Posted on Authorea 5 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162552379.93685989/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. hs td fsnl n eetoa oe fGK497A a GSK3439171A, participants Haws of adult Thomas healthy doses in oral inhibitor, repeat H-PGDS and selective single highly of study 1 phase A hmsHw 69Ws ynD etCetrP 98 USA 19382 PA Chester West Dr Lynn West 1609 Haws Thomas completed *Author author: was USA UK; Corresponding study PA, Middlesex, the Collegeville, after Development, Brentford, GlaxoSmithKline and House, from Research departed GSK GlaxoSmithKline Group, Development, Leader and Development Research GlaxoSmithKline partment, USA; PA, legeville, USA; PA, Collegeville, Development, USA; PA, Collegeville, Development, USA; PA, Collegeville, Affiliations: H-PGDS selective highly Zhang-Roper a Rebecca ofGSK3439171A, doses oral Authors: repeat participants and adult single healthy of in study inhibitor, 1 for was phase potential therapeutic GSK3439171A A offers injury. Conclusion: H-PGDS following GSK3439171A recovery of when observed. muscular inhibition was similar and Selective Dystrophy) levels were SAEs. Muscular tPGDM Results no Duchenne of were (e.g. hours. suppression there mainly disorders and 12 consistent muscle-related participants drug, to No healthy up study in food. was tolerated to significant without were GSK3439171A well clinically related days; or AUC(0–inf) of or and 14 (AEs) with half-life (SAEs) Cmax taken for events in AEs mean was increases mg adverse serious geometric Dose-proportional 11 no had the parameters. were and and (12%) laboratory There (5 or observed, participants electrocardiogram, rash). doses Seven signs, skin once-daily vital transient in repeat non-serious, changes administered. and [7%]; were (n=4 mg) days) hypersensitivity (5–180 were markers 7 drug participants doses inflammatory Sixty-six for of Single Results: Levels mg GSK3439171A. samples. years. 40 receiving urine 18–65 57 in aged measured males with were Single healthy enrolled, (tPGDM) to study. metabolite dose-escalation administered first-time-in- placebo-controlled, D were a double-blind, tetranor-prostaglandin GSK3439171A randomized, including performed of 1, doses we food phase of oral data, a effect was repeat preclinical the This and and favourable GSK3439171A, potent, Methods: on of promoter a pharmacodynamics parameters. Based and key these is pharmacokinetics, a on tolerability, types). GSK3439171A safety, (H-PGDS, the cell synthase assess inflammatory diseases. D to study several prostaglandin inflammatory human in haematopoietic of of production pathophysiology inhibitor PGD2 the urea of in azetidine selective implicated highly is and (PGD2) reversible, D2 Prostaglandin Aim: Abstract 2021 5, July 2 1 Zhang-Roper Rebecca lxSihln eerhadDevelopment and Research GlaxoSmithKline GlaxoSmithKline hmsHaws Thomas 1 lnclPamclg xeietlMdcn,DsoeyMdcn,GlaxoSmithKline, Medicine, Discovery Medicine, Experimental & Pharmacology Clinical 1 ia Thakkar Nilay , 5 isaitc,GaomtKieAi v t,Bnauu India; Bengaluru, Ltd, Pvt Asia GlaxoSmithKline Biostatistics, 6 ,GoDerimanov Geo *, 2 lnclPamclg,Mdln n iuain lxSihln eerhand Research GlaxoSmithKline Simulation, and Modeling Pharmacology, Clinical 1 2 ,NlyThakkar Nilay *, e Derimanov Geo , 2 umrGoodson Summer , 3 4 lblCiia n td eiey lxSihln eerhand Research GlaxoSmithKline Delivery, Study and Clinical Global iaayi,Imngnct imres lxSihln,Col- GlaxoSmithKline, Biomarkers, & Immunogenicity Bioanalysis, 1 ai Neil David , 2 umrG Goodson G. Summer , 1 ai Neil David , 1 1 ,Vcoi Ballard Victoria *, 2 aoieSychterz Caroline , 1 n itraBallard Victoria and , 3 ,Crln Sychterz Caroline *, 7 * 1 ih George Nisha , 4* 6 lblSft De- Safety Global 2 ih George Nisha , 7 1 Early , 4,5 , Posted on Authorea 5 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162552379.93685989/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. niiino -GSoesteaetcptnilfrmsl-eae iodr eg uhneMuscular Duchenne (e.g. NCT03627494 disorders Identifier: muscle-related ClinicalTrials.gov for injury. following potential recovery muscular therapeutic observed. and was offers Dystrophy) levels when H-PGDS signs, tPGDM similar of of vital were suppression Results inhibition in consistent hours. changes No 12 significant to food. Conclusion: up without C clinically was or or in GSK3439171A with of taken (SAEs) increases half-life was participants AEs mean Dose-proportional GSK3439171A Seven geometric serious administered. the non-serious, parameters. no were and [7%]; days) observed, were (n=4 laboratory 7 hypersensitivity There or for drug mainly mg electrocardiogram, drug, 40 rash). study days; to skin 14 related for transient (AEs) mg events adverse 11 had and of (12%) (5 Levels doses urine once-daily in years. repeat 18–65 measured aged were males Results: (tPGDM) healthy metabolite to D administered tetranor-prostaglandin were samples. GSK3439171A including of markers doses inflammatory oral parameters. these repeat haematopoietic on and food of of effect tolerabil- inhibitor safety, the the Methods: and urea assess GSK3439171A, to of study azetidine first-time-in-human