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TransCon PTH is a sustained-release, essentially inactive prodrug transiently bound to an inert carrier, designed to release PTH(1-34), and in development for hypoparathyroidism (HP). This phase 1, randomized, placebo-controlled, single and multiple ascending dose (SAD and MAD, respectively) trial evaluated safety, tolerability, pharmacodynamics (PD), and pharmacokinetics (PK) of TransCon PTH in healthy adults. SAD and MAD cohorts consisted of 10 subjects (eight active, two placebo) who received up to seven single or six multiple ascending doses of TransCon PTH, respectively. TransCon PTH doses ranged from 3.5 to 124 µg PTH(1-34) for the SAD cohorts and 3.5 to 24 µg PTH(1-34)/day for the MAD cohorts. The primary PK endpoint was Free PTH. The PD endpoints included albumin adjusted serum calcium (sCa), fractional excretion of calcium (FECa), intact endogenous PTH(1-84), bone turnover markers, renal tubular maximum reabsorption of phosphate/glomerular filtration rate (TMP/GFR), serum phosphate (sP) and magnesium, and 1,25 dihydroxyvitamin D. TransCon PTH was generally well tolerated; there were no drug-related serious adverse events (SAEs), and all AEs were transient in nature. Free PTH demonstrated an effective half-life of approximately 60 hours and a dose-dependent, sustained exposure with an infusion-like profile within the calculated physiologic range for active PTH at steady-state. Albumin-adjusted sCa demonstrated a dose-dependent, sustained response with complete control of FECa despite modest hypercalcemia at higher doses. Renal tubular maximum reabsorption of phosphate/glomerular filtration rate (TMP/GFR) showed a dose-dependent decrease, resulting in a dose-dependent decrease in sP. TransCon PTH administered daily for 10 days showed no increase in the osteoblastic bone formation markers, serum bone-specific alkaline phosphatase (BSAP) or P1NP, or the osteoclastic bone resorption marker, urine NTx, but modestly and transiently increased the osteoclast marker, serum CTx. These phase 1 data support TransCon PTH as a daily replacement therapy for HP providing physiological levels of PTH 24 hours per day and advancement into phase 2 clinical development. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

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TransCon growth hormone (GH) is a sustained-release inactive prodrug consisting of unmodified GH transiently bound to an inert carrier molecule designed to release fully active GH over a one-week period. This was a first-in-man phase 1 randomized trial was to evaluate the safety, tolerability, immunogenicity, pharmacokinetics (PK), and pharmacodynamics (PD) of a single dose of TransCon GH as compared to equivalent doses of daily GH (Omnitrope) or placebo in healthy adults. Forty-four healthy male adults were randomized to 4 cohorts of 11 subjects, distributed in a 7:2:2 ratio (TransCon GH: Omnitrope: placebo). A single injection of 4 possible TransCon GH doses (i.e., 0.04, 0.08, 0.16, or 0.24mg GH/kg/wk) or two different Omnitrope doses (i.e., 0.08 or 0.16mg GH/kg/wk divided into 7 equal daily doses) were administered with subjects evaluated for adverse events, immunogenicity, and GH and insulin-like growth factor-1 (IGF-1) levels. TransCon GH was well tolerated; no serious adverse events occurred, no injection site reaction differences between TransCon GH, Omnitrope, or placebo were identified, no nodules or lipoatrophy were reported, and no anti-GH binding antibodies or ECG changes were detected. Overall, the exposure of GH (Cmax) and IGF-1 (AUC0-168h) following administration of equivalent doses of TransCon GH and Omnitrope were similar. GH and IGF-1 kinetics showed a dose-proportional increase following a single SC administration of TransCon GH and indicated that the prodrug is suitable for weekly administration. These results support advancement of TransCon GH to pediatric and adult GHD trials. Clinical trial registration numbers: NCT01010425 (clinicaltrials.gov).

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The fundamental challenge of developing a long-acting growth hormone (LAGH) is to create a more convenient growth hormone (GH) dosing profile while retaining the excellent safety, efficacy and tolerability of daily GH. With GH receptors on virtually all cells, replacement therapy should achieve the same tissue distribution and effects of daily (and endogenous) GH while maintaining levels of GH and resulting IGF-1 within the physiologic range. To date, only two LAGHs have gained the approval of either the Food and Drug Administration (FDA) or the European Medicines Agency (EMA); both released unmodified GH, thus presumably replicating distribution and pharmacological actions of daily GH. Other technologies have been applied to create LAGHs, including modifying GH (for example, protein enlargement or albumin binding) such that the resulting analogues possess a longer half-life. Based on these approaches, nearly 20 LAGHs have reached various stages of clinical development. Although most have failed, lessons learned have guided the development of a novel LAGH. TransCon GH is a LAGH prodrug in which GH is transiently bound to an inert methoxy polyethylene glycol (mPEG) carrier. It was designed to achieve the same safety, efficacy and tolerability as daily GH but with more convenient weekly dosing. In phase 2 trials of children and adults with growth hormone deficiency (GHD), similar safety, efficacy and tolerability to daily GH was shown as well as GH and IGF-1 levels within the physiologic range. These promising results support further development of TransCon GH.

