A Phase 1 Study of INCB057643 Monotherapy in Patients with Relapsed or Refractory Myelofibrosis (INCB 57643-103)

Background: Activation of transcription factors that regulate oncogenic processes is frequently observed in cancers such as myelofibrosis (MF). In preclinical studies, tumors associated with dysregulation of transcription factors appear to be responsive to inhibition of bromodomain and extra-terminal motif (BET) protein [Delmore JE, et al. Cell 2011; Shimamura T, et al. Clin Cancer Res 2013]. In addition to exerting a direct effect on tumor cells, BET inhibitors may also modulate tumorigenic inflammation; in a mouse model of MF, BET inhibition in combination with the Janus kinase inhibitor ruxolitinib resulted in decreased inflammation and reduced disease burden [Kleppe M, et al. Cancer Cell 2018]. In the first-in-human study INCB 57643-101, the small-molecule BET inhibitor INCB057643, was safe and generally well tolerated as monotherapy, and demonstrated preliminary efficacy in 2 out of 3 patients with MF when administered alone or in combination with ruxolitinib [Falchook G, et al. Clin Cancer Res 2020]. The INCB 57643-103 trial is designed to further evaluate the safety and tolerability of INCB057643 monotherapy in patients with relapsed or refractory MF. Methods: INCB 57643-103 (NCT04279847) is a phase 1, single-arm, open-label, two-part dose confirmation and expansion study evaluating INCB057643 in patients with measurable histologically or cytologically confirmed (World Health Organization criteria 2016), relapsed or refractory primary MF or secondary MF (post-polycythemia vera, post-essential thrombocythemia). Patients must be ≥18 years of age, have received ≥1 line of prior therapy including ruxolitinib and have no option for therapy known to provide clinical benefit, have a risk category of intermediate-2 or high according to the Dynamic International Prognostic Scoring System, have an Eastern Cooperative Oncology Group performance status 0-2, have a life expectancy of 24 weeks or more, and be willing to provide a pretreatment bone marrow biopsy and/or aspirate at baseline (or an archival sample obtained after most recent therapy). Patients will be excluded if they have received prior treatment with a BET inhibitor; received anticancer treatment within specified intervals before the first administration of study drug or receiving concurrent anticancer therapy; received allogeneic hematopoietic stem cell transplant (6 months or less before enrollment) or have active graft versus host disease or received immunosuppressive therapy after allogeneic transplant 2 weeks or less before study drug treatment; have significant and uncontrolled medical events such as gastrointestinal or cardiovascular; have a history of bleeding disorder or at a high risk of bleeding; or have abnormal hematologic, hepatic, renal, coagulation, or metabolic laboratory values. Approximately 15 patients will be enrolled. Part 1 will evaluate initial safety and tolerability of INCB057643. Up to 6 patients will self-administer oral INCB057643 4 mg once daily (QD) continuously. Doses will be declared tolerable if dose-limiting toxicities (DLT) occur in ≤2 patients and discontinuation due to treatment-related adverse events (TRAEs) occurs in ≤2 patients during the DLT evaluation period. Part 2 will further characterize safety and tolerability as well as evaluate preliminary efficacy. Up to 9 patients will receive INCB057643 at 4 mg QD if the dose is deemed tolerable in Part 1; if not, the starting dose will be 2 mg QD. Treatment may continue as long as benefit is derived and discontinuation criteria are not met. The primary study objective is assessment of safety and tolerability of INCB057643 monotherapy by monitoring the frequency and severity of AEs, performing physical examinations, and collecting vital signs and laboratory values. Secondary objectives include evaluation of anemia response by International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) Consensus Report, red blood cell transfusion dependence, spleen volume, rate of spleen response and duration of spleen response by IWG-MRT and ELN Consensus Report, and impact on quality of life. Patients will be assessed every 3 cycles and will receive follow-up for safety for 30-35 days after last dose of study drug. Disclosures Lihou: Incyte: Current Employment, Current equity holder in publicly-traded company. Zhou:Incyte: Current Employment, Current equity holder in publicly-traded company. Zheng:Incyte: Current Employment, Current equity holder in publicly-traded company.

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Real-World Outcomes with Fedratinib Therapy in Patients Who Discontinued Ruxolitinib for Primary Myelofibrosis

Blood ◽

10.1182/blood-2021-148188 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3645-3645

Author(s):

Francesco Passamonti ◽

Quynh Do ◽

Youbei Lou ◽

Manoj Chevli ◽

Pranav Abraham

Keyword(s):

