lead product in the ADC Franchise of the Daiichi Sankyo Cancer Enterprise. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary ADC technology, DS-8201 is a smart chemotherapy comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

DS-8201 is currently in phase 2 clinical development for HER2-positive unresectable and/or metastatic breast cancer resistant or refractory to T-DM1 (DESTINY-Breast01), phase 2 development for HER2-positive advanced gastric resistent or refractory to trastuzumab (DESTINY-Gastric01) and phase 1 development for other HER2-expressing advanced/unresectable or metastatic solid tumors.

DS-8201 has been granted Breakthrough Therapy designation for the treatment of patients with HER2-positive, locally advanced or metastatic breast cancer who have been treated with trastuzumab and pertuzumab and have disease progression after ado-trastuzumab emtansine (T-DM1), and Fast Track designation for the treatment of HER2-positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2-targeted therapies including T-DM1 by the U.S. Food and Drug Administration (FDA). DS-8201 is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

About NERLYNX (neratinib)

Neratinib was approved by the FDA in July 2017 for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX (neratinib) tablets.

Important Safety Information (ISI)
NERLYNX (neratinib) tablets, for oral use

INDICATIONS AND USAGE: NERLYNX is a kinase inhibitor indicated for the extended adjuvant treatment of adult patients with early-stage HER2 overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.

CONTRAINDICATIONS: None

WARNINGS AND PRECAUTIONS:

Diarrhea: Aggressively manage diarrhea occurring despite recommended prophylaxis with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold NERLYNX in patients experiencing severe and/or persistent diarrhea. Permanently discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade ≥ 2 diarrhea that occurs after maximal dose reduction.

Hepatotoxicity: Monitor liver function tests monthly for the first 3 months of treatment, then every3 months while on treatment and as clinically indicated. Withhold NERLYNX in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX in patients experiencing Grade 4 liver abnormalities.

Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.

ADVERSE REACTIONS: The most common adverse reactions (≥ 5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased and urinary tract infection.

To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at
1-844-NERLYNX (1-844-637-5969) and www.NERLYNX.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS:

Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors (PPI) and H2-receptor antagonists. Separate NERLYNX by 3 hours after antacid dosing.
Strong or moderate CYP3A4 inhibitors: Avoid concomitant use.
Strong or moderate CYP3A4 inducers: Avoid concomitant use.
P-glycoprotein (P-gp) substrates: Monitor for adverse reactions of narrow therapeutic agents that are P-gp substrates when used concomitantly with NERLYNX.

USE IN SPECIFIC POPULATIONS:

Lactation: Advise women not to breastfeed.

Please see Full Prescribing Information for additional safety information.

The recommended dose of NERLYNX is 240 mg (six 40 mg tablets) given orally once daily with food, continuously for one year. Antidiarrheal prophylaxis should be initiated with the first dose of NERLYNX and continued during the first 2 months (56 days) of treatment and as needed thereafter.

To help ensure patients have access to NERLYNX, Puma has implemented the Puma Patient Lynx support program to assist patients and healthcare providers with reimbursement support and referrals to resources that can help with financial assistance. More information on the Puma Patient Lynx program can be found at www.NERLYNX.com or 1-855-816-5421.

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On December 12, 2017 Actinium Pharmaceuticals, Inc. (NYSE American:ATNM) ("Actinium" or "the Company"), reported data at the 59th Annual American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting & Exposition on the labeling of daratumumab, a CD38 targeting antibody which is marketed commercially by Johnson and Johnson (JNJ) under the trade name Darzalex, with the radioisotope Actinium-225 (Press release, Actinium Pharmaceuticals, DEC 12, 2017, View Source [SID1234522567]). The ARC or Antibody Radio-Conjugate of daratumumab labeled with the radioisotope Actinium-225 demonstrated enhanced targeted cancer cell killing in vitro compared with naked daratumumab. Actinium is a clinical-stage biopharmaceutical company focused on developing and commercializing targeted therapies for safer myeloablation and conditioning of the bone marrow prior to a bone marrow transplant, and for the targeting and killing of cancer cells, This initiative comes from Actinium’s AWE or Actinium Warhead Enabling Technology Platform that combines the isotope Actinium-225 with monoclonal antibodies to create ARC’s.

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The poster highlighted the capabilities of the Company’s recently announced AWE or Actinium Warhead Enabling Program that studied the effect of Actinium-225 labeled daratumumab on DAUDI, 28BM and 28PE cell lines at the 48, 72 and 96 hour time points as well as U226, a cell line that does not express CD38. The results showed that when daratumuamb is labeled with Actinium-225, cell death was increased as much as ten-fold, approaching one-hundred percent cell death in certain cell lines and at certain time points, and in all three cell lines tested the Actinium-225 labeled daratumumab had higher cell death compared to naked daratumumab. In addition, immunogenicity was preserved with most or all of daratumumab’s CD38 targeting ability maintained, high rates of radioisotope labeling of the antibody from 82-85% was demonstrated, as was high rates of stability from 73-87% at various temperatures forty-eight hours post labeling. As a result of this promising data, Actinium is continuing to investigate Actinium-225 labeled daratumumab further, with in vivo experiments ongoing.

