Development of Pediatric Dosing for Mepolizumab in Severe Asthma Based on Extrapolation of Data From Adult Patients and a Phase II Open‐Label Pediatric Trial

Abstract

The benefit–risk profile of mepolizumab in severe asthma was established through clinical trials in adults, leading to EU and US approvals in 2015. To support a pediatric indication (≥6 years), an extrapolation approach was implemented. This extrapolation and its validation were informed by data from Phase III trials in adults (N = 1841) and adolescents aged 12‐17 years (N = 37) with severe asthma, an open‐label trial in children aged 6‐11 years (N = 36), and a trial in children aged 2‐11 years (N = 32) and adolescents aged 12‐17 years (N = 27) with eosinophilic esophagitis. Population pharmacokinetic and pharmacokinetic/pharmacodynamic meta‐analyses demonstrated consistent mepolizumab pharmacokinetic and blood eosinophil reduction across age groups and diseases, with bodyweight the only covariate of exposure and absolute bioavailability also a covariate in children aged 6‐11 years. Baseline blood eosinophil count and disease type were the only covariates of response. In severe asthma, mepolizumab reduced the annualized rate of clinically significant exacerbations by 40% in adolescents and 54% in adults versus placebo. Bootstrap resampling and Bayesian analyses supported similar efficacy between adolescents and adults, and responses in children aged 6‐11 years were consistent with older groups. Safety evaluations revealed no unique safety concerns in pediatric patients with severe asthma. This extrapolation strategy, implemented as an innovative approach to pediatric clinical development of mepolizumab in severe asthma, was validated and provided the scientific basis for dosing recommendations and for EU regulatory approval in patients aged ≥6 years in 2018.

Introduction

Mepolizumab is a humanized monoclonal antibody targeting interleukin 5 (IL‐5), a key cytokine in eosinophil differentiation, activation, and survival. ¹ Evidence suggests that elevated levels of IL‐5 drive eosinophilic inflammatory processes leading to epithelial barrier dysfunction, airway remodeling, and disease progression. ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ By targeting IL‐5, mepolizumab reduces eosinophil counts in blood, sputum, and airway tissue to physiologically normal levels. ¹² , ¹³ , ¹⁴ , ¹⁵

Clinical trials have demonstrated that in adults (≥18 years) and adolescents (12‐17 years) with severe asthma, mepolizumab significantly decreases exacerbation rates and oral corticosteroid use, improves lung function and asthma control, and enhances health‐related quality of life compared with placebo, while maintaining a safety profile similar to placebo. ¹² , ¹⁶ , ¹⁷ , ¹⁸ Phase II and Phase III trials in severe asthma supported the 2015 approval of mepolizumab for adults in the EU and for adults and adolescents (≥12 years) in the United States. In the EU, pediatric approval for patients aged 6 to <18 years with severe asthma was granted in 2018 following the availability of additional clinical data in children and clinical data analyses as part of the agreed EU Paediatric Investigation Plan (PIP).

The initial PIP in severe asthma, agreed in 2011 under the EU Paediatric Regulation (implemented in 2007), proposed a traditional clinical development program in pediatric patients (6‐17 years), that involved the enrollment of both adolescents and adults in the pivotal trials and a fully powered, randomized, placebo‐controlled efficacy trial in children aged 6‐11 years. However, recruitment of adolescents (12‐17 years) in the pivotal trials was likely to prove extremely challenging. Indeed, only one adolescent was enrolled into the Phase II trial MEA112997 (Table 1), reflecting the low prevalence of severe asthma in pediatric populations and the complexity of pediatric trials. Additional barriers included parental hesitancy and requirements for assent or proxy consent, which led to prolonged timelines and limited the generation of efficacy data. ¹⁹

Table 1.

