VARSITY - Entyvio (vedolizumab) vs adalimumab for moderate-to-severe colitis (UC)

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Evaluating the safety of Entyvio and adalimumab
Patients in clinical remission when treated with Entyvio or adalimumab
Rate of mucosal healing completed for patients treated with Entyvio or adalimumab
Reduction in use of steroids for patients treated with Entyvio or adalimumab
Speed of clinical responses in patients treated with Entyvio or adalimumab
Minimal histologic disease activity when treating with Entyvio or adalimumab
Disease clearance at Week 52 for patients treated with Entyvio or adalimumab
Adverse effects
Safety profile

VARSITY Summary

This is a summary on the vedolizumab versus adalimumab for moderate-to-severe Ulcerative Colitis (UC) head-to-head trial.

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The first head-to-head trial evaluating the efficacy and safety of Entyvio (vedolizumab) with adalimumab in patients with moderately-to-severely active ulcerative colitis (UC) completed^1,2

Patients enrolled in the study had failed conventional therapies and were either biologic-naïve or anti-TNFα completed failure patients. Patients who had discontinued treatment with a TNF inhibitor (except adalimumab) because of documented reasons other than safety were also eligible, with enrollment capped at 25%.

Moderate to severe UC N=769
	N=383		N=386
	Entyvio 300mg IV	PBO SC	ADA SC	PBO IV
Week	Induction phase
0
2
4
6
Week	Maintenance phase
14
22
30
38
46
52
	18 Week follow up period
(52 - 68)

Endoscopy at baseline, Week 14 and Week 52.

The primary endpoint was clinical remission, defined a s a complete Mayo score <2 and no individual subscore >1 at Week 52.

ADA adalimumab
IV intravenous
PBO placebo
Q2W every 2 weeks
SC subcutaneous
TNF tumour necrosis factor
UC ulcerative colitis

1. NCT02497467. Available at clinicaltrials.gov/ct2/show/NCT02497469.

2. Sands BE, et al. N Eng J Med 2019;381:1215-1226

Statistically more patients treated with Entyvio were in clinical remission vs adalimumab at Week 52¹

Among the patients who did not have previous exposure to a TNF inhibitor (Entyvio n=305; adalimumab n=305), clinical remission at Week 52 was observed in:

34.2% of patients with Entyvio

24.3% of patients with adalimumab

Among the patients who had previous exposure to a TNF inhibitor other than adalimumab (Entyvio n=80; adalimumab n=81), clinical remission at Week 52 was observed in:

20.3% of patients with Entyvio

16.0% of patients with adalimumab

Primary endpoint: Clinical remission*
in moderate-to-severe patients with UC at Week 52

bar

Drug	x Axis Label	Colour	Number
Entyvio	Entyvio (n=120/383)	#A00081	31.3
adalimumab	adalimumab (n=87/386)	#a3a3a3	22.5

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*Defined as a complete Mayo score ≤2 and no individual subscore >1.

TNF, tumour necrosis factor.

1. Sands BE, et al. N Engl J Med 2019; 381:1215-1226

Entyvio achieved significantly higher rates of mucosal healing vs adalimumab at Week 52¹

Among the patients who did not have previous exposure to a TNF inhibitor (Entyvio n=305; adalimumab n=305), mucosal healing at Week 52 was observed in:

43.1% of patients with Entyvio

29.5% of patients adalimumab

Among the patients who had previous exposure to a TNF inhibitor other than adalimumab (Entyvio n=80; adalimumab n=81), mucosal healing at Week 52 was observed in:

26.6% of patients with Entyvio

21.0% of patients with adalimumab

Secondary endpoint: Mucosal healing* at Week 52

bar

Drug	x Axis Label	Colour	Number
Entyvio	Entyvio (n=152/383)	#A00081	39.7
adalimumab	adalimumab (n=107/386)	#a3a3a3	27.7

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*Defined as a subscore of 0 or 1 on the Mayo endoscopic component.

