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Background: Achondroplasia is the most common short-limbed skeletal dysplasia resulting from gain-of-function pathogenic variants in fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone formation. Most treatment options are symptomatic, targeting medical complications. Infigratinib is an orally bioavailable, FGFR1–3 selective tyrosine kinase inhibitor being investigated as a direct therapeutic strategy to counteract FGFR3 overactivity in achondroplasia. Objectives: The main objective of PROPEL is to collect baseline data of children with achondroplasia being considered for future enrollment in interventional studies sponsored by QED Therapeutics. The objectives of PROPEL 2 are to obtain preliminary evidence of safety and efficacy of oral infigratinib in children with achondroplasia, to identify the infigratinib dose to be explored in future studies, and to characterize the pharmacokinetic (PK) profile of infigratinib and major metabolites. Design: PROPEL (NCT04035811) is a prospective, noninterventional clinical study designed to characterize the natural history and collect baseline data of children with achondroplasia over 6−24 months. PROPEL 2 (NCT04265651), a prospective, phase II, open-label study of infigratinib in children with achondroplasia, consists of a dose-escalation, dose-finding, and dose-expansion phase to confirm the selected dose, and a PK substudy. Methods and analysis: Children aged 3−11 years with achondroplasia who completed ⩾6 months in PROPEL are eligible for PROPEL 2. Primary endpoints include treatment-emergent adverse events and change from baseline in annualized height velocity. Four cohorts at ascending dose levels are planned for dose escalation. The selected dose will be confirmed in the dose-expansion phase. Ethics: PROPEL and PROPEL 2 are being conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, principles of the Declaration of Helsinki, and relevant human clinical research and data privacy regulations. Protocols have been approved by local health authorities, ethics committees, and institutions as applicable. Parents/legally authorized representatives are required to provide signed informed consent; signed informed assent by the child is also required, where applicable. Discussion: PROPEL and PROPEL 2 will provide preliminary evidence of the safety and efficacy of infigratinib as precision treatment of children with achondroplasia and will inform the design of future studies of FGFR-targeted agents in achondroplasia. Registration: ClinicalTrials.gov: NCT04035811; NCT04265651.

Achondroplasia is a genetic skeletal condition that results in disproportionately short stature and medical complications throughout life. Infigratinib is an orally bioavailable FGFR1-3 selective tyrosine kinase inhibitor in development for achondroplasia. In this phase 2 dose-finding study, we evaluated the safety and efficacy of oral infigratinib in children with achondroplasia between the ages of 3 and 11 years. A total of 72 children were enrolled in five sequential cohorts to receive daily infigratinib at doses of 0.016 mg per kilogram of body weight (cohort 1), 0.032 mg per kilogram (cohort 2), 0.064 mg per kilogram (cohort 3), 0.128 mg per kilogram (cohort 4), and 0.25 mg per kilogram (cohort 5) for 6 months, followed by 12 months of extended treatment in which the dose in cohorts 1 and 2 could be escalated to the next ascending level at months 6 and 12. The primary safety outcome was the incidence of adverse events that led to a decrease in the dose or discontinuation of infigratinib. The primary efficacy outcome was the change from baseline in the annualized height velocity. During treatment, all the children had at least one adverse event, most of which were mild or moderate in severity; none resulted in treatment discontinuation. In cohort 5, an increased annualized height velocity was observed, which persisted throughout the duration of the study, with a mean change from baseline at 18 months of 2.50 cm per year (95% confidence interval [CI], 1.22 to 3.79; P = 0.001). The mean change from baseline in height z score was 0.54 (95% CI, 0.35 to 0.72) relative to an untreated achondroplasia reference population at 18 months; the mean change from baseline in the upper-to-lower body segment ratio was -0.12 (95% CI, -0.18 to -0.06). The administration of oral infigratinib did not result in any apparent major safety signal and increased the annualized height velocity and z score and decreased the upper-to-lower body segment ratio at 18 months of treatment in cohort 5. (Funded by BridgeBio Pharma; PROPEL2 ClinicalTrials.gov number, NCT04265651.).