Summary of Mepolizumab Studies in Children and Adolescents with Eosinophilic Diseases Included in the Partial Extrapolation Strategy

		Patients Included in the Partial Extrapolation Strategy
Disease	Study Details	Total N	Pediatric n	Adult n
Severe asthma *	DREAM (16) MEA112997 [NCT01000506] Phase II double‐blind, randomized, placebo‐controlled interventional study	616	1 (<1%) adolescent †	615
	MENSA (12) MEA115588 [NCT01691521] Phase III double‐blind, randomized, placebo‐controlled interventional study	576	25 (4%) adolescents †	551
	SIRIUS (18) MEA115575 [NCT01691508] Phase III double‐blind, randomized, placebo‐controlled interventional study	135	2 (1%) adolescents †	133
	MUSCA (17) 200862 [NCT02281318] Phase III double‐blind, randomized, placebo‐controlled interventional study	551	9 (2%) adolescents †	542
	200363 [NCT02377427] (21, 22) 2‐part Phase II open‐label interventional study [Part A & Part B]	36	36 (100%) children ‡	0
	COSMOS (30) MEA115661 [NCT01842607] Phase III open‐label extension of SIRIUS and MENSA §	651	26 (4%) adolescents †	625
Eosinophilic esophagitis	MEE103219 [NCT00358449] (31) Phase II double‐blind, randomized interventional study	59	59 (100%) children and adolescents ¶	0
Hypereosinophilic syndrome	MHE104317/MHE112562 [NCT00244686] Open‐label compassionate use program § , **	282	25 (9%) children and adolescents ††	257

^*Study NCT03292588 (MUPPITS‐2) (20) was ongoing at the time of the extrapolation and therefore data from this study was not included.

^† Aged 12‐17 years.

^‡ Aged 6‐11 years.

^§ Patients from these studies were only included in the safety assessments.

^¶ Including patients aged 2‐17 years.

^**Study was ongoing at the time of analysis (reported patient numbers are as of the interim data cut‐off date [July 1, 2016]).

^†† Including patients aged 5‐17 years at entry into compassionate use program.

To address these challenges and avoid delaying access to a therapy now proven to be effective in adults, an alternative approach, partial extrapolation, was proposed and agreed with regulators in 2013. This strategy leveraged adult clinical data and the similarity in disease pathophysiology between adult and pediatric patients, supplemented by an open‐label pharmacokinetics/pharmacodynamics (PK/PD) study in children aged 6‐11 years to validate extrapolation assumptions. Unlike complete extrapolation, which assumes fully comparable disease progression and exposure–response relationships, partial extrapolation is applied when some uncertainty remains regarding these similarities. ²⁰

The agreed PIP was executed and validated by the European Medicines Agency (EMA), culminating in pediatric approval in 2018. ¹⁴ This article describes the innovative partial extrapolation approach implemented in 2013, the methods used, and the outcomes that supported dosing recommendations and regulatory approval for pediatric patients with severe asthma.

Methods

An extrapolation approach was considered based on three key factors: (i) evidence supporting similar pathophysiology of severe asthma between adults and pediatric patients aged ≥6 years; ²⁸ , ²⁹ (ii) availability of a validated PD endpoint related to the drug's mechanism of action (blood eosinophil count); and (iii) relevance of clinical efficacy (exacerbation reduction) and safety endpoints assessed in pivotal adult Phase III trials for the pediatric population. Additionally, extensive mepolizumab data were available from other eosinophilic diseases, including a prior PK/PD study in children aged 2 to <18 years with eosinophilic esophagitis. ²¹

To leverage these considerations, a five‐step partial extrapolation strategy was implemented alongside a small (N = 36) open‐label pediatric trial (NCT02377427 [Part A]). This trial used eligibility criteria consistent with adult studies and evaluated PK/PD, safety, and tolerability of mepolizumab administered every 4 weeks in children aged 6 to <12 years (40 mg for bodyweight <40 kg; 100 mg for bodyweight ≥40 kg). ²² , ²³ This strategy formed the complete pediatric clinical development plan for mepolizumab in severe asthma, as agreed in the final PIP with the regulators.

Five‐Step Partial Extrapolation Strategy

The five‐step partial extrapolation components with the methods used to address them were as follows:

• Step 1. Confirm efficacy of mepolizumab and benefit–risk profile in adults with severe asthma

• Method: Pivotal Phase III trials demonstrating mepolizumab efficacy and favorable safety profile versus placebo in adult patients with severe asthma.