TNF, tumour necrosis factor

1. Sands BE, et al. N Engl J Med 2019:381:1215-1226

Absolute reduction in steroid use was greater with Entyvio than adalimumab, but no significant treatment differences were observed in steroid free remission¹

The median change in the oral corticosteroid dose from baseline to Week 52 was:

10.0mg with Entyvio
7.0mg with adalimumab

The median corticosteroid dose at Week 52 was:

0mg (range, 0-40) with Entyvio
2.5mg (range, 0-70) with adalimumab

Secondary endpoint: Steroid
free remission at Week 52

bar

Drug	x Axis Label	Colour	Number
Entyvio	Entyvio (n=14/111)	#581d53	12.6
adalimumab	adalimumab (n=26/119)	#a3a3a3	21.8

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*Corticosteroid free remission was defined as participants using oral corticosteroids at Baseline (Week 0) who had discontinued oral corticosteroids and were in clinical remission at Week 52. Clinical remission was defined as a complete Mayo score of < 2 points and no individual subscore > 1 point.

NS, not significant

1. Sands BE et al. N Engl J Med 2019;381:1215-1226;

Entyvio delivered a similar speed of clinical response* as adalimumab at weeks 2-6¹

Patients with Clinical Response / Patients with available data

	Week 2	Week 4	Week 6	Week 14	Week 22	Week 30	Week 38	Week 46	Week 52
Entyvio (n=383)	161 / 367	233 / 357	263 / 356	276 / 344	278 / 325	262 / 298	263 / 293	251 / 280	233 / 265
adalimumab (n=386)	176 / 374	217 / 366	232 / 364	229 / 342	229 / 295	222 / 270	206 / 245	200 / 228	193 / 221

Clinical response measured as change
in partial Mayo score from baseline

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Drug	Colour	Number
Entyvio	#581d53	42, 60, 68, 71, 72, 65, 66, 61, 55
adalimumab	#a3a3a3	45, 55, 58, 57, 53, 50, 48, 44, 42

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*The assessment of clinical response was based on the change in the partial score on the Mayo scale from baseline to trial visit. A clinical responses was defined as a reduction in the partial Mayo score of at least 2 points and at least 25% from baseline, with an accompanying decrease of at least 1 point on the rectal bleeding component of the Mayo scale or a rectal bleeding subscore of 0 or 1.

1. Sands BE, et al. N Engl J Med 2019; 381:1215-1226

Entyvio was superior to adalimumab in achieving minimal histologic disease activity at week 52 in ulcerative colitis (UC)¹

Minimal histologic disease
activity (Geboes Score < 3.2)

bar

Drug	x Axis Label	Colour	Number
Entyvio	Entyvio (n=128/383)	#581d53	33.4
adalimumab	adalimumab (n=53/386)	#a3a3a3	13.7

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Minimal histologic disease activity
(Robarts Histopathology Index [RHI] <5)

bar

Drug	x Axis Label	Colour	Number
Entyvio	Entyvio (n=162/383)	#581d53	42.3
adalimumab	adalimumab (n=99/386)	#a3a3a3	25.6

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Full analysis set includes all randomised patients who received at least 1 dose of study drug. To determine the outcome, patients with missing data were considered non-responders. RHI, Robarts Histopathology Index.

1. Sands BE, et al. N Engl J Med 2019; 381:1215-1226. Supplementary appendix.

More patients treated with Entyvio achieved disease clearance* at week 52 than those created with adalimumab

More patients in the Entyvio treatment group than the adalimumab group achieved disease clearance at Week 52:

29.2% (n=112/383; 95% CI: 24.7 - 34.1) of patients with Entyvio

16.3% (n=63/386; 95% CI: 12.8 - 20.4) of patients with adalimumab

Disease clearance at Week 52 by
baseline inflammatory burden^✝

bar

Drug	x Axis Label	Colour	Number
Inflammatory burden at baseline	Entyvio (n=32/153) (n=70/157)	#A00081	31.1
No inflammatory burden at baseline	adalimumab (n=15/96) (42/153)	#4d4d4d	15.6
No inflammatory burden at baseline	Entyvio (n=32/153) (n=70/157)	#FEBAEF	44.6
Inflammatory burden at baseline	adalimumab (n=15/96) (42/153)	#929292	27.5

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*Disease clearance was defined as a composite outcome based on clinical remission (partial Mayo score <2 and no individual subscore >1 excluding sigmoidoscopy subscore), endoscopic improvement (endoscopic subscore <1) and absence of active histologic disease (minimum histological disease activity; Robarts Histology index [RHI] < 5).

