Study to assess the changing pattern of clinical profile and determine the prognosis in hepatic encephalopathy

Background: Hepatic encephalopathy (HE) is a common complication of liver disease that requires intensive care management. The prevalence of HE is increasing during recent period. The most important factors of HE are alcohol consumption, chronic hepatitis, hepatotoxic drugs and unhealthy changes in life style. There were only relatively few studies from our region on the changing profile of hepatic encephalopathy under the background of life style changes. This study was conducted with the aim to detect the changing pattern of clinical profile, precipitants and to assess the prognosis of patients with hepatic encephalopathy.Methods: This was a prospective study for a period of 18 months since January 2012 at Academy of Medical Sciences, Pariyaram, Kannur, a tertiary care centre situated in the northern part of Kerala. Patients admitted in the medical and gastroenterology wards and intensive care units that fulfilled the inclusion criteria were enrolled in this study.Results: Among the 76 patients with HE, 60 were suffering from CLD and 16 due to acute liver failure. The common etiologies for HE in CLD patients were Alcoholic cirrhosis (63%), Cryptogenic cirrhosis (17%) and cirrhosis due to chronic HBV (10%) and HCV hepatitis (7%) respectively. Among the CLD patients at the start of observation majority were in Child Pugh class B and C. Based on West Haven grading most of them had Grade 2 and 3 HE. Majority with Grade 1, 2 and 3 improved where as those with Grade 4 and Grade 3 in Child Pugh class C worsened. The common precipitants of HE were GI bleed, dyselectrolemia, constipation and infections. Among these precipitants a statistically significant association for a worse outcome was present only with infection. Leptospirosis and deliberate self-harm due to ingestion of hepatotoxic rodenticide and paracetamol were the leading cause of hepatic encephalopathy in acute liver failureConclusions: In present study HE was most commonly seen in patients with alcoholic liver disease. Cryptogenic cirrhosis associated with other life style diseases was the second common condition. Among all precipitating factors infection appeared as a statistically significant factor predicting a worse outcome. Health education among alcoholic patients and life style modifications to prevent cryptogenic cirrhosis are of paramount importance in curtailing the increase in incidence of HE in this region

Initial Dose Escalation of ISB 1442, a Novel CD38 Biparatopic x CD47 Bispecific Antibody, in Patients with Relapsed / Refractory Multiple Myeloma (RRMM)

Introduction: ISB 1442 is a fully human bispecific, biparatopic antibody that targets CD38 and CD47, generated using Ichnos' Bispecific Engagement by Antibodies based on the T cell receptor (BEAT ®) platform. ISB 1442 is designed to kill CD38-expressing tumor cells through multiple mechanisms of action including blocking CD47-signal regulatory protein alpha (SIRPα) axis to increase several antibody effector functions: antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) through optimized architecture, affinity to targets, and Fc engineering. ISB 1442 has 2 Fab domains binding to distinct CD38 epitopes that do not compete functionally with daratumumab. ISB 1442 is expected to have optimized tolerability with low potential for adverse effects on red blood cells (RBC) such as hemagglutination, platelet aggregation and RBC depletion (Sammicheli at al., ASH 2021, Blood (2021) 138 (Supplement 1): 73). We report here initial findings from the early dose-escalation portion of an ongoing, multi-center, open-label, single-agent phase 1/2 study (NCT05427812) of ISB 1442 in patients with RRMM. Methods: Adult patients with relapsed refractory multiple myeloma (RRMM) to prior therapies, including a proteasome inhibitors (PIs), an immunomodulatory drugs (IMiDs), and an anti-CD38 antibodies received subcutaneous (SC) doses of ISB 1442 weekly (QW) in 28-day cycles. Patients had measurable disease per the International Myeloma Working Group (IMWG) criteria (2016). Dose escalation began at 6 mg dose with single patient accelerated titration phase for the first 3 cohorts, followed by a standard titration phase with a “3 + 3” design. The primary study objective for phase 1 is to assess the safety and tolerability to determine the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D) of ISB 1442. For phase 2 the primary study objective is to evaluate efficacy of ISB 1442. Secondary objectives include evaluation of pharmacokinetics (PK) and immunogenicity of ISB 1442. Exploratory objectives include assessment of minimal residual disease (MRD), assessment of cellular biomarkers in blood and bone marrow, and soluble factors in blood, and their correlation with efficacy, safety and other clinical endpoints of interest. Results: As of July 18, 2023, based on preliminary data from ongoing clinical database, 10 subjects had received once weekly SC injections of ISB 1442 in 4 dose-escalation groups from 6 mg to 150 mg. The majority were male (60%) and white (90%). The median age was 67 years (range 57-79). The median number of prior anti-myeloma lines of therapy was 6 (range 3-7); 70% were exposed to 5 drugs (2PIs, 2IMiDs, and CD38). The median number of ISB 1442 cycles was 1(range 1-2). Eight subjects (80%) experienced treatment-related adverse events (TRAEs), all were grade 1 or 2: cytokine release syndrome (CRS) (50%), injection site reactions (injection site erythema 20%, injection site bruising 10%), anemia (10%, 1 subject, grade 2) (Table 1). No grade 5 TRAE was observed. Following QW SC injection, ISB 1442 was slowly absorbed into the systemic circulation with T max generally occurring on day 2 of dosing. The ISB 1442 serum concentrations generally remained quantifiable over the entire dosing duration from 20 mg and above. The available PK data suggest an approximately dose-linear increase in serum concentration up to DL 3 (60 mg), followed by a supra-proportional increase in serum levels in subjects treated at DL 4 (150 mg). To date, 5 subjects treated at DL4 (150 mg) have experienced clinical symptoms of CRS (Grade 1-2) following the first dose of ISB 1442. Assessment of a panel of 63 soluble factors (including multiple cytokines, chemokines and growth factors) in the peripheral blood revealed that several subjects at DL3-4 exhibited transient increases (>10-fold) in macrophage inflammatory protein-1b (MIP-1b/CCL4) within 24h after treatment with ISB 1442, consistent with a macrophage-associated mechanism of action. Conclusions: Treatment with ISB 1442 was well tolerated at the dose levels evaluated. The observed clinical CRS events were moderate and potentially related to macrophage activation following ISB 1442 administration. Updated clinical, biomarker and PK data will be presented for this ongoing study