pharmacodynamics a selective and performed pharmacokinetics, we ity, highly data, PGD preclinical of and favourable promoter on key Based reversible, a (H-PGDS, synthase potent, D prostaglandin a is GSK3439171A Aim: Abstract beneficial. be could approach adds treatment study this this that D suggest What TAS-205 prostaglandin diseases. inhibitor inflammatory H-PGDS of selective of promoter the pathophysiology of key the Studies in a role is important an (H-PGDS) plays synthase which D subject prostaglandin this Haematopoietic about known limit) already (4,000-word 3,259 is = What references) and abstract (excluding count Word DN). Keywords: (RZR, programme development clinical the head: for Running and (GD) study the for bility Investigator: Principal 302-521-9971 +1 Tel: mi:Tom Email: • • • hs eut arn ute tde fGK497Ai h agtpplto ihinflammatory with population target the in GSK3439171A 5–180 (range of doses studies single further diseases. mg). in warrant 5–40 tolerated (range results well doses was These once-daily and repeat profile and participants. safety mg) male favourable adult a healthy results showed tolerability, 57 present safety, GSK3439171A evaluate we in to Here, pharmacodynamics performed GSK3439171A, and inhibitor. of H-PGDS pharmacokinetics, study selective 1 phase highly first-time-in-human, and the reversible, from potent, a is GSK3439171A rsalni D Prostaglandin it-i atcpnswr nold ih5 eevn S3311.Snl oe 510m)and mg) (5–180 doses Single GSK3439171A. receiving 57 with enrolled, were participants Sixty-six hswsapae1 admzd obebid lcb-otold oeeclto td.Single study. dose-escalation placebo-controlled, double-blind, randomized, 1, phase a was This [email protected] S3311,HPD niio,pamckntc,pamcdnmc,pae1 tolerability 1, phase pharmacodynamics, pharmacokinetics, inhibitor, H-PGDS GSK3439171A, S3311 a eltlrtdi elh atcpnsadteewr oSE.Selective SAEs. no were there and participants healthy in tolerated well was GSK3439171A hs td fGSK3439171A of study 1 Phase 2 hr sn rnia netgtrfrti td.Atoshdmdclresponsi- medical had Authors study. this for Investigator Principal no is There (PGD 2 sipiae nteptohsooyo namtr diseases. inflammatory of pathophysiology the in implicated is ) 2 2 rdcini eea namtr eltypes). cell inflammatory several in production max n AUC and 2 production, (0–inf) were Posted on Authorea 5 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162552379.93685989/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. P)adboakr n S3311 eaoi ahas(lsa rnr,adblay nhealthy in [12]. biliary) protocol study and the urinary, in pharmacodynamics available (plasma, of are pathways evaluation objectives the the metabolic included of GSK3439171A details objectives effect Further GSK3439171A and exploratory the of participants. assess GSK3439171A; biomarkers to PK of was and and objective tolerability, PK secondary safety, (PD) the The the on participants. assess healthy food to in doses were of oral study repeat the and dose-escalation single of FTiH, following placebo-controlled, objectives unblinded), primary (sponsor The double-blind randomized, study. 1, phase a was This participants and design Study 2.1 METHODS AND MATERIALS 2 dosing inhibitory The half-maximal volunteers. healthy target in [12]. the conducted [12]. parameters predictions, GSK3439171A, effects of these PK reversible genotoxic study on human and (FTiH) no based predict human dogs but was to in rats, assessment (IC used juvenile effects clinical concentration in were hepatic initial gland animals minor mdx for pituitary and in produced strategy and wild-type drug studies gland, both the (PK) mammary in studies, Pharmacokinetic ovary, placebo toxicity the treatment versus mouse injury, preclinical in function a muscle changes In limb induce In of to H-PGDS. [12]. recovery repetitions of contraction nowmice superior inhibitor eccentric is enabled urea of assessment azetidine GSK3439171A challenge selective a efficacy with issues). involving highly robust tolerability DMD, and enable of no reversible, to model and potent, patients a placebo of is as numbers GSK3439171A [AEs] sufficient events in TAS-205 adverse TAS-205 of difference profile of of [11]. significant safety underway study incidence The No 3 similar TAS-205 index. small, [7]. phase high-dose volume A but DMD muscle A (i.e. distance), leg [10]. with favourable walk lower DMD 6-minute patients also right a with in in was in boys conducted baseline reduction in from the been tPGDM (change attenuated has urinary endpoint significantly primary of drug my- suppress the suppression this can in in enable of seen H-PGDS expressed to was trial of trial is 2 inhibition 1 cells, phase phase that a 24-week immune shown in have in shown studies was mediator Animal 205 key [8]. the patients H-PGDS, PGD DMD in [9]. areas respectively) onecrotic L-PGDS, and indicating PGDS patients, DMD ambulant [8]. versus severity other PGD non-ambulant and with children in progression or higher disease subjects with are healthy age-matched levels relationship in tetranor- a tPGDM than of DMD Urinary with PGD excretion children [8]. of in Urinary diseases higher metabolite be [3,6,7]. major to (DMD) reported