A randomised, multicentre, double-blind, placebo-controlled study of a targeted release oral ciclosporin formulation in the treatment of mild to moderate ulcerative colitisEfficacy resultsS. Bloom, T. Iqbal, C. Nwokolo, M. Smith, D. O'Donoghue, J. Hall, B. Dzyngel

Copenhagen, Denmark, March 08 2019

Disclosure• Advisory boards for Pfizer, Takeda, Johnson & Johnson, Shire, Janssen.

Background• Ciclosporin:

• Effective treatment for acute severe ulcerative colitis• Impact on disease activity comparable to the anti-TNF agent, infliximab1,2

• Concerns regarding systemic toxicities

• ST-0529:• Novel orally-administered, low dose, controlled release formulation of

ciclosporin• Utilises multiparticulate beads coated with polymers which allow the

release of the drug in the ileum and colon• Released luminally on colonic epithelial cells to reduce systemic absorption• Acts topically with limited systemic bioavailability• Phase 1 dose-ranging study demonstrated improved tissue concentrations

when given twice daily3

1. Williams J, Alam M, Alrubaiy L et al. Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial. Lancet Gastroenterol Hepatol. 2016;1(1):15-24. doi:10.1016/s2468-1253(16)30003-6.2. Ordás I, Domènech E, Mañosa M et al. Long-Term Efficacy and Safety of Cyclosporine in a Cohort of Steroid-Refractory Acute Severe Ulcerative Colitis Patients from the ENEIDA Registry (1989–2013): A Nationwide Multicenter Study. Am J Gastroenterol. 2017;112(11):1709-1718. doi:10.1038/ajg.2017.180.3. Sigmoid Pharma. PK, Safety & Tolerability of CyCol® Versus Sandimmune® in Healthy Subjects (CYC102). Available from: https://clinicaltrials.gov/ct2/show/study/NCT02130414?term=CYC+102&rank=1. Last updated 2015. ClinicalTrials.gov Identifier: NCT02130414. Accessed November 8, 2018.

BackgroundA Solution In A Solid Oral Dosage Form

ST-0529 involves:

• Pre-solubilising active pharmaceutical ingredients (“API”) into a solution

• Extruding the resulting liquid into a cooling mixture

• Forming a spherical solid of between 1–2 mm in diameter, within which liquid droplets are dispersed

uniformly

• Coating the minisphere to enable targeted delivery to specific regions of the gastro-intestine

• Encapsulating the minispheres into capsules

CrystallineSolid Drug

Solvent & solubilisers added

Solubilised Drug Solubilised drug is dispersed within aqueous phase. Mixture is converted

to minispheres

Drug in liquid droplets within minispheres in dosage form

Fluid bed coating for targeted release

Methods• Multicentre study in 26 centres in Ireland and UK

• Diagnosis of mild (baseline mUCDAI <6) to moderate (baseline mUCDAI ≥6) ulcerative colitis

• mUCDAI of 4 to 10 inclusive of mucosal sub-score ≥1

• Patients with severe of fulminant UC, colitis limited to the rectum, topical treatment within 4 weeks, steroids in a dose higher than 10 mg/day within 4 weeks of baseline, or biologics administered within 2 months, were excluded from the study

• Concomitant UC medication allowed (i.e. 5-aminosalicylates, low dose steroids, and immunosuppressives)

• 4-week treatment duration with week 8 follow-up visit

mUCDAI, Modified Ulcerative Colitis Disease Activity Index.1. Schroeder KW, Tremaine WJ, Ilstrup DM. N Engl J Med. 1987;317(26):1625-1629; 2. Lichtenstein GR, Kamm MA, Sandborn WJ, Lyne A, Joseph RE. Aliment Pharmacol Ther. 2008;27(11):1094–102.

