Anna Mosikian, Russian Federation
GEROPHARM OOO Medical DepartmentPresenter of 3 Presentations
ANTI-INSULIN ANTIBODY CONCENTRATION IN TYPE 1 DIABETES MELLITUS PATIENTS INJECTING DIFFERENT TYPES OF INSULIN
Abstract
Background and Aims
Regulatory guidelines for insulin products (IPs) development require to test immunogenicity in a reasonable number of patients with type 1 diabetes mellitus (T1DM). The problem of sample size for immunogenicity comparison is substantial in insulin biosimilar development since the required samples are sizeable however still incapable to detect any immunogenicity difference, because the biosimilar and a reference drug are very similar in all terms. The aim of this study was to estimate the input of IP into immune response development.
Methods
Blood samples of 180 T1DM patients were taken to estimate an anti-insulin antibody concentration (AIAC) via enzyme-linked immunosorbent assay. The information on insulin international non-proprietory name (INN) was gathered. Influence of basal and bolus insulin INNs on AIAC was estimated with ANOVA. One-to-one comparisons were made with Mann-Whitney U-test.
Results
Patients were administered 4 INNs of basal insulin (glargine, detemir, degludec, isofan) and 4 INNs of bolus insulin (lispro, aspart, apidra, human soluble). AIAC did not depend on INN of insulin administered to a patient (p=0.765 for basal insulin, p=0.283 for bolus insulin). AIAC did not differ in patients receiving insulin analogues and human insulins (p=0.374 for basal insulin, p=0.751 for bolus insulin).
Conclusions
IP’s input into immune response development was nonsignificant, thus the huge sample is required to detect immunogenicity difference. This leads to dramatic increase of clinical trials cost and breaks the idea of cost-affordable biosimilars. Thus immunogenicity risk assessment should be provided mostly at preclinical stage, and immunogenicity should be studied via pharmacovigilance.
INSULIN GLARGINE BIOSIMILAR (GP40061) SHOWS SIMILAR PHARMACOKINETICS AND PHARMACODYNAMICS AS COMPARED TO THE REFERENCE DRUG
Abstract
Background and Aims
A biosimilar is a biological medicine highly similar to already approved biological reference medicine. The program of clinical trials of insulin biosimilars includes pharmacology studies: pharmacokinetics (PK) – concentration-time and pharmacodynamics (PD) – glucose infusion rate (GIR)-time. The aim of this study was to test if GP40061 – a biosimilar to reference insulin glargine (RIG) – has similar PK and PD profiles in a hyperinsulinemic euglycaemic clamp (HEC) setting in patients with type 1 diabetes mellitus (T1DM).
Methods
A double-blind, randomized, crossover study enrolled 42 adult patients with T1DM. The study was conducted in accordance with international guidelines for HEC studies. Each patient received a single dose of insulin (0.6 U/kg) subcutaneously. Regular blood sampling was performed. The amount of insulin glargine in the samples was determined by enzyme-linked immunosorbent assay. The primary endpoints were AUCins.0-24 (PK) and AUCGIR.0-24 (PD).We calculated the 90% (PK) and 95% (PD) confidence intervals (CI) of the GP40061/RIG geometric mean ratio for primary endpoints. Similarity of PK and PD is proved if CIs fall within the specified limits of 80%─125%. Secondary endpoints were AUCins.0-12 and AUCins.12-24 (PK), AUCGIR.0-12 and AUCGIR.12-24 (PD). Safety was also assessed.
Results
CIs were 81.02%─120.62% for AUCins.0-24 and 85.43%─115.64% for AUCGIR0-24. Ratio of AUCins.0-12 was 95.39%, AUCins.12-24 – 106.45%, AUCGIR.0-12 – 93.39% and AUCGIR.12-24 – 92.55%. Adverse events were registered in 11 patients in GP40061 and 9 patients on RIG (p=1.000).
Conclusions
GP40061 demonstrated similar PK and PD profiles to RIG. The study results proved biosimilarity of GP40061 to reference insulin glargine.
INSULIN GLARGINE BIOSIMILAR (GP40061) SHOWS NO DIFFERENCE OF IMMUNOGENICITY AS COMPARED TO THE REFERENCE DRUG
Abstract
Background and Aims
A biosimilar is a biological medicine highly similar to already approved reference biological medicine. GP40061 – is a biosimilar to reference insulin glargine (RIG). Its similarity to RIG has been proved through head to head analytical, preclinical and euglycemic clamp comparability studies. A comparative safety (immunogenicity) study of insulin biosimilar and reference drug is the last stage of the development program. This study aimed to confirm the similar immunogenicity of the drugs.
Methods
This randomized open-label, 26-week clinical trial (NCT02059187) enrolled 180 participants with type 1 diabetes mellitus randomized 1:1 to once-daily GP40061 (n=90) or RIG (n=90). The primary endpoint was frequency of immune response development at 26th week. Secondary endpoints included change of anti-insulin antibody (AIA) concentration at weeks 12 and 26 from baseline (at screening), percentage of participants with neutralizing AIA formation. AIA concentration was assessed via enzyme-linked immunosorbent assay. Neutralizing activity was established via binding of insulin alfa-chain and CD220 receptor. The data was compared with Mann-Whitney U-test or X2-test.
Results
Immune response was detected in 2 patients in GP40061 and in 2 patients in RIG (p=1.000). Change of AIA concentration (IU/ml) at week 12 from baseline was -0.19±2.49 (GP40061) and 1.38±10.98 (RIG) (p=0.399), and -0.02±2.85 (GP40061) and 0.30±4.07 at week 26 (p=0.167). Number of patients with neutralizing AIA formation was 17 (19%) in GP40061 and 15 (17%) in RIG (p=1.000).
Conclusions
GP40061 demonstrated similar immunogenicity to the RIG. Considering the whole development program, the biosimilarity of GP40061 to reference insulin glargine was proved.