Stock Ownership Research Articles

Analyst recommendations, acquirer’s valuation, and M&A performance: evidence from China

ABSTRACT This study investigates the effects of premerger analyst recommendations on mergers and acquisitions (M&A) announcement returns. We find that M&A announcement returns decrease with premerger analysts’ favourable recommendations (PAFR). Furthermore, we find that increasing acquirers’ valuations in the preannouncement period is a possible channel that allows PAFR to reduce M&A announcement returns. We explore three alternative explanations including, ‘analyst information role’, ‘analyst pressure’ and ‘informed trading’ explanations for our main nexus, and our findings are still robust. In an additional analysis, we find that this negative relationship is more pronounced among acquirers with (a) high information uncertainty (b), low media criticism, and (c) high investor attention. Moreover, we identify three sources of conflicts of interest in analyst recommendations: M&A relations, controlling shareholder share pledging, and stock ownership composition. Our research enriches the impact of analysts’ recommendations on M&A outcomes and provides new empirical evidence of analysts’ strengthening of overvaluation.

Feeling like owners: the impact of high-performance work practices and psychological ownership on employee outcomes in employee-owned companies

ABSTRACT A central finding of scholarship on employee ownership (EO) is that EO has the strongest impacts on employee outcomes when implemented with other management practices that are typically associated with high-performance work systems (HPWS). However, our explanations for why these complementary practices matter remain underdeveloped. In this paper, we examine whether the extent to which employees feel like owners, using the construct of psychological ownership (PO), mediates the impact of three HPWS practices on four employee outcomes in a dataset of 881 employees in nine companies with employee stock ownership plans (ESOPs) in the United States. Our findings support our core argument that these practices make it more likely that employees will feel like owners, which in turn leads to positive impacts on employee outcomes. More specifically, we find that the extent to which employees perceive that they have influence, are engaged as owners through information sharing and business literacy training, and receive high quality communications about EO are positively associated with PO, and that PO is positively associated with organizational commitment, turnover intention, voice behavior, and helping behavior. We discuss the theoretical, management, and policy implications of our analysis and findings.

Employee Stock Ownership Plans (ESOPs) as social enterprise

ABSTRACT Discontinuities between the positive outcomes for business entities in Western capitalist countries and low-quality standards of living for large segments of their populations have grown in recent decades. Combined with environmental degradation worldwide and a poor quality of life for many, the future does not look bright for the ability of these societies and their economies to continue to prosper. Proposed institutional solutions include the development of a different form of organization, the social enterprise, broadly defined as a mission focused and profit-making entity. In the United States, these organizations are few, of varied legal form, relatively small and relatively young. Sometimes a mission focus is the reason for the organization’s existence, while for others, the business is the focus with the mission secondary. The Employee Stock Ownership Plan company (ESOP) has been in existence in the United States for decades. It is also varied in legal form, always profit-focused, and often focused on the welfare of workers and communities. Can the ESOP business fill any part of the societal need for which the social enterprise is justified? This paper examines the argument for, purpose, and features of social enterprises and ESOPs to consider possible commonalities in purpose and outcomes.

The first study of majority employee-owned enterprises in the U.S.: an historical retrospective analysis

ABSTRACT Research conducted in 2010 to identify and collect information about majority employee-owned enterprises in the U.S. is documented in this paper. This research identified 1,289 firms that were majority owned by their employees and their basic characteristics are reported here. Overwhelmingly, these companies were owned through an employee stock ownership plan (ESOP). They were characteristically older and larger than conventionally owned firms, as well as more concentrated in manufacturing and wholesale trade, and more likely to be located in the Midwest than U.S. firms overall. The paper argues that because the effects of employee ownership are likely to be correlated with the degree of employee ownership, research on ESOPs should endeavor to identify the degree of plan ownership of equity rather than simply the presence of a plan. This may also provide a method to address the non-random assignment of ESOPs to firms. The majority employee-owned ESOPs documented in this paper provide a viable population to study the effect of residual claimancy on employee behavior in isolation from other potentially confounding factors.

Environmental, social, and governance performance: The role of Chinese employee stock ownership plans

The challenges of global warming, resource depletion, and environmental protection require immediate action from corporations, governments, and communities globally. Implementing environmental, social, and governance (ESG) measures represents a key strategy for corporations in addressing sustainability concerns. This study investigates how the ESG performance of publicly listed companies in China is influenced by employee stock ownership plans (ESOPs). Utilizing a dataset covering 4,464 publicly listed Chinese corporations from 2009 to 2022, this analysis employs fixed-effects regressions to reveal the beneficial impact of ESOPs on corporate ESG ratings. A firm’s transition from non-ESOP to ESOP status raises ESG ratings by 1.213, representing 22% of the ESG score’s standard deviation. The findings indicate that greater involvement of the top management team in an ESOP weakens the positive impact of the ESOP on corporate ESG performance. The positive impact of ESOPs on ESG performance is insignificant in the agriculture sector but more pronounced in the manufacturing and service sectors, where the transition to ESOP status results in ESG score increases of 1.122 and 1.500, respectively. The issue of endogeneity is addressed by utilizing a lagged ESOP independent variable and applying two-stage least squares regression with the average ESOP serving as the instrumental variable. The findings confirm that causality runs from ESOP to ESG rather than ESG influencing ESOP. AcknowledgmentThis study was supported by the Department of Education of Zhejiang Province – General Program (Y202249981, Y202353438), the Wenzhou Association for Science and Technology – Service and Technology Innovation Program (jczc0254), the Wenzhou-Kean University Student Partnering with Faculty Research Program (WKUSPF202404, WKUSPF202411), the Wenzhou-Kean University International Collaborative Research Program (ICRP2023002, ICRP2023004), and the Wenzhou-Kean University Internal Research Support Program (IRSPG202205, IRSPG202206).

Follow which leader? Spatial mimicry and broad‐based equity‐ and profit‐sharing plans

AbstractOrganizations have both local and nationally prominent peers from which they can model their human resource management practices. How does a focal organization reconcile the influence of smaller, spatially proximate peer organizations with the influence of prominent, distant organizations? We develop the concept of spatial mimetic gravity to estimate the mimetic pressures a focal organization feels from its geographically proximate and distant peers. We examine the population of craft beer brewers in the United States between 2013 and 2019 and find that the propensity to offer a stock ownership or profit‐sharing plan is a function of a focal brewery's spatial proximity to its peers and their prominence. We help explain why some firms offer broad‐based equity‐sharing and profit‐sharing plans and others do not. In doing so, we argue that organizational spatial mimicry is best understood from a gravity approach, adding a field‐level explanation to previously individually focused theory about organizational choices.

