Abstract: Introduction: Gemtuzumab ozogamicin (GO; MylotargTM) is an antibody-drug conjugate composed of an anti-CD33 monoclonal antibody covalently linked to the potent antibiotic calicheamicin. Previous studies have shown GO is generally well tolerated and can induce durable second remissions when administered as monotherapy or in combination with chemotherapy in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). We report safety data from an expanded-access protocol (EAP) that allowed compassionate use of GO in patients with R/R AML or acute promyelocytic leukemia (APL) and no access to comparable or alternative therapy. Methods: Conducted in the United States, the GO EAP (NCT02312037) was an open-label study in patients aged ≥3 months with R/R AML (including myelodysplastic syndrome) or APL who were considered to have the potential to derive clinical benefit and had exhausted other treatment options. The protocol allowed for treatment regimens tested in clinical trial settings and reported in the Mylotarg Investigators Brochure or peer-reviewed journals. Data from these trials indicated these regimens could potentially benefit a patient with R/R AML or APL. For R/R AML patients, the regimens included GO as monotherapy or in combination with anthracyclines and/or nucleoside-analogue containing regimens or hypomethylating agents. For patients with APL, these included GO as monotherapy or in combination with all-trans retinoic acid and/or arsenic trioxide. Patients were permitted to re-enroll in treatment, and their data are summarized according to each enrollment treatment. Results: A total of 331 patients received GO either as monotherapy for R/R AML (adult [aged ≥18 years]: n=118; pediatric [aged 〈 18 years]: n=21), combination therapy for R/R AML (adult: n=99; pediatric: n=84), or treatment for APL (adult: n=9; pediatric: n=0). Mean age in the monotherapy, combination therapy, and APL groups was 55, 32, and 57 years, respectively. The most frequently administered doses of GO in the monotherapy group were 9 mg/m2 (1 dose: n=21 [15%]; doses on ≥2 days: n=29 [21%] ) and 3 mg/m2 (1 dose: n=10 [7%]; doses on ≥2 days: n=33 [24%] ). Nearly all patients in the combination-therapy group received 3 mg/m2 (1 dose: n=96 [53%]; doses on ≥2 days: n=76 [42%] ). GO 6 mg/m2 was the most frequently administered dose in the APL group (1 dose: n=3 [33%]; doses on ≥2 days: n=4 [44%] ). Treatment was discontinued in 94 (68%), 71 (39%), and 3 (33%) patients in the monotherapy, combination-therapy, and APL groups, respectively. Common reasons for discontinuation included resistant disease (monotherapy: n=25 [18%]; combination therapy: n=16 [9%] ; APL: n=1 [11%]), adverse events (AEs) not related to study drug (monotherapy: n=7 [5%] ; combination therapy: n=3 [2%]; APL: n=1 [11%] ), and AEs related to study drug (monotherapy: n=6 [4]%; combination therapy: n=4 [2%] ; APL: n=0). All-causality grade 5 AEs were reported in 114 (34%) patients: 72 (52%), 40 (22%), and 2 (22%) in the monotherapy, combination-therapy, and APL groups, respectively. The most common grade 5 AEs (excluding disease progression and AML) were sepsis in the monotherapy group (n=7 [5%]; 4 treatment-related), respiratory failure in the combination-therapy group (n=5 [3%] ; 1 treatment-related), and intracranial hemorrhage in the APL group (n=1 [11%], not treatment-related). Grade ≥3 treatment-related, treatment-emergent AEs (TEAEs) were reported for 84 (60%) patients in the monotherapy group, 102 (56%) patients in the combination-therapy group, and 7 (78%) patients in the APL group; hematologic TEAEs were most common, followed by hepatic TEAEs (Table). Possible hepatotoxicity was reported in 5 patients: 1 case each of veno-occlusive disease (VOD) and drug-induced liver injury in the monotherapy group and 2 cases of veno-occlusive liver disease (1 fatal) and 1 case of VOD in the combination-therapy group. Conclusions: GO was generally well tolerated; only a small proportion ( 〈 5%) of patients in each group discontinued treatment due to treatment-related TEAEs. The most frequent treatment-related, grade ≥3 TEAEs were hematologic. The incidence of hepatotoxicity was low across all cohorts. The results suggest GO is an important treatment option for patients with R/R AML or APL. Disclosures Wang: Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Amgen: Consultancy; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Chirnomas:Pfizer Inc: Employment, Equity Ownership. Fazal:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Lin:Jazz Pharmaceuticals: Honoraria. Nand:Pfizer: Honoraria. Pierce:Pfizer Inc: Employment, Equity Ownership. Shami:JSK Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Lone Star Biotherapies: Equity Ownership; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy. Vermette:Pfizer: Employment, Equity Ownership. Abboud:Agios: Honoraria; Jazz: Honoraria, Speakers Bureau.

