`
`
`
`
`
`
`
`
`
`
`
`
`
`A Randomized, Double-blind,Placebo-Controlled, Single-, Ascending-, Oral-Dose Safety, TolerabHity and Pharmacok1netk
`
`
`
`
`
`�ge,jte DiseaseWeek,SailllE110: 10(),!
`
`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.
`
`SP-3041mprovesstoolconslsteocy
`Sl'-lll45ing/e-Dosellata
`
`, Subjectsmm�eted a7-daybowa movement diary during
`
`
`
`
`the14-dayscreaiingperiod
`17consecutivedays
`
`, BrlstolStooIFromSca�(BSFS)usedloilS!ISconsisto,cy
`
`of bowel movements
`
`
`
`
`
`
`
`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, I n animal mode�,
`
`
`
`
`
`oral administration of SP-304 promotes inl!stinal secretion
`
`
`
`
`andamelioratesgastrointeslinalinflammat�n.Thepurpose
`
`
`
`
`
`
`
`
`oftl1isstudywastocharacterizethesafely,tolera�lity,
`unltstall
`pharmacoijnetic(PK)andpharmacodynamic(PD)effectsof
`
`
`
`, Olnsistencyofthes1Dolwasgradedbytl1ePhaselunit
`
`SP·304inhealll,yvolunteers.
`
`
`
`staffusingBSFSandwasreconledinadiary
`
`
`
`1Subjectsd1eckedintothePhaselunltldaypriortodosing
`
`, Pre'ilose lab b!Sl5 wae performed to confirm �igibility
`
`
`��·!dffi1l!00!/a,llllllllllllll'DO!i!llli)!lib!f(�art!ffi,f!llllll'DI
`
`
`
`
`
`
`(hematology, blood chemisby, urinalysi� fecal OCOJlt �ood
`
`exam,drugsofaoose)
`
`
`
`
`
`, Subjectswaedosedat9:DOam(fasling)
`
`SP-l04improvesstoolcon;,tency
`, Randomized6:2(adive:p�cebo)
`S/-304Smgle-Dcsella1'
`
`, 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
`
`Metl1ods:Adouble-blind,placelbo-controlled,randomized
`
`
`
`
`
`singl� oral, ascending dose ( 0 ,1 mg to 4&6 mg) study was
`
`
`, Thepurposeofthiswastodlaracterizethesafety,
`
`
`, Cohortl:SP-3040.lmgonceormab:hing�acebo
`
`
`
`performed in 71 healthyvoluntee�. Subjects were
`
`
`tolerabilily, phannacokinet� (PK) and pharmacodynamic
`
`, Cohort2:SP-3040,3mgonceormab:hing�acebo
`
`
`evaluatedforsafety,to�rability,PKandPDeffectsof
`
`
`(PD) effects of SP-304 in healthy voluntee�
`
`, Cohort3:SP-3040,9mgonceormab:hing�acebo
`
`
`
`
`SP· 304, Adverse events (AE) were evaluated using Common
`
`
`
`
`
`
`Tennino�gy Criteria for Adverse Events (CTCAE), version 3,
`
`, Cohort4:SP-3042,7mgonceormab:hing�acebo
`
`
`Pharmacodynamic effects were evaluated by the time to
`
`
`
`, Healthy ma� or female, between 18 and 64 yean of age
`
`
`
`, Cohort5:SP-3045,4mgonceormab:hing�acebo
`, Common Tenninology Criteria for Adverse Events
`
`
`
`
`
`
`firsistoolandbythe7-pointBristolStoolFonnScale(BSFS)
`
`
`with a body mass index (BM!) between 18 and 29 kg/ ml
`
`
`, Cohort6:SP-3048,tmgonceormab:hing�acebo
`
`
`
`(CTCAE), ve��n 3.0, was used to assess all adverse
`
`
`to monitor stool consistency,
`events
`
`, Cohort7:SP-3041Umgonceormab:hingplacelbo
`
`
`
`, Negativetestfordrugsofabuse,hepatitisBandC and
`HIV
`
`, Cohort8 :SP-3042t3mgonceormab:hingplacelbo
`
`
`Results:SP·304waswell-toleratedatalldoseleve�andno
`
`• 12outof63suijects(l9%)reportedmi�AEs
`
`
`
`SAEs were observed throughout the study, No measurab�
`
`, Cohort9:SP-30448.6mgonceormab:hingplacelbo
`
`
`
`, Abstainfromcaffeinatedbeverages,alcoholandnicotine
`
`
`, AIIAEsresolvedwitl1in2houraofdosing
`
`
`
`
`1't51e111icabsolption of oral� administered SP-304 ocamed
`foraper�dof36hou�pre-dosethrough48-hou�
`
`
`atalldoselevelsstudied(O,lmgto48.6mg;validated
`post-dose
`
`
`
`
`
`SP-304 serum assay sensitive down to 10 ng/ ml), Alll,ough
`, Per CTCAE criteria, diarrhea is defined as an inaease in
`
`
`
`
`
`
`Subject Characteristics
`, Abstainfromandhavenoclinicalneedforsupp�mental
`
`
`
`
`
`
`
`
`11,is trial was not powered for statistical significa� SP-304
`
`
`
`
`the number of bowel movements per day compared to
`
`
`fiber30dayspriortostudyentry
`!Im+!!
