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Low discontinuation rates

due to treatment-emergent adverse events that are comparable to placebo1a

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Rates of serious infection were low and comparable to placebo in clinical trials2bc

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Demonstrated safety profile

and long-term safety data observed for over 4 years1-3

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aOverall rates of discontinuation were 6.5% with ZEPOSIA (N=429) vs 11.1% with placebo (N=216) in the induction phase, and 20% with ZEPOSIA (N=230) vs 45.4% with placebo (N=227) in the maintenance phase. Discontinuation rates due to TEAEs in induction were 3.3% for patients taking ZEPOSIA vs 3.2% for patients taking placebo. In maintenance, TEAE discontinuation rates were 1.3% for patients taking ZEPOSIA vs 2.6% for patients taking placebo.1,2

bOverall rates of infection were 9.9% with ZEPOSIA (N=496) vs 10.7% with placebo (N=281) in the induction phase, and 23% with ZEPOSIA (N=230) vs 12% with placebo (N=227) in the maintenance phase. Serious infection rates in the induction phase (UC Study 1 and UC Study 3/TOUCHSTONE) were 0.8% with ZEPOSIA vs 0.4% with placebo. Serious infection rates in the maintenance phase were 0.9% with ZEPOSIA vs 1.8% with placebo.2

cAdditional data from the induction period of a randomized, double-blind, placebo-controlled study (UC Study 3/TOUCHSTONE) included 67 patients who received ZEPOSIA 0.92 mg once daily.2

Adverse Reactions With an Incidence of at Least 2% in ZEPOSIA-Treated Patients and at Least 1% Greater Than Placebo in Patients With UC (Pooled UC Study 1 and Study 3)2
Induction (UC Study 1 and Study 3)d
Adverse Reaction
ZEPOSIA
0.92 mg
(n=496)gh
Placebo
(n=281)g
Upper Respiratory Infectione 5% 4%
Liver Test Increasedf 5% 0%
Headache 4% 3%
Pyrexia 3% 2%
Nausea 3% 2%
Arthralgia 3% 1%
Adverse Reactions With an Incidence of at Least 4% in ZEPOSIA-Treated Patients and at Least 1% Greater Than Placebo in Patients With UC (UC Study 2)2
Maintenance
(UC Study 2)
Adverse Reaction
ZEPOSIA
0.92 mg
(n=230)
Placebo
(n=227)
Liver Test Increasedi 11% 2%
Headache 5% <1%
  • dAdditional data from the induction period of a randomized, double-blind, placebo-controlled study (UC Study 3/TOUCHSTONE) included 67 patients who received ZEPOSIA 0.92 mg once daily.2
  • eIncludes the following terms: streptococcal pharyngitis, pharyngotonsillitis, bacterial pharyngitis, nasopharyngitis, upper respiratory tract infection, pharyngitis, sinusitis, tonsillitis, viral upper respiratory tract infection, laryngitis, acute sinusitis, catarrh, chronic sinusitis, upper respiratory tract inflammation, chronic tonsillitis, viral pharyngitis, viral sinusitis, bacterial sinusitis, bacterial upper respiratory tract infection, viral labyrinthitis, laryngeal inflammation, and pharyngeal inflammation.2
  • fIncludes the following terms: gamma-glutamyl transferase increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hyperbilirubinemia, liver function test increased, blood alkaline phosphatase increased, and transaminases increased.2
  • gPercentages were calculated as the sum of each individual study percentage multiplied by its Cochran-Mantel-Haenszel weight.2
  • hZEPOSIA was initiated with a 7-day titration.2
  • iIncludes the following terms: gamma-glutamyl transferase increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hyperbilirubinemia, liver function test increased, and blood alkaline phosphatase increased.2

UC Study 3 (8-week induction): TOUCHSTONE is a phase 2, multicenter, randomized, double-blind, placebo- controlled parallel-group study to evaluate the clinical efficacy and safety of induction therapy with ZEPOSIA in 199 patients with moderately to severely active UC. Participants who completed the induction period and were responders at Week 8 continued to receive the same dose of ZEPOSIA during the maintenance period up to Week 32.4

For full study design of UC Study 1 and Study 2, click here.

