Final Abbreviated Clinical Study Report
Protocol C4181005

CLINICAL STUDY REPORT SYNOPSISSYNOPSIS
Study Title: A Phase 2 Multiple Dose, Randomized Study to Assess the Safety, Tolerability,
Pharmacokinetics and Efficacy of Recifercept in Children With Achondroplasia
Study Number: C4181005
Regulatory Agency or Public Disclosure Identifier Number: ClinicalTrials.gov ID:
NCT04638153; EudraCT Number: 2020-001189-13; US IND Number: 136773
Study Phase: 2b
Name of Study Intervention: Recifercept (PF-07256472)
Name of Sponsor/Company: Pfizer Inc.
CSR Version and Report Date: Final CSR (Last Participant Last Visit date [LPLV])
Version 1.0, 14 September 2023
Number of Study Center(s) and Investigator(s): A total of 58 participants wererandomized at 11 centers in 8 countries (Australia, Belgium, Denmark, Italy, Japan, Portugal,
Spain, and United States). A list of study centers and investigators involved in this study isprovided in Appendix 16.1.4.1.
Publications: None.
Study Period:
Study Initiation Date (First Participant First Visit): 02 December 2020.
Study Completion Date (Last Participant Last Visit): 27 March 2023.
Following the results of an interim analysis in this study (C4181005), a temporary halt was
implemented on 20 October 2022 and Pfizer Inc. made the decision to terminate this study asof 18 November 2022 (date of decision of the global study termination by the sponsor). The
decision to terminate this study was due to not meeting the pre-specified 6-month efficacy
criteria at the tested doses and not due to any safety concerns.
Rationale:
Recifercept is under development to address the unmet need in children with achondroplasia
including the treatment of short stature and cranial, axial and appendicular skeletal
complications. Recifercept is a novel class of compound (decoy receptor) that has not beenstudied before in achondroplasia.

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The purpose of the study was to investigate the safety, tolerability, pharmacokinetics (PK)and efficacy of recifercept in children with achondroplasia. Safety had been demonstrated in
preclinical studies and in healthy adult volunteers in single and multiple ascending doses.
Multiple changes had been made in the manufacturing process of the drug product(process 2) which was to be used in Phase 3. Therefore, an additional PK cohort (at selectedsites only) was planned to evaluate the PK of single subcutaneous doses of 2 recifercept
formulations, Phase 2 formulation (process 1c) and Phase 3 formulation (process 2). The
additional PK cohort for 2 formulations was not completed as the study was terminated earlyprior to enrolling any participants in the PK cohort.
Objectives, Endpoints, and Statistical Methods:
The study objectives and endpoints are presented in Table S1 (main study cohort) and in
Table S2 (PK study cohort only).
A primary efficacy estimand was used for the primary efficacy endpoint, and was intended toprovide a population level estimate of the effect of recifercept on a continuous endpoint.
Population-level summary: ratio between participants in the trial and a reference population1
in growth of height at 12-month; ratio between treated and reference population wasobserved change-from-baseline of treated participants standardized by reference participant
given age and gender. A secondary estimand was the population treatment effect of the meanchange from baseline of a continuous response, defined as the decline in the difference ofarm span to standing height.
The Full Analysis Set (FAS) and safety analysis set were defined as all participants receiving
at least 1 dose of recifercept. Participants were analyzed according to the dose they actually
received. The Per-Protocol Analysis Set (PPAS) was defined as all participants receiving atleast 1 dose of recifercept and had complete data at baseline through Month 12 and without
protocol deviations that were thought to impact the efficacy evaluation during the treatment
period. Participants were analyzed according to the randomized intervention. The PKconcentration set was defined as all participants who received at least 1 dose of recifercept
and had at least 1 evaluable concentration.

