Children born small for gestational age (SGA) represent a heterogeneous population with an increased risk of persistent short stature and adverse metabolic outcomes later in life. Although most SGA infants exhibit spontaneous catch-up growth during early childhood, approximately 10-15% fail to do so and remain short as adults. Growth hormone (GH) therapy has been used for several decades in this subgroup and is currently approved in many countries worldwide. This review summarizes the biological rationale for GH treatment in SGA children, current indications for therapy, and differences among international guidelines regarding age at initiation and dosing strategies. Available evidence on growth response, predictors of treatment efficacy, and expected gains in near-adult height is discussed, together with data on safety and metabolic monitoring. Particular attention is given to the importance of early treatment initiation, individualized dose adjustment, and sustained therapy through the prepubertal years. The response to GH in syndromic forms of SGA, including Silver-Russell syndrome, is also reviewed. Finally, emerging data on long-acting GH formulations are briefly addressed, highlighting current knowledge gaps and the need for long-term outcome studies.

BACKGROUND:Central precocious puberty (CPP), which is traditionally defined as the development of secondary sexual characteristics before age 8 years in girls and age 9 years in boys, results from the premature activation of the hypothalamic-pituitary-gonadal (HPG) axis. CPP can be associated with short adult stature, adverse psychosocial outcomes, and increased cardiometabolic and cancer risks in adulthood. Gonadotropin-releasing hormone (GnRH) agonists can effectively suppress premature activation of the HPG axis and have the potential to increase adult height as well as improve psychosocial and long-term health outcomes among patients with CPP. However, as secular trends have continued to shift toward earlier age of pubertal onset, some subpopulations of children with CPP, as it is currently defined, may not require the same extent of diagnostic evaluation and treatment. OBJECTIVE:Develop evidence-based recommendations related to the diagnosis and treatment of CPP. METHODS:A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to address 10 clinical questions related to the diagnosis and treatment of CPP. Systematic reviews of health-related benefits and harms were conducted for each clinical question. The guideline development panel (GDP) also used the GRADE evidence-to-decision (EtD) framework to address stakeholder values and preferences, costs and required resources, cost-effectiveness, acceptability, feasibility, and potential impacts on health equity. RESULTS:In girls with thelarche (Tanner stage B2) between ages 7.0 and 8.0 years, the GDP suggests watchful waiting via periodic physical examinations (every 4-6 months) rather than immediately performing evaluation with laboratory testing or radiologic imaging. In addition, the GDP suggests that all girls with breast development (ie, Tanner stage B2) before age 7 years should first be observed for 4 to 6 months to differentiate unsustained or slowly progressive puberty vs rapidly progressive puberty. These recommendations are largely based on evidence that girls with slowly progressive puberty attain a normal adult height without treatment. When hormonal evaluation is performed to confirm central (GnRH-dependent) activation as the cause of precocious puberty, the GDP suggests starting the evaluation with ultrasensitive basal luteinizing hormone (LH) concentration rather than routine GnRH/GnRH agonist (GnRHa) stimulation testing for all patients. While brain magnetic resonance imaging has been a traditional part of CPP evaluation, the GDP suggests that it should not be routinely performed in girls ages 6.0 to 8.0 years and boys ages 8.0 to 9.0 years without central nervous system (eg, neuro-ophthalmologic) symptoms, largely based on a low prevalence of pathologic intracranial findings in these age groups. The GDP suggests against routine genetic testing for patients with CPP, although they judged that genetic testing (eg, MKRN3 sequencing) should be considered for patients with familial CPP through a shared decision-making process. The GDP suggests GnRHa treatment for many children with CPP, although available evidence suggests that some patient subgroups (eg, older girls with slowly progressive CPP) may be less likely to receive a net benefit with this treatment. Rather than always starting GnRHa treatment with a monthly injectable formulation, the GDP suggests that treatment should be initiated with the formulation (such as a longer-acting formulation) that is anticipated to be used long-term. The GDP suggests against routine addition of growth hormone therapy to increase adult height. They also suggest against the routine biochemical testing (eg, LH, sex steroids) to monitor pubertal suppression while receiving GnRHa, instead reserving biochemical testing to confirm clinically suspected treatment failure. Finally, the GDP suggests against routinely continuing GnRHa treatment beyond chronologic age 10.0 to 11.0 years (girls) or 11.0 to 12.0 years (boys) and/or bone age 11.0 to 12.0 years (girls) or 12.0 to 13.0 years (boys). CONCLUSION:These clinical recommendations were developed to address important uncertainties in the diagnosis and treatment of children with CPP. They are based on the best available scientific evidence regarding clinical outcomes judged to be most important to patients and families. The GDP's overarching goal was to suggest diagnostic and therapeutic strategies that will most likely provide net clinical benefits while simultaneously considering important contextual factors such as cost and feasibility. The guideline-development process highlighted important knowledge gaps and the substantial need for additional research.