• Step 2. Confirm predictability of PK in pediatric patients from adults using available pediatric PK data (intravenous [IV] and subcutaneous [SC]) in severe asthma and eosinophilic esophagitis, adjusted for bodyweight and bioavailability

• Step 3. Confirm predictability of PD in pediatric patients from adults using available pediatric blood eosinophil count data in severe asthma and eosinophilic esophagitis

• Method for Steps 2 and 3: Validity of PK and PD extrapolation from adults (≥18 years) to adolescents (12‐17 years) and children (6‐11 years) was assessed using population PK/PD meta‐analysis by nonlinear mixed effects modeling method. Full details of the population PK and PK/PD models are provided in Supplemental Information. Individual post hoc pediatric predicted mepolizumab plasma concentrations and blood eosinophil counts were plotted against the observed values. Model performance was evaluated via goodness‐of‐fit diagnostics, individual plasma concentration–time and blood eosinophil count–time profile plots, and box plots of clearance and central volume by bodyweight category. Mepolizumab plasma concentrations were quantified as previously described. ²⁴

• Step 4. Provide supportive evidence that mepolizumab efficacy in severe asthma could be extrapolated from adult to pediatric population

• Method: Comparison of annualized clinically significant exacerbation rates between adults and adolescents using MENSA (MEA115588/NCT01691521) and combined MENSA and MUSCA (200862/NCT02281318) study data analyzed via negative binomial models. ²⁵ Bootstrap resampling of matched adult and adolescent sample sizes from MENSA (the study with the highest number of adolescents enrolled) were analyzed to allow comparison for this endpoint between these groups. Details of the models are provided in Supplemental Information. Bayesian robust mixture prior analysis (SAS version 9.4) assessed extrapolation acceptability using a two‐component weighted informative adult prior and weak non‐informative prior, as previously described. ²⁶ Extrapolation from adolescents to children was evaluated descriptively due to the absence of a placebo arm and short treatment duration (12 weeks) in Part A of study NCT02377427. ²² , ²³

• Step 5. Evaluate safety profile of mepolizumab in pediatric patients with severe asthma and compare with overall Phase III severe asthma clinical development program

• Method: Descriptive comparison of safety data between pediatric (6‐17 years) and adult patients across all mepolizumab indications, including eosinophilic esophagitis and hypereosinophilic syndrome.

Successful completion of Steps 1‐4, combined with an observed safety profile comparable to adults (Step 5), validated partial extrapolation of PK, PD, and efficacy data from adults to pediatric patients, supported by inference from adult safety data in severe asthma. Pediatric and adult trials, including patient numbers and key demographics, used to inform the extrapolation strategy are summarized in Tables 1 and 2.

Table 2.

Demographic Characteristics of Adults, Adolescents, and Children Included in the Partial Extrapolation Strategy

Studies	Adults	Adolescents	Children
DREAM, MENSA, SIRIUS, MUSCA (combined) — Severe Asthma
N	1841	37	‐
Age (years), range	18‐82	12‐17	‐
Weight (kg), range	42.0‐177.0	40.0‐205.5	‐
200363 Part A — Severe Asthma
N	‐	‐	36
Age (years), range *	‐	‐	5‐12
Weight (kg), range	‐	‐	20.2‐60.6
MEE103219 — Eosinophilic Esophagitis
N	‐	27	32
Age (years), range	‐	12‐17	2‐11
Weight (kg), range	‐	29.6‐84.4	10.6‐58.7

^*Only year of birth collected, with age derived using an imputed birth date of June 30. Therefore, derived age may not represent the actual age of a subject upon entry to the study.

Dosing Regimen Selection

Simulations of various dosing scenarios were performed using SAS 9.2 across a bodyweight range of 15 to 70 kg for children aged 6 to <12 years and compared with adult target exposure (70 kg) using root mean square error (RMSE) as the selection criterion (lower RMSE indicates better fit). Closed‐form solutions for RMSE were derived to identify optimal dosing regimens, which were then compared with simulated scenarios.

Ethical Statement

The studies included in the extrapolation strategy described here were performed in accordance with International Council for Harmonisation, Good Clinical Practice, the Declaration of Helsinki, and applicable country‐specific requirements. Institutional Review Board approvals were obtained prior to each study start. All patients provided written informed consent prior to participation in the study. For pediatric patients, parents or guardians provided consent.