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Table S1. Study Objectives and Endpoints
Type
Primary
SafetyEfficacy
SecondaryPK

Objectives

Endpoints

Evaluate the safety and tolerability ofrecifercept doses and dosing regimes inparticipants aged ≥2 to <11 years withachondroplasia
To assess efficacy of recifercept to increaseheight growth in children with achondroplasia



Safety and tolerability of recifercept as assessed through frequency and severity ofAEs/SAEs

Increase in height growth above expected in reference population1

To evaluate the PK of recifercept in children
aged ≥2 to <11 years old with achondroplasia



Population PK characterization in children aged ≥2 to <11 years old withachondroplasia. CL/F and other PK parameters of recifercept to assess exposures indifferent age group
Efficacy
To assess efficacy of recifercept to improve Sitting height/standing height ratio.
achondroplasia-related complications
 Arm span to height/length difference.
 Knee height:lower segment ratio.
 Occipito-frontal circumference.
 Ratio of occipito-frontal distance to occipito-mid-face measurements.
 z-score of the above proportionality and skull morphology where achondroplasia
reference datasets existed (occipito-frontal circumference, arm span, sitting height).
 Fixed flexion angles at elbow.
 Polysomnography parameters in those with pre-existing sleep-disordered breathingat the time of enrollment.
 BMI.
 Waist:chest circumference ratio.
 Change from baseline in CHAQ (adapted for achondroplasia) component and index
scores, QoLISSY Brief total score.
Safety;Assess change in individual safety parameters
 Change from baseline in safety labs, vital signs, physical examination.
Immunogenicity
 Rate of ADAs
Abbreviations: ADA = anti-drug antibody; AE = adverse event; BMI = body mass index; CHAQ = Childhood Health Assessment Questionnaire;
CL/F = clearance; CSR = clinical study report; PK = pharmacokinetic(s); QoLISSY = Quality of Life in Short Stature Youth; SAE = serious adverse event.

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Table S2. Study Objectives and Endpoints for PK Study Cohort OnlyType
PrimaryPK

Objectives
To evaluate the PK of single
subcutaneous doses of
2 formulations (process 1c andprocess 2) of recifercept inchildren aged ≥2 to <11 years old
with achondroplasia.

EndpointsPK endpoints after single dose recifercept:
Cmax, Tmax, AUC168, AUC360, AUCinf, and t½.

Secondary
SafetyTo assess the safety and AE monitoring, injection/infusion site
tolerability of single SC doses ofassessment.
2 formulations (process 1c andprocess 2) of recifercept inchildren aged ≥2 to <11 years old
with achondroplasia.
Abbreviations: AE = adverse event; AUC168 = area under the serum concentration-time profile from time
0 to 168 hours, AUC360 = area under the serum concentration-time profile from 0 to 360 hours;
AUCinf = area under the serum concentration-time profile from time 0 extrapolated to infinite time;
Cmax = maximum serum concentration; PK = pharmacokinetic(s); SC = subcutaneous; t½ = terminal
elimination half-life; Tmax = time for Cmax.
The PK study cohort was not enrolled due to early study termination, therefore, the endpoints for the PK
cohort were not analyzed.

Methodology:
This was a phase 2, randomized, 3-arm (3 active doses of recifercept), parallel groupdose-finding study of safety, tolerability, PK and efficacy.
The main cohort: The study was planned to enroll approximately 54 children withachondroplasia aged 2-10 years (inclusive) who were enrolled and randomized to receive oneof 3 doses of recifercept (1 mg/kg once weekly [QW], 2 mg/kg twice weekly [BIW] or
1.5 mg/kg once daily [QD], n=18 per dose) such that approximately 45 participants were
evaluable (up to 15 participants per dose). Additionally, an exploratory cohort ofapproximately 9 children with achondroplasia, aged 3 months to 2 years, was planned to beenrolled later in the study (n=3 per dose). All these 63 participants in this part of the study
were planned to receive recifercept for 12 months.
Enrollment followed an age and dose-staggered approach (descending age and ascendingdose) with review of safety and PK data by the study team before progression to the nextenrollment block (Figure S1).
An interim analysis was performed when approximately 45 participants (up to 15 participants
per dose) aged ≥2 to <11 years had received 6 months of treatment with recifercept. The
external data monitoring committee (eDMC) reviewed safety, PK and efficacy data to
confirm ongoing positive benefit:risk in participants. The decision of terminating this study
was made by the sponsor based on the interim analysis results that the pre-specified 6-month
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efficacy criteria were not met. All participants who completed the study prior to the earlytermination and in the opinion of the investigator, continued to have a positive risk:benefit
profile, were offered to enroll into an open-label extension (OLE) study.
Figure S1. Study Schema for Blocks A-D