Adverse Events From TRUE NORTH (UC Study 1) Induction Period1
ZEPOSIA 0.92 mg
(n=429)
Placebo
(n=216)
Adverse Event 40.1% 38%
Serious
Adverse Event
4% 3.2%
Adverse Events From TRUE NORTH (UC Study 2) Maintenance Period1
ZEPOSIA 0.92 mg
(n=230)
Placebo
(n=227)
Adverse Event 49.1% 36.6%
Serious
Adverse Event
5.2% 7.9%
In ZEPOSIA-treated patients, rates of thromboembolic events or major adverse cardiac events were similar to patients treated with placebo in TRUE NORTH.5jk
  • jIn the TRUE NORTH phase 3 studies, 1 case of ischemic stroke (0.2%) was reported in ZEPOSIA-treated patients vs no reports in patients treated with placebo.5
  • kThromboembolic events include pulmonary embolism and venous arterial thrombosis. Major or adverse cardiac events include cardiovascular death, myocardial infarction, and stroke.5

TEAE=treatment-emergent adverse event; UC=ulcerative colitis.

UC Study 1 and Study 2
Adverse Reaction
Induction
Maintenance
ZEPOSIA
0.92 mg
(n=429)
Placebo
(n=216)
ZEPOSIA
0.92 mg
(n=230)
Placebo
(n=227)
ALT ≥3x ULN
2.6% 0.5% 2.3% 0%
ALT ≥5x ULN
0.9% 0.5% 0.9% 0%
  • In controlled and uncontrolled UC studies, the majority (96%) of patients with ALT >3X ULN continued treatment with ZEPOSIA, with values returning to <3X ULN within ~2-4 weeks2
  • The overall discontinuation rate because of elevations in hepatic enzymes was 0.4% in patients treated with ZEPOSIA 0.92 mg and none in patients who received placebo in the controlled UC studies2
  • Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have hepatic enzymes checked, and ZEPOSIA should be discontinued if significant liver injury is confirmed2

ALT=alanine aminotransferase; LFT=liver function test; UC=ulcerative colitis; ULN=upper limit of normal.

In controlled clinical trials with ZEPOSIA, mean lymphocyte counts decreased to approximately 45% of baseline at 3 months (approximate mean blood lymphocyte counts 0.8 x 109/L), and low lymphocyte counts were maintained during treatment with ZEPOSIA.2

  • The proportion of patients treated with ZEPOSIA with lymphocytes less than 0.2 x 109/L was 2.0% in UC Study 1 and Study 3 (phase 2) and 2.3% in UC Study 22
  • These values generally returned to greater than 0.2 x 109/L while patients remained on treatment with ZEPOSIA2
  • After discontinuing treatment, the median time for peripheral blood lymphocytes to return to the normal range was approximately 30 days2
    • Approximately 80% to 90% of patients were in the normal range within 3 months2
Pooled Analysis of Controlled and Uncontrolled Trials6
Pooled Analysis of Controlled and Uncontrolled Trials: Mean Absolute Lymphocyte Count by Visit Line Graph Pooled Analysis of Controlled and Uncontrolled Trials: Mean Absolute Lymphocyte Count by Visit Line Graph
  • Descriptive pooled analysis of controlled and uncontrolled trials including the 32-week phase 2 TOUCHSTONE trial, the 52-week phase 3 TRUE NORTH trial, and an open-label extension study. Patients completing ≥1 year of the TOUCHSTONE OLE could roll over into the TRUE NORTH OLE6
  • Reductions in ALC were observed at Week 5 (the first post-baseline assessment) and sustained through treatment6
  • 60 patients (5.3%) had ALC <0.2 x 109/L at least once during ZEPOSIA treatment6
    • Most patients (98.3%; n=59) returned to ALC ≥0.2 x 109/L at the time of the analysis; 89.8% returned to ≥0.2 x 109/L while continuing treatment with ZEPOSIA6
  • lPatients may be included in both placebo and ZEPOSIA treatment groups. The total count in the placebo group includes 227 patients who were treated with ZEPOSIA in the induction period and were re-randomized to placebo in the maintenance period of TRUE NORTH.6

OLE=open-label extension; UC=ulcerative colitis.

