Longitudinal Observation of Children with Achondroplasia: Findings from a Global Natural History Study (ACHieve)

Abstract

Introduction

The ACHieve study assessed growth velocity, body proportionality, and clinical events in children with achondroplasia not receiving growth-promoting therapy.

Methods

ACHieve was a global, longitudinal, prospective, observational study. Children ≤8 years old with achondroplasia were enrolled and evaluated every 6 months for anthropometric parameters and clinical events.

Results

ACHieve enrolled 259 children in 15 countries, including 83 from China. Median follow-up was 21 months; median age of diagnosis was approximately 52 weeks in China and 2 weeks elsewhere. Growth parameters were similar regardless of region. Mean annualized growth velocity was 9.3 cm/year for males and 10.4 cm/year for females at age 1 and decreased to 4.1 cm/year and 4.6 cm/year, respectively, at age 4. Upper-to-lower-body segment ratio was generally consistent across regions. Overall, 77.2% of participants experienced clinical events, 34.0% of which were considered related to achondroplasia. Two deaths occurred (one accident and one cardiac arrest of unknown origin).

Conclusion

ACHieve was one of the largest longitudinal natural history studies of achondroplasia to date and included the largest prospective Chinese achondroplasia cohort. The results demonstrated common trajectories in growth parameters regardless of region, indicating the generalizability of findings.

Introduction

Achondroplasia is a rare genetic condition affecting more than 250,000 people worldwide [1], caused by variants in the fibroblast growth factor receptor (FGFR3) gene that lead to constitutive activation of the receptor. In bone, this constitutive FGFR3 activation inhibits chondrocyte differentiation and impairs endochondral bone growth, resulting in short stature that is phenotypic of patients with achondroplasia [2–9]. In addition to its role in linear bone growth, FGFR3 is expressed in multiple tissues throughout the body, and its constitutive activation in achondroplasia contributes to a wide range of clinical complications across multiple organ systems [2]. These complications include limb malalignment, cranio-cervical and spinal stenosis, respiratory and sleep disorders, musculoskeletal abnormalities, and reduced muscle strength and stamina, which may negatively impact quality of life, physical functioning, and psychosocial well-being [2, 3, 9–14].

Historically, the management of achondroplasia has focused on supportive care and surgical interventions to address complications, such as limb malalignment, foramen magnum stenosis, and spinal stenosis. These procedures, including cervicomedullary decompression, laminectomy, and limb realignment surgeries, are often repeated and do not modify the underlying pathology associated with constitutive FGFR3 activation. Recently, novel therapeutic options have been developed to target pathologic downstream FGFR3 signaling. C-type natriuretic peptide (CNP), a positive regulator of endochondral bone growth, serves as an inhibitor of downstream FGFR3 signaling in chondrocytes in achondroplasia. This mechanism has been validated as a therapeutic target with the approval of vosoritide, a CNP analog with a modified N-terminal domain, administered as a daily subcutaneous injection, to improve linear growth in children with achondroplasia [15].

To better understand the natural course of achondroplasia and to inform the design of future interventional studies, the prospective natural history ACHieve study (NCT03875534) was initiated to generate robust, globally representative longitudinal growth data in untreated children with achondroplasia. Despite increasing awareness of the burden of achondroplasia, limited prospective data are available for children living outside of North America and Europe, including in China [13, 16]. ACHieve addresses this gap by capturing anthropometric and clinical event data in one of the largest global cohorts to date, including the largest prospective Chinese achondroplasia cohort [13, 16–18].

Here, we report the baseline characteristics, growth parameters, body proportionality, and clinical events in children with achondroplasia enrolled in the ACHieve study and describe, to the best of our knowledge, the largest prospective cohort of pediatric achondroplasia in China to date. This study provides globally relevant benchmarks to inform both clinical care and future therapeutic development, including ongoing interventional studies of navepegritide (TransCon CNP), an investigational prodrug of CNP administered once weekly and designed to provide continuous systemic exposure to active CNP, and other investigational therapies for people with achondroplasia.