The adoption of automated milking systems (AMS) has transformed the dairy industry by improving efficiency, animal welfare, and milk production. DeLaval's Batch Voluntary Milking System (Batch VMS) provides a structured alternative to traditional AMS for larger dairy herds. Unlike continuous voluntary milking, Batch VMS organizes cows into groups and schedules their milking at set intervals, enhancing herd management while reducing labor demands. As a hybrid approach, it offers a seamless transition from conventional milking methods to automation. Through a literature review and two research studies, this thesis explores how Batch VMS may affect cow health and performance.Chapter 1 contains the literature review. It introduces the changes in the AMS technologies in recent years and compares it to Batch VMS. Secondly, it discusses the effects of pre-milking waiting time on milking performance and cow health in terms of mastitis and lameness. And lastly, it discusses selection behavior in cows, comparing behaviors in conventional and automated milking systems.Chapter 2 explores the effects of pre-milking waiting time (WT) in an automated batch milking system (ABMS). Visit information was collected to calculate pre-milking WT, defined as the time elapsed between the entrance of the cow to the milking barn, as indicated by pedometers attached to each cow that were read by sensors located at the parlor, and the entrance of each individual cow to the robot milking box. WT were categorized into quartiles within each parity group as Q1 ≤ 9 min, Q2 = 10 to 24 min, Q3 = 25 to 46 min and Q4 ≥ 47 mins for primiparous and Q1 ≤ 11 min Q2 = 12 to 30 min, Q3 = 31 to 51 min and Q4 ≥ 52 mins for multiparous. To assess the association between lameness and WT, individual cow WT averages were calculated separately for primiparous and multiparous groups. Lameness was treated as a categorical variable, where 1 indicated a cow diagnosed with lameness and 0 indicated non-lame cow.The results show that the average waiting time for all milking events was 33.6 min (± SD = 28.5), 34.5 ± 28.9 for PP, and 30.7 ± 27.3 for MP. The means for each breed were 25.6 ± 15.2, 42.3 ± 16.8, and 42.3 ± 23.4, for HO, JE, and HJ, respectively. While significant differences in LSM were observed between breeds for most variables, there was little to no significant association between WT and the analyzed outcomes. An increase of 10 minutes in WT was associated with a 23.7% increase in the odds of lameness in multiparous cows (95% CI: 10.2–39.0; p < 0.001). However, no significant association was found in primiparous cows (OR: 1.09, 95% CI: 0.85–1.38, p = 0.462).Chapter 3 discusses selection behavior in an ABMS where cows select between 22 robots each time there are brought to the milking parlor. The objective of this study was to analyze the robotic milking station selection behavior of three breeds including Holstein, Jersey, and Holstein × Jersey crossbred cows in a multibreed dairy farm with a batch milking system with automatic milking units. The study used data from 1,762,461 milking events in 3705 HO (n=1355), JE (1876) and HJ (475) cows from May 2023 to September 2024 in a commercial organic grass-fed dairy in TX. Cows were moved to the milking center twice per day, where they could select their milking visits among 22 robot units (DeLaval, Sweden).For the analysis, robots were also classified by barn location [East (n=11); West] and arm configuration [left (n=11); right]. Milking visit information was collected to determine the frequency of specific robot usage per cow during the study period. Subsequently, the frequencies of selection for the top 1, 3, and 5 robotic milking stations, top barn location, and top arm configuration were calculated for each cow. Preference consistency scores (PCS) were calculated considering the frequency of access to each robotic milking station, barn side, and arm configuration in 30 days periods. Overall, multiparous and HO cows evidenced more consistent behaviors in milking station preference. Dairy cow selection behavior should be considered when analyzing the efficiency of milking procedures.

