Valentina Peterkova

Autoimmune Polyglandular Syndrome Type 1 in Russian Patients: Clinical Variants and Autoimmune Regulator Mutations

Background: Autoimmune polyglandular syndrome type 1 (APS-1) (OMIM 240300) is a rare autosomal recessive disorder associated with three major manifestations: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. There are, however, multiple minor components of APS-1 that induce significant phenotype variability. Subsequently, the diagnosis of APS-1 during early stages is often challenging. Aim: We aimed to provide clinical and mutational data for a large number of APS-1 patients in the Russian population. Methods: We analyzed clinical variations and component prevalence in APS-1 patients. DNA screening for autoimmune regulator (AIRE) gene mutations was performed in established APS-1 patients and in patients with the single components of chronic mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency, or alopecia. Results: We identified 46 patients from 42 families with APS-1. Eighteen different components were present in the patients, including very rare conditions – bone dysplasia and retinitis pigmentosa. We identified 10 different mutations, 3 of which were novel (M1T, E298K, c1053_1060del). The common Finnish mutation, R257X, was the most frequent in our population, present in 64/92 (70%) of the alleles. Conclusion: We found that the R257X AIRE mutation is common in Russian APS-1 patients. The majority of children with hypoparathyroidism and chronic mucocutaneous candidiasis were carriers of the AIRE mutations.

Biosimilars: controversies as illustrated by rhGH

Abstract Background and scope: Similar biological medicinal products, also called ‘biosimilars’, are copies of biopharmaceutical products whose patent has expired. Whether biosimilars are truly comparable and interchangeable with their reference biopharmaceutical products in terms of quality, efficacy and tolerability, is still a matter of debate. This review discusses the controversies related to the criteria for regulatory approval of biosimilars. These concerns are illustrated using recombinant human growth hormone (rhGH) biosimilars as an example. Methods: Publications on the regulatory approval of biosimilars in general and rhGH biosimilars in particular were searched in MEDLINE by exploding and combining the medical subject heading terms ‘human growth hormone’, ‘efficacy’ or ‘safety’ and the free-text words ‘biosimilar’, ‘biopharmaceutical’, ‘similar biological medicinal product’, ‘follow-up biologic’ or ‘biogeneric’. Searches were limited to full-text English-language articles. The websites from the European Medicines Agency (EMA) and from the American Food and Drug Administration were also consulted. Regulatory status: To obtain regulatory approval of a biosimilar product by EMA, demonstration of comparability with an approved reference biopharmaceutical product in terms of quality, efficacy and tolerability is needed. Thus, comparative quality studies, non-clinical and clinical efficacy and tolerability studies are required. However, in contrast to the reference product, comparative non-clinical pharmacokinetics, safety pharmacology, reproduction toxicology, mutagenicity and carcinogenicity studies are not mandatory to obtain approval of a biosimilar. In addition, comparable efficacy and tolerability only needs to be established by one study in a single population during a limited time interval (12 months) and often allows extrapolation to all other approved indications of the reference product. Consequently, for the currently approved rhGH biosimilars, long-term efficacy and tolerability in all indications has not been proven to the same degree as for the reference products. Conclusions: The validity of the current criteria for comparability and interchangeability of biosimilars and their reference products remains controversial. The authors conclude that long-term clinical investigations and systematic monitoring of the efficacy and tolerability of rhGH biosimilars in all indications are needed. In addition, the medico-economical environment should allow physicians to take a free and informed decision about the type of rhGH to be prescribed.

The carriage of the type 1 diabetes-associated R262W variant of human LNK correlates with increased proliferation of peripheral blood monocytes in diabetic patients.

Lavrikova EY, Nikitin AG, Kuraeva TL, Peterkova VA, Tsitlidze NM, Chistiakov DA, Nosikov VV. The carriage of the type 1 diabetes‐associated R262W variant of human LNK correlates with increased proliferation of peripheral blood monocytes in diabetic patients.