Methods

Study Design

ACHieve (NCT03875534) was a global, multi-center, longitudinal, observational study that included both prospective and retrospective data collection of children with achondroplasia, with the aim of evaluating linear growth, body proportionality, and clinical events over time. As this was an observational, natural history study, no study medication was administered.

At screening (∼90 days prior to the enrollment visit), participant eligibility was assessed after their legally authorized representative provided informed consent, with a signed assent from the child when appropriate per local requirements. Upon confirmation of eligibility and enrollment, trial participants were evaluated every 6 months for anthropometric parameters and clinical events and were followed for up to 60 months. Historical data on height as well as medical history were also collected from medical records. Enrolled children who met all eligibility criteria were invited to participate in interventional trials with navepegritide; those who enrolled in an interventional trial discontinued participation in ACHieve. This study, which was conducted in accordance with GCP as outlined in ICH E6 (R2) and regional regulations, was terminated by the sponsor on 16-Jan-2024. This decision followed the completion of recruitment and sufficient follow-up in the ACHieve study and enrollment in the pivotal ApproaCH trial (NCT05598320) of navepegritide in achondroplasia [19].

Study Population

The study planned to enroll approximately 200 children with achondroplasia from approximately 25 study sites in 15 countries in North America, Europe, Asia, and Oceania (Australia and New Zealand). Key inclusion criteria were investigator-confirmed clinical diagnosis of achondroplasia, age between 0 and 8 years at enrollment, and ability to stand without assistance for children 24 months and older. Children having received human growth hormone or other medicinal products intended to affect stature or body proportionality at any time for more than 3 months were excluded. Genetic confirmation of clinical diagnosis of achondroplasia was not required for participation. In total, 6.2% of participants lacked confirmatory genetic testing. However, diagnosis was made clinically by investigators at specialized centers with extensive experience in achondroplasia. A complete list of enrollment criteria is included in the online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000550169).

Ethics Declaration

This study was conducted in accordance with Good Clinical Practice as outlined in ICH E6 (R2) and regional regulations. The protocol was approved by a centralized institutional review board (Advarra). The legally authorized representative provided informed consent for each participant, with a signed assent from the child when appropriate per local requirements. Participant data were de-identified.

Study Assessments

Primary assessments were annualized growth velocity (AGV) and body proportionality based on protocol-standardized, semi-annual measurements of standing height (or equivalent), and sitting height (or equivalent). Additional anthropometric evaluations included body weight, head circumference, arm span, lower body segment, upper and lower leg length, upper and lower arm length, chest circumference, and hand and foot length. All anthropometric data were an average of three consecutive measurements.

Secondary assessments included severity, timing, and frequency of clinical events; attainment of specific developmental milestones (communication, feeding, motor), as well as medical interventions associated with achondroplasia, including assessment of foramen magnum size and apnea-hypopnea index. Study assessments were made during enrollment visit (Day 1) and during study visits every 6 months thereafter for up to 60 months (±2 weeks). Of the assessments listed above, this manuscript reports findings from anthropometric measurements and clinical events.

Clinical Events

In this observational study, the term “clinical event” was used to describe any untoward medical occurrence, regardless of causality, observed by the investigator or reported by the participant or their legally authorized representative. This terminology aligns with the standard definition of adverse events but was used in this context to reflect the real-world nature of the natural history study in the absence of growth-promoting therapy. A clinical event was determined to be related to achondroplasia at the discretion of the investigator and was defined as any clinical event with causal relationship (either known or suspected) to achondroplasia regardless of temporal association with participation in the study. All clinical events were rated based on severity (mild, moderate, or severe) and were classified by the investigator as serious or not serious; a clinical event was considered serious if the event required hospitalization, was life threatening, or resulted in death.