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TransCon growth hormone is a sustained-release human growth hormone prodrug under development in which unmodified growth hormone is transiently linked to a carrier molecule. It is intended as an alternative to daily growth hormone in the treatment of growth hormone deficiency. This was a multi-center, randomized, open-label, active-controlled trial designed to compare the safety (including tolerability and immunogenicity), pharmacokinetics and pharmacodynamics of three doses of weekly TransCon GH to daily growth hormone (Omnitrope). Thirty-seven adult males and females diagnosed with adult growth hormone deficiency and stable on growth hormone replacement therapy for at least 3 months were, following a wash-out period, randomized (regardless of their pre-study dose) to one of three TransCon GH doses (0.02, 0.04 and 0.08 mg GH/kg/week) or Omnitrope 0.04 mg GH/kg/week (divided into 7 equal daily doses) for 4 weeks. Main outcomes evaluated were adverse events, immunogenicity and growth hormone and insulin-like growth factor 1 levels. TransCon GH was well tolerated; fatigue and headache were the most frequent drug-related adverse events and reported in all groups. No lipoatrophy or nodule formation was reported. No anti-growth hormone-binding antibodies were detected. TransCon GH demonstrated a linear, dose-dependent increase in growth hormone exposure without accumulation. Growth hormone maximum serum concentration and insulin-like growth factor 1 exposure were similar after TransCon GH or Omnitrope administered at comparable doses. The results suggest that long-acting TransCon GH has a profile similar to daily growth hormone but with a more convenient dosing regimen. These findings support further TransCon GH development.

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Chronic hepatitis B virus (HBV) infection screening usually includes only HBV surface antigen (HBsAg) testing; HBV core and surface antibody (anti-HBc, anti-HBs) assays, indicating resolved infection and immunity, are not routinely performed. Yet, serum HBV DNA is measurable in approximately 10% of HBsAg-negative/anti-HBc-positive cases, representing occult HBV infection (OBI). Patient blood samples from 2 Veterans Affairs medical center look-back investigations were screened for HBV infection using HBsAg enzyme immunoassays. Supplementary testing included anti-HBc and anti-HBs enzyme immunoassays. For anti-HBc-positive samples, HBV DNA testing was performed. Background OBI prevalence was further estimated at these 2 facilities based on HBV serology testing results from 1999-2012. Finally, a literature review was performed to determine OBI prevalence in the published literature. Of 1887 HBsAg-negative cohort patients, 98 (5.2%) were anti-HBc positive/anti-HBs negative; and 175 (9.3%), anti-HBc positive/anti-HBs positive. Six of 273 were HBV DNA positive, representing 0.3% of the total tested and 2.2% who were anti-HBc positive/anti-HBs negative or anti-HBc positive/anti-HBs positive. Among 32,229 general population veterans at these 2 sites who had any HBV testing, 4/108 (3.7%) were HBV DNA positive, none of whom were part of the cohort. In 129 publications with HBsAg-negative patients, 1817/1,209,426 (0.15%) had OBI. However, excluding blood bank studies with greater than 1000 patients, the OBI rate increased to 1800/17,893 (10%). OBI is not rare and has implications for transmission and disease detection. HBsAg testing alone is insufficient for detecting all chronic HBV infections. These findings may impact blood donation, patient HBV screening, follow-up protocols for patients assumed to have cleared the infection, and initiation of immunosuppression in patients with distant or undetected HBV.