Context Delayed puberty is a frequent complaint in males. The differential diagnosis between self-limited delayed puberty (SLDP) and congenital hypogonadotropic hypogonadism (CHH) is challenging. Commonly used endocrine tests, focusing on stimulated levels of LH or testosterone, are not satisfactory in making a diagnosis. Because FSH action on Sertoli cells results in testis enlargement and anti-M & uuml;llerian hormone (AMH) and inhibin B increased secretion, and the FSH-Sertoli cell axis function is detectable during normal childhood and early puberty, we tested whether the assessment of serum FSH, AMH, and inhibin B would be informative to distinguish between SLDP and CHH. Design We performed a prospective, nested case-control study in a cohort of male adolescents presenting with delayed puberty, comparing baseline serum reproductive hormone levels to identify predictive biomarkers of CHH, after having followed all participants prospectively until a final diagnosis was ascertained based on gold-standard criteria (age 18 years or >= 4 years after testis volume reached 4 mL). Results Of 65 participants who completed follow-up, 33 had a final diagnosis of SLDP and 32 of CHH. Serum FSH, AMH, and inhibin B showed better diagnostic efficiency than LH and testosterone for these differential diagnoses. FSH (IU/L)xinhibin B (ng/mL) < 92 and FSH (IU/L)xAMH (pmol/L) < 537 showed high sensitivity (>93%), specificity (>= 92%), predictive values (>92%), and positive likelihood ratio (>12) for CHH. The diagnostic performance remained 89.7% and 88.2% for FSH x inhibin B and FSH x AMH, respectively, when analyzed in patients without red flags (micropenis, cryptorchidism, and/or microorchidism). Conclusion Serum FSH combined with inhibin B or AMH is highly predictive to accurately distinguish between SLDP and CHH in adolescent males.

El crecimiento es un fenómeno biológico continuo resultante del equilibrio entre la cantidad, calidad y función de la materia, que permite adquirir de forma paulatina una conformación estable y un desempeño maduro, que se debe expresar en forma plena y óptima en todos los humanos. Su expresión debe considerarse un signo de salud y por ello debe ser analizado por todos los médicos en la vigilancia de cada paciente desde el nacimiento hasta el término de la pubertad, ya que al ser un indicador objetivo nos permite cuantificar y calificar las variaciones en las dimensiones físicas y la composición corporal a las diferentes edades, y refleja el equilibrio entre la expresión de las condiciones genéticas y los factores permisivos o restrictivos del medio ambiente. El método más recomendable es comparar las medidas auxológicas de una población con la expresión individual, aunque debe considerarse que los estudios poblacionales señalan solo lo que es “habitual” en una población, lo que no forzosamente es sinónimo de normal ni de óptimo, ya que: varones y mujeres muestran diferencias en la edad e intensidad del crecimiento, el crecimiento prenatal puede afectar al crecimiento posnatal, existen variaciones étnicas o raciales en la expresión del crecimiento posnatal, hay variaciones entre familias de la misma etnia en el crecimiento posnatal, y existen variaciones en la velocidad de maduración incluso dentro de miembros de la misma familia. Se describen las principales medidas antropométricas, las características de los instrumentos que las cuantifican y cómo se debe analizar el resultado. PALABRAS CLAVE: Crecimiento, antropometría, talla, peso, índice de masa corporal, proporcionescorporales, velocidad de crecimiento

