Design and Rationale for the heiGHtTrial, a Phase 3 ...€¦ · Design and Rationale for the...
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Design and Rationale for the heiGHt Trial, a Phase 3 TransCon hGH Study in Children with Growth Hormone Deficiency Michael Beckert 1 , David B. Karpf 2 , Eva Mortensen 2 , Jacqueline Mardell 2 , Eva Dam Christoffersen 1 , Jonathan A. Leff 2 1 Ascendis Pharma A/S, 2 Ascendis Pharma Inc. This trial was sponsored by Ascendis Pharma A/S. Background TransCon Growth Hormone (hGH) is a novel sustained- release recombinant human GH (somatropin) prodrug in development for children with growth hormone deficiency (GHD) intended to provide comparable efficacy, safety, tolerability, and immunogenicity to daily hGH with once- weekly dosing. Phase 3 heiGHt Trial Design Phase 2 Trial Results Comments Based on results from a Phase 2 trial, which demonstrated comparable safety, efficacy, immunogenicity, and tolerability of once-weekly TransCon hGH to daily hGH therapy in children with GHD, a Phase 3 trial has been initiated. A global Phase 3 randomized open-label active-controlled parallel-group trial has been initiated to investigate the safety, tolerability, and efficacy of weekly TransCon hGH versus standard daily hGH over 52 weeks in prepubertal children with GHD. Approximately 100 sites in 20 countries in North America, Europe, the Middle East, North Africa, and Oceania have been selected with plans to enroll approximately 150 treatment-naïve prepubertal children with GHD. The Phase 2 trial demonstrated safety and efficacy of TransCon hGH 0.14, 0.21, and 0.30 mg/kg/week. In the Phase 3 trial, TransCon hGH 0.24 mg/kg/week will be used to accommodate global dosing practices. The length of the trial is 12 months to qualify as a pivotal trial. Following completion of the trial, subjects will be invited to participate in an extension trial to evaluate long-term safety and efficacy. During the extension trial, subjects will be switched from TransCon hGH in vials to an auto-injector. Subjects will be randomized in a 2:1 ratio and receive either once-weekly TransCon hGH 0.24 mg/kg/week or dose equivalent once-daily somatropin for 52 weeks. Screening ≤ 6 weeks The Phase 2 pediatric trial was designed to compare the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of three TransCon hGH doses to that of commercially available daily hGH in prepubertal children with GHD. 1 11.9 12.9 13.9 11.6 0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0 18.0 20.0 Annualized Height Velocity (cm/yr) (+SD) Dose hGH/kg/week: 0.14 mg 0.21 mg 0.30 mg 0.21 mg TransCon Growth Hormone b Genotropin ® Same weekly dose No Serious Adverse Events (SAEs) related to trial drug The results suggest that long-acting TransCon hGH was comparable to daily Genotropin for PK, PD, safety, and efficacy, and supported advancement into Phase 3 development. • Adverse events consistent with daily hGH therapy observed and not different between cohorts Immunogenic profile comparable to daily hGH • >1100 TransCon Growth Hormone injections administered in the Phase 2 pediatric trial • No reports of lipoatrophy or nodule formation • Favorable immunogenic profile comparable to daily hGH • No occurrence of neutralizing antibodies Injection site tolerability comparable to daily hGH VISIT SCHEDULE TransCon Growth Hormone (0.24 mg/kg/week) Long-Term Extension Trial Key Device Features • Easy to operate with few user steps • Weekly, single low-volume injections (<0.6 mL) • Small needle (31G, 4mm) • Room temperature storage • No waste (empty-all design) • Reusable, with a 4-year lifespan • Bluetooth ® -enabled Auto-injector for commercialization in Extension Trial TransCon Growth Hormone Target Product Profile ü Efficacy ü Safety (including immunogenicity) ü Tolerability = Comparable to Daily Human Growth Hormone ü Weekly subcutaneous administration ü Single injection/dose ü Convenience ü 31G needle ü Room temperature storage ü Device ü Easy to use ü Empty-all design (controlled substance) Key Endpoints • Annualized height velocity (HV) at 52 weeks (primary endpoint) • Annualized HV at earlier time points • Change in height SDS over 52 weeks • Change in serum IGF-1 and IGFBP-3 * levels • Change in IGF-1 SDS and IGFBP-3 SDS • Normalization of IGF-1 SDS * insulin-like growth factor-binding protein 3 Growth Comparable to Daily hGH in Phase 2 Trial a a Intergroup differences not statistically significant. b Conducted with a previous lower strength version of TransCon Growth Hormone. Genotropin (34 µg/kg/d = 0.24 mg/kg/week) Key Inclusion Criteria • Prepubertal children with GHD • Height SDS ≤ -2.0 • IGF-1 SDS ≤ -1.0 • GHD with 2 GH stim. tests (GH ≤ 10 ng/mL) • Bone age ≥ 6 months behind chronological Week 1 Week 5 Week 13 Week 26 Week 39 Week 52 References: 1: JCEM 2017 Feb 14. doi: 10.1210/jc.2016-3776. [Epub ahead of print]
Transcript of Design and Rationale for the heiGHtTrial, a Phase 3 ...€¦ · Design and Rationale for the...
