Clinical manifestations

Achondroplasia is a rare, genetic, skeletal dysplasia. It has distinct clinical features including short stature with disproportionate shortening of limbs relative to trunk, macrocephaly with frontal bossing and midfacial hypoplasia with depressed nasal bridge, hypotonia, and joint hypermobililty. Achondroplasia may lead to multisystemic health effects1,2

Learn more about the multisystemic effects of achondroplasia

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FGFR3 signaling in
skeletal dysplasias

Achondroplasia is a fibroblast growth factor receptor 3 (FGFR3)-driven skeletal dysplasia caused by activating pathogenic variants of the FGFR3 gene. FGFR3 downstream signaling is responsible for regulating endochondral bone growth by inhibiting chondrocyte proliferation and differentiation.3 Watch the video for more information on FGFR3 signaling and its dysregulation in achondroplasia.

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What is being studied?

The PROPEL clinical study (QBGJ398-001) aims to deepen our understanding of the natural progression of achondroplasia and medical outcomes that may be impacted by FGFR3 inhibition.4,5

We are studying whether the oral investigational agent infigratinib has the potential to address the root cause of irregular bone growth in achondroplasia by decreasing the overactivity of FGFR3.4-8 Watch the video to learn how infigratinib may impact FGFR3-driven skeletal dysplasias, such as achondroplasia or hypochondroplasia.

Infigratinib is currently the only oral agent under investigation in a double-blinded Phase 3 trial for achondroplasia (PROPEL 3, QBGJ398-303).7 Upon study completion, participants have the option to continue using infigratinib through the open-label extension study (PROPEL OLE, QBGJ398-203) until their growth is completed.8

Infigratinib is not currently approved for the treatment of achondroplasia by the U.S. FDA or any other health authority.

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For more details, visit clinicaltrials.gov external link icon

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Details of the study designs are available

Resources

Latest data releases

Month 6 results from the PROPEL 2 dose-finding study are now available

PROPEL trial design and baseline image

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

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Activity in murine models of achondroplasia and hypochondroplasia image

Activity in murine models of achondroplasia and hypochondroplasia

Elena Muslimova, Benoit Demuynck, Léa Loisay, Morgan Paull, Laurence Legeai-Mallet

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Bone mineral density in a cohort of children with ACH participating in the PROPEL studies

Bone mineral density in a cohort of children with ACH participating in the PROPEL studies

Ravi Savarirayan, Josep Maria De Bergua, Paul Arundel, Jean Pierre Salles, Antonio Leiva-Gea, Melita Irving, Vrinda Saraff, Helen McDevitt, Maria Salcedo Montejo, Marc Nicolino, Valerie Cormier-Daire, Peter Kannu, Mars Skae, Michael B. Bober, John Phillips III, Toby Candler, Paul Harmatz, Howard Saal, Julie Hoover-Fong, Elena Muslimova, Terry Cho, Richard Weng, Daniela Rogoff

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Evaluation of bone mineral density in a PROPEL 2 cohort of children image

Infigratinib in children with achondroplasia: Design of the PROPEL, PROPEL 2, and PROPEL OLE studies

Ravi Savarirayan, Josep Maria De Berga, Paul Arundel, Helen McDevitt, Valerie Cormier-Daire, Vrinda Saraff, Mars Skae, Borja Delgado, Antonio Leiva-Gea, Fernando Santos-Simarro, Jean Pierre Salles, Marc Nicolino, Massimiliano Rossi, Peter Kannu, Michael B. Bober, John Phillips III, Howard Saal, Paul Harmatz, Christine Burren, Garrett Gotway, Terry Cho, Elena Muslimova, Richard Weng, Daniela Rogoff, Julie Hoover-Fong, Melita Irving

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PROPEL and PROPEL 2 trials in progress

PROPEL, PROPEL 2, and PROPEL 2 image

PROPEL, PROPEL 2, and PROPEL 2 OLE trial designs ENDO 2022

Infigratinib in children with achondroplasia: design of the PROPEL, PROPEL 2, and PROPEL OLE studies

Ravi Savarirayan, Josep Maria De Berga, Paul Arundel, Helen McDevitt, Valerie Cormier-Daire, Vrinda Saraff, Mars Skae, Borja Delgado, Antonio Leiva-Gea…

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PROPEL trial design and baseline image

PROPEL trial design and baseline characteristics data ASBMR 2021

Study design and baseline characteristics of children enrolled in PROPEL: a prospective clinical assessment study in children with achondroplasia

Ravi Savarirayan, Josep Maria De Berga, Paul Arundel, Jean Pierre Salles, Antonio Leiva-Gea, Vrinda Saraff, Helen McDevitt, Fernando Santos-Simarro…

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PROPEL2 trial design ASBMR 2021 image

PROPEL2 trial design ASBMR 2021

PROPEL2: a phase 2, open-label, dose-escalation and dose-expansion study of infigratinib in children with achondroplasia

Ravi Savarirayan, Paul Arundel, Josep Maria De Bergua, Helen McDevitt, Valerie Cormier-Daire, Vrinda Saraff, Mars Skae, Fernando Santos-Simarro, Jean Pierre

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PROPEL2 trial design ENDO 2021 image

PROPEL2 trial design ENDO 2021

Infigratinib in children with achondroplasia (ACH): design of PROPEL2 – a phase 2, open-label, dose-escalation and dose-expansion study

Ravi Savarirayan, Peter Kannu, Carl L. Dambkowski, Daniela Rogoff, Melita Irving

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PROPEL trial design ENDO 2020 image

PROPEL trial design ENDO 2020

Prospective clinical assessment study in children with achondroplasia: the PROPEL trial