Symptom Normal(Score = 0)

Mild(Score = 1)

Moderate(Score = 2)

Severe(Score = 3)

Traditional Mayo Endoscopic Subscore1

Rectal Bleeding None Streaks of blood Obvious blood Mostly blood Idem

Stool Frequency Normal 1-2/day >normal 3-4/day >normal >4/day >normal Idem

MucosalAppearance Normal

Erythema; decreased vascular pattern; no

friability

Marked erythema; absent vascular

pattern; friability; erosions

Ulceration; spontaneousbleeding

Differs in the mild score:

Erythema, decreased vascular pattern, mild

friability

Physician’s GlobalAssessment Normal Mild Moderate Severe Idem

Modified Ulcerative Colitis Disease Activity Index Scoring2

MethodsPrimary endpoint: Efficacy in inducing clinical remission (mUCDAI score ≤2, with no individual score >1 and rectal bleeding subscore of 0 or 1)

PlaceboN=65

RandomisedN= 118

ST-0529 (75 mg OD)N=53

RSecondary endpoints: clinical response, mucosal and histological healing, safety and tolerability.

Demographic variable ST-0529 75 mg(N=53)

Placebo(N = 65)

Sex, n (%)

Male 28 (52.8) 39 (60.0)

Age (years) (derived)a

Mean ± SD 41.9 ± 14.63 43.8 ± 13.99

Weight (kg)

Mean ± SD 74.9 ± 13.82 78.0 ± 16.62

Time since onset of UC [years] (derived)b

Mean ± SD 6.14 ± 5.47 9.60 ± 7.51

mUCDAI – Total Patient Score

Mean ± SD 7.2 ± 1.81 7.5 ± 1.72

Baseline Demographic Characteristics

mUCDAI, Modified Ulcerative Colitis Disease Activity Index. OD, once daily.aCalculated from screening date; bCalculated from date of first dose.

Disposition of the subjects (n=118)

All randomised subjectsaReported as single reason or in combination with other reasons.

Number of subjects (%)

ST-0529 75 mg(n=53)

Placebo(n=65)

Completed Study 43 (81.1) 42 (64.6)

Discontinued Study Prematurely 10 (18.9) 23 (35.4)

Reason for Discontinuationa

Adverse Event 6 (11.3) 16 (24.6)

Lack of Efficacy 4 (7.5) 5 (7.7)

Other 0 1 (1.5)

Unknown 0 1 (1.5)

Results

6.3%

13.2%

0%

10%

20%

30%

40%

Remission (N=117)

Prop

ortio

n of

sub

ject

s

18.5%

30.2%

0%

10%

20%

30%

40%

Response (N=117)

Prop

ortio

n of

sub

ject

s

n=4/65 n=7/53 n=12/65 n=16/53

ITT population; mUCDAI, Modified Ulcerative Colitis Disease Activity Index.Remission: mUCDAI score ≤2, with no individual subscore >1 and a rectal bleeding subscore of 0 or 1 at Week 4; Response: Reduction in mUCDAI score of ≥3 at Week 4 with a decrease in the rectal bleeding subscore of ≥1, or with an absolute rectal bleeding subscore of 0 or 1.

Remission (n=118) Response (n=118)

p=0.2175

p=0.1915

Placebo

ST-0529

Clinical Remission and Response

Results

ITT population; mUCDAI, Modified Ulcerative Colitis Disease Activity Index.*Statistically significant; †Subjects with mUCDAI score ≥6, regardless of baseline therapy.Response: Reduction in mUCDAI score of ≥3 at Week 4.

18.5% 17.0%

30.2%

35.0%

0%

10%

20%

30%

40%

Overall treatment population (N=117) Sub-population with moderate disease, variedtherapy (n=93)

Prop

ortio

n of

sub

ject

s

p=0.1915 p=0.0499*

Overall Treatment Population

mild and moderate disease, varied therapy (n=118)

Subpopulationmoderate disease, varied

therapy† (n=93)

n=12/65 n=16/53 n=9/53

n=14/40

n=14/40

Placebo

ST-0529

Post hoc Subgroup Analysis: Response in Different Populations

Results

Number of subjects (%)

Treatment-emergent AE ST-0529 75 mg (n=53) Placebo (n=65)

Any TEAE 41 (77.4) 53 (81.5)

Treatment-related TEAEa 11 (20.8) 18 (27.7)

Severe TEAEb 13 (24.5) 13 (20.0)

