Abstract: Disclosure: R. Savarirayan: Advisory Board Member; Self; Biomarin, Ascendis. Consulting Fee; Self; BridgeBio. C. McDonnell: Advisory Board Member; Self; Pfizer. Research Investigator; Self; Ascendis, KyowaKirin. Other; Self; Honoraria: Biomarin, Pfizer; Travel, Accommodations, and Expenses: Pfizer. D.G. Hoernschemeyer: Consulting Fee; Self; Orthopediatrics. Grant Recipient; Self; Zimvie. Research Investigator; Self; Zimvie, Biomarin. Speaker; Self; Zimvie. Stock Owner; Self; Orthopediatrics. Other; Self; Travel, Accommodations, Expenses: Orthopediatrics; Honoraria: Biomarin; Patents, Royalties, Other IP: Orthopediatrics; Other relationship: Orthopediatrics, Zimvie. H.B. Hove: Advisory Board Member; Self; Pfizer. Consulting Fee; Self; Pfizer, Ascendis Pharma. Y.A. Zarate: None. M.B. Bober: Advisory Board Member; Self; Biomarin, Ultragenyx. Consulting Fee; Self; Biomarin, QED, Ascendis. Grant Recipient; Self; Biomarin. Research Investigator; Self; Biomarin, Pfizer/Therachon, QED, Ascendis, Takeda, Ultragenyx, MedLife, Sobi. Speaker; Self; Alexion. Other; Self; Honoraria: Novo Nordisk. C.A. Bacino: Consulting Fee; Self; Best Doctors, Inc (Teladoc). Grant Recipient; Self; Ascendis, Roche, Ionis, BioMarin. Other; Self; Patents, Royalties, Other IP: UpToDate. J.M. Legare: Grant Recipient; Self; BioMarin. Research Investigator; Self; BioMarin. Speaker; Self; BioMarin. Other; Self; Honoraria (Self): BioMarin. W. Högler: Advisory Board Member; Self; Biomarin, Alexion. Consulting Fee; Self; Alexion, Pfizer. Grant Recipient; Self; Novo Nordisk. Research Investigator; Self; Alexion, Kyowa Kirin, Amgen. Other; Self; Honorara (Self): Alexion; Travel, Accommodations, Expenses: Alexion, Kyowa Kirin. T. Quattrin: Consulting Fee; Self; ProventionBio, Ascendis, Merck, Janssen. Research Investigator; Self; Ascendis, Janssen, Merck, Pfizer, ProventionBio. M. Abuzzahab: Advisory Board Member; Self; Pfizer, NovoNordisk, Ascendis, Rhythm. Consulting Fee; Self; Ascendis, Rhythm. Research Investigator; Self; Ascendis, NovoNordisk, Rhythm, Lumos, Soleno, Saniona, Levo, Affreza, Medtronic. P.L. Hofman: Other; Self; Honoraria (Self): Novo Nordisk and Eli-Lilly. K.K. White: Research Investigator; Self; Biomarin, Ascendis, Pfizer, Ultragenyx. Other; Self; Honorara (Self): Biomarin; Patents, Royalties, Other IP: UpToDate.com. N. Ma: Research Investigator; Self; Ascendis Pharma (site-PI), Ultragenyx (Sub-I), Amgen (site-PI). Other; Self; Patents, Royalties, Other IP (Self): UpToDate peer reviewer royalties, Co-Editor of Pediatrics section of Current Osteoporosis Reports. D. Schnabel: Advisory Board Member; Self; Biomarin, Novo Nordisk, Sandoz, Kyowa Kirin. Consulting Fee; Self; Kyowa Kirin. Other; Self; Honoraria: Kyowa Kirin, Sandoz; Travel, Accommodations, Expenses: Kyowa Kirin. S.B. Sousa: Advisory Board Member; Self; Biomarin, Ascendis. Other; Self; Honoraria (Self): Biomarin, Ascendis, Kiowa Kirin; Travel, Accomodations, Expenses: Biomarin. X. Fan: Employee; Self; Ascendis Pharma Inc. M. Chakraborty: Employee; Self; Ascendis Pharma Inc. A. Giwa: Employee; Self; Ascendis Pharma Inc. S.E. Smith: Employee; Self; Ascendis Pharma Inc. B. Volck: Employee; Self; Ascendis Pharma A/S. A.D. Shu: Employee; Self; Ascendis Pharma, Inc. Background: Achondroplasia (ACH) is the most common form of hereditary disproportionate short stature and is associated with complications that can diminish functional capacity and quality of life. ACH is caused by a pathogenic variant in the FGFR3 gene resulting in fibroblast growth factor 3 pathway overactivation leading to impaired endochondral ossification. C-type natriuretic peptide (CNP) promotes chondrocyte development by inhibiting the FGFR3 pathway. TransCon CNP is an investigational prodrug of CNP, designed to provide sustained release of CNP supporting continuous CNP exposure and a once-weekly dosing regimen. The ACcomplisH trial assessed TransCon CNP for the treatment of children with ACH aged 2 to 10 years. Methods: ACcomplisH is a phase 2, multicenter, double-blind, randomized, placebo-controlled, dose-escalation trial of once-weekly TransCon CNP in prepubertal children aged 2-10 years with ACH. Participants were randomized to TransCon CNP dosed at 6, 20, 50 and 100 μg CNP/kg/week across 4 cohorts or placebo in a 3:1 ratio. The primary objectives were safety and annualized height velocity (AHV) at 52 weeks. Results: 57 participants were enrolled; 42 received TransCon CNP: 6 μg CNP/kg/week (n=10), 20 μg CNP/kg/week (n=11), 50 μg CNP/kg/week (n=10), or 100 μg CNP/kg/week (n=11 of which 55% female, 73% ≥5 years); or pooled placebo (n=15; 33% female, 47% ≥5 years). TransCon CNP was well tolerated with no treatment discontinuations. No serious treatment-emergent adverse events (TEAEs) were reported as related to TransCon CNP. Most TEAEs were mild (grade 1) with no grade 3 or 4 TEAEs reported. There was a low frequency of injection site reactions (ISRs). In & gt;2,000 TransCon CNP injections, only 11 ISRs in 8 participants over 52 weeks were reported. There were no reports of symptomatic hypotension and no trends to suggest worsening of disproportionality. TransCon CNP 100 μg CNP/kg/week resulted in significantly higher AHV vs placebo at 52 weeks (least square [LS] mean 5.42 vs 4.35 cm/year; p=0.022) resulting in improved ACH-specific height SDS from baseline vs placebo (LS mean 0.22 vs -0.08; p=0.028). There was a dose-dependent treatment effect on AHV of 4.09 cm/year (6 μg CNP/kg/week) to 5.42 cm/year (100 μg CNP/kg/week; p=0.003). All participants completed blinded treatment and continued in the 2-year open-label extension (OLE), receiving 100 μg CNP/kg/week of TransCon CNP. Preliminary OLE data suggest sustained efficacy and safety. Conclusion: Once-weekly TransCon CNP dosed up to 100 μg CNP/kg/week was generally safe and well tolerated with mild TEAEs, few ISRs, and no discontinuations. TransCon CNP at 100 μg CNP/kg/week provided statistically significant improvement in AHV vs placebo. These results support continued investigation of TransCon CNP for children with ACH in the ongoing Phase 2b ApproaCH trial (NCT05598320) including treatment impact on ACH-related complications. Presentation: Thursday, June 15, 2023

