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 mu g PTH(1-34) for the SAD cohorts and 3.5 to 24 mu g 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. (c) 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Background: With growth hormone (GH) receptors present on virtually all cells, GH replacement therapy should aim for the same exposure and tissue distribution as endogenous GH and current daily GH therapies. The challenge to developing a long-acting GH (LAGH) is to establish the same safety, efficacy, and tolerability of daily GH, which includes maintaining GH and IGF-1 levels within the physiological range. To create a LAGH, two approaches have been used: 1) combine unmodified GH with a prolongation technology, or 2) modify GH providing a longer half-life. TransCon GH is a LAGH prodrug in development for pediatric growth hormone deficiency (GHD) with GH transiently bound to an inert carrier. It was designed to release unmodified GH over 7 days to achieve the same exposure, safety, efficacy, and tolerability as daily GH with more convenient once weekly dosing. This profile was successfully demonstrated in the Phase 2 trial in pediatric GHD. TransCon GH is also being developed with an autoinjector for ease of administration and improved adherence. Aims: We aim to present the topline 52-week pivotal Phase 3 results of TransCon GH in treatment of pediatric GHD. Methods: The phase 3 heiGHt trial was designed to compare safety, tolerability, and efficacy of weekly TransCon GH versus daily GH over 52 weeks in treatment-naive prepubertal children with GHD. Study endpoints include annualized height velocity (AHV), IGF-1 response, immunogenicity, and safety. Results: Top-line 52-week results of the heiGHt trial (N = 161) including AHV, Δ height SDS, IGF-1 levels, Δ bone age, and adverse events, will be available for presentation at PENS 2019. Conclusions: Only LAGHs based on unmodified GH have succeeded in providing both accelerated height velocity as well as reducing truncal adiposity in line with currently available daily GH therapies. Top-line data from the pivotal heiGHt trial of TransCon GH, a LAGH prodrug releasing unmodified GH, will be available in March 2019. Clinical Implications: A GH prodrug that provides sustained release of unmodified GH for the treatment of pediatric GHD would likely maintain the same tissue distribution as endogenous GH, with comparable efficacy, safety, tolerability, with the benefit of improved compliance due to weekly dosing via an autoinjector.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

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.

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 0.24 mg GH/kg/wk) or two different Omnitrope doses (i.e., 0.08 or 0.16 mg 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 (C.) and IGF-1 (AUCo-isa h) 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.

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.

ContextTransCon Growth Hormone (GH) (Ascendis Pharma) is a long-acting recombinant sustained-release human GH prodrug in development for children with GH deficiency (GHD).ObjectiveTo compare the pharmacokinetics, pharmacodynamics, safety, and efficacy of weekly TransCon GH to that of daily GH in prepubertal children with GHD.DesignRandomized, open-label, active-controlled study of three doses of weekly TransCon GH versus daily Genotropin (Pfizer).SettingThirty-eight centers in 14 European countries and Egypt.PatientsPrepubertal male and female treatment-naïve children with GHD (n = 53).InterventionsSubjects received one of three TransCon GH doses (0.14, 0.21, or 0.30 mg GH/kg/wk) or Genotropin 0.03 mg GH/kg/d for 26 weeks.Main Outcome MeasuresGH and insulinlike growth factor-1 (IGF-1) levels, growth, adverse events, and immunogenicity.ResultsBoth GH maximum concentration and area under the curve were similar following TransCon GH or Genotropin administration at comparable doses. A dose response was observed, with IGF-1 standard deviation scores increasing into the normal range for all three TransCon GH doses. Annualized mean height velocity for the three TransCon GH doses ranged from 11.9 cm to 13.9 cm, which was not statistically different from 11.6 cm for Genotropin. Adverse events were mild to moderate, and most were unrelated to the study drug. Injection site tolerance was good. One TransCon GH subject developed a low-titer, nonneutralizing antibody response to GH.ConclusionsThe results suggest that long-acting TransCon GH is comparable to daily Genotropin for GH (pharmacokinetics) and IGF-1 (pharmacodynamics) levels, safety, and efficacy and support advancement into phase 3 development.