Real World ◽

Research Funding ◽

Group Performance ◽

Performance Status ◽

Primary Myelofibrosis ◽

Index Patient ◽

Pharmacological Therapy ◽

Janus Kinase ◽

Publicly Traded ◽

Once Daily

Abstract Introduction: Myelofibrosis (MF) is a rare myeloproliferative disorder in whichdysregulation of the janus kinase 2 (JAK2) hematopoiesis-signaling pathway disruptsbone marrow production of blood cells, leading to anemia, fatigue and splenomegaly.Until recently, the dual JAK1/JAK2 inhibitor, ruxolitinib (RUX), has been the onlyapproved pharmacological therapy for intermediate/high-risk MF. However, manypatients receiving RUX experience a suboptimal response or develop cytopenia, leadingto discontinuation. Fedratinib (FEDR), an oral, selective inhibitor with activity againstwild-type and mutationally activated JAK2 and the receptor tyrosine kinase FLT3, wasapproved in the US in August 2019. The real-world effectiveness of FEDR in the post-RUX setting has not yet been assessed. Aim: To assess the baseline characteristics and survival outcomes among patientsdiagnosed with MF who discontinued RUX and were subsequently treated with FEDR ornot. Methods : Adult US patients who received RUX after an initial diagnosis of primary MF(identified by ICD-9/10-CM codes) were identified using Flatiron Health's nationwideelectronic health record (EHR)-derived database. Patients were stratified by whetherthey subsequently received post-ruxolitinib fedratinib (FEDR group) or not (non-FEDRgroup). The non-FEDR group was further stratified by time of RUX discontinuation(before [non-FEDR subgroup A] and after [non-FEDR subgroup B] US approval of FEDRin August 2019) to enable a contemporaneous comparison with the FEDR group. Indexdate was the start of FEDR therapy in the FEDR group, and last date of RUX therapy inthe non-FEDR groups. Patients were included if they had ≥2 recorded visits in theFlatiron network on or after January 1, 2011- Oct 31, 2020; were aged ≥18 years atindex; had ≥1 months' data before and also after index; and had no record of receivingunclassified clinical study drugs prior to index. Patient demographics and clinical characteristics were assessed at index. Overall survival (OS) was defined as time fromindex until death or censoring, and was assessed by Kaplan-Meier analysis. Landmarksurvival was defined as the proportion of patients who survived at a given point.Association of baseline variables and survival were assessed by Cox proportionalhazards model and p<0.05 was considered statistically significant. Results: Overall, 229 MF patients were evaluated (FEDR group: n=70; non-FEDRgroup: n=159). The median age at index for the FEDR group and non-FEDR group was71.0 and 70.0 years, 55.7% and 50.3% were female, 64.3% and 68.6% were white, andmedian follow-up from index was 7.0 and 6.0 months, respectively. Among patients withEastern Cooperative Oncology Group performance status (ECOG PS) at index, 90.2%(46/51) and 74.3% (84/113) had an ECOG score of 0-1, respectively (Table). Median(range) duration of FEDR therapy in the FEDR group was 3.7 (0-12.2) months; 47.1%(33/70) of patients receiving FEDR initiated therapy with 400 mg FEDR once daily, and21.4% (15/70) initiated with 200 mg FEDR once daily. Median OS was not reached in theFEDR group and was 17 months in the non-FEDR group. Landmark survival in theFEDR and non-FEDR groups was 91.3% and 76.5% at 3 months, and 71.6% and 53.5%at 12 months, respectively. In the non-FEDR subgroup B, the corresponding survivalrates at 3 months and 12 months were 75.0% and 47.9%. The Cox proportional hazardsmodel suggested that being male, 'other' (non-white, non-black/African-American, non-Asian, non-missing) race, Charlson comorbidity index ≥1, ECOG score 2-4, and bodymass index <18.5 kg/m were significantly associated with poorer survival. Conclusions: This real-world analysis demonstrates that these two groups of patientswith primary MF who had received prior RUX had broadly comparable baselinecharacteristics. FEDR appeared to be associated with improved survival up to 1 yearafter index compared with non-FEDR therapy. When the FEDR group and non-FEDR Bsubgroup were compared, the differences in survival rate remained. FEDR may offersubstantially improved survival probability in patients receiving post-ruxolitinib therapy of primary MF in routine clinical practice. Figure 1 Figure 1. Disclosures Passamonti: Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau. Do: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lou: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Chevli: Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Abraham: Bristol Myers Squibb: Current Employment.

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Rker-050 Rescued Ruxolitinib (Rux)-Associated Reductions in Red Blood Cell Volume

Blood ◽

10.1182/blood-2021-152729 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 934-934

Author(s):

Remya Nathan ◽

Marina Feigenson ◽

Joshua Lamora ◽

Claire C Tseng ◽

Ffolliott Fisher ◽

...

Keyword(s):

Group Treatment ◽

Potential Benefit ◽

Phase 1 ◽

Clinical Signs ◽

Preclinical Study ◽

Erythropoietin Receptor ◽

Janus Kinase ◽

Vehicle Group ◽

Control Group ◽

Publicly Traded

Abstract Myelofibrosis (MF) is characterized by the dysfunctional Janus kinase/signal transducers and activators of transcription signaling (JAK/STAT) pathways leading to progressive proliferation of granulocytic and megakaryocytic cells in the bone marrow at the expense of other hematopoietic lineages. Clinical signs of MF include cytopenias, splenomegaly and transformation to acute leukemia. Jakafi® (ruxolitinib, or rux), a JAK2 inhibitor, is a therapeutic for MF and functions to impair the activated mutations that cause the expansion of megakaryocytic precursors. However, JAK2 also transduces signals of the erythropoietin receptor, thrombopoietin receptor, and the granulocyte colony-stimulating factor receptor. Therefore, individuals being treated with rux are susceptible to treatment-associated effects on normal hematopoiesis resulting in thrombocytopenia, neutropenia and anemia. The TGF-β superfamily plays a vital role in the regulation of hematopoiesis; specifically, SMAD 2/3 activation results in cell quiescence and inhibits precursors from progressing through later stages of hematopoiesis. KER-050, a modified ActRIIA extracellular domain fused to the Fc of human IgG1, is designed to inhibit ligands including activin A, activin B, GDF8 and GDF11, that activate SMAD 2/3. In a preclinical study, administration of KER-050 in mice led to upregulation of erythropoiesis by mobilizing early- and late-stage erythroid precursors and facilitating their terminal maturation into red blood cells (RBCs). In a Phase 1 clinical study, administration of KER-050 to healthy volunteers led to sustained increases in RBCs and hemoglobin (HGB) along with increases in platelets. Given the observed effect of KER-050 on increasing RBCs, we evaluated whether treatment with a research form of KER-050 (RKER-050) could reverse rux-associated reductions in RBCs. Additionally, preclinical studies have shown that KER-050 potentially functioned as a muscle anabolic by increasing lean mass in rodents. We first established anemia in C57Bl/6 mice by dosing with rux before administering RKER-050. Anemia was confirmed on study day 37; mice receiving 120 mg/kg rux via oral gavage (PO) BID had significantly lower RBC (-7.4%, p=0.0001), HGB (-4.0%, p=0.002) and hematocrit (HCT; -5.7%, p=0.0006) levels compared to the control group. Treatment with RKER-050 was initiated on study day 41 and mice received 7.5 mg/kg RKER-050 or vehicle intraperitoneally (IP) twice weekly for approximately 14 days. Mice receiving rux alone continued their decline in RBCs and, on day 55, continued to have significant reductions in RBC (-6.7%, p<0.0001), HGB (-6.0, p<0.00001) and HCT (-5.6%, p=0.0002) levels compared to the control group. These findings are consistent with the progressive effect of JAK2 inhibition on suppressing erythrocyte development and production. In contrast, treatment with RKER-050 abrogated the observed rux-associated reductions in RBCs, HGB, and HCT in the rux-RKER-050 cohort with significant observed increases (+15.8%, +12.2%, +11.2%, respectively, all p<0.0001) when compared to the rux-vehicle group. The rux-RKER-050 cohort also had significantly increased body mass, measured between study day 41 and study day 55 versus the rux-vehicle group (+9.9%, p= 0.006, and +0.69%, respectively). These data demonstrate that rux treatment reduced RBCs, HGB, and HCT in mice, and that coadministration of RKER-050 reversed rux-associated reductions in RBC parameters. Therefore, treatment with KER-050 has the potential to mitigate the dose limiting effects of rux and enhance duration of therapy in MF patients. RKER-050 also increased body weight in mice receiving rux through its anabolic effect on muscle, a potential benefit in elderly MF patients. These data support the potential benefit of KER-050 as a monotherapy and in combination with rux in patients with MF and anemia. KER-050 will be assessed in a Phase 2 clinical trial (KER050-MF-301), which we expect to commence in 2021. Disclosures Nathan: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Feigenson: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lamora: Keros Therapeutics: Current Employment. Tseng: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Fisher: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Seehra: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lachey: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