Launching a European Employee Stock Ownership Plan (European ESOP)

Launching a European Employee Stock Ownership Plan (European ESOP)

12537 Once Daily Oral Atumelnant (CRN04894) Induces Rapid And Profound Reductions Of Androstenedione And 17-Hydroxyprogesterone In Participants With Classical Congenital Adrenal Hyperplasia: Initial Results From A 12-Week, Phase 2, Open-Label Study

Abstract Disclosure: R.J. Auchus: Consulting Fee; Self; Corcept Therapeutics, H Lundbeck A/S, Quest Diagnostics, Sparrow Pharmaceuticals, Neurocrine Biosciences, Novo Nordisk, Recordati Rare Diseases, Diurnal, Xeris Pharmaceuticals. Research Investigator; Self; Corcept Therapeutics, Adrenas Therapeutics, Neurocrine Biosciences, Diurnal, Spruce Biosciences. P.J. Trainer: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc.. K.J. Lucas: None. D. Bruera: None. J. Marko: Consulting Fee; Self; Crinetics Pharmaceuticals, Inc. A. Ayala: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. Y. Wu: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. C.T. Ferrara-Cook: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. E. De La Torre: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. A. Krasner: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. H. Lagast: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. R. Luo: Employee; Self; Crinetics Pharmaceuticals Inc.. Stock Owner; Self; Crinetics Pharmaceuticals Inc. T.A. Bachega: Research Investigator; Self; Spruce Biosciences. R.S. Struthers: Employee; Self; Crinetics Pharmaceuticals Inc.. Stock Owner; Self; Crinetics Pharmaceuticals Inc. S.F. Betz: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. U. Srirangalingam: Consulting Fee; Self; Diurnal, H Lundbeck A/S. Atumelnant (CRN04894) is a potent, once-daily, orally bioavailable, nonpeptide, first-in-class competitive and selective melanocortin type 2 receptor (MC2R, or ACTH receptor) antagonist being developed for the treatment of CAH and ACTH-Dependent Cushing’s Syndrome. Here we report initial results from an open-label, dose-finding phase 2 study of atumelnant in patients with CAH (NCT05907291). Patients (aged ≥18-75, ≥16 years in USA) with classical CAH on a stable dose of GC replacement for at least 6 months were enrolled and received once daily, oral atumelnant for 12 weeks. Key efficacy endpoints include early morning androstenedione (A4) and 17-hydroxyprogesterone (17-OHP) levels. Ten (10) participants have been enrolled and dosed. Data from the first 4 participants (3 females, median age 34 [range 25-42] years, methylprednisone 8 mg/day [hydrocortisone equivalent {HCeq} 32 mg/day, n=2], prednisone 10 mg/day [HCeq 40 mg/day, n=2]) who received 80 mg once daily, oral atumelnant are available. Baseline morning A4 levels in these participants ranged from 116 to 604 ng/dL (reference range [RR]: females 30-200 ng/dL; males 40-150 ng/dL). In these 4 participants, treatment with atumelnant resulted in rapid and profound A4 reductions within 2 weeks which were maintained for the duration of therapy. A4 reductions ranged from 74% to 99% throughout the study. There have been no instances of A4 being above the upper limit of normal on treatment with atumelnant. Baseline 17-OHP levels in these participants ranged from 4740 to 6905 ng/dL (RR: females <80 ng/dL [follicular], <285 ng/dL [luteal]; males <220 ng/dL). In these 4 participants, treatment with atumelnant resulted in rapid and profound 17-OHP reductions within 2 weeks which were maintained for the duration of therapy. 17-OHP reductions ranged from 68% to >99% throughout the study. Two female participants in this cohort menstruated for the first time in over 2 years. Mean baseline morning ACTH ranged from 155 to 1009 pg/mL (RR: 7.2-63 pg/mL), and while modest variations were seen with atumelnant, no consistent directional trend was observed. In conclusion, these data demonstrate rapid, profound, and sustained suppression of A4 and 17-OHP with 80 mg once daily, oral atumelnant. There were no serious or treatment-related adverse events and atumelnant was generally well-tolerated. This ongoing study will explore further the safety and efficacy of various doses of atumelnant. Support: Crinetics Pharmaceuticals, Inc. Presentation: 6/3/2024

7519 Withdrawal of DCCR (Diazoxide Choline) Extended-Release Tablets Worsens Hyperphagia and Increases Weight and BMI in a 16-week Double-blind, Placebo-controlled, Randomized Withdrawal Period in Patients with Prader Willi Syndrome

Abstract Disclosure: E.F. Gevers: Advisory Board Member; Self; Pfizer, Inc., Soleno. Research Investigator; Self; Soleno Therapeutics, Inc.. Speaker; Self; Pfizer, Inc., Novo Nordisk, Soleno Therapeutics, Inc. J.L. Miller: Research Investigator; Self; Soleno Therapeutics, Inc. N.A. Bridges: Research Investigator; Self; Soleno Therapeutics, Inc. E.I. Felner: Research Investigator; Self; Soleno Therapeutics, Inc. P. Salehi: Research Investigator; Self; Soleno Therapeutics, Inc. D. Stevenson: Research Investigator; Self; Soleno Therapeutics, Inc. J. Yanovski: Research Investigator; Self; Soleno Therapeutics, Inc. L. Bird: Research Investigator; Self; Soleno Therapeutics, Inc. V. Kimonis: Research Investigator; Self; Soleno Therapeutics, Inc. A.H. Shoemaker: Research Investigator; Self; Soleno Therapeutics, Inc. K.S. Obrynba: Research Investigator; Self; Soleno Therapeutics, Inc. M. Lah: Research Investigator; Self; Soleno Therapeutics, Inc. E. Littlejohn: Research Investigator; Self; Soleno Therapeutics, Inc. N. Cowen: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. N. Cowen: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. K. Yen: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. S. Ballal: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. P. Hirano: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. M. Huang: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. A. Bhatnagar: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc.. Background: Prader-Willi syndrome (PWS) is a rare genetic neurobehavioral-metabolic disease characterized by hyperphagia, endocrinopathies, weight gain, hypotonia, behavioral problems, and an increased risk of mortality and reduced life expectancy. There are currently no approved treatments for hyperphagia in PWS. Diazoxide choline extended-release (DCCR) is a novel, once daily oral therapy being developed for the treatment of PWS. Herein, we present results of the Randomized Withdrawal Period (RWP) of Clinical Study C602, a long-term treatment study of DCCR in people with PWS. Objectives and Methods: This was a 16-week multi-center, double-blind, placebo-controlled RWP that enrolled participants ≥4 years of age who were actively enrolled in the open label period of Clinical Study C602 and had received 2-4 years of DCCR treatment (target dose: ≥3.3 mg/kg; optimal range: 4.2-5.8 mg/kg) at the time of RWP entry. RWP-eligible participants were randomized 1:1 to continue DCCR or withdraw from DCCR and receive Placebo. The primary objective was to evaluate the effect of continued DCCR administration versus Placebo on hyperphagia based on the change in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score from Baseline to Week 16. Additional endpoints included: the Clinical Global Impression of Severity (CGI-S) and Clinical Global Impression of Improvement (CGI-I) at Week 16; changes in body composition (weight, BMI, and BMI z-scores) at Week 16; and the safety profile of DCCR. Results: DCCR (n=38) and Placebo (n=39) groups were generally balanced for demographic and baseline characteristics. At Week 16, a statistically significant difference in change from baseline in HQ-CT Total Score was observed between DCCR and Placebo groups with HQ-CT Total Scores increasing markedly (indicating worsening hyperphagia) in the Placebo group compared to the DCCR group (LSMean difference [SE] -5.0 [1.57], p=0.002). CGI-S and CGI-I showed trends towards worsening in the Placebo group versus the DCCR group (p=0.079 and 0.092, respectively). The Placebo group also experienced significantly greater increases in weight, BMI, and BMI z-scores (p=0.035, 0.034, and 0.023, respectively) than the DCCR group. DCCR was well-tolerated, with no new or unexpected safety signals, and no serious adverse events or discontinuations due to adverse events in the DCCR group. Conclusions: In this 16-week RWP, the Placebo group experienced significant worsening in hyperphagia and increases in body weight, BMI, and BMI z-scores, along with worsening trends for the CGI-S and CGI-I, compared to the DCCR group. DCCR was well tolerated, with a safety profile that was consistent with prior experience. These data suggest treatment with DCCR may lead to clinical benefits in people with PWS by reducing hyperphagia and improving body composition. Presentation: 6/2/2024