A Randomized, Double-Blind Study to Assess the Efficacy and Safety of Valtropin, a Biosimilar Growth Hormone, in Children with Growth Hormone Deficiency

Valtropin is a recombinant human GH (rhGH) manufactured using a novel yeast expression system, classed as a ‘biosimilar’. Valtropin was compared with Humatrope in children with GH deficiency (GHD). Treatment-naive, prepubertal children with GHD were randomized to Valtropin (n = 98) or Humatrope (n = 49) for 1 year. Standing height was measured 3-monthly and height velocity (HV) calculated. Serum IGF-I, IGFBP-3 and GH antibodies were determined centrally. HV at 1 year was 11.3 ± 3.0 cm/year with Valtropin and 10.5 ± 2.8 cm/year with Humatrope. Treatment difference was 0.09 cm/year with 95% confidence limits of –0.71, 0.90, within the preset non-inferiority limit of –2.0 cm/year. Height standard deviation (SD) scores were increased in both treatment arms with no acceleration of bone maturation. IGF-I and IGFBP-3 were increased comparably for both treatments. Adverse events showed no clinically relevant differences between treatment groups. Anti-GH antibodies were detected in 3 (3.1%) Valtropin and 1 (2.0%) Humatrope patients and the growth pattern was indistinguishable from the rest of the cohort. The 1-year efficacy and safety profile of Valtropin, a new biosimilar rhGH, are equivalent to the comparator rhGH, Humatrope. Valtropin can be used for the treatment of children with GHD and longer term data will fully establish its efficacy and safety profile.

Treatment with insulin detemir or NPH insulin in children aged 2–5 yr with type 1 diabetes mellitus

Thalange N, Bereket A, Larsen J, Hiort LC, Peterkova V. Treatment with insulin detemir or NPH insulin in children aged 2–5 yr with type 1 diabetes mellitus.

Mutations and pituitary morphology in a series of 82 patients with PROP1 gene defects.

Background/Aims: Defects of the PROP1 gene are the most prevalent genetic cause of combined pituitary hormone deficiency. Previous observations in affected patients have shown pituitary size ranging from hypoplasia to overt pituitary mass and evolution of size over the lifespan. Methods: We evaluated pituitary size and morphology in PROP1-mutation carriers who originated from Central and Eastern Europe. We analyzed 112 pituitary magnetic resonance imaging (MRI) scans from 82 patients (42 males) aged 2.5–72.7 (median 16.6) years from 60 kindreds. Results: Among the 120 independent PROP1 alleles, the most prevalent mutations were delGA301/302 (99 alleles) and delA150 (13 alleles). Median pituitary height at first MRI was 4.7 mm (range 1.0–20.7) and median volume was 127.6 mm3 (range 7.5–3,087.0). Pituitary size did not differ between sexes and did not correlate with hormonal phenotype, but significantly decreased with increasing age. However, evaluation of individual values suggested a biphasic mode with increasing volume during childhood, peak in adolescence, and subsequent regression in adulthood. Conclusion: Although pituitary size was increased in a number of PROP1-deficient patients, none of them suffered permanent damage from pituitary mass; therefore, any proposed surgery should be postponed as long as possible and ultimately may not be necessary due to the self-limiting nature of the pituitary enlargement.

Long-Acting C-Terminal Peptide–Modified hGH (MOD-4023): Results of a Safety and Dose-Finding Study in GHD Children

Context Daily injections are required for growth hormone (GH) replacement therapy, which may cause low compliance as a result of inconvenience and distress in patients. Objective C-terminal peptide-modified human GH (MOD-4023) is developed for once-a-week dosing regimen in GH-deficient (GHD) adults and children. The present trial was a safety and dose-finding study for weekly MOD-4023 in GHD children. Design A multicenter, open-label, randomized, controlled phase 2 study in children with GHD, evaluating the safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy of three different weekly MOD-4023 doses, compared with daily recombinant human GH (r-hGH). Setting The trial was conducted in 14 endocrinology centers in Europe. Patients Fifty-three prepubertal children with GHD completed 12 months of treatment with either MOD-4023 (N = 42) or r-hGH (N = 11). Interventions C-terminal peptide-modified hGH (MOD-4023) was administered weekly at a dose of either 0.25, 0.48, or 0.66 mg/kg/wk and compared with daily hGH at a dose of 0.24 mg/kg/wk. Results MOD-4023 showed an estimated half-life approximately fivefold to 10-fold longer when compared with daily r-hGH. Insulin-like growth factor (IGF)-I and IGF-binding peptide 3 showed a dose-dependent increase during MOD-4023 treatment. IGF-I standard deviation score for MOD-4023 did not exceed +2. All MOD-4023 cohorts demonstrated adequate catch-up growth. The 0.66 mg/kg/wk dose demonstrated efficacy closest to daily r-hGH. No serious adverse events were observed during MOD-4023 treatment, and its tolerability was consistent with known properties of r-hGH. Conclusions This study confirms the long-acting properties of MOD-4023 and shows a promising safety and tolerability profile. This provides support for initiation of a phase 3 study in GHD children using a single weekly injection of MOD-4023.

