Unmet Need For Therapies Research Articles

Phase II trial assessing safety and preliminary efficacy of high-dose intravenous ascorbic acid in patients with TET2-mutant clonal cytopenias of undetermined significance.

TPS7076 Background: Clonal cytopenias of undetermined significance (CCUS) is operationally defined as unexplained persistent cytopenias arising in the context of leukemia-associated somatic driver mutations in hematopoietic stem and progenitor cells, without morphologic evidence for an underlying hematological neoplasm. Patients with TET2 mutant ( TET2MT) CCUS have a high probability of progression to myeloid neoplasms, with approximated 10-year cumulative rates of progression being 90%. To date, no FDA-approved treatment for CCUS has been established, and we have shown that these patients can have transfusion burdens akin to patients with myelodysplastic syndrome (MDS) (Li M et al. Blood Adv 2020). Thus there is an urgent and unmet need for therapies for these patients. Intravenous (IV) ascorbic acid (AA) dosed at pharmacologic concentrations could have anti-cancer activity via two mechanisms: (1) hydrogen peroxide-induced oxidative stress and (2) DNA demethylation mediated by TET activation (cofactor for TET1/2/3). TET2, the primary enzyme for catalyzing oxidative reactions, converts 5-methylcytosine to 5-hydroxymethylcytosine, a crucial step leading to iterative DNA demethylation. Our study hypothesis is that IV AA in TET2MT CCUS will restore hematopoiesis and limit clonal progression by stimulating TET2 (the unmutated allele) and TET3 activities. Methods: LS1781 (NCT03418038) is an investigator-initiated, prospective, single-arm, single-institution, phase II trial assessing the safety and preliminary efficacy of high dose of IV AA for patients with TET2MT CCUS (harboring ≥1 TET2MT or TET2MT combined with concurrent spliceosome MTs). IV AA (1g/kg, maximum 100g) is given 3 times weekly for 12 weeks through a central line with assessments being carried out before each cycle (4 weeks), at 12 weeks, and one year. The primary endpoint is the hematologic response rates determined by MDS IWG 2018 criteria. Secondary endpoints include safety and side effects. Exploratory endpoints include the impact of AA on TET2MT variant allele fraction, plasma cytokine levels, DNA methylation, and hydroxymethylation (as measured by Infinium MethylationEPIC array), and TET activity. Patients 18 years or older with TET2MT CCUS, and with any of the following laboratory criteria: (1) hemoglobin ≤10g/dL, (2) absolute neutrophil count (ANC) ≤1000/mm3, (3) platelet count ≤100,000/mm3 are eligible. Fifteen patients will be enrolled at Mayo Clinic Rochester and the Mayo Clinic Health System. Dose modifications have been established and will be considered based on adverse events. Treatment will be discontinued for disease progression or in the event of ≥Grade 3 adverse events that don’t resolve promptly. Enrollment to the trial began in June 2021, with 7 patients enrolled at abstract submission. Clinical trial information: NCT03418038.

New Treatment Strategies for IgA Nephropathy: Targeting Plasma Cells as the Main Source of Pathogenic Antibodies.

Immunoglobulin A nephropathy (IgAN) is a rare autoimmune disorder and the leading cause of biopsy-reported glomerulonephritis (GN) worldwide. Disease progression is driven by the formation and deposition of immune complexes composed of galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1 autoantibodies (anti-Gd-IgA1 antibodies) in the glomeruli, where they trigger complement-mediated inflammation that can result in loss of kidney function and end-stage kidney disease (ESKD). With the risk of progression and limited treatment options, there is an unmet need for therapies that address the formation of pathogenic Gd-IgA1 antibody and anti-Gd-IgA1 antibody-containing immune complexes. New therapeutic approaches target immunological aspects of IgAN, including complement-mediated inflammation and pathogenic antibody production by inhibiting activation or promoting depletion of B cells and CD38-positive plasma cells. This article will review therapies, both approved and in development, that support the depletion of Gd-IgA1-producing cells in IgAN and have the potential to modify the course of this disease. Ultimately, we propose here a novel therapeutic approach by depleting CD38-positive plasma cells, as the source of the autoimmunity, to treat patients with IgAN.

Concept End Points Informing Design Considerations for Confirmatory Clinical Trials in Osteoarthritis.