This clinical study report (CSR) presents the final analyses results for all endpoints as of
LPLV.
Number of Participants (planned and analyzed):
Approximately 63 participants were planned to be randomized to one of 3 doses (1 mg/kg
QW, 2 mg/kg BIW, 1.5 mg/kg QD) for 12 months.
A total of 63 participants were screened with 58 participants assigned to treatment and57 participants treated. All 57 treated participants were included in the FAS and safety
analysis set.
Diagnosis and Main Criteria for Inclusion and Exclusion:
Enrolled in this study were participants with achondroplasia, aged ≥2 years to <11 years (upto the day before the eleventh birthday inclusive) for main cohort who were able to standindependently for height measurements, and aged ≥3 months to <2 years (up to the day
before the second birthday inclusive) for exploratory cohort who had a documented historical
Magnetic Resonance Imaging (MRI) brain/cervical spine within the previous 12 months.
Participants were Tanner stage 1 and completed the C4181001 natural history study with
≥2 valid height/length measurements (at least 3 months apart and one measurement within
3 months prior to enrollment).
Study Interventions, Dose, Mode of Administration, and Batch Number(s):Study intervention in the study was recifercept (PF-07256472) provided as lyophilized
powder for solution for injection, 50 mg/vial. All doses were given by subcutaneous
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injection. The manufacturing lot numbers for the study interventions dispensed in this study
are provided in Table S3.
Table S3. Study Interventions Administered
Investigational Product Description
PF-07256472 Powder for Solution for
Injection, 50 mg/vial
PF-07256472 Powder for Solution for
Injection, 50 mg/vial
PF-07256472 Powder for Solution for
Injection, 50 mg/vial
PF-07256472 Powder for Solution for
Injection, 50 mg/vial
PF-07256472 Powder for Solution for
Injection, 50 mg/vial
PF-07256472 Powder for Solution for
Injection, 50 mg/vial
PF-07256472 Powder for Solution for
Injection, 50 mg/vial
PF-07256472 Powder for Solution for
Injection, 50 mg/vial
Abbreviation: N/A = not applicable.

Vendor Lot
Number

Pfizer Lot
NumberStrength/
Potency

DosageForm

20-003970

20-DP-00277

50 mg

LYOPHILE

N/A

21-DP-00649

50 mg

LYOPHILE

N/A

22-DP-00925

50 mg

LYOPHILE

N/A

22-DP-01008

50 mg

LYOPHILE

N/A

22-DP-01105

50 mg

LYOPHILE

20-DP-00146

20-001010

50 mg

LYOPHILE

N/A

22-DP-00992

50 mg

LYOPHILE

FY620122-DP-01143

50 mg

LYOPHILE

Duration of Study Intervention:
The planned duration of study intervention in main study cohort was 12 months.
Summary of Results:
Demographic and Other Baseline Characteristics:
Of the 57 participants in FAS, 33 (57.9%) were male participants and 24 (42.1%) werefemale participants. The study populations were generally comparable across the 3 dosegroups with respect to age, race and ethnicity.
The median (range) of age was 5.0 (1-10) years. Of the 57 participants in FAS,
3 participants were 1 year, 27 participants were 2-5 years, and 27 participants were
6-10 years of age. The number of participants of 2-10 years of age was 18 in each of the
3 dose groups.



Most of the participants were White (84.2%) and not Hispanic or Latino (87.7%).

In recifercept 1 mg/kg QW group, recifercept 2 mg/kg BIW group and recifercept 1.5 mg/kg
QD group, the mean standing height was 92.53 cm, 89.23 cm and 93.24 cm, respectively.
The mean weight was 16.33 kg, 16.01 kg and 19.23 kg, respectively. The mean body massindex (BMI) was 19.83 kg/m2, 20.18 kg/m2 and 21.57 kg/m2, respectively.