Design and Rationale for the heiGHt Trial, a Phase 3 TransCon hGH Study in Children with Growth Hormone DeficiencyMichael Beckert1, David B. Karpf 2, Eva Mortensen 2, Jacqueline Mardell 2, Eva Dam Christoffersen1, Jonathan A. Leff 2
1 Ascendis Pharma A/S, 2 Ascendis Pharma Inc.
This trial was sponsored by Ascendis Pharma A/S.
BackgroundTransCon Growth Hormone (hGH) is a novel sustained-release recombinant human GH (somatropin) prodrug indevelopment for children with growth hormone deficiency(GHD) intended to provide comparable efficacy, safety,tolerability, and immunogenicity to daily hGH with once-weekly dosing.
Phase 3 heiGHt Trial DesignPhase 2 Trial Results
Comments
Based on results from a Phase 2 trial, which demonstratedcomparable safety, efficacy, immunogenicity, and tolerabilityof once-weekly TransCon hGH to daily hGH therapy inchildren with GHD, a Phase 3 trial has been initiated.
A global Phase 3 randomized open-label active-controlledparallel-group trial has been initiated to investigate thesafety, tolerability, and efficacy of weekly TransCon hGHversus standard daily hGH over 52 weeks in prepubertalchildren with GHD. Approximately 100 sites in 20 countriesin North America, Europe, the Middle East, North Africa, andOceania have been selected with plans to enrollapproximately 150 treatment-naïve prepubertal children withGHD.
The Phase 2 trial demonstrated safety and efficacy ofTransCon hGH 0.14, 0.21, and 0.30 mg/kg/week. In thePhase 3 trial, TransCon hGH 0.24 mg/kg/week will be usedto accommodate global dosing practices. The length of thetrial is 12 months to qualify as a pivotal trial. Followingcompletion of the trial, subjects will be invited to participate inan extension trial to evaluate long-term safety and efficacy.During the extension trial, subjects will be switched fromTransCon hGH in vials to an auto-injector.
Subjects will be randomized in a 2:1 ratio and receive either once-weekly TransCon hGH 0.24 mg/kg/week or dose equivalent once-daily somatropin for 52 weeks.
Screening ≤ 6 weeks
The Phase 2 pediatric trial was designed to compare thepharmacokinetics (PK), pharmacodynamics (PD), safety, andefficacy of three TransCon hGH doses to that ofcommercially available daily hGH in prepubertal children withGHD.1
11.9 12.9 13.9 11.6
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
16.0
18.0
20.0
Annualized Height Velocity (cm/yr)
(+SD)
Dose hGH/kg/week: 0.14 mg 0.21 mg 0.30 mg 0.21 mg
TransCon Growth Hormoneb Genotropin®
Same weekly dose
No Serious Adverse Events (SAEs) related
to trial drug
The results suggest that long-acting TransCon hGH wascomparable to daily Genotropin for PK, PD, safety, andefficacy, and supported advancement into Phase 3development.
• Adverse events consistent with daily hGH therapy observed and not different between cohorts
Immunogenic profile comparable
to daily hGH
• >1100 TransCon Growth Hormone injections administered in the Phase 2 pediatric trial
• No reports of lipoatrophy or nodule formation
• Favorable immunogenic profile comparable to daily hGH
• No occurrence of neutralizing antibodies
Injection site tolerability
comparable to daily hGH
VISI
T SC
HED
ULE
TransCon Growth Hormone (0.24 mg/kg/week)Long-Term
Extension Trial
Key Device Features
• Easy to operate with few user steps• Weekly, single low-volume injections (<0.6 mL)• Small needle (31G, 4mm) • Room temperature storage• No waste (empty-all design)• Reusable, with a 4-year lifespan• Bluetooth®-enabled
Auto-injector for commercialization in Extension Trial
TransCon Growth Hormone Target Product Profile
ü Efficacy
ü Safety (including immunogenicity)
ü Tolerability= Comparable to
Daily HumanGrowth Hormone
ü Weekly subcutaneous administration
ü Single injection/dose
ü Convenienceü 31G needle
ü Room temperature storage
ü Deviceü Easy to use
ü Empty-all design (controlled substance)
Key Endpoints• Annualized height velocity (HV) at 52 weeks
(primary endpoint)
• Annualized HV at earlier time points
• Change in height SDS over 52 weeks
• Change in serum IGF-1 and IGFBP-3* levels
• Change in IGF-1 SDS and IGFBP-3 SDS
• Normalization of IGF-1 SDS*insulin-like growth factor-binding protein 3
Growth Comparable to Daily hGH in Phase 2 Triala
a Intergroup differences not statistically significant.b Conducted with a previous lower strength version of TransCon Growth Hormone.
Genotropin (34 µg/kg/d = 0.24 mg/kg/week)
Key Inclusion Criteria• Prepubertal children with GHD
• Height SDS ≤ -2.0
• IGF-1 SDS ≤ -1.0
• GHD with 2 GH stim. tests (GH ≤ 10 ng/mL)
• Bone age ≥ 6 months behind chronological
Week 1 Week 5 Week 13 Week 26 Week 39 Week 52
References:1: JCEM 2017 Feb 14. doi: 10.1210/jc.2016-3776. [Epub ahead of print]