Low Discontinuation Rates

Discontinuation Rates Due
to TEAEs That Are Comparable
to Placebo1

Overall Discontinuation Rates1

UC Study 1—Induction:
6.5% for ZEPOSIA | 11.1% for Placebo

UC Study 2—Maintenance:
20.0% for ZEPOSIA | 45.4% for Placebo

Discontinuation Rates Due
to Treatment-Emergent
Adverse Events (TEAEs)1

Induction

3.3%
ZEPOSIA

vs 3.2%
for placebo

Maintenance

1.3%
ZEPOSIA

vs 2.6%
for placebo

One case of macular edema was reported during the maintenance phase in 1 person with preexisting risk factors at baseline; it resolved after discontinuation of treatment.1,7

Overall, the discontinuation rate because of elevations in hepatic enzymes was 0.4% in patients treated with ZEPOSIA 0.92 mg and none in patients who received placebo in the controlled UC studies.2

TEAEs=treatment-emergent adverse events; UC=ulcerative colitis.

Infections and Malignancies

Rates of Serious Infection Were Low and Comparable to Placebo in Clinical Trials2

Rates of Serious Infection in
Clinical Trials2
Inductionm
Maintenance
Infection
ZEPOSIA 0.92 mg
(n=496)
Placebo
(n=281)
ZEPOSIA 0.92 mg
(n=230)
Placebo
(n=227)
Overall Rate of Infection
9.9% 10.7% 23% 12%
Serious Infections
0.8% 0.4% 0.9% 1.8%
Herpes Zoster
0.4% 0% 2.2% 0.4%
  • Malignancies, such as melanoma, basal cell carcinoma, breast cancer, seminoma, cervical carcinoma, and adenocarcinomas, including rectal adenocarcinoma, were reported with ZEPOSIA in controlled trials of multiple sclerosis and UC. An increased risk of cutaneous malignancies has been reported with another S1P receptor modulator2
  • mAdditional data from the induction period of a randomized, double-blind, placebo-controlled study (UC Study 3/TOUCHSTONE) included 67 patients who received ZEPOSIA 0.92 mg once daily.2
Rates of Malignancies in Clinical Trials1
Induction
Maintenance
Malignancies
Malig-
nancies
ZEPOSIA 0.92 mg
(n=429)
Placebo
(n=216)
ZEPOSIA 0.92 mg
(n=230)
Placebo
(n=227)
Basal Cell
Carcinoma
0% 0% 0.4% 0%
Rectal Adenocar-
cinoma
0% 0% 0.4% 0%
Adenocar-
cinoma of
the Colon
0% 0% 0% 0.4%
Breast
Cancer
0% 0% 0% 0.4%
Infections and Malignancies Across All UC Trials With ZEPOSIA8
ZEPOSIA 0.92 mg
(n=1158)
PY=1922.5n
Placebo
(n=508)
PY=249.2n
% (n) IR, per 100 PYo % (n) IR, per 100 PYo
Any
Infection
29.1 (337) 22.81 14.0 (71) 31.43
Any
Serious
Infection
2.2 (25) 1.32 1.4 (7) 2.84
Malignan-
cies
1.0 (12) 0.63 0.4 (2) 0.81
  • Safety outcomes were analyzed using descriptive statistics on pooled data from all controlled and uncontrolled UC trials: participants from 32-week TOUCHSTONE trialp (phase 2), 52-week TRUE NORTH trial (phase 3), and the respective OLE trials8
  • Median treatment duration in weeks for ZEPOSIA 0.92 mg and placebo was 65.79 and 17.21, respectively8
  • TEAEs identified in the pooled data from all controlled and uncontrolled UC trials were consistent with the controlled UC trials8
  • nTotal PY equals the sum of the number of years on study contributed by each patient from time of first dose per treatment group in the pool to last date on study per treatment group in the pool. The algorithm for the last date on study is dependent on patient disposition and whether the patient enrolled into an extension study.8
  • oIncidence rate per 100 PY, calculated as number of patients/PY x 100 for specific SOC category or PT subcategory. Analysis was based on the treatment group to which a patient was assigned when the event occurred, including patients who were
    re-randomized to placebo.8
  • pTOUCHSTONE patients randomized to ZEPOSIA 0.46 mg unapproved dose were only analyzed upon entering TOUCHSTONE OLE and receiving daily ZEPOSIA 0.92 mg.9