Statistical Analysis

Retrospective data from medical records and prospectively collected data were used for analysis. No formal power calculation was performed for determination of sample size. Approximately 200 children were considered appropriate to obtain sufficient data on growth parameters and clinical events. The statistical analysis was descriptive in nature. For categorical variables, frequencies and percentages were summarized and for continuous variables, descriptive statistics were calculated. Analyses were performed based on available data for all participants enrolled in the study. Pre-planned subgroup analyses included sex and region (China vs. other regions). All descriptive statistics were generated using software SAS Version 9.4.

In general, standing height was used for analysis of height. If only body length was reported, it was converted to height by subtracting 0.7 cm [17]. Height Z-score was derived using CDC 2000 (USA) [20]. Growth curves (including 5th, 25th, 50th, 75th, and 95th percentile) for anthropometric parameters were estimated using the Box-Cox Cole and Green distribution (using R package GAMLSS) [21]. For comparison to other natural history studies, summary data (percentiles, means) were graphed when available; when unavailable, percentiles, and mean heights were estimated from growth curves provided in the respective manuscripts. For the subgroup analysis comparing China versus other regions, the appropriateness of pooling data from North America, Europe, and Oceania was evaluated by examining baseline demographic and clinical characteristics across regions.

Results

Study Population

Between 19 June 2019 and 16 January 2024, 259 children were enrolled at centers in Australia, Austria, Canada, China, Denmark, France, Germany, Ireland, Italy, New Zealand, Portugal, Spain, Switzerland, the USA, and the United Kingdom (online suppl. Table 1). Of these, 83 (32%) participants were enrolled in China, representing the largest prospective natural history cohort of children with achondroplasia in the region. The remaining 176 children were enrolled in North America, Europe, and Oceania (Australia and New Zealand) [18]. Baseline characteristics of the study population are shown in Table 1. Age of participants ranged from 2 months to 9.0 years, with a median age of 3.4 years. Fifty-one percent of the participants were male and 54% were White. Median (interquartile range) duration of follow-up was 21 (12, 30) months (range: 0–48 months).

Table 1.

Baseline demographics and clinical characteristics

​	Global (N = 259)	China (n = 83)	North America, Europe, Oceania (n = 176)
Age at enrolment, years
Median (IQR)	3.36 (2.08, 5.47)	3.31 (2.19, 4.26)	3.54 (1.91, 6.14)
Range	0.24, 8.99	0.24, 8.06	0.26, 8.99
Age group at enrolment, n (%)
0 to ≤2 years	63 (24.3)	17 (20.5)	46 (26.1)
2 to ≤5 years	121 (46.7)	55 (66.3)	66 (37.5)
5 to ≤8 years	63 (24.3)	10 (12.0)	53 (30.1)
>8 years	12 (4.6)	1 (1.2)	11 (6.3)
Sex, male, n (%)	132 (51.0)	42 (50.6)	90 (51.1)
Race, n (%)
White	140 (54.1)	0 (0.0)	140 (79.5)
Asian	98 (37.8)	83 (100.0)	15 (8.5)
Other	13 (5.0)	0 (0.0)	13 (7.4)
Black or African American	4 (1.5)	0 (0.0)	4 (2.3)
American Indian or Alaska Native	2 (0.8)	0 (0.0)	2 (1.1)
Native Hawaiian or Pacific Islander	2 (0.8)	0 (0.0)	2 (1.1)
Ethnicity, n (%)
Hispanic or Latino	15 (5.8)	0 (0.0)	15 (8.5)
Not Hispanic or Latino	235 (90.7)	83 (100.0)	152 (86.4)
Not reported	9 (3.5)	0 (0.0)	9 (5.1)
Follow-up time, months	​	​	​
Median (IQR)	21 (12, 30)	23 (13, 30)	19 (9, 30)
Range	0, 48	1, 36	0, 48
Age at diagnosis, years
N	257	83	174
Median (IQR)	0.18 (0.01, 0.74)	0.99 (0.45, 2.24)	0.04 (0.00, 0.28)
Range	0.00, 5.73	0.01, 5.73	0.00, 3.22
FGFR3 variant, n (%)
c.1138G>A	232 (89.6)	83 (100.0)	149 (84.7)
c.1138G>C	6 (2.3)	0 (0.0)	6 (3.4)
Other*	5 (1.9)	0 (0.0)	5 (2.8)
Unknown	16 (6.2)	0 (0.0)	16 (9.1)
Parents or siblings with achondroplasia, n (%)
No	246 (95.0)	78 (94.0)	168 (95.5)
Yes	11 (4.2)	4 (4.8)	7 (4.0)
Unknown	2 (0.8)	1 (1.2)	1 (0.6)