Results

• Step 1. Efficacy of mepolizumab and benefit–risk profile in adults with severe asthma

The favorable benefit–risk profile of mepolizumab in adults with severe asthma was primarily established through three pivotal Phase III trials (DREAM, MENSA, and SIRIUS) which formed the basis of the clinical development program and supported the granting of regulatory marketing authorizations in several regions including in the EU (EMA) and the United States (Food and Drug Administration [FDA]) in 2015. Another Phase III trial, MUSCA, complemented the clinical program in 2016. These trials demonstrated significant reductions in exacerbation rates, improved asthma control, and a safety profile comparable to placebo. ¹² , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸

• Step 2. Predictability of mepolizumab PK (IV and SC) in pediatric patients from adults

It was hypothesized that similar mepolizumab exposure would translate to a similar effect on the PD marker (i.e., blood eosinophils) and therefore into similar efficacy. Consequently, a key pillar supporting the validity of the extrapolation strategy was demonstrating mepolizumab PK in pediatric patients could be predicted based on adult data. A population PK meta‐analysis (including data from DREAM, MENSA, and SIRIUS) conducted in healthy participants and patients with various eosinophilic diseases (asthma, eosinophilic esophagitis, and hypereosinophilic syndrome), following IV or SC administration and across a wide age range (2‐82 years) showed that mepolizumab PK is consistent with that of a standard immunoglobulin G1 monoclonal antibody targeting a soluble ligand, with no evidence of target‐mediated drug disposition. Over the wide dose range studied, mepolizumab PK was found to be linear, dose proportional, and time independent, with bodyweight as the only covariate of mepolizumab exposure. After adjusting for bodyweight, age was not a covariate. Furthermore, the meta‐analysis showed that the PK of IV administration of mepolizumab in children and adolescents with eosinophilic esophagitis, and IV and SC administration in adolescents with severe asthma, could be simultaneously predicted with adult data after adjustment only for bodyweight (Figures S1–S3). Furthermore, the same meta‐analysis model accurately described SC mepolizumab PK in children enrolled in the open‐label PK/PD pediatric study (NCT02377427 Part A), which was conducted to validate the extrapolation assumptions, after adjustment for bodyweight and absolute bioavailability (Figure 1). The main finding from study NCT02377427 was that mepolizumab exposures following SC administration were higher than anticipated in children aged 6‐11 years (105% [95% confidence interval: 55, 155]), most likely due to the bioavailability being marginally higher (complete absorption), compared with the historic adult value of 76% (95% confidence interval: 71, 79), on account of their lower body mass index (BMI, 18 kg/m² in NCT02377427 vs ∼28 kg/m² for adults in Phase III trials). These results, previously presented, support the robustness of the extrapolation approach. ²² , ²³

• Step 3. Predictability of mepolizumab PD (blood eosinophil count data) in pediatric patients from adults

Figure 1.

Model‐predicted mepolizumab PK plasma concentration–time profile in children aged 6‐11 years with observed data (study NCT02377427 Part A). N = 10,000 bootstrap resampled trials are shown with data and final model predictions. Patients received mepolizumab SC every 4 weeks (40 mg for bodyweight <40 kg; 100 mg for bodyweight ≥40 kg) at Baseline (Day 0), Week 4 (Day 28), and Week 8 (Day 56). Outcomes were assessed on‐treatment until Week 12 (Day 84), and off‐treatment at Week 16 (Day 112) and Week 20 (Day 140). Shaded bands represent the 5th and 95th percentile bounds. P5/P95, model predicted 5th and 95th percentiles; PK, pharmacokinetics; SC, subcutaneous; VPC, visual predictive check.

As for Step 2, another key pillar in support of the validity of the extrapolation strategy was to demonstrate the predictability of mepolizumab PD in the pediatric population from adults. A population PK/PD meta‐analysis (including the same studies as described in Step 2) demonstrated that blood eosinophil count reduction in pediatric patients with eosinophilic esophagitis and severe asthma could be simultaneously predicted with adult data after adjustment for baseline blood eosinophil count and disease type (Figures S4 and S5). The same model, as in Step 2, predicted PD responses in children from NCT02377427 Part A with good precision (Figure 2).

Figure 2.

