Stock Ownership Research Articles

The nonlinear relationship between employee stock ownership plans and firm performance: Evidence from China

Two opposing forces (positive and negative) have been theoretically expounded to explain the relationship between employee stock ownership plans (ESOPs) and firm performance. However, the direction of this relationship remains a puzzle, especially in countries where state ownership is significant. This paper draws on the “Guidance on the pilot implementation of employee stock ownership plan (ESOP) by listed companies” issued by the China Securities Regulatory Commission (CSRC) to assess the moderating effect of state ownership on the relationship between ESOPs and firm performance. Using employee and executive stock ownership data from 620 Chinese listed companies between 2014 and 2020, I find an inverted U-shaped relationship between employee stock ownership and firm performance. However, the inverted U-shaped relationship holds only for non-state-owned Chinese firms. Finally, a U-shaped relationship between executive ownership and company performance has been found.

Farmer’s Perception and Efficacy of Adaptation Strategies to Climate Change in North Eastern Transition Zone of Karnataka State in India

A primary survey during the year 2021-22 was carried out among the 240 farmers of Bidar and Gulbarga districts of North Eastern Transition Zone in Karnataka to study the farmer’s perception on climate change for the period 1979 to 2019 and validate their opinions with the change in the meteorological indicators. About 74 percent of farmers expressed that there is a decline in crop yield while 83 percent of farmers opined that is a shift of employment from farm to non-farm activities during the period of forty years. Farmers practice various farm adaptation strategies activities to overcome the effect of climate change. Through Garatte ranking, it is revealed that most of the farmers prefer to practice alteration of sowing dates of crop (rank 1) as adaptation strategy followed by using of drought tolerant varieties (rank 2) and mixed cropping (rank3). Binary Logit analysis was used to identify the socio- economic attributes of households influencing the adoption of adaptation strategy to climate change. The results showed that, the variables like farm size, access to institutional credit, live stock ownership and climate information are the factors which positively shows significant influence on adoption. Economic incentives play an important role in the adoption of modern technologies. Access to institutional credit will support the farmers financially in adopting water conservation techniques like farm ponds, micro irrigation products.

The impact of environmental, social and governance (ESG) score on dividend payment of large family firms: What is the role of financial constraints? International evidence

AbstractThis article studies the relationship between environmental, social and governance (ESG) score and dividend payment for 274 large family firms in the period 2015–2021. This research has three contributions to the literature. First, to the best of our knowledge this is the first article to focus on large family firms considering their greater importance in stock ownership around the world. Second, this sample covers both developed and emerging nations. Third, our study not only establishes a connection between ESG (Environmental, Social, and Governance) criteria and dividend payments but also considers how financial constraints moderate the relationship between ESG scores and dividend payments. The results indicate a positive influence of ESG scores on dividend payments. Furthermore, financial constraints of family firms are negatively related to dividend payments. Finally, the moderating effect of financial constraints on the relationship between dividend payment and ESG show that for high levels of financial constraints that dividends are less sensitive to ESG score. The opposite effect is reported when firms show low levels of financial constraints. Practically speaking, the study demonstrates the value of creating a dividend policy that is in line with the ESG score because they are complementary signals. Additionally, it is important to consider financial limitations when planning financial reserves in family firms. This is due to the diminished correlation between ESG score and dividend payments in the presence of financial constraints.

Employee stock ownership plans and within-firm income inequality: evidence from China

Purpose Drawing on bargaining power and the inequality aversion perspective, this study aims to probe employees’ influence on addressing income inequality between top executives and nonexecutive employees. Meanwhile, it examines the moderating role of employee-related factors and plan attributes. Design/methodology/approach This study uses a staggered difference-in-differences design with a propensity scoring match approach and verification of the parallel trend assumption to test the hypotheses. Findings The results support the hypothesis that employee stock ownership plans (ESOPs) significantly reduce within-firm income inequality. The negative effect is amplified by both the presence of trade unions and the unemployment rate at the regional level, as well as the duration of the lock-in period and the scale of participants within the stock ownership plan. Practical implications This study has implications for income inequality research and ESOP design and provides theoretical support for policymakers and corporate governance. Originality/value This study contributes to the literature on income inequality by examining the implementation of ESOPs from the employee perspective. Furthermore, it extends the current literature by investigating the strengthening effects of regional factors and ESOP attributes on the relationship between ESOPs and income inequality. The conclusions provide new empirical evidence to promote the effective implementation of ESOPs by combining internal and external factors.