IQR, interquartile range.

*Type of variant was listed as “Other” for 5 participants and include: 3 participants with FGFR3 (variant not provided); 1 participant with 1043C>G; and 1 participant for whom genetic testing was not done. These participants were included based on investigator-confirmed clinical diagnoses consistent with achondroplasia at experienced study centers.

Baseline demographics and clinical characteristics were similar between regions except for age of achondroplasia diagnosis: participants in China were diagnosed with achondroplasia at a median age of approximately 52 weeks while participants from other regions were diagnosed at a median age of approximately 2 weeks of age. In North America, Europe, and Oceania, 42 (23.9%) participants were diagnosed in utero and 29 (16.5%) were diagnosed at birth. In China, no participants were diagnosed in utero or at birth. All participants in China were documented to have the FGFR3 c.1138G>A variant. From other regions, 84.7% of participants were documented to have the c.1138G>A, with additional or unspecified FGFR3 variants reported for 11 participants (6.2% of the subgroup), and unknown genetic cause reported for 16 participants (9.1% of the subgroup). Across regions (North America, Europe, Oceania vs. China) approximately 95% of participants had de novo FGFR3 variants and/or no family history of achondroplasia. No notable baseline differences were observed when comparing North America, Europe, and Oceania individually (data not shown).

Growth Parameters

Compared to children of average stature [22–24], children with achondroplasia had lower AGV across age groups. AGV declined rapidly in the first 2 years of life and continued to decline at a slower rate for up to 4 years before stabilizing thereafter (Fig. 1; online suppl. Table 2). Similar patterns in AGV were observed between sexes, with mean AGV (SD) of 9.3 (2.64) cm/year for males and 10.4 (2.12) cm/year for females at age 1 year, and 4.1 (0.94) cm/year and 4.6 (1.32) cm/year, respectively, at age 4 years (Fig. 1a, b). Regional differences appeared to be minimal among males; among females, AGV growth curves demonstrated a steeper rate of decline for participants in China compared with those in other regions. At age 4 years, the mean (SD) AGV was 3.9 (1.08) cm/year for females in China vs. 4.9 (1.34) for females in other countries (Fig. 1c, d). Height Z-scores, with reference to the CDC database for average stature children, are shown in online supplemental Table 3. Height Z-scores were generally consistent across sex, age, and region.

Fig. 1.

Twelve-month AGV (cm/year) in male participants (a) and female participants (b) globally, and male participants (c) and female participants (d) by region. Age is defined as the midpoint age for the AGV interval. Percentiles (5, 25, 50, 75, 95) for all participants by sex provided as overlay. Percentiles (5, 50, 95) for participants by geographic region. Average stature reference from Hoover-Fong et al. [24] 2008 (0–3 years [estimated from Brandt [22] 1985]; percentile: 10, 50, 90) and Tanner and Davies [23] 1985 (3–12 years; percentile: 3, 50, 97).

Body length/standing height of study participants is shown in online supplemental Table 4 and online supplemental Figure 1 by sex and region. Trends were similar between different regions and sexes. Data points for standing height with and without historical data are superimposed for comparison in online supplemental Figure 2. Inclusion of historical (i.e., retrospective) height data produced effectively similar mean (SD) heights by age across sexes, indicating strong alignment with protocol-standardized height assessments.