Ravi Savarirayan, Peter Kannu, Carl L. Dambkowski, Daniela Rogoff, Melita Irving

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PROPEL natural history data

PROPEL BMI and metabolism image

PROPEL BMI and metabolism

Evaluation of body mass index and metabolic parameters in children with achondroplasia participating in the PROPEL study

Ravi Savarirayan, Josep Maria De Bergua, Paul Arundel, Jean Pierre Salles, Antonio Leiva-Gea, Melita Irving, Vrinda Saraff, Helen McDevitt, Fernando…

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PROPEL medical history image

PROPEL medical history

Medical history of children enrolled in PROPEL: a prospective clinical assessment study in children with achondroplasia

Ravi Savarirayan, Josep Maria De Bergua, Paul Arundel, Jean Pierre Salles, Antonio Leiva-Gea, Vrinda Saraff, Helen McDevitt, Fernando Santos-Simarro…

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Quality of life research

Medical challenges and impacts image

Medical challenges and impacts

Qualitative research in children with achondroplasia and parents of children with achondroplasia: medical challenges and impacts

Susan D. Mathias, Julie Hoover-Fong, Ravi Savarirayan, Chandler Crews, Inês Alves, Susana Noval Iruretagoyena, Amer Haider, Terry Cho, Anne Lee, Hilary…

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Qualitative research on patient-reported outcome measures image

Qualitative research on patient-reported outcome measures

Qualitative research in children and parents of children with achondroplasia to cognitively debrief three patient-reported outcome measures and confirm the content validity of a clinically assessed measure

Susan D. Mathias, Julie Hoover-Fong, Ravi Savarirayan, Chandler Crews, Inês Alves, Susana Noval Iruretagoyena, Amer Haider, Terry Cho, Anne Lee, Hilary…

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Infigratinib preclinical research

Activity in preclinical models of hypochondroplasia

Low-dose infigratinib, an oral selective fibroblast growth factor receptor tyrosine kinase inhibitor, demonstrates activity in preclinical models of hypochondroplasia

Carl Dambkowski, Benoit Demuynck, Léa Loisay, Laurence Legeai-Mallet

Potency and selectivity of FGFR-selective TKIs image

Potency and selectivity of FGFR-selective TKIs

FGFR-selective tyrosine kinase inhibitors, such as infigratinib, show potency and selectivity for FGFR3 at pharmacologically relevant doses for the potential treatment of achondroplasia

Katherine Dobscha, Ge Wei, Carl L Dambkowski, Daniela Rogoff

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No changes in phosphorous levels image

No changes in phosphorous levels

Low-dose infigratinib treatment does not lead to changes in phosphorus in preclinical animal studies

Maribel Reyes, Uma Sinha, Gary Li, David Martin

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Therapeutic approach in a preclinical image

Therapeutic approach in a preclinical achondroplasia model

Support for a new therapeutic approach of using a low-dose FGFR tyrosine kinase inhibitor (infigratinib) for achondroplasia

Benoit Demuynck, Justine Filpo, Gary Li, Carl Dambkowski, Laurence Legeai-Mallet

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Activity in a preclinical download

Activity in a preclinical achondroplasia model

Low dose, daily or intermittent administration of infigratinib (BGJ398), a selective FGFR inhibitor, as treatment for achondroplasia in a preclinical mouse model

Benoit Demuynck, Gary Li, Carl Dambkowski, Laurence Legeai-Mallet

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Achondroplasia information

External resources

Consensus statement

International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia

Ravi Savarirayan , Penny Ireland, Melita Irving, Dominic Thompson, Inês Alves, Wagner A. R. Baratela, James Betts, Michael B. Bober, Silvio Boero, Jenna…

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Comprehensive clinical review

Achondroplasia: a comprehensive clinical review

Richard M. Pauli

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Preclinical mechanisms

Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model

Davide Komla-Ebri, Emilie Dambroise, Ina Kramer, Catherine Benoist-Lasselin, Nabil Kaci, Cindy Le Gall, Ludovic Martin, Patricia Busca, Florent Barbault, Diana Graus-Porta, Arnold Munnich, Michaela Kneissel, Federico Di Rocco, Martin Biosse-Duplan, and Laurence Legeai-Mallet

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References

  1. Pauli RM. Achondroplasia: a comprehensive clinical review. Orphanet J Rare Dis. 2019;14(1):1.
  2. Unger S et al. Current care and investigational therapies in achondroplasia. Curr Osteoporos Rep. 2017;15(2):53-60.
  3. Savarirayan R et al. International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia. Nat Rev Endocrinol. 2022;18(3):173-189.
  4. Savarirayan R et al. Infigratinib in children with achondroplasia: the PROPEL and PROPEL 2 studies. Ther Adv Musculoskelet Dis. 2022;14:1759720X221084848.
  5. Prospective clinical assessment study in children with achondroplasia (ACH). ClinicalTrials.gov identifier: NCT04035811. Updated April 8, 2022. Accessed November 11, 2022. https://clinicaltrials.gov/ct2/show/record/NCT04035811.
  6. Study of infigratinib in children with achondroplasia. ClinicalTrials.gov identifier: NCT04265651. Updated April 7, 2022. Accessed November 11, 2022. https://clinicaltrials.gov/ct2/show/NCT04265651.
  7. A study to evaluate the efficacy and safety of infigratinib in children and adolescents with achondroplasia (PROPEL 3). ClinicalTrials.gov identifier: NCT06164951. Updated December 21, 2023. Accessed January 12, 2024. https://clinicaltrials.gov/study/NCT06164951?cond=achondroplasia&term=PROPEL3&rank=2.
  8. Extension study of infigratinib in children with achondroplasia (ACH). ClinicalTrials.gov identifier: NCT05145010. Updated April 7, 2022. Accessed November 11, 2022. https://clinicaltrials.gov/ct2/show/NCT05145010.