There is an unmet need for therapies that target the underlying pathophysiology of osteoarthritis (OA). However, defining appropriate measures for clinical trials of such therapies is challenging. Our objective was to propose concept clinical end points that directly capture clinical benefit in this setting and evaluate the feasibility of their use. This analysis used the multicenter, longitudinal, observational Osteoarthritis Initiative (OAI) database. OAI participants primarily had knee OA, with follow-up of up to 9 years and assessments of joints, surgical interventions, performance outcomes, and patient-reported outcomes. We examined this data set to identify existing outcome measures of direct clinical benefit. We evaluated the feasibility of conducting trials using these candidate end points by estimating incidence rates and resulting required sample sizes and study durations in time-to-event analyses. We identified candidate end points based on total knee replacement (TKR) and composite end points defined by TKR and conservative thresholds of patient-reported outcomes of pain and function. Using time to TKR as an end point, a study with an average follow-up time of 3 years requires approximately 3,000 to 18,000 subjects, depending on effect size. Alternatively, for a composite end point, such as "time to TKR or severe pain or severely impaired functioning," the required sample sizes ranged from approximately 2,000 to 11,000 for a 3-year study. The proposed concept end points can reliably and feasibly evaluate the effectiveness of therapies for this unmet need. In particular, the composite end point approach can substantially reduce sample sizes (up to approximately 40%) compared to the use of TKR alone.

Growing role of SGLT2i in heart failure: evidence from clinical trials

ABSTRACT Introduction : There is an unmet need for therapies that improve overall mortality and morbidity for patients with preserved ejection fraction, who comprise roughly half of all heart failure (HF) cases. The growing role of sodium–glucose cotransporter-2 inhibitors (SGLT2is) in cardiovascular outcomes provides a paradigm shift in the treatment of HF. Areas covered : This review article provides a general overview of the growing role of SGLT2is and summarizes the mechanism of action, side effects, and contraindications for the treatment of HF. We also discuss recent clinical trials measuring the effects of different SGLT2is as possible treatment options for HF with reduced ejection fraction and HF with mid-range and preserved EF. We conducted a review of all the randomized, controlled studies with SGLT2is in patients with known heart failure with and without type-2 diabetes (T2DM). We performed a literature search in PubMed, Google Scholar, the Web of Science, and the Cochrane Library while screening results by the use of titles and abstracts. Expert opinion : The promising pathophysiological profile of SGLT2i and their role in cardioprotective effects demonstrate an invaluable discovery in the management of patients with HF irrespective of their diabetes status.

Treatment of cutaneous neurofibromas with carbon dioxide laser: Technique and patient experience

Cutaneous neurofibromas (cNF) are one of the hallmarks of neurofibromatosis 1 (NF1). The number of cNFs varies between individuals from a few to hundreds or even thousands and increases throughout adult life. cNFs cause a significant disease burden to adult patients and constitute an unmet need for therapy, since they may cause itch and pain and, being conspicuous and unsightly, stigmatize the patient. There is a lack of reports on how the outcome of various treatment options are perceived by the patients. Here we describe a technique for cNF removal using CO2 laser, and report how patients experience the procedure. Questionnaires were sent to patients who had had CO2 laser surgery in the French Referral Center for Neurofibromatoses, and in the Turku University Hospital, Finland, to retrospectively evaluate the patients’ global satisfaction of the procedure, treatment indications, and reasons for withdrawal from treatment, if this was the case. The number of returned questionnaires was 233/473 in France and 23/27 in Finland. The results showed that the most important indications for cNF removal were esthetic, and pain and itch caused by the tumors. In general, the procedure was well tolerated, and the degree of satisfaction was 8–10 on a scale from 0 to 10. For those 30% who discontinued the tumor removal program, the main reasons were organizational constraints, a non-satisfactory esthetic result, too many cNFs to treat, or problems with healing. Thus, the CO2 laser method is well tolerated but does not fully answer to the needs of the patients. Since medical treatment is not yet available, we encourage the use of laser removal of cNFs as a feasible method to decrease the tumor burden of the patients.

Addressing a New Challenge in Chronic Lymphocytic Leukemia: Outcomes of Therapies after Exposure to Both a Covalent Bruton's Tyrosine Kinase Inhibitor and Venetoclax

Addressing a New Challenge in Chronic Lymphocytic Leukemia: Outcomes of Therapies after Exposure to Both a Covalent Bruton's Tyrosine Kinase Inhibitor and Venetoclax

Human induced pluripotent stem cell-derived macrophages ameliorate liver fibrosis.