✝ Inflammatory burden defined at C-reactive protein ≥5 mg/L and fecal calprotectin >100 μg/g.

CI, confidence interval

1. Danese S, et al. J Crohns Colitis 2021; 15(Suppl 1):S305

The majority of adverse events in VARSITY were mild to moderate¹

Incidence of AEs and SAEs (safety population)*

	Entyvio (N=383)	adalimumab (N=386)
Any AE, n (%)	240 (62.7%)	267 (69.2%)
Mild, n (%)	111 (29.0%)	118 (30.6%)
Moderate, n (%)	92 (24.0)	109 (28.2%)
Severe, n (%)	37 (9.7%)	40 (10.4%)
SAE, n (%)	42 (11.0%)	53 (13.7%)
Exposure adjusted infection rate, incidence rate / 100 patient years	23.4	34.6

Few infections were considered serious in either group

*The safety population was defined as all patients who received at least one dose of a trial medicine.

AE adverse event

SAE serious adverse event

1. Sands BE, et al. N Engl J Med 2019; 381:1215-1226

Entyvio demonstrated a comparable safety profile to adalimumab¹

Most frequent AEs (safety population)*

Event, n (%)	Entyvio (n=383)	adalimumab (n=386)
>1 AE	126 (32.9)	138 (35.8)
Ulcerative colitis	44 (11.5)	63 (16.3)
Nasopharyngitis	27 (7.0)	30 (7.8)
Headache	27 (7.0)	21 (5.4)
Anaemia	20 (5.2)	26 (6.7)
Abdominal pain	18 (4.7)	20 (5.2)
Upper respiratory tract infection	20 (5.2)	17 (4.4)

* The safety population was defined as all patients who received at least one dose of a trial medicine

AE adverse event

1. Sands BE, et al. N engl J Med 2019; 381:1215-1226. Supplementary appendix.

Discussion and points of interest

VARSITY was the first head-to-head trial evaluating the efficacy and safety of Entyvio (vedolizumab) with adalimumab in patients with moderately-to-severely active ulcerative colitis^{1, 2}
Entyvio demonstrated statistically superior rates of clinical remission (31.3% vs 22.5%; p<0.001) and mucosal healing (39.7% vs 27.7%; P<0.001) vs adalimumab at week 52²
Absolute reduction in steroid use was greater with Entyvio than adalimumab, but no significant difference was observed in corticosteroid free remission between the two groups²
Entyvio delivered a similar speed of response as adalimumab at Weeks 2-6²
Entyvio was superior to adalimumab in minimal histologic disease activity at Week 52 in ulcerative colitis³
- Geboes Score <3.2: 33.4% with Entyvio vs 13.7% with adalimumab
- Robarts (RHI) <5: 42.3% with Entyvio vs 25.6% with adalimumab
More patients treated with Entyvio achieved disease clearance at week 52 than those treated adalimumab (26.2% vs 16.3%)⁴
Entyvio demonstrated a comparable safety profile to adalimumab^2,3

RHI, Robarts Histopathology Index.

NCT024977467. Available at clinicaltrials.gov/ct2/showNCT02497469. Accessed March 2022;
Sands BE, et al. N Eng J Med 2019; 381:1215-1226;
Sands BE, et al. N Engl J Med 2019; 381:1215-1226. Supplementary appendix.
Danese S, et al. J Crohns Colitis 2021; 15(suppl 1):S305

Adverse Events should be reported to the Pharmacovigilance Unit at the Health Products Regulatory Authority. Reporting forms and information can be found at: www.hpra.ie. Adverse events should also be reported to Takeda at: AE.GBR-IRL@takeda.com.

C-APROM/IE/GI/0011 | June 2024

ENTYVIO® (vedolizumab) PRESCRIBING INFORMATION for IRELAND

Refer to the Summary of Product Characteristics (SmPC) before prescribing.

