THU156 Significantly Improved Annual Height Velocity With Once-Weekly TransCon CNP In Children With Achondroplasia: The ACcomplisH Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Trial
Authors: Savarirayan Ravi , McDonnell Ciara , Hoernschemeyer Daniel G , Hove Hanne B , Zarate Yuri A , Bober Michael B , Bacino Carlos A , Legare Janet M , Högler Wolfgang , Quattrin Teresa , Abuzzahab M Jennifer , Hofman Paul L , White Klane K , Ma Nina , Schnabel Dirk , Sousa Sérgio B , Fan Xiaolin , Chakraborty Mukta , Giwa Adebola , Smith Sharon E , Volck Birgitte , Shu Aimee D 
Published: October 2023

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