OBJECTIVES:We wished to evaluate the effects of an antigranulocyte-macrophage colony-stimulating factor monoclonal antibody (KB003) on forced expiratory volume in 1 s (FEV1), asthma control and asthma exacerbations in adult asthmatics inadequately controlled by long-acting bronchodilators and inhaled/oral corticosteroids.SETTINGS:47 ambulatory asthma care centres globally.PRIMARY OUTCOME MEASURES:Change in FEV1 at week 24.PARTICIPANTS:311 were screened, 160 were randomised and 129 completed the study.INTERVENTIONS:7 intravenous infusions of either 400 mg KB003 or placebo at baseline and weeks 2, 4, 8, 12, 16 and 20.PRIMARY AND SECONDARY OUTCOME MEASURES:FEV1 at week 24, asthma control, exacerbation rates and safety in all participants as well as prespecified subgroups.MAIN RESULTS:In the KB003 treated group, FEV1 at week 24 improved to 118 mL compared with 54 mL in the placebo group (p=0.224). However, FEV1 improved to 253 vs 26 mL at week 24 (p=0.02) in eosinophilic asthmatics (defined as >300 peripheral blood eosinophils/mL at baseline) and comparable improvements were seen at weeks 20 (p=0.034) and 24 (p=0.077) in patients with FEV1 reversibility ≥ 20% at baseline and at weeks 4 (p=0.029), 16 (p=0.018) and 20 (p=0.006) in patients with prebronchodilator FEV1 ≤ 50% predicted at baseline. There were no effects on asthma control or exacerbation rates. The most frequent adverse events in the KB003 group were rhinosinusitis and headache. There was no significant difference in antidrug antibody response between placebo and treated groups. There were no excess infections or changes in biomarkers known to be associated with the development of pulmonary alveolar proteinosis.CONCLUSIONS:Higher doses and/or further asthma phenotyping may be required in future studies with KB003.TRIAL REGISTRATION NUMBER:NCT01603277; Results.

BACKGROUNDIn two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients.METHODSIn this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis.RESULTSIn the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P=0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P=0.16) or in rates of death from any cause (P=0.10) or from idiopathic pulmonary fibrosis (P=0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P=0.01) and from idiopathic pulmonary fibrosis (P=0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation.CONCLUSIONSPirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.)

Pirfenidone is an oral antifibrotic agent that is approved in several countries for the treatment of idiopathic pulmonary fibrosis (IPF). We performed a comprehensive analysis of safety across four clinical trials evaluating pirfenidone in patients with IPF.

Background: Three multinational, randomised, phase 3 trials of PFD (ASCEND and CAPACITY Studies) with similar study designs and populations have been performed in patients with IPF (N Engl J Med 2014; 370:2083-92; Lancet 2011; 377:1760-9). Data through the prespecified primary endpoint assessment in each study were pooled to provide robust estimates of the pirfenidone treatment effect. Methods: Analyses included all randomized patients and all observations through Week 52 in ASCEND and Week 72 in CAPACITY, and used Cox proportional hazards model and log rank test. Outcomes included time to FVC decline ≥10% or death, progression-free survival (FVC decline ≥10% or 6MWD decline ≥50 m or death), and 4 mortality outcomes. Results: A total of 1247 patients were analysed (PFD, N=623; placebo, N=624). PFD reduced FVC decline (hazard ratio [HR] 0.48; 95% confidence interval [CI] 0.37, 0.63), prolonged PFS (HR 0.62; 95% CI 0.52, 0.75) and reduced all-cause mortality (HR 0.63; 95% CI 0.41, 0.98). The most common adverse events were gastrointestinal and skin-related, and were generally mild to moderate in severity and infrequently led to discontinuation. Conclusions: These pooled analyses showed a favourable and persistent PFD treatment effect on FVC, PFS, and all-cause mortality through 72 weeks of follow-up. PFD was generally safe and well tolerated.

