A Randomized, Double-blind,Placebo-Controlled, Single-, Ascending-, Oral-Dose Safety, TolerabHity and Pharmacok1netk
`Study of SP-3041n Healthy Adult Human Male and Female Volunteers
`Kunwar Shailubhai, Ph.D., William Gerson, D.O., Craig Talluto, Ph.D., Gary Jacob, Ph.D.
`
`~ge,jteDiseaseWeek,SailllE110: 10(),!
`
`Purpose:SP·304isasyntl1eticanalogofureguanylin,a
`natriurelichormonell1atregulal!s~nandfluidtransportin
`the GI tract. The compound is a new member of a novel
`class of non-systemk drugs for treabnent of chronk
`constipation (CC), initable bowel syndrome with
`constipation(IBS-C)andotherGldiseases.Oral~
`administeredSP.304bindstoandactivatesguan~ate
`cydaseC(GC-C),expressedontheepithelialcellsliningll,e
`GI mucosa. Activation of Gc-C slimulal!s intracellu~r cydic
`GMPsynthesis,resumnginactivationofcysticfibrosis
`transmembrane conductance regu~r (CFTR), whid1 leads
`to an augmented flow of dlloride and water into the lumen
`of the gut to facilitate bowel movement, In animal mode~,
`oral administration of SP-304 promotes inl!stinal secretion
`andamelioratesgastrointeslinalinflammat~n.Thepurpose
`oftl1isstudywastocharacterizethesafely,tolera~lity,
`pharmacoijnetic(PK)andpharmacodynamic(PD)effectsof
`SP·304inhealll,yvolunteers.
`
`Metl1ods:Adouble-blind,placelbo-controlled,randomized
`singl~ oral, ascending dose (0,1 mg to 4&6 mg) study was
`performed in 71 healthyvoluntee~. Subjects were
`evaluatedforsafety,to~rability,PKandPDeffectsof
`SP· 304, Adverse events (AE) were evaluated using Common
`Tennino~gy Criteria for Adverse Events (CTCAE), version 3,
`Pharmacodynamic effects were evaluated by the time to
`firsistoolandbythe7-pointBristolStoolFonnScale(BSFS)
`to monitor stool consistency,
`
`Results:SP·304waswell-toleratedatalldoseleve~andno
`SAEs were observed throughout the study, No measurab~
`1't51e111icabsolption of oral~ administered SP-304 ocamed
`atalldoselevelsstudied(O,lmgto48.6mg;validated
`SP-304 serum assay sensitive down to 10 ng/ ml), Alll,ough
`11,is trial was not powered for statistical significa~ SP-304
`appeared to decrease the time to first bowel movement and
`elicitedanincreaseinthepost-doseBSFSvellUSp~b~
`
`Condusions: SP-304 was well-to~rated at all doses studied
`(0.1 mg to 48.6 mg) and exhibited pharmacodynamic
`activity in healthy voluntee~ with no detectable systemic
`absorpt~n.Theseclinicaldatasupportadvancingtl1isnovel
`analogofureguan~inforfurtherclinicaldeve~pmentto
`treat patients will, CC and IBS-~
`
`Uroguan~in NaturalHormone
`
`• 16-maranalogofuroguan~in
`NDOCELCVHVAC1GCJ.
`.. Singlekeyaminoacidchange
`~
`.. udedintostableai:tive
`confonner
`
`'1
`
`SP-304 Urofllln/inAna,g
`
`NDECELCVNVACTGCL
`
`~ ,,
`
`GC-C Receptor
`
`Single!ell!rsdeootedifferen!amiiio
`aci!ls Col.m<!inesdeno+.ed~~philla
`
`.,.