8404 Use of the Acromegaly Symptom Diary (ASD) in a Phase 3, Placebo-Controlled Study of Once-Daily, Oral Paltusotine in Patients With Acromegaly Switched From Injected Octreotide or Lanreotide

Abstract Disclosure: M.R. Gadelha: Consulting Fee; Self; Crinetics, Ipsen, Novo Nordisk, and Recordati. Research Investigator; Self; Crinetics and Recordati. Speaker; Self; Ipsen, Novo Nordisk, and Recordati. A. Casagrande: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. C.J. Strasburger: Consulting Fee; Self; Amolyt Pharma, Consilient Health, Novo Nordisk, Recordati, and Sandoz-Hexal. Research Investigator; Self; Crinetics. M. Bidlingmaier: Consulting Fee; Self; Crinetics, Ionis, Novo Nordisk, Pfizer, Roche, and Sandoz. Research Investigator; Self; Amolyt, Camurus, Chiasma, Crinetics, IDS, Ionis, Lumos, and OPKO. Speaker; Self; Euroimmun, Novo Nordisk, and Pfizer. P.J. Snyder: Research Investigator; Self; Crinetics. M.A. Guitelman: Consulting Fee; Self; Recordati, Sanofi Aventis, and Varifarma. Research Investigator; Self; Crinetics. Speaker; Self; Recordati, Sanofi Aventis, and Varifarma. C.L. Boguszewski: Consulting Fee; Self; Ipsen, Novo Nordisk, and Recordati. Research Investigator; Self; Crinetics. Speaker; Self; Ipsen, Novo Nordisk, and Recordati. M. Buchfelder: Research Investigator; Self; Crinetics. I. Shimon: Consulting Fee; Self; Medison and Pfizer. Research Investigator; Self; Crinetics and Debiopharm. Speaker; Self; Medison and Pfizer. G. Raverot: Consulting Fee; Self; Amolyt, Crinetics, Ipsen, Novo Nordisk, Pfizer, and Recordati. Research Investigator; Self; Crinetics. Speaker; Self; Ipsen, Pfizer, and Recordati. M. Toth: Consulting Fee; Self; Ipsen, Lilly, Novartis, and Recordati. Research Investigator; Self; Crinetics. Speaker; Self; Ipsen, Lilly, Novartis, and Recordati. E. Mezosi: Research Investigator; Self; Crinetics. M. Doknic: Advisory Board Member; Self; Pfizer in CEE. Research Investigator; Self; Crinetics. X. Fan: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. D. Clemmons: Consulting Fee; Self; Crinetics. M. Keeley: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. P.J. Trainer: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. R. Struthers: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. A. Krasner: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. B.M. Biller: Consulting Fee; Self; Amryt, Camurus, Crinetics, and Recordati. Research Investigator; Self; Crinetics and Ionis. Paltusotine is a once-daily, selective, non-peptide, SST2 receptor agonist in development as an oral treatment for patients with acromegaly or carcinoid syndrome. The Acromegaly Symptom Diary (ASD) is a novel patient-reported outcome tool developed in accordance with US FDA guidance to assess disease-related symptom burden. The ASD consists of 7 core items (headache, joint pain, sweating, fatigue, leg weakness, swelling, numbness/tingling, score range: 0-70; higher scores indicate greater symptom burden) plus 2 additional items (sleep difficulty, memory difficulty) and is completed daily. We previously reported the topline results of PATHFNDR-1 (NCT04837040), a phase 3 trial evaluating the efficacy and safety of paltusotine in adults with acromegaly who were previously controlled (IGF-I ≤1.0 ×ULN) on stable (≥12 weeks) injected octreotide or lanreotide. Patients were randomly allocated to once-daily paltusotine 40 mg or placebo for 36 weeks, with uptitration to 60 mg/day permitted through week 24. IGF-I and GH levels (IDS-iSYS) and pituitary tumor volume (MRI) were measured centrally. Fifty-eight patients (paltusotine, n=30; placebo, n=28) were enrolled: mean (±SD) age 54.9±13.7 years; 55.2% female; prior treatment octreotide LAR (n=34) or lanreotide depot (n=24). The primary endpoint (proportion of patients maintaining IGF-I ≤1.0 ×ULN [mean of weeks 34 and 36]) was met by significantly more patients on paltusotine (83.3%) versus placebo (3.6%; odds ratio: 126.53; 95% CI: 13.73, >999.99; P<0.0001). All secondary endpoints were met: mean (±SE) change in IGF-I of 0.04±0.09 ×ULN versus 0.83±0.1 ×ULN (P<0.0001); and GH maintained at <1.0 ng/mL in 87.0% versus 27.8% of patients (odds ratio: 16.61; 95% CI: 2.86, 181.36; P<0.001). The most common adverse events (AEs) were typical of the somatostatin receptor ligand (SRL) class or acromegaly symptoms. There were no severe or serious AEs in the paltusotine group. One patient in the placebo group discontinued study participation (patient decision). There were no clinically significant changes in pituitary tumor volume. The mean completion rate of the daily ASD questionnaire was 79.1%. At the end of randomized treatment, the ASD total score was significantly increased from baseline (indicating worsening) in the placebo group compared with the paltusotine group, meeting the secondary endpoint (-0.6±1.5 versus 4.6±1.6; P=0.02). For individual ASD symptoms, mean scores were consistently indicative of improvement with paltusotine compared to placebo; the between-group difference was statistically significant for joint pain (P<0.05), numbness/tingling (P<0.01), and the “most bothersome” symptom (P<0.05). In conclusion, once-daily oral paltusotine maintained symptom control in concert with biochemical values in well-controlled patients switched from injected SRLs and was well tolerated. Support: Crinetics Pharmaceuticals Presentation: 6/3/2024

12481 Evaluating The Device Handling And Preference Assessment Questionnaire For Growth Hormone Deficiency: Results From Content Validation Interviews