With an increasing number of patients with degenerative hepatic diseases, such as liver fibrosis, and a limited supply of donor organs, there is an unmet need for therapies that can repair or regenerate damaged liver tissue. Treatment with macrophages that are capable of phagocytosis and anti-inflammatory activities such as secretion of matrix metalloproteinases (MMPs) provide an attractive cellular therapy approach. Human induced pluripotent stem cells (iPSCs) are capable of efficiently generating a large-scale, homogenous population of human macrophages using fully defined feeder- and serum-free differentiation protocol. Human iPSC-macrophages exhibit classical surface cell markers and phagocytic activity similar to peripheral blood-derived macrophages. Moreover, gene and cytokine expression analysis reveal that these macrophages can be efficiently polarized to pro-inflammatory M1 or anti-inflammatory M2 phenotypes in presence of LPS + IFN-γ and IL-4 + IL-13, respectively. M1 macrophages express high level of CD80, TNF-α, and IL-6 while M2 macrophages show elevated expression of CD206, CCL17, and CCL22. Here, we demonstrate that treatment of liver fibrosis with both human iPSC-derived macrophage populations and especially M2 subtype significantly reduces fibrogenic gene expression and disease associated histological markers including Sirius Red, αSMA and desmin in immunodeficient Rag2-/- γc-/- mice model, making this approach a promising cell-based avenue to ameliorate fibrosis.

Subretinal Transplantation of Human Embryonic Stem Cell-Derived Retinal Tissue in a Feline Large Animal Model.

Retinal degenerative (RD) conditions associated with photoreceptor loss such as age-related macular degeneration (AMD), retinitis pigmentosa (RP) and Leber Congenital Amaurosis (LCA) cause progressive and debilitating vision loss. There is an unmet need for therapies that can restore vision once photoreceptors have been lost. Transplantation of human pluripotent stem cell (hPSC)-derived retinal tissue (organoids) into the subretinal space of an eye with advanced RD brings retinal tissue sheets with thousands of healthy mutation-free photoreceptors and has a potential to treat most/all blinding diseases associated with photoreceptor degeneration with one approved protocol. Transplantation of fetal retinal tissue into the subretinal space of animal models and people with advanced RD has been developed successfully but cannot be used as a routine therapy due to ethical concerns and limited tissue supply. Large eye inherited retinal degeneration (IRD) animal models are valuable for developing vision restoration therapies utilizing advanced surgical approaches to transplant retinal cells/tissue into the subretinal space. The similarities in globe size, and photoreceptor distribution (e.g., presence of macula-like region area centralis) and availability of IRD models closely recapitulating human IRD would facilitate rapid translation of a promising therapy to the clinic. Presented here is a surgical technique of transplanting hPSC-derived retinal tissue into the subretinal space of a large animal model allowing assessment of this promising approach in animal models.

Real-world treatment patterns and effectiveness outcomes in patients with early-stage triple-negative breast cancer.

Background: This retrospective, observational study examined real-world treatment patterns and effectiveness outcomes in 450 patients with stage II-IIIB early-stage triple-negative breast cancertreated in the community oncology setting. Methods: Kaplan-Meier methods were used to evaluate event-free survival (EFS), time to recurrenceand overall survival (OS). Cox regression models were used to evaluate predictors of EFS and OS by pathological complete response (pCR) status. Results: Among patients receiving neoadjuvant systemic therapy only, pCR was a predictor of EFS and OS. Conclusion: These results highlight the unmet need for therapies that improve outcomes for patients with early-stage triple-negative breast cancer including increasing rates of pCR among patients receiving neoadjuvant therapy.

Confirmed tumor response by molecular subtype in patients with metastatic breast cancer: Sub-analysis from a phase 3 clinical study comparing oral paclitaxel and encequidar to IV paclitaxel.

1073 Background: Paclitaxel, a foundation treatment in MBC, is hydrophobic and must be formulated for IV administration with Cremophor EL, increasing the risk of infusion reactions and necessitating pre-treatment with corticosteroids and antihistamines. Paclitaxel cannot be administered orally because it is a substrate for P-gp. The oral bioavailability of paclitaxel is improved when administered 1 hour after the highly selective, potent, and minimally absorbed P-gp inhibitor encequidar. As oral paclitaxel is Cremophor-free there is no need for pretreatment for infusion reactions. While targeted therapies have improved outcomes in patients with HER2+ tumors there is still an unmet need for therapies that prolong survival with reduced toxicity across all tumor subtypes. Methods: A phase 3, open-label, randomized, multicenter study in women with histologically- or cytologically-confirmed MBC for whom treatment with IV paclitaxel monotherapy had been recommended by their oncologist randomized 402 patients 2:1 to either oral paclitaxel and encequidar (oPac+E) or IV paclitaxel (IVPac). Oral paclitaxel 205 mg/m2 was administered once daily for 3 consecutive days, weekly. Encequidar 12.9 mg was administered 1 hour before each dose of oral paclitaxel. IV paclitaxel 175 mg/m2 was infused over 3 hours on day 1 of every 3 weeks. Results: In the ITT population oPac+E was superior to IV paclitaxel with a confirmed tumor response rate of 35.8% vs 23.4% for IVPac: a difference of 12.4% (p = 0.0107). A post-hoc subgroup efficacy analysis was conducted based on tumor subtypes, however, the study was not powered to detect statistical differences within these subgroups. Patients in the HR+/HER2- subgroup had a better tumor response to oPac+E (44.8% vs 21.4% IVPac-response rate difference of 23.4%) as did patients in the TNBC (30.5% vs 20.2%-response rate difference of 10.3%) subgroup. Responses were similar (49% vs 47.4% IVPac) in the HER2+ subgroup. Patients with unknown HER2 status receiving oPac+E had a 58.8% response rate vs 14.3% with IVPac (response rate difference of 44.5%). Conclusions: oPac+E is the first oral taxane to demonstrate superiority in radiologically confirmed tumor response rate compared to IVPac in a group of 402 women with metastatic breast cancer. Patients with HR+/HER2-, TNBC, and Unknown subtypes responded considerably better to oPac+E vs IVPac—especially the HR+/HER2- subtype which represented 63% of the patients treated with oPac+E and 55% of the patients treated with IVPac. Clinical trial information: NCT 02594371 .