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Comparative Safety of Two Bendamustine Hydrochloride Formulations; A Ready-to-Dilute Low-Volume, Rapid Infusion Solution, and a Lyophilized Powder: Results from a Phase 1 Study

Blood ◽

10.1182/blood.v126.23.4861.4861 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4861-4861

Author(s):

Bassam Mattar ◽

Stephen P Anthony ◽

W Jeffrey Edenfield ◽

Mark Smith ◽

Adrian Hepner

Keyword(s):

Abdominal Pain ◽

Study Design ◽

Group Performance ◽

Phase 1 ◽

Study Drug ◽

Rapid Infusion ◽

Safety Population ◽

Low Volume ◽

Grade 3 ◽

Treatment Sequences

Abstract Introduction: This phase 1, open-label, randomized, crossover study was performed to test the bioequivalence and safety of an investigational, ready-to-dilute, rapid infusion (low volume) solution of bendamustine hydrochloride (test product [T]), and the approved bendamustine lyophilized powder formulation (reference product [R]). [ClinicalTrials.gov Identifier: NCT02162888] Methods: Patients were eligible to participate if they had a histologically confirmed diagnosis of any malignant disease (excluding chronic lymphocytic leukemia) for which no curative or standard therapy was available. All patients received bendamustine 120 mg/m2 intravenously as T (in 50 mL; 0.9% NaCl) over 10 min and R (in 500 mL; 0.9% NaCl) over 60 min on days 1 and 2 of two consecutive 28-day cycles. Patients were randomly assigned to one of three treatment sequences for the first three doses of study drug: TRR, RTR, RRT; T was given to all patients at cycle 2, day 2 (dose 4) (Figure). Safety was assessed throughout the 56-day treatment period, with events of special interest (expected reactions to bendamustine or underlying disease) recorded during and up to 1 h after administration; up to 24 h after administration; and on cycle 1 days 21 and 28; cycle 2 day 28; and at the end-of-study visit. Safety assessments included reported adverse events (AEs), Eastern Cooperative Oncology Group performance status, vital sign measurements, physical examination, and clinical laboratory assessments. Results: A total of 83 patients were randomized to the 3 treatment sequences; 81 received at least one dose of study drug and comprised the safety population. Fifty-nine (71.1%) patients received four doses of study treatment, with a similar number (67%-77%) of patients in each treatment sequence arm. Reasons for discontinuation were AEs (4 patients), death (3 patients), insufficient therapeutic response (4 patients), lost to follow-up (1 patient), sponsor request (2 patients), investigator request (3 patients), withdrew consent (5 patients), and other (2 patients). The frequency of treatment-emergent AEs (TEAEs) by most recent study treatment are shown in the Table. The most commonly occurring AEs (> 10%) overall were nausea (R 25%, T 19%), fatigue (R 21%, T 22%), dehydration (R 12%, T 15%), decreased appetite (R 11%, T 15%), anemia (R 12%, T 15%), pyrexia (R 6%, T 16%), constipation (R 11%, T 11%), vomiting (R 11%, T 8%), dyspnea (R 5%, T 12%), hypokalemia (R 4%, T 12%), diarrhea (R 6%, T 10%), abdominal pain (R 5%, T 10%), and thrombocytopenia (R 2%, T 11%). The most common AEs occurring during the infusion and within 1 h after infusion were nausea (R 6%, T 8%) and fatigue (R 5%, T 6%); nausea (R 11%, T 9%) and fatigue (R 8%, T 9%) were also most common in the first 24 h. Infusion reactions were experienced by ≤ 2% of patients treated with either T or R. Serious AEs occurring in > 1 patient were abdominal pain (R 1%, T 5%), chest pain (R 2%, T 0), deep vein thrombosis (R 2%, T 0), dehydration (R 1%, T 1%), pericardial effusion (R 1%, T 1%), and vomiting (R 1%, T 3%). Six deaths were reported; the primary cause of death for all six patients was progressive disease. Conclusions: No new safety signals were observed. The fact that all patients who received 4 doses received T as their final dose introduces a source of bias and may explain the increased overall number of TEAEs attributed to T. Sponsor: Eagle Pharmaceuticals, Inc. Table. TEAEs by Most Recent Treatment (Safety Population) Rn = 81 Tn = 73 Events Patients n (%) Events Patients n (%) During or within 1 h after infusion All TEAEs 40 26 (32.1) 38 21 (28.8) Grade 3-4 0 0 1 1 (1.4) Serious AEs 0 0 1 1 (1.4) Within 24 h of infusion All TEAEs 65 34 (42.0) 50 23 (31.5) Grade 3-4 5 4 (4.9) 10 6 (8.2) Serious AEs 2 2 (2.5) 5 2 (2.7) Overall All TEAEs 263 60 (74.1) 348 49 (67.1) Grade 3-4 46 19 (23.5) 66 20 (27.4) Serious AEs 23 12 (14.8) 12 12 (16.4) Figure 1. Study design. Figure 1. Study design. Disclosures Anthony: Eagle Pharmaceuticals, Inc.: Research Funding. Edenfield:Novartis, Astellas/Medivation: Speakers Bureau. Smith:Eagle Pharmaceuticals, Inc.: Employment. Hepner:Eagle Pharmaceuticals, Inc.: Employment, Equity Ownership.