Disclosure: A. Roslan: None. T. Garner: None. E. Brincks: Lumos Pharma, Inc. J.C. McKew: Lumos Pharma, Inc. P. Pitukcheewanont: Lumos Pharma, Inc. M. Thorner: Lumos Pharma, Inc. F. Cassorla: Lumos Pharma, Inc. P. Clayton: Lumos Pharma, Inc. A. Stevens: Lumos Pharma, Inc.. Background: Both patterns as well as amounts of GH secretion influence stature and growth rate in normal children1. We have shown the investigational oral GH secretagogue, LUM-201 restores normal GH secretion in GH deficient (GHD) children and alters the pattern of variation within growth hormone secretion profiles2. We have now explored the use of higher order interactions (HOI) in the GH secretion profiles induced by LUM-201 defining the relationships between all points within the time series. Objective: To assess HOIs impacted by LUM-201 treatment with a hypergraph model on a matrix of the whole time series with coordination quantified using a random walk (RW) to measure the probability of a relationship between time points in GHD children between baseline and 6m. Methods: Pulsatile GH secretion was assessed at baseline and after 6 months on LUM-201 (1.6 and 3.2mg/kg/day) in 12-hour (08.00-20.00) profiles with 10minute sampling (n=73) in moderate pediatric GHD (n=22). As GH secretion was not different between LUM-201 doses, the 22 subjects were studied together. Responsiveness was defined at 6m by annualised height velocity (AHV), in tertiles: High [8.9], Medium [7.7] and Low [6.7] [mean cm/year]. Hypergraphs were generated from points in the series (in a 73 x 73 matrix) above median GH-secretion. RWs3 derived from the hypergraphs were used to measure the probabilities for each point in the matrix. Fisher’s exact test was used to generate odds ratios (OR) and confidence intervals (CI) in the early and late time points in the series. Results: Comparison of the RWs at baseline and 6m revealed a shift of HOI coordination in response to LUM-201 in the AHV tertiles: early time points [0-240 mins] High response increase 36.5% OR 6.4 [CI 3.2-14.1] p<0.001; Low response increase 45.5% OR 11.7 [CI 5.2-29.5] p<0.001; later time points [490-720mins] High response decrease 43.0% OR 7.7 [CI 3.8-16.5] p<0.001; Low response decrease 29.5% OR 3.6 [CI 1.9-7.0] p<0.001. The magnitude of these changes are different between High and Low responders to LUM-201 (p<0.001) indicating the pattern of time series coordination is a biomarker of response. Conclusions: In response to LUM-201, there are distinct shifts in the pattern of GH secretion which are related to AHV tertiles. This implies that there is signalling information in all parts of the GH time series. 1. Gill et al. (2001), JCEM, p.5860 2. Clayton et al. ESPE (2024), FC15.2 3. Carletti et al 2020.Physical review E, p.022308 Presentation: Saturday, July 12, 2025

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

Abstract Context Adolescents and young women (AYA) with type 1 diabetes (T1D) may require hormonal contraception for an extended period. However, it is unclear what effect hormonal contraception has on telomere length, a marker of the risk for complications. Objectives To investigate the relative telomere length (RTL) in AYA with T1D (AYA-T1D) and healthy young women (AYA-C) after 18 months of combined oral contraception use (COC) with ethinyl estradiol/desogestrel, or a subdermal etonogestrel implant (IM). Methods A non-randomized prospective study was performed. Thirty-nine AYA-T1D and forty AYA-C chose the COC or the IM. RTL was measured by monochrome multiplex quantitative PCR in DNA from peripheral blood mononuclear cells (PBMC). The impact of contraceptives and clinical variables on RTL was assessed using lineal regression analysis. Results Longer RTL compared to baseline was observed in AYA-T1D (P&lt; 0.05) and AYA-C (P&lt;0 .01) after using the IM. However, the total of AYA and the AYA-C group treated with COC decreased RTL after 18 months of treatment compared to baseline (P&lt; 0.05). The type of contraceptive used was determinant for the changes in RTL compared to baseline in all subjects and controls (P≤ .006). For AYA-T1D, HbA1c levels were not associated with RTL, but the high-sensitivity C-reactive protein was negatively related with the changes in RTL at eighteen months compared to baseline (standardized R2: .230, P=.003). Conclusion IM was associated with longer RTL in AYA-T1D and AYA-C. In contrast, a shortening of telomere length in PMNC was observed after using COC.