Disclosure: R. Savarirayan: Advisory Board Member; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Sanofi. Consulting Fee; Self; BioMarin. Grant Recipient; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Therachon. Research Investigator; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Therachon. J. De Bergua: None. P. Arundel: None. H. McDevitt: None. V. Cormier-Daire: Advisory Board Member; Self; BioMarin. V. Saraff: None. M. Skae: None. B. Delgado: None. A. Leiva-Gea: None. M. Salcedo: None. J. Salles: None. M.P. Nicolino: None. M. Rossi: Advisory Board Member; Self; BioMarin. P. Kannu: Advisory Board Member; Self; Novartis, Ipsen. Grant Recipient; Self; CIHR. M. Bober: Advisory Board Member; Self; Biomarin. Consulting Fee; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. Grant Recipient; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. Research Investigator; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. J. Phillips III: None. H. Saal: Advisory Board Member; Self; Alexion. Grant Recipient; Self; Alexion, BioMarin, Pfizer, QED Therapeutics. Research Investigator; Self; Alexion, BioMarin, Pfizer, QED Therapeutics. P. Harmatz: Consulting Fee; Self; Audentes, Aeglea, Homology, JCR, Denali, Inventiva, Paradigm, Capsida, Chiesi, Avrobio. Grant Recipient; Self; BioMarin, Inventiva. Research Investigator; Self; BioMarin, Shire/Takeda, QED Therapeutics, RegenXbio, Denali, Ascendis, Amicus, Allievex, JCR, Orphazyme, Idorsia, Sangamo. C. Burren: Grant Recipient; Self; Amgen, Pfizer, QED Therapeutics. Research Investigator; Self; Amgen, Pfizer, QED Therapeutics. T. Candler: None. T. Cho: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. E. Muslimova: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. R. Weng: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. D. Rogoff: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. J. Hoover-Fong: Consulting Fee; Self; Pfizer/Therachon, BioMarin, QED Therapeutics, Sanofi, Ascendis Pharma. Grant Recipient; Self; Pfizer/Therachon, BioMarin, Ascendis Pharma. Research Investigator; Self; Pfizer/Therachon, BioMarin, Ascendis Pharma. M. Irving: Advisory Board Member; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Sanofi, Therachon/Pfizer. Speaker; Self; BioMarin, QED Therapeutics. Background: Achondroplasia (ACH), the most common short-limbed skeletal dysplasia, is characterized by defective endochondral ossification resulting from gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone formation. Infigratinib is a selective, orally bioavailable FGFR1-3 tyrosine kinase inhibitor being investigated for the treatment of ACH in the observational and 2 interventional studies, as detailed below. Methods: PROPEL (NCT04035811) is a non-interventional clinical assessment study designed to characterize the natural history of ∼250 children 2.5 to <17 years of age with ACH over a 6−24-month period. Primary objective: collect baseline height velocity measurements in children who may participate in an interventional study with infigratinib. Primary endpoint: annualized growth velocity (AGV). Further objectives: collect other baseline growth measurements; evaluate exploratory biomarker indicators of growth; assess ACH-related medical events reported as medical history, or non-treatment adverse events (AEs), health-related quality of life, body pain, functional abilities and cognitive functions in children with ACH. PROPEL 2 (NCT04265651) is a phase 2, open-label study of infigratinib in children 3−11 years of age with ACH who completed ≥6 months of observation in PROPEL. This study includes dose-escalation (extended dose-finding treatment phase, n≥40), a pharmacokinetics sub-study (n≥18), and a dose-expansion phase (n≈20) to confirm the selected dose and provide evidence of efficacy. Primary endpoints: AEs; change from baseline in AGV; and infigratinib pharmacokinetics. Secondary endpoints: safety/tolerability of infigratinib; changes from baseline in anthropometric parameters. Exploratory outcomes: changes in quality of life (QoL) and other parameters of disease burden. PROPEL OLE (NCT05145010) is a phase 2, open-label extension study in ∼230 children who completed an interventional study with infigratinib and, potentially, in ≤50 infigratinib-naïve children. Primary objectives: safety, tolerability; and efficacy of long-term daily doses of infigratinib. Secondary objectives: changes in other indicators of growth/development, skeletal abnormalities, QoL/disease burden, and cognitive functions. Children may receive infigratinib until they reach final height. Summary: The PROPEL, PROPEL 2, and PROPEL OLE studies are ongoing. Together, they are intended to contribute to the understanding of the natural history of ACH, provide key evidence on the safety and efficacy of oral infigratinib, including QoL and skeletal changes in children with ACH, and inform the design of future studies in this setting. Presentation: Thursday, June 15, 2023

