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Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits the classical complement pathway at C1s, rapidly halted hemolysis in the single-arm CARDINAL study in recently transfused patients with cold agglutinin disease (CAD). CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in patients with CAD without recent (within 6 months prior to enrollment) transfusion history. Forty-two patients with screening hemoglobin ≤10 g/dL, elevated bilirubin, and ≥1 CAD symptom received sutimlimab (n = 22) or placebo (n = 20) on days 0 and 7 and then biweekly. Composite primary endpoint criteria (hemoglobin increase ≥1.5 g/dL at treatment assessment timepoint [mean of weeks 23, 25, 26], avoidance of transfusion, and study-prohibited CAD therapy [weeks 5-26]) were met by 16 patients (73%) on sutimlimab, and 3 patients (15%) on placebo (odds ratio, 15.9 [95% confidence interval, 2.9, 88.0; P < .001]). Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint. Sutimlimab normalized mean bilirubin by week 1. Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization. Twenty-one (96%) sutimlimab patients and 20 (100%) placebo patients experienced ≥1 treatment-emergent adverse event. Headache, hypertension, rhinitis, Raynaud phenomenon, and acrocyanosis were more frequent with sutimlimab vs placebo, with a difference of ≥3 patients between groups. Three sutimlimab patients discontinued owing to adverse events; no placebo patients discontinued. These data demonstrate that sutimlimab has potential to be an important advancement in the treatment of CAD. This trial was registered at www.clinicaltrials.gov as #NCT03347422.

Complement activation in human diseases is characterized by the local covalent deposition of the long-lived C3 fragments iC3b/C3dg/C3d. Previously, TT30, a complement alternative pathway (AP)-selective inhibitor, was designed as a fusion protein linking the first four short consensus repeats (SCRs) of human complement receptor type 2 (CR2) with the first five SCRs of human factor H (fH). TT30 acts by utilizing CR2 SCR1–4 to bind the initially formed iC3b/C3dg/C3d fragments and delivering surface-targeted inhibition of AP C3 and C5 convertases through fH SCR 1-5. In order to combine classical (CP) and lectin (LP) pathway inhibitory abilities employing CR2-mediated targeting, TT32 was developed. TT32 is a CR2-CR1 fusion protein using the first ten SCRs of CR1, chosen because they contain both C3 and C5 convertase inhibitory activity through utilization of decay-acceleration and cofactor activity for both AP and CP. In Wieslab assays, TT32 showed potent inhibition of the CP and AP with IC50 of 11 and 46 nM, respectively. The TT32 inhibitory activity is partially blocked with a molar excess of a competing anti-CR2 mAb, thus demonstrating the importance of the CR2 targeting. TT32 was studied in the type II (CII) collagen-induced arthritis (CIA), an active immunization model, and the CII antibody-induced arthritis (CAIA) passive transfer model. In CIA, injection of 2.0 mg TT32 at day 21 and 28 post disease induction, but not untargeted CR1 alone, resulted in a 51.5% decrease in clinical disease activity (CDA). In CAIA, treatment with TT32 resulted in a 47.4% decrease in CDA. Therefore, a complement inhibitor that targets both the AP and CP/LP C3/C5 convertases was shown to limit complement-mediated tissue damage and inflammation in disease models in which all three complement activation pathways are implicated.

Increasing demand for modern treatments and significant profit margins are strong incentives for investors and producers. However, the production and use of medical devices is subject to a number of laws, regulations, strict standards, and certification processes. Therefore, the aim of this paper is to analyze patent activity based on the example of the selected country (Czech Republic), compare it with selected foreign countries, and discuss the development of this industry in the context of new medical device regulation (MDR) implementation. The paper is based on the theoretical concept of the relationship between regulation and innovation. The main challenge in the implementation of the new medical device regulations lies in the area of innovation. This is because most innovative research in the medical device sector is undertaken by small to medium enterprises (SMEs) rather than by large companies. SMEs are more vulnerable than big companies when it comes to development because the accompanying administrative costs can be so high that it may force the company to leave the market. Given that the main reason for the existence of economic regulations are various forms of market failure, which occurs when market mechanisms do not lead to results that benefit society, any attempts to redress this situation should naturally lead to greater benefits for society and hence benefits for the given industry as well.

Background Rare diseases are often serious, life-threatening and debilitating group of disorders. Nowadays, there are approximately 8,000 rare diseases and it is estimated that 350 million people are affected by these conditions worldwide. Unfortunately, rare diseases are quite complex and chronic, only a small number of these diseases can be relevantly diagnosed and treated, and lifelong treatment is often required. Objective The purpose of this mini review is to explore the issue of rare diseases, describe their classification, discuss the current treatment and management and set future research in this field. Methods The methods applied in this review include literature review of the world's acknowledged databases such as PubMed, Springer and Web of Science, especially in the period of 2000 to 2015. Furthermore, a method of comparison and evaluation of the findings from the relevant sources is used. Results The findings confirm that rare diseases are still quite difficult to diagnose due to their comorbidities. Once they are diagnosed, they demand costly and long-term treatment, which raises concerns of national governments. Conclusion Therefore more research should be done in the space of rare diseases in order to broaden knowledge about them, their diagnosis and treatment, which will then lead to better training of medical staff, and ultimately will benefit the patients.