Imbalance in the blood antioxidant system in growth hormone-deficient children before and after 1 year of recombinant growth hormone therapy

The aim of our study was to examine the effects of 12-month therapy with recombinant growth hormone (rGH) on the blood antioxidant system in children with growth hormone deficiency (GHD). Total antioxidant capacity (TAC) of plasma was measured by FRAP (ferric reducing antioxidant power or ferric reducing ability of plasma); activities of superoxide dismutase (SOD) and catalase (CAT) in erythrocytes were assessed; non-protein thiols (NT) and ceruloplasmin (CP) levels were also measured. These parameters were determined before and after 12 month of rGH treatment. Eleven treatment-naive prepubertal children with growth hormone deficiency were included in the study. Another 11 prepubertal children comprised a control group. Before rGH treatment, TAC of plasma and NT level in the control group were significantly lower (726 ± 196 vs. 525 ± 166 µmol/L, P = 0.0182 and 0.92 ± 0.18 vs. 0.70 ± 0.22 µmol/ml, P = 0.0319, before and after the therapy, respectively). The only parameter that significantly (19.6 ± 4.7 vs. 14.5 ± 3.4 Units/g Hb, P = 0.0396) exceeded the same in the control group after rGH therapy was SOD activity. However, none of the measured parameters of antioxidant system in GHD children, except for TAC (525 ± 166 vs. 658 ± 115 µmol/L, P = 0.0205), exhibited significant improvement toward the end of the 12-month treatment period, although non-significant changes in CAT activity and CP level were also observed. This work has demonstrated that some parameters of the blood antioxidant system are out of balance and even impaired in GHD children. A 12-month treatment with rGH resulted in a partial improvement of the antioxidant system.

Studying progression from glucose intolerance to type 2 diabetes in obese children.

AIM Identification of metabolic and genetic factors capable to mediate progression from normal glucose tolerance (NGT) through impaired glucose tolerance (IGT) to type 2 diabetes (T2D) in childhood obesity. PATIENTS AND METHODS Three groups of obese children with NGT (n=54), IGT (n=35), and T2D (n=62) were evaluated. A control group of non-obese normal children (n=210) was also studied. In obese patients, an oral glucose tolerance test (OGTT) was performed. Insulin resistance (IR) was assessed using HOMA-IR index. Insulin sensitivity (IS) was assessed according to the Matsuda formula. Genomic DNA from obese and control children was genotyped for genetic variants of PPARG, ADIPOQ, ADIPOR1, FTO, TCF7L2, and KCNJ11 using a real-time PCR strategy. The unpaired Students t-test and Kruskal-Wallis one-way test were used to compare quantitative data in two and more groups. To assess the extent to which the various genetic variants were associated with pathology, ORs (odds ratios) and 95% CI (confidence interval) were estimated. RESULTS In T2D children, HOMA-IR value (7.5±3.1) was significantly (P<0.001) higher than that in IGT (4.21±2.25) and NGT (4.1±2.4) subjects. The Matsuda IS index was significantly increased in normoglycemic patients compared to IGT individuals (2.8±1.75 vs. 2.33±1.2, P<0.05). The Pro12Ala polymorphism of PPARG was significantly associated with obesity (OR=1.74, 95% CI=1.19-2.55, P=0.004) and T2D in obesity (OR=2.01, 95% CI=1.24-3.26, P=0.004). CONCLUSION IR is a major risk factor that mediates progression from NGT to clinical T2D in Russian obese children. This progression may be genetically influenced by the Pro12Ala variant of PPARG.

Response of pure red cell aplasia to cyclophosphamide after failure of mycofenolate mofetil in a patient with polyglandular syndrome type I.

A 26-year-old female with the classic major and minor components of autoimmune polyglandular syndrome type 1 was diagnosed as having pure red cell aplasia. Treatment with 1.5 g/d mycofenolate mofetil for 3 months failed to restore erythroid production. Treatment with cyclosporine A produced a good partial response but led to renal toxicity and was therefore substituted with cyclophosphamide, which had a good partial effect and lasted for 18 months. The relapse of anemia was not observed during the 6-month follow-up period after the cessation of treatment.