Abstract Disclosure: J. Neergaard: Employee; Self; Novo Nordisk. S. Akhtar: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. B. Berg: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. S. Hamilton: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. E. Hildebrand: Consulting Fee; Self; Novo Nordisk. J. Medina: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. G. Ter-Borch: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. N. Rasmussen: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. Background: Patient experiences with injection devices may affect treatment adherence, and hence it is important to ensure patient-reported outcomes (PRO) instruments used to assess experience are supported by evidence of validity. As part of a study that compared patient preference and ease of use between the devices used to administer Somapacitan (Sogroya®, Novo Nordisk A/S) and Somatrogon (Ngenla®, Pfizer), we assessed relevance, comprehensiveness and comprehension of a PRO instrument, the Device Handling and Preference Assessment Questionnaire (DHPAQ), in adolescent patients with growth hormone deficiency (GHD) and their caregivers. Methods: We recruited 33 adolescent patients with GHD and 37 caregivers across five sites in the US for an open label, randomized, crossover study in which participants simulated an injection with each device using an injection pad or mannequin. The DHPAQ was used to assess patients’ device preference. Two-sided statistical tests with 5% significance levels were performed using DHPAQ responses. After completing the DHPAQ, a random subgroup of 10 adolescents and 10 caregivers were offered additional compensation to participate in a cognitive interview (CI). The CIs were conducted in accordance with the US Food and Drug Administration 2022 Principles for PRO Instruments and 2009 PRO Guidance for Industry. Trained interviewers used a structured guide to evaluate questions, statements, tasks and response options in the DHPAQ. Participants’ interview responses for each question were coded and added to summary tables. These summary tables were evaluated by the study team to determine the relevance, comprehensiveness and participant comprehension of instructions, item stems and response options. Results: When asked if any questions in the DHPAQ did not seem relevant to their device experience, all 20 CI participants answered “no”. Questions on “learning how to use the device”, “selecting the correct dose” and “injecting the dose” were ranked as most relevant. Participants responses from the CIs supported perceived comprehensiveness of all DHPAQ items. All CI participants reported comprehension of all test items in the DHPAQ, and only three items did not receive a “no difficulty” response from all 20 participants. In the main study, the number of participants who preferred the somapacitan device was significantly greater than those who preferred the somatrogon device (84.3% vs 12.9%, p<0.0001). More participants found the somapacitan device easy or very easy to use compared with the somatrogon device (98.6% vs 74.3%). Conclusions: The results from the CIs indicated that the instructions, item stems and response options of the DHPAQ were relevant, comprehensive and fully comprehended by all participants. In the main study, patients with GHD and their caregivers were found to prefer the somapacitan device to the somatrogon device. Presentation: 6/2/2024

9330 Atumelnant (crn04894) Induces Rapid And Sustained Reductions In Serum And Urine Cortisol In Patients With Acth-Dependent Cushing Syndrome During A Phase 1b/2a, Single Center, 10-day, Inpatient, Open-Label Study

Abstract Disclosure: H. Elenius: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. R. McGlotten: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. C. Moore: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. Y.B. Omotosho: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. A. Ayala: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. Y. Wu: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. P.J. Trainer: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. R.S. Struthers: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. A. Krasner: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. S.F. Betz: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. L.K. Nieman: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc.. Atumelnant is a potent, once-daily oral, nonpeptide, first-in-class competitive and selective melanocortin type 2 receptor (MC2R) antagonist that blocks ACTH-mediated G-protein activation and subsequent signaling. It is being developed for the treatment of ACTH-dependent Cushing Syndrome (ADCS) and classic congenital adrenal hyperplasia. We report preliminary data from the first-in-disease, dose-finding study of atumelnant in patients with ADCS (NCT05804669). Inpatient participants with active ADCS (24h urine free cortisol (UFC) >1.3xULN, ACTH >10 pg/mL) received atumelnant 80 mg once daily at 08.00 for 10 days (D1-10) followed by a 4-day washout. Endpoints included changes in UFC (upper limit of normal (ULN) 45 ug/d), early morning cortisol (EMC), and early morning ACTH (EMA, ULN 46 pg/mL). Daily questionnaires assessed adverse events (AEs) and signs and symptoms of adrenal insufficiency (AI) and ADCS. Data are shown as median (range). We report 5 participants (4 men; 4 Cushing disease, 1 ectopic ACTH; age 47 years (34-55)); each completed the study. All participants developed biochemical evidence of AI (EMC <5 mcg/dL) after 2 days (1-10) of atumelnant administration and then commenced physiologic hydrocortisone (HC) add-back. Compared to D1, biochemical disease control (normal UFC plus EMC <5 mcg/dL) was shown on D11 in all participants, while receiving HC replacement: UFC 252 mcg (99-293) vs 24 mcg (3.9-51); EMC 14 mcg/dL (10.7-18.1) vs 1.4 (1.0-4.7). This was associated with an increase in EMA: 52.1 pg/mL (33-1088) vs 78 pg/mL (48.8-4045). HC was discontinued when EMC was ≥7 mcg/dL, on D13 (D12-18). Many pre-existing features of ADCS improved during atumelnant administration, including poor concentration, insomnia (n=3 each); brain fog, anxiety, irritability (n=2 each); fatigue, poor memory, low libido, depression, edema and bloating (n=1 each). Low testosterone, neutrophilia (n=3 each) and leukocytosis (n=2) observed at baseline resolved during atumelnant administration. Anti-hypertensive therapy was paused or reduced in 3 subjects. New fatigue, headache, nausea, anorexia, edema (n=2 for each) all coincided with development of biochemical AI; most symptoms improved with HC add-back. Serious adverse events included AI and one non-treatment related transient GI bleed 19 days after the last dose. All other AEs were mild or moderate: transient increases of creatinine (n=2), and ALT (<3xULN, n=2). In conclusion, the first 5 patients with ADCS to receive once daily, oral atumelnant experienced rapid lowering of serum and urine cortisol and improvement or resolution of some signs and symptoms of ADCS. Atumelnant was generally well-tolerated. The observed compensatory increase in ACTH was not associated with loss of efficacy or clinical sequelae. This ongoing study will further explore the relationship between atumelnant dose, including lower doses, and therapeutic response. Presentation: 6/3/2024

5162 Oral LUM-201 Restores Pulsatile Growth Hormone Secretion and Growth Response in Moderate Pediatric Growth Hormone Deficiency (PGHD): Key Discoveries from Phase 2 of OraGrowtH212 Trial

