Follow-on products of pentosan polysulfate, but not the original drug substance activate contact system and generate the anaphylatoxin C5a similar to the heparin falsification OSCS

Background Pentosan polysulfate (PPS) is a semi-synthetic, heparin-like polysaccharide produced by a complex procedure using beech wood as starting material. PPS consists of a mixture of heterogenous sulfated glucuronoxylans and exhibits manifold therapeutic actions [1]. It is approved for treatment of bladder pain syndrome/interstitial cystitis in humans and musculoskeletal diseases in animals. Meanwhile, several follow-on products of the originator PPS are offered. However, as known for other biological drug substances, follow-on products cannot be structurally identical, but are at best ‘biosimilar’ [2]. Using highly sensitive, orthogonal physicochemical methods, our recent comparison of five original PPS preparations (O-PPS) and five follow-on products (M-PPS) from different manufacturers revealed that the M-PPS significantly differed in their composition and structure from the original PPS as well as among each other [3]. The aim of this study was to investigate whether the found physicochemical differences between original and follow-on PPS are associated with differences in their biological effects. Method The test compounds included five O-PPS and five M-PPS preparations as well as unfractionated heparin (UFH) and oversulfated chondroitin sulfate (OSCS) as reference substances. They were examined in the following assays: (1) time- and concentration-dependent kallikrein generation in citrated plasma, (2) FXII activation in buffer, (3) haemolytic complement modulation (CM), and (4) C5a generation in hirudin, citrated, and EDTA plasma. Results Contrary to O-PPS and UFH, M-PPS exhibited noticeable contact activation potencies. M-PPS led to strong kallikrein generation similar to OSCS, the heparin contaminant that had caused severe side effects including hundreds of deaths in 2008 [4]. Additionally, M-PPS induced FXII activation, partly even stronger than OSCS. All the test compounds concentration-dependently inhibited complement activation in the CM and C5a (hirudin plasma) assays with PPS being superior to UFH and OSCS. However, in citrated plasma, both M-PPS and OSCS increased the C5a generation by 50-80 %. In EDTA plasma, where the complement pathway-mediated C5a generation is completely blocked, only M-PPS concentration-dependently increased the C5a generation without any inhibitory effect, which suggests stimulation of C5 cleavage by enzymes other than the C5a convertases of the complement system. Conclusion The study showed that the investigated PPS follow-on products differed not only structurally, but also biologically from original PPS. Similar to OSCS, they activated the contact system and resulted in generation of the anaphylatoxin C5a. Given the severe side effects caused by heparin falsified with OSCS in 2008 [4,5], these results demand further investigations on the safety of these PPS follow-on products and their modes of action.