Analysis of the motivation and impact of the implementation of the employee stock ownership plan

Equity incentive can be divided into executive equity incentive (Executive Stock Option) and employee equity incentive (Employee Stock Option). Employees here refer to the intermediate managers, core technical personnel and other employees except for the senior executives of the company. The ESOP is a mechanism by which the employees of the company share the ownership of the company by holding the stock or options of the company. From the perspective of the implementation of the employee stock ownership plan motivation, its main theoretical basis can be divided into three categories, respectively is incentive theory (incentive theory, reduce agent costs, attract, retain quality employees and limited to financing constraints, reduce cash pressure), signal theory (undervalued company more inclined to internal equity incentives, let investors aware that the current company price relative to its internal value deviation) and major shareholders self-interest theory. From the theoretical point of view, this paper discusses the possible motives and results of domestic listed companies to launch the stock ownership plan, in order to provide theoretical support for small and medium investors to rationally understand the employee stock ownership plan, and provide regulatory suggestions to the regulatory authorities to be vigilant about the self-interest behavior of major shareholders.

Immigrants and natives’ financial decision making: Evidence from Türkiye

This study investigates the causal effects of Syrian migrants on the financial behavior of natives in Türkiye. Utilizing a comprehensive administrative data set, we employ a two-stage least square (2SLS) estimation technique that isolates causal effects by exploiting substantial exogenous variation in the share of migrants relative to natives, arising from the geographical proximity to Syrian governorates of a specific province. Results indicate that immigrants have no significant overall effects on the financial decisions of natives. We find no conclusive evidence that migrant influx promotes overall stock market participation at both extensive and intensive margins. Moreover, our investigation reveals a minimal variation in direct stock ownership or the wealth invested in stocks. We observe neither economically nor statistically significant effects on the share of natives holding bonds or funds. Additionally, no discernible impact of migrants on the wealth per capita invested in bonds, funds, and the overall stock market emerges. However, we find limited evidence suggesting that migrants contribute to an increase in the share of wealth invested in stocks, albeit with a corresponding decrease in the share of wealth allocated to funds. Lastly, we explore the heterogeneity in the effects of immigrants by gender, but our findings reveal no significant variation by gender.

Happiness or trouble? Employee stock ownership plans and employee well-being in new ventures

Happiness or trouble? Employee stock ownership plans and employee well-being in new ventures

Pengaruh Employee Stock Ownership Program (ESOP) terhadap Kinerja Bank Syariah Indonesia

and are involved in decision making. One of the compensations is the granting of shares or known as the Employee Stock Ownership Program (ESOP). The existence of ESOPs is expected to provide incentives for employees to increase productivity efforts. The application of ESOPs to performance is associated with agency theory where there is a contractual attachment between principals (shareholders/owners) and agents (management/employees). In this study, the research method used was paired sample t test. It was found that there was an effect of ESOP application on ROA and no effect of ESOP application on PBV.

Time Variation in the News–Returns Relationship

Abstract The speed of stock price reaction to news exhibits substantial time variation. Higher risk-bearing capacity of financial intermediaries, lower passive ownership of stocks, and more informative news increase price responses to contemporaneous news; surprisingly, these interaction variables also increase price responses to lagged news (underreaction). A simple model with limited attention and three investor types (institutional, noninstitutional, and passive) predicts the observed variation in news responses. A long–short trading strategy based on news sentiment earns high returns, which increase when conditioning on the interaction variables. The interactions we document are robust to the choice of news source.

Pengaruh Leverage, Profitabilitas, Struktur Kepemilikan Saham Dan Kompleksitas Perusahaan Terhadap Audit Delay

The study aims to determine the Effect of Leverage, Profitability, Stock Ownership Structure, and Complexity of Company on Audit Delay. The sample selection technique in this study used the purposive sampling method and obtained 26 food and beverage companies listed on the Indonesia Stock Exchange for the period 2018 – 2021. The data analysis used in this study was multiple linear regression analysis using SPSS version 19 software. The results of the study can be concluded that the leverage and profitability of the auditor have a negative and significant effect on audit delay, while stock ownership structure and complexity of company have no effect on audit delay.