Disclosure: R. Savarirayan: Advisory Board Member; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Sanofi, Sanofi. Consulting Fee; Self; BioMarin. Grant Recipient; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Therachon. Research Investigator; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Therachon. J. De Bergua: None. P. Arundel: None. J. Salles: None. A. Leiva-Gea: None. M. Irving: Advisory Board Member; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Sanofi, Therachon/Pfizer. Speaker; Self; BioMarin, QED Therapeutics. V. Saraff: None. H. McDevitt: None. M. Salcedo: None. M.P. Nicolino: None. V. Cormier-Daire: Advisory Board Member; Self; BioMarin. P. Kannu: Advisory Board Member; Self; Novartis, Ipsen. Grant Recipient; Self; CIHR. M. Skae: None. M. Bober: Advisory Board Member; Self; Biomarin. Consulting Fee; Self; Ascendis Pharma, Biomarin, Pfizer, QED Therapeutics. Grant Recipient; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. Research Investigator; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. J. Phillips III: None. T. Candler: None. P. Harmatz: Consulting Fee; Self; Audentes, Aeglea, Homology, JCR, Denali, Inventiva, Paradigm, Capsida, Chiesi, Avrobio. Grant Recipient; Self; BioMarin, Inventiva. Research Investigator; Self; BioMarin, Shire/Takeda, QED Therapeutics, RegenXbio, Denali, Ascendis, Amicus, Allievex, JCR, Orphazyme, Idorsia, Sangamo. H. Saal: Advisory Board Member; Self; Alexion. Grant Recipient; Self; Alexion, BioMarin, Pfizer, QED Therapeutics. Research Investigator; Self; Alexion, BioMarin, Pfizer, QED Therapeutics. J. Hoover-Fong: Consulting Fee; Self; Pfizer/Therachon, BioMarin, QED Therapeutics, Sanofi, Ascendis Pharma. Grant Recipient; Self; Pfizer/Therachon, BioMarin, Ascendis Pharma. Research Investigator; Self; Pfizer/Therachon, BioMarin, Ascendis Pharma. E. Muslimova: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. T. Cho: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. R. Weng: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. D. Rogoff: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. Background: Achondroplasia (ACH) is the most common form of short-limbed skeletal dysplasias and is caused by an activating pathogenic variant of the fibroblast growth factor receptor 3 (FGFR3) gene. People with ACH are at risk for several significant co-morbidities, including foramen magnum stenosis, obstructive sleep apnea, chronic otitis media with conductive hearing loss, spinal stenosis, and a propensity towards obesity. Decreased bone mass has been observed previously in gain-of-function mutation Fgfr3 mice, and adults with ACH can have a decrease in bone mineral density (BMD). Here we describe baseline BMD of a cohort of children with ACH participating in PROPEL 2, a proof-of-concept study evaluating preliminary efficacy and safety of infigratinib, an oral FGFR-1-3 tyrosine kinase inhibitor in development for ACH. Methods: Dual energy X-ray absorptiometry (DXA) scans of the spine (L1-4) were collected at baseline in children participating in PROPEL 2 using a Hologic or GE Lunar scanner following a pre-specified image acquisition procedure. Images were evaluated by a single reviewer. Results are expressed as z-score for age and sex based on average-height children. Results: 52 children (mean±SD age: 7.97±1.9 years; 29 female; mean±SD height z-score: -5.4±1) were included in this analysis. BMD of the lumbar spine was -0.96±0.9 SDS (min -4.1; max 0.7 SDS). No statistical difference was found between males and females. 85% of children (n=44) had a BMD <0 SDS, from which 21 (40%) had a BMD between -2 and < -1 SDS, 18 (35%) presented a BMD between -1 and 0, and 5 (10%) presented a BMD < -2 SDS. Eight children (15%) had a BMD >0 SDS. No correlations were observed between BMD and age, height z-score or BMI. Conclusion: Our findings show that lumbar spine BMD is lower in children with ACH compared with normative data from children of average height. Low BMD in the context of short stature is difficult to interpret, raising the question of the degree to which low bone status can be attributed to smaller bone size relative to age. Even though our findings do not take into account children’s height, no correlation between BMD and baseline height z-score was identified in this cohort, suggesting that the findings may not be solely attributable to overall height. These findings reinforce the need to better understand how to circumvent this limitation in children with skeletal dysplasias in order to improve DXA interpretation and avoid misdiagnoses. Presentation: Thursday, June 15, 2023