The mitochondria-targeted hydrogen sulfide donor AP39 improves health and mitochondrial function in a C. elegans primary mitochondrial disease model.

Primary mitochondrial diseases (PMD) are inherited diseases that cause dysfunctional mitochondrial oxidative phosphorylation, leading to diverse multisystem diseases and substantially impaired quality of life. PMD treatment currently comprises symptom management, with an unmet need for therapies targeting the causative mitochondrial defects. Molecules which selective target mitochondria have been proposed as potential treatment options in PMD but have met with limited success. We have previously shown in animal models that mitochondrial dysfunction caused by the disease process could be prevented and/or reversed by selective targeting of the "gasotransmitter" hydrogen sulfide (H2 S) to mitochondria using a novel compound, AP39. Therefore, in this study we investigated whether AP39 could also restore mitochondrial function in PMD models where mitochondrial dysfunction was the cause of the disease pathology using C. elegans. We characterised several PMD mutant C. elegans strains for reduced survival, movement and impaired cellular bioenergetics and treated each with AP39. In animals with widespread electron transport chain deficiency (gfm-1[ok3372]), AP39 (100 nM) restored ATP levels, but had no effect on survival or movement. However, in a complex I mutant (nuo-4[ok2533]), a Leigh syndrome orthologue, AP39 significantly reversed the decline in ATP levels, preserved mitochondrial membrane potential and increased movement and survival. For the first time, this study provides proof-of-principle evidence suggesting that selective targeting of mitochondria with H2 S could represent a novel drug discovery approach to delay, prevent and possibly reverse mitochondrial decline in PMD and related disorders.

Apolipoprotein A-I mimetics attenuate macrophage activation in chronic treated HIV.

Despite antiretroviral therapy (ART), there is an unmet need for therapies to mitigate immune activation in HIV infection. The goal of this study is to determine whether the apoA-I mimetics 6F and 4F attenuate macrophage activation in chronic HIV. Preclinical assessment of the in-vivo impact of Tg6F and the ex-vivo impact of apoA-I mimetics on biomarkers of immune activation and gut barrier dysfunction in treated HIV. We used two humanized murine models of HIV infection to determine the impact of oral Tg6F with ART (HIV+ART+Tg6F+) on innate immune activation (plasma human sCD14, sCD163) and gut barrier dysfunction [murine I-FABP, endotoxin (LPS), LPS-binding protein (LBP), murine sCD14]. We also used gut explants from 10 uninfected and 10 HIV-infected men on potent ART and no morbidity, to determine the impact of ex-vivo treatment with 4F for 72 h on secretion of sCD14, sCD163, and I-FABP from gut explants. When compared with mice treated with ART alone (HIV+ART+), HIV+ART+Tg6F+ mice attenuated macrophage activation (h-sCD14, h-sCD163), gut barrier dysfunction (m-IFABP, LPS, LBP, and m-sCD14), plasma and gut tissue oxidized lipoproteins. The results were consistent with independent mouse models and ART regimens. Both 4F and 6F attenuated shedding of I-FABP and sCD14 from gut explants from HIV-infected and uninfected participants. Given that gut barrier dysfunction and macrophage activation are contributors to comorbidities like cardiovascular disease in HIV, apoA-I mimetics should be tested as therapy for morbidity in chronic treated HIV.