Company Life Cycle, Merger Activities in Indonesia

This study aims to explain and analyze the influence of the company's life cycle on the probability of conducting mergers, shareholder wealth, percentage of company stock ownership and payment methods by mergers . The sample of the research is 36 companies that have merged and acquired in Indonesia which are listed on the Indonesia Stock Exchange (BEI) in the period 2018-2022. Data analysis uses logistic regression and multiple linear regression methods . The results showed the company's life cycle did not significantly affect the probability of companies doing mergers . The company's life cycle has a significant effect on shareholder wealth. the company's life cycle has no significant effect on the percentage of share ownership , the company's life cycle has a positive and significant effect on payment methods for companies that have made mergers . The theoretical implications of this study provide an overview / explanation of the company's life cycle of the activities of mergers in company policy seen from the company's growth prospects. Keywords: Company life cycle, Merger Activities

The Effect of Asymmetry Information, Company Size, Profitability, Leverage and Employee Stock Ownership Programs in Earnings Management

This research aimed to examine the effect of Asymmetry Information, Company Size, Profitability, Leverage and Employee Stock Ownership Programs on Earnings Management. The population used in this research was consumer cyclicals sector companies listed on the Indonesia Stock Exchange (BEI) from 2019 until 2021. Sample was determined by the purposive sampling method. In line with that, there was 57 companies as the sample with 171 observation data. The method of analysis used was multiple regression analysis. Based on the result of testing the hypothesis in this study indicate that Asymmetry Information, Profitability, and Employee Stock Ownership Programs has no effect on earnings management, meanwhile Compnay Size and Leverage has a negative effect on earning management.

DAMPAK ASIMETRI INFORMASI, ESOP, KUALITAS AUDIT TERHADAP MANAJEMEN LABA DENGAN VARIABLE PEMODERASI KESULITAN FINANSIAL

The fundamental purpose of this research is to obtain empirical evidence about the influence of information asymmetry, Employee Stock Ownership Program (ESOP), and audit quality on the practice of earnings management using discretionary revenue components of manufacturing firms in Indonesia and examine the moderating effect of financial distress on these factors. Firms used as references are manufacturing companies in the basic materials, industrials, consumer non-cyclical, consumer cyclical, and healthcare pharmaceuticals sectors listed in the Indonesia Stock Exchange from 2019-2021. This study uses purposive sampling method with panel data moderation and obtains total of 546 sample data units. Based on the research conclusion, information asymmetry can trigger a higher risk of earnings management, while the existence of an ESOP and audit quality can be used to suppress earnings management. Financial distress itself has no direct effect on earnings management. Financial distress has not been proven to strengthen the positive influence of information asymmetry or weaken the negative influence of the ESOP. Meanwhile, the financial distress conditions can weaken the role of audit quality in an effort to minimize earnings management practices of the company.

FRI058 Treatment With Mibavademab, A Novel Leptin Receptor Agonist, Is Associated With Improvement In Metabolic Parameters In Individuals With Generalized Lipodystrophy