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A Phase 1/2 Study of INCB000928 As Monotherapy or in Combination with Ruxolitinib in Patients with Anemia Due to Myelofibrosis (INCB 00928-104)

Blood ◽

10.1182/blood-2020-134574 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-3

Author(s):

Stephen T. Oh ◽

Jason Gotlib ◽

Sanjay Mohan ◽

Haris Ali ◽

Ekatherine Asatiani ◽

...

Keyword(s):

Treatment Group ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Elevated Serum ◽

Study Drug ◽

Risk Category ◽

Publicly Traded ◽

Advisory Committees ◽

Rbc Transfusion

Background: Anemia represents a challenge in the management of patients with myelofibrosis (MF); at least a third of patients with MF are reported to have hemoglobin levels <10 g/dL and approximately 25% of these patients are red blood cell (RBC) transfusion-dependent at the time of diagnosis. Elevated serum hepcidin levels have been shown to be associated with anemia, increased requirement for RBC transfusions, and reduced overall survival in patients with MF. Hepcidin levels are regulated by the serine/threonine kinase, activin receptor-like kinase 2 (ALK2); in preclinical studies, knockdown or loss of ALK2 leading to decreased hepcidin production results in elevated serum iron levels. INCB000928 is a potent, orally bioavailable, and highly selective small molecule inhibitor of ALK2, and may represent a potential therapeutic strategy for hepcidin-induced anemia. INCB 00928-104 is designed to evaluate the safety and tolerability of INCB000928 as monotherapy or in combination with ruxolitinib in patients with anemia due to MF. Methods: INCB 00928-104 (NCT04455841) is a phase 1/2, open-label, multicenter, dose-escalation and -expansion study assessing INCB000928 alone (treatment group A [TGA]) or in combination with ruxolitinib (treatment group B [TGB]), in patients with MF who are transfusion-dependent or present with symptomatic anemia (Figure). For TGA, patients must have been intolerant, resistant, refractory, or lost response to prior therapy (≥12 weeks) with Janus kinase inhibitors and have a risk category of intermediate-2 or high according to the Dynamic International Prognostic Scoring System (DIPSS); for TGB, patients must have been on a therapeutic and stable regimen of ruxolitinib for ≥12 consecutive weeks prior to first dose of study treatment and have a DIPSS risk category of intermediate-1 or -2, or high. To be eligible patients must be ≥18 years of age, have an Eastern Cooperative Oncology Group performance status 0-1 for the dose-escalation stages or 0-2 for the dose-expansion stage, have life expectancy > 6 months, and have histologically confirmed primary or secondary (post-polycythemia vera, post-essential thrombocythemia) MF. Patients are ineligible if they have any other hematologic malignancy; have undergone any prior allogeneic or autologous stem cell transplantation; have undergone major surgery within 28 days of first dose of study drug; or have received prior disease-directed therapy within 5 half-lives or 28 days before first dose of study drug. In Part 1 (dose escalation) of the study, patients will be enrolled into TGA or TGB. INCB000928 monotherapy will be administered orally at a starting dose of 50 mg/day in TGA (28-day cycles). The dose-escalation stage will use a Bayesian optimal interval design to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), with dose increases not exceeding 100% (2-fold) until a treatment-related toxicity Grade ≥2 is observed. Dose escalation in TGB will start 2 dose levels below the maximum evaluated dose determined to be safe and tolerable in TGA; patients in TGB will receive INCB000928 in combination with ruxolitinib. In each treatment group in Part 1, ≤24 patients will be treated in the dose-escalation stage. In Part 2 (dose expansion), the RDE in TGB will be evaluated in combination with ruxolitinib in approximately 25 patients. Patients will receive treatment for up to 12 months, and treatment may continue if patients are deriving clinical benefit and have no evidence of progressive disease. The primary study objective is to determine the safety and tolerability of INCB000928 monotherapy or in combination with ruxolitinib, and to identify dose-limiting toxicities, MTD, and RDE for TGB). Secondary objectives are: to determine the efficacy of INCB000928 monotherapy or in combination with ruxolitinib (assessed by anemia response, duration of anemia response, mean change from baseline in hemoglobin, and rate of RBC transfusion through week 24 and 48); to evaluate pharmacokinetics of INCB000928; and to evaluate the effect of INCB000928 as monotherapy or in combination with ruxolitinib on hepcidin level, and other measures of iron homeostasis and erythropoiesis. Disclosures Oh: Incyte Corporation: Consultancy; Gilead Sciences: Consultancy; Novartis: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Blueprint Medicines: Consultancy; Kartos Therapeutics: Consultancy; Disc Medicine: Consultancy; PharmaEssentia: Consultancy; Constellation: Consultancy; CTI Biopharma: Consultancy. Gotlib:Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding; Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding. Mohan:Incyte Corporation: Research Funding; Novartis: Research Funding. Ali:Incyte Corporation: Consultancy. Asatiani:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Seguy:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Zhou:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Verstovsek:NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Sierra Oncology: Consultancy, Research Funding; ItalPharma: Research Funding; Protagonist Therapeutics: Research Funding; CTI Biopharma Corp: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Novartis: Consultancy, Research Funding; Promedior: Research Funding; Blueprint Medicines Corp: Research Funding; AstraZeneca: Research Funding; PharmaEssentia: Research Funding.