Model‐predicted blood eosinophil count–time profile in children aged 6‐11 years with observed data (study NCT02377427 Part A). Patients received mepolizumab SC every 4 weeks (40 mg for bodyweight <40 kg; 100 mg for bodyweight ≥40 kg) at Baseline (Day 0), Week 4 (Day 28), and Week 8 (Day 56). Outcomes were assessed on‐treatment until Week 12 (Day 84), and off‐treatment at Week 16 (Day 112) and Week 20 (Day 140). Model predictions show the summary of 300 bootstrap trial simulations with model parameter uncertainty. Where a result of zero was recorded, a small value (5 cells/L) was added prior to log transformation. Baseline was defined as the latest value recorded prior to the first dose of investigational product. Shaded bands represent the 5th and 95th percentile bounds. CI, confidence interval; P5/P95, model predicted 5th and 95th percentiles; SC, subcutaneous; VPC, visual predictive check.

At Week 12 following mepolizumab 100 mg SC every 4 weeks, mean blood eosinophil count reductions from baseline were 80%‐87% in adults (MENSA: reduction from 290 to 40 cells/µL; MUSCA: reduction from 300 to 60 cells/µL) and 88%‐92% in adolescents receiving either SC (100 mg) or IV (75 mg) dosing every 4 weeks (MENSA: reduction from 264 to 33 cells/µL; MUSCA: reduction from 390 to 32 cells/µL) (Table S1). Comparable reductions were observed at Week 12 in children receiving mepolizumab SC every 4 weeks (40 mg for <40 kg; 100 mg for ≥40 kg) with decreases from baseline of 83%‐89% (40 mg: reduction from 386 to 42 cells/µL; 100 mg: reduction from 331 to 55 cells/µL) in study NCT02377427. ²³ These findings confirmed consistent and predictive PD responses across age groups.

• Step 4. Supportive evidence for efficacy extrapolation from adult to pediatric patients

As the MENSA and MUSCA placebo‐controlled trials included adolescents, albeit a modest number sufficient for approval in that age group, a comparison of mepolizumab efficacy between adolescent and adult patients was assessed in these trials. In MENSA and MUSCA, adolescents and adults treated with mepolizumab achieved 40% and 54% reductions, respectively, in annualized rate of clinically significant exacerbations versus placebo (Figure 3). ²⁵ Due to the small adolescent sample size, bootstrap resampling and Bayesian robust mixture prior analyses were performed (Figures S6 and S7). ²⁶ Both analyses found no apparent difference in exacerbation reductions, suggesting comparable efficacy between adolescents and adults.

Figure 3.

Rate ratios of clinically significant exacerbations in adolescents and adults treated with mepolizumab versus placebo in a meta‐analysis of studies MENSA (MEA115588) and MUSCA (200862). Rate of clinically significant exacerbations were estimated separately for each study (MENSA and MUSCA) and age group (adults and adolescents) using negative binomial generalized linear models including covariates for treatment group, maintenance oral corticosteroids use, geographic region, number of exacerbations in the previous year, baseline percentage of the predicted FEV₁, age group, and the interaction of age group with treatment. Estimates were combined within each age group using inverse‐variance weighting. Figure adapted from Yancey et al. https://creativecommons.org/licenses/by/4.0/. CI, confidence interval; FEV₁, forced expiratory volume in 1 second.

Furthermore, comparison of baseline data between adults/adolescents and children in NCT02377427 Part A (12‐week duration) showed similar disease characteristics and exacerbation history. Comparison of efficacy results showed that observed exacerbation incidence was 27.8% in children and 12.2%‐30.0% in adults/adolescents; ≥0.5‐point improvement in Asthma Control Questionnaire‐5 scores occurred in 55% of children, 33%‐63% of adolescents, and 52%‐56% of adults. ²⁷ These results provide supportive evidence that effectiveness in children aligns with adolescents and adults.

• Step 5. Safety profile of mepolizumab in pediatric patients compared with overall Phase III clinical program

Comparison of the descriptive safety data showed that the safety profile of mepolizumab in pediatric patients (including those with severe asthma, eosinophilic esophagitis, or hypereosinophilic syndrome) was consistent with that observed in the overall Phase III population with severe asthma. ¹² , ¹⁶ , ¹⁷ , ¹⁸ , ²² , ²³ No unique safety concerns were identified. Common adverse events included headache, injection site reactions, and nasopharyngitis. Major safety considerations such as systemic allergic and non‐allergic reactions (including anaphylaxis), local injection site reactions, immunogenicity, and infection risk were infrequent and comparable to adults.

Dosing Regimen Selection in the Pediatric Population

Having demonstrated that similar mepolizumab exposure produced comparable reductions in blood eosinophils and efficacy across age groups, the pediatric dosing regimen was selected to match adult exposure as closely as possible.