Disclosure: R. Savarirayan: Advisory Board Member; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Sanofi. Consulting Fee; Self; BioMarin. Grant Recipient; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Theracon. Research Investigator; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Theracon. J. De Bergua: None. P. Arundel: None. J. Salles: None. V. Saraff: None. B. Delgado: None. A. Leiva-Gea: None. H. McDevitt: None. M.P. Nicolino: None. M. Rossi: Advisory Board Member; Self; BioMarin. M. Salcedo: None. V. Cormier-Daire: Advisory Board Member; Self; BioMarin. M. Skae: None. P. Kannu: Advisory Board Member; Self; Novartis, Ipsen. Grant Recipient; Self; CIHR. M.B. Bober: Advisory Board Member; Self; Biomarin. Consulting Fee; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. Grant Recipient; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. Research Investigator; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. J. Phillips: None. H. Saal: Advisory Board Member; Self; Alexion. Grant Recipient; Self; Alexion, BioMarin, Pfizer, QED Therapeutics. Research Investigator; Self; Alexion, BioMarin, Pfizer, QED Therapeutics. P. Harmatz: Consulting Fee; Self; Audentes, Aeglea, Homology, JCR, Denali, Inventiva, Paradigm, Capsida, Chiesi, Avrobio. Grant Recipient; Self; BioMarin, Inventiva. Research Investigator; Self; BioMarin, Shire/Takeda, QED, RegenXbio, Denali, Ascendis, Amicus, Allievex, JCR, Orphazyme, Idorsia, Sangamo. C.P. Burren: Grant Recipient; Self; Amgen, Pfizer, QED Therapeutics. Research Investigator; Self; Amgen, Pfizer, QED Therapeutics. T. Candler: None. T. Cho: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. E. Muslimova: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. R. Weng: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. S. Raj: None. J. Hoover-Fong: Consulting Fee; Self; Pfizer/Therachon, BioMarin, QED Therapeutics, Sanofi, Ascendis Pharma. Grant Recipient; Self; Pfizer/Therachon, BioMarin, Ascendis Pharma. Research Investigator; Self; Pfizer/Therachon, BioMarin, Ascendis Pharma. M. Irving: Advisory Board Member; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Sanofi, Therachon/Pfizer. Speaker; Self; BioMarin, QED Therapeutics. D. Rogoff: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. Background: Achondroplasia (ACH), the most common short-limbed skeletal dysplasia, is characterized by impaired endochondral ossification resulting from gain-of-function pathogenic variants in the fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone growth. People with ACH are at risk for several significant co-morbidities, including compression of the brainstem due to foramen magnum stenosis, sleep-disordered breathing, chronic otitis media with conductive hearing loss, and symptomatic spinal stenosis. Infigratinib is an oral, selective FGFR1-3 tyrosine kinase inhibitor being investigated for the treatment of children with ACH in a phase 2 interventional study (PROPEL 2). Methods: PROPEL 2 (NCT04265651) is a phase 2 dose-finding, open-label study of infigratinib in children 3−11 years of age with ACH who participated for ≥6 months in PROPEL (NCT04035811), a non-interventional clinical assessment study. The PROPEL 2 dose-escalation (DE) phase comprises 5 ascending dose cohorts ranging from 0.016 mg/kg/day to 0.25 mg/kg/day. The primary endpoints are safety; change from baseline (BL) in annualized height velocity (AHV); and infigratinib pharmacokinetics in this population. Secondary endpoints include changes from BL in body proportions, and changes in quality of life. Other parameters of disease burden are evaluated as exploratory endpoints. Summary: Children enrolled in the PROPEL 2 DE phase completed ≥6 months of treatment at the assigned cohort dose. Cohorts 1-3 (n=37; doses 0.016, 0.032, and 0.064 mg/kg/day) did not show a significant increase in AHV and these doses were assessed as non-efficacious. Treatment at the cohort 4 dose (0.128 mg/kg/day) resulted in an increase in AHV from BL of 1.52 cm/year in children ≥5 years old (n=11; p=0.02). Infigratinib at the cohort 5 dose (n=10 with month 6 data, 0.25 mg/kg/day) resulted in a significant mean increase from BL of 