a Dystrophy been (tPGDM, Muscular metabolite Duchenne D of prostaglandin pathology [2,3,6]. the animals in in involved injury muscle following myogenin) PGD and and H-PGDS (MyoD of myogenesis levels of tissue knock-out markers Additionally, dystrophin recovery. increase functional using and PGD manipulation, remodelling the gene muscle or PGD via H-PGDS of either signal kinetics of the this inflammation inhibition erates of small-molecule of and Blockade mechanisms mice, mdx [3]. the (KO) repair in PGD muscle (H-PGDS)-mediated role skeletal synthase key ( pairs D prostaglandin a increases haematopoietic plays large demonstrates It Accordingly, evidence PGD activation. [1–4]. of cellular asthma els or and injury allergy to in response in cells) D Prostaglandin INTRODUCTION 1 2 2 2 2 rdcin mloaemsl erss n mrv ucesrnt 3.TeHPD niio TAS- inhibitor H-PGDS The [3]. strength muscle improve and necrosis, muscle ameliorate production, a lobe soitdwt ucencoi n PGD and necrosis muscle with associated been also has ytei spooe ytotpso rsalni ytae amtpitcadlpcln(H- lipocalin and haematopoietic synthase: D prostaglandin of types two by promoted is synthesis r lvtdi ctl nue iseadcrnclyiflmdtsu.Ntby -GSinhibitors H-PGDS Notably, tissue. inflamed chronically and tissue injured acutely in elevated are 2 aebe eotdi shaptet pnepsr oa legn[] togbiological Strong [5]. allergen an to exposure upon patients asthma in reported been have 2 50 (PGD n h rciia oiiypol 1] eew eotdt rmtefirst-time-in- the from data report we Here [12]. profile toxicity preclinical the and ) 2 ssnhssdb el fteimn ytm(..ms el,antigen-presenting cells, mast (e.g. system immune the of cells by synthesised is ) 3 > 5-od nbocolelrlvg udlev- fluid lavage bronchoalveolar in 150-fold) 2 mdae namto ssgetdt be to suggested is inflammation -mediated 2 n akro PGD of marker a and 2 eetr DP receptors 2 2 1 rdcin has production) n DP and rdcinim- production 2 accel- Posted on Authorea 5 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162552379.93685989/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 0m oeo S3311 ihri atdsaeo fe ihftma.Priiat eedischarged were Participants oral meal. single high-fat a a received after and or clinic state the fasted to a admitted in either were GSK3439171A participants a 7-day of in session, a dose sequences by study separated treatment mg each two sessions 60 study of In 4-day one two to comprising period. 1:1 fasted/fed) washout assigned or (fed/fasted randomly design were crossover participants 2-period 12 approximately C, Part In last effect) [13]. their (food metabolites receiving C after drug Part days of 2.4 14 assessment Cohort approximately In qualitative visit tissue. a follow-up muscle provide a were in to for levels biopsies Entero-Test prostanoid muscle returned for on Skeletal dose. cohort the GSK3439171A mg/day each days. using of 5 GSK3439171A in 7 sampled effect of 1, Participants for the administration was Cohort mg/day after assess bile 40 and to follows: 3, before was 2, as anaesthetic, Cohort This were local days; placebo. selected under 14 or lateralis regimens for vastus tolerability, repeat-dosing The mg/day the safety, from the of 11 cohort. review obtained dose 2, when a preceding last Cohort after dose chosen the the days; last and after from 14 sequentially the days administered data after were (3 PK study days 13 the and (3 of Day assessments. part on 20 this study discharged Day in of Doses were or completion consisting Participants following days) regimen for days), days. 7 repeat-dosing collected 14 14 was a were was to began samples period period up subsequently randomly urine repeat-dosing participants for were and the and day participants Plasma dose, when 12 per ratio). first cohorts, dose the (3:1 three one after placebo of of hours or each 72 GSK3439171A In to of groups. up dose study one parallel to with assigned conducted was mg, B 120 dose) Part mg, ascending 60 receiving (multiple and after 1 days B Cohort 14 Part for approximately 2.3 mg visit 30 follow-up and a mg, for based 10 returned determined mg, Participants escalations 5 dose. dose 2. were last subsequent Cohort selected each their with for doses between GSK3439171A, mg The days mg 180 data. 5 and 7 PK was approximately and A drug safety of Part active on for period of dose levels washout starting dose a The two with received assigned limit participant placebo, exposure randomly each single-dose of were that the session. participants dose so to dosing cohort, close (1:1:1) one was each conducted sequences and A2 not treatment Within Cohort (GSK3439171A) was three in were A3 data). of mg) Cohort cohorts toxicity one (180 level participants. ascending-dose preclinical to dose nine sequential to last involving Two according the each at (defined planned, periods. seen three treatment exposure the the three of as with A2) and design (A1 crossover enrolled a was A written dose) Part provided ascending participants (single All A Helsinki. Part of 2.2 require- Declaration study. regulatory the the applicable of of all start principles and the Practice guiding For before Clinical the consent data. Good dose. as informed of