Head to Head Comparison of the Formulation and Stability of Concentrated Solutions of HESylated versus PEGylated Anakinra

Liebner, Robert; Meyer, Martin; Hey, Thomas; Winter, Gerhard; Besheer, Ahmed

doi:10.1002/jps.24253

Cited by 28 publications

(15 citation statements)

References 79 publications

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“…However, recently, new technologies are being tested to increase the half-life of the drug, enhancing the possible competitiveness in clinical setting. The processes of PEGylation and HESylation, the attachment of polyethylene glycol (PEG) or hydroxyethyl starch (HES) to a drug molecule, have shown to increase the half-life of anakinra without any effect on the protein’s secondary structure, thus developing a possibly more suitable molecule to be used in clinical setting [33].…”

Section: Discussionmentioning

confidence: 99%

Anti-interleukin-1 treatment in patients with rheumatoid arthritis and type 2 diabetes (TRACK): A multicentre, open-label, randomised controlled trial

et al. 2019

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BackgroundThe inflammatory contribution to type 2 diabetes (T2D) has suggested new therapeutic targets using biologic drugs designed for rheumatoid arthritis (RA). On this basis, we aimed at investigating whether interleukin-1 (IL-1) inhibition with anakinra, a recombinant human IL-1 receptor antagonist, could improve both glycaemic and inflammatory parameters in participants with RA and T2D compared with tumour necrosis factor (TNF) inhibitors (TNFis).Methods and findingsThis study, designed as a multicentre, open-label, randomised controlled trial, enrolled participants, followed up for 6 months, with RA and T2D in 12 Italian rheumatologic units between 2013 and 2016. Participants were randomised to anakinra or to a TNFi (i.e., adalimumab, certolizumab pegol, etanercept, infliximab, or golimumab), and the primary end point was the change in percentage of glycated haemoglobin (HbA1c%) (EudraCT: 2012-005370-62 ClinicalTrial.gov: NCT02236481).In total, 41 participants with RA and T2D were randomised, and 39 eligible participants were treated (age 62.72 ± 9.97 years, 74.4% female sex). The majority of participants had seropositive RA disease (rheumatoid factor and/or anticyclic citrullinated peptide antibody [ACPA] 70.2%) with active disease (Disease Activity Score-28 [DAS28]: 5.54 ± 1.03; C-reactive protein 11.84 ± 9.67 mg/L, respectively). All participants had T2D (HbA1c%: 7.77 ± 0.70, fasting plasma glucose: 139.13 ± 42.17 mg). When all the enrolled participants reached 6 months of follow-up, the important crude difference in the main end point, confirmed by an unplanned ad interim analysis showing the significant effects of anakinra, which were not observed in the other group, led to the study being stopped for early benefit. Participants in the anakinra group had a significant reduction of HbA1c%, in an unadjusted linear mixed model, after 3 months (β: −0.85, p < 0.001, 95% CI −1.28 to −0.42) and 6 months (β: −1.05, p < 0.001, 95% CI −1.50 to −0.59). Similar results were observed adjusting the model for relevant RA and T2D clinical confounders (male sex, age, ACPA positivity, use of corticosteroids, RA duration, T2D duration, use of oral antidiabetic drug, body mass index [BMI]) after 3 months (β: −1.04, p < 0.001, 95% CI −1.52 to −0.55) and 6 months (β: −1.24, p < 0.001, 95% CI −1.75 to −0.72). Participants in the TNFi group had a nonsignificant slight decrease of HbA1c%. Assuming the success threshold to be HbA1c% ≤ 7, we considered an absolute risk reduction (ARR) = 0.42 (experimental event rate = 0.54, control event rate = 0.12); thus, we estimated, rounding up, a number needed to treat (NNT) = 3. Concerning RA, a progressive reduction of disease activity was observed in both groups. No severe adverse events, hypoglycaemic episodes, or deaths were observed. Urticarial lesions at the injection site led to discontinuation in 4 (18%) anakinra-treated participants. Additionally, we observed nonsevere infections, including influenza, nasopharyngitis, upper respiratory tract infection, urinary tract infection, an...

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Section: Discussionmentioning

confidence: 99%

Anti-interleukin-1 treatment in patients with rheumatoid arthritis and type 2 diabetes (TRACK): A multicentre, open-label, randomised controlled trial

et al. 2019

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“…Linear polyglycerol (LPG), hyperbranched polyglycerol (hPG), or poly(ethylene glycol) (PEG), all bearing a single aldehyde group, were conjugated to the N-terminus of anakinra via reductive amination at pH 5 with sodium cyanoborohydride as a reducing agent (Scheme ), as previously described . Briefly, 1–10 mg of protein was diluted into 1 mL prechilled 0.1 M acetate buffer pH 5 in a 2 mL glass vial followed by addition of 3-fold molar excess of the polymer in the same buffer.…”

Section: Methodsmentioning

confidence: 99%

“…Protein conjugate analysis was performed by the Wyatt protein conjugate application, which was included in the Astra software. UV extinction coefficient for anakinra was 13 392 M –1 cm –1 , d n /d c (differential refractive index) for anakinra was 0.1850 mL/g, d n /d c values for PEG, LPG, and hPG were measured on an SEC-3010 RI detector (WGE Dr. Bures GmbH, Dallgow, Germany) that was calibrated against potassium chloride and determined as 0.143 mL/g (PEG), 0.142 mL/g (LPG), and 0.149 mL/g (hPG) at 25 °C.…”

Section: Methodsmentioning

confidence: 99%

Polyglycerol for Half-Life Extension of Proteins—Alternative to PEGylation?

et al. 2021

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Since several decades, PEGylation is known to be the clinical standard to enhance pharmacokinetics of biotherapeutics. In this study, we introduce polyglycerol (PG) of different lengths and architectures (linear and hyperbranched) as an alternative polymer platform to poly(ethylene glycol) (PEG) for half-life extension (HLE). We designed site-selective Nterminally modified PG-protein conjugates of the therapeutic protein anakinra (IL-1ra, Kineret) and compared them systematically with PEG analogues of similar molecular weights. Linear PG and PEG conjugates showed comparable hydrodynamic sizes and retained their secondary structure, whereas binding affinity to IL-1 receptor 1 decreased with increasing polymer length, yet remained in the low nanomolar range for all conjugates. The terminal half-life of a 40 kDa linear PG-modified anakinra was extended 4-fold compared to the unmodified protein, close to its PEG analogue. Our results demonstrate similar performances of PEG-and PG-anakinra conjugates and therefore highlight the outstanding potential of polyglycerol as a PEG alternative for half-life extension of biotherapeutics.

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“…12 However, for conjugated molecules, such as PEGylated peptides or proteins, these parameters do not significantly influence viscosity. 11 In contrast, polymer type, size (e.g., 20 vs. 40 kD polyethylene glycol), size distribution, and structure (e.g., linear vs. branched polyethylene glycol) matter.…”

Section: Introductionmentioning

confidence: 95%