Standing height was also compared to other natural history databases for achondroplasia by age and sex (Fig. 2), using natural history databases from various regions of the world [16, 25–33]. For males (Fig. 2a) and females (Fig. 2b) from birth to age 18 years, the median body length/standing height across regions was comparable to median heights reported in the retrospective, controlled US CLARITY study as well as mean heights reported in another large multinational, prospective, observational study of achondroplasia [32]. Median and mean standing height values from other regional reports confirmed comparable growth patterns, particularly during the first 8 years of life in children with achondroplasia.

Fig. 2.

Body length/standing height comparison to other natural history databases of achondroplasia in male (a) and female (b) participants. The 50th percentile from CLARITY is shown as a dotted black line, with 5th to 95th percentile as the gray-shaded area [30]. Asterisks are used to identify which studies report mean height rather than median height. Natural history databases from various regions of the world are included for comparison [16, 25–28, 31–33].

Body Proportionality

As expected in achondroplasia, upper-to-lower body segment ratio (Fig. 3; online suppl. Table 5), calculated based on upper body segment (online suppl. Table 6) and lower body segment (online suppl. Table 7), decreased over time, reflecting the expected age-related decline reported for children with achondroplasia. The decreasing trend was similar to that of individuals with average stature [34], however, upper-to-lower body segment ratio remained numerically higher in individuals with achondroplasia across all ages (Fig. 3a, b) [35].

Fig. 3.

Upper-to-lower body segment ratio in male participants (a) and female participants (b) globally, and male participants (c) and female participants (d) by region. Age is defined as the participant’s actual age at the time of assessment. Percentiles (5, 25, 50, 75, 95) for all participants by sex provided as overlay. Percentiles (5, 50, 95) for participants by geographic region. Average stature reference from Hall et al. 1989 [35].

For males with achondroplasia, at age 1 year, the mean (SD) upper-to-lower body segment ratio was 2.5 (0.22); this decreased to 2.2 (0.15) at age 5 years, 2.0 (0.12) at age 8 years, and 1.9 (0.03) at age 10 years. Similar trends were observed regardless of region (Fig. 3c, d). For females with achondroplasia in North America, Europe, and Oceania, the decreasing trend was comparable to males, decreasing from 2.6 (0.32) at age 1 year, to 2.1 (0.18) at age 5 years, 2.0 (0.15) at age 8 years, and 1.9 (0.21) at age 10 years. Interestingly, for females in China, the ratio was 2.5 (0.22) at age 1 year and decreased to 2.3 (0.10) at age 5, before aligning with values in other regions at older ages. It should be noted that data on body proportionality was relatively sparse for females in China after age 6 years, with no data available beyond age 9 years.

Online supplementary Tables 8–14 show additional growth parameters and body proportionality measurements. Body weight (online suppl. Table 8) increased with age in a similar pattern for males and females, though individuals in China displayed slightly less weight gain compared to those in other countries. At age 5 years, males in China had a mean (SD) body weight of 14.5 (1.06) kg, while females in China had a mean (SD) weight of 14.6 (1.59) kg. In comparison, males in other countries had a mean (SD) body weight of 16.2 (2.19) kg, and females had a mean (SD) of 15.9 (2.21) kg. A similar trend was observed for body mass index (online suppl. Table 9), with increases occurring at comparable rates between sexes but remaining generally lower in children from China.

Growth patterns for head circumference, limb lengths, chest circumference, body segment ratios, and foot length (online suppl. Tables 10–20) were largely consistent across sexes and regions. However, hand length (online suppl. Table 14) and arm span (online suppl. Table 15) were generally slightly shorter in participants from China with increasing age. At age 7 years, the mean (SD) hand length was 10.4 (1.05) cm for males and 9.9 (0.78) cm for females in China vs. 10.7 (0.39) cm and 10.7 (0.68) cm, respectively, in other countries. Similarly, at age 7 years, females in China had shorter arm span (81.2 [6.00] cm vs. 86.7 [5.59] cm in other countries), mirroring trends in the upper-to-lower body segment ratio. Chest circumference (online suppl. Table 16) was also generally consistent across sex and region, with slightly smaller values in females from China with increasing age (age 7 years: 52.4 [2.97] cm in China vs. 56.4 [4.71] cm in other countries).

