The safety and efficacy of protein therapeutics are limited by three interrelated pharmaceutical issues, in vitro and in vivo instability, immunogenicity and shorter half-lives. Novel drug modifications for overcoming these issues are under investigation and include covalent attachment of poly(ethylene glycol) (PEG), polysialic acid, or glycolic acid, as well as developing new formulations containing nanoparticulate or colloidal systems (e.g. liposomes, polymeric microspheres, polymeric nanoparticles). Such strategies have the potential to develop as next generation protein therapeutics. This review includes a general discussion on these delivery approaches. KeywordsProtein delivery; PEGylation; Liposomes; hyperglycosylation; Poly(lactic/glycolic) acid INTRODUCTIONSince the late 20 th century numerous therapeutic proteins and peptides have emerged in the market. PHARMA 2010 reported that biotech products accounted for more than 35% of the 37 new active substances launched in 2001.1 In 2007, global biotech drug sales grew at twice the rate of traditional small molecule drugs (12.5% vs 6.4%) with total revenues of $75 billion US. Biotech drugs accounted for one fifth of all blockbuster drugs in the market as of 2008.2 From a therapeutic perspective, proteins offer the distinct advantage of specific mechanisms of action and are highly potent. Despite these advantages, biotech products must overcome the hurdles posed by high molecular weight, short half-lives, instability, and immunogenicity. Several strategies have been evaluated in an effort to improve the current limitations of therapeutic peptides and proteins in the creation of so called "second generation" protein therapeutics. Most efforts center around one of two approaches-either a change in the agent itself (e.g. mutations in protein structure or covalent attachment of moieties) or by a change in formulation.3 In contrast to modifying the protein structure, covalent chemical attachment of compounds such as poly(ethylene glycol) (PEG) or polysialic acid (PSA) to therapeutic protein represent a relatively new approach. Drug formulation systems, such as liposomes, polymeric microspheres, and polymeric nanoparticles, are another means to help overcome the current limitations of protein therapeutics.4 , 5The intent of this review is to provide a general discussion of approaches being applied to improve safety and efficacy of protein therapeutics. This includes the areas of PEGylation, PEGYLATIONThe conjugation of polymers to proteins had been in practice since the 1950s, but it was the development of PEGylation that provided the real breakthrough in enhancing the pharmaceutical properties of proteins and peptides in a viable manner 6 PEGylation, the covalent attachment of PEG moieties to a therapeutic agent, was first reported in the 1970s. 7,8 Experiments attempting to improve delivery aspects via PEGylation found not only the intended benefits, but overall enhancement of stability, pharmacokinetics, and therapeutic utility of molecules. [9][10][11][1...

Treatment with glecaprevir and pibrentasvir for 12 weeks resulted in a high rate of sustained virologic response in patients with stage 4 or 5 chronic kidney disease and HCV infection. (Funded by AbbVie; ClinicalTrials.gov number, NCT02651194 .).

Glecaprevir/pibrentasvir is approved to treat hepatitis C virus genotype 1–6 infection. Patients coinfected with human immunodeficiency virus type 1 achieved high cure rates after 8- (without cirrhosis) and 12- (compensated cirrhosis) week treatment, without adjustments to antiretroviral therapy regimens.NCT02738138.

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Objective. To assess the efficacy and safety of the anti-interleukin-1α/β (anti-IL-1α/β) dual variable domain immunoglobulin lutikizumab (ABT-981) in patients with knee osteoarthritis (OA) and evidence of synovitis.Methods. Patients (n = 350; 347 analyzed) with Kellgren/Lawrence grade 2-3 knee OA and synovitis (determined by magnetic resonance imaging [MRI] or ultrasound) were randomized to receive placebo or lutikizumab 25, 100, or 200 mg subcutaneously every 2 weeks for 50 weeks. The coprimary end points were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at week 16 and change from baseline in MRI-assessed synovitis at week 26.Results. The WOMAC pain score at week 16 had improved significantly versus placebo with lutikizumab 100 mg (P = 0.050) but not with the 25 mg or 200 mg doses. Beyond week 16, the WOMAC pain score was reduced in all groups but was not significantly different between lutikizumab-treated and placebo-treated patients. Changes from baseline in MRI-assessed synovitis at week 26 and other key symptom-and most structure-related end points at weeks 26 and 52 were not significantly different between the lutikizumab and placebo groups. Injection site reactions, neutropenia, and discontinuations due to neutropenia were more frequent with lutikizumab versus placebo. Reductions in neutrophil and high-sensitivity C-reactive protein levels plateaued with lutikizumab 100 mg, with further reductions not observed with the 200 mg dose. Immunogenic response to lutikizumab did not meaningfully affect systemic lutikizumab concentrations.Conclusion. The limited improvement in the WOMAC pain score and the lack of synovitis improvement with lutikizumab, together with published results from trials of other IL-1 inhibitors, suggest that IL-1 inhibition is not an effective analgesic/antiinflammatory therapy in most patients with knee OA and associated synovitis.ClinicalTrials.gov identifier: NCT02087904.