Abstract Disclosure: F. Cassorla: Consulting Fee; Self; Lumos Pharma, Inc. Research Investigator; Self; Lumos Pharma, Inc. R. Roman: Research Investigator; Self; Lumos Pharma, Inc. M.L. Johnson: Consulting Fee; Self; Lumos Pharma, Inc. A. Avila: Research Investigator; Self; Lumos Pharma, Inc. G. Iñiguez: Research Investigator; Self; Lumos Pharma, Inc. I. Baier: Research Investigator; Self; Lumos Pharma, Inc. D. Said: Research Investigator; Self; Lumos Pharma, Inc. A. Bruchey: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. C. Smith: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. E. Brincks: Employee; Self; Lumos Pharma. Stock Owner; Self; Lumos Pharma, Inc. J. McKew: Employee; Self; Lumos Pharma. Stock Owner; Self; Lumos Pharma. M.O. Thorner: Consulting Fee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Ammonett Pharma LLC. P. Pitukcheewanont: Employee; Self; Lumos Pharma. Stock Owner; Self; Lumos Pharma. Objectives: The primary objective was to examine the pharmacokinetic/pharmacodynamic (PK/PD) aspects of oral LUM-201 at doses of 1.6 and 3.2 mg/kg/d with moderate PGHD, involving frequent GH sampling for 12 hours post-administration. Using deconvolutional analysis, the study compared the GH secretion patterns before & after 6 months (m) daily administration of LUM-201. LUM-201, an investigational agonist of the growth hormone (GH) Secretagogue Receptor 1a (GHSR1a), was employed as part of a predictive enrichment marker (PEM) test to identify moderate PGHD subjects likely to respond, based on baseline insulin-like growth factor-1 (IGF-1) level >30 ng/mL & a peak GH of ≥5 ng/mL post a single 0.8 mg/kg dose of LUM-201. Methods: The OraGrowtH212 Trial, conducted at Santiago, Chile, monitors subjects until they approach their near final height. The current report focuses on data analysis at 6 and 12m, with ongoing subject follow-ups extending to 24m. This trial randomized 22 PEM+ moderate PGHD subjects into two LUM-201 dosage groups: 1.6 or 3.2 mg/kg/d. To assess GH secretion, each child was sampled every 10 min from 0800-2000h at baseline & 6m. Safety was assessed throughout the study and growth evaluated at 6 & 12m intervals. Results: At start of the study, basal GH secretion in the LUM-201 1.6mg/kg/d group (all values expressed as mean ± SD µg/kg body weight) was 0.19 ±0.09, pulsatile GH was 1.17 ± 0.66, and total GH was 1.35 ± 0.66. At 6m, each of these parameters had significantly increased to 0.36 ± 0.21, 1.8 ±0.74 and 2.2 ±0.89 respectively (p values from 0.02-0.04). Similar significant increases were seen for LUM-201 3.2mg/kg/d. Combining the data from both LUM-201 doses demonstrated that GH secretion determined by deconvolution analysis was 3.3-4.0 µg/kg/24hrs compared to 5 µg/kg/24hrs derived from published data on normal children (Zadik et al, Horm Res 1992), indicating restoration of GH secretion by LUM-201. These values are considerably less than 25-34µg/kg/d of recombinant human GH used in the treatment of PGHD. At 6m, the annualized height velocity (AHV) was 7.2cm/yr for the LUM-201 1.6mg/kg/d and 8.1cm/yr for the 3.2 mg/kg/d dose. At 12m, AHV for a subset was 6.9cm/yr for the 1.6 dose and 7.2cm/yr for the 3.2 dose. Baseline IGF-1 SDS (mean ±SD) were -1±0.63 in 1.6mg/kg/d group & -0.85±0.47 in 3.2mg/kg/d group. The change over 12m was +0.9 on 1.6 dose and +1.1 on 3.2 dose, indicating similar efficacy for IGF-1 generation. LUM-201 showed good tolerability in this study, with no observed safety concerns in adverse events (AEs), labs, and ECGs. Conclusions: At 6m LUM-201 was able to restore endogenous GH pulsatile secretion to a similar level to that seen in normal children, while normalizing serum IGF-1 concentrations. These results indicate that by restoring endogenous GH secretion, LUM-201 facilitates growth utilizing a much lower amount of GH than that provided by daily exogenous rhGH administration. Presentation: 6/3/2024

6461 VRDN-003, A Full Antagonist Antibody To The IGF-1 Receptor For Thyroid Eye Disease (TED): Safety And Pharmacokinetic Results Of Subcutaneous Administration In Healthy Volunteers

Abstract Disclosure: K. Foster: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. B. Dickinson: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. A. Matthew: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. J. Vijayaraghavan: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. C. Michalsky: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. V. Bedian: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. Introduction: While VRDN-001 is a full antagonist antibody to the IGF-1 receptor (IGF-1R) with phase 2 proof-of-concept data showing clinically meaningful improvements in thyroid eye disease (TED) symptoms after 2 intravenous (IV) infusions, VRDN-003 is a next-generation half-life extended version of VRDN-001. VRDN-003’s half-life extension has the potential to provide sustained pharmacokinetics (PK) and pharmacodynamics (PD) with less frequent administration. We present results from an ongoing study to assess the safety, PK, PD, and bioavailability of VRDN-003 for subcutaneous (SC) administration. Methods: Healthy volunteers (HVs) were randomized to receive a single dose of VRDN-003 or placebo in the following 4 IV or SC dose cohorts: IV 5.0 mg/kg, IV 15.0 mg/kg, SC 300 mg, or SC 600 mg. Preliminary treatment-emergent adverse events (AEs) were assessed through December 12, 2023, and will continue to be assessed through study exit (120 days). Preliminary PK parameters including bioavailability were assessed by noncompartmental analysis, and a 2-compartment Population PK model was employed to simulate exposures following repeat SC dosing. Results: Twenty-eight HVs received either VRDN-003 IV (n=8), VRDN-003 SC (n=12), placebo IV (n=4), or placebo SC (n=4). AEs were reported by 25% (2/8) of participants who received VRDN-003 IV, 25% (3/12) who received VRDN-003 SC, and 13% (1/8) who received placebo. Of the AEs, 3 were deemed treatment related, all occurring in VRDN-003 SC-treated patients and all grade 1/mild as follows: injection site reaction, insomnia, and hepatic enzyme increased. No serious AEs were reported. VRDN-003 half-life was estimated at 40-50 days, 4-5 times longer than VRDN-001; bioavailability is currently estimated to be approximately 60% after SC administration. Simulated dosing regimens show the potential for VRDN-003 to be administered SC Q4W or Q8W and reach exposure levels observed with the VRDN-001 parent molecule in its prior phase 2 study. Conclusions: A single dose of VRDN-003 administered IV or SC to HVs was well tolerated and showed favorable PK for SC administration including a half-life of 40-50 days, 4-5 times longer than its parent molecule, VRDN-001. These results show the potential for VRDN-003 SC dosing regimens with the goal of reducing the treatment burden associated with achieving IGF-1R blockade in TED. Safety and efficacy of VRDN-003 SC will be further assessed in planned clinical studies enrolling patients with TED. Presentation: 6/1/2024

9318 Growth Response To Oral Growth Hormone Secretagogue LUM-201 In Children With Moderate GH Deficiency (GHD) Is Dependent On The Pattern Of Pulsatile GH Secretion Induced By LUM-201

