UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

 

Form 6-K

 

Report of Foreign Private Issuer

Pursuant to Rule 13a-16 or 15d-16

under the Securities Exchange Act of 1934

 

April 2019

 

Commission file number: 001-36288

 

Akari Therapeutics, Plc

(Translation of registrant's name into English)

 

75/76 Wimpole Street

London W1G 9RT

United Kingdom

(Address of principal executive offices)

 

Indicate by check mark whether the registrant files or will file annual reports under cover of Form 20-F or Form 40-F.

 

Form 20-F  x       Form 40-F ¨

 

Indicate by check mark if the registrant is submitting the Form 6-K in paper as permitted by Regulations S-T Rule 101(b)(1):_____

 

Indicate by check mark if the registrant is submitting the Form 6-K in paper as permitted by Regulations S-T Rule 101(b)(7):_____

 

 

 

 

CONTENTS

 

Further to a Form 6-K of Akari Therapeutics Plc dated April 26, 2019, on April 28, 2019, a poster presentation was made at the Association for Research in Vision and Ophthalmology annual meeting in Vancouver titled “Targeting the leukotriene B4 pathway and/or complement C5 via dual-functional recombinant coversin (nomacopan) in Experimental Autoimmune Uveitis (EAU)”. A copy of the poster is attached hereto as Exhibit 99.1.

  

Exhibit No.

 

99.1	Poster titled “Targeting the leukotriene B4 pathway and/or complement C5 via dual-functional recombinant coversin (nomacopan) in Experimental Autoimmune Uveitis (EAU)”.

 

 

  

 

 

SIGNATURES

 

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned, thereunto duly authorized.

 

	Akari Therapeutics, Plc
	(Registrant)
	By:	/s/ Clive Richardson
	Name:	Clive Richardson
	Interim Chief Executive Officer and Chief Operating Officer

       

Date: April 29, 2019

 

 

 

 

 

 

 

Exhibit 99.1

 

 