Abstract: Chronic myeloid leukemia (CML) is a clonal disorder of the hematopoietic system, leading to increased production of mature and progenitor myeloid cells. Although protein tyrosine kinase inhibitors (TKI) have been successful in managing the disease, there are exceptions where drug resistance and onset of blast crisis occur. Furthermore TKIs are ineffective against leukemic stem cells (LSC) that are responsible for disease initiation and maintenance. We have shown mRNA changes in primitive hematopoietic cells do not correlate directly to protein changes. Therefore to elucidate fundamental cellular differences between CML and normal cells we employed a proteomic approach (mass spectrometry with isobaric tagging for relative quantification). This approach permits unbiased analyses using direct comparative quantification of peptides and thus proteins from chronic phase CML and normal CD34+ human samples. Systematic data analysis identified that the majority of deregulated proteins are connected and regulated by two oncogenes with well defined roles in human disease, p53 and c-myc. The direction of regulation inferred suppression of p53 and up-regulation of c-myc. Altered expression of key proteins was validated using western blotting and immuno-fluorescence approaches. All (6/6) candidate/hub proteins identified using mass spectrometry were confirmed using these orthogonal approaches. Based on our systematic analysis, we targeted the candidate hubs using the drugs RITA (activates p53) and CPI-203 (inhibits c-myc expression; provided by Constellation Pharmaceuticals). In CML CD34+ cells, RITA reduced cell expansion in a concentration-dependent manner and induced significant levels of apoptosis as confirmed by positive staining of Annexin V and 4',6-diamidino-2-phenylindole (DAPI) using flow cytometry. CPI-203 also reduced cell expansion, but importantly induced differentiation in addition to apoptosis, as supported by flow cytometric monitoring of levels of carboxyfluorescein succinimidyl ester (CFSE) and CD34. Overlays of CFSE plots for untreated control vs. CPI-203 demonstrated that as cells divided in the presence of CPI-203, there was clear and rapid loss of CD34 expression which was not seen with RITA treatment. By measuring the dose-effect relationship of each drug alone and in combination, we demonstrated potent synergy with combination index (CI) values ranging from 0.034-0.286 based on loss of cell viability. Using flow cytometry we gated on CD34+38- CML cells to enable quantification of the differential effects of each drug alone and in combination against the most primitive and quiescent 1-5% of total CD34+ cells. Critically the apoptotic effect was inclusive of primitive CD34+38- cells and quiescent CFSEmax populations. In addition, experiments combining RITA and CPI-203 demonstrated undetectable colony forming cell units at the highest concentrations of drug used. Importantly, it appears that combining these two drugs has negligible effects on normal CD34+ cell counts, apoptosis and CFSE profiles. Currently NOD-SCID IL2R gamma null (NSG) repopulation assays are underway to determine if these drugs affect stem cells capable of engrafting immunocompromised mice. Our systems biology approach suggests that altered c-myc and p53 function underlie the most significant cellular differences within CML CD34+ cells, which has not been previously demonstrated. We confirm that in CML, p53 and c-myc hub proteins have the ability to modulate downstream defined target proteins thereby enhancing survival and proliferation and thus allowing maintenance of disease. Disclosures: No relevant conflicts of interest to declare.

Abstract: A novel recombinant factor VIII with prolonged half-life, rFVIIIFc, was developed to reduce prophylactic injection frequency. rFVIIIFc was well-tolerated in patients with severe hemophilia A, and resulted in low bleeding rates when dosed 1 to 2 times per week.