Economic Burden of Newly Diagnosed Acute Myeloid Leukemia: A Retrospective Study Using the SEER-Medicare Database

Economic Burden of Newly Diagnosed Acute Myeloid Leukemia: A Retrospective Study Using the SEER-Medicare Database

Evans' Syndrome in Adults: An Observational Multicentre Study

Evans' syndrome is a rare condition (estimated prevalence of 1-9 per million), characterized by the association (concomitant or not) of immune thrombocytopenia (ITP), with autoimmune hemolytic anemia (AIHA), and/or autoimmune neutropenia (AIN). Here we investigated 106 adult patients (male to female ratio 0.89, median age 50 years) followed for a median of 7.5 years in 12 European tertiary centers. Hematological data and associated conditions at diagnosis, treatments, complications, and outcome were retrospectively collected. The vast majority of patients had the combination of ITP plus AIHA, whereas 6.6% had ITP plus AIN, 2.8% AIHA plus AIN, and 8.5% had triple lineage cytopenia. At presentation, thrombocytopenia, anemia, and concomitant cytopenias were equally frequent (about 1/3 each), whilst AIN was rarer. An associated condition was present in 29% of cases, and included: a) other autoimmune diseases (11.3%), namely Hashimoto thyroiditis (N=7), anti-phospholipid syndrome (N=3), systemic lupus erythematosus (N=1), rheumatoid arthritis (N=1); b) tumors/clonal disorders (12.2%), consisting of colorectal cancers (N=3), thymoma (N=1), Ewing sarcoma (N=1), lymphoproliferative disorders (N=3), multiple myeloma (N=1), MGUS (N=3), and paroxysmal nocturnal hemoglobinuria (N=1); and c) immunodeficiencies (5.6%), including common variable immunodeficiency (N=5), and Kabuki syndrome (N=1). Laboratory values are detailed in table 1, and show a great heterogeneity depending on the predominant cytopenia. Direct antiglobulin test was positive in 93/106 cases, diagnosing 82 warm AIHA (57 IgG, 23 IgG+complement, and 2 IgA), 4 cold and 7 mixed AIHA. Anti-platelets antibodies were positive in 41/48 patients (85%), and anti-neutrophil antibodies in 10/22 (45%). Immunoglobulin levels showed high variability consistently with the underlying conditions, with hypo-IgA present in 5/49 (10%), and hypo-IgG or IgM in 9 (18%) and 8 (16%), respectively. Additionally, anti-nuclear antibodies were positive in 33/88 (37.5%), ENA in 5/63 (8%), anti-DNA in 4/66 (6%), anti-cardiolipin antibodies in 12/64 (18.7%), anti-beta2 glycoprotein antibodies in 8/50 (16%), and lupus anticoagulant in 9/60 (15%). Regarding therapies, all patients received steroids as first-line and 84% intravenous immunoglobulins (mainly for ITP). Rituximab was administered in 51.8% (7 in first, 22 in second, and 26 in subsequent lines), immunosuppressors in 49% (mycophenolate mofetil N=15, azathioprine N=14, cyclophosphamide N=12, and cyclosporine N=11), and splenectomy was performed in 20% of patients. Notably, thrombopoietin receptor analogues (TPO-RA) were given in 38% of cases, namely eltrombopag (N=24), romiplostim (N=16) or both (N=4). Additional therapies included plasma exchange (N=4), recombinant erythropoietin (EPO, N=3), GCSF (N=2), bortezomib (N=2), fostamatinib (N=1), and parsaclisib (N=1). Response rate to first line steroids+/-IVIG was 85%, however, 21 patients required further concomitant treatment (including 2 splenectomies). Response rates beyond first line therapy are difficult to evaluate given that AIHA or ITP relapses required different treatments (i.e. EPO versus TPO-RA), and that many relapses were treated with multiple concomitant treatments. On the whole, relapses were very frequent with 81/106 (76.4%) experiencing at least one, 53.7% two, and 27.3% three or more relapses. Regarding complications, bleeding was observed in 45/106 (42.4%), thrombosis in 27 (25.4%), and CTCAE >3 infections in 46 (43.3%). Death occurred in 26% of cases. In conclusion, these data highlight the clinical severity and the unmet need for therapy in adult Evans' syndrome. Moreover, the great frequency of relapses and burden of complications underline the poor clinical outcome of this condition. Disclosures Michel: Bioverativ: Consultancy; Rigel: Consultancy; Alexion Pharmaceuticals: Consultancy. McDonald:Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bianchi:Agios Pharmaceuticals: Other: Scientific Advisor. Barcellini:Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Other: invited speaker , Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: invited speaker , Research Funding.