Abstract Disclosure: A. Roslan: None. R. Roman: None. A. Avila: None. D. Said: None. I. Baier: None. E. Brincks: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. A. Bruchey: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. J. McKew: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. P. Pitukcheewanont: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc.. M. Johnson: None. T. Garner: Consulting Fee; Self; Lumos Pharma, Inc.. Grant Recipient; Self; Novo Nordisk. M.O. Thorner: Consulting Fee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. P.E. Clayton: Advisory Board Member; Self; Lumos Pharma, Inc.. Consulting Fee; Self; Lumos Pharma, Inc.. Grant Recipient; Self; Novo Nordisk. A. Stevens: Consulting Fee; Self; Lumos Pharma, Inc. F. Cassorla: Consulting Fee; Self; Lumos Pharma, Inc.. Background: Oral GH secretagogue, LUM-201, increases growth rates in children with moderate GHD in Phase 2 trials (OraGrowtH210 and 212) [ENDO 2023, OR21-06]. GH pulse profiles at baseline (D1) and 6 months (6M) were assessed in OraGrowtH212. This study aims to understand relationships between pulse profiles and growth response to LUM-201. Methods: The OraGrowtH212 trial is being conducted at a single site (Chile). 22 prepubertal children (M 14: F 8) with moderate GHD (peak GH level on two stimulation tests >3 and <10ng/ml), who had basal IGF-I >30ng/ml and an acute GH response to 0.8mg/kg LUM-201 of ≥5ng/ml, were randomised to receive LUM-201 1.6 or 3.2 mg/kg/day. 10min samples over 12hrs (08.00-20.00) were collected at D1 and M6 for measurement of GH concentration (ng/ml), with GH secretion rates (ng/ml/min) derived by deconvolution analysis. A univariate Spearman’s rank correlation matrix was used to screen for relationships (significant at p<0.05) between D1 characteristics, D1 height velocity, 6M annualised height velocity (AHV) and interpulse, pulsatile and total GH secretion at D1 and M6.The pattern of pulsatile GH secretion in the 12hr profile was characterised using Functional Principal Component Analysis (FPCA) - used to explore the dominant modes of variation in functional data, in this case the GH time series. Subjects were grouped into tertiles based on 6M AHV (High [mean 8.9cm/yr], Medium [7.7], and Low [6.7]), and the 12hr profiles were divided into three 4hr intervals. The interquartile range (IQR) for mean GH secretion (representing variation in amount) and principal components [PCs] (variation in pattern) for all subjects in each AHV tertile at D1 and M6 were generated. Results: All GH secretion parameters increased significantly from D1 to M6 (p<0.01). Age was negatively associated with 6m AHV (rs= -0.46), and D1 pulsatile GH secretion was positively associated with D1 AHV (rs = +0.51). However, GH secretion at D1 and M6 was not correlated with 6m AHV. In the FPCA, the difference in IQR for mean GH secretion from D1 to 6M was highest over 0-4hrs for subjects in the high and medium AHV tertiles (5- and 3.3-fold greater respectively compared to the other time intervals), while subjects with low AHV had the highest difference over 8-12hrs (42-fold greater). Using the first PC (which accounts for ∼50% of total variation), the change in IQR was highest over 0-4 and 4-8hrs in the high AHV tertile (3-fold greater compared to other time intervals), over 0-4hrs in the medium tertile (46-fold greater) and over 8-12hrs in the low tertile (3.4-fold greater). Conclusions: Oral LUM-201 stimulates significant increases in GH secretion over 6 months in children with moderate GH deficiency. Complex relationships exist between growth response and both the amount and pattern of GH secretion, with the highest growth responses to LUM-201 associated with the greatest pulsatile activity early in the profile. Presentation: 6/3/2024

12497 Stage 1 Results Of The Phase 2 Daybreak Trial Assessing Setmelanotide In Patients With Early-onset, Severe Obesity And Hyperphagia Who Carried A Confirmed Variant Related To The Melanocortin-4 Receptor Pathway

Abstract Disclosure: G. Ortiz: Speaker; Self; Rhythm Pharmaceuticals, Inc. S.B. Ten: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc. Speaker; Self; Rhythm Pharmaceuticals, Inc. W. Herring: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc, Novo Nordisk. O. Pinhas-Hamiel: None. E.A. Oral: Consulting Fee; Self; Rhythm Pharmaceuticals, Inc., Akcea Therapeutics, Ionis Pharmaceuticals Inc., Morphic Medical, Fractyl Laboratories, Regeneron Pharmaceuticals, Amryt Pharmaceuticals (now Chiesi), Third Rock Ventures, Rejuvenate Bio, NIDDK. Other; Self; Has patents for use of metreleptin in lipodystrophy and recombinant leptin or analogues in NASH. N. Rosano: Consulting Fee; Self; Novo Nordisk. Speaker; Self; Rhythm Pharmaceuticals, Inc. D. Koren: Employee; Self; Rhythm Pharmaceuticals, Inc.. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. H. Lee: Employee; Self; Rhythm Pharmaceuticals, Inc.. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. J. Garrison: Employee; Self; Rhythm Pharmaceuticals, Inc.. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. O. Ohayon: Employee; Self; Rhythm Pharmaceuticals, Inc.. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. P. Sleiman: Employee; Self; Rhythm Pharmaceuticals, Inc.. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. M. Wabitsch: Consulting Fee; Self; Rhythm Pharmaceuticals, Inc.. Speaker; Self; Rhythm Pharmaceuticals, Inc.. Other; Self; Rhythm Pharmaceuticals, Inc. E. van den Akker: Speaker; Self; Federatie Medisch Specialisten, Stichting Kwaliteitsgelden Medisch Specialisten, Medialane TV, Pfizer, Inc.. Other; Self; Nederlandse Hartstichting/ZonMW, Stichting Erasmus Trustfonds, Rhythm Pharmaceuticals, Inc. J. Argente: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc. Speaker; Self; Rhythm Pharmaceuticals, Inc.. I. Farooqi: None. Background: DAYBREAK (NCT04963231) was designed to evaluate setmelanotide in individuals who carried a confirmed variant in ≥1 of 31 genes with strong or very strong relevance to the melanocortin-4 receptor (MC4R) pathway, which regulates energy balance and satiety. Methods: DAYBREAK is a 2-stage, double-blind, placebo-controlled trial conducted at 37 sites across 8 countries. Individuals aged 6 to 65 years with body mass index (BMI) ≥40 kg/m2 (aged ≥18 years) or ≥97th percentile (aged ≥6 to <18 years) and hyperphagia who carried variants classified as uncertain significance (VUS), likely pathogenic, or pathogenic according to the American College of Medical Genetics (ACMG) criteria in ≥1 of the 31 genes were eligible. Individuals with ≥5% BMI reduction from baseline (ie, responders) at the end of the 16-week, open-label run-in period (Stage 1) were eligible to enter a 24-week, double-blind, randomized, placebo-controlled period (Stage 2). The primary endpoint of Stage 1 was the proportion of responders per gene cohort at the end of the Stage. Results: A total of 164 individuals were enrolled; 100 patients who completed Stage 1 and 12 who discontinued treatment within a prespecified 2 weeks before the end of Stage 1 were included in the completers analysis. Participants were divided into 15 gene cohorts; of 7 cohorts with ≥5 patients, 6 (SEMA3[A-G], PLXNA[1-4], PHIP, TBX3, MAGEL2, and SIM1) showed potential setmelanotide efficacy (KSR2 did not). Response rates across cohorts (range, 25.0%-56.3%), intracohort response magnitudes (percent BMI change from baseline to Week 16; range, −6.4% to −4.0%), and intracohort variant types varied. While response rate was highest in the PHIP cohort (56.3% of the full cohort and 69.2% of completers), ≥1 patient per cohort achieved ≥10% BMI reduction. Because ∼80% of VUS are eventually reclassified to benign or likely benign, the inclusion of VUS may have contributed to response variability. An ad hoc analysis showed an increased response rate with updated versus starting ACMG variant classification. Overall, 49 responders across 6 gene cohorts were randomized into Stage 2. Setmelanotide was well tolerated with no new safety concerns. Conclusions: DAYBREAK Stage 1 identified 6 additional genes or gene families in the MC4R pathway that respond to setmelanotide. Response was associated with predicted variant pathogenicity, allowing for further refinement of patient selection. Stage 2 results will further elucidate Stage 1 findings. Presentation: 6/3/2024