Abstract: Background Patients with high risk (HR) myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have significant toxicities such as mucositis, protracted neutropenia and severe infections when treated with standard chemotherapy. This had led to the development of ‘less intense’ chemotherapy (targeted therapy, TT). These treatments are expected to produce less toxicities, especially less immunosuppression. Antibiotic and antifungal prophylaxis are routinely given to patients undergoing intensive chemotherapy. It is not clear if the same strategy should be used for patients receiving less intensive chemotherapy. The objective of this study is to evaluate the outcome of patients receiving TT according to the use of antimicrobial prophylaxis. Methods We retrospectively reviewed the medical records of patients with AML and HR MDS that received TT as induction therapy from January 2000 to July 2007 at our institution. Baseline characteristics and antibiotic usage was recorded. All courses of TT received from start of therapy until outcome (response or failure) was assessed were evaluated, and infections or death occurring during any of these courses constituted an event. Results 225 patients received TT [decitabine or azacitidine n = 137 (61%); miscellaneous (tipifarnib, PKC412, imatinib, SAHA, and others) n=88 (39%)] for a total of 583 courses (median course per patient = 2). Median age was 72 years (range 13–89), 60% were male, 95% had Zubroad performance status ≤ 2 and 28% were neutropenic at the start of TT. None of the patients were placed in HEPA-filtered rooms (‘protected environment’) at any time. Each course of therapy was grouped into 1 of 4 groups based on the strategy use for infectious prophylaxis (table 1). Clinically documented infections and FUO were the most frequent type of infection reported in all the groups, followed by bacterial infections. Fungal infections were infrequent (total 5; group 1 = 1; group 2 = 2, group 3 = 2). There was no significant difference in the number of infectious episodes per course between the groups that received both antibacterial and antifungal prophylaxis vs. those who received no prophylaxis (p= 0.984). However, mortality was significantly higher during courses of TT administered without prophylaxis (p= 0.005). Conclusions As opposed to standard chemotherapy, fungal infections are infrequent in the patients treated with TT. Mortality is significantly higher in patients who did not receive any anti-microbial prophylaxis. The use of antibacterial and antifungal prophylaxis should be considered in patients receiving TT. Table 1: Groups based on antimicrobial strategy Strategy Strategy No. of courses No. of infectious episodes (%) No. of death (%) * p=0.984; # p=0.005 No prophylaxis 202 45 (22%) * 12 (5.94%) # Both bacterial and fungal prophylaxis 171 38 (18%) * 1 (0.58%) # Only bacterial prophylaxis 206 31 (15%) 6 (2.91%) Only fungal prophylaxis 4 0 (0%) 0 (0%)

Abstract: Current factor IX (FIX) products display a half-life (t1/2) of ∼ 18 hours, requiring frequent intravenous infusions for prophylaxis and treatment in patients with hemophilia B. This open-label, dose-escalation trial in previously treated adult subjects with hemophilia B examined the safety and pharmacokinetics of rFIXFc. rFIXFc is a recombinant fusion protein composed of FIX and the Fc domain of human IgG1, to extend circulating time. Fourteen subjects received a single dose of rFIXFc; 1 subject each received 1, 5, 12.5, or 25 IU/kg, and 5 subjects each received 50 or 100 IU/kg. rFIXFc was well tolerated, and most adverse events were mild or moderate in intensity. No inhibitors were detected in any subject. Dose-proportional increases in rFIXFc activity and Ag exposure were observed. With baseline subtraction, mean activity terminal t1/2 and mean residence time for rFIXFc were 56.7 and 71.8 hours, respectively. This is ∼ 3-fold longer than that reported for current rFIX products. The incremental recovery of rFIXFc was 0.93 IU/dL per IU/kg, similar to plasma-derived FIX. These results show that rFIXFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia B. The trial was registered at www.clinicaltrials.gov as NCT00716716.

