Oral infigratinib for children with achondroplasia: Month 18 results from the PROPEL 2 study demonstrate safety and durability of treatment effect on linear growth with improved body proportionality

Ravi Savarirayan; De Bergua Josep Maria; Paul Arundel; Salles Jean Pierre; Vrinda Saraff; Borja Delgado; Antonio Leiva-Gea; Helen McDevitt; Marc Nicolino; Massimiliano Rossi; Maria Salcedo; Valerie Cormier-Daire; Mars Skae; Peter Kannu; III John Phillips; Howard Saal; Paul Harmatz; Toby Candler; Elena Muslimova; Richard Weng; Yun Bai; Supriya Raj; Julie Hoover-Fong; Melita Irving; Daniela Rogoff

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ESPE Abstracts (2024) 98 FC15.4

ESPE2024 Free Communications Late Breaking (6 abstracts)

Oral infigratinib for children with achondroplasia: Month 18 results from the PROPEL 2 study demonstrate safety and durability of treatment effect on linear growth with improved body proportionality

Ravi Savarirayan ¹ , Josep Maria De Bergua ² , Paul Arundel ³ , Jean Pierre Salles ⁴ , Vrinda Saraff ⁵ , Borja Delgado ⁶ , Antonio Leiva-Gea ⁶ , Helen McDevitt ⁷ , Marc Nicolino ⁸ , Massimiliano Rossi ⁸ , Maria Salcedo ⁹ , Valerie Cormier-Daire ¹⁰ , Mars Skae ¹¹ , Peter Kannu ¹² , John Phillips III ¹³ , Howard Saal ¹⁴ , Paul Harmatz ¹⁵ , Toby Candler ¹⁶ , Elena Muslimova ¹⁷ , Richard Weng ¹⁷ , Yun Bai ¹⁷ , Supriya Raj ¹ , Julie Hoover-Fong ¹⁸ , Melita Irving ¹⁹ & Daniela Rogoff ¹⁷

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¹Murdoch Children’s Research Institute, Melbourne, Australia. ²Hospital Vithas San José, Vitoria-Gasteiz, Spain. ³Sheffield Children’s NHS Foundation Trust, Sheffield, United Kingdom. ⁴Hôpital des Enfants – Toulouse, Toulouse, France. ⁵Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom. ⁶Hospital Universitario Virgen de la Victoria, Malaga, Spain. ⁷NHS Greater Glasgow and Clyde, Glasgow, United Kingdom. ⁸Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Lyon, France. ⁹Hospital Universitario La Paz, Madrid, Spain. ¹⁰Hôpital Necker-Enfants Malades, Paris, France. ¹¹Manchester University NHS Foundation Trust, Manchester, United Kingdom. ¹²University of Alberta – Stollery Children’s Hospital, Edmonton, Canada. ¹³Vanderbilt University Medical Center, Nashville, USA. ¹⁴Cincinnati Children’s Hospital Medical Center, Cincinnati, USA. ¹⁵Benioff Children’s Hospital Oakland, Oakland, USA. ¹⁶University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United Kingdom. ¹⁷QED Therapeutics, a BridgeBio company, San Francisco, USA. ¹⁸Johns Hopkins University, Baltimore, USA. ¹⁹Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom

Objectives: Achondroplasia (ACH) is characterized by disproportionate short stature and is associated with medical complications and functional constraints. Infigratinib is an oral FGFR3 inhibitor that targets overactive FGFR3 signaling at its origin and is under development as a treatment option for children with ACH. We report Month 18 results from PROPEL 2 (NCT04265651), a Phase 2, multicenter, open-label, dose-escalation and dose-expansion study to evaluate the preliminary safety, tolerability, and efficacy of infigratinib in children with ACH aged 3-11 years at screening.

Methods: All subjects completed ≥6 months of growth assessments in the observational PROPEL study (NCT04035811) prior to enrollment in PROPEL 2. The 6-month dose-escalation phase of PROPEL 2 comprised 5 ascending dose cohorts ranging from 0.016 mg/kg/day to 0.25 mg/kg/day, followed by a 12-month extended treatment period. Annualized height velocity (AHV), height z-score and body proportion ratio were analyzed for up to 18 months. Safety is presented across cohorts. Efficacy results are presented for Cohort 5.

Results: 72 children enrolled (58.3% female; mean (SD) age = 7.5 (2.2) years; age range 3.1 – 11.5 years) and 67 completed 18 months of treatment. All children experienced at least one TEAE, with the most common ones in the category of infections and infestations. No SAEs or TEAEs led to treatment discontinuation. A statistically significant increase in AHV was observed in children in Cohort 5 (0.25 mg/kg/day), with a mean (SD) change from baseline in AHV at Month 6 of +3.38 (2.70) cm/year (P = 0.0012, n = 12), which persisted at Month 12 (+2.51 (2.21) cm/year, P = 0.0037, n = 11) and Month 18 (+2.50 (1.91) cm/year, P = 0.0015, n = 11). Of 10/11 children with positive AHV changes from baseline at Month 18, 73% experienced a >25% AHV increase. Mean (SD) change from baseline in height z-score was +0.54 (0.28) (P <0.0001) at Month 18 relative to an untreated ACH population. A statistically significant improvement in upper:lower body segment ratio was observed, with mean (SD) change from baseline of -0.12 (0.09) (P = 0.0012) at Month 18.

Conclusions: Oral infigratinib was well-tolerated for up to 18 months. Daily doses of 0.25 mg/kg infigratinib resulted in significant and sustained increases in AHV as well as improvement in body proportionality, suggesting the potential to provide meaningful benefits to children with ACH. The safety and efficacy of oral infigratinib at the 0.25 mg/kg/day dose are currently being evaluated in PROPEL 3, a phase 3, randomized, placebo-controlled study (NCT06164951).