8406 A Phase 1 Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZP-3813, a Novel Small Peptide Growth Hormone Receptor Antagonist, in Healthy Subjects

Abstract Disclosure: S. Allas: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. G. Ravel: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. C. Farrell: Employee; Self; ICON plc. S. Fillon: Employee; Self; Amolyt Pharma. O. Taha: Employee; Self; Amolyt Pharma. M.D. Culler: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. M. Ovize: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. M. Sumeray: Employee; Self; Amolyt Pharma. Stock Owner; Self; Amolyt Pharma. A.J. Van der Lely: Consulting Fee; Self; Amolyt Pharma. Acromegaly is a rare disease typically caused by a benign growth hormone (GH)-secreting pituitary adenoma that stimulates over-production of insulin-like growth factor-1 (IGF1) from the liver. Treatment with somatostatin analog (SSA) monotherapy does not provide optimal control of circulating IGF-1 levels in the majority of patients. AZP-3813, a 16-amino acid, bicyclic GH receptor antagonist (GHRA) binds to the GH receptor and prevents endogenous GH from stimulating the production of IGF-1. The compound is being developed as an add-on therapy for the treatment of acromegaly in patients insufficiently controlled with SSAs. In normal animals, AZP-3813 potently decreases circulating levels of IGF-1 and further suppressive effects are observed when combined with the SSA, octreotide. Randomized double-blind placebo-controlled single and multiple ascending dose studies (SAD and MAD, respectively) are being conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AZP-3813 in healthy subjects. Here we report data from all SAD cohorts and the first 3 MAD cohorts. In the SAD study, 5 subjects received a single subcutaneous administration of 3 mg AZP-3813 or placebo (3:2) and 8 subjects received 10, 20, 40, 60, 90, 120 mgAZP-3813 or placebo (6:2). In the MAD study, 8 subjects received 10, 20, 40 mg AZP-3813 or placebo (6/2) QD for 14 consecutive days. In both SAD and MAD studies, treatment was well tolerated in all subjects with no safety concerns. Cmax and AUC increased in a dose-proportional manner. The half-life of AZP-3813 was estimated to be 18-22 hours. In the SAD study, AZP-3813 induced a dose-related decrease in circulating IGF-1 levels at doses of 10 mg and above with a more prolonged reduction up to 72 hours at higher doses. In the MAD study, AZP-3813 induced a gradual and sustained dose-related decrease in circulating IGF-1 levels at 20 and 40 mg/day, with a larger effect after 2 weeks of dosing as compared to single administration at the same dose, consistent with a cumulative effect of repeated administration. Mean placebo-adjusted % change from baseline for the 20 and 40 mg cohorts were 19% and 44%, respectively. This study is ongoing, and updates on additional MAD cohorts will be reported at the meeting. These data clearly demonstrate that AZP-3813, the novel GHRA, substantially decreases circulating IGF-1 levels in healthy individuals, thereby supporting further testing in patients with acromegaly. Presentation: 6/1/2024

8172 Retrospective Analysis of mRNA Expression Based Signatures of Thyroid Tumor Invasion and Metastases

Abstract Disclosure: S. Ahmadi: None. E. Namiranian: None. M. Alshalalfa: Employee; Self; Veracyte, Inc.. Stock Owner; Self; Veracyte, Inc. R. Jiang: Employee; Self; Veracyte, Inc.. Stock Owner; Self; Veracyte, Inc. Y. Hao: 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.. E. Marqusee: None. The American Thyroid Association thyroid cancer risk stratification system is driven primarily by the extent of vascular and extrathyroidal extension, as well as lymph node metastases. Minimizing surgical intervention for thyroid tumors from indeterminate thyroid nodules (ITN - Bethesda III and IV cytology) is often preferred to mitigate surgical complications and lessen the need for thyroid hormone supplementation post-operatively if clinical outcomes are not worsened. By leveraging the whole transcriptome derived Afirma Genomic Sequencing Classifier (GSC) thyroid nodule molecular testing platform, mRNA expression-based signatures were developed to predict thyroid tumors with a low risk of clinically significant invasion and metastases with a > 95% negative predictive value as part of the Afirma Genomics Resource for Intelligent Discovery (GRID). The objective of this study was to analyze the performance of these signatures on a retrospective cohort of patients with ITN who had Afirma GSC suspicious findings and thyroid surgery. Two hundred three subjects were evaluated, and pathology reports were scored for the extent of thyroid tumor invasion or metastases. Tumors with extensive vascular invasion or extrathyroidal extension are labeled as high risk (and otherwise are low risk). Tumors with lymph node metastases that either have documented > 2mm tumor deposits, > 40% of central nodes involved, or lateral lymph node metastases are labeled as high risk (and otherwise are low risk). The Afirma GRID invasion and metastases signatures were applied to correlate with the pathology scoring. The cohort was comprised of 144 (70%) female and 59 (30%) male patients with median age of 54 [IQR 40-65]. The cohort was mostly Bethesda III (n= 152, 75%). Fifty three percent (n=109) of the samples were malignant upon histology review. Two samples were scored as high risk for lymph node metastases (LNM) and 4 samples were scored as high risk for invasion (INV) based on final pathology. The LNM signature ruled out 55% of samples with 100% NPV and 55% specificity. No samples with high risk LNM scores were erroneously ruled out by the LNM GRID signature. The rule out % was similar in female (58%) and males (46%) (chi-squared test p=0.1). For the invasion model, 57% of samples were ruled out with 99% NPV and 57% specificity. One sample with extra-thyroidal invasion had a false negative GRID INV signature. The INV rule out % was similar in female (57%) and males (54%) (chi-squared test p=0.19). In summary, the Afirma GRID INV and LNM signatures ruled out clinically significant thyroid tumor features in > 50% of the studied cohort with > 95% NPV. Prospective studies should be performed to confirm the potential for Afirma GRID tumor behavior signatures to optimize and individualize surgical decision-making, decreasing the burden of unnecessary extent of thyroid surgery while maintaining outstanding clinical outcomes. Presentation: 6/3/2024