A novel therapeutic reagent TT30 was designed to be effective in diseases of the alternative pathway of complement such as paroxysmal nocturnal hemoglobinuria and other diseases. TT30 is constructed from the first four short complement regulator (SCR) domains of complement receptor type 2 (CR2) that bind to complement C3d, followed by the first five SCR domains of complement factor H that bind to complement C3b. In order to assess how TT30 binds to C3d and C3b, we determined the TT30 solution structure by a combination of analytical ultracentrifugation, X-ray scattering and constrained modeling. The sedimentation coefficients and radius of gyration of TT30 were unaffected by citrate or phosphate-buffered saline buffers and indicate an elongated monomeric structure with a sedimentation coefficient of 3.1 S and a radius of gyration R(G) of 6.9 nm. Molecular modeling starting from 3000 randomized TT30 conformations showed that high-quality X-ray curve fits were obtained with extended SCR arrangements, showing that TT30 has a limited degree of inter-SCR flexibility in its solution structure. The best-fit TT30 structural models are readily merged with the crystal structure of C3b to show that the four CR2 domains extend freely into solution when the five complement factor H domains are bound within C3b. We reevaluated the solution structure of the CR2-C3d complex that confirmed its recent crystal structure. This recent CR2-C3d crystal structure showed that TT30 is able to interact readily with C3d ligands in many orientations when TT30 is bound to C3b.

NMR echo techniques have proven to be important to study dynamics in ion conductors and other solid materials. Using the spin-3/2 nucleus (7)Li as a probe, both the quadrupolar and the often neglected homonuclear dipolar interactions modulate the NMR frequency as the ion performs jump processes. Retaining only the local-field term of the many-body Hamiltonian, the impact of the dipolar interaction on various echo experiments was studied using spin dynamics calculations yielding products of dipolar and quadrupolar correlation functions. Using a simple stochastic model these functions were simulated with particular emphasis on the impact of ionic motions and on the conditions under which the dipolar and quadrupolar contributions factorize. The results of the computations and of the random-walk simulations are compared with experimental data obtained for various lithium borate and lithium borophosphate glasses. It is concluded that the local-field approximation is a useful means of treating the Li-Li dipole interactions and that the simple model that we introduce is capable of describing many experimentally observed features. Furthermore, because the dipolar and quadrupolar contributions essentially factorize, a selective determination of the corresponding correlation functions becomes possible.

Cyclic pyranopterin monophosphate (1), isolated from bacterial culture, has previously been shown to be effective in restoring normal function of molybdenum enzymes in molybdenum cofactor (MoCo)-deficient mice and human patients. Described here is a synthesis of 1 hydrobromide (1·HBr) employing in the key step a Viscontini reaction between 2,5,6-triamino-3,4-dihydropyrimidin-4-one dihydrochloride and D-galactose phenylhydrazone to give the pyranopterin (5aS,6R,7R,8R,9aR)-2-amino-6,7-dihydroxy-8-(hydroxymethyl)-3H,4H,5H,5aH,6H,7H,8H,9aH,10H-pyrano[3,2-g]pteridin-4-one (10) and establishing all four stereocenters found in 1. Compound 10, characterized spectroscopically and by X-ray crystallography, was transformed through a selectively protected tri-tert-butoxycarbonylamino intermediate into a highly crystalline tetracyclic phosphate ester (15). The latter underwent a Swern oxidation and then deprotection to give 1·HBr. Synthesized 1·HBr had in vitro efficacy comparable to that of 1 of bacterial origin as demonstrated by its enzymatic conversion into mature MoCo and subsequent reconstitution of MoCo-free human sulfite oxidase-molybdenum domain yielding a fully active enzyme. The described synthesis has the potential for scale up.

To selectively modulate human complement alternative pathway (CAP) activity implicated in a wide range of acute and chronic inflammatory conditions and to provide local cell surface and tissue-based inhibition of complement-induced damage, we developed TT30, a novel therapeutic fusion protein linking the human complement receptor type 2 (CR2/CD21) C3 fragment (C3frag = iC3b, C3dg, C3d)-binding domain with the CAP inhibitory domain of human factor H (fH). TT30 efficiently blocks ex vivo CAP-dependent C3frag accumulation on activated surfaces, membrane attack complex (MAC) formation and hemolysis of RBCs in a CR2-dependent manner, and with a ∼ 150-fold potency gain over fH, without interference of C3 activation or MAC formation through the classic and lectin pathways. TT30 protects RBCs from hemolysis and remains bound and detectable for at least 24 hours. TT30 selectively inhibits CAP in cynomolgus monkeys and is bioavailable after subcutaneous injection. Using a unique combination of targeting and effector domains, TT30 controls cell surface CAP activation and has substantial potential utility for the treatment of human CAP-mediated diseases.

