ABSTRACT
PURPOSE: Evaluate the type and quantity of quality information (i.e. Chemistry, Manufacturing, and Control) requested by the US FDA and EMA in queries pertaining to biosimilar applications. METHODS: Numbers/types of queries received following regulatory submissions (FDA/EMA, n = 7/n = 5) for seven biosimilars (PF-filgrastim [Nivestym], PF-rituximab [Ruxience®], PF-trastuzumab [Trazimera®], PF-bevacizumab [Zirabev®], PF-pegfilgrastim [Nyvepria®], PF-adalimumab [Abrilada™/Amsparity®], PF-infliximab [Ixifi]) from a single product portfolio were analyzed considering published regulatory authority (RA) guidance and in relation to sections/subsections of Module 3: Quality from the Common Technical Document regulatory dossier and topics based on keyword assignment. RESULTS: Queries were most frequently assigned (FDA/EMA %, range) to Drug Substance Manufacture (subsection 3.2.S.2; 21-35%/13-50%), Control of Drug Substance (3.2.S.4; 3-11%/5-17%), Drug Product Pharmaceutical Development (3.2.P.2; 1-12%/1-15%) and Manufacture (3.2.P.3; 17-41%/2-13%), and Analytical Similarity (3.2.R; 4-21%/4-20%). The proportion of Drug Substance and Drug Product queries was significantly different between RAs (n1 = 952, n2 = 468, p-value <0.001; two-sample proportion z-test). Topic assignments included: Control (12-27%/12-28%), Manufacturing (56-72%/34-66%), Stability (1-12%/2-24%), Biosimilarity (5-16%/5-25%), and Container Closure (0-3%/0-9%). CONCLUSION: The focus of both RAs on topics related to manufacturing and controls is valuable in understanding expectations for scientific and technical content related to gaining biosimilar approval.
Subject(s)
Biosimilar Pharmaceuticals , Drug Industry , United States Food and Drug Administration , Biosimilar Pharmaceuticals/standards , Humans , United States , Drug Industry/legislation & jurisprudence , Drug Industry/standards , Drug Approval/legislation & jurisprudence , Quality Control , European UnionABSTRACT
Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.
Subject(s)
Amides/chemistry , Complement C1s/antagonists & inhibitors , Drug Design , Polyethylene Glycols/chemistry , Protease Inhibitors/chemical synthesis , Thiophenes/chemistry , Animals , Complement C1s/metabolism , Half-Life , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , RatsABSTRACT
A novel series of 4-azetidinyl-1-aryl-cyclohexanes containing indazole or benzoisoxazole moiety have been identified as potent CCR2 antagonists with high selectivity versus hERG.
Subject(s)
Indazoles/chemistry , Indazoles/pharmacology , Oxazoles/chemistry , Oxazoles/pharmacology , Receptors, CCR2/antagonists & inhibitors , Animals , Cell Line , Cyclohexanes/chemical synthesis , Cyclohexanes/chemistry , Cyclohexanes/pharmacokinetics , Cyclohexanes/pharmacology , Dogs , Drug Design , Humans , Indazoles/chemical synthesis , Indazoles/pharmacokinetics , Oxazoles/chemical synthesis , Oxazoles/pharmacokinetics , Rats , Receptors, CCR2/metabolism , Structure-Activity Relationship , Trans-Activators/metabolism , Transcriptional Regulator ERGABSTRACT
A series of 4-azetidinyl-1-aryl-cyclohexanes as potent CCR2 antagonists with high selectivity over activity for the hERG potassium channel is discovered through divergent SARs of CCR2 and hERG.
Subject(s)
Azetidines/pharmacology , Drug Discovery , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Hippurates/pharmacology , Receptors, CCR2/antagonists & inhibitors , Azetidines/chemical synthesis , Azetidines/chemistry , Dose-Response Relationship, Drug , Ether-A-Go-Go Potassium Channels/metabolism , Hippurates/chemical synthesis , Hippurates/chemistry , Humans , Molecular Structure , Receptors, CCR2/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Complement activation has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury, acute respiratory distress syndrome, and acute transplant rejection. Even though the complement cascade provides several protein targets for potential therapeutic intervention only two complement inhibitors have been approved so far for clinical use including anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and purified C1-esterase inhibitor replacement therapy for the control of hereditary angioedema flares. In the present study, optimization of potency and physicochemical properties of a series of thiophene amidine-based C1s inhibitors with potential utility as intravenous agents for the inhibition of the classical pathway of complement is described.
Subject(s)
Complement C1s/antagonists & inhibitors , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Animals , Binding Sites , Half-Life , Models, Molecular , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
We have discovered a novel series of 4-azetidinyl-1-aryl-cyclohexanes as CCR2 antagonists. Divergent SAR studies on hCCR2 and hERG activities led to the discovery of compound 8d, which displayed good hCCR2 binding affinity (IC50, 37 nM) and potent functional antagonism (chemotaxis IC50, 30 nM). It presented an IC50 of >50 µM in inhibition of the hERG channel and had no effect on the QTc interval up to 10 mg/kg (i.v.) in anesthetized guinea pig and dog CV studies. It also displayed high selectivity over other chemokine receptors and GPCRs, and amendable oral bioavailability in dogs and primates. In a thioglycollate-induced inflammation model in hCCR2KI mice, it had ED50 of 3 mg/kg on inhibition of the influx of leukocytes, monocytes/macrophages, and T-lymphocytes.
ABSTRACT
Inhibiting the classical pathway of complement activation by attenuating the proteolytic activity of the serine protease C1s is a potential strategy for the therapeutic intervention in disease states such as hereditary angioedema, ischemia-reperfusion injury, and acute transplant rejection. A series of arylsulfonylthiophene-2-carboxamidine inhibitors of C1s were synthesized and evaluated for C1s inhibitory activity. The most potent compound had a Ki of 10nM and >1000-fold selectivity over uPA, tPA, FX(a), thrombin, and plasmin.