Death 0 0

TE SAE 5 (9.4) 5 (7.7)

Treatment-related TE SAE 0 1(1.5)

TEAE leading to discontinuation 6 (11.3) 15 (23.1)

a Each subject was counted only once as the strongest relationship of any event for that subject. b Each subject was counted only once as the maximum intensity of any event for that subject.Safety population. All AEs with onset on or after first dosing or that worsened after first dosing are considered TEAEs.AE, adverse event; SAE, serious adverse event; TE, treatment emergent; TEAE, treatment emergent adverse event

Overall Summary of Treatment-Emergent Adverse Events

Listing of Subjects Who Reported a Serious Adverse Event

F = female; M = male; SAE = serious adverse event; Unk = unknowna Relative to the first dose of study treatment.b Investigator considered the event to be probably related to study treatment.

Subject ID[Age(yrs)/Sex]

SAE Preferred Term Start Date (Daya) Stop Date (Daya) Intensity Outcome Relationship

ST-0529 75 mg

1608 [63/M]

Liver function test abnormal 29-Oct-2010 (43) 16-Nov-2010 (61) Severe Resolved with sequelae Not related

Lower respiratory tract infection 29-Oct-2010 (43) Nov-2010 (Unk) Severe Resolved completely Not related

Gallbladder polyp 29-Oct-2010 (43) Unk Severe Ongoing Not related

1701 [20/M]

Colitis ulcerative 21-Nov-2010 (3) 29-Nov-2010 (11) Severe Resolved with sequelae Not related

Therapeutic response decreased 03-Dec-2010 (15) 09-Dec-2010 (21) Severe Resolved with sequelae Not related

Colectomy 21-Nov-2010 (3) 29-Nov-2010 (11) Severe Resolved with sequelae Not related

1704 [46/F]Body temperature increased 20-Mar-2011 (4) 23-Mar-2011 (7) Moderate Resolved completely Not related

Pyelonephritis 24-Mar-2011 (8) 26-Mar-2011 (10) Moderate Resolved completely Not related

3602 [21/F] Colitis ulcerative 22-Sep-2010 (4) Sep-2010 (Unk) Severe Resolved completely Not related

3901 [37/F] Colitis ulcerative 22-Dec-2010 (53) 06-Jan-2011 (68) Moderate Resolved with sequelae Not related

Placebo

1102 [61/M] Colitis ulcerative 04-May-2010 (6) Unk Severe Ongoing Not related

1901b [18/F] Colitis ulcerative 24-Jul-2010 (17) 30-Jul-2010 (23) Severe Resolved completely Possibly related

3201 [27/M] Colitis ulcerative 27-Sep-2010 (10) Unk Severe Ongoing Not related

3606 [33/F] Colitis ulcerative 15-Jan-2011 (28) 31-Jan-2011 (44) Moderate Resolved completely Not related

4801 [30/M]Colitis ulcerative Apr-2011 (Unk) 15-Apr-2011 (66) Severe Resolved completely Not related

Frequent bowel movements Feb-2011 (Unk) 15-Apr-2011 (66) Severe Resolved completely Not related

Limitations

• Imbalance in randomisation between placebo and active drug

• Short term study (four weeks)

• No data collected at week 8 (follow-up period)

• Early discontinuation within the first two weeks

• Only single low dose of ST-0529 was tested

• Early formulation used in trial: substantial refinement has taken place and a new formulation being used in ongoing phase 2 trial

Conclusions

Safety and tolerability

ST-0529 75 mg OD was safe and well tolerated

after 4 weeks of treatment

5-ASA, 5-aminosalicylates; OD, once daily; UC, ulcerative colitis.*Not statistically significant

Remission rate

ST-0529 75 mg OD showed a numerically higher difference* in patients with mild to

moderate UC vs. placebo after 4 weeks of

treatment

Post hoc analysis

ST-0529 75 mg OD showed statistically significant clinical response rate vs.

placebo inmoderate UC patients

These preliminary data support further development of ST-0529 as a treatment for the induction and maintenance of remission in UC patients with moderate disease