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

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

Study Objective: To determine the metabolic effects of the subcutaneous etonogestrel implant compared with an oral contraceptive in adolescents and young adults (AYAs) with type 1 diabetes (T1D) on body weight, body composition, glucose, lipids, and C-reactive protein levels. Methods: This was a non-randomized, interventional, prospective study. Thirty-nine AYAs with T1D participated; 20 used the implant (Implant-T1D), and 19 used an oral combined contraceptive (OC-T1D). Body composition, HbA1c, intermittent continuous glucose monitoring, lipids, and high-sensitivity C-reactive protein (hsCRP) levels were evaluated. Results: All participants were followed for at least 12 months, and 26 completed the 24-month follow-up. No women discontinued the intervention due to adverse effects. Body weight increased by 0.8 +/- 3.5 and 1 +/- 2.9 kg in the OC-T1D and the Implant-T1D group at 12 months and by 2.6 +/- 3.9 and 3.3 +/- 3.6 kg at 24 months, respectively. OC-T1D and Implant-T1D had similar HbA1c, mean interstitial glucose levels, and time in range throughout the study; no significant difference over time was observed. hsCRP levels increased in both groups and were associated with BMI and HbA1c (P < .001 for both variables). Women in the OC-T1D group had higher total cholesterol, HDL-C, and triglyceride levels compared with the Implant-T1D. Conclusion: Glucose levels were similar in youth using the subdermal progestin implant and an OC. However, both AYA groups showed increased BMI, fat mass, and subclinical inflammation. Changes in lipid levels were associated with the OC method. These data highlight the importance of weight gain prevention in young women with T1D using hormonal contraception.

Context: Adolescents and young women (AYA) with type 1 diabetes (T1D) may require hormonal contraception for an extended period. However, it is unclear what effect hormonal contraception has on telomere length, a marker of the risk for complications. Objective: To investigate the relative telomere length (RTL) in AYA with T1D (AYA-T1D) and healthy young women (AYA-C) after 18 months of combined oral contraception use (COC) with ethinyl estradiol/desogestrel, or a subdermal etonogestrel implant (IM). Methods: A nonrandomized prospective study was performed in which 39 AYA-T1D and 40 AYA-C chose the COC or the IM. RTL was measured by monochrome multiplex-quantitative PCR in DNA from peripheral blood mononuclear cells (PBMC). The impact of contraceptives and clinical variables on RTL was assessed using lineal regression analysis. Results: Longer RTL compared to baseline was observed in AYA-T1D (P < .05) and AYA-C (P < .01) after using the IM. However, the total of AYA and the AYA-C group treated with COC decreased RTL after 18 months of treatment compared to baseline (P < .05). The type of contraceptive used was determinant for the changes in RTL compared to baseline in all subjects and controls (P <= .006). For AYA-T1D, HbA1c levels were not associated with RTL, but the high-sensitivity C-reactive protein was negatively related with the changes in RTL at 18 months compared to baseline (standardized R-2: 0.230, P = .003). Conclusion: IM was associated with longer RTL in AYA-T1D and AYA-C. In contrast, a shortening of telomere length in PBMC was observed after using COC.

Abstract Disclosure: F. Cassorla: Research Investigator; Self; Lumos Pharma, Inc. Speaker; Self; Lumos Pharma, Inc. R. Román: 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.L. Brincks: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. J.C. McKew: None. D.B. Karpf: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. M.O. Thorner: Consulting Fee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. Objective: To evaluate acute GH, IGF-1, AHV at 6 mos of treatment of iPGHD subjects. Background: LUM-201 is an investigational oral GH secretagogue (GHS) currently in 3 Phase 2 iPGHD trials. The LUM-201 predictive enrichment marker (PEM) may be used to identify patients previously diagnosed with iPGHD who are likely to respond to LUM-201. PEM positivity is defined as a baseline IGF-1 level >30 ng/mL and a peak GH of ≥5 ng/mL in response to a single 0.8 mg/kg LUM-201 dose. LUM-201, a potent, durable oral GHS agonist, acts on the GHS Receptor 1a in the hypothalamus and anterior pituitary. LUM-201 enhances the amplitude of endogenous GH pulsatile release over 24 hrs, while also acting as a functional antagonist of the somatostatin receptor. The increased IGF-1 and GH reach the growth plates and promote linear growth. Three advantages of LUM-201 as a potential therapeutic for iPGHD are that it is a small oral tablet, it enhances natural GH pulses over 24 hr, and GH release is subject to the endogenous negative feedback mechanisms, so serum IGF-1 is expected to remain within the normal range. Method: Each subject is screened with the PEM test, which includes determining the max GH concentration in the first 90 min after a single 0.8 mg/kg dose of LUM-201. Additionally, each of these PEM positive subjects was assessed for increasing doses of LUM-201 to induce further acute GH secretion on their first day of therapeutic dosing with either a 1.6 or 3.2 mg/kg dose. The first 10 subjects with 6 months of growth on LUM-201 (5 subjects on each dose) were evaluated on their IGF-1 levels and AHVs. Results: The mean (+SD, n) peak GH for the 0.8 mg/kg dose was 26.04 ng/mL (+10.6, 22), at the 1.6 mg/kg dose 35.50 ng/mL (+17.5, 9), and at a 3.2 mg/kg dose 38.34 ng/mL (+10.4, 8). Serum IGF-1 levels of the 5 subjects in each cohort were monitored at baseline and at 6 months of treatment. The mean (+ SD) serum IGF-1 levels showed a change from baseline of 84.6 ng/mL (+30.1) at 6 months for the 1.6 mg/kg cohort and 113.8 (+49.9) at the 3.2 mg/kg dose. The pretreatment HV were 4.9 (+ 0.4) at 1.6 mg/kg and 4.3 (+ 0.9) cm/year at 3.2 mg/kg respectively and the respective mean AHVs (+ SD) at 6 months were 7.14 cm/year (+0.65) and 8.60 cm/year (+1.22). The acute GH response demonstrated a dose response between the 0.8 and 1.6 mg/kg doses, but the 1.6 and 3.2 mg/kg doses produced similar GH responses. These two doses of LUM-201 induced comparable changes from baseline values of IGF-1 after 6 months of treatment. In addition to these pharmacodynamic changes, the AHVs generated from each dose also appear similar. Conclusion: LUM-201 generated the expected AHV in this naive iPGHD population. The dose-response for GH secretion after an initial dose of LUM-201 and increases from baseline of serum IGF-1 after 6 months of treatment suggest that 1.6 mg/kg/day is the optimum dose for efficacy and durability. The results from this small study are corroborated by the larger OraGrowtH210 study data. Presentation: Saturday, June 17, 2023