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Exposure:
The mean (standard deviation [SD]) duration of treatment (ie, duration from first dose to andincluding the last dose) was 307.5 (125.27) days in recifercept 1 mg/kg QW group,355.2 (37.48) days in recifercept 2 mg/kg BIW group, and 255.9 (10.82) days in recifercept
1.5 mg/kg QD group. The mean (SD) duration of treatment (ie, actual dosing days) was
44.6 (18.02) days in recifercept 1 mg/kg QW group, 102.1 (10.62) days in recifercept
2 mg/kg BIW group, and 251.7 (99.38) days in recifercept 1.5 mg/kg QD group.
Efficacy Results:
Primary Efficacy Endpoint
Increase in Height Growth Above Expected in Reference Population: Height growth was
defined as the ratio of observed change from baseline in standing height to the expectedchange from baseline in the reference population. An Mixed-Effect Repeated Measures(MMRM) method was used to analyze height growth at Months 3, 6, 9 and 12 relative to thereference population in the FAS. The least-square (LS) mean height growth compared to thereference population as the ratio was 1.1 in recifercept 1 mg/kg QW group, 0.9 in recifercept
2 mg/kg BIW group, and 0.6 in recifercept 1.5 mg/kg QD group at Month 3. At Month 12,
the LS mean height growth compared to the reference population as the ratio was 1.0 in
recifercept 1 mg/kg QW group, 1.0 in recifercept 2 mg/kg BIW group, and 0.9 in recifercept
1.5 mg/kg QD group. The LS mean height growth was comparable across the 3 dose groups
at Months 6, 9 and 12, with the greatest LS mean difference of 0.1 across the dose groups.
Secondary Efficacy Endpoint
Arm Span to Standing Height/Length Difference: An MMRM method was used to analyze
arm span to standing height/length difference at Months 3, 6, 9 and 12 in the FAS. The LSmean of change from baseline in arm span to standing height/length difference was 1.0 cm inrecifercept 1 mg/kg QW group, 0.9 cm in recifercept 2 mg/kg BIW group, and 0.3 cm inrecifercept 1.5 mg/kg QD group at Month 12. The LS mean change from baseline in arm
span to standing height/length difference was numerically greater in recifercept 1 mg/kg QWgroup and recifercept 2 mg/kg BIW group compared with recifercept 1.5 mg/kg QD group at
Months 9 and 12.
Sitting/Standing Height Ratio: For the participants of 2-10 years of age with observed values,
the mean change from baseline in sitting/standing height ratio was 0.0 for each dose group ateach visit (Months 3, 6, 9 and 12).
Knee Height : Lower Segment Ratio: The mean change from baseline in knee height : lower
segment ratio was comparable across the 3 dose groups at Months 3, 6, 9 and 12, with thegreatest mean change from baseline of 0.02 or -0.02.
Occipito-Frontal Circumference: For each dose group, the mean change from baseline in
occipito-frontal circumference generally increased from Months 3 to 9. At Months 12, the
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mean change from baseline was 0.87 cm in recifercept 1 mg/kg QW group, 0.53 cm inrecifercept 2 mg/kg BIW group, and 0.00 cm in recifercept 1.5 mg/kg QD group.
Occipito-Frontal to Occipito-Mid-Face Ratio: The mean change from baseline in
occipito-frontal to occipito-mid-face ratio was comparable across the 3 dose groups at
Months 3, 6, 9 and 12, with the greatest mean change from baseline of -0.04.
Height Standard Deviation Score [SDS] (z-score): For the participants of 2-10 years of age,the mean change from baseline in height SDS (z-score) was 0.0 at each visit in each dosegroup, except for recifercept 2 mg/kg BIW group at Month 12(mean change from baseline of0.1) and recifercept 1.5 mg/kg QD group at Month 12 (mean change from baseline of -0.2).
Annualized Height Velocity: For the participants of 2-10 years of age, the mean annualizedheight velocity was 3.9 cm/year in recifercept 1 mg/kg QW group, 4.3 cm/year in recifercept
2 mg/kg BIW group, and 4.0 cm/year in recifercept 1.5 mg/kg QD group at Month 6. The
mean annualized height velocity was 4.0 cm/year in recifercept 1 mg/kg QW group,
4.6 cm/year in recifercept 2 mg/kg BIW group, and 3.4 cm/year in recifercept 1.5 mg/kg QD
group at Month 12.
Fixed Flexion Angles at Elbow: The mean baseline fixed flexion angle at elbow was -11.33°
in recifercept 1 mg/kg QW group, -18.31° in recifercept 2 mg/kg BIW group, and -6.45° in
recifercept 1.5 mg/kg QD group. Mean increase from baseline in fixed flexion angles at
elbow was observed at most visits, with the greatest mean increase of 4.83° in recifercept
2 mg/kg BIW group at Month 9.
BMI: Mean increase and decrease from baseline in BMI were observed at visits of the 3 dosegroups. The greatest mean increase from baseline in BMI was 0.36 kg/m2 in recifercept
1 mg/kg QW group at Month 9, and the greatest mean decrease from baseline in BMI
was -0.50 kg/m2 in recifercept 1.5 mg/kg QD group at Month 12.
Waist : Chest Circumference Ratio: The mean waist : chest circumference ratio at baseline
was 0.93 in recifercept 1 mg/kg QW group, 0.94 in recifercept 2 mg/kg BIW group, and 0.97
in recifercept 1.5 mg/kg QD group. At Month 12, the mean change from baseline in waist :chest circumference ratio was 0.05 in recifercept 1 mg/kg QW group, 0.00 in recifercept
2 mg/kg BIW group, and -0.01 in recifercept 1.5 mg/kg QD group.
Polysomnography: At Month 12,For apnea-hypopnea index (obstructive) and apnea-hypopnea index (total), mean
decrease from baseline or minimal mean increase from baseline was observed inrecifercept 1 mg/kg QW group (0.31 and -1.03, respectively) and recifercept 2 mg/kg
BIW group (-1.90 and -2.90, respectively).

