Long-acting polypeptides and methods of producing and administering same
Inventors
Assignees
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Publication Number
US-11197915-B2
Publication Date
2021-12-14
Expiration Date
Abstract
CTP-modified human growth hormone polypeptides and pharmaceutical formulations and pharmaceutical compositions comprising the same and methods of producing, and using the same are disclosed.
Core Innovation
The invention relates to a CTP-modified human growth hormone (hGH) long-acting polypeptide for treating growth hormone deficiency in a pre-pubertal child. The polypeptide consists of chorionic gonadotropin carboxy terminal peptide (CTP) modified growth hormone in a defined architecture, wherein one CTP is attached to the amino terminus of the growth hormone and two CTPs are attached in tandem to the carboxy terminus.
The treatment concept administers the CTP-modified growth hormone in a pharmaceutical composition, with CTP-hGH-CTP-CTP administered once per week as a therapeutically effective amount. The polypeptide optionally consists of a signal peptide attached to the amino terminus of the one CTP, and the amino acid sequence is set forth in amino acids 27-301 of SEQ ID NO: 39.
Additional defined structural features include glycosylated CTP and optional linker attachment between CTP and growth hormone, optionally via a peptide bond. The disclosure also frames formulation and product-supporting concepts for the CTP-modified growth hormone, including preparation and use of pharmaceutical formulations and pre-filled syringes.
Claims Coverage
The identified independent claims cover treatment methods for growth hormone deficiency in a pre-pubertal child using a CTP-modified growth hormone administered once per week. Across the independent claims, the inventive features comprise the specific CTP attachment pattern, sequence information and optional structural refinements, and administration/dosing regimens including a defined stepwise dose increase in one claim.
CTP attachment architecture for growth hormone
A polypeptide consisting of chorionic gonadotropin carboxy terminal peptide (CTP) modified growth hormone, wherein one chorionic gonadotropin carboxy terminal peptide (CTP) is attached to the amino terminus of said growth hormone, and two chorionic gonadotropin CTPs are attached in tandem to the carboxy terminus of said growth hormone.
Optional amino-terminus signal peptide on the CTP-modified growth hormone
The polypeptide optionally consists of a signal peptide attached to the amino terminus of said one CTP.
Once-weekly administration with a therapeutically effective dose
The CTP-modified growth hormone is administered once per week and said therapeutically effective amount comprises a dosage of about 0.66 mg/kg/week.
Specified sequence region for the CTP-modified growth hormone amino acids
The amino acid sequence of said CTP-modified growth hormone is set forth in amino acids 27-301 of SEQ ID NO: 39.
Once-weekly stepwise dose increase to a final dose
The CTP-modified growth hormone is administered in a stepwise dose increase at two-week intervals until a final dose is reached.
Across the independent claims, the core inventive coverage is the use of a CTP-modified growth hormone with one CTP at the amino terminus and two tandem CTPs at the carboxy terminus, optionally with an amino-terminus signal peptide, administered in a pre-pubertal child once per week at a therapeutically effective dose. One independent claim additionally requires the CTP-modified growth hormone amino acid sequence to be set forth in amino acids 27-301 of SEQ ID NO: 39, and another independent claim further defines a stepwise dose increase at two-week intervals to reach a final dose.
Stated Advantages
Prolonged circulatory half-life/serum stability.
Maintained or enhanced bioactivity/biological activity.
Reduced dosing frequency (administered once per week).
Low immunogenicity; immunogenicity comparable to hGH.
Prolonged and greater IGF-1 serum elevation compared with comparators.
Higher Cmax.
Markedly longer terminal half-life.
IGF-1 exposure within therapeutic range.
Extended half-life.
Annualized height velocity increase.
Reduced dosing frequency relative to daily growth hormone, including compliance.
Efficacy and safety supported by clinical outcomes and PK/PD data.
Documented Applications
Treating growth hormone deficiency in a pre-pubertal child subject by administering a pharmaceutical composition comprising a CTP-modified growth hormone polypeptide.
Treating a growth hormone deficiency in a pre-pubertal child subject with a pharmaceutical composition containing a CTP-modified growth hormone polypeptide administered once per week, including embodiments with stepwise dose increase and pediatric Phase II evaluation of IGF-1 exposure and annualized height velocity.
Nonclinical pharmacokinetic/pharmacodynamic support in hypophysectomized rats using a CTP-modified hGH construct (CTP-hGH-CTP-CTP) administered as a single subcutaneous dose, with IGF-1 pharmacodynamic measurements and PK analysis.
Nonclinical pharmacokinetic support in rhesus monkeys for the CTP-modified hGH approach (including MOD-4023 as weekly dosing).
Clinical support for weekly MOD-4023 efficacy and safety, including adult Phase II and pediatric Phase II data with reported IGF-1 exposure and height velocity outcomes.
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