Abstract Disclosure: B. Olenchock: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Podgrabinska: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. C. Hou: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B. Musser: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. J. Mendell: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. A. Harman: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R.J. Sanchez: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. K. Miller: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. P. Parasoglou: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Hectors: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Karnik: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. O.E. Pagovich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R. SinhaRoy: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. C.A. Harris: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B. Akinci: Advisory Board Member; Self; Regeneron Pharmaceuticals, Amryt Pharmaceuticals. Consulting Fee; Self; Amryt Pharmaceuticals, Regeneron Pharmaceuticals, Third Rock Ventures, AstraZeneca, Lilly USA, LLC, Novartis Pharmaceuticals, Novo Nordisk, Boehringer Ingelheim, Servier, Sanofi-Aventis, MSD. I. Yildirim simsir: None. S. Ozen: None. E. Sorkina: Advisory Board Member; Self; Amryt Pharmaceuticals, Regeneron Pharmaceuticals. A. Garg: Consulting Fee; Self; Aegerion Pharmaceuticals, Regeneron Pharmaceuticals. Grant Recipient; Self; Aegerion Pharmaceuticals, Pfizer, Inc., Regeneron Pharmaceuticals, Amryt Pharmaceuticals, Ionis Pharmaceuticals Inc. R.J. Vargas Gonzalez: None. D.M. Weinreich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. G. Herman: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. E.A. Oral: Consulting Fee; Self; Regeneron Pharmaceuticals, Third Rock Ventures, Amryt Pharmaceuticals, Rejuvenate Inc, Ionis Pharmaceuticals. Grant Recipient; Self; Gemphire Theraputics, Amryt Pharmaceuticals, Ionis Pharmaceuticals. R.J. Brown: Grant Recipient; Self; Regeneron Pharmaceuticals. Background: Generalized lipodystrophy (GLD) is characterized by the deficiency of adipose tissue and consequently, low levels of the adipose-derived hormone leptin. Leptin deficiency in GLD leads to metabolic abnormalities which are often refractory to treatment with conventional agents. Recombinant human leptin, the only approved therapeutic, improves metabolic abnormalities of GLD, however, daily dosing is required and there is a risk of immunogenicity. There is an unmet need for effective therapies in GLD that are safe, administered less frequently, and can treat patients who have developed neutralizing antibodies to recombinant leptin. Mibavademab is an investigational human leptin receptor agonist monoclonal antibody. We report here the safety, tolerability and pharmacodynamic (PD) responses to mibavademab in a Phase 2 trial (NCT04159415) in patients with GLD. Methods: Patients ≥12 years with acquired or congenital GLD were randomized to mibavademab or placebo. After a single-blind placebo run-in, patients were randomized 1:1 to one of two fixed sequence arms comprising sequential 8-week treatment periods (Arm A: placebo, low-dose mibavademab, high-dose mibavademab; Arm B: low-dose mibavademab, high-dose mibavademab, high-dose mibavademab). Patients in each arm received an IV loading dose of placebo or mibavademab followed by weekly SC administration of study drug tiered by body weight (≥50 kg or <50 kg). Both arms were followed by an open-label high-dose mibavademab treatment period. Safety, pharmacokinetics, and PD of mibavademab were assessed. Primary efficacy endpoints, glycated hemoglobin (HbA1c) and fasting triglycerides (TGs) were measured at Week 8 and at predetermined time points thereafter until study completion. Results: Sixteen patients with GLD and baseline diabetes (mean HbA1c 9.6%, range 6.0%-12.2%) or hypertriglyceridemia (median TGs 669 mg/dL, range 107-2899 mg/dL) were randomized and completed ≥28 weeks of mibavademab treatment. After 8 weeks of low-dose mibavademab, drug levels were significantly lower than predicted in the active arm, and clinically meaningful differences were not observed for any of the primary efficacy endpoints as compared to placebo. In an exploratory pooled analyses after 28 weeks of mibavademab administration, serum drug concentrations were significantly higher than observed at Week 8, and clinically significant reductions from baseline in HbA1c (mean: -1.9%, SD: 2.0) and in TGs (median: -102.1 mg/dL, IQR: 1355.5 mg/dL, -49.3% [57.2%]). Mibavademab was generally well tolerated with no serious adverse events related to administration. Conclusions: Treatment with high-dose mibavademab for up to 28 weeks was associated with clinically meaningful improvements in metabolic parameters, and was generally well-tolerated. Mibavademab represents a potential new therapeutic option for patients with GLD. Presentation: Friday, June 16, 2023

FRI415 Patient Preference And Proof-of-concept For A Once-daily Follicle Stimulating Hormone (FSH) Biosimilar Delivered Via An Orally Ingestible Robotic Pill (RT-112)