Abstract: 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

Abstract: Objectives: Vosoritide is a potent stimulator of endochondral bone growth and is in development for the treatment of achondroplasia, the most common form of disproportionate short stature. We previously reported on a 52-week, phase 3, pivotal study that demonstrated a highly statistically significant improvement in annualized growth velocity (AGV) when vosoritide was compared to placebo in children with achondroplasia aged 5-18 years (Savarirayan et al, Lancet, 2020). This is an analysis of data after an additional 52 weeks of treatment in the ongoing phase 3 extension study. Methods: After completion of the phase 3 placebo-controlled study, 119 children were enrolled into the extension study, where they all receive open label 15 μg/kg/day vosoritide. AGV, height Z-score and body proportion ratio were analyzed to assess efficacy of vosoritide in children who were treated with vosoritide for up to 2 years. Fifty-eight continued treatment with vosoritide and 61 switched from placebo to vosoritide. Two participants on continuous vosoritide treatment discontinued before the Week 52 timepoint. Four participants on continuous vosoritide treatment and 7 participants who switched from placebo to vosoritide missed the Week 52 assessment due to Covid-19. Results: In children randomized to receive daily vosoritide, baseline mean (SD) AGV was 4.26 (1.53) cm/year. After the first 52 weeks of treatment, mean (SD) AGV was 5.67 (0.98) cm/year. Mean (SD) AGV over the second year was 5.57 (1.10) cm/year. Mean (SD) change from baseline in height Z-score improved by +0.24 (0.31) at Week 52 in the pivotal study and +0.45 (0.56) at Week 52 in the extension study. Mean (SD) upper-to-lower body segment ratio improved with a change from baseline of -0.03 (0.11) at Week 52 in the pivotal study and -0.09 (0.11) at Week 52 in the extension study. In children who switched from placebo to vosoritide after 52 weeks, baseline AGV was 4.06 (1.20) cm/year and 3.94 (1.07) cm/year after 52 weeks on placebo. In the second year, after receiving 52 weeks of vosoritide, mean AGV was 5.65 (1.47) cm/year, the mean (SD) change in height Z-score was +0.24 (0.34), and the change in upper-to-lower body segment ratio was -0.03 (0.08). No new adverse events associated with vosoritide treatment were detected with up to 2 years of continuous daily, subcutaneous treatment. Most adverse events were mild and no serious adverse events were attributed to vosoritide. The most common adverse event remains mild and transient injection site reactions. Conclusions: The effect of vosoritide administration on growth as measured through AGV and height Z-score was maintained for up to 2-years in children with achondroplasia aged 5 to 18 years, with an improvement of body proportions.

Abstract: 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.

Abstract: 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 & lt;0 SDS, from which 21 (40%) had a BMD between -2 and & lt; -1 SDS, 18 (35%) presented a BMD between -1 and 0, and 5 (10%) presented a BMD & lt; -2 SDS. Eight children (15%) had a BMD & gt;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

Abstract: 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 & lt;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