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Phase 1/2 Study of Oral TP-0184 for the Treatment of Anemia in Adults with Low- or Intermediate-Risk Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2021-147594 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1534-1534

Author(s):

Amit Verma ◽

Andrew M. Brunner ◽

Gregory Pennock ◽

Dragana McMullen ◽

Mark Wade ◽

...

Keyword(s):

Myelodysplastic Syndromes ◽

Research Funding ◽

Group Performance ◽

Phase 1 ◽

Inadequate Response ◽

Cell Transplant ◽

Intermediate Risk ◽

Phase 2 ◽

Publicly Traded ◽

Downstream Signaling

Abstract Patients with anemia due to lower-risk myelodysplastic syndromes (MDS) have limited treatment options. The transforming growth factor β (TGF-β) pathway has been implicated in contributing to ineffective hematopoiesis in patients with MDS. Members of the TGF-β superfamily include activin receptor-like kinase 2 (ALK2) and ALK5. ALK2 signaling plays a key role in modulating hepcidin, an important regulator of iron homeostasis (and thus erythropoiesis). Increased levels of hepcidin have been linked to anemia in patients with chronic inflammation and cancer, including multiple myeloma (Maes K, et al. Blood. 2010;116:3635-44). The role of hepcidin in MDS-related anemia is unknown and needs to be explored. ALK5 signaling through SMAD2/3 phosphorylation is constitutively active in bone marrow precursor cells from patients with MDS (Zhou L, et al. Blood. 2008;112:3434-43). Inhibition of ALK5 suppresses phosphorylation of SMAD2 in MDS hematopoietic progenitor cells and stimulates hematopoiesis in cells derived from patients with MDS. Collectively, these data suggest that blockade of the TGF-β-SMAD2/3 signaling pathway with an ALK5 inhibitor has the potential to benefit patients with anemia due to MDS. TP-0184 is a small-molecule, dual inhibitor of ALK2 and ALK5. In vitro, TP-0184 inhibits downstream signaling from ALK2 by reducing the phosphorylation of SMAD1/5/8 and blocks hepcidin expression (Peterson PW, et al. Blood. 2017;130 [suppl_1]: 937). Ex vivo, TP-0184 inhibits downstream signaling from ALK5 by reducing SMAD2/3 phosphorylation (data on file). By inhibiting both the ALK2 and ALK5 signaling pathways, TP-0184 may reduce ineffective erythropoiesis in patients with MDS. An open-label, single-arm, phase 1/2 study (NCT04623996) is being undertaken to evaluate the preliminary safety and efficacy of TP-0184 in treating anemia in adults (aged ≥18 years) with MDS. To be eligible, patients must have low- or intermediate-risk MDS (de novo or secondary) per the Revised International Prognostic Scoring System and have relapsed, exhibited an inadequate response to, or been refractory, resistant, or intolerant to treatment with an erythropoiesis-stimulating agent. Patients may have low or high red blood cell transfusion burden, must exhibit adequate major organ function, and must have an Eastern Cooperative Oncology Group performance status of 0-2. Key exclusion criteria include the presence of concomitant severe cardiovascular disease, such as congestive heart failure, myocardial infarction, angina, and/or uncontrolled cardiac arrhythmia; history of stroke, deep venous thrombosis, or pulmonary or arterial embolism; presence of clinically significant anemia due to iron, vitamin B12, or folate deficiencies, autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding; and prior allogeneic or autologous stem cell transplant. In this study, TP-0184 will be administered orally once daily for 24 weeks. The primary and secondary endpoints of each study phase are summarized in the table. Recruitment is ongoing, with approximately 30 patients targeted for enrollment in phase 1 and 10-60 patients targeted for enrollment in phase 2. In phase 1, increasing dose levels of TP-0184 ranging from 20 to 270 mg will be evaluated, with 1-6 patients dosed at each level. Dose escalation will be performed using a two-parameter Bayesian logistic regression model. Determination of the recommended phase 2 dose (RP2D) will be informed by the maximum tolerated or maximum administered dose in phase 1. In phase 2, the efficacy of TP-0184 at the RP2D will be monitored using Bayesian posterior probability to optimize enrollment with Bayesian stopping rules. Bayesian monitoring of responses will be started after the first 10 enrolled patients are evaluable for efficacy. Figure 1 Figure 1. Disclosures Verma: Medpacto: Research Funding; Curis: Research Funding; Eli Lilly: Research Funding; Stelexis: Consultancy, Current equity holder in publicly-traded company; Novartis: Consultancy; Acceleron: Consultancy; Celgene: Consultancy; Stelexis: Current equity holder in publicly-traded company; Throws Exception: Current equity holder in publicly-traded company; Incyte: Research Funding; GSK: Research Funding; BMS: Research Funding. Brunner: Celgene, Forty Seven Inc, Jazz: Other: Advisory Board; Novartis, Celgene, Takeda, AstraZeneca: Research Funding. Pennock: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. McMullen: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Wade: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Yang: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Xie: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Whatcott: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Foulks: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Melear: Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; TG Therapeutics: Speakers Bureau.

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403 Early results from a phase 1 study to evaluate safety, pharmacokinetics, and efficacy of AMG 404, a programmed death-1 (PD-1) antibody, in patients with advanced solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0403 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A428-A428

Author(s):

Timothy Price ◽

Sant Chawla ◽

Gerald Falchook ◽

Hans Prenen ◽

Iwona Lugowska ◽

...