`
`eCompactstablemolecule
`• Th•moandacidstablellOOC,pH
`2),highresistancetoproteases
`• Behaveslikeasmallmolec,ledrug
`.. Morepotentthanthenatural
`llonnone
`
`, Thepurposeofthiswastodlaracterizethesafety,
`tolerabilily, phannacokinet~ (PK) and pharmacodynamic
`(PD) effects of SP-304 in healthy voluntee~
`
`, Healthy ma~ or female, between 18 and 64 yean of age
`with a body mass index (BM!) between 18 and 29 kg/ ml
`, Negativetestfordrugsofabuse,hepatitisBandCand
`HIV
`, Abstainfromcaffeinatedbeverages,alcoholandnicotine
`foraper~dof36hou~pre-dosethrough48-hou~
`post-dose
`, Abstainfromandhavenoclinicalneedforsupp~mental
`fiber30dayspriortostudyentry
`
`, Any pre-existing medical condlt~n considered dinically
`significantbythePrincipallnvestigator(PQ
`, Cinicallysignificantabnonnallaboratoryresullsat
`Screening
`, Partkipationinaclinicallrialusinganinvestigat~nal
`drugwitl1in30daysofthe5creeningvisit
`1 lngested,injected,orappliedanypresaiplion,OTC,or
`herbal medications within 30 days pr~r to Day I dosing
`, Receivedanytreabnentagents,herns,orfoods(e,g,,
`grapefnlitjuice) known to inhibit or induce enzymes
`withinthecytod1romeP4SOsystem,witl1in7daysprior
`to Day I dosing
`, Takenanyclassofphosphodiesteraseinhibito~witl1in3
`dayspriortoDayldosing
`, Any e~sode of abnonnal bowel habit ( e.g., constipation
`ordiarrhea)witl1in30daysofDayl
`, Failure to com~ete the Screening bow~ movement diary
`aa:uratelyandcomplete~for7conserutivedays(during
`thel4daySaeeningperiod)priortoDayldosing
`, Donation of blood ~I ~nt) witl1in 8 weeks, donation of
`plasma witl1in 2 weeks prior to the Screening visi~ or
`receipt of blood products witl1in 8 weeks prior to Day I
`
`, Subjectsmm~eted a7-daybowa movement diary during
`the14-dayscreaiingperiod
`17consecutivedays
`, BrlstolStooIFromSca~(BSFS)usedloilS!ISconsisto,cy
`of bowel movements
`1Subjectsd1eckedintothePhaselunltldaypriortodosing
`, Pre'ilose lab b!Sl5 wae performed to confirm ~igibility
`(hematology, blood chemisby, urinalysi~ fecal OCOJlt ~ood
`exam,drugsofaoose)
`, Randomized6:2(adive:p~cebo)
`, Subjectswaedosedat9:DOam(fasling)
`, PK blood draws we~ taken pre-dose and 0,5, I, 1.5, ~ 3, 4,
`6,8,1~2~36and48hounpost-dose
`, All post-dose bowel movements were reported to Phase I
`unltstall
`, Olnsistencyofthes1Dolwasgradedbytl1ePhaselunit
`staffusingBSFSandwasreconledinadiary
`
`, Cohortl:SP-3040.lmgonceormab:hing~acebo
`, Cohort2:SP-3040,3mgonceormab:hing~acebo
`, Cohort3:SP-3040,9mgonceormab:hing~acebo
`, Cohort4:SP-3042,7mgonceormab:hing~acebo
`, Cohort5:SP-3045,4mgonceormab:hing~acebo
`, Cohort6:SP-3048,tmgonceormab:hing~acebo
`, Cohort7:SP-3041Umgonceormab:hingplacelbo
`, Cohort8:SP-3042t3mgonceormab:hingplacelbo
`, Cohort9:SP-30448.6mgonceormab:hingplacelbo
`
`Subject Characteristics
`
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`BristolScoreoffintBowelinvmnt
`Follov.ingaSingoli<lleofSP-304
`
`SP-3041mprovesstoolconslsteocy
`Sl'-lll45ing/e-Dosellata
`
`~~·!dffi1l!00!/a,llllllllllllll'DO!i!llli)!lib!f(~art!ffi,f!llllll'DI
`
`SP-l04improvesstoolcon;,tency
`S/-304Smgle-Dcsella1'
`
`, Common Tenninology Criteria for Adverse Events
`(CTCAE), ve~~n 3.0, was used to assess all adverse
`events
`• 12outof63suijects(l9%)reportedmi~AEs
`, AIIAEsresolvedwitl1in2houraofdosing
`1 All AES resolved will,in 24 hou~ of being reported
`, Per CTCAE criteria, diarrhea is defined as an inaease in
`the number of bowel movements per day compared to
`baseline
`, NotbasedonchangesinconsistencyaspertheBristol
`StoolfonnScale(BSFS)
`
`Number of AEs Reported with an Assigned Relationship to
`SP-304
`
`SP-304 Sl~o<Ole data In ~lunleeo
`Allrajl'rillle!G/il!IOOll'ft!IIOl'!lnlliruu!IIUl!rpait-!ilst
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`
`* Dianhea is defined as an increase in the number of bowel
`movements pe,- day compared to baseline
`
`, SP-304 was safe and well-tolerated aaoss all doses
`I NoSAEs
`, Noseveredianheaevenatveryhighdoses
`, NosystemicabsorptionoforallyadministeredSP.304
`, SP-304 decreased the time to first bowel movement and
`increasedtheBristol(BSFS)score
`
`Bausch Health Ireland Exhibit 2003, Page 1 of 1
`Mylan v. Bausch Health Ireland - IPR2022-01104
`
`