with first well accordance interpretation the as in before the ments, days conducted with 30 was interfering approximately study or occurred The intervention screening study, of study the capable the of disorders taking part neurological body when each or a (Figure risk and haematological, C) kg, a endocrine, (Part [?]50.0 constituting gastrointestinal, PK of bodyweight renal, on a kg/m hepatic, food with 18.5–31.0 respiratory, of years, of 18–65 effect (BMI) aged the index participants A), and mass male (Part B), healthy doses enrolled Part ascending study rising, single This (dose parts: days three 14 comprised to and up centre 1). doses US repeat single a and at single conducted was study The 2 e xlso rtraicue itr rpeec fcardiovascular, of presence or history included criteria exclusion Key . 4 Posted on Authorea 5 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162552379.93685989/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. nttl 4% fpriiat nPr ,1 5% nPr ,ad4(3)i atCworcie active received who C in Part AEs No in intensity. (33%) in 4 moderate and or mild B, were Part AEs in All (59%) 2). 16 (Table AE A, an Part experienced in GSK3439171A participants of of doses (44%) 8 total, In American, African of (58%). or majority heritage Black Safety were White/Caucasian/European The (50%) of 3.2 A–C. were C Parts approximately Part B in Part in of participants in participants age the participants among mean of of similar a half majority Participant were and the with C. (67%) Part and BMI male, in A and were 12 Part weight, and participants in B, height, participants All Part Mean in 1. 36 years. Table A, 43 Part in in summarised treatment to are randomised characteristics were participants 18 total, In characteristics Participant 3.1 online the to refer Please samples). RESULTS (bile 3 dose mg 11 the or samples) details. urine administration for and after Methods (plasma obtained Information: samples dose bile Supporting mg and 40 urine, plasma, the in of analysed were GSK3439171A of Metabolites metabolism GSK3439171A of Assessment 2.8 Please details. values. for tPGEM Methods and to Information: tPGDM used Supporting of online was correction the enabling method to samples, colorimetric urine refer validated in A concentrations creatinine methods. high-performance assess validated spectrometry by determined mass were chromatography–tandem samples urine liquid and muscle in prostaglandins online WinNonlin of the Concentrations Phoenix in using provided calculated are were Details parameters concentra- PK samples. measure All (Certara urine and to Methods. homogenate, used Information: muscle was Supporting plasma, spectrometry in mass GSK3439171A of tandem tions with chromatography liquid prostaglandins High-performance and GSK3439171A of tissue. muscle Determination in 2.7 H-PGDS the of assess tPGDM, inhibition to including examined the were markers, and biopsies GSK3439171A PD Muscle of inflammatory creatinine. relationship and and PK-PD prostaglandin (tPGEM), measure metabolite E to tetranor-prostaglandin analysed were samples Urine assessments and Pharmacodynamic testosterone, 2.6 total adreno- (FSH), (T4), hormone monitored: thyroxine were follicle-stimulating free hormones (LH), (T3), following (DHT). hormone tri-iodothyronine the dihydrotestosterone electrocardiograms (TSH), luteinizing of of levels hormone cortisol, recording thyroid-stimulating addition, and (ACTH), In partners, mon- hormone female telemetry timepoints. corticotropic cardiac of pressure), predefined status blood at pregnancy diastolic (ECGs) tests, and (oral laboratory systolic signs and vital clinical examinations, rate, itoring, physical respiratory AEs, rate, of pulse monitoring included temperature, study the throughout assessments Safety approximately visit follow-up a assessments for Safety returned 2.5 and assessments dose. PK last and their safety receiving of after days completion 14 after 4 Day on ® ). 5 ® software Posted on Authorea 5 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162552379.93685989/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 22 or fe eevn oe fpaeo g n 0m fGK497A(uprigInformation Part (Supporting In GSK3439171A values. of aggregated mg tPGDM 30 creatinine-corrected and for mg, reported baseline 5 were to observations compared placebo, as Similar of two-fold increased GSK3439171A doses S1). were with Table receiving values suppression aggregated after consistent tPGDM hours urinary no PGD 12–24 A, but Part participants, In i.e. was in observed. samples, detected modulation was muscle was no the tPGDM but biomarker in participants, urinary tested from biomarkers F1 biopsies prostaglandin the muscle keto of in any detected in was observed GSK3439171A of presence The mg 60 single a Pharmacodynamics following GSK3439171A 3.4 mean of 5). profile estimated (Table PK an food the with without in observed or participants, were with healthy differences taken notable dose in no points C, was Part time GSK3439171A In measured QD. mg the 0.4. 