A phase i, single ascending dose study of cimaglermin alfa (neuregulin 1β3) in patients with systolic dysfunction and heart failure _ jacc_ basic to translational science

• Forty patients with significant left ventricular dysfunction and heart failure were randomized in a phase 1 double blind, placebo controlled, single ascending dose study to examine safety and tolerability.

A first-in-human, phase 1, double blind, placebo-controlled, single ascending dose study examined the safety, tolerability, and exploratory efficacy of intravenous infusion of a recombinant growth factor, cimaglermin alfa, in patients with heart failure and left ventricular systolic dysfunction (LVSD). Antiemetic drugs list In these patients on optimal guideline-directed medical therapy, cimaglermin treatment was generally tolerated except for transient nausea and headache and a dose-limiting toxicity was noted at the highest planned dose.

Antiemetic medications There was a dose-dependent improvement in left ventricular ejection fraction lasting 90 days following infusion. Antiemetic in pregnancy Thus, cimaglermin is a potential therapy to enhance cardiac function in LVSD and warrants further investigation. Antiemetic definition Key Words

Heart failure (HF) is a complex clinical syndrome characterized by inadequate cardiac function and a characteristic pattern of hemodynamic, renal, and neurohormonal responses leading to poor peripheral perfusion and impaired exercise tolerance. Antiemetic drug names HF is among the leading causes of mortality and morbidity worldwide (1). Antiemetic medicine Despite advances in medical therapy, the mortality for HF remains elevated, with overall rates of 35% to 40% at 1 year and 50% at 5 years (2). Antiemetic for child A significant proportion of HF patients, particularly those with severe left ventricular systolic dysfunction (LVSD), do not adequately respond to current medical therapy that may include beta blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, diuretics, and vasodilators (3). Antiemetic for pregnancy Despite many medication- and device-based improvements that have become guideline-based therapy, there is still a compelling clinical need to enhance cardiac function and outcomes in HF patients (4,5).

Recombinant neuregulin (NRG)-1β is a naturally occurring growth factor that acts directly on cardiomyocytes and is being explored as a potential therapy for HF. Antiemetic tablets NRG-1β regulates cardiac development through receptor tyrosine kinases in the epidermal growth factor receptor family, ERBB2-4 (6). Antiemetic for dogs The importance of this NRG-1/ERBB signaling pathway in the adult heart was demonstrated clinically when unexpectedly high rates of cardiotoxicity were observed in association with the chemotherapeutic agent trastuzumab, a monoclonal antibody that blocks the ERBB2 receptor (7,8). Antiemetic drugs for child These clinical results and the ability of NRG-1β to activate cytoprotective mechanisms in cardiac myocytes has prompted investigations of its potential to enhance cardiac function in HF (9,10). Antiemetic safe in pregnancy Recent animal data support this notion. Safest antiemetic in pregnancy NRG-1β is released in response to ischemia, stress, and exercise, and is beneficial in animal models of cardiac injury by promoting restorative remodeling (11–13). Antiemetic during pregnancy A recombinant peptide representing the epidermal growth factor–like domain of NRG-1β (Neucardin, Zensun USA Inc., San Diego, California) has been studied in humans with stable chronic HF, where it improved hemodynamics acutely (14) and when given by prolonged infusion over many days increased left ventricular (LV) systolic function (15).

A larger full-length recombinant NRG-1β3 known as cimaglermin alfa (cimaglermin; also known as NRG-1β3, glial growth factor [GGF]-2) is also being examined as a possible treatment for HF (12,13). Antiemetic drugs classification Although cimaglermin and Neucardin both act on ERBB receptor tyrosine kinases, the larger cimaglermin is distinct in structure, containing kringle and immunoglobulin-like domains (16,17), and is manufactured in a mammalian cell expression system leading to complex glycosylation. Antiemetics for chemotherapy The other domains of cimaglermin, beyond the epidermal growth factor–like domain, provide additional differences from the fragment including receptor binding, signaling, recycling, and extracellular matrix binding (18–22). Antiemetics definition Cimaglermin improves cardiac function in rats and swine after myocardial infarction, even when administered as brief intravenous infusions twice per week (11–13). Antiemetic drugs for chemotherapy In addition to the HF models, cimaglermin has been shown to protect cardiomyocytes from toxicity both in vitro (23,24) and in vivo (25).

Given the preclinical promise of cimaglermin, we conducted a first-in-human, phase 1, randomized, placebo-controlled clinical trial to examine the safety and tolerability of single intravenous infusions of cimaglermin over a range of doses in human subjects with LVSD (left ventricular ejection fraction [LVEF] ≤40%) and HF.

Two-dimensional echocardiography was performed at screening (day 0) and on days 8, 14, 28, and 90. Antiemetic drugs brand names LVEF, left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) were measured from orthogonal apical views using the Biplane Simpson’s method (28). List of antiemetic medications Ultrasound contrast was used for technically difficult studies according to the American Society of Echocardiography guidelines (29). Antiemetic drugs side effects All studies were reviewed in a blinded fashion by 2 experienced cardiologists with echocardiographic expertise. Antiemetic medications for chemotherapy Blood sampling for safety assessments (hematology, biochemistry, and liver function), standard clinical and exploratory biomarkers, and assessment of antitherapeutic and neutralizing antibody formation were performed at similar time intervals. Iv antiemetic medications More frequent sampling was performed the first day for pharmacokinetics. Antiemetic for motion sickness Safety monitoring for rhythm disturbances included continuous telemetry, Holter monitoring, and electrocardiography at multiple time points during the initial hospital stay and at each subsequent visit. Non drowsy antiemetic The final patient evaluation was at day 90 post dose, and patients were contacted by telephone at 6 months for status assessment. Best antiemetic for children Figure 2 summarizes protocol events.