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OBJECTIVE: To investigate Acinetobacter baumannii infection, colonization, and transmission related to a long-term care facility (LTCF) providing subacute care (facility A). METHODS: We reviewed facility A and affiliated local hospital records for facility A residents with A. baumannii isolated during the period January 2009 through February 2010 and compared A. baumannii antimicrobial resistance patterns of residents with those of hospital patients. During March 2010, we implemented a colonization survey of facility A residents who received respiratory support or who could provide sputum samples and looked for A. baumannii colonization risks. Available clinical and survey isolates underwent pulsed-field gel electrophoresis (PFGE); PFGE strains were linked with overlapping stays to identify possible transmission. RESULTS: During the period January 2009 through February 2010, 33 facility A residents had A. baumannii isolates; all strains were multidrug resistant (MDR), which was a significantly higher prevalence of MDR strains than that found among isolates from hospital patients (81 [66%] of 122 hospital patient isolates were MDR; P < .001). The sputum survey found that 14 (20%) of 70 residents had A. baumannii colonization, which was associated with ventilator use (adjusted odds ratio, 4.24 [95% confidence interval, 1.06-16.93]); 12 (86%) of 14 isolates were MDR. Four facility A resident groups clustered with 3 PFGE strains and overlapping stays. One of these facility A residents also clustered with 3 patients at an affiliated hospital. CONCLUSIONS: We documented substantial MDR A. baumannii infections and colonization with probable intra- and interfacility spread associated with a single LTCF providing subacute care. Given the limited infection prevention and antimicrobial stewardship resources in such settings, regional collaborations among facilities across the spectrum of health care are needed to address this MDR threat.

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BACKGROUND: Asthma was the most common chronic condition among adults hospitalized for 2009 pandemic influenza A (H1N1) (pH1N1). OBJECTIVES: We describe the epidemiology and factors for severe outcomes among adults with asthma who were hospitalized or died from pH1N1 in California. METHODS: We reviewed California Department of Public Health pH1N1 reports from April 23, 2009 through August 11, 2009. Reports were included if the patient had pH1N1 (or non-subtypeable influenza A) infection by polymerase chain reaction in an adult (age≥18 years) with asthma who was hospitalized or died. Patients were classified as having intermittent or persistent asthma on the basis of regular medications. Risk factors associated with severe outcomes (i.e., intensive care unit admission or death) vs those with less severe outcomes were assessed by chi-square tests and logistic regression. RESULTS: Among 744 identified patients, 170 (23%) had asthma (61% intermittent, 39% persistent). 132 of 142 (93%) patients had other chronic medical conditions. Severe outcomes occurred in 54 of 162 (33%), more commonly among those with renal disease (64% versus 31%; P=0.04) and chest radiograph infiltrates (54% versus 11%; P<0.01), less commonly among those who received antivirals within 48 hours of symptom onset (22% versus 44%; P=0.02). In multivariable analysis, chest radiograph infiltrates were associated with severe outcomes (adjusted odds ratio 9·38, 95% confidence interval 3·05-28·90). CONCLUSIONS: One third of adults with asthma who died or were hospitalized with pH1N1 experienced severe outcomes. Early empiric antiviral therapy should be encouraged, especially among asthma patients.

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BACKGROUND: Emotional stress is considered a risk factor for cardiovascular events, the underlying pathophysiology remains unclear. METHODS: To evaluate how emotional stress effects hemodynamics, thirteen healthy German soccer fans (mean 37.6 years, 24-56 years) were studied during live TV coverage of the finals with German national team participation (GP) and the respective finals without German participation (noGP). Peripheral blood pressure, heart rate, central blood pressure, augmentation pressure and index, cardiac output and peripheral resistance were measured. RESULTS: In the 1st hour before the match all parameters were not significantly different between the groups. In the GP group peripheral systolic pressure (1st halftime noGP 118 ± 1(s.e.m) versus GP 126 ± 2 mmHg, p<0.05, 2nd 117 ± 1 vs. 125 ± 2 mmHg, p<0.05), mean blood pressure, diastolic blood pressure, heart rate (1st 73 ± 2 vs. 86 ± 3 bpm, p<0.05, 2nd 75 ± 2 vs. 87 ± 2 bpm, p<0.05), cardiac output (1st 4,4 ± 0,1 versus 4,8 ± 0,1L/min, p<0.05, 2nd 4,6 ± 0,1 versus 4,7 ± 0,11 L/min, p>0.05) and peripheral resistance were significantly increased compared to the noGP group during the matches. Systolic central aortic pressure (noGP: 101 ± 2 versus GP 107 ± 2 mmHg, p<0.05) and central pulse pressure (noGP: 31.3 ± 1.3 mmHg vs. GP: 38.5 ± 2.7 mmHg, p<0,05) remained elevated during the second hour after the match. CONCLUSIONS: We observed persistent changes in central hemodynamics 2h after emotional stress. Despite normalization of peripheral values after the end of the finals, we observed prolonged elevation of central systolic blood and pulse pressure. Our findings contribute to the understanding of the increased risk of cardiovascular events in emotional stress.

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