`
`
`
`
`
`appeared to decrease the time to first bowel movement and
`baseline
`Ii\�
`
`
`elicitedanincreaseinthepost-doseBSFSvellUSp�b�
`
`
`
`
`
`1 All AES resolved will,in 24 hou� of being reported
`
`, Any pre-existing medical condlt�n considered dinically
`
`
`
`
`
`
`
`Condusions: SP-304 was well-to�rated at all doses studied
`
`
`significantbythePrincipallnvestigator(PQ
`
`( 0. 1 mg to 48.6 mg) and exhibited pharmacodynamic
`•• '��
`"'""' ll"'
`
`
`
`
`activity in healthy voluntee� with no detectable systemic
`lt,111:M�III
`
`
`, Cinicallysignificantabnonnallaboratoryresullsat
`
`
`absorpt�n.Theseclinicaldatasupportadvancingtl1isnovel
`lklilpfflrlJli!o
`Screening
`
`
`
`
`Number of AEs Reported with an Assigned Relationship to
`
`
`
`analogofureguan�inforfurtherclinicaldeve�pmentto
`B ristolScoreoffintBowelinvmnt
`SP-304
`
`
`
`, Partkipationinaclinicallrialusinganinvestigat�nal
`
`
`
`treat patients will, CC and IBS-�
`Follov.ingaSingoli<lleofSP-304
`
`drugwitl1in30daysofthe5creeningvisit
`
`...
`
`'��
`11"'1
`
`, NotbasedonchangesinconsistencyaspertheBristol
`
`
`
`StoolfonnScale(BSFS)
`
`41.l+IU!
`
`-�,
`''"'1
`l!li.aJ
`..
`
`
`
`Uroguan�in NaturalHormone
`
`1 lngested,injected,orappliedanypresaiplion,OTC,or
`
`
`
`
`
`herbal medications within 30 days pr�r to Day I dosing
`
`!·�
`
`.
`
`··• ..... _
`
`, SP-304 was safe and well-tolerated aaoss all doses
`
`, Receivedanytreabnentagents,herns,orfoods(e,g,,
`
`
`
`
`• 16-maranalogofuroguan�in
`
`
`
`
`
`grapefnlitjuice) known to inhibit or induce enzymes
`NDOCELCVHVAC1GCJ.
`
`withinthecytod1romeP4SOsystem,witl1in7daysprior
`
`.. Singlekeyaminoacidchange
`�
`to Day I dosing
`.. udedintostableai:tive
`* Dianhea is defined as an increase in the number of bowel
`
`
`
`
`confonner
`'1
`, Takenanyclassofphosphodiesteraseinhibito�witl1in3
`
`
`
`
`
`movements pe,-day compared to baseline
`SP-304 Sl�o<Ole data In �lunleeo
`
`
`
`
`dayspriortoDayldosing
`
`SP-304 Urofllln/inAna,g
`Allrajl'rillle!G/il!IOOll'ft!IIOl'!lnlliruu!IIUl!rpait-!ilst
`
`
`
`
`, Any e�sode of abnonnal bowel habit ( e.g., constipation
`NDECELCVNVACTGCL
`eCompactstablemolecule
`
`
`ordiarrhea)witl1in30daysofDayl
`�
`
`
`
`• Th•moandacidstablellOOC,pH
`
`
`
`
`, F ailure to com�ete the Screening bow� movement diary
`
`
`2),highresistancetoproteases
`I NoSAEs
`
`aa:uratelyandcomplete�for7conserutivedays(during
`,,
`,. F,
`
`
`• Behaveslikeasmallmolec,ledrug
`
`
`
`, Noseveredianheaevenatveryhighdoses
`
`thel4daySaeeningperiod)prior toDayldosing
`GC-C Receptor
`!,
`
`
`.. Morepotentthanthenatural
`
`
`, NosystemicabsorptionoforallyadministeredSP.304
`l
`, Donation of blood �I �nt) witl1in 8 weeks, donation of
`
`
`
`
`
`llonnone
`
`
`
`
`
`, SP-304 decreased the time to first bowel movement and
`Single!ell!rsdeootedifferen!amiiio
`
`
`
`
`
`
`plasma witl1in 2 weeks prior to the Screening visi� or
`aci!ls Col.m<!inesdeno+.ed��philla
`
`increasedtheBristol(BSFS)score
`
`
`
`
`
`
`receipt of blood products witl1in 8 weeks prior to Day I
`
`.,.
`
`IIIO,IH11lDJ ll " U 1UIU U
`
`Bausch Health Ireland Exhibit 2003, Page 1 of 1
`Mylan v. Bausch Health Ireland - IPR2022-01105
`
`