Abstract Disclosure: M.J. Tansey: Research Investigator; Self; Lumos Pharma, Inc. S.A. Bowden: Research Investigator; Self; Lumos Pharma, Inc. A.N. Dauber: Research Investigator; Self; Lumos Pharma, Inc. B. Wikiera: Research Investigator; Self; Lumos Pharma, Inc. B. Pyrzak: Research Investigator; Self; Lumos Pharma, Inc. A.T. Bossowski: Research Investigator; Self; Lumos Pharma, Inc. E. Petriczko: Research Investigator; Self; Lumos Pharma, Inc. R. Stawerska: Research Investigator; Self; Lumos Pharma, Inc. E. Moszczynska: Research Investigator; Self; Lumos Pharma, Inc. F. Cassorla: Research Investigator; Self; Lumos Pharma, Inc. Speaker; Self; Lumos Pharma, Inc. M.M. Feldt: Research Investigator; Self; Lumos Pharma, Inc. A.J. Lunsford: Research Investigator; Self; Lumos Pharma, Inc. M.E. Gottschalk: Research Investigator; Self; Lumos Pharma, Inc. M. Marin: Research Investigator; Self; Lumos Pharma, Inc. S.N. Nayak: Research Investigator; Self; Lumos Pharma, Inc. S. Bhuvana: Research Investigator; Self; Lumos Pharma, Inc. D.R. Repaske: Research Investigator; Self; Lumos Pharma, Inc. L.A. Soyka: Research Investigator; Self; Lumos Pharma, Inc. J.S. Fuqua: Research Investigator; Self; Lumos Pharma, Inc. O. Escobar: Research Investigator; Self; Lumos Pharma, Inc. D.A. Bowlby: Research Investigator; Self; Lumos Pharma, Inc. P.Y. Fechner: Research Investigator; Self; Lumos Pharma, Inc. E. Wiltshire: Research Investigator; Self; Lumos Pharma, Inc. M. Harris: Research Investigator; Self; Lumos Pharma, Inc. K.A. Wintergerst: Research Investigator; Self; Lumos Pharma, Inc. A.R. Lafferty: Research Investigator; Self; Lumos Pharma, Inc. B.S. Miller: Research Investigator; Self; Lumos Pharma, Inc. P. Simm: 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. D.B. Karpf: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. J.C. McKew: Employee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. M.O. Thorner: Consulting Fee; Self; Lumos Pharma, Inc. Stock Owner; Self; Lumos Pharma, Inc. Background: LUM-201 (ibutamoren), a growth hormone (GH) secretagogue receptor 1a (GHSR1a) agonist, is a potent, long-acting investigational oral GH secretagogue currently studied in three Idiopathic Pediatric GH Deficiency (iPGHD) studies. The LUM-201 predictive enrichment marker (PEM) is used to identify patients diagnosed with iPGHD (peak stimulated GH >3<10 ng/mL) who are likely to respond to LUM-201. PEM positivity is defined as a baseline insulin-like growth factor-1 (IGF-1) level >30 ng/mL and a peak GH of ≥5 ng/mL in response to a single 0.8 mg/kg dose of LUM-201. Objectives: Report the growth response analyzing the combined interim analysis (IA) data from two Phase 2 trials studying LUM-201 at two different doses (1.6 mg/kg/day or 3.2 mg/kg/day). Methods: IA data from both studies were combined and analyzed for calculated annualized height velocity (AHV). Baseline demographics were analyzed for the two combined cohorts. Results: After 6 months of treatment with LUM-201, the calculated AHV (mean ±SD ) was 8.1±1.9 cm/year in the 1.6 mg/kg/day group and 8.0±1.5 cm/year in the 3.2 mg/kg/day group (N=15 in both groups). After 9 months of treatment, the calculated AHV was 7.8±1.7 cm/year in the 1.6 mg/kg/day group and 7.3±1.7 cm/year in the 3.2 mg/kg/day group (N=10 in both groups). After 12 months of treatment, the calculated AHV was 7.8±1.7 cm/year in the 1.6 mg/kg/day group and 7.4 ±1.2 cm/year in the 3.2 mg/kg/day group (N=6 in both groups). LUM-201 was well tolerated; no safety concerns were identified across the dose range in adverse events (AE) data, laboratory values, and ECG values. Conclusions: As the growth velocity was comparable for the two doses of oral LUM-201, this analysis of the combined IA data appears to strongly support 1.6 mg/kg/day as the optimal dose for the Phase 3 trial, as doubling the dose appeared to offer no meaningful improvement in efficacy. Final determination will await final full data set analysis of both studies. Presentation: Saturday, June 17, 2023