Limb proportions remained stable throughout the study, with upper-to-lower arm and leg ratios showing little variation across ages, sexes, and regions (online suppl. Tables 13, 19). Foot length (online suppl. Table 20) increased with age similarly between regions and sexes, with some variation at different timepoints. At age 7 years, the mean foot length (SD) was 15.7 (0.87) cm for males in China and 15.3 (0.81) cm for males in other countries, while for females, it was 15.3 (1.14) cm in China and 15.6 (0.86) cm in other countries.

Clinical Events

Overall, 77.2% of participants experienced a clinical event over the course of the study, the most common of which were upper respiratory tract infection (26.3%), pyrexia (23.2%), and nasopharyngitis (15.4%). Upper respiratory tract infection was reported in a greater proportion of participants in China (60.2%) compared to other regions (10.2%). Additionally, 10.4% of participants experienced a clinical event considered serious, the most common of which were pneumonia (n = 4), foramen magnum stenosis (n = 4), obstructive sleep apnea syndrome (n = 3), middle ear effusion (n = 3), and cervical spinal stenosis (n = 3). All but two serious clinical events occurred in participants ≤5 years of age, and the majority qualified as serious due to hospitalization. Two deaths were reported during the study, one in Denmark and one in China. The child in Denmark was a 6-month-old male diagnosed with achondroplasia at 4 months of age who experienced an accidental fall and subsequent cardiac arrest. The individual was hospitalized but did not recover and was removed from life support. The participant in China was a 7-year-old male diagnosed with achondroplasia after the first year of life who experienced a sudden cardiac arrest. Overall, 88 (34.0%) participants experienced a clinical event considered related to achondroplasia while in the study. The incidence of achondroplasia-related clinical events was lower in China (n = 12, 14.5% of China subgroup) compared to other regions (n = 76, 43.2%).

Discussion

The ACHieve natural history study, conducted across 15 countries, collected longitudinal retrospective, and standardized prospective anthropometric data in one of the larger studies of pediatric achondroplasia (N = 259). To the best of our knowledge, this study also represents the largest prospective dataset for pediatric achondroplasia in China (n = 83). Prospective and historical linear growth data demonstrated that children with achondroplasia follow similar growth patterns with increasing age regardless of geographical region or ethnicity. Baseline demographics and clinical characteristics were generally consistent between regions. The consistent impact of pathologic FGFR3 variants on growth parameters worldwide has important clinical implications. These findings suggest that natural growth patterns and clinical characteristics may be broadly consistent across geographic regions, race, and ethnicity, supporting the potential applicability of global reference standards and the development of future endpoints for interventional studies in achondroplasia.

Previous natural history studies of achondroplasia have reported various growth parameters such as body length or standing height in individuals with achondroplasia from different regions, including Australia [27, 32], Japan [25], South Korea [33], Czechia/Slovakia [31], Argentina [26], Egypt [36], Europe [28, 32], China [29], and the USA [16, 32]. Findings from the current study were consistent with previous natural history studies, supporting the validity of the ACHieve data. They further highlight the highly conserved patterns of linear growth observed with pathogenic FGFR3 variants. The data collected from a relatively large Chinese population with achondroplasia in the present study expands our understanding of the natural evolution of achondroplasia. Most results from this study, including AGV and height Z-scores, were similar across different regions of the world, although a relatively higher upper-to-lower body segment ratio in females in China from ages 3 through 7 years was observed. These changes were driven by minor differences in lower body segment, and the interpretation of these data is confounded by the small number of females in China older than 5 years (ranging between 6 and 10 individuals per age category).