Keyword(s):

Partial Response ◽

Solid Tumors ◽

Clear Cell ◽

Phase 1 ◽

Cell Cancer ◽

Objective Response ◽

Study Endpoint ◽

Primary Study ◽

Pharmacokinetic Parameters ◽

Advanced Solid Tumors

BackgroundEnhancement of antitumor immunity through inhibition of the checkpoint PD-1 receptor has been effective in the treatment of many malignancies. AMG 404 is a monoclonal antibody (mAb) targeting PD-1. This phase 1, open-label, multicenter first-in-human study (NCT03853109) will evaluate the safety, tolerability, pharmacokinetics, and efficacy of AMG 404 monotherapy in adult patients with advanced solid tumors.MethodsThe primary study endpoint is dose-limiting toxicity (DLT) and safety; key secondary endpoints include pharmacokinetic parameters, objective response rate (assessed Q8W), duration of response, and progression-free survival. Key inclusion criteria include histologically or cytologically proven metastatic or locally advanced solid tumors not amenable to curative treatment with surgery or radiation for which standard therapies have been exhausted or not available. Prior anti-PD-(L)1 or other checkpoint inhibitors were not allowed. Five dose-finding cohorts, including 2 expansion cohorts, ranged from 3–20 patients each. AMG 404 was given until disease progression, intolerance, or consent withdrawal.ResultsAs of the data cutoff date of May 4, 2020, 62 patients received at least 1 dose of AMG 404 and were included in the safety and efficacy analysis sets. Fifty percent were men, 72% had ECOG 1 performance status, median age was 62 years (range: 28–83), and 42% had ≥3 lines of prior anticancer therapy. Median AMG 404 exposure was ~3 months (maximum: ~12 months). No DLTs were observed. Treatment-related adverse events (TRAEs) were reported for 29 patients (47%): those reported for ≥2 patients were fatigue (n=7); hypothyroidism (n=6); increased blood thyroid stimulating hormone and nausea (n=4 each); increased aspartate aminotransferase, decreased appetite, and pyrexia (n=3 each); and increased alanine aminotransferase, arthralgia, diarrhea, and increased weight (n=2 each). AEs leading to withdrawal of AMG 404 were reported for 3 patients (5%); all were serious and considered to be not related to AMG 404. Sixteen (26%) patients died on study; no deaths were considered related to AMG 404. Preliminary pharmacokinetic results were consistent with those of other therapeutic anti-PD-1 mAbs. Three patients had a confirmed partial response (pancreatic cancer, clear cell cancer, and pleomorphic sarcoma); an additional 4 patients had one scan with a partial response and are pending a confirmatory scan (clear cell renal carcinoma, undifferentiated nasopharyngeal carcinoma, sarcomatoid carcinoma of unknown primary, and colon cancer).ConclusionsAMG 404 is tolerable at the tested doses with no DLTs reported. All observed TRAEs are consistent with other anti-PD-1 therapies. Encouraging anti-tumor activity has been observed in heavily pretreated patients. The study is continuing enrollment into additional cohorts.Trial RegistrationNCT03853109Ethics ApprovalThe study was approved by the Ethics Board of each institution involved in this study and can be produced upon request.

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MO283IMPACT OF VIS649, AN APRIL-NEUTRALIZING IGG2 MONOCLONAL ANTIBODY, ON TETANUS- AND DIPHTHERIA-TOXOID VACCINATION-ELICITED IMMUNE RESPONSES IN HEALTHY VOLUNTEERS: PHASE 1, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab104.0041 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Jonathan Barratt ◽

Mohit Mathur ◽

Yusuke Suzuki ◽

Frank Engler ◽

Jill Yarbrough ◽

...

Keyword(s):

Monoclonal Antibody ◽

Intravenous Administration ◽

Phase 1 ◽

Study Drug ◽

Fold Increase ◽

Antibody Responses ◽

Diphtheria Toxoid ◽

Double Blind ◽

Double Blind Placebo ◽

Serum Iga

Abstract Background and Aims VIS649, a humanized immunoglobulin G (IgG2) monoclonal antibody that binds to and blocks the biological actions of a proliferation-inducing ligand (APRIL), is in clinical development as a potential treatment for immunoglobulin A (IgA) nephropathy (IgAN). In a Phase 1 study, VIS649 was associated with dose-dependent reductions in serum IgA, IgG and IgM, which were reversible and showed a dose-response effect with respect to time-to-recovery. The aim of the present analysis was to determine if VIS649 suppression of APRIL influences antibody responses to tetanus and diphtheria toxoid vaccination. Method This was a Phase 1, randomized, double-blind, placebo-controlled, single ascending dose study of VIS649 in healthy adult male and female volunteers (ClinicalTrials.gov identifier: NCT03719443). In one cohort within the study, participants were randomized in a 2:1 ratio to receive intravenous administration of VIS649 6.0 mg/kg or placebo, followed by a vaccine composed of tetanus and diphtheria toxoids (TENIVAC®, Sanofi Pasteur Limited), in order to evaluate the effect of VIS649 on recipients’ ability to generate a vaccine booster response (exploratory endpoint). Participants received intravenous administration of study drug on Day 1, were discharged from the institution on Day 2, received a single intramuscular dose of vaccine at the Week 4 visit, and were followed for 16 weeks in total on an outpatient basis. Blood samples were taken at regular intervals, and anti-tetanus toxoid and anti-diphtheria toxoid IgG, IgM and IgA quantitative ELISA assays were performed. Tetanus and diphtheria anti-toxoid IgG titers ≥0.1 IU/mL are generally considered to be protective. Results In the vaccination cohort, 15 participants were randomized and dosed with study drug or placebo, of whom 14 completed the study, and one participant who received VIS649 was lost to follow-up prior to receiving the vaccine. Both groups (placebo and VIS649) demonstrated increased tetanus anti-toxoid IgG titers following immunization, with a mean 7.9-fold increase in IU/mL at Week 6 for placebo recipients and a mean 6.4-fold increase in IU/mL for VIS649 recipients (Figure). At visits after Week 6, tetanus anti-toxoid IgG titers declined faster in the VIS649 group than in the placebo group (consistent with the reduction in total IgG associated with VIS649 administration) but remained above the protective threshold of 0.1 IU/mL for all participants throughout the study. Similar trends were observed for diphtheria anti-toxoid IgG titers, with a mean 5.5-fold increase in IU/mL at the Week 6 visit for placebo recipients and a mean 5.1-fold increase for VIS649 recipients (Figure). There was no evidence of tetanus- or diphtheria-toxoid elicited IgM responses in either the placebo or VIS649 groups, consistent with the recall nature of the vaccination. In a post hoc analysis, pre-existing serum tetanus/diphtheria anti-toxoid IgA titers fell between Day 1 and Week 4 in the VIS649 group, consistent with the overall suppression of total serum IgA, were boosted after vaccination in both groups, and declined faster in the VIS649 recipients thereafter. Conclusion VIS649 treatment did not interfere with participants’ ability to mount an antigen-specific serum IgG or IgA boost response to tetanus and diphtheria toxoid vaccination. There was no evidence of tetanus- or diphtheria-specific IgM responses in either the placebo or VIS649 groups, consistent with recall vaccination exposure. These data indicate that qualitative antibody responses are preserved during APRIL suppression.