Abstract Abstract 4893 EphA3 is a receptor tyrosine kinase important in fetal development but apparently not in healthy adults. It is expressed in hematologic malignancies including AML, CML, MDS, MPN and Multiple Myeloma and in a range of solid tumors in particular in the stromal and vascular tissue. KB004 is a high-affinity non-fucosylated, recombinant antibody to EphA3 that triggers apoptosis and has potent antibody-dependent cellular cytotoxicity (ADCC) activity against EphA3+ cells. Direct apoptosis of EphA3+ leukemic cells ex vivo was demonstrated at antibody concentrations of 10μg/mL or greater. Expression on a CD34+ CD38− CD123+ cell population in primary AML patient bone marrow, and inhibition of long-term culture initiating cells by KB004, indicates that EphA3 may be present on leukemic stem cells (Palath et al 2010). EphA3 expression in bone marrow biopsies from AML patients was characterized by immunohistochemistry (IHC). EphA3 was detected on tumor cells by IHC in 4/10 samples analyzed. EphA3 was also present on the vasculature in AML bone marrow (6/10 samples) but not in similar tissues in bone marrow biopsies (n=2) from non-leukemic individuals. This suggests tumor vasculature as a potential further therapeutic target for KB004 in AML in addition to targeting leukemia cells directly. We are further characterizing the expression level of EphA3 in different hematologic malignancies, tumor microenvironment, and at various stages of disease progression from primary human samples. The Cynomolgus macaque was selected as a relevant species for toxicity testing since KB004 binds with equivalent affinity to human and Cynomolgus EphA3 and CD16. IHC studies demonstrated the absence of cellular expression of EphA3 in normal human or Cynomolgus monkey tissues. KB004 administered to Cynomolgus monkeys (n=44) twice weekly for 13 weeks at doses up to 100 mg/kg was well tolerated and there were no clinical or pathology adverse findings. Cardiovascular, respiratory and central nervous system functions were measured in primates after KB004 dosing 5 times over 15 days to reach steady-state exposure at doses of 10mg/kg (n=4) or 100 mg/kg (n=4). There were no KB004-related effects on body weight, food consumption, mean arterial pressure, heart rate, body temperature, neurological parameters, respiration rate, oxygen saturation, or blood gas parameters, or changes in serum concentrations of Troponin I. Qualitative evaluation of the electrocardiogram (ECG) did not reveal any electrocardiographic abnormalities and there were no effects on measured ECG intervals (i.e., duration of the QT and RR intervals, derived QTc values). The effect of KB004 on wound healing was tested in a primate incisional wound healing model in the Cynomolgus monkey. No statistically significant differences in healing were detected between control and KB004 (2×10 or 2×100mg/kg) treated animals (n=24). A Phase I clinical study has been initiated in subjects with hematologic malignancies including AML, CML, ALL, MDS and MPN. Subjects are being assessed for EphA3 protein expression at study entry and at various time points throughout the treatment period. Study objectives are to determine a maximum tolerated dose, examine the safety and tolerability profile of KB004, obtain pharmacokinetic data, describe the immunogenicity profile, and explore cell subpopulations and pharmacodynamic effects of treatments with KB004. This is an open-label, repeat administration study of weekly IV dosing of up to 17 cycles (3 doses per 21-day cycle). Dosing levels are scheduled for 20 mg (∼0.3 mg/kg), 70 mg (∼1 mg/kg), 200 mg (∼3 mg/kg) and 700 mg (∼10 mg/kg). Therapeutic antibody levels (target level 10μg/mL) are predicted to be achieved from the first dose cohort for a portion of the dosing interval. The higher doses should provide blood levels in excess of 10 μg/mL for the entire one-week dosing interval. The first cohort (n=3) has been successfully completed, and a subject with AML remains on study having received 8 doses to date. Recruitment of the next dose cohort is ongoing. Pharmacokinetic data and tumor expression profiles will be presented. Disclosures: Hagey: KaloBios Pharmaceuticals, Inc.: Employment, Equity Ownership. Lancet:KaloBios Pharmaceuticals, Inc.: Research Funding. Palath:KaloBios Pharmaceuticals, Inc.: Employment, Equity Ownership. Wei:KaloBios Pharmaceuticals, Inc.: Research Funding. Lackmann:KaloBios Pharmaceuticals, Inc.: Research Funding. Cortes:KaloBios Pharmaceuticals, Inc.: Research Funding. Boyd:KaloBios Pharmaceuticals, Inc.: Research Funding. Shochat:KaloBios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yarranton:KaloBios Pharmaceuticals, Inc.: Employment, Equity Ownership. Bebbington:KaloBios Pharmaceuticals, Inc.: Employment, Equity Ownership. Leff:KaloBios Pharmaceuticals, Inc.: Employment, Equity Ownership.

OBJECTIVETo evaluate safety, efficacy, and radiographic progression in patients with early rheumatoid arthritis (RA) undergoing longterm treatment with etanercept.METHODSPatients with early RA (disease duration of 3 years or less) who had completed a 2-year efficacy study comparing etanercept and methotrexate (MTX) were followed in an extension where they received 25 mg etanercept twice weekly. Safety was summarized descriptively and compared with data from the efficacy study. Efficacy and radiographic progression were assessed using American College of Rheumatology response criteria, disease activity scores, and Total Sharp Score (TSS).RESULTSRates of serious adverse events and serious infections did not increase with longterm exposure to etanercept, and were similar to rates reported for the blinded portion of the efficacy study. Efficacy was sustained in patients who completed 5 years of etanercept treatment at the time of this report (N = 201), even in those who decreased or discontinued use of MTX or corticosteroids. No radiographic progression (change in TSS < or = 0) was seen in 55% of patients with 5-year radiographs; negative change (TSS < 0) was seen in 11%.CONCLUSIONEtanercept treatment in patients with early RA was generally well tolerated for up to 5 years. The results indicate sustained efficacy and decreased rate of radiographic progression. The rate of radiographic progression was low compared with other studies, emphasizing the benefit gained in patients with early aggressive RA who undergo longterm treatment with etanercept.