Another important difference between China and other regions was the incidence of achondroplasia-related clinical events. Numerically, the incidence of such clinical events was substantially lower in Chinese participants compared to those in other regions. As participants enrolled from China were diagnosed at age 1 year or older, substantially older than in other regions, it is likely that several common clinical events related to achondroplasia occurring early in life were not observed or reported in the Chinese population during this study. The observed differences in clinical events may also be related to cultural differences in reporting, as well as regional or socioeconomic disparities in healthcare in China. Nonetheless, this discrepancy may not reflect a truly lower incidence of clinical events among Chinese children with achondroplasia. Additional studies in China are needed to further clarify the reasons for this observation. Importantly, the findings of the ACHieve study highlight the value of early diagnosis and intervention and suggest that there may be an opportunity to improve outcomes in achondroplasia through increased education and awareness.

ACHieve gathered both retrospective (historical) and prospective height data, with historical height records contributing the majority of measurements at birth and during early childhood. While combining retrospective and prospective data can raise concerns about measurement accuracy, comparisons with protocol-standardized prospective data showed that height trajectories were closely aligned for both males and females. This consistency underscores the reliability of the historical data, which are particularly important in pediatric studies, where early-life measurements (e.g., birth length) are often only available through retrospective historical records. These findings support the utility of ACHieve data for evaluating growth-related outcomes in future clinical trials.

There are several limitations to this study. First, although the diversity of the participant population across multiple centers and countries is a strength of this study, it may also introduce variability based on differences in healthcare systems, access to care, medications that participants may have been receiving (or not receiving), or differences in other regional practices. For example, the intensity in monitoring clinical events related to achondroplasia in this observational study may have varied depending on the region due to differences in standard practice. Second, anthropometric data were only available through age 12, limiting evaluation of pubertal growth and near-final adult height. Lastly, this study enrolled children with a clinical diagnosis of achondroplasia, resulting in 6.2% of enrolled participants having no genetic confirmation of their achondroplasia diagnosis. It should be noted, however, that this study was conducted at sites with substantial experience in the diagnosis and treatment of achondroplasia, reducing the likelihood that a diagnosis of achondroplasia was incorrectly applied, even in the absence of genetic confirmation. All enrolled participants were determined by investigators to exhibit clinical and radiographic features consistent with classic achondroplasia. This included a small subset of participants with rare or unspecified FGFR3 variants, who were included only if their phenotype aligned with that of classic achondroplasia.

The major strength of this study is that it is one of the most extensive and robust natural history studies for achondroplasia conducted to date, with the largest prospective cohort of Chinese participants with achondroplasia. These longitudinal data add to an ever-increasing literature of reference standards for children with achondroplasia and serve as a valuable tool for evaluating the safety and efficacy of new and emerging therapies. These insights are particularly important for interpreting treatment effects in interventional trials where long-term placebo use may not be feasible or ethical.

ACHieve provides important confirmation of existing knowledge and growth patterns established in previous natural history studies in achondroplasia, adding data from the largest cohort of Chinese children with achondroplasia. These results will be instrumental in evaluating the long-term effects of treatment on anthropometric parameters and clinical characteristics in future clinical trials. The ACHieve study offers a globally relevant, real-world reference for understanding clinical burden, anticipating complications, and developing effective therapeutic strategies.

Acknowledgments

Medical writing assistance was provided by Nisha Cooch, PhD, an employee of Ascendis Pharma.

Statement of Ethics

This study was conducted in accordance with Good Clinical Practice as outlined in ICH E6 (R2) and regional regulations. The protocol was approved by a centralized institutional review board, Advarra IRB, which is registered with OHRP and FDA under IRB#00000971. Clinical trial sites are listed in the study overview section of the clinicaltrials.gov posting (Study Details | NCT03875534 | A Multi-center, Longitudinal, Observational Study of Children with Achondroplasia | ClinicalTrials.gov). The legally authorized representative provided written informed consent for each participant, with a signed written assent from the child when appropriate per local requirements.