Or Targeting the leukotriene B4 pathway and/or complement C5 via dual-functional recombinant coversin(nomacopan) in Experimental Autoimmune Uveitis (EAU) Mali Eskandarpour1, XiaozheZhang1, GrazynaGalatowicz1, Miles Nunn2,3, Wynne Weston-Davies2, Virginia Calder1 1Institute of Ophthalmology, London, United Kingdom. 2Akari Therapeutics plc, London, United Kingdom. 3UCL Haemostasis Research Unit, London UK. m.eskandarpour@ucl.ac.uk Methods EAU:Asdescribed1. Treatments:Forintravitrealadministration,miceweretreatedondays15and18postimmunizationbynomacopan,longactingnomacopan(PAS-nomacopan),longactingLTB4bindingonlynomacopan(PAS-Leukasin),dexamethasone(Maxidex;DEX)orsaline.Fortopicaladministrationthemiceweretreatedtwicedailywith2-5µlofnomacopan,PAS-nomacopan,LTB4bindingonlynomacopan(Leukasin),DEXorsalinefor7days.Diseaseprogressionwasgradedclinicallybyretinalfundoscopypre-andpost-treatmentandscoredhistologically. Immunofluorescence microscopy:FFPE blocks were prepared and analysed as described before1. Tissuedissection:Forretinalflowcytometry,retinallayerswerecollected,minced,filteredandre-suspendedinmediaforexvivostimulation(PMA&Ionomycine,4hours)andstainedforcellsurfaceandintracellularmarkers1. Results Intravitreal (IVT) administration of Nomacopanand long acting versions WefoundthatPAS-LeukasinmitigateddiseaseprogressionpostIVTadministrationasdeterminedbyclinicalscoring(Figure2A-C;meanscore±SEM;3.81±1.01;n=16)relativetosalinecontrols(12.36±1.01;n=16;P=0.0001). DecreasesinTh17(IL-17A+CD4+)cellsinthenomacopanandPAS-nomacopantreatedgroups(mean%±SEM;14.67±3.53and7.02±3.01respectively,n=8)weredetectedrelativetosalinecontrols(27.47±3.46;n=8;P=0.02and0.0007). Asignificantdecreaseinretinaldouble-positiveTh1/Th17(ROR.t+T-bet+)cells(4.717±2.627;n=8)wasalsoobservedinPAS-nomacopantreatedEAUmiceascomparedtosalinecontrols(21.28±3.54;n=8;P=0.003).aftertwoIVTtreatments(day15and18)(Figures3,4)whiletherewasnosignificantdifferenceintheexpressionlevelsofotherTcellsubsets(datanotshown). Topicaladministrationofnomacopanandlong-actingvariants WefoundthatPAS-Leukasinmitigateddiseaseprogressionposttopicaladministrationasdeterminedbyclinicalscoring(Figure2D;meanscore±SEM;8.08±0.85;n=12)relativetosalinecontrols(10.33±0.67;n=12;P=0.048).However,wedidnotobserveanysignificantchangesinCD4+Tcellnumbersorsubtypesintreatedmice. PresenceofLTB4receptor(BLT1)andC5areceptor(C5aR)ininfiltratingimmunecells ImmunofluorescencestainingofretinaltissuesectionsusingMAbsrecognisingLTB4receptors(BLT1;green)andC5areceptors(red)counterstainedwithDAPI(bluetoindicatenuclei),showedthatbothreceptorsexpressedininflammatorycells.Someindividualcellsco-expressedbothreceptors,whilstmanysinglereceptor-expressingcellswerealsoobserved(Figure5). Cartoon structure of Coversin(nomacopan) determined to 1.9 Åby X-ray crystallography •Bifunctional and equally active on C5 and LTB4 from mice to men •Compact globular 17kDa protein with 3-disulphide bridges •Highly soluble and low viscosity (like water at 150mg/mL) •No post-translational modifications •Clinical efficacy proven with approved products inhibiting C5 (Soliris®) & LTB4 (Zileuton®) •Applicable to many orphan inflammatory diseases where steroids (with their many off-target effects) are SOC •Growing use of combination and bifunctional biotherapeutics in recognition that diseases are multifactorial Figure2.Diseasesuppression;A.Fundoscopicevaluationofdiseasewasperformedonday15(pre-treatment)and22(posttreatment)forindividualeyes(n=16).Onday15and18EAUmiceweretreatedintravitreallywith1-2ulofindicatedconcentrationofcompounds.B.Representativefundusandcorrespondinghistopathologyimages.C.GraphicalsummaryshowinghistologyscorefromIVTtreatedmice(n=3ineachgroup).D.Fundusexaminationforindividualeyes(n=12)after7daysoftopicaltreatmentonday21postimmunization.BarsindicateSDorSEM(histologyandfundusscores,respectively)andtwotailednonparametricttesthasbeenapplied. Reference 1. M Eskandarpour et al. (2017) Pharmacological Inhibition of BromodomainProteins Suppresses Retinal Inflammatory Disease and Downregulates Retinal Th17 Cells. J Immunol. 