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For desaturation index (ie, number of desaturations per hour >3% from baseline),mean change from baseline was -4.61 in recifercept 1 mg/kg QW group and 0.20 inrecifercept 2 mg/kg BIW group.

For percentage time spent <90% oxygen saturation (SaO2), mean change frombaseline was -48.95% in recifercept 1 mg/kg QW group and -99.00% in recifercept
2 mg/kg BIW group.

For percentage time spent with end-tidal carbon dioxide >50 mmHg, mean change
from baseline was -14.03% in recifercept 1 mg/kg QW group and -38.00% in
recifercept 2 mg/kg BIW group.



For SaO2 nadir, mean change from baseline was -2.67% in recifercept 1 mg/kg QWgroup and 1.00% in recifercept 2 mg/kg BIW group.

No value was observed for participants in recifercept 1.5 mg/kg QD group for theabove parameters.

Childhood Health Assessment Questionnaire (CHAQ, Adapted for Achondroplasia): No
consistent trend over the treatment period was observed for the CHAQ components in any ofthe dose groups.
Quality of Life in Short Stature Youth (QoLISSY) Brief: No significant improvement over
the treatment period was observed for the 9 items in any of the dose groups.
Acceptability and Tolerability Questionnaire – Achondroplasia: Throughout the visits, thegeneral results showed good acceptability and tolerability of the injection, including
pain/stinging/bruising/bleeding/swelling ratings, satisfaction with the overall experience andwillingness to continue injection, etc. No significant changes over the treatment period wereobserved for the 10 items in any of the dose groups.
Euro-Qol 5 Dimensions - Youth (EQ-5D-Y) and Youth Proxy (EQ-5D-Y Proxy): In eachdose group, the majority of participants with reported responses indicated “no problems” or“some problems” for each dimension at most visits. The mean rating score of health was≥80.0 at each visit in each dose group.
Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change(PGIC): In each dose group, the majority of participants with reported responses indicatedthe impact of achondroplasia on the ability to do physical activities or overall emotional andsocial well-being over the past 7 days was “none” or “mild” at most visits. In each dosegroup, the majority of participants with reported responses indicated no change in the ability
to do physical activities or overall emotional and social well-being since they started taking
the treatment at most visits. More participants indicated improvement in the ability to dophysical activities or overall emotional and social well-being compared with those indicating
worsening at each visit.
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Tanner Staging: Tanner stage of development at screening were Stage I for all evaluatedmale and female participants (100%). At each visit after screening, most participants(≥80.0% for male and ≥94.4% for female) with reported results were Tanner stage I.
Safety Results:
Most participants experienced at least 1 treatment-emergent adverse event (TEAE) (85.0% in
recifercept 1 mg/kg QW group, 100% in recifercept 2 mg/kg BIW group, and 88.9% in
recifercept 1.5 mg/kg QD group). Treatment-related adverse events (AEs) were reported in
35.0% in recifercept 1 mg/kg QW group, 78.9% in recifercept 2 mg/kg BIW group, and77.8% in recifercept 1.5 mg/kg QD group.
The most frequently reported all-causality TEAEs were severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) test positive (14 [24.6%] participants), Injection
site erythema (13 [22.8%] participants), Nasopharyngitis (12 [21.1%] participants), andInjection site rash (10 [17.5%] participants). The most frequently reported
treatment-related TEAEs were Injection site erythema (13 [22.8%] participants), andInjection site rash (10 [17.5%] participants).