Abstract: Minor histocompatibility (H) antigens crucially affect the outcome of human leukocyte antigen (HLA)–identical allogeneic stem cell transplantation (SCT). To understand the basis of alloimmune responses against minor H antigens, identification of minor H peptides and their antigenicity-determining mechanisms is essential. Here we report the identification of HA-3 and its encoding gene. The HA-3 peptide, VTEPGTAQY (HA-3T), is encoded by the lymphoid blast crisis (Lbc) oncogene. We thus show for the first time that a leukemia-associated oncogene can give rise to immunogenic T-cell epitopes that may have participated in antihost and antileukemic alloimmune responses. Genotypic analysis of HA-3- individuals revealed the allelic counterpart VMEPGTAQY (HA-3M). Despite the lack of T-cell recognition of HA-3- cells, the Thr→Met substitution had only a modest effect on peptide binding to HLA-A1 and a minimal impact on recognition by T cells when added exogenously to target cells. This substitution did not influence transporter associated with antigen processing (TAP) transport, but, in contrast to the HA-3T peptide, HA-3M is destroyed by proteasome-mediated digestion. Thus, the immunogenicity of minor H antigens can result from proteasome-mediated destruction of the negative allelic peptide.

Abstract: Using a high throughput combination screening strategy, we have discovered that agonism of either adenosine A2A receptors (A2A) or beta-2 adrenergic receptors (bAR) demonstrate significant, synergistic, anti-proliferative effects in preclinical Multiple Myeloma (MM) models. Using quantitative synergy analysis, we observe that A2A and bAR agonists have significant anti-proliferative effects in a broad panel of 10 MM cell lines when combined with each other or with standard MM agents. Individual A2A agonists CGS-21680 and HE-NECA inhibited proliferation 25–80% with EC50s ranging from 2–20 nM. Individual bAR agonists salmeterol and formoterol inhibited proliferation 35–75% with EC50s ranging from 10–30 pM. Potent, highly synergistic, inhibition of proliferation, up to 95%, was demonstrated with combinations of A2A or bAR agonists and multiple agents including dexamethasone, lenalidomide, bortezomib, melphalan, doxorubicin, HDAC inhibitors and HSP90 inhibitors at clinically relevant concentrations. These combinations exceeded Loewe additivity, and demonstrated both substantial increases in efficacy over maximal single agent levels as well as significant potency shifting with many combination indices (CIs) in the range of 0.1 to 0.3. Synergistic anti-proliferative effects were observed broadly across several MM cell lines and when using cell lines unresponsive to standard MM drugs, e.g. A2A agonists CGS-21680 and HE-NECA in combination with dexamethasone inhibited 75–85% of the proliferation of EJM, and MOLP-8 dexamethasone-insensitive cell lines as compared to 35–60% for the single agent A2A agonists. The selective A2A antagonist SCH58261 but not A1, A2B and A3 selective antagonists DPCPX, MRS1754 and MRS1523 blocked the synergy and antiproliferative activity of HE-NECA, demonstrating that the effect is mediated via the A2A receptor. siRNA directed against adenosine and adrenergic receptor isoforms, caused a concomitant reduction in the antiproliferative effects of HE-NECA and salmeterol. Synergy (CI & lt;0.4) observed between A2A and bAR agonists suggested that while both these targets signal through Gs coupled signaling pathways, the two targets contribute to the antiproliferative effect via distinct molecular mechanisms. Anti-proliferative effects occurred through a synergistic induction of apoptosis. Combinations of either agonist with dexamethasone demonstrate 50–75% Annexin V positive MM.1S cells after 24 hours treatment whereas single agents show less than 10%. The activity, synergy and selectivity of A2A and bAR combinations were observed in xenograft models of MM. SCID CB17 mice received subcutaneous inoculation of RPMI-8226 cells and once tumors were palpable, mice were treated with vehicle, bortezomib (0.5 mg/kg IV Q3D), salmeterol (10 mg/kg s.c QD) or the combination of both agents. After 19 days of treatment, the combination showed significantly greater reduction in tumor volume than either of the single agents alone (70% vs. 34%; p & lt;0.05, ANOVA). High throughput combination screening facilitated the discovery of two novel and related classes of drug targets with highly synergistic and selective anti-tumor activity in MM. These preclinical data provide a strong rationale for the investigation of A2A and bAR agonists in the treatment of MM.