5–40 of at doses ratio tissue for muscle:plasma observed muscle was in PK time-invariant detected and C C accumulation, and in predicted AUC to increases in time Dose-proportional over accumulation dose. to GSK3439171A led (QD) once-daily mg AUC 40 C the concentration studied to plasma Trough highest corresponding 4. the Table in of presented mean are B Part half-life hours. from mean (C GSK3439171A 12.0 geometric of to observed PK 9.8 The multiple-dose from The mg. ranged 5–180 A the of Part C doses of in in single increases GSK3439171A mean following Dose-proportional of geometric GSK3439171A. GSK3439171A of for The dose observed mg 3. (AUCwere 180 Table single time in a infinite to presented to corresponding are extrapolated A zero (C Part time concentration from observed maximum GSK3439171A studied of highest PK single-dose The show not Pharmacokinetics did 3.3 study the of part changes. repeat-dose parameters significant the laboratory clinically during or ECG, monitoring or signs, consistent Hormone vital study. any in the changes during significant clinically reported or were (SAEs), AEs serious tachycardia deaths, ventricular No drug-related non-sustained other and 1). The pain, treatment. = abdominal with any intermittent n consistent without flushing, (all infil- plexus, spontaneously facial perivascular vascular resolved headache, mild all superficial were a events the AEs be showed These surrounding to which reaction. eosinophils considered biopsy allergic scattered were any skin an with without cases a lymphocytes and the to non-pruritic, of of consented in appearance, trate Three participant allergic in likely C). One maculo-papular intensity, most Part complications. were in in systemic they moderate participant participant assessment, were (1 dermatologist 1 rashes GSK3439171A on The and to based nature. exposed B, and, (7%) Part treatment pre- participants GSK3439171A events in 57 to These participants the hypersensitivity. related of 2 drug out was A, 4 study Part in the rash in of skin parts non-serious and all a Part gastroenteritis as C. across in sented AE Part mild rash drug-related in allergic AEs; common tachycardia moderate most ventricular non-serious The and and to pain rash be due abdominal allergic study to moderate moderate A, the determined and Part B, from were in procedural events withdrew pharyngitis was part these streptococcal B moderate each participants; Part in in (30%) AE participants 8 common Two by most drug. reported The study participant. biopsy, the one muscle to than the unrelated more to in related reported were pain C or A Parts trough (0–τ) ausidctdta taysaewsahee ytesxhdyo ramn.Tegeometric The treatment. of day sixth the by achieved was state steady that indicated values ) eeosre vrteds ag f54 gQ.Mlil-oeamnsrto fGSK3439171A of administration Multiple-dose QD. mg 5–40 of range dose the over observed were α 6KT-G) rsalni 2 PFA,adtrmoaeB TB) The (TXB2). B2 thromboxane and (PGF2A), F2a prostaglandin (6-KETO-PGF), max n AUC and max (0–T) (0–inf) aus bevdsed-tt cuuainwscomparable was accumulation steady-state Observed values. ee11. gm n 15. ghm,respectively, ng*h/mL, 11851.0 and ng/mL 1016.3 were ee23. gm n 64. gm,respectively, ng/mL, 46844.6 and ng/mL 2938.0 were ) max 6 n raudrtecnetaintm uv from curve concentration-time the under area and ) 2 rsalni E prostaglandin , max n AUC and 2 (PGE max (0–inf) 2 ,6- ), and Posted on Authorea 5 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162552379.93685989/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. lvtd ihascae nrae ntGMlvl 78.Teeoe ti nupiigta GSK3439171A that is unsurprising activity is H-PGDS it that Therefore, by DMD) individuals. necrosis, [7,8]. suppressed healthy muscle levels in not inflammation, tPGDM low is increased are in H-PGDS L-PGDS increases (e.g. gen- of associated settings male levels with [2,14,15]. certain Basal and elevated, in cells H-PGDS. heart, only for muscle system, distinct selective is nervous in are is It central drug expression L-PGDS the the (lower-level) of in as further synthesis principally patterns GSK3439171A, prostaglandin located with expression ongoing is The organs, of L-PGDS ital result H-PGDS: conditions. a of sup- non-inflammatory be those consistently may basal, from not This were under levels participants. L-PGDS tPGDM healthy via urinary in of biopsies, GSK3439171A findings muscle by the in pressed and whether detected populations. food, confirm was patient without to GSK3439171A target or needed Although the are with to studies taken Further partic- applicable was male are drug hours. healthy study 10–15 the in was our whether profile half-life of PK mean treating regardless linear geometric consistent of and the were method dose-proportional parameters a a PK has as ipants. GSK3439171A inhibition consistency that H-PGDS showed suggest of study results viability changesOur These the significant for support clinically need levels. or and [7,10]. hormone the TAS-205 SAEs diseases including without of any inflammatory parameters spontaneously profile of cohort lack safety resolved laboratory each a the or that in with with ECG, rash patients hypersensi- raised, signs, skin of drug were vital minority non-serious commonly concerns in A most as safety further GSK3439171A, manifested drug. by No [7%]), study caused treatment. 