Background Dupilumab has demonstrated efficacy and acceptable safety in adults and children (aged 6–17 years) with moderate‐to‐severe atopic dermatitis (AD), but effective systemic therapy with a favorable risk–benefit profile in younger children remains a significant unmet need. Objectives To determine the pharmacokinetics, safety and efficacy of single‐dose dupilumab in children with severe AD aged ≥6 months to <6 years. Methods This open‐label, multicenter, phase 2, sequential, two‐age cohort, two‐dose level study (LIBERTY AD PRE‐SCHOOL; NCT03346434) included an initial cohort of older children aged ≥2 to <6 years, followed by a younger cohort aged ≥6 months to <2 years. Pharmacokinetic sampling, safety monitoring and efficacy assessments were performed during the 4‐week period after a single subcutaneous injection of dupilumab, in two sequential dosing groups (3 mg/kg, then 6 mg/kg). The use of standardized, low‐to‐medium potency topical corticosteroids was allowed. Results Forty patients were enrolled (20/age cohort, 10/dose level within a cohort) between December 20, 2017 and July 22, 2019. Within each age cohort, pharmacokinetic exposures after a single injection of dupilumab increased in a greater than dose‐proportional manner. At week 3, treatment with 3 and 6 mg/kg dupilumab reduced scores of mean Eczema Area and Severity Index by −44.6% and −49.7% (older cohort) and −42.7% and −38.8% (younger cohort), and mean Peak Pruritus NRS scores by −22.9% and −44.7% (older cohort) and −11.1% and −18.2% (younger cohort), respectively. At week 4, improvements in most efficacy outcomes diminished in both age groups, particularly with the lower dose. The safety profile was comparable to that seen in adults, adolescents and children. Conclusions Single‐dose dupilumab was generally well tolerated and substantially reduced clinical signs/symptoms of AD. Slightly better responses were seen in older than younger children. The pharmacokinetics of dupilumab were non‐linear, consistent with previous studies in adults and adolescents.

Background Children aged ≥ 6 to < 12 years with severe atopic dermatitis (AD) have limited treatment options. In a 16-week, randomized, placebo-controlled, phase III trial in children, dupilumab, a monoclonal antibody inhibiting interleukin (IL)-4/ IL-13 signalling, significantly improved signs and symptoms with acceptable safety; longer-term safety and efficacy data are lacking. Objectives To report the pharmacokinetic profile and long-term safety and efficacy of dupilumab in children (aged ≥ 6 to < 12 years) with severe AD. Methods Children (aged ≥ 6 to < 12 years) with severe AD were enrolled in a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study and subsequent open-label extension (OLE) study. Patients received single-dose dupilumab 2 or 4 mg kg À1 followed by 8-week pharmacokinetic sampling, then 2 or 4 mg kg À1 weekly for 4 weeks (phase IIa), followed by the same weekly regimen (OLE). Primary endpoints were dupilumab concentration-time profile and treatment-emergent adverse events (TEAEs); secondary assessments included Eczema Area and Severity Index (EASI) and Peak Pruritus Numeric Rating Scale (PP-NRS) score. Results Of 38 children enrolled, 37 completed phase IIa and 33 continued to the OLE. Nonlinear, target-mediated pharmacokinetics characterized dupilumab concentrations (week 24-48 mean serum concentrations: 2 mg kg À1 , 61-77 mg L À1 ; 4 mg kg À1 , 143-181 mg L À1 ). TEAEs were mostly mild to moderate and transient; none led to treatment discontinuation. The most commonly reported TEAEs were nasopharyngitis (2 mg kg À1 , 47%; 4 mg kg À1 , 56%) and AD exacerbation (29% and 13%, respectively). Single-dose dupilumab rapidly improved AD with further improvements through week 52. Mean EASI and PP-NRS improved by À37%/À33% and À17%/À20% at week 2 (phase IIa) and À92%/ À84% and À70%/À58% at week 52 (OLE), respectively.