8518 Prevalence of Hearing Dysfunction in Patients with Autoimmune Thyroid Disorders, Thyroid Eye Disease and the General US population: A Claims Database Analysis

Abstract Disclosure: T.J. Smith: Consulting Fee; Self; Amgen Inc, Viridian, Minghui, Lassen, Lundbeck. Other; Self; US patents covering the use of IGF-1 receptor inhibitors in TED which are held by UCLA and the Lundquist Institute. A. Meyers: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. Q. Fu: Stock Owner; Self; Amgen Inc. Other; Self; Amgen Inc, former employee. R.J. Holt: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. K. Zhu: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. Background: Autoimmune thyroid conditions including Graves’ disease (GD) have been associated with hearing impairment.([1]-3) Approximately 90% of patients (pts) with thyroid eye disease (TED) have hyperthyroidism/GD. Teprotumumab, an insulin-like growth factor-I receptor inhibitor, significantly improves TED signs/symptoms and became the first FDA-approved treatment for TED in 2020. Hearing-related adverse events were identified in pivotal trials of teprotumumab in TED.4 This epidemiology study aims to describe the prevalence of hearing loss/ototoxicity via claims data in commercially insured pts with autoimmune thyroid conditions, TED, and those receiving teprotumumab, as well as the general population (gen pop). Methods: Five mutually exclusive cohorts were created using deidentified claims data (Merative MarketScan®): GD pts (index is first GD diagnosis [dx] code), TED pts (index is later of both GD dx or eye symptom codes within 1 yr), teprotumumab pts (index is first claim for teprotumumab), other Thyroid Disorders (TD) pts (index is TD dx), and gen pop pts. Pts with teprotumumab claim were excluded from other cohorts. Eligible pts were ≥18 years (yrs) of age, continuously enrolled for ≥6 months pre and post index, between 1/1/2020-12/21/2021. Demographics (age, sex) were described between the cohorts and the gen pop. Proportions of pts with inpatient and outpatient claims for hearing loss/ototoxicity claims and proportions with hearing loss/ototoxicity claims in the 3 yrs preceding index were calculated. Age-standardized prevalence was presented using gen pop as the reference. Results: Of 21,256,714 eligible pts, 82,629 GD, 4,455 TED, 2,758 teprotumumab, 1,261,250 TD and 4,857,408 gen pop pts were identified. 47% pts in the gen pop cohort were female vs 72.1-75.7% in the other cohorts. Gen pop cohort was younger (mean [SD] age: 53 [15.1] yrs) vs 58.0-61.5 [15.1-15.6] yrs in other cohorts. Age-standardized prevalence of hearing loss/ototoxicity claims on/after index date was 3.3% for GD, 5.2% for TED, 4.3% for teprotumumab, 3.9% for TD, and 3.9% for gen pop pts. Hearing loss/ototoxicity claims were prevalent in the 3 years prior to index among these patients: 30.8% GD, 36.6% TED, 35.4% teprotumumab, 31.5% TD, and 27.3%) gen pop pts had a hearing loss/ototoxicity claim. Conclusions: In this descriptive unadjusted analysis, we observed similar prevalence of hearing loss/ototoxicity claims across thyroid disorders, TED pts, teprotumumab pts, and the gen pop group. Between 27%-37% had claims prior to thyroid diagnosis or receiving teprotumumab. It is expected that future analyses could adjust the rates for potential confounders across cohorts.

8366 Weight Reduction is Associated with Improved Quality of Life in Patients in SURMOUNT-3

Abstract Disclosure: T.H. Gibble: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. D. Cao: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. T.D. Forrester: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. J.F. Brumm: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. Tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, is approved in the US for treatment of type 2 diabetes and obesity. In SURMOUNT-3, a phase 3, 72-week, randomized, double-blind clinical trial in adults with obesity/overweight, after 12 weeks intensive lifestyle intervention, treatment with tirzepatide resulted in significantly greater weight reduction than placebo. This post-hoc analysis assessed whether weight reduction was associated with patient-reported outcomes (PRO) improvements in adults treated with tirzepatide. Of 806 adults with obesity (body mass index [BMI] ≥30 kg/m2)/overweight (BMI ≥27 kg/m2) + ≥1 obesity-related complication enrolled in SURMOUNT-3, 579 achieved ≥5% weight reduction with 12 weeks of intensive lifestyle intervention and were randomized to placebo (N=292) or tirzepatide (10/15mg, N=287) for 72 weeks. Adults completed patient-reported outcomes (PRO) questionnaires at randomization and endpoint (72 weeks or early discontinuation), including Short Form-36 Version 2 Health Survey acute form (SF-36v2) and Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT). Mean change in SF-36v2 norm-based and IWQOL-Lite-CT scores from randomization to endpoint were summarized descriptively by weight reduction targets (≥5%, ≥10%, ≥15%, ≥20%, ≥25%) for adults who received TZP, using the last observation carried forward method. At endpoint, adults with weight reduction showed improvements from randomization in most PRO scores. For SF-36v2, improvements by weight reduction target were seen for General Health (≥5%, 2.6; ≥10%, 2.7; ≥15%, 3.0; ≥20%, 3.3; ≥25%, 3.4), Physical Functioning (3.4, 3.4, 3.8, 4.4, 4.3), Mental Health (0.4, 0.4, 0.7, 0.8, 0.4), Bodily Pain (2.3, 2.5, 3.1, 3.7, 3.9), Role-Physical (1.9, 1.8, 2.2, 2.9, 2.8), Vitality (1.3, 1.3, 1.5, 1.8, 1.4), Social Functioning (0.8, 0.9, 1.1, 2.2, 2.4), Role-Emotional (0.9, 0.8, 1.0, 1.5, 0.9), and Physical Component Score (3.2, 3.3, 3.8, 4.5, 4.7); improvements were less consistent for Mental Component Score (-0.1, -0.2, -0.1, 0.3, -0.2). For IWQOL-Lite-CT, improvements by weight reduction target were seen for total (18.2, 18.6, 19.7, 22.9, 24.1), Physical Function composite (13.6, 14.1, 14.9, 17.1, 17.3), Physical Composite (14.3, 14.9, 15.7, 18.3, 19.3), Physical Pain/Discomfort Composite (16.0, 16.7, 17.8, 21.1, 24.1), and Psychosocial Composite Scores (20.3, 20.6, 21.8, 25.3, 26.7). Adults meeting greater weight reduction targets generally showed greater improvements from randomization in PRO scores. Weight reduction was associated with improvement in most domains of health-related quality of life, including those relating to physical function and mental health. Adults who lost the most weight generally showed the greatest quality of life improvements. Presentation: 6/1/2024