TT30 is a novel, recombinant human fusion protein, linking the C3d-binding domain of human complement receptor 2 (CR2) with the complement regulatory domain of human factor H (fH). TT30 is designed to inhibit the complement alternative pathway (CAP) at sites of local activation; it has been shown to be effective in preventing hemolysis and C3b-mediated opsonization in paroxysmal nocturnal hemoglobinuria (PNH) in vitro. This first in human study, TT30-PNH-002, was a multi-center open-label, single-dose, dose-escalation study of two formulations of TT30, ALXN1102 (10mg/ml) and ALXN1103 (50mg/ml). The study was conducted in patients with a diagnosis of PNH, defined as a PNH clone size of ≥10% or a PNH clone size between 5% and 10% with evidence of intravascular hemolysis documented within the previous 12 months; patients were not receiving concurrent treatment or treatment with a complement inhibitor within 60 days prior to screening. The primary endpoint of the study was assessment of the safety and tolerability of a single dose of TT30 when administered by IV infusion or separately by SC injection; secondary endpoints included pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity. The ALXN1102 formulation was administered by IV infusion to the 0.1 (n=1), 0.3 (n=1), and 1 mg/kg (n=3) dose level cohorts. The ALXN1103 formulation was administered by IV infusion to the 3 mg/kg (n=1) dose level cohort and by SC injection to the 1 (n=2) and 3 mg/kg (n=2) dose level cohorts. Patients were dosed one at a time, and each patient was evaluated before the next patient could be dosed. All 10 patients completed the study as planned; across all groups, 28 mild and 5 moderate treatment-emergent adverse event (TEAEs) were experienced. Treatment with both formulations of TT30 was considered safe, with no apparent dose-related safety risks. One patient who received ALXN1102 at 1.0 mg/kg IV experienced transient hypocalcemia associated with transient asymptomatic prolongation of the QT interval, both of which spontaneously resolved by 24 hours without intervention and may have been related to citrate in the formulation. Subsequent patients supplemented with oral calcium at the start of the infusion did not experience these events, nor were citrate-related toxicities seen in patients who received ALXN1103, which contains a lower amount of citrate. The secondary endpoints of the study were to characterize the PK of a single dose of TT30, to assess CAP, complement classical pathway (CCP) inhibition, PD effects on markers of intravascular hemolysis such as lactate dehydrogenase (LDH), and to characterize the immunogenicity of TT30. Serum TT30 total and peak (AUCs and Cmax) exposures increased with increase in IV or SC dose. Serum CAP activity declined in a dose-dependent manner following dosing in all IV dose cohorts, and approached zero % of baseline value (complete CAP inhibition) in the 1 mg/kg and 3 mg/kg IV dosing cohorts, when circulating levels of TT30 were in the range of approximately 5-10 ug/ml. CAP activity returned to baseline by 24 hours, when circulating TT30 was below 1 ug/ml, and appeared to remain stable thereafter. Serum CCP activity remained near baseline in all patients at all times. LDH levels dropped by 20% in the 1 mg/kg and 3 mg/kg IV dose cohorts and rose over time after CAP activity returned to baseline. Similarly, there was a decline in serum CAP activity and LDH levels in the 1 mg/kg and 3 mg/kg SC dose cohorts that returned to pre-treatment baseline over time, by 24 hours. No immunogenicity was observed in any patient, following either IV or SC dosing of a single dose of TT30. In conclusion, both TT30 formulations were safe and well tolerated; preliminary PK and PD data support the concept that treatment by targeted complement inhibitors like TT30 result in pharmacologically relevant CAP inhibition in PNH, as demonstrated by LDH decrease. Nevertheless, such therapeutic inhibition is short-lasting, and further strategies are needed to sustain pharmacological levels of TT30 for chronic treatment in PNH. Disclosures Risitano: Alnylam: Consultancy, Research Funding; Novartis: Research Funding; Pfizer: Consultancy; Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rapharma: Consultancy, Research Funding. Off Label Use: The presentation will include discussion of a clinical trial with a non-approved medication. Storek:Alexion Pharmaceuticals, Inc.: Employment, Other: stock owner. Sahelijo:Alexion Pharmaceuticals: Employment, Equity Ownership. Doyle:Alexion Pharmaceuticals, Inc.: Employment, Other: stock owner. Dai:Alexion Pharmaceuticals, Inc.: Employment. Weitz:Alexion Pharmaceuticals, Inc.: Consultancy, Speakers Bureau. Elebute:Alexion Pharmaceuticals, Inc.: Speakers Bureau. O'Connell:Celgene: Speakers Bureau; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Portola: Membership on an entity's Board of Directors or advisory committees. Kulasekararaj:Alexion: Consultancy. Lundberg:Alexion Pharmaceuticals, Inc.: Employment.