Given the substantial overlap in bodyweight and BMI between adolescents and adults, along with adolescents’ rapid growth during puberty and the favorable safety profile of mepolizumab, no dose adjustment was considered necessary for adolescents (a widely adopted convention for many therapeutics). ²⁸ Consequently, adolescents were recommended the same dosing regimen as adults: 100 mg SC every 4 weeks.

However, with bodyweight being a significant determinant of mepolizumab exposure, dose adjustment is necessary in children aged 6 to <12 years to maintain exposure within the adult target range. Simulations across a 15‐70 kg body weight identified 40 mg SC every 4 weeks for children aged 6 to <12 years as the dosing regimen with the lowest RMSE and maintaining exposure within 38% of adult targets on average. ¹⁴ , ¹⁵ Furthermore, the model for both ratio to target exposure and RMSE showed that for the weight range 15 to 50 kg, the optimal dose ratio after adjustment for differences in absolute bioavailability (100% vs 76%) was 0.37 and the RMSE for this regimen was only 25% of adult target exposure. This further supported the recommendation of 40 mg SC every 4 weeks identified from the simulations.

Discussion

The introduction of the Paediatric Regulation in the EU (2007) and the Pediatric Research Equity Act in the United States (2003) aimed to improve development and availability of therapeutics tailored for pediatric populations. Since their implementation, however, challenges inherent to conducting clinical trials in this population have become increasingly apparent, particularly for diseases that are less prevalent in pediatric populations than in adults, such as severe asthma. In such instances, traditional clinical development approaches based on randomized, placebo‐controlled trials pose significant challenges including prolonged recruitment, incomplete data, and ultimately delayed access to new therapies for pediatric patients. Consequently, there emerged a need to reconsider development approaches for diseases that occur less frequently in the pediatric population.

One alternative approach is the implementation of extrapolation strategies from adults to pediatric populations, either full (without new data) or partial (where limited clinical data are collected in the target pediatric population to validate assumptions). For diseases not exclusive to pediatrics, development programs typically begin in the adult population, and by the time pediatric studies commence, efficacy in adults has usually been established. This growing body of adult data can then be leveraged through emerging methodologies such as Bayesian approaches. Depending on the disease, adolescents may be included in the adult studies.

Partial extrapolation, as implemented in this program, combined robust adult data with limited data in the pediatric population which included a small pediatric study to validate assumptions. This approach is grounded in the principle that similar exposures in adults and children will yield comparable PD responses and clinical outcomes, provided disease pathophysiology and endpoints are aligned. For mepolizumab, the following conditions were met: severe eosinophilic asthma exhibits similar pathophysiology in adults and children aged ≥6 years; blood eosinophil count is a validated PD marker linked to drug mechanism and efficacy; clinical eligibility criteria, efficacy endpoints (exacerbation reduction), and safety assessments were consistent across age groups; a large safety database existed that was supplemented by pediatric data from other eosinophilic diseases.

This program represents one of the earliest fully executed and validated partial extrapolation strategies forming the basis for pediatric dosing and regulatory approval for mepolizumab in severe eosinophilic asthma. The analyses were conducted between 2013 and 2017, culminating in EMA approval in 2018 and FDA approval in 2019. ¹⁴ , ¹⁵ This was only 3 years after adult approval, demonstrating the efficiency of this extrapolation approach. Since then, similar strategies have been adopted for other biologics, such as benralizumab (a monoclonal antibody targeting IL‐5 receptor) which incorporated extrapolation into its PIP in 2022 alongside a small PK/PD study (N = 30) in children aged 6‐11 years. Completion of the benralizumab PIP is projected for 2032. ²⁹

The observation of marginally higher bioavailability in children compared with adults, which was likely due to lower BMI rather than leanness, highlights the importance of accounting for physiological differences in dosing recommendations. For mepolizumab, body weight was the only significant covariate of exposure, supporting weight‐based dose adjustment in children but not adolescents, whose body size overlaps with adults.