Presentation: Entyvio intravenous (IV): 300 mg powder for concentrate for solution for infusion. Entyvio subcutaneous (S/C): 108 mg solution for injection in pre-filled syringe or pen.

Indication: Entyvio IV and Entyvio S/C: Adult patients with moderately to severely active ulcerative colitis (UC)/Crohn’s disease (CD) who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumour necrosis factor-alpha (TNFα) antagonist. Entyvio IV only: Adult patients with moderately to severely active chronic pouchitis, who have undergone proctocolectomy and ileal pouch anal anastomosis for UC, and have had an inadequate response with or lost response to antibiotic therapy. Dosage and administration: Treatment should be initiated and supervised by a specialist healthcare professional experienced in diagnosis and treatment of UC, CD or pouchitis. Entyvio IV: Patients should be monitored during and after infusion in a setting equipped to manage anaphylaxis.
UC: Recommended dose regimen 300 mg administered by IV infusion over 30 minutes at 0, 2, 6 weeks and every 8 weeks thereafter. Discontinue treatment if no evidence of therapeutic benefit by week 10. If patients experience a decrease in response, they may benefit from increased dosage frequency to 300 mg every 4 weeks. Corticosteroids may be reduced/discontinued in patients who respond to treatment with Entyvio. If therapy is interrupted and needs to be restarted, Entyvio dosing every 4 weeks may be considered.
CD: Recommended dose regimen is 300 mg administered by IV infusion over 30 minutes at 0, 2, 6 weeks and every 8 weeks thereafter. Patients who have not shown evidence of therapeutic benefit may benefit from a dose at week 10. Continue therapy every 8 weeks from week 14 in responding patients. Therapy should be discontinued if no evidence of therapeutic benefit is observed by week 14. If therapy is interrupted and needs to be restarted, Entyvio dosing every 4 weeks may be considered.
Pouchitis: Recommended dose regimen is 300 mg administered by IV infusion at 0, 2 and 6 weeks and then every 8 weeks thereafter. Treatment should be initiated in parallel with standard of care antibiotic (e.g., four-week of ciprofloxacin). Therapy discontinuation should be considered if no evidence of therapeutic benefit is observed by week 14. There are no retreatment data available if therapy is interrupted and needs to be restarted.
Entyvio S/C: UC and CD: Recommended dose regimen, following at least two IV infusions, is 108mg administered by subcutaneous injection once every 2 weeks. The first S/C dose should be administered in place of the next scheduled IV dose and every 2 weeks thereafter. Insufficient data to determine if patients who experience a decrease in response on maintenance treatment with Entyvio S/C would benefit from an increase in dosing frequency. No data on transition of patients from Entyvio S/C to Entyvio IV during maintenance therapy.

Paediatric populations: No data available in children aged 0-17 years. Not recommended.

Elderly patients: No dosage adjustment required.

Renal or hepatic impairment: Entyvio has not been studied in these populations. No dose recommendation can be given.

Contraindications: Hypersensitivity to Entyvio or any of the excipients. Active severe infections such as tuberculosis (TB), sepsis, cytomegalovirus, listeriosis and opportunistic infections such as Progressive Multifocal Leukoencephalopathy (PML).

Warnings and precautions: Entyvio IV: Patients should be observed continuously during infusions for signs/symptoms of hypersensitivity reactions. Patients should continue to be observed for two hours following infusion completion for the first two infusions and one hour for subsequent infusions.

Infusion-related reactions (IRR): Hypersensitivity reactions have been reported, the majority were of mild to moderate severity. Discontinue treatment if anaphylaxis or other serious allergic reactions occur and initiate appropriate treatment. In mild to moderate IRR, slow or interrupt infusion. Consideration for pre-treatment with antihistamine, hydrocortisone and/or paracetamol should be given prior to next infusion, for patients with history of mild/moderate IRR to Entyvio.

Entyvio IV and Entyvio S/C: Infections: Not recommended in patients with active, severe infections until infections are controlled. Consider withholding in patients who develop severe infection while on treatment with Entyvio. Before initiating treatment, patients must be screened for TB. If latent TB is diagnosed, anti-tuberculosis appropriate treatment must be initiated prior to Entyvio treatment.