4 the been = to have (n may unrelated reported. tivity male that were being adult AEs study SAEs healthy experienced no our 57 ([?]17%) with in in tolerated, observed GSK3439171A well AEs was of Most GSK3439171A PD that and show PK, results tolerability, safety, The the participants. evaluated study FTiH This oxida- of products DISCUSSION included 4 urine, in GSK3439171A. dose unchanged the was In benzothiazole material of thereof. the drug-related dose combinations less of only the and the oxidation or dehydrogenation, of bile, methylation, to 3% majority plus duodenal related representing hydration The 23% sulfation, each approximately glucuronidation, urine. metabolites, tion, with in Minor metabolites, dose as the ring. eliminated of was 8% urine comprised approximately in these represented 10% and GSK3439171A approximately aniline, for Unchanged accounting an metabolite to plasma. major ring potential the DRM). benzothiazole a circulating in (including the of DRM (DRM) of total material oxidation of 14% by drug-related approximately formed of were 82% metabolites approximately Several comprised GSK3439171A Unchanged a 2. after Metabolism Figure baseline in 3.6 to presented is ratio A reference tPGDM Part A urinary in urinary studied. dose creatinine-corrected creatinine-corrected doses mg different versus between 60 the concentration relationship single at GSK3439171A no concentrations was GSK3439171A of and there plot baseline overall, from trends, change some tPGDM were there Although interaction PK/PD 3.5 assessed. baseline were from creatinine-corrected with changes that dose-dependent and biomarkers baseline No (aggregated the versus B. values of Part Changes or tPGEM any the A in S2). Part after smaller. observed in Table were hours were baseline Information timepoints from 12–24 change (Supporting other baseline little showed 17 at versus aggregated) Day and increase doses on two-fold other GSK3439171A a the of showed dose value mg aggregated 5 tPGDM urinary the B, 7 Posted on Authorea 5 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162552379.93685989/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ttetm ftesuy l uhr eeepoeso lxSihln n H T S Z,adVB and RZR, CS, NT, TH, and GlaxoSmithKline of employees were authors GlaxoSmithKline. all in study, stocks/shares the held of time the At Spirit of interest division of a Conflict Aura, of Reardon Tony and GlaxoSmithKline. by Williams funded Chris Ltd, by Group provided Communications was Medical with agreement support license writing and Medical collaboration development and research Pharmaceuticals. a Astex under discovered was GSK3439171A Acknowledgements further to no H-PGDS required were of are Inhibition there studies follow-up GSK3439171A. administered. and although were of participants diseases, days potential inflammatory 7–14 healthy the over treating in investigate doses to once-daily approach tolerated and promising well doses a single was is of GSK3439171A range A that shows SAEs. study FTiH This further a CONCLUSIONS represents circulation 5 systemic in as Mea- well as doses. (muscle) single tissue in as strengths target rare inhibition Study well the as of H-PGDS participants. in multiple male of detection PD of of strength. effects for selection and administration the our small PK and hence investigating of too design, males, to surement in was double-blind precursor likely are randomized, study disease a are the our this as whom included of that in of conducted cases possible patients many all was is Almost of diseases, study DMD. It inflammatory number FTiH with observed. The This patients be in treatment. AEs. not different long-term could slightly efficacy require be clinical to will its profile and PGD safety inhibitor) of the inflam- H-PGDS levels of (an basal lack GSK3439171A only was PGD of that limitation basal important meaning this An participants, that study participants. healthy the in in conducted mation was following study recovery exploratory muscular This and DMD) (e.g. PGD disorders than muscle-related other for injury. metabolites potential levels acid therapeutic on offers arachidonic effect PGDS of measurable effects no For has beneficial GSK3439171A the that [16]. showed structures, efficacious We PGE associated the be [17,18]. their of healing and not tendon tendons may involving block interventions can [NSAIDs]) surgical NSAIDS drugs from recovering anti-inflammatory patients in non-steroidal example, (e.g. signalling E matory prostaglandin as from such pathway tissue, clearance PGD alternative to possible contrast a In have indicating methylthioaniline dose), resulting matrix. the the either of on (˜21% in urine, aniline. sulphur urine the detected and the human not plasma of in was oxidation identified in metabolites further been identified glutathione-conjugated by was or generated (aniline) aniline metabolites GSK3439171A However, the of of of metabolite metabolism levels reactive further pre-treatment higher potentially with a patients effect. Although in an studies show volunteers; to healthy needed in are levels tPGDM tPGDM reduce not does 2 eaoietGM ugsigta hsdu ol epcnrliflmainwtotreducing without inflammation control help could drug this that suggesting tPGEM, metabolite 2 oepout faahdncai eaoimpouebnfiilsgaln nmuscle in signalling beneficial produce metabolism acid arachidonic of products some , 2 a rmrl yteie yLPD,maigta h hraoyai effects pharmacodynamic the that meaning L-PGDS, by synthesized primarily was 2 n rsalni F prostaglandin and 8 2α . hrfr,tetet htdces lblinflam- global decrease that treatments Therefore, 2 3.Tu,slcieihbto fH- of inhibition selective Thus, [3]. 