Abstract: Current factor VIII (FVIII) products display a half-life (t1/2) of ∼ 8-12 hours, requiring frequent intravenous injections for prophylaxis and treatment of patients with hemophilia A. rFVIIIFc is a recombinant fusion protein composed of a single molecule of FVIII covalently linked to the Fc domain of human IgG1 to extend circulating rFVIII t1/2. This first-in-human study in previously treated subjects with severe hemophilia A investigated safety and pharmacokinetics of rFVIIIFc. Sixteen subjects received a single dose of rFVIII at 25 or 65 IU/kg followed by an equal dose of rFVIIIFc. Most adverse events were unrelated to study drug. None of the study subjects developed anti-rFVIIIFc antibodies or inhibitors. Across dose levels, compared with rFVIII, rFVIIIFc showed 1.54- to 1.70-fold longer elimination t1/2, 1.49- to 1.56-fold lower clearance, and 1.48- to 1.56-fold higher total systemic exposure. rFVIII and rFVIIIFc had comparable dose-dependent peak plasma concentrations and recoveries. Time to 1% FVIII activity above baseline was ∼ 1.53- to 1.68-fold longer than rFVIII across dose levels. Each subject showed prolonged exposure to rFVIIIFc relative to rFVIII. Thus, rFVIIIFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia A. This trial was registered at www.clinicaltrials.gov as NCT01027377.

Abstract: The hydroxamic acid vorinostat (SAHA) is an HDAC inhibitor that induces differentiation, growth arrest and/or apoptosis of malignant cells both in vitro and in vivo, and is currently being tested in the clinic for a variety of indications. In particular, vorinostat has demonstrated an overall response rate of approximately 30% in advanced cutaneous T-cell lymphoma (CTCL). The purpose of this study was to identify biomarkers that predict response to vorinostat in CTCL using preclinical model systems based upon gene expression profiling and pathogenesis of lymphoma. Herein we report the results of our evaluation of the STAT (signal transducer and activator of transcription) signaling pathway. The relative level of mRNA and protein expression as well as activation status of several members of this family have been evaluated in lymphoid cell lines with diverse vorinostat sensitivity (proliferation/viability IC50 range: 0.3–14 mM). Among them, the more responsive CTCL cells lines HH and HUT102 exhibited an IC50 ≃ 0.8 mM. These cells underwent apoptosis in response to vorinostat as assessed by TUNEL assay, in contrast to Hut78 and MJ cells (IC50 & gt; 2 mM) that did not show signs of DNA fragmentation upon incubation in vorinostat-containing media for 48 h. Our results indicate that in lymphoma cell lines elevated protein levels and persistent activation of STAT1, 3 and 5 correlate with resistance to vorinostat. Immunofluorescence microscopy studies revealed that STAT proteins preferentially localize to the nuclear compartment in cells with impaired vorinostat response, consistent with the expected distribution for this group of transcription factors in the active state. Simultaneous treatment with a pan-JAK inhibitor (JAK inhibitor I; Calbiochem) resulted in an additive antiproliferative effect consistent with a survival, antiapoptotic role for STAT proteins in the response to vorinostat treatment. Immunohistochemical analysis of STAT1 in skin biopsies isolated from CTCL patients (N = 49) enrolled in the vorinostat Phase IIb clinical trial showed that malignant T cells were positively stained in approximately half of the samples (21 positively stained; 25 negatively stained; 3 poor quality specimens), and in those cases a relationship between nuclear accumulation of STAT1 and lack of response to treatment exists (p=0.007 & lt;0.05; Fisher’s exact test). In conclusion, our results suggest that deregulation of STAT signaling plays a role in resistance to vorinostat in CTCL and strategies that block this pathway may improve response to vorinostat.