Progressive Multifocal Leukoencephalopathy (PML): John Cunningham (JC) virus infection resulting in PML and death has occurred in patients treated with other integrin receptor antagonists and systemic immunosuppressive agents. A risk of PML cannot be ruled out. Monitor patients for any new or worsening neurological signs/symptoms.

Malignancy: Underlying increased risk of malignancy in UC and CD. Immunomodulatory products may increase risk. Prior and concurrent use of biological products: No clinical data available for Entyvio use in patients previously treated with natalizumab or rituximab. Patients previously exposed to natalizumab should wait at least 12 weeks prior to initiating Entyvio therapy. Entyvio not recommended for concomitant use with biologic immunosuppressants as no clinical data available. Live and oral vaccines: Patients may continue to receive non-live vaccines. Patients recommended to be up-to-date with all appropriate immunisations prior to initiating Entyvio. Live vaccines may be administered concurrently only if benefit clearly outweighs risk.

Interactions: No interaction studies performed.
UC and CD: Concomitant administration of corticosteroids, immunomodulators (azathioprine, 6-mercaptopurine, and methotrexate) and aminosalicylates did not have a clinically meaningful effect on Entyvio pharmacokinetics.
Pouchitis: Concomitant administration of antibiotics have been observed. The effect on the pharmacokinetics of commonly coadministered medicinal compounds has not been studied.

Fertility, pregnancy and lactation: There are no data on the effects of vedolizumab on human fertility. Women of childbearing potential should use adequate contraception and continue for at least 18 weeks after last Entyvio treatment. Preferable to avoid use of Entyvio during pregnancy unless benefits clearly outweigh potential risk to both the mother and foetus. Entyvio has been detected in human milk. The effects on breast-fed infants and milk production are unknown. Use of Entyvio in lactating women should consider the benefit of therapy against potential risks to the infant.

Undesirable effects: No clinically relevant differences in overall safety profile and adverse reactions observed in patients who received Entyvio S/C compared with Entyvio IV except for injection site reactions (with S/C administration).
Very Common (≥1/10): nasopharyngitis, headache, arthralgia.
Common (≥1/100, <1/10): injection site reactions (Entyvio S/C only), bronchitis, gastroenteritis, upper respiratory tract infection, influenza, sinusitis, pharyngitis, paraesthesia, hypertension, oropharyngeal pain, nasal congestion, cough, anal abscess, anal fissure, nausea, dyspepsia, constipation, abdominal distension, flatulence, haemorrhoids, rectal haemorrhage*, rash, pruritus, eczema, erythema, night sweats, acne, muscle spasm, back pain, muscular weakness, fatigue, pain in extremities, pyrexia, infusion related reaction* (asthenia and chest discomfort). *Reported in the EARNEST pouchitis study.
Other serious undesirable effects: respiratory tract infection, pneumonia, anaphylactic reaction, anaphylactic shock, interstitial lung disease. Refer to the SmPC for details on full side effect profile and interactions.

Legal Classification: POM.

Marketing authorisation (MA): Entyvio IV: EU/1/14/923/001. Entyvio S/C: EU/1/14/923/002, EU/1/14/923/005.

Name and Address of MA holder: Takeda Pharma A/S, Delta Park 45, 2665 Vallensbaek Strand, Denmark. Additional information is available on request at: medinfoemea@takeda.com.

PI Approval Code: pi-01912.

Date of revision: February 2022.

VARSITY - Entyvio (vedolizumab) vs adalimumab for moderate-to-severe colitis (UC)

Contents

VARSITY Summary

The first head-to-head trial evaluating the efficacy and safety of Entyvio (vedolizumab) with adalimumab in patients with moderately-to-severely active ulcerative colitis (UC) completed^1,2

Statistically more patients treated with Entyvio were in clinical remission vs adalimumab at Week 52¹

Primary endpoint: Clinical remission*
in moderate-to-severe patients with UC at Week 52

Entyvio achieved significantly higher rates of mucosal healing vs adalimumab at Week 52¹

Secondary endpoint: Mucosal healing* at Week 52

Absolute reduction in steroid use was greater with Entyvio than adalimumab, but no significant treatment differences were observed in steroid free remission¹

