IGF-1 Treatment for Individuals With Short Stature Due to PAPP-A2 Deficiency

Treatment With Recombinant Human Insulin-like Growth Factor 1 (rhIGF-1) in Patients With Pappalysin-2 (PAPP-A2) Gene Mutation.

With this study we want to investigate the pharmacokinetic (PK) effect of a single injection of rhIGF-1 in patients with PAPP-A2 mutations compared to heterozygous carriers and healthy controls. This will be followed by treatment of PAPP-A2 deficient patients with IGF-1 for a period of one-year to assess growth velocity. Additionally we want to further describe the phenotypic characteristics of patients with PAPP-A2 deficiency.

The 24-hour pharmacokinetic response of free and total IGF-1 and IGF binding protein-3 (IGFBP-3) to a single dose of rhIGF-1 (120 mcg/kg) in three patients with PAPP-A2 mutation compared to up to four unaffected heterozygous relatives and 2 healthy adult controls. One-year trial of rhIGF-1 at standard dose given to the two youngest males with PAPP-A2 mutation. The primary end point of this trial will be first year height velocity. Secondary outcomes will include change in height SDS, change in height velocity SDS, and change in whole body and lumbar spine bone mineral density. The study was amended to extend the treatment period to continue until the subject has stopped growing. All study procedures remain the same. Important note: the treatment phase continues to follow the youngest affected male. The older affected male developed an adverse event that resulted in discontinuation of treatment. A post-treatment follow up visit (either in-person or remote) will be completed for the study participant who remained on Increlex approximately one-year after their discontinuation of therapy. Description of additional phenotypic characteristics of patients with PAPP-A2 mutation will be studied by collecting information on glucose and insulin metabolism, body composition, bone geometry and bone density before and after treatment with rhIGF-1. These measures will be collected at the 12 month time period, and every year thereafter until the completion of the study. All three affected siblings will take part in the phenotyping activities.

Assess the PK/PD relationship (PD marker being IGFBP-3) during the one year of treatment and until completion of the study

PAPP-A2 deficient Inclusion Criteria: Defect in PAPP-A2 (heterozygous or homozygous mutation) Exclusion Criteria: None Healthy Volunteers Inclusion Criteria: Between the ages of 18 and 30 In general good health Exclusion Criteria: Any medications (with the exception of contraceptives) Pregnancy

De-identifiable data may be shared with physician that is treating the only other two patients in the world with this genetic mutation.

The participant data will be available when the treatment trial is actively ongoing. Per study protocol, the study will provide clinical updates to the participants primary Endocrinologist. Should the family request any further information be shared once the study is closed, it can be given to a physican spcecified by the family.

De-identifiable data may be shared with physician that is treating the only other two patients in the world with this genetic mutation.

Cabrera-Salcedo C, Mizuno T, Tyzinski L, Andrew M, Vinks AA, Frystyk J, Wasserman H, Gordon CM, Hwa V, Backeljauw P, Dauber A. Pharmacokinetics of IGF-1 in PAPP-A2-Deficient Patients, Growth Response, and Effects on Glucose and Bone Density. J Clin Endocrinol Metab. 2017 Dec 1;102(12):4568-4577. doi: 10.1210/jc.2017-01411.