2 eeosre.W hypothesize We observed. were Posted on Authorea 5 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162552379.93685989/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. h aaesue n/raaye uigtecretsuyaeaalbefrom available are References study manuscript and current interpretation, analyses/ data study, this of conduct the and writing. design the to contributed authors All during analyzed contributions Author and/or used request. reasonable on datasets www.clinicalstudydatarequest.com The availability Data GlaxoSmithKline. by supported was study This funding Study Euh ,Euh ,OaH ta.Epeso flpclntp rsalni ytae(beta-trace) synthase D prostaglandin lipocalin-type non-invasive of Expression for approach al. simple et a H, Entero-Test, Oda of N, Eguchi Use Y, al. Eguchi et 14. SR, pharmacokinet- Thomas C, Beaumont tolerability, WJ, Guiney safety, 13. evaluate to study dystrophy FTiH muscular three-part Duchenne A with patients in TAS-205 GlaxoSmithKline. of of 12. study study I 3 phase A phase S. Takeda A M, Sasaki ClinicalTrials.gov. A, Ishiyama 11. Y, Shimizu-Motohashi H, Komaki E, Takeshita 10. LeK e H i H h ilg fpotgadn n hi oea agtfralri airway allergic for target a as role their and prostaglandins of biology The TH. Kim muscular Duchenne SH, as Lee metabolites K, prostaglandin Duchenne Lee Urinary with patients al. 9. in et TAS-205 H, of Tachimori trial H, 2 Komaki phase 8:619. E, Early Takeshita 2019; al. Cells 8. et prostaglandin. T, Matsumura hematopoietic Y, of 2011; Maegaki potential Biol H, Therapeutic Vasc Komaki A. Thromb 7. Heinemann Arterioscler S, Rittchen inflammation. and 6. 111:6209-6230. muscular 2011; Prostaglandins suppresses Rev GA. synthase Chem FitzGerald D receptors. E, prostaglandin Prostanoid Ricciotti of S. 5. Narumiya Inhibition T, 58:89-120. al. Hirata 2000; et Horm 4. H, Vitam Taniguchi function. K, and structure Aritake, the of synthase: I, characterization D Mohri and Prostaglandin cloning O. 3. Hayaishi Molecular Y, M. Urade Abramovitz K, 2. Metters D, Slipetz N, Sawyer Y, Boie 1. nhmnhatadisacmlto ntecrnr iclto fagn ains rcNt Acad Natl Proc 2019. patients. angina of circulation participants. 94:14689-14694. coronary 1997; the adult A in 72:133-142. S accumulation healthy 2011; U its Pharmacol Sci and in Clin heart J human Br GSK3439171A in drugs. of of randomized, disposition dose biliary the a the evaluate oral of in evaluation to clinical single GSK3439171A, and of a study doses on escalation oral food dose https://clinicaltrials.gov/ProvidedDocs/94/NCT03627494/Prot repeat of placebo-controlled, and unblinded), effect single of (sponsor double-blind pharmacodynamics and ics Ac- https://clinicaltrials.gov/ct2/show/NCT04587908. 2021. 7, June 2021. 5:1338-1349. cessed February 2018; Neurol Updated Transl Clin (REACH-DMD). Ann dystrophy. muscular Duchenne with patients in TAS-205 21:1851. 2020; Sci Mol J Int therapy. disease 40:918-925. 2018; Dev Brain markers. progression dystrophy 7:181-190. 2020; Neurol Transl Clin Ann dystrophy. muscular 31:986–1000. 174:1735-1744. 2009; Pathol J Am necrosis. 270:18910-18916. 1995; Chem Biol J receptor. DP prostanoid human 9 0.d.Acse ue7 2021. 7, June Accessed 000.pdf. Posted on Authorea 5 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162552379.93685989/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. AL 1 TABLE Tables utpe001(8) 1 0 27) = (N B Part 18) = (N 0 12 A Part deviation. standard SD, AEs index; of mass Incidence body BMI, event; adverse AE, Abbreviations: (100) (83) 12 10 Multiple heritage (10.9) 43.1 White/Caucasian/European 36 heritage C Asian Part East – Asian American African (100) or 36 Black (94) (%) 34 n Race, (SD) (9.6) mean 42.7 (kg), Weight (SD) mean (cm), B Height Part (SD) 18 (kg/m (%) BMI n (100) AEs, 18 to due study (89) the 16 from Withdrew (8.4) n 42.4 (%) reason, any for study the from Withdrawn (%) n A Completed, Part male % Sex, (SD) mean Age, N characteristics Participant Cniz K ansoiS,Tce J ta.Tedtietleet fssei bpoe delivery ibuprofen systemic of effects detrimental The al. et JJ, tendon- Tucker cuff SM, rotator Yannascoli impair BK, celecoxib Connizzo and Indomethacin 18. S. inflammatory Rodeo and J, health Ehteshami in S, Kawamura cascade D, acid Cohen arachidonic lipocalin. 17. muscle enzymic skeletal The an IE. as Lundberg synthase M, Korotkova D 16. prostaglandin Lipocalin-type O. Hayaishi N, Eguchi Y, Urade 15. ntno eln r iedpnet lnOto ea e 04 472:2433-2439. 2014; Res Relat Orthop Clin dependent. time are healing tendon 34:362-369. on 2006; Med Sports J Am healing. 2000–2013. to-bone Bioscience; 10:295-303. 