Abstract Disclosure: A. Yamaguchi: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. K. Horlen: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. N. Patel: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. V. Tran: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A.T. Vo: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. R. Medida: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. J.T. Myers: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. L.C. Fung: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. K. Kaminskaya: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. D. Mohan: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. V. Nguyen: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. S. Nguyen: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. B. Syed: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A.K. Dhalla: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. M. Imran: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. M.A. Hashim: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. Background: Biotherapeutics offer effective treatments for reproductive disorders, but require painful parenteral (e.g., subcutaneous (SC)) injections, representing a burden for patients which interferes with comfort and quality of life. We have developed an orally ingestible robotic pill (RP) that can deliver biotherapeutic agents with bioavailability rivalling or surpassing that of parenteral injections. Here, we provide 1) clinical evidence of patient preference for the daily oral RP over parenteral injection therapy and 2) data from a study of awake canines demonstrating comparable serum exposures of FSH via the oral RP versus SC injection. Methods:Patient Preference Study: A total of 150 participants currently using parenteral injections were enrolled and given a mock-RP having the same physical characteristics of a RP but without a needle or drug inside. After swallowing the mock-RP, participants were asked to complete a questionnaire evaluating their experience and their preference for a pill vs. parenteral injection. Nonclinical Proof-of-Concept: Single doses of RT-112 (150 IU (n=7) and 450 IU (n=8)) were orally administered to awake, fasted Beagle dogs (7.0-13.0 kg body weight); a control group (n=3) received a dose of 20 IU/kg (∼180 IU) FSH via SC injection. Serial blood samples were collected over 5 days and serum FSH concentrations were quantified via a qualified ELISA. Results: All participants (150/150) in the patient preference study were able to swallow the mock-RP without any adverse events. Based on the questionnaire, the overall preference for an oral pill over parenteral injection was 91%, irrespective of age (21-50, 51-65, 66-75 years). Oral administration of FSH at the 2 doses via RT-112 to awake canines elicited dose proportional increases in serum drug concentrations. AUC0-t values for the 150 IU and 450 IU dose groups were 2101 ± 185 and 8179 ± 733 mIU*hr/mL, and Cmax values were 65 ± 13 and 224 ± 24 mIU/mL, respectively. The pharmacokinetic (PK) profile of the lower RT-112 dose was similar to that of the SC Control dose (AUC0-t: 2131 ± 67 mIU*hr/mL, Cmax: 52 ± 1 mIU/mL), with a relative bioavailability nearly identical (99%) to that of the SC injection. Conclusions: Patients strongly prefer an oral therapeutic option over parenteral therapy. In awake canines, FSH delivered via oral RP yielded bioavailability very similar to SC injection. These data provide early proof-of-concept of the feasibility of replacing the current parenteral injections of FSH with orally ingestible capsules utilizing the RP. Presentation: Friday, June 16, 2023

SAT236 Pharmacokinetics (PK) And Pharmacodynamics (PD) Of The Parathyroid Hormone Analog PTH (1-34) (Teriparatide) Delivered Via An Orally Administered Robotic Pill (RT-102)

Abstract Disclosure: K. Horlen: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. K. Kaminskaya: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A. Yamaguchi: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. L.C. Fung: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. H. Kennedy: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. S. Nguyen: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A. Dasari: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A. Toledo Vo: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. B. Archana: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. N. Patel: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. D. Mohan: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. B. Syed: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A.K. Dhalla: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. M. Imran: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. M.A. Hashim: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. Background: An orally administered robotic pill (RP) protects the drug from digestion during transit through the gastrointestinal tract before painlessly injecting the drug trans-enterically into the peritoneal space. Although parenteral, this unique delivery route can result in altered PK/PD profiles as drug absorption is primarily via mesenteric vasculature which drains into the portal vein. Here we report on two nonclinical studies which, 1) in awake canines, compared the PK profiles of orally delivered teriparatide via the RP (RT-102) versus subcutaneous (SC) injections; and 2) in an ovariectomized (OVX) rat model of osteoporosis, compared the PD (osteoanabolic) effect of intraperitoneal (IP) vs SC administered teriparatide on bone mineral density (BMD).Methods:PK Study: Beagle dogs (n = 43) received a single RT-102 capsule orally containing 20, 40, 80, or 160µg of teriparatide or a SC or intravenous (IV) injection of 20µg of the FDA-approved PTH(1-34) commercial product (Forteo®). Teriparatide concentrations in serial blood samples (collected for up to 300 minutes) were quantitated via a validated ELISA.PD Study: OVX Sprague-Dawley rats (n=50) underwent an 8-week bone depletion period followed by 6-weeks of daily treatment with teriparatide at a dose of 2, 5, or 15 µg/kg via IP injection or 5 µg/kg via SC injection (Forteo®) (n = 10 per treatment). A sham-operated control group received daily saline injections. BMD was assessed via dual-energy X-ray absorptiometry (DXA). Results:PK Study: RT-102 yielded steep increases in serum PTH concentrations followed by rapid declines to baseline levels, similar to the overall PK profile of Forteo® SC. RT-102 yielded more sustained exposures resulting in a prolonged Tmax compared to Forteo® SC (Tmax 37 to 48 vs 21 min). At 80 µg, PK curves of RT-102 tracked closely with SC, albeit with RT-102 yielding higher peak concentrations (Cmax = 3511 vs 1342 pg/mL). PD Study: DXA imaging of whole-body skeleton, femur, femur diaphysis, and lumbar vertebrae showed that intraperitoneally administered teriparatide yielded dose dependent increases in BMD in all areas examined. Animals receiving teriparatide via either IP or SC injections at equivalent doses showed no significant differences in the BMD increases between the two routes of administration. Conclusions: Orally administered RT-102 capsules to canines yielded steep rises in serum teriparatide concentrations followed by rapid elimination within three hours. When administered intraperitonially to mimic RT-102 delivery in a rodent model of osteoporosis, teriparatide was osteoanabolic similar to equivalent drug doses injected SC. These data provide the PK/PD proof-of-concept data for oral RT-102 capsules indicating their potential to replace current injection therapy for the treatment of osteoporosis. Presentation: Saturday, June 17, 2023