Clinical characteristics and health-related quality of life of patients with recurrent pericarditis in the United States: findings from a patient survey

Abstract Background Recurrent pericarditis (RP) is characterized by recurrence of symptoms of pericarditis after the original episode has ceased for 4–6 weeks. Though RP is associated with significant morbidity, there is little information regarding the impact of RP on patients' health-related quality of life (HRQOL). Purpose To describe clinical characteristics of and HRQOL burden in patients with RP in the United States. Methods An IRB-approved web-based survey was conducted among patients ≥18 years old with RP who experienced ≥1 recurrence during the prior 12 months. Respondents were recruited from the RHAPSODY clinical trial recruitment database. Patients who met the survey inclusion criteria were asked to provide information on their demographic/clinical characteristics, treatments for RP, and to complete an 11-point pericarditis pain numerical rating scale, the Patient Global Impression of Pericarditis Severity scale, the Patient-Reported Outcomes Measurement Information System® (PROMIS®) Global Health and Sleep Disturbance scales, and questions about the impact of RP on daily life. Results Of the 83 respondents with RP included in the study, 25% responded while experiencing a recurrence. Most respondents were Caucasian (76%) and 55% were female, with mean (standard deviation [SD]) age of 49.3 (13.7) years. Patients frequently reported history of hypertension (39%), anxiety (37%), and depression (34%); 16% and 15% of patients reported having pre-existing autoimmune disease and diabetes, respectively. About half (49%) of patients reported ≥3 recurrences in the prior year, and 40% visited the ER and 25% were hospitalized for their most recent recurrence. Among patients not actively experiencing a recurrence, 37% reported that the duration of their prior episode lasted ≥8 days. Medications most frequently used for RP and pain in the prior year included non-steroidal anti-inflammatory drugs (82%), colchicine (63%), and corticosteroids (29%). Commonly reported symptoms included chest pain (93%), shortness of breath (66%), weakness/fatigue (64%), and heart palpitations (52%). Two-thirds of patients rated the severity of symptoms during the most recent RP episode as moderately severe to very severe, and 48% reported “quite a bit” or “very much” fear of pericarditis recurrence. The mean (SD) value for worst pericarditis pain (0–10 scale) during the recent recurrence was 6.1 (2.3), with 48% reporting severe pain (≥7 on the scale). Patients had substantially worse mean [SD] T scores for PROMIS physical health (37.6 [8.6]), mental health (42.8 [9.9]), and sleep disturbance (60.6 [8.3]) than the general population (50 [10]). Conclusions RP is a burden on the daily lives of patients, resulting in severe pain and impaired quality-of-life including poor physical and mental health, sleep disturbance, and fear of recurrence. This study demonstrates the unmet need for therapies that can rapidly resolve symptoms and prevent recurrences. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Kiniksa Pharmaceuticals Corp.

Plasma adiponectin is a potential biomarker for organ involvement in male Fabry disease patients

Phenylketonuria (PKU) is an autosomal recessive disease caused by mutations in the PAH gene, resulting in deficiency of phenylalanine hydroxylase (PAH), an enzyme that converts phenylalanine (Phe) to tyrosine (Tyr). The purpose of this study was to capture real-world data associated with managing PKU under current standard of care and to characterize a representative population for a planned gene therapy trial.A retrospective chart review was conducted at two U.S. clinics for individuals 10–40 years old diagnosed with PKU-related hyperphenylalaninemia (HPA). Demographics, medical history, treatments and blood Phe data were collected from electronic medical records spanning a five-year period ending in November 2017.152 patients were enrolled (65.8% had classical PKU). Although >95% of patients were prescribed a Phe-restricted diet, blood Phe concentrations remained substantially elevated, particularly in patients diagnosed with classical PKU. As the Phe threshold was lowered (Phe < 600, 360, 120 or 30 μmol/L), the number of patients with consecutive lab values below the threshold decreased, suggesting that many patients' Phe levels are inadequately controlled. 62.5% of patients were reported as having a history of at least one neuropsychiatric comorbidity, and adults were more likely than adolescents (69.5% vs. 54.3%). 92 of 98 PAH genotypes collected were distinct mutations; the 6 null-null genotypes were associated with classical PKU. Overall the demographics and clinical data were consistent across both sites.Despite dietary restrictions, mean Phe concentrations were > 360 μmol/L (a level considered well-controlled based on current U.S. treatment guidelines) for mild, moderate, and classical PKU patients. There remains an unmet need for therapies to control Phe concentrations.