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MO258SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF VIS649, AN APRIL-NEUTRALIZING IGG2 MONOCLONAL ANTIBODY, IN HEALTHY VOLUNTEERS: PHASE 1, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE ASCENDING DOSE STUDY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab104.0016 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Yusuke Suzuki ◽

Mohit Mathur ◽

Jonathan Barratt ◽

Frank Engler ◽

Jill Yarbrough ◽

...

Keyword(s):

Phase 1 ◽

Study Drug ◽

Dependent Manner ◽

Double Blind ◽

Serum Iga ◽

Dose Study ◽

Dose Response Effect ◽

Japanese Descent ◽

Dose Dependent ◽

Single Ascending Dose Study

Abstract Background and Aims Immunoglobulin A (IgA) nephropathy (IgAN) is a glomerulonephritis characterized by the presence of circulating and glomerular immune complexes containing galactose-deficient (Gd) IgA1. A proliferation-inducing ligand (APRIL), a member of the tumor necrosis factor superfamily of ligands, is thought to play a key role in the pathogenesis of IgAN by virtue of its role in class-switching to IgA production. VIS649, a humanized immunoglobulin G (IgG2) monoclonal antibody that binds to and blocks the biological actions of APRIL, is in clinical development as a potential treatment for IgAN. The primary objective of this first-in-human study was to evaluate the safety and tolerability of VIS649 in healthy volunteers. Secondary objectives included characterization of the pharmacokinetics (PK) and pharmacodynamics (PD) of VIS649. Method This was a Phase 1, randomized, double-blind, placebo-controlled, single ascending dose study of VIS649 in healthy adult male and female volunteers (ClinicalTrials.gov identifier: NCT03719443). The study was conducted in sequential dosing cohorts. The first four cohorts (0.5, 2.0, 6.0, and 12.0 mg/kg, respectively) each enrolled 9 participants (4 of Japanese descent and 5 of non-Japanese descent) who were randomized to VIS649 or placebo in a ratio of 7:2. In addition, a fifth cohort enrolled 15 adults randomized to receive VIS649 6.0 mg/kg or placebo (10:5), followed by tetanus/diphtheria vaccine challenge after 28 days (TENIVAC®, Sanofi Pasteur Limited; the effect of APRIL inhibition on vaccine response is described in a companion abstract). Participants received intravenous administration of study drug on Day 1, were discharged from the institution on Day 2, and were followed for 16–24 weeks on an outpatient basis. Standard safety assessments and blood sampling for PK and PD were performed at regular intervals. Results 51 participants were randomized and dosed with study drug, of whom 47 (92.2%) completed the study. VIS649 was well tolerated, with no serious adverse events (AEs) or AEs that led to study discontinuation. Most treatment-emergent AEs (TEAEs) were mild; the incidence and severity of TEAEs were not dose dependent. One participant in the 2.0 mg/kg group experienced a severe TEAE of syncope following phlebotomy that the investigator considered unlikely to be related to study drug. There was no clinically relevant effect of treatment on laboratory tests, vital signs, electrocardiogram parameters, or physical examinations. VIS649 had non-linear PK: half-life (t½) increased with dose, while drug exposure (AUC) increased in a greater than dose proportional manner. Serum IgA, Gd-IgA1, IgG, and IgM were reversibly suppressed in a dose-dependent manner following VIS649 administration. The maximum mean percentage reductions from baseline occurred at Week 12 for the 12.0 mg/kg dose: IgA, -57.2% (Figure); Gd-IgA1, -71.6% (Figure); IgG, -33.6%; and IgM, -67.2%. These reductions were reversible and showed a dose-response effect with respect to time-to-recovery. Mean free (non-VIS649 bound) serum APRIL levels decreased to the lower limit of quantification (50 pg/mL) for all VIS649 doses at Week 1, and also showed a dose-response effect with respect to time-to-recovery. No depletions in circulating lymphocyte populations were observed. There were no significant PK or PD differences between Japanese and non-Japanese participants. Conclusion A single dose of VIS649, up to 12.0 mg/kg, was safe and well tolerated in healthy adults and was able to suppress free serum APRIL to the lower level of quantification. Serum Gd-IgA1 decreased in parallel with total serum IgA and recovered in a dose-dependent manner following reappearance of free APRIL in serum. These data support the further clinical development of VIS649 as a potential treatment for IgAN.

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A phase 1 study of single and repeat oral doses of GSK3439171A, a highly selective H-PGDS inhibitor, in healthy adult participants

10.22541/au.162552379.93685989/v1 ◽

2021 ◽

Author(s):

Thomas Haws ◽

Nilay Thakkar ◽

Summer Goodson ◽

Caroline Sychterz ◽

Nisha George ◽

...