Most of the TEAEs were mild in severity. No events of death were reported in the study.
One SAE of Sinus bradycardia was reported for 1 (5.0%) participant in recifercept 1 mg/kg
QW group, with onset day on Day 50 and resolved on the same day. The event was severe
and considered not related to treatment. No participants discontinued from study or study
intervention due to AE.
Injection site reactions were considered AE of special interest. Most injection site reactions
were mild in severity. The mean time from the most recent dosing to occurrence of injection
site reaction was 0.5 day, 0.3 day, and 0.1 day in recifercept 1 mg/kg QW group, recifercept
2 mg/kg BIW group, and recifercept 1.5 mg/kg QD group, respectively. The mean duration
for injection site reaction was 2.3 days, 2.8 days, and 6.9 days in recifercept 1 mg/kg QWgroup, recifercept 2 mg/kg BIW group, and recifercept 1.5 mg/kg QD group, respectively.
No clinically significant trends were noted for laboratory test. No clinically meaningful
findings in the vital signs measurements, electrocardiograms (ECGs), physical examinationassessments, or other observations related to safety were observed in this study.
Pharmacokinetic Results:
Intact PK of recifercept were assessed as trough serum concentration (pre-dose) at visits of
Day 8, Day 15 and Months 1, 2, 3, 6, 9 and 12 in all 3 dose groups. PK samples were alsocollected 20 hours post-dose at Month 2 and 40 hours post-dose at Month 3 for recifercept
1 mg/kg QW and 2 mg/kg BIW groups. As expected, recifercept concentration increased
from 1 mg/kg QW to 1.5 mg/kg QD dose. Looking at the pre-dose (trough) concentration atsteady-state (trough serum concentration [Ctrough]), it appeared that recifercept concentrations
were stable over 12 months of dosing. Observed steady-state serum recifercept exposures inachondroplasia participants at dosing regimens of 1 mg/kg QW, 2 mg/kg BIW and 1.5 mg/kg
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QD were consistent with the exposures predicted earlier (at the start of the study) by a
Population PK model developed using healthy participants data.
Other Results:
Rate of anti-drug antibody (ADA)/ neutralizing antibody (NAb):
At screening, no participants were ADA positive or NAb positive in recifercept 1 mg/kg QWgroup and 2 mg/kg BIW group, and 1 (5.6%) participant was ADA and NAb positive inrecifercept 1.5 mg/kg QD group. Most participants (80.0% in recifercept 1 mg/kg QW group,
94.7% in recifercept 2 mg/kg BIW group and 94.4% recifercept 1.5 mg/kg QD group) had
ADA positive result for at least 1 visit post baseline. The majority of participants (65.0% in
recifercept 1 mg/kg QW group, 84.2% in recifercept 2 mg/kg BIW group and 88.9%
recifercept 1.5 mg/kg QD group) had NAb positive result for at least 1 visit post baseline.
Intact and Total Recifercept Concentration by ADA/NAb Status:
No apparent relationship between recifercept exposures and ADA status or ADA titers wasobserved in the study.
Conclusions:

Recifercept doses at 1 mg/kg QW, 2 mg/kg BIW and 1.5 mg/kg QD were safe andwell-tolerated in participants aged ≥3 months to <11 years with achondroplasia.

The study did not meet the pre-specified 6-month efficacy criteria at the tested doses atinterim analysis. Recifercept did not demonstrate meaningful changes in the efficacy
endpoints at 12 months.

Observed steady-state serum recifercept exposures were consistent with the exposures
predicted at the start of the study using healthy participants data.



Majority of the participants in the study had ADA positive (>80%) and NAb positive(>65%) results for at least 1 visit post baseline.

References:1.

Merker A, Neumeyer L, Hertel NT, et al. Growth in achondroplasia: development ofheight, weight, head circumference, and body mass index in a European cohort. Am J
Med Genet A. 2018;176(8):1723–34.

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