A global disease patient registry for neuronopathic Gaucher

Phenylketonuria (PKU) is an autosomal recessive disease caused by mutations in the PAH gene, resulting in deficiency of phenylalanine hydroxylase (PAH), an enzyme that converts phenylalanine (Phe) to tyrosine (Tyr). The purpose of this study was to capture real-world data associated with managing PKU under current standard of care and to characterize a representative population for a planned gene therapy trial.A retrospective chart review was conducted at two U.S. clinics for individuals 10–40 years old diagnosed with PKU-related hyperphenylalaninemia (HPA). Demographics, medical history, treatments and blood Phe data were collected from electronic medical records spanning a five-year period ending in November 2017.152 patients were enrolled (65.8% had classical PKU). Although >95% of patients were prescribed a Phe-restricted diet, blood Phe concentrations remained substantially elevated, particularly in patients diagnosed with classical PKU. As the Phe threshold was lowered (Phe < 600, 360, 120 or 30 μmol/L), the number of patients with consecutive lab values below the threshold decreased, suggesting that many patients' Phe levels are inadequately controlled. 62.5% of patients were reported as having a history of at least one neuropsychiatric comorbidity, and adults were more likely than adolescents (69.5% vs. 54.3%). 92 of 98 PAH genotypes collected were distinct mutations; the 6 null-null genotypes were associated with classical PKU. Overall the demographics and clinical data were consistent across both sites.Despite dietary restrictions, mean Phe concentrations were > 360 μmol/L (a level considered well-controlled based on current U.S. treatment guidelines) for mild, moderate, and classical PKU patients. There remains an unmet need for therapies to control Phe concentrations.

5-year retrospective analysis of patients with phenylketonuria (PKU) and hyperphenylalaninemia treated at two specialized clinics

BackgroundPhenylketonuria (PKU) is an autosomal recessive disease caused by mutations in the PAH gene, resulting in deficiency of phenylalanine hydroxylase (PAH), an enzyme that converts phenylalanine (Phe) to tyrosine (Tyr). The purpose of this study was to capture real-world data associated with managing PKU under current standard of care and to characterize a representative population for a planned gene therapy trial. MethodsA retrospective chart review was conducted at two U.S. clinics for individuals 10–40 years old diagnosed with PKU-related hyperphenylalaninemia (HPA). Demographics, medical history, treatments and blood Phe data were collected from electronic medical records spanning a five-year period ending in November 2017. Results152 patients were enrolled (65.8% had classical PKU). Although >95% of patients were prescribed a Phe-restricted diet, blood Phe concentrations remained substantially elevated, particularly in patients diagnosed with classical PKU. As the Phe threshold was lowered (Phe < 600, 360, 120 or 30 μmol/L), the number of patients with consecutive lab values below the threshold decreased, suggesting that many patients' Phe levels are inadequately controlled. 62.5% of patients were reported as having a history of at least one neuropsychiatric comorbidity, and adults were more likely than adolescents (69.5% vs. 54.3%). 92 of 98 PAH genotypes collected were distinct mutations; the 6 null-null genotypes were associated with classical PKU. Overall the demographics and clinical data were consistent across both sites. ConclusionDespite dietary restrictions, mean Phe concentrations were > 360 μmol/L (a level considered well-controlled based on current U.S. treatment guidelines) for mild, moderate, and classical PKU patients. There remains an unmet need for therapies to control Phe concentrations.

Ticagrelor versus placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: Rationale and design of a randomized, double-blind, parallel-group, multicenter phase 3 study (HESTIA3)

BackgroundAn unmet need for therapies exists to reduce sickle cell disease (SCD) complications in pediatric patients. Activated platelets contribute to the formation of cellular aggregates during sickling and vaso-occlusive crises (VOCs). Ticagrelor is an oral, direct-acting, and reversible adenosine diphosphate P2Y12 receptor antagonist that inhibits platelet activation and aggregation. Although ticagrelor was well tolerated in two phase 2 studies in children and young adults with SCD, larger and longer-term treatment studies are needed to assess ticagrelor's efficacy to reduce VOCs. HESTIA3 will evaluate the efficacy, safety, and tolerability of ticagrelor versus placebo over a minimum of 1 year (maximum 2 years) in pediatric patients with SCD. MethodsApproximately 180 patients (aged ≥ 2 to <18 years) with SCD (≥ 2 VOCs in the prior year) from 18 countries will be randomized 1:1 to ticagrelor or placebo. Primary endpoint: number of VOCs (a composite endpoint of painful crises and/or acute chest syndrome); key secondary endpoints: hospitalizations, pain intensity and analgesic use during VOCs, acceptability of formulation, and health-related quality of life. The weight-based doses of ticagrelor are set by modeling and simulation. Platelet inhibition data, measured by the vasodilator-stimulated phosphoprotein assay, will be collected for exploratory purposes. ConclusionsHESTIA3 aims to demonstrate that using greater target platelet inhibition than previous studies on SCD, ticagrelor will decrease the frequency of VOC in pediatric patients.Trial Identifier: NCT03615924; EudraCT2017-002421-38.

