A Randomized, Double-blind,Placebo-Controlled, Single-, Ascending-, Oral-Dose Safety, Tolerability and Pharmacokinetic
`Study of SP-304 in Healthy Adult Human Male and Female Volunteers
`Kunwar Shailubhai, Ph.D., William Gerson, D.O., Craig Talluto, Ph.D., Gary Jacob, Ph.D.
`
`DigfSiveDiseaseWllek.Sanlliego:1008,
`
`Purpose: SP·304 is a synthetic analog of uroguan~in, a
`nabiuretic honnone that regulab!s ion and fluid transport in
`the GI tract The compound is a new member of a novel
`class of non-systemic drugs for treabnent of chronic
`constipation (CC), irritable bowel syndrome with
`constipation (IBS-C) and other GI diseases. Orally
`administered SP-304 binds to and activates gua~ab!
`cyclase C (GC-C), expressed on the epithelial cells lining the
`GI mucosa, Activation of GC·C stimulates intracellular cyclic
`GMP synthesi~ resulting in activation of cystic fibrosis
`transmembrane conductance regulalDr (CFTR), whidl leads
`to an augmented flow of chloride and wab!r into the lumen
`of the gut to facilitate bowel movement In animal models,
`oral administration of SP·304 promotes inb!stinal secretion
`and ameliorab!s gastrointestinal inflammation. The purpose
`of this study was to characterize the safety, tolerability,
`phannacokinetic (PK) and pharmacodynamic (PD) effects of
`SP-304 in healthy volunb!ers.
`
`Methods: A double-blind, placebo-controlled, randomized
`single, oral, ascending dose (0.1 mg to 48.6 mg) study was
`performed in 71 healthy volunteers, Subjects were
`evaluab!d for safety, tolerability, PK and PD effects of
`SP-304. Adverse events (AE) were evaluab!d using Common
`Tenninology Crib!ria for Adverse Events (CTCAE), version 3.
`Pharmacodynamic effects were evaluated by the time ID
`first stool and by the 7-point Bristol Stool Form Sc.ale (BSFS)
`to monitor stool consistency.
`
`Results: SP-304 was well-tolerated at all dose levels and no
`SAEs were observed throughout the study, No measurab~
`systemic absorption of orally administered SP-304 occurred
`at all dose levels studied (0.1 mg ID 48.6 mg; validab!d
`SP·304 serum assay sensitive down to 10 ng/ml), Although
`this trial was not powered for statistical significance, SP-304
`appeared to deaease the time to first bowel movement and
`elicited an inaease in the post-dose BSFS versus placebo,
`
`Conclusions: SP-304 was well-tolerab!d at all doses studied
`(0.1 mg ID 48.6 mg) and exhibited pharmacodynamic
`activity in healthy volunteers with no detectable systemic
`absorption. These clinical data support advancing this novel
`analog of urogua~in for further clinical development to
`treat patients with CC and IBS-C,
`
`Uroguanylin Na~ralHonnone
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`SP-304 Uroguan~inAnalog
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`, Compact stable molecule
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`21,highresistancetoproteases
`• Behaveslikeasmallm~eculedrug
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`1 The purpose of this was to characterize the safety,
`tolerability, pharmacokinetic (PK) and pharmacodynamic
`(PD) effects of SP-304 in healthy volunb!ers
`IIIIIIMIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
`1 Healthy male or female, between 18 and 64 years of age
`with a body mass index (BM!) between 18 and 29 kg/m2
`1 Negative test for drugs of abuse, hepatitis Band C and
`HIV
`1 Abstain from caffeinab!d beverages, alcohol and nicotine
`for a period of 36 hours pre-dose throogh 48-hours
`post-dose
`1 Abstain from and have no clinical need for supplemental
`fiber 30 days prior to study entry
`
`1 Any pre-existing medical condition considered dinical~
`significant by the Principal Investigator (Pl)
`1 Clinical~ significant abnormal laboratory results at
`Screening
`1 Participation in a clinical trial using an investigational
`dnig within 30 days of the Screening visit
`1 Ingested, injected, or applied any prescription, OTC, or
`herbal medications within 30 days prior to Day 1 dosing
`1 Received any treabnent age~ herbs, or foods (e.g.,
`grapefruit juice) known to inhibit or induce enzymes
`within the cytochrome P450 sysb!m, within 7 days prior
`to Day 1 dosing
`1 Taken any cla55 of phosphodiesb!rase inhibitors within 3
`days prior ID Day 1 dosing
`1 Any episode of abnormal bowel habit (e.g., constipation
`or diarrhea) within 30 days of Day 1
`1 Failure to complete the Screening bowel movement diary
`accurately and complete~ for 7 consecutive days (during
`the 14 day Screening period) prior ID Day 1 dosing
`1 Donation of blood ~1 pint) within 8 weeks, donation of
`plasma within 2 weeks prior to the Screening visi~ or
`receipt of blood products within 8 weeks prior to Day 1
`
`1 Subjects mmpleted a 7-day bowel movement diary during
`the 14-day saeening period
`, 7 consecutive days
`, Bristol Stool From Sf.ale (BSFS) used to asses consisb!ncy
`of bowel movements
`1 Subjects dlecked into the Phase 1 unit 1 day prior to dosing
`1 Pre-dose iab tests were performed to confirm eligibility
`(hematology, blood chemisby, urinalysis, fecal occult blood
`exam, drugs of abuse)
`1 Randomized 6:2 (active:placebo)
`1 Su~ects were dosed at 9:00am (fasting)
`1 PK blood draws were taken pre-dose and 0.5, ~ 1.5, ~ 3, 4,
`6, 8, 1~ 24, 36 and 48 hours post-dose
`1 All post-dose bowel movements were reported to Phase I
`unitstaff
`, Consistency of the stool was graded by the Phase I unit
`staff using BSFS and was recorded in a diary
`
`1 Cohort 1: SP-304 0.1 mg once or matching placebo
`1 Cohort 2: SP-304 0.3 mg once or matching placebo
`1 Cohort 3: SP-304 0.9 mg once or matching placebo
`1 Cohort 4: SP-304 2.7 mg once or matching placebo
`1 Cohort 5: SP-304 5,4 mg once or matching placebo
`1 Cohort 6: SP-304 8.1 mg once or matching placebo
`1 Cohort 7: SP-30416.2 mg once or matdling piacebo
`1 Cohort 8: SP-304 24.3 mg once or matdling piacebo
`1 Cohort 9: SP-304 48,6 mg once or matdling piacebo
`
`Subject Characteristics
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`1 Common Terminology Crib!ria for Adverse Events
`(CTCAE), version 3.0, was used to assess all adverse
`events
`1 12 out of 63 su~ects (19%) reported mild AEs
`1 All Afs resolved within 2 hours of dosing
`1 All AEs resolved within 24 hours of being reported
`1 Per CTCAE criteria, diarrhea is defined as an inaease in
`the number of bowel movements per day compared to
`baseline
`1 Not based on changes in consistency as per the Bristol
`Stool form Sc.ale (BSFS)
`
`Number of Afs Reported with an Assigned Relationship ID
`SP·304
`
`* Diarrhea is defined as an inirease in the number of bowel
`movements per day compared ID baseline
`
`1 SP-304 was safe and well·tolerab!d across all doses
`1 NoSAEs
`1 No severe dianhea even at very high doses
`1 No systemic absorption of orally administered SP-304
`1 SP-304 decreased the time to first bowel movement and
`increased the BrislDI (BSFS) score
`
`Bausch Health Ireland Exhibit 2003, Page 1 of 1
`Mylan v. Bausch Health Ireland - IPR2022-01102
`
`