SAT235 An Orally Administered Robotic Pill (RP) Reliably And Safely Delivers the Human Parathyroid Hormone Analog hPTH(1-34) (Teriparatide) With High Bioavailability in Healthy Human Volunteers: A Phase 1 Study

Abstract Disclosure: J.T. Myers: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A. Dasari: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A. Battiwala: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. N. Patel: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A. Toledo Vo: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A. Yamaguchi: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. K. Horlen: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. L.C. Fung: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. B. Syed: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. S. Nguyen: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. J. Van Dam: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. M. Imran: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. M. Hashim: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A.K. Dhalla: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. Background/Purpose: Teriparatide, an effective osteoanabolic agent, requires a chronic regimen of daily subcutaneous (SC) injections, representing a burden for patients which may interfere with compliance and quality of life. We have developed a novel oral robotic pill (RP) to deliver biotherapeutic agents with bioavailability rivaling or surpassing that of parenteral injections. Here we present data from a Phase 1 study in healthy women volunteers designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of 20- and 80 µg of hPTH (1-34) administered orally via RP (RT-102) at single doses. Methods: The study was approved by the Alfred Health HREC in Australia. Participants received a single dose of either RT-102 at 20 µg (RT-102/20 µg group; N=15) or 80 µg (RT-102/80 µg group; N=14) or a single 20 µg dose of the commercially available teriparatide (Forteo®) via SC injection (SC group; N=10). Fluoroscopic images were taken to track the transit/deployment of RT-102 and confirm excretion of remnants. Drug concentration in serum samples serially collected over 6 hours were measured by a validated ELISA assay. Results: All 29 participants in the RT-102 arms were able to swallow RT-102 and none experienced any adverse events (AEs) upon device deployment. Both doses of RT-102 were safe and well-tolerated with no serious adverse events (SAEs) reported. In the SC group, a total of six drug-related AEs were reported in four participants. There were no AEs reported in the RT-102/20 µg group. Mild and transient AEs attributed to the drug were observed in one participant in the RT-102/80 µg group. No AEs related to the RP were reported. Imaging confirmed excretion of all RP device remnants within an average of 2.7 ± 1.4 days. Based on serum analyses, drug was successfully delivered by RT-102 in 12 of 15 participants in the 20 µg group and in all 14 participants in the 80 µg group. PK analyses indicated that RT-102 delivered drug with more sustained peak concentrations than the SC group. The Cmax of RT-102 was 98 ± 10 pg/mL for the 20 µg dose and 971 ± 223 pg/mL for the 80µg dose compared to 128 ± 20 pg/mL for the 20 µg SC injection group. The Tmax for RT-102 delivery was 68 and 60 min for the 20 µg and 80 µg doses, respectively, compared to 13 min for the SC injection. Based on AUC calculations of the PK curves, the relative bioavailability of RT-102 dose groups was 3- to 4-fold higher compared to the SC injection group. Conclusions: This study provides the first clinical evidence of safe and successful delivery of hPTH (1-34) via an orally administered RP with high reliability and bioavailability. These data suggest that RT-102 can potentially offer an easier and more convenient treatment option to osteoporosis patients, and given the high bioavailability, RT-102 may be effective at doses lower than the currently approved 20 µg SC dose of teriparatide. Presentation: Saturday, June 17, 2023

FRI538 Discovery And Characterization Of Orally Bioavailable Nonpeptide Thyroid Stimulating Hormone Receptor (TSHR) Antagonists For The Treatment Of Graves’ Disease