IR=incidence rate; OLE=open-label extension; PT=preferred term; PY=patient-years; S1P=sphingosine 1-phosphate; SOC=system organ class; TEAE=treatment-emergent adverse event; UC=ulcerative colitis.

Long-Term Safety Data Observed Over ~4 Years With ZEPOSIA3,10

This Safety Analysis Includes Patients With UC From the TRUE NORTH Parent Study Who Entered the TRUE NORTH OLE for up to 194 Weeks of ZEPOSIA Exposure10

Estimated Annual Risk = 2.5 per 100 treated patients10

2.5 out of 100 Patients Highlighted Icon 2.5 out of 100 Patients Highlighted Icon

TEAEs Leading
to
Treatment Discontinuation10

2.5

EAIR per
100 PYq


Serious TEAEs10

7.0

EAIR per
100 PYq


Serious Infection10

1.8

EAIR per
100 PYq

Safety From All TRUE NORTH Patients in OLE (N=823)10,11
Adverse Events
All Patients
in OLE
(N=823)
EAIR per 100 PYq
TEAEs 85.5
Serious TEAEs 7.0
TEAEs Leading to Treatment
Discontinuation
2.5
Most Frequent TEAEs (Occurring in ≥8% of Patients)
Lymphopeniar 6.1
COVID-19 4.3
Nasopharyngitis 3.8
Anemiar 3.7
Lymphocyte Count Decreasedr 3.7
Alanine Aminotransferase Increasedr 3.2
Arthralgia 3.2
Headache 2.8
Infection (Occurring in ≥3.0% of Patients)
COVID-19 4.3
Nasopharyngitis 3.8
Upper Respiratory Tract Infection 2.4
Serious Infection 1.8
Herpes Zoster 1.2
Sinusitis 1.2
Bronchitis11 1.1
Influenza11 1.0
Malignancy (Serious TEAE)11
Basal Cell Carcinoma 0.04
Colon Adenocarcinoma 0.04
Pancreatic Adenocarcinoma 0.04
B-Cell Lymphoma 0.04
Follicular Lymphoma, Stage IV 0.04
Malignant Lung Neoplasm 0.04
Prostate Cancer 0.04
Rectal Adenocarcinoma 0.04
Rectal Cancer Stage II 0.04
Cardiovascular Disorders
Hypertension 2.3
Hypertensive Crisis 0.16
Bradycardia 0.12
Myocardial Ischemia 0.12
Ischemic Stroke 0.12
Pulmonary Embolism 0.12
Deep Vein Thrombosis 0.12
Third-Degree AV Block 0.04
Macular Edema 0.2

Three deaths were reported during the OLE: 1 sudden death, 1 due to COVID-19, and 1 due to adenocarcinoma. These deaths were deemed to be unrelated to ZEPOSIA treatment by investigators.3,10

Infection (Occurring in ≥3.5% of Patients)10

COVID-19:
4.3 EAIR per 100 PYq


Nasopharyngitis:
3.8 EAIR per 100 PYq


Upper Respiratory Tract Infection:
2.4 EAIR per 100 PYq

  • qEAIRs were calculated as numbers of patients/PY × 100.10
  • rLaboratory values were flagged by the central laboratory if they fell outside the standard reference range; investigators decided whether laboratory values qualified as adverse events.12

AV=atrioventricular; EAIR=exposure-adjusted incidence rate; OLE=open-label extension; PY=patient-years; TEAE=treatment-emergent adverse event; UC=ulcerative colitis.

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