Keyword(s):

Therapeutic Potential ◽

Drug Hypersensitivity ◽

Phase 1 ◽

Geometric Mean ◽

Human Study ◽

Study Drug ◽

Prostaglandin D2 ◽

Dose Escalation Study ◽

Double Blind ◽

Oral Doses

Aim: Prostaglandin D2 (PGD2) is implicated in the pathophysiology of inflammatory diseases. GSK3439171A is a potent, reversible, and highly selective azetidine urea inhibitor of haematopoietic prostaglandin D synthase (H-PGDS, a key promoter of PGD2 production in several inflammatory cell types). Based on favourable preclinical data, we performed a first-time-in-human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK3439171A, and the effect of food on these parameters. Methods: This was a phase 1, randomized, double-blind, placebo-controlled, dose-escalation study. Single and repeat oral doses of GSK3439171A were administered to healthy males aged 18–65 years. Levels of inflammatory markers including tetranor-prostaglandin D metabolite (tPGDM) were measured in urine samples. Results: Sixty-six participants were enrolled, with 57 receiving GSK3439171A. Single doses (5–180 mg) and repeat once-daily doses (5 and 11 mg for 14 days; 40 mg for 7 days) were administered. Seven participants (12%) had adverse events (AEs) related to study drug, mainly drug hypersensitivity (n=4 [7%]; non-serious, transient skin rash). There were no serious AEs (SAEs) or clinically significant changes in vital signs, electrocardiogram, or laboratory parameters. Dose-proportional increases in Cmax and AUC(0–inf) were observed, and the geometric mean half-life of GSK3439171A was up to 12 hours. Results were similar when GSK3439171A was taken with or without food. No consistent suppression of tPGDM levels was observed. Conclusion: GSK3439171A was well tolerated in healthy participants and there were no SAEs. Selective inhibition of H-PGDS offers therapeutic potential for muscle-related disorders (e.g. Duchenne Muscular Dystrophy) and muscular recovery following injury.

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Fitusiran Treatment Impacts on Health-Related Quality of Life in Subjects with Hemophilia A and B with Inhibitors Assessed with the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL)

Blood ◽

10.1182/blood-2020-142266 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 23-24

Author(s):

Sylvia Von Mackensen ◽

Pratima Chowdary ◽

Sarah Mangles ◽

Qifeng Yu ◽

Baisong Mei ◽

...

Keyword(s):

Quality Of Life ◽

Hemophilia A ◽

Phase 1 ◽

Phase 2 ◽

Publicly Traded ◽

Advisory Committees ◽

Related Quality ◽

Health Related ◽

Dose Dependent

Background: Fitusiran, an investigational RNA interference treatment for people with hemophilia A or B (PwH), with or without inhibitors, has shown dose-dependent lowering of antithrombin, increase in thrombin generation, and decrease in bleeding frequency in clinical trials. The novel mechanism of action and long pharmacodynamic effect enables once-monthly subcutaneous administration. This sustained hemostatic protection and less burdensome administration may improve patient-reported outcomes (PRO). Objective: To evaluate changes in PRO in terms of patient-relevant improvements in health-related quality of life (HRQoL) in PwH with inhibitors (PwHI) on prophylactic fitusiran treatment. Methods: Fitusiran was evaluated in a phase 1 dose-escalation study (NCT02035605) followed by a phase 2 open-label extension (OLE) study (NCT02554773) with monthly subcutaneous fixed doses of 50 mg or 80 mg. HRQoL was assessed using the Haem-A-QoL and the EuroQol 5 Dimensions (EQ-5D) questionnaires at baseline and at end of study in a cohort of 17 PwHI (Hemophilia A, n=15; Hemophilia B, n=2) from the phase 1 study. Results: Subjects previously treated on-demand or prophylactically had a mean (standard deviation [SD]) age of 34.6 (10.3) years and a mean (SD) number of bleeding episodes in the 6 months before baseline of 16.6 (10.7). Mean (SD) changes from baseline to end of study (day 84 or later) in Haem-A-QoL total (-9.2 [11.2]) and physical health (−12.3 [15.1]) domain scores suggest clinically meaningful improvement (lower scores indicate better HRQoL). Numeric reduction (i.e., improvement) in all other domains appeared to be dose-dependent (greater improvement in the 80 mg group) (Table 1). Changes in EQ-5D utility and EQ-VAS scores were not clinically meaningful. Further analyses in PwH with and without inhibitors from the phase 2 OLE will be presented. Conclusions: Fitusiran prophylaxis may improve HRQoL - particularly the Haem-A-QoL 'Physical health' domain (painful swelling, joint pain, pain with movement, difficulty walking, and time to get ready) as shown in a cohort of 17 PwHI . Additional analyses from ongoing OLE and phase 3 studies are planned to quantify the patient-relevant changes with fitusiran treatment in all hemophilia patients over time. Disclosures Von Mackensen: Sanofi, Bayer, Sobi, Chugai, Kedrion, Spark: Consultancy; Biotest, Sobi, CSL Behring: Honoraria; Novo Nordisk, Sobi: Research Funding. Chowdary:BioMarin: Honoraria; Bayer, CSL Behring, Freeline, Novo Nordisk, Pfizer and Sobi: Research Funding; Chugai, CSL Behring, Novo Nordisk, Pfizer, Roche, Sobi: Speakers Bureau; Bayer, Chugai, CSL Behring, Freeline, Novo Nordisk, Pfizer, Roche, Sanofi, Shire (Baxalta), Sobi, Spark: Membership on an entity's Board of Directors or advisory committees. Mangles:Roche, Takeda, Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi, Octapharma, Novo Nordisk, Shire and Roche/Chugai: Other: travel funding. Yu:Sanofi: Other: was an employee and stockholder of Sanofi, at the time of study; Albireo Pharmaceuticals, Inc: Current Employment. Mei:Sanofi: Current Employment, Current equity holder in publicly-traded company. Andersson:Sanofi: Current Employment, Current equity holder in publicly-traded company. Dasmahapatra:Sanofi: Current Employment, Current equity holder in publicly-traded company.

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