Abstract Disclosure: M.A. Fowler: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. C. Regan: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. J. Zhao: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. E. Coutinho: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. B. Fleck: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. A.A. Castellanos: Employee; Self; Crinetics Pharmaceuticals. E. Muller: Employee; Self; Crinetics Pharmaceuticals. M. Johns: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. Y. Tang: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. E. Sturchler: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. M. Chen: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. K. Retting: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. D. Dalvie: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. S.F. Betz: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. S. Markison: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. Graves’ disease is an autoimmune condition that affects approximately 1 in 100 people in the United States and 2-3% of the population worldwide. It is characterized by the production of autoantibodies against TSHR, and the pathology of Graves’ disease is driven by TSHR stimulatory antibodies (TSAb) that result in heightened activation of TSHR. This overstimulation results in hyperthyroidism due to excessive production of thyroid hormones. Approximately 30% of Graves’ disease patients also develop thyroid eye disease (TED or Graves’ orbitopathy) due to overactivation of TSHR in orbital fibroblasts leading to excessive production of hyaluronic acid, adipogenesis, cytokine production, and fibrosis. This can cause a myriad of debilitating symptoms including pain, swelling, blurry vision, diplopia, and proptosis. Several treatments for Graves’ hyperthyroidism are available including anti-thyroid drugs, radioactive iodine (RAI), and surgery. RAI and surgery are definitive treatments for Graves’ hyperthyroidism, but often result in hypothyroidism. In addition, none of the current treatments for Graves’ hyperthyroidism are effective in treating TED and, in some cases, such as with RAI, worsen the condition. Blocking TSHR activation directly via a TSHR antagonist may provide an important new therapeutic mechanism to treat patients with Graves’ disease that would effectively treat both the hyperthyroidism and TED. We have identified several potent and orally bioavailable nonpeptide allosteric antagonists with acceptable drug-like properties. One analog, TSHRant-1, demonstrated potent negative allosteric modulator activity at both the human and rat TSHR. To evaluate the in vivo pharmacodynamics of TSHant-1, we developed a rat model of hyperthyroidism. In this model, subcutaneous administration of the TSAb, M22, to female rats resulted in a robust and long-lasting rise in levels of the thyroid hormone thyroxin (T4). Oral administration of TSHRant-1 dose-dependently suppressed M22-stimulated T4, providing evidence that a nonpeptide allosteric antagonist of TSHR may serve as an effective treatment for Graves’ disease and associated orbitopathy (TED). Presentation: Friday, June 16, 2023

SAT630 Analytical Validation Of A Telomerase Reverse Transcriptase (TERT) Promoter Mutation Assay

Abstract Disclosure: P. Iyer: None. R. Dadu: Advisory Board Member; Self; Exelixis, Inc., Bayer, Inc. Research Investigator; Self; Merck, Exelixis, Inc., AstraZeneca. A. Barque: Employee; Self; Veracyte, Inc. Stock Owner; Self; Veracyte, Inc. Z. Cleslei: Employee; Self; Veracyte, Inc. Stock Owner; Self; Veracyte, Inc. H. Jiang: Employee; Self; Veracyte, Inc. Stock Owner; Self; Veracyte, Inc. S. Walsh: Employee; Self; Veracyte, Inc. Stock Owner; Self; Veracyte, Inc. X. Zheng: Employee; Self; Veracyte, Inc. Stock Owner; Self; Veracyte, Inc. Y. Hao: Employee; Self; Veracyte, Inc. Stock Owner; Self; Veracyte, Inc. J. Huang: Employee; Self; Veracyte, Inc. Stock Owner; Self; Veracyte, Inc. J.P. Klopper: Employee; Self; Veracyte, Inc. Stock Owner; Self; Veracyte, Inc. R.T. Kloos: Employee; Self; Veracyte, Inc. Stock Owner; Self; Veracyte, Inc. M. Cabanillas: Advisory Board Member; Self; Exelixis, Inc., Bayer, Inc. Consulting Fee; Self; Lilly USA, LLC, Bayer, Inc. Research Investigator; Self; Genentech, Inc., Merck. TERT promoter mutations are relatively enriched in larger, aggressive thyroid cancers and these malignancies carry an independently decreased rate of disease free and disease specific survival when compared to thyroid cancers with wild type TERT promoter gene sequences. High quality analytical validation of a diagnostic test promotes confidence in the results which inform clinical decision making. TERT promoter mutation testing is now offered as a complement to Afirma Genomic Sequencing Classifier (GSC) testing in thyroid nodules that are not designated as molecularly benign. The Afirma TERT test was developed at Veracyte, Inc. based on the AmpliSeq-for-Illumina technology to detect TERT promoter variants C228T and C250T in genomic DNA (gDNA) extracted from patient thyroid fine needle aspirates (FNAs) sent for Afirma GSC testing, without any need for increased needle passes or sample volume. Herein, we describe the analytical performance of the Afirma TERT test. We examined the analytical sensitivity of the Afirma TERT test to varied input DNA amounts and the limit of detection (LOD) of variant allele frequency (VAF). We determined the negative percent agreement (NPA) and the positive percent agreement (PPA) of the Afirma TERT test against a reference primer pair. We also evaluated the analytical specificity from potential interfering substances such as RNA and blood gDNA. Further, the intra-run, inter-run and inter-laboratory reproducibility of the assay were examined. Analytical sensitivity analysis showed that the Afirma TERT test is tolerant to variation in DNA input amount (7-13 ng) and can detect expected positive TERT promoter variants down to 5% VAF LOD at 7ng DNA input with > 95% sensitivity. Both NPA and PPA were 100% against the reference primer pair. Analytical specificity studies demonstrated that the Afirma TERT test remains accurate in presence of 20% RNA or 80% blood gDNA for an average patient sample that typically has 30% VAF. The Afirma TERT test results are highly reproducible across different operators, runs, reagent lots, and laboratories. The Afirma TERT test also demonstrated a 100% confirmation rate when compared with an external NGS-based reference assay executed in a non-Veracyte laboratory. The analytical robustness and reproducibility of the Afirma TERT test support its routine clinical use among thyroid nodules with indeterminate cytology that are Afirma GSC suspicious or Bethesda V/VI nodules. Presentation: Saturday, June 17, 2023