Long‐term data from NCT02377427 (Part B) confirmed sustained PD effects after treatment reinitiation, and subsequent publication of the MUPPITS‐2 efficacy trial in 2022 validated the extrapolation‐based dosing recommendations. ²² , ³⁰ These findings reinforce the scientific rigor and practical benefits of extrapolation approaches, which are now reflected in EMA and FDA guidelines and have been formalized in the recently adopted International Council for Harmonisation E11 revision. ³¹ , ³² , ³³ While not universally applicable, such strategies offer a pathway to accelerate pediatric drug development, reduce trial burden, and ensure timely access to effective therapies.

Conclusion

This article describes the successful implementation and validation of a partial extrapolation strategy for the pediatric clinical development of mepolizumab in severe eosinophilic asthma, which is an uncommon condition in pediatric populations. The approach demonstrated that adult PK, PD, and efficacy data for mepolizumab could reliably predict pediatric outcomes. This extrapolation strategy provided the scientific basis for pediatric dosing recommendations and regulatory approvals. It enabled EU approval for patients aged ≥6 years in 2018, 3 years post‐adult approval (2015). In the United States, it supported approval for the 6‐11 year age group in 2019, following the 2015 US approval for adults and adolescents (12‐17 years).

Author Contributions

Atul Gupta and Wanda Phipatanakul: Visualization; investigation; writing—original draft; writing—review and editing. Isabelle J. Pouliquen, Daren Austin, Robert G. Price, and Jonathan Steinfeld: Conceptualization; methodology; visualization; data curation; formal analysis; writing—original draft; writing—review and editing. Glenn Whelan and Tricia Finney‐Hayward: Visualization; writing—original draft; writing—review and editing. Sabine Derey: Conceptualization; methodology; visualization; writing—original draft; writing—review and editing.

Conflicts of Interest

Atul Gupta has received clinical trial grants and personal fees from GSK, and personal fees from Boehringer Ingelheim, Novartis, and AstraZeneca. Wanda Phipatanakul declares consulting fees from GSK, Novartis, Genentech, Regeneron, and Sanofi, and clinical trial support from these companies Isabelle J. Pouliquen is a former employee of GSK and holds financial equities in GSK and is a former employee of AstraZeneca and holds financial equities in AstraZeneca. Glenn Whelan and Jonathan Steinfeld are former employees of GSK and hold financial equities in GSK. Daren Austin, Robert G. Price, Tricia Finney‐Hayward, and Sabine Derey are employed by GSK and hold financial equities in GSK.

Funding

These analyses were funded by GSK. The sponsor was involved in study design and implementation, as well as data collection, analysis, interpretation, writing the study report and reviewing this article. The sponsor did not place any restrictions on access to data or statements made in the article. All authors had full access to the data upon request and had final responsibility for the decision to submit for publication.

Disclosure of Prior Publication

Data included herein were previously presented at the American Thoracic Society meeting, ATS 2024, May 17‐22, 2024, San Diego, CA, USA.

W. Phipatanakul, A. Gupta, I. Pouliquen, D. Austin, G. Whelan, R.G. Price, T. Finney‐Hayward, and J. Steinfeld. Effects of Mepolizumab in a Pediatric Population With Severe Asthma: Pharmacological Modeling, Simulation and Extrapolation of Data From Adult Patients (abstract). Am J Respir Crit Care Med. 2024;209:A6702

Supporting information

Table S1. Summary of blood eosinophil counts for the overall and adolescent populations from the MENSA (MEA115588) and MUSCA (200862) studies.

Figure S1. Mepolizumab population PK meta‐analysis goodness‐of‐fit plots

Figure S2. Mepolizumab population PK meta‐analysis Prediction‐Corrected Visual Predictive Check by bodyweight

Figure S3. Individual post hoc clearance (L/day) (A) and steady‐state volume (L) (B) by age and weight category (mepolizumab population PK meta‐analysis)

Figure S4. Mepolizumab population PKPD meta‐analysis goodness‐of‐fit plots (blood eosinophil count)

Figure S5. Mepolizumab population PK/PD meta‐analysis Prediction‐Corrected Visual Predictive Check

Figure S6. Bootstrap resampled treatment effects from adult trials (N = 25); 3000 adult replicates drawn from MENSA study. All trials are matched for treatment (16/9 mepolizumab/placebo)

Figure S7. Probability density functions of log(rate ratio) for pediatric and adult trials (N = 25). Overlap is in the range –1.593 to 0.063.

Data Availability Statement

For requests for access to anonymized subject level data, please contact the corresponding author.