The abstract for the poster can be accessed through the following link: View Source

Dr. Mark Berger, Actinium’s Chief Medical Officer said, "These promising results showcase the power of our AWE Technology Platform. The ability to increase the cell killing power of an antibody while preserving its targeting ability is a powerful premise that can have profound impacts on the treatment of patients and outcomes. Given these initial positive results we look forward to continuing to expand our AWE Program by labeling additional antibodies, and even other targeting moeities, with Actinium-225 to fully leverage the targeted potency of Actinium-225, our proprietary technology, and our team’s expertise and know how."

Daratumumab (Darzalexâ, Janssen) is an immunoglobulin G1 kappa (IgG1к) cytolytic human monoclonal antibody directed against the CD38 antigen that is approved to treat patients with multiple myeloma. First approved in 2015 as a monotherapy for patients who have received three prior therapies, daratumumab is now approved for use in combination and has also received approvals in earlier lines of treatment and has achieved blockbuster sales in excess of one billion dollars in the last twelve months. Daramtumumab’s effective targeting of the CD38 antigen and its success in the clinical setting indicates a high efficacy baseline, making it an ideal candidate antibody for which to demonstrate additional benefits in efficacy as a result of Actinium-225 enablement. While daratumumab is increasingly being used to treat patients, infusion reactions are common, likely due in part to administration of a large dose at 16 mg/kg, which requires long infusion times. Additionally, the infusions must take place frequently – weekly for the first 8 weeks, followed by bi-weekly infusions up to week 25, after which monthly infusions are required.

Sandesh Seth, Actinium’s Chairman and CEO added, "There has been a renaissance in radioisotope based therapies of late while antibodies continue to prove to be beneficial therapies for patients in numerous oncology indications. Our AWE Technology Platform is able to combine the strengths of these modalities to create ARC’s or Antibody Radio-Conjugates that leverage the targeted potency of the actinium-225 isotope and our proprietary technology. With this detailed data now available, we look forward to showcasing this capability to potential partners and collaborators as an example of the value generating potential of our AWE Program. We are confident that enhanced cell killing power via Actinium-225 will be attractive to developers of both novel and approved antibodies as a means to generate pipeline opportunities via de novo efforts and life cycle management. We look forward to actively promoting our AWE program in 2018 based on the 2017 enhancements in technology, scientific capabilities and team at Actinium."

About Our Actinium Warhead Enabling Technology Platform

The Actinium Warhead Enabling (AWE) Technology Platform enables a highly potent and selective form of targeted therapy that combines the powerful alpha-emitting radioisotope actinium-225 with targeting agents, which are designed to seek out cancer cells in the body that express particular markers. Actinium-225 emits significant alpha radiation making it a potent treatment modality against targeted cancer cells while limiting damage to healthy tissues as its radiation travels extremely short distances in the body. When labeled to targeting agents, actinium-225 can be delivered directly to cancer cells where the high linear energy transfer resulting from the emission of alpha particles results in irreparable DNA double stranded breaks and ultimately cancer cell death. Despite this superior cell killing power, actinium-225 when delivered in a targeted manner is sparing of the surrounding environment in the body due to the short path length of its alpha-particle radiation and can result in a superior safety profile. Actinium Pharmaceuticals owns or has licensed the rights to several issued and pending patents that pertain to its AWE Technology Platform including technology to manufacture Actinium-225 in a cyclotron. In addition, the Company obtains actinium-225 from various sources such as the U.S. Department of Energy at Oak Ridge National Laboratories and has developed considerable know-how, expertise and validated processes related to production of antibody radio-conjugates (ARC), management of the supply chain and dealing with various regulatory bodies. The AWE Technology Platform can be utilized to potentially improve the cell-killing power of targeting agents such as antibodies, peptides, Fab fragments, nanobodies etc. via labeling with Actinium-225. In addition to increased efficacy, these Actinium-225 enhanced targeting agents can offer optimized dosing or administration and in the case of approved targeting agents provide an opportunity to extend intellectual property protection by the creation of biobetters or improved versions of the approved agent. The Company’s Actinium Warhead Enabling (AWE) Program can be accessed by biopharmaceutical companies that are interested in creating biobetters through the utilization of the AWE Platform Technology. To learn more about the AWE Technology Platform or the AWE Program please contact Keisha Thomas, Ph.D., Corporate Development at [email protected].

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.

