THU181 Evaluation Of Bone Mineral Density In A Cohort Of Children With ACH Participating In The PROPEL 2 Study Of Infigratinib
Bibliographic record
Abstract
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 <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
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".