Secondary endpoint: Steroid
free remission at Week 52

Entyvio delivered a similar speed of clinical response* as adalimumab at weeks 2-6¹

Patients with Clinical Response / Patients with available data

Clinical response measured as change
in partial Mayo score from baseline

Entyvio was superior to adalimumab in achieving minimal histologic disease activity at week 52 in ulcerative colitis (UC)¹

Minimal histologic disease
activity (Geboes Score < 3.2)

Minimal histologic disease activity
(Robarts Histopathology Index [RHI] <5)

More patients treated with Entyvio achieved disease clearance* at week 52 than those created with adalimumab

Disease clearance at Week 52 by
baseline inflammatory burden^✝

The majority of adverse events in VARSITY were mild to moderate¹

Entyvio demonstrated a comparable safety profile to adalimumab¹

Discussion and points of interest

ENTYVIO® (vedolizumab) PRESCRIBING INFORMATION for IRELAND

Refer to the Summary of Product Characteristics (SmPC) before prescribing.

This content is intended for Healthcare Professionals in Ireland only.

VARSITY - Entyvio (vedolizumab) vs adalimumab for moderate-to-severe colitis (UC)

Contents

VARSITY Summary

The first head-to-head trial evaluating the efficacy and safety of Entyvio (vedolizumab) with adalimumab in patients with moderately-to-severely active ulcerative colitis (UC) completed1,2

Statistically more patients treated with Entyvio were in clinical remission vs adalimumab at Week 521

Primary endpoint: Clinical remission*in moderate-to-severe patients with UC at Week 52

Entyvio achieved significantly higher rates of mucosal healing vs adalimumab at Week 521

Secondary endpoint: Mucosal healing* at Week 52

Absolute reduction in steroid use was greater with Entyvio than adalimumab, but no significant treatment differences were observed in steroid free remission1

Secondary endpoint: Steroidfree remission at Week 52

Entyvio delivered a similar speed of clinical response* as adalimumab at weeks 2-61

Patients with Clinical Response / Patients with available data

Clinical response measured as changein partial Mayo score from baseline

Entyvio was superior to adalimumab in achieving minimal histologic disease activity at week 52 in ulcerative colitis (UC)1

Minimal histologic diseaseactivity (Geboes Score < 3.2)

Minimal histologic disease activity(Robarts Histopathology Index [RHI] <5)

More patients treated with Entyvio achieved disease clearance* at week 52 than those created with adalimumab

Disease clearance at Week 52 bybaseline inflammatory burden✝

The majority of adverse events in VARSITY were mild to moderate1

Entyvio demonstrated a comparable safety profile to adalimumab1

Discussion and points of interest

ENTYVIO® (vedolizumab) PRESCRIBING INFORMATION for IRELAND

Refer to the Summary of Product Characteristics (SmPC) before prescribing.

This content is intended for Healthcare Professionals in Ireland only.

The first head-to-head trial evaluating the efficacy and safety of Entyvio (vedolizumab) with adalimumab in patients with moderately-to-severely active ulcerative colitis (UC) completed^1,2

Statistically more patients treated with Entyvio were in clinical remission vs adalimumab at Week 52¹

Primary endpoint: Clinical remission*
in moderate-to-severe patients with UC at Week 52

Entyvio achieved significantly higher rates of mucosal healing vs adalimumab at Week 52¹

Absolute reduction in steroid use was greater with Entyvio than adalimumab, but no significant treatment differences were observed in steroid free remission¹

Secondary endpoint: Steroid
free remission at Week 52

Entyvio delivered a similar speed of clinical response* as adalimumab at weeks 2-6¹

Clinical response measured as change
in partial Mayo score from baseline

Entyvio was superior to adalimumab in achieving minimal histologic disease activity at week 52 in ulcerative colitis (UC)¹

Minimal histologic disease
activity (Geboes Score < 3.2)

Minimal histologic disease activity
(Robarts Histopathology Index [RHI] <5)

Disease clearance at Week 52 by
baseline inflammatory burden^✝

The majority of adverse events in VARSITY were mild to moderate¹

Entyvio demonstrated a comparable safety profile to adalimumab¹