3.03 cm/year (p=0.0022). In children considered responders (Δ in AHV ≥25% from BL, n=8/10), the mean change in AHV at the cohort 5 dose was +3.81±1.8 cm/year, with a median of +4.14 cm/year. Infigratinib was well tolerated with no serious AEs or AEs that led to study discontinuation, with most AEs mild or moderate in severity. At the cohort 5 dose level, no grade 3 AEs or treatment-related AEs were reported. Conclusion: Oral infigratinib in children with ACH, up to a dose of 0.25 mg/kg/day, was well tolerated and showed dose-dependent increases in AHV, with a significant mean change from BL of +3.03cm/year at the cohort 5 dose. The safety and efficacy of this oral, once-daily dose of infigratinib at 0.25 mg/kg/day will be further explored in a phase 3 randomized controlled study. If these phase 2 data are confirmed, infigratinib could potentially offer children with ACH the first safe and effective oral therapy to improve growth, enhance functionality and decrease medical complications. Presentation: Saturday, June 17, 2023

In this paper, we examine the distribution of distances between adult children and their parents in the U.S. We make use of the 1987 National Survey of Families and Households to first describe the distance distribution. We then suggest that the spatial separation between parents and their adult children varies with location and with demographic and socioeconomic characteristics. The results of multiple regression analyses indicate that adult children that (1) are single, (2) have high levels of education, (3) have residential locations in the western U.S., and (4) have an active mobility history are associated with greater degrees of spatial separation from their parents. Age is also a significant factor, with older adult children residing at greater distances from their parents. Life-cycle events are thus seen to play an important role in understanding separation distances. In the paper, we discuss the implications for intergenerational caregiving and support, particularly in light of the aging and the migration of the baby-boom generation.

Background: Achondroplasia is the most common short-limbed skeletal dysplasia resulting from gain-of-function pathogenic variants in fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone formation. Most treatment options are symptomatic, targeting medical complications. Infigratinib is an orally bioavailable, FGFR1-3 selective tyrosine kinase inhibitor being investigated as a direct therapeutic strategy to counteract FGFR3 overactivity in achondroplasia. Objectives: The main objective of PROPEL is to collect baseline data of children with achondroplasia being considered for future enrollment in interventional studies sponsored by QED Therapeutics. The objectives of PROPEL 2 are to obtain preliminary evidence of safety and efficacy of oral infigratinib in children with achondroplasia, to identify the infigratinib dose to be explored in future studies, and to characterize the pharmacokinetic (PK) profile of infigratinib and major metabolites. Design: PROPEL (NCT04035811) is a prospective, noninterventional clinical study designed to characterize the natural history and collect baseline data of children with achondroplasia over 6-24 months. PROPEL 2 (NCT04265651), a prospective, phase II, open-label study of infigratinib in children with achondroplasia, consists of a dose-escalation, dose-finding, and dose-expansion phase to confirm the selected dose, and a PK substudy. Methods and analysis: Children aged 3-11 years with achondroplasia who completed ⩾6 months in PROPEL are eligible for PROPEL 2. Primary endpoints include treatment-emergent adverse events and change from baseline in annualized height velocity. Four cohorts at ascending dose levels are planned for dose escalation. The selected dose will be confirmed in the dose-expansion phase. Ethics: PROPEL and PROPEL 2 are being conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, principles of the Declaration of Helsinki, and relevant human clinical research and data privacy regulations. Protocols have been approved by local health authorities, ethics committees, and institutions as applicable. Parents/legally authorized representatives are required to provide signed informed consent; signed informed assent by the child is also required, where applicable. Discussion: PROPEL and PROPEL 2 will provide preliminary evidence of the safety and efficacy of infigratinib as precision treatment of children with achondroplasia and will inform the design of future studies of FGFR-targeted agents in achondroplasia.