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"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 Astellas Pharma Inc. (TSE: 4503, President and CEO: Yoshihiko Hatanaka, "Astellas") reported the first data of the investigational agent gilteritinib from the ongoing, open-label, dose escalation/expansion Phase 1 study (NCT02236013) in newly diagnosed patients with acute myeloid leukemia (AML) (Press release, Astellas Pharma US, DEC 11, 2017, View Source [SID1234522546]). The data are being presented today in an oral presentation at the 2017 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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"These initial data shed encouraging light on the safety and tolerability of gilteritinib when combined with intensive chemotherapy for newly diagnosed AML patients," said Keith W. Pratz, M.D., of John Hopkins Sidney Kimmel Comprehensive Cancer Center, who is the principal investigator for the study. "In addition, while evaluating antitumor effects is an exploratory goal, the response rates in FLT3mut+ patients are promising and warrant expanded investigation of gilteritinib in this upfront treatment setting. Continuing research to evaluate the potential role for a FLT3 inhibitor in newly diagnosed patients and other stages of AML should continue to be a priority in our collective efforts to improve outcomes for patients."

The primary objective of this Phase 1 study is to assess the safety/tolerability profile, including dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD), of gilteritinib when combined with 7+3 induction (cytarabine and idarubicin) and high-dose cytarabine (HiDAC) consolidation chemotherapy, followed by single agent maintenance therapy in patients 18 years of age and older who have been newly diagnosed with AML. Assessment of antitumor effects of this combination therapy is an exploratory objective.

The two-part trial first enrolled patients to successive cohorts to determine the MTD. Successive cohorts received gilteritinib doses of 40, 80 or 120 mg/day. Dose escalation decisions were made based on DLTs that occurred following the first dose of gilteritinib during induction. Patients in the dose expansion cohort received gilteritinib at the recommended expansion dose established during dose escalation. Patients also received gilteritinib during consolidation, and then received maintenance therapy with once-daily gilteritinib over a 28-day cycle for up to 26 cycles.

"We are very encouraged by this initial data from our ongoing study of gilteritinib in combination with intensive chemotherapy in newly diagnosed AML patients, and pleased that it earned selection for oral presentation at ASH (Free ASH Whitepaper)," said Steven Benner, M.D., senior vice president and global therapeutic area head, Oncology Development, Astellas. "Mutations of FLT3 in AML are associated with a poor prognosis across the course of disease treatment and, through our comprehensive clinical development program, Astellas is committed to understanding how selective inhibition by gilteritinib might be beneficial to as many patients as possible."

As of July 9, 2017, 50 patients (n=17, dose escalation cohort; n=33, dose expansion cohort) had been enrolled in this ongoing study and 49 had received at least one dose of gilteritinib. Of the 48 patients with documented FLT3 mutation status, 23 (47.9%) were FLT3mut+, of whom 13 (56.5%) had internal tandem duplications (ITD).

Additional key findings include:

During dose escalation, two subjects in the 40 mg/day cohort who had received gilteritinib on days 1-14 experienced DLTs (neutropenia, thrombocytopenia and decreased ejection fraction). After gilteritinib induction schedule modification, no additional DLTs were observed.
The maximum tolerated dose was not reached; gilteritinib 120 mg/day was chosen as the recommended expansion dose.
Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurring in ≥ 10% of subjects were febrile neutropenia (36.7%), thrombocytopenia (18.4%), neutropenia (16.3%) and decreased platelet count (12.2%).
Serious drug-related TEAEs occurring in >1 subject were febrile neutropenia (n=8), sepsis (n=2), small intestinal obstruction (n=2), lung infection (n=2), and decreased ejection fraction (n=2).
In FLT3mut+ and FLT3 wild type subjects, end-of-treatment CRc rates were 100% and 60.9%, respectively.
About Acute Myeloid Leukemia

Acute Myeloid Leukemia (AML) is a cancer that impacts the blood and bone marrow, and its incidence increases with age. The American Cancer Society estimates that in 2017, approximately 21,000 new patients will be diagnosed with AML in the United States and about 10,000 cases will result in death.

About Gilteritinib

Gilteritinib is an investigational compound that has demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) as well as FLT3 tyrosine kinase domain (TKD), two common types of FLT3 mutations that are seen in approximately one-third of patients with AML. Further, gilteritinib has also demonstrated inhibition of the AXL receptor in AML cell lines, which has been reported to be associated with therapeutic resistance. Astellas is currently investigating gilteritinib in various AML patient populations through several additional Phase 3 trials. Visit d to learn more about ongoing gilteritinib clinical trials.

Gilteritinib was discovered through a research collaboration with Kotobuki Pharmaceutical Co., Ltd., and Astellas has exclusive global rights to develop, manufacture and potentially commercialize gilteritinib. Gilteritinib has been granted Orphan Drug designation and Fast Track designation by the U.S. FDA, and SAKIGAKE designation by the Japan Ministry of Health, Labor and Welfare.

The safety and efficacy of the agent discussed herein are under investigation and have not been established. There is no guarantee that the agent will receive regulatory approval and become commercially available for the uses being investigated. Information about pharmaceutical products (including products currently in development), which is included in this press release are not intended to constitute an advertisement or medical advice.