THU402 New Heterotopic Ossification Lesions In Patients With Fibrodysplasia Ossificans Progressiva Measured By PET/CT vs CT Only

Abstract Disclosure: D. Gonzalez Trotter: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. J. McGinniss: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. A.N. Economides: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. K. Mohammadi: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. A.J. Rankin: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B. Musser: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Mellis: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. E. Forleo-Neto: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. G. Herman: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder caused by mutations in the activin-A receptor type 1 (ACVR1) gene that render it responsive to activin-A, a ligand that normally antagonizes signaling from ACVR1. FOP is characterized by the deposition of bone in soft tissues known as heterotopic ossification (HO) and episodic painful flare-ups. Garetosmab, a fully human monoclonal antibody against activin-A, is being investigated for the prevention of new HO lesions in patients with FOP. This post hoc analysis compared the change from baseline in the number and volume of new HO lesions identified by 18F-labeled sodium fluoride (a bone-seeking tracer that measures bone deposition and turnover) positron emission tomography (PET/CT) and X-ray computed tomography (CT) imaging (which measures bone volume). Methods: Baseline and 28-week PET/CT and CT-only scans acquired during the initial double-blind placebo-controlled period of the LUMINA-1 (NCT03188666) phase 2 study were independently read by two sets of blinded readers and an adjudicator for the presence and volume of new lesions. Number and volume of new lesions were compared between the two imaging modalities. Results: The number of patients with new lesions as detected by PET/CT and CT only was 14/44 (31.8%) and 12/44 (27.3%), respectively. The mean number (standard deviation) of new lesions per patient by PET/CT through Week 28 was 0.68 (1.57) vs 0.86 (1.95) as detected by CT only. In patients with new lesions, the mean number of new lesions per patient was 2.14 (2.18) vs 3.17 (2.62) as detected by PET/CT vs CT only, respectively. The mean volume (cm3) of new lesions per patient detected by PET/CT was 6.05 (14.88) vs 5.94 (21.13) by CT only, through Week 28. In the subset of patients with new lesions, the mean volume of new lesions per patient detected by PET/CT was 19.02 (21.60) vs 21.79 (36.98) by CT only. Moderate agreement between PET/CT and CT-only detection was observed when identifying patients with new lesions, with a kappa coefficient of 0.46 (standard error: 0.146; 95% confidence interval: 0.17, 0.74). Placebo vs garetosmab groups, respectively, showed aggregate new lesion number/volume (cm3) of 27/245.0 vs 3/21.3 by PET/CT, and 37/261.5 vs 1/0.05 by CT only. Conclusions: CT imaging showed similar performance to PET/CT in the detection and characterization of new HO lesions and provides a viable option for the assessment of therapies that may inhibit the formation of new HO lesions in patients with FOP. Presentation: Thursday, June 15, 2023