Abstract: Prophylaxis with factor VIII (FVIII) in patients with severe hemophilia A requires frequent intravenous injections (3–4 per week), impacting compliance and outcomes. A long-lasting recombinant FVIII Fc fusion protein (rFVIIIFc) was developed to reduce the frequency of injections. The pharmacokinetics (PK), safety, and efficacy of rFVIIIFc were evaluated in the phase 3 A-LONG study and the primary results were reported recently (Mahlangu J, J Thromb Haemost 2013). To illustrate differences in dosing regimens and clinical outcomes with rFVIIIFc and currently available FVIII products, we compared the prestudy and on-study dose, dose interval, and bleeding rates for subjects in A-LONG who reported receiving a prophylactic regimen with any FVIII product prior to study entry. We also used population PK models to estimate trough FVIII levels on various dosing regimens of rFVIIIFc and rFVIII (Advate®). Methods Previously treated male patients who were ≥12 years old with severe hemophilia A were enrolled in A-LONG and assigned to 1 of 3 treatment arms: Arm 1, individualized prophylaxis with PK-driven dose and dose interval adjustments (25–65 IU/kg every 3–5 days); Arm 2, once weekly prophylaxis (65 IU/kg); and Arm 3, episodic treatment (10–50 IU/kg) for bleeding episodes. A 2-compartmental population PK model of rFVIIIFc was developed based on activity-time profiles in 180 severe hemophilia A subjects aged 12-65 years old (16 from a phase 1/2a study and 164 from A-LONG collected over ≤ 52 weeks of treatment). A 2-compartment population PK model of Advate® was developed based on the single-dose PK profiles from 16 subjects in the phase 1/2a study and 30 subjects in the sequential PK subgroup in A-LONG. The population PK estimates for Advate® and rFVIIIFc from A-LONG were used for dosing simulations. We identified Arm 1 subjects who reported use of a prophylactic regimen at least 2 times a week with any FVIII product prior to study entry and compared their dosing regimens and bleeding rate in the 12 months prior to study with their rFVIIIFc dosing regimens and annualized bleed rate (ABR) on study. Only subjects on study for ≥ 6 months were included. The median ABR, dose, and dose interval during the last 3 months on study were analyzed. Results Of 165 total patients, 118 were in Arm 1, of whom 80 received a prophylactic regimen at least 2 times a week prestudy and were in the study for ≥ 6 months. Subjects were grouped by prestudy dosing interval. The table below provides prestudy and on study dose, dose interval, and bleeding rates for these groups. The majority of patients (65/80) reported a dosing interval of 3 times a week, with the most common dose of 25 IU/kg FVIII, and a median of 5.5 bleeding events 12 months prior to study entry. At the end of the study, these same patients were receiving ∼40 IU/kg rFVIIIFc twice a week (every 3.5 days) with a median ABR of 0. Population PK simulation indicated that 76.1% of patients treated with 40 IU/kg of rFVIIIFc twice a week would maintain FVIII levels above 1% at all times. In contrast, population PK simulation indicated that 42.3% of patients treated with 25 IU/kg of Advate® 3 times a week would maintain FVIII levels above 1% at all times. Overall, rFVIIIFc was well tolerated and no inhibitor development was detected during the A-LONG study. Conclusion The results from this descriptive analysis of dose, dose interval, and bleeding rates for subjects with severe hemophilia A who were on prophylaxis suggest that switching from current FVIII products to a rFVIIIFc regimen may allow for less frequent dosing to maintain FVIII activity 〉 1%. Disclosures: Shapiro: Baxter: Consultancy, Global steering committees Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Global steering committees, Global steering committees Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Inspiration: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding; Biogen Idec: Research Funding. Ragni:Biogen Idec: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Smith Kline Glaxo: Consultancy, Research Funding; Tacere Benitec: Consultancy; Baxter: Research Funding; Bayer: Research Funding; CSL Behring: Research Funding; Merck: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding. Kulkarni:Biogen Idec, Novo Nordisk, Baxter : Membership on an entity’s Board of Directors or advisory committees. Kulke:Biogen Idec: Employment. Potts:Biogen Idec: Employment. Neelakantan:Biogen Idec: Employment. Nestorov:Biogen Idec: Employment. Dumont:Biogen Idec: Employment; Biogen Idec: Equity Ownership. Jiang:Biogen Idec: Employment; Biogen Idec: Equity Ownership. Brennan:Biogen Idec: Employment; Biogen Idec: Equity Ownership. Pierce:Biogen Idec: Employment, Equity Ownership.