BACKGROUND:Cryptorchidism is one of the most common congenital disorders in boys and it is associated with a higher risk of sub-fertility and testicular cancer. Testicular descent occurs during embryo-fetal development in two phases, transabdominal and inguino-scrotal. In the latter process, androgens play a leading role. The androgen receptor has in its N-terminal domain, two aminoacidic repeats encoded by polymorphic nucleotide repetitions: (CAG)nCAA and GGN. The number of repetitions of these trinucleotides has been associated with different transactivation capacities and sensitivities of the androgen receptor response. OBJECTIVE:To determine whether pediatric Chilean individuals with idiopathic inguinal cryptorchidism have a different number of CAG and/or GGN repeats polymorphisms compared with controls. MATERIALS AND METHODS:A total of 109 cases with idiopathic inguinal cryptorchidism (26 bilateral and 83 unilateral) were studied by polymerase chain reaction amplification from DNA extracted from peripheral blood, followed by fragment size analysis by capillary electrophoresis, which were compared with 140 controls. RESULTS:The CAG26 repeats allele was increased in the total cases (8.3% vs. 1.4%; p = 0.012; odds ratio = 6.21, 95% confidence interval 1.31-29.4), and in bilateral cases compared to controls (11.5% vs. 1.4%; p = 0.028; odds ratio = 9 CI 95% 1.43-56.8). Similarly, CAG > 22 alleles were increased in the total cases (62.4% vs. 49.3%, p = 0.041), and more significantly in bilateral cases (73.1% vs. 49.3%; p = 0.032; odds ratio = 2.79, 95% confidence interval 1.1-7.1). In addition, CAG < 18 alleles were not observed among cases, but were present in 5.7% of controls (p = 0.01). Regarding the GGN repeats, no differences were observed between cases and controls either when analyzing separately unilateral and bilateral cryptorchidism. The joint analysis of the distribution of CAG and GGN alleles showed that the CAG26 allele was present with GGN23, hence the combination CAG26/GGN23 alleles was equally increased in bilateral cases compared with controls (11.5% vs. 1.4%). In contrast, CAG < 18 was preferably observed in the combination CAG < 18/GGN≠23 and was absent in the total cases (4.3% vs. 0%; p = 0.037). DISCUSSION:These results suggest that greater lengths of CAG alleles may contribute to a diminished androgen receptor function. The CAG26 allele alone or in combination with GGN23 was associated with a higher risk of bilateral cryptorchidism. On the other hand, CAG < 18 and the CAG < 18/GGN≠23 allele combination may reduce the probability of cryptorchidism.