198(3):1093-1103.2. D A Copland, et al. (2009) Systemic and local anti-C5 therapy reduces the disease severity in experimental autoimmune uveoretinitis. ClinExpImmunol159: 303–314. 3. L Zhang, et al. (2016) Complement anaphylatoxinreceptors C3aR and C5aR are required in the pathogenesis of experimental autoimmune uveitis. J. Leukoc. Biol. 99: 447–454.4. T Liao,eral. (2006) Blockade of the Interaction of Leukotriene B4 with Its Receptor Prevents Development of Autoimmune Uveitis. Invest OphthalmolVis Sci. 47:1543–1549. 5. P Roversi,etal. (2013) BifunctionalLipocalinAmeliorates Murine Immune Complex-induced Acute Lung Injury. J BiolChem26, 288, 18789–18802. Figure 3. Suppression of double-positive ROR.t+T-bet+CD4+T cells. A. Representative retina flow plots on infiltrating cells derived from EAU mice treated intravitreallywith saline control and compared with indicated treatments. B.Graphical summary showing the expression levels ROR.t and T-bet in CD4+T cells. Bars indicate SEM. p=0.003 by two tailed nonparametric t test. The graph shows means of 8 mice in each group (DEX n=6). A B C D A B B A Figure4.SuppressionofIL-17+CD4+Tcells.A.RepresentativeretinaflowplotsoninfiltratingcellsderivedfromEAUmicetreatedintravitreallywithsalinecontrolandcomparedwithindicatedtreatments.B.GraphicalsummaryshowingtheexpressionlevelsIL-17AinCD4+Tcells.BarsindicateSEM.P=0.007andP=0.02bytwotailednonparametricttest.Thegraphshowsmeansof8miceineachgroup(DEXn=6). Figure 5. Immunofluorescentstaining for LTB4 receptor (BLT1, Green), C5aR (Red) on EAU sections. Infiltrating cells captured in vitreous show cells expressing only BLT1 (Green) or C5aR (Red) while there are cells expressing both receptors (yellow). Cells indicated by arrows. LTB4 receptor C5a receptor 20µm 100µm Figure 1 intravitreal;clinicalscore Saline PAS-Leukasin Conclusion ThesedatasuggestthatbothLTB4andtheterminalcomplementpathwaysmaybeimportantintheaetiologyofEAU,andraisethepossibilityofclinicalinterventionwithadualfunctionalmolecule.AdministeredIVTbothofthelong-actingversions(PAS-nomacopanandPAS-Leukasin)appearedtomoreeffectivelydecreaseTeffectorcellsthanunmodifiednomacopan.ThesuggestionthatLeukasinshowedactivityaftertopicaladministrationraisesthepossibilitythatcombinationtherapybyintravitrealinjectionandtopicaldropsmaybeatherapeuticoption. # B0275 Background Non-infectiousposterioruveitis,amajorcauseofblindness,hasanunclearetiology,andmanypatientsfailtorespondtotreatment. UsingtheExperimentalAutoimmuneUveitis(EAU)modelofretinalinflammation,weareabletovalidatetheefficacyofanti-inflammatorydrugs,studythemechanismofdrugactionandlearnmoreaboutocularinflammatorydiseases.Asaresult,itisasuccessfulpreclinicalmodelfortranslationalstudies.Uveitisanditsmousemodelaremultifactorialdiseasescausedbymanycontributingfactorsandinflammatorypathways.Simultaneouslytargetingdifferentpathwaysinvolvedindiseasedevelopmentthereforehassignificanttherapeuticpotential. PreventingthecleavageofC5andgenerationofthemajorpro-inflammatoryfactorsC5aandC5b-9hastherapeuticpotentialtoprotectagainsttissuedamageinorgan-specificimmuneresponsesincludingEAU2.Whilst,targetingtheleukotrieneB4(LTB4)receptor(BLT1)byapplyingaBLT1antagonistinmouseuveitishasbeenshowntosignificantlydownregulatedisease3.Theleukotrienes(LT)arealsoimportantmultifunctionalmediatorsofinflammation. Coversin(nomacopan)isabifunctionalrecombinantproteinderivedfromblood-feedingticksthatspecificallypreventscomplement(C)-mediatedC5activationandalsosequestersleukotrieneB4(LTB4)withinaninternalbindingpocket4(Figure1). Inthisstudywehaveinvestigatedthetherapeuticeffectof: -Nomacopan–inhibitsC5andLTB4 -Variantnomacopan(Leukasin)-inhibitsLTB4only -PAS-nomacopan-long-acting,inhibitsC5andLTB4 -VariantPAS-nomacopan(PAS-Leukasin)-longactingLTB4only Purpose Toexploretheimpactofnomacopan,Leukasinandtheirlong-actingengineeredforms,whenadministeredintravitreallyortopicallyduringactiveEAU.