Forty patients of a planned 42 (7 cohorts of 6 patients) were enrolled as study recruitment was suspended following a serious adverse event (SAE) in the 40th patient. Strong antiemetic Eighty-three percent (n = 33) of patients enrolled were male, 60% had NYHA functional class II, and 40% had NYHA functional class III symptoms. Over the counter antiemetic uk Seventy-three percent (n = 29) had known significant coronary disease and established ischemic HF. Antiemetic drugs safe in pregnancy The mean age was 57.4 ± 9.8 years. Antiemetic safe during pregnancy Other patient characteristics and concomitant medications during the study period are shown in Tables 1 and 2. Otc antiemetic uk Patients were maintained on optimal medical therapy for at least 3 months before enrollment in the trial ( Table 2). Pregnancy safe antiemetics Given the small size of the study, the demographics were relatively well matched. New antiemetic for chemotherapy There were no clinically significant treatment effects of a single dose of cimaglermin on hematologic, electrical, or the majority of biochemical safety laboratory testing performed, with the exception of the DLT described in more detail below.

The transient liver transaminase elevation and hyperbilirubinemia that occurred in 1 patient who received 1.5 mg/kg of cimaglermin, the highest planned dose, defined a DLT. Meclizine hcl 25 mg antiemetic This patient presented to a local emergency department approximately 48 h after release from the study hospital with abdominal pain and was found to have elevated liver transaminases and bilirubin. Antiemetic medications for pregnancy Normalization of the liver enzymes and bilirubin, along with resolution of abdominal pain, occurred over 96 h under careful observation and symptom management. Cerenia antiemetic for dogs At the next observed time point of 14 days after dosing, the liver enzymes returned to baseline values.

All study patients had age-appropriate cancer screenings that were negative before enrollment. Antiemetic drugs in pakistan One patient with intermittent microscopic hematuria before enrollment was ultimately diagnosed with bladder cancer 3 months after receiving study drug. Anti emetic for kids External review of the details of this case by an expert urogenital oncologist determined that this was not likely related to study drug based upon the natural history and risk factors for the development of bladder cancers.

Serial echocardiogram measurements were measured and evaluated in a blinded fashion. Antiemetic drugs list The results of LVEF, LVEDV, LVESV, heart rate, and blood pressure are summarized in Table 4, and the primary exploratory efficacy measure of LVEF is displayed in Figure 3 with additional data provided in the Supplemental Figure. Antiemetic medications There was a sustained, dose-related increase in LVEF through 90 days after dosing in the high-dose cimaglermin group when compared with the placebo group, (p < 0.01) ( Figures 3 and 4B). Antiemetic in pregnancy There was no change in LVEF in placebo-treated patients. Antiemetic definition In low-dose cimaglermin treated patients, there was a small nonsignificant increase in LVEF which returned to baseline by 90 days. Antiemetic drug names In the high-dose cimaglermin treated patients, there was a mean increase of 9 absolute percentage units of LVEF, and changes reached their maximum increase at day 28 ( Figure 3) and were sustained throughout the duration of the safety measurements. Antiemetic medicine Additionally, at the 90-day time point there was a nonsignificant trend toward a reduction in LVESV, especially at the higher doses (-23.2 ml compared with baseline). Antiemetic for child The AUC for absolute changes in LVEF during the 90 days of observation by dose groups is shown in Figures 4A and 4B; the high-dose group (0.189-mg/kg, 0.378-mg/kg, 0.756-mg/kg, and 1.512-mg/kg cohorts) was significantly increased compared with placebo and low-dose (0.007-mg/kg, 0.021-mg/kg, and 0.063-mg/kg cohorts) treated patients (p < 0.01). Antiemetic for pregnancy Even when censoring the data from the highest dose cohort with the DLT (cohort 7, 1.512 mg/kg), the sustained increases in LVEF persist over 90 days ( Figures 3 and 4A). Antiemetic tablets When mean changes in LVEF over 90 days are plotted for each individual dose cohort ( Figure 4B), there is a significant correlation between dose and LVEF change (R 2 = 0.6735; p = 0.0012).

A single intravenous dose of cimaglermin was tolerated in the majority of patients with systolic LV dysfunction and HF in a first-in-human safety study. Antiemetic for dogs The most common AEs, occurring more frequently at the higher doses, were headache (33%) followed by nausea (27%). Antiemetic drugs for child Serious TEAEs were uncommon, and the DLT at the highest planned dose (1.5 mg/kg) was a case of transient liver transaminase elevation and hyperbilirubinemia meeting U.S. Antiemetic safe in pregnancy Food and Drug Administration guidance for drug-induced liver injury (Hy’s law) that resolved completely within 2 weeks. Safest antiemetic in pregnancy There was a suggestion of improvement in LV function based on a sustained increase in LVEF over 90 days at the higher doses of cimaglermin. Antiemetic during pregnancy These findings support continued clinical development of the investigational drug cimaglermin, including further safety evaluations and detailing the potential improvement on clinical HF outcome measures.

COMPETENCY IN MEDICAL KNOWLEDGE: In patients with symptomatic HF due to LVSD on optimal medical therapy, a single intravenous dose of cimaglermin appears to result in a dose-dependent improvement in LVEF for up to 90 days. Antiemetic drugs classification This therapy was associated with nausea and headache, and at a higher dose there was transient liver transaminase elevation and hyperbilirubinemia. Antiemetics for chemotherapy The implications of toxicity must be balanced with potential therapeutic benefit.

TRANSLATIONAL OUTLOOK: Larger prospective randomized studies are needed with carefully selected doses, as well as repeat dosing, to establish patient safety and improvement in ventricular remodeling, functional status, and other measures of cardiac function.