Background Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia, affecting between 1 in 15,000 to 1 in 30,000 live births. Children and adults with ACH have disproportionate short stature and are at risk for several significant co-morbidities, including obstructive sleep apnea, chronic otitis media with conductive hearing loss, and spinal stenosis. Obesity is a health problem in ACH and aggravates breathing difficulties (i.e. sleep apnea), back and joint pain, and reduced mobility. Individuals with ACH are predisposed to abdominal obesity, although the cause is not completely understood. The metabolic effect of visceral obesity does not suggest an association with the development of a diabetic profile. The objective of this study is to evaluate body mass index (BMI) and metabolic parameters in children with ACH participating in the PROPEL study, a prospective, non-interventional study designed to examine baseline growth parameters and health status in children being assessed for potential enrollment into interventional studies with infigratinib, an oral FGFR1–3 inhibitor in development for ACH. Methods Data were analyzed from 86 children (mean age 6.1±2.5 years; female n=52) enrolled in PROPEL. BMI was calculated at enrollment and compared with sex- and age-specific BMI curves for children with ACH in the United States. Cholesterol, triglycerides, and hemoglobin A1c were measured centrally in a subset of children. Results BMI (mean±SD) was 21.2±2.2 in females (range 16.8–26.2) and 20.5±1.6 in males (range 17.9–24.6), with 8/52 girls (15%) and 1/34 boys (2.9%) presenting BMI above the 95% of the sex- and age-specific BMI curves for ACH. The mean±SD for cholesterol and triglycerides measured in a subset of 43 children were 4.2±0.7 mmol/L (normal range [NR] 2.59–4.66) and 0.9±0.5 mmol/L (NR 0.56–1.36), respectively. Cholesterol was elevated in 9/43 children (20.9%), while triglycerides were high in 8/43 (18.7%). Hemoglobin A1c (HbA1c) was measured in 28 children and had a mean±SD of 0.052±0.002 (NR Hb fraction 0.04–0.06). Although all values were within normal ranges, 19/28 (68%) of children had values above the mean for laboratory reference values. Conclusion Results from this work illustrate the importance of using BMI tables developed for children with ACH when providing guidance on weight management. Furthermore, our findings suggest that, in this cohort, average cholesterol and HbA1c levels, although normal, are above the mean for the reference population; this highlights the importance of a healthy diet, weight management and regular physical activity starting at young age. Additional studies are needed to understand the relationship between BMI and body composition in individuals with short stature and to further investigate the clinical relevance of these findings given that no association between increased BMI and metabolic syndrome has been described in adults with ACH. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Background Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia, affecting between 1 in 15,000 to 1 in 30,000 live births. People with ACH are at risk for several significant co-morbidities, including foramen magnum stenosis, obstructive sleep apnea, chronic otitis media with conductive hearing loss, spinal stenosis, and a propensity towards obesity. PROPEL is a prospective, non-interventional study designed to examine baseline growth parameters and health status in children being assessed for potential enrollment into interventional studies with infigratinib, an oral FGFR1–3 inhibitor in development as a therapeutic option for ACH. Here we describe the medical complications reported as medical history in the PROPEL study. Methods Children with ACH between the ages of 2.5 and 10 years are eligible for enrollment in PROPEL and are evaluated at screening/baseline, month 3, month 6, and every 6 months thereafter. Medical history collected at screening/baseline is summarized using system organ class and preferred terms. Results A total of 86 children with ACH (60% female, mean±SD age 6.1±2.5 years) have been enrolled to date at 19 sites in Europe, Australia and North America. Fifty-eight children had undergone surgical and medical procedures with a mean of 2.9 procedures per child (1–11 surgeries/subject). The most common procedures were pressure-equalizing ear tube insertion, adenoidectomy and tonsillectomy. Twenty-one (24%) children had undergone at least 1 surgery (1–5 surgeries/child) for spine or cranial decompression. History of infections and respiratory disorders were reported in 46 (53%) and 40 (47%) children, respectively, the most common being ear infections and obstructive sleep apnea. Musculoskeletal disorders were described in 33 (38%) children, with kyphosis being the most common. Hydrocephalus was reported in 2 children, while 4 had ventriculomegaly without intracranial hypertension. Congenital cardiovascular abnormalities were found in 4 children, 2 of whom presented with patent ductus arteriosus and 2 had patent foramen ovale. A comprehensive summary of medical histories will be presented at the conference. Conclusions The PROPEL study has a planned total enrollment of 200 children and seeks to contribute to the deeper understanding of the natural history of ACH. Data described here highlight the significant complications and high number of interventions that children with ACH undergo throughout infancy and childhood. This stresses the importance of expert management of this complex condition. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:05 p.m. - 1:10 p.m.