Biologics in eosinophilic gastrointestinal diseases

Eosinophilic gastrointestinal diseases are a constellation of conditions categorized by the location of eosinophilic infiltration in the gastrointestinal tract. Symptoms vary based on location of eosinophils and age of the patient. There are no approved medications at the current time with individuals using off-label steroids or dietary therapy. Translational research has identified potential pathways to target in the treatment of eosinophilic esophagitis (EoE), gastritis (EoG), and enteritis (EoN), including type 2 pathways, mast cells, and eosinophils. Preliminary studies found cendakimab (anti–interleukin [IL]-13) and dupilumab (anti–IL-4 receptor alpha) to have an effect on eosinophil count and symptoms with dupilumab recently approved. In addition, mepolizumab (anti–IL-5), reslizumab (anti–IL-5), and lirentelimab (anti–Siglec 8) were found to have reduction in eosinophils without reduction of symptoms. For EoG and EoN, both benralizumab (anti–IL-5 receptor) and lirentelimab were found to have histologic and symptom improvement. There are no agents studied for eosinophilic colitis. Results of ongoing phase 3 trials in EoE and EoG/EoN are also anticipated     

Similar Names for Similar Biologics

Approval of the first biosimilar in the USA may occur by the end of 2014, yet a naming approach for biosimilars has not been determined. Biosimilars are highly similar to their biologic reference product but are not identical to it, because of their structural complexity and variations in manufacturing processes among companies. There is a need for a naming approach that can distinguish a biosimilar from its reference product and other biosimilars and ensure accurate tracing of adverse events (AEs) to the administered product. In contrast, generic small-molecule drugs are identical to their reference product and, therefore, share the same nonproprietary name. Clinical trials required to demonstrate biosimilarity for approval may not detect rare AEs or those occurring after prolonged use, and the incidence of such events may differ between a biosimilar and its reference product. The need for precise biologic identification is further underscored by the possibility of biosimilar interchangeability, a US designation that will allow substitution without prescriber intervention. For several biologics, the US Food and Drug Administration (FDA) has used a naming approach that adds a prefix to a common root nonproprietary name, enabling healthcare providers to distinguish between products, avoid medication errors, and facilitate pharmacovigilance. We recommend that the FDA implement a biosimilars naming policy that likewise would add a distinguishable prefix or suffix to the root nonproprietary name of the reference product. This approach would ensure that a biosimilar could be distinguished from its reference product and other biosimilars in patient records and pharmacovigilance databases/reports, facilitating accurate attribution of AEs.     

Preclinical Cardiovascular Safety Evaluations of Biologics

Standard therapeutic agents (STA) are usually relatively small and simple molecules, which are synthesized as highly pure and consistent molecules. However, their target specificity can be low so that there is a liability for side effects at non-targeted receptors, enzymes or ion channels. Alternatively, highly specific and targeted small molecules can elicit cardiovascular liabilities due to their target-based effects. As a result of their long existence in pharmaceutical practice, their safety evaluation is fairly well standardized and their potentially promiscuous, non-specific actions mandate broad evaluations. Biologics include a wide variety of products, ranging from relatively small synthesized polypeptides, which are also highly consistent, to very complex products, the composition of which may vary widely between production batches and sources. Biologics are usually highly specific for a single target, so that side effects at other targets are very rare. Their toxicities are more related to immune systems and to infection complications than to cardiovascular repercussions. The standard preclinical cardiac safety evaluations, derived from experience with STA, are frequently not appropriate or warranted for the evaluation of biologics. Indeed, because of the specificity of such biologic products, smaller test batteries than the ones needed for STA may be sufficient. However, because of the potential variability in composition of biologics between production batches and sources, evaluations of such products needs to be performed more frequently than for uniformly produced STA.     

Biologics in the prevention and treatment of graft rejection

Biologics are used in solid organ allografting and hematopoietic stem cell transplantation (HSCT) for the induction and maintenance of immunosuppression. In solid organ transplantation, antibodies targeting T cells are part of induction protocols administered for initiation of immunosuppression during organ transfer and during sustained post transplant periods for prevention of graft rejection. Several clinical trials in renal allografting provide data for the efficacy and safety of biologics in this clinical setting. Application of biologics also allows the reduction of calcineurin inhibitors, thereby reducing toxicity and improving long-term graft function. In acute rejection periods, anti T cell antibodies are established in steroid-resistant cases. Strategies interfering with the activity of soluble cytokines are less frequently applied for solid organ transplantation. In HSCT, T cell directed antibodies as part of conditioning protocols improve engraftment and reduce the incidence of detrimental graft vs host disease (GvHD). In acute GvHD, both antibodies targeting T cells and cytokines like TNF-α are established therapeutics for remission induction.     

Evaluation of Rabies Biologics against Irkut Virus Isolated in China

An Irkut virus (IRKV) was recently isolated from a bat in China. The protective ability of rabies biologics available in the Chinese market and experimental biologics against the rabies virus (RABV) and IRKV were assessed in a hamster model via preexposure prophylaxis (PrEP) and postexposure prophylaxis (PEP) experiments. The results demonstrated that a single dose of rabies vaccine did not induce adequate protection against IRKV infection. However, routine PrEP with three doses of vaccine induced complete protection against IRKV infection. Higher doses of RABV immunoglobulins and alpha interferon were required during PEP to protect hamsters against IRKV versus RABV infection. Experimental recombinant vaccines containing IRKV glycoproteins induced more-reliable protection against IRKV than against RABV infection. Those findings may be explained by limited cross-neutralization of these viruses (confirmed via in vitro tests) in conjunction with antigenic distances between RABV and IRKV. These results indicate that the development and evaluation of new biologics for PrEP and PEP are required to ensure sufficient protection against IRKV infection in China and other territories where this virus is present.