2014; Landes Rheumatol (TX): Rev Nat Austin disease. [Internet]. 2021. Database 7, June Bioscience Accessed Curie https://www.ncbi.nlm.nih.gov/books/NBK6621/. Madame In: 2 atcpn characteristics Participant ,mean ), 6 0 (42) 5 (50) 6 (58) 21 (6) 2 (6.9) 82.4 (5.2) (17) 177 2 (36) 13 (1.9) 26.5 (17) 2 (33) (8.2) 6 81.5 (6.8) 0 176.6 (2.6) (67) 26.1 12 (6) 2 (13.9) 84.4 (6) 2 (9.8) 178.4 (2.6) 26.4 (11) 2 (11) 2 10 Posted on Authorea 5 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162552379.93685989/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 0( )Dy174. 2.)626(48 19(89 . (57.2) 2.9 (36.6) 2.2 (103.1) (18.9) 1.3 11.9 (32.4) 14.3 (24.8) 682.6 (26.6) 15.4 (20.8) 192.6 (21.1) 7943.9 (25.1) 117.4 (25.2) 1892.9 (20.4) 1171.4 1 Day 1 Day 1 9) Day = (n 40 7) = (37.4) (n 2.8 11 Visit (28.6) 3.4 (77.5) (78.6) 1.4 9) 1.5 = (n 5 (87.6) (103.4) 1.1 1.3 (mg) Dose (22.1) 11.1 (19.3) 11.8 (17.8) (7.5) 11.2 12.0 (44.6) 11.2 (46.4) dose) 9.8 mg (40 (21.2) days 2938.0 7 for (19.1) and 2132.5 doses) (19.4) 1272.3 4 (26.8) TABLE 635.4 (28.1) t 214.0 (15.2) half-life; (10.9) 46844.6 phase 111.0 (26.1) 36478.0 C (28.7) 17257.9 AUC Abbreviations: (22.2) 9441.8 (34.5) 2305.3 (51.9) 1247.2 6) = (n 180 6) = (n 120 6) = (n 60 5) = (n 30 6) = (n 10 6) = (n 5 (mg) Dose a 2 TABLE (17) 2 (7) (%) 2 n drug, study to (17) related 3 AE any with participants of Number (33) 4 (59) 16 (%) (44) n 8 AE, any with participants of Number 12) = (N C Part AL 3 TABLE event. adverse AE, viation: nldsoeptetwt rghypersensitivity. drug with patient one Includes max, b a a a a aiu bevdcnetain V,btenpriiatceceto aito;t variation; of coefficient between-participant CVb, concentration; observed maximum b umr favreevents adverse of Summary hraoiei aaeesfloigGK497Asnl rldose oral single GSK3439171A following parameters Pharmacokinetic hraoiei aaeesfloigGK497Arpa oigfr1 as( n 1mg 11 and (5 days 14 for dosing repeat GSK3439171A following parameters Pharmacokinetic max ieo curneo aiu bevdconcentration. observed maximum of occurrence of time , a 71810(17 063(43 09(84 . (22.1) 2.8 (28.6) 2.4 (54.2) 2.3 (18.4) 10.9 (11.3) 11.6 (24.3) 1016.3 (23.8) 13.3 (28.0) 243.9 (21.7) 11851.0 (19.3) 138.1 (34.0) 2903.3 (24.3) 1627.4 17 Day 17 Day 17 Day (0–inf) (%CVb) mean, geometric (ng.h/mL), AUC raudrcnetaintm uv rmtm eoetaoae oifiietime; infinite to extrapolated zero time from curve concentration-time under area , (0–inf) (%CVb) mean, geometric (νγ.η/μΛ), ΑΥ῝ (0–τ) (%CVb) mean, geometric C max b α nldstoptet ihdu yesniiiy Abbre- hypersensitivity. drug with patients two Includes 11 (ng/mL), (%CVb) mean, geometric (ng/mL), C max t (%CVb) mean, geometric 1/2 (h), t (%CVb) mean, geometric 1/2 (h), (%CVb) mean, geometric T max 1/2 terminal , (h), (%CVb) mean, geometric T max (h), Posted on Authorea 5 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162552379.93685989/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. iue1 td design Study 1. Figure t half-life; phase C AUC Abbreviations: = 11) (n fed mg 60 = 11) (n fasted mg 60 (mg) Dose C AUC Abbreviations: a AL 5 TABLE t 1/2 eest taysaeAUC steady-state to Refers max, max, emnlpaehl-ie t half-life; phase terminal , aiu bevdcnetain V,btenpriiatceceto aito;Q,oc daily; once QD, variation; of coefficient between-participant CVb, concentration; observed maximum aiu bevdcnetain V,btenpriiatceceto aito;t variation; of coefficient between-participant CVb, concentration; observed maximum hraoiei aaeesfloigsnl-oeGK497Ai e essfse state fasted versus fed in GSK3439171A single-dose following parameters Pharmacokinetic max ieo curneo aiu bevdconcentration. observed maximum of occurrence of time , (0–τ) (0–inf) 49. 2.)12 2.)1. 1.)32(34.2) 3.2 (54.5) 2.5 (19.7) 11.7 (13.7) 10.8 (21.2) 1025 (16.3) 1156 (29.7) 14995.0 (27.4) 16458.9 (%CVb) mean, geometric (νγ.η/μΛ), ΑΥ῝ raudrcnetaintm uv rmtm eot h n ftedsn period; dosing the of end the to zero time from curve concentration-time under area , raudrcnetaintm uv rmtm eoetaoae oifiietime; infinite to extrapolated zero time from curve concentration-time under area , (0–τ) (0–τ) max 1 tDy1 o gad1 gQ oe n a 0fr4 gdose. mg 40 for 10 Day and dose, QD mg 11 and mg 5 for 17 Day at ieo curneo aiu bevdconcentration. observed maximum of occurrence of time , (%CVb) mean, geometric C max 12 (ng/mL), t (%CVb) mean, geometric 1/2 (h), (%CVb) mean, geometric T max 1/2 terminal , (h), Posted on Authorea 5 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162552379.93685989/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. inhibitor-in-healthy-adult-participants 1-study-of-single-and-repeat-oral-doses-of-gsk3439171a-a-highly-selective-h-pgds- 2.pptx Figure file Hosted inhibitor-in-healthy-adult-participants 1-study-of-single-and-repeat-oral-doses-of-gsk3439171a-a-highly-selective-h-pgds- 1.pptx Figure file Hosted hr). 24 and hr 12 hr, 8 hr, 6 hr, 4 A). hr, (2 (Part points creatinine-corrected dose time against 6 plotted mg for is baseline 60 GSK3439171A to of single ratio concentration tPGDM a subject, urinary each urinary following For creatinine-corrected baseline subject. versus individual concentration to GSK3439171A ratio of plots tetranor Reference 2. 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