Conflict of Interest Statement

The following are disclosures as submitted by the authors: C.A.B., G.B., T.A.B., C.G.F., M.F., P.H., M.I., H.M., D.S., and S.U. received research support from Ascendis Pharma; C.G. received research support from Ascendis Pharma and VISEN pharmaceuticals; D.G.H.: research support/site PI for Ascendis Pharma, BioMarin and Bridge Bio/QED, royalty stock holder for OrthoPediatrics, and speaker faculty for Highridge; W.H. received research support from Ascendis Pharma, consulting fees from BioMarin, travel support from Ascendis Pharma and BioMarin, and participated in a data safety monitoring board for BioMarin; H.B.H. received consulting fees from and is an advisory board member for Ascendis Pharma; J.M.L. is a site PI for Ascendis Pharma and Bridge Bio/QED, speaker for Ascendis Pharma and BioMarin, Advisory Board Member for BioMarin, and Medical Board member for Little People of America and Little Legs Big Heart; X.L. received research support from Ascendis Pharma and VISEN pharmaceuticals; C.M.: received research support grants from, participated in advisory boards for, and was a speaker for Ascendis Pharma, Abbott, Pfizer, Kyowa Kirin, Ultragenyx, BioMarin, Regeneron, and Alexion; S.M. received consulting fees from Calcilytix, honoraria from Inozyme, Alexion, and Kyowa Kirin, travel support from Kyowa Kirin and was a member of data safety monitoring boards for Ascendis Pharma, Calcilytix, and BioMarin; K.K.W. received contracts from Ascendis Pharma, Bridge Bio/QED, Tyra, and Ultragenyx, consulting fees and honoraria from BioMarin and Bridge Bio/QED, Medical Board member for Little People of America; Scientific Advisory Board member for National MPS Society, and Board of Directors for Camp Korey; Y.Y. received research support from Ascendis Pharma and VISEN pharmaceuticals; R.S. received consulting fees and honoraria from BioMarin, Ascendis Pharma, QED, and Tyra; C.Z., M.A.M. and A.D.S. are employees of Ascendis Pharma, Inc and may own stock in the company. Prof. Dr. Wolfgang Högler was a member of the journal’s Editorial Board at the time of submission.

Funding Sources

This study was funded by Ascendis Pharma. The sponsor, Ascendis Pharma, was involved in the design and conduct of the trial, the collection, management, analysis, and interpretation of the data, and preparation, review, or approval of the manuscript. The first author accessed and verified the trial data and made the final decisions regarding the content of the submitted manuscript. All authors reviewed and revised a draft of the manuscript and approved the final submitted manuscript.

Author Contributions

Conceptualization: M.A.M. and A.D.S.; formal analysis: C.Z.; investigation: M.A.M. and C.Z.; project administration and resources: A.D.S.; visualization: M.A.M.; writing – original draft: C.M., M.A.M., A.D.S., and C.Z.; writing – review and editing; C.M., H.B.H., M.I., K.K.W., C.G.F., J.M.L., W.H., D.G.H., D.S., S.U., C.A.B., P.H., Y.Y., H.M., C.G., X.L., T.A.B., G.B., S.M., M.F., M.A.M., C.Z., and R.S.

Funding Statement

This study was funded by Ascendis Pharma. The sponsor, Ascendis Pharma, was involved in the design and conduct of the trial, the collection, management, analysis, and interpretation of the data, and preparation, review, or approval of the manuscript. The first author accessed and verified the trial data and made the final decisions regarding the content of the submitted manuscript. All authors reviewed and revised a draft of the manuscript and approved the final submitted manuscript.

Data Availability Statement

The datasets generated and/or analyzed during the study are not publicly available but are available for noncommercial, academic purposes from the sponsor, absent legal reasons to the contrary, upon reasonable request. Further inquiries can be directed to ADS@ascendispharma.com.