1876-P: Impact of Diabetes on Liver Disease Progression in Patients with Advanced Fibrosis Due to Nonalcoholic Steatohepatitis (NASH)

Background: Diabetes is a risk factor for advanced fibrosis due to NASH, but the effect of diabetes on disease progression is not well-characterized. Here, we describe clinical outcomes for patients with and without diabetes in two negative, randomized, placebo-controlled trials of simtuzumab. Methods: 217 patients with bridging fibrosis (F3) and 258 subjects with compensated cirrhosis (F4) were enrolled. Liver biopsies were reviewed by a central pathologist at screening and weeks 48 and 96. Patients were stratified based on the presence or absence of diabetes. Adjudicated clinical outcomes included: esophageal varices, variceal bleeding, ascites, hepatic encephalopathy, ≥2 point increase in Child-Pugh-Turcotte score, MELD &amp;gt;15, or death. Results: 145 (67%) of patients with F3 and 179 (69%) of patients with F4 had diabetes at baseline. Median age was 56 years. By week 96, 25% (31/129) of F3 patients with diabetes had progressed to cirrhosis, compared to 18% (11/67) of patients without diabetes [p=0.27]. Cirrhotic (F4) patients with diabetes had a higher rate of clinical events (Figure). Conclusion: Diabetes is common in patients with advanced fibrosis due to NASH and associated with numerically higher rates of progression. Larger studies are needed to confirm these findings. Patients with diabetes have a high unmet need for therapies that target advanced fibrosis due to NASH. Disclosure A.J. Sanyal: Consultant; Self; Ardelyx, Boehringer Ingelheim Pharmaceuticals, Inc., Exhalenz, Gilead Sciences, Inc., Hemoshear, Intercept Pharmaceuticals, Inc., Lilly, Mallinckrodt Pharmaceuticals, Nimbus Therapeutics, Nitto Denko, Novartis Pharmaceuticals Corporation, Pfizer Inc. Employee; Self; Sanyal Bio. Research Support; Self; Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Echosens, Galectin Therapeutics Inc., Immuron Ltd, Merck &amp; Co., Inc., Salix Pharmaceuticals, Sequanna. Stock/Shareholder; Self; Akarna Therapeutics, GENFIT, Natural Shield, NewCo LLC, Tiziana. Other Relationship; Self; Elsevier, UpToDate. M.F. Abdelmalek: Advisory Panel; Self; Allergan, Bristol-Myers Squibb Company, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Prometic Life Sciences Inc. Consultant; Self; TaiwanJ Pharmaceuticals Co., Ltd. Research Support; Self; Akcea Therapeutics, Allergan, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Galectin Therapeutics Inc., GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Novartis Pharmaceuticals Corporation, Prometheus, Shire, TaiwanJ Pharmaceuticals Co., Ltd. Speaker's Bureau; Self; Alexion Pharmaceuticals, Inc. S. Caldwell: Research Support; Self; Conatus Pharmaceuticals Inc., Galmed Pharmaceuticals Ltd., GENFIT, Gilead Sciences, Inc., Halyard, Mallinckrodt Pharmaceuticals, TARGET PharmaSolutions, Vital Therapy, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Dova. M.L. Shiffman: Advisory Panel; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc. Research Support; Self; Allergan, Conatus, Enanta Pharmaceuticals, Inc., Exhalenz, GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Novartis AG, Shire. Speaker's Bureau; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc. R. Ghalib: None. E. Lawitz: Research Support; Self; birdrock bio, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Durect Corporation, Enanta Pharmaceuticals, Inc., Galmed Pharmaceuticals Ltd., GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., madrigal, Novartis AG, octeta, Zydus Cadila. D. Jiang: Employee; Self; Gilead Sciences, Inc. R.E. Aguilar Schall: Employee; Self; Gilead Sciences, Inc. Stock/Shareholder; Self; Gilead Sciences, Inc. B.J. McColgan: Employee; Self; Gilead Sciences, Inc. Stock/Shareholder; Self; Gilead Sciences, Inc. R. Myers: Employee; Self; Gilead Sciences, Inc. Stock/Shareholder; Self; Gilead Sciences, Inc. S. Djedjos: Employee; Self; Gilead Sciences, Inc. A. Muir: Advisory Panel; Self; AbbVie Inc., Gilead Sciences, Inc. Research Support; Self; AbbVie Inc., Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., NGM Biopharmaceuticals. V. Ratziu: Other Relationship; Self; Gilead Sciences, Inc. N. Afdhal: Advisory Panel; Self; Gilead Sciences, Inc., Ligand Pharmaceuticals, Inc. Consultant; Self; Echosens. Employee; Self; Spring bank Pharmaceuticals. Z. Goodman: None. J. Bosch: Advisory Panel; Self; Actelion Pharmaceuticals US, Inc., Conatus Pharmaceuticals Inc., Exhalenz. S.A. Harrison: Advisory Panel; Self; Gilead Sciences, Inc. Funding Gilead Sciences, Inc.