The Latest MedicalTreatment Advances in IBD

Nancy McGreal, MDAssociate Professor of Medicine and Pediatrics

Divisions of Adult and Pediatric GastroenterologyDuke University Medical Center

Disclosures

• None

IBD Medical Treatment Options in 2019

Anti-inflammatory

5-ASA

Steroids

Antibiotics

Immunomodulators

6-MP, AZA, MTX

CSA, FK506, GMCSF

Thalidomide

Anti-TNF α

Infliximab

Adalimumab

Certolizumab

Golimumab

Anti-integrin

Natalizumab

Vedolizumab

Anti-cytokine

Ustekinumab

JAK inhibitor

Tofacitinib

Duijvestein M et al. Curr Treat Options Gastro 2018; 16:129-146

Choosing an IBD Therapy….

Latest Additions to the IBD Armamentarium

• Biologics

- Vedolizumab (UC/CD) 2014

- Ustekinumab (CD) 2016

• Small molecules

- Tofacitinib (UC) 2018

Case

• 31 yo ♀ with a history of multiple sclerosis is diagnosed with ileocolonic Crohn’s disease on colonoscopy and confirmed by MRE. No strictures noted but a small entero-enteric fistula is present on MRE. She is started on prednisone but needs steroid sparing therapy. Which would you start?

- Thiopurine monotherapy

- Infliximab +/- immunomodulator

- Adalimumab +/- immunomodulator

- Ustekinumab +/- immunomodulator

Case

• 31 yo ♀ with a history of multiple sclerosis is diagnosed with ileocolonic Crohn’s disease on colonoscopy and confirmed by MRE. No strictures noted but a small entero-enteric fistula is present on MRE. She is started on prednisone but needs steroid sparing therapy. Which would you start?

- Thiopurine monotherapy

- Infliximab +/- immunomodulator

- Adalimumab +/- immunomodulator

- Ustekinumab +/- immunomodulator

Ustekinumab

Deepak P et al. Drug, Design, Develop and Ther 2016; 10:3685-3698

6 Real World Cohorts – 578 Ustekinumab Treated Crohn’s Patients97.7% Anti-TNF Experienced

Engel T et al. Dig Liv Dis 2019; 51: 1232-1240Feagan B et al. NEJM 2016; 375(20): 1946-1960

CERTIFI Week 6 - 39%

CERTIFI Week 22 – 69.4%

IM-UNITI Week 44 – 53.1%

• Week 24 – 39%

• Week 52 – 51% (IM-UNITI: 46.9%)

Pooled Remission

Steroid-free Response

• Week 52 – 66%

• Week 52 – 31% (IM-UNITI: 33%)

Endoscopic Response

Mucosal Healing

• Positive – colonic disease, concurrent IS

• Negative – stricturing disease, prior resectionPredictors of Clinical

Response

• 88 patients

• Response/Remission – 31% to 61% (CERTIFI - 47%)Perianal Disease

• Common 21% – Musculoskeletal, HA, URI

• Serious 3.2% - ALS, pancreatitis, CRC Safety

Engel T et al. Dig Liv Dis 2019; 51: 1232-1240

Barre A et al. AP&T 2018; 47: 896-905

Clinical trials suggest better response in anti-TNF naïve pts

Ustekinumab is Associated with Low Immunogenicity

Adverse Effects are Uncommon with Ustekinumab

Ustekinumab Prescribing InformationShim H et al. JGHF 2018; 2: 223-234

• Larger volume of safety data in psoriasis than CD; lower dose in psoriasis

• No ↑ risk of malignancy (including skin ca), cardiovascular events

• Lower risk of active TB than anti-TNF (0.02/100 pt yrs vs. 0.28/100 pt yrs)

Safety in Special Populations

Elderly

No increased risk of AE in pts over 65 yrs in psoriasis study at

1 yr

Pregnancy

Compatible with pregnancy and lactation

Perioperative

No ↑ risk of surgical site infection

Shim H et al. JGHF 2018; 2: 223-234Mahadevan U et al. Gastroenterology 2019; 156: 1508-1524

DDW 2019

• Clinical response as early as week 3

• Anti-TNF >> Anti-cytokine >> Anti-integrinInduction of Remission

• Efficacy/durability = anti-TNF, anti-integrin

• Better efficacy in anti-TNF naïve – start first?Maintenance of

Remission

• Anti-TNF contraindications: MS, CHF, lymphoma

• Concomitant psoriasis

• Low immunogenicity – monotherapy

Patient Factors/

Safety

• Injectable, fewest injections of biologics

• Savings programCost/Convenience

Engel T et al. Dig Liv Dis 2019; 51: 1232-1240

Considerations in Positioning Ustekinumab for CD

Case

• 25 yo ♂ with a history of left-sided UC on maintenance 5-ASA develops a flare. Colonoscopy shows extension of disease with moderate to severe pancolitis. He responds to prednisone but demonstrates steroid dependence. What is your next management choice?

- Thiopurine monotherapy- Methotrexate monotherapy- Adalimumab +/- immunomodulator- Vedolizumab +/- immunomodulator

Case

• 25 yo ♂ with a history of left-sided UC on maintenance 5-ASA develops a flare. Colonoscopy shows extension of disease with moderate to severe pancolitis. He responds to prednisone but demonstrates steroid dependence. What is your next management choice?

- Thiopurine monotherapy- Methotrexate monotherapy- Adalimumab +/- immunomodulator- Vedolizumab +/- immunomodulator

Vedolizumab

Vedolizumab – anti-α4β7 integrin antibody: gutNatalizumab – anti-α4β1 integrin antibody: brain, bone marrow, skin, gut

Honap S et al. Curr Opin Gastroenterol 2019; 35(4): 296-301

Amiot A et al. AP&T 2019; 50: 40-53Shim H et al. JGHF 2018; 2: 223-234

GEMINI 2Clinical remission Wk 52Anti-TNF failure 27.7%

98% Anti-TNF Experienced

Amiot A et al. AP&T 2019; 50: 40-53Shim H et al. JGHF 2018; 2: 223-234

GEMINI 1Clinical remission Wk 52

41.8%

98% Anti-TNF Experienced

Amiot A et al. AP&T 2019; 50: 40-53

Feagan B et al. JCC 2018; 621-626

Barre A et al. AP&T 2018; 47: 896-905

Treatment Response by Prior Anti-TNF Exposure

Vedolizumab Adalimumab P Value

Clinical Remission

Anti-TNF naïve 34.2% 24.3% 0.007

Anti-TNF exposed 20.3% 16% Not significant

Mucosal Healing

Anti-TNF naïve 43.1% 29.5% 0.0005

Anti-TNF exposed 26.6% 21% Not significant

Vedolizumab Shows Superior Efficacy Versus AdalimumabResults of VARSITY – The First Head-to- Head Study of Biologic Therapy

in Moderate to Severe UC

• Randomized: 385 VDZ vs. 386 ADA

• Prior IFX use limited to 25% of patients

• Groups equivalent: prior anti-TNF use, concomitant steroids/IS, Mayo score

• Safety equivalent except ↑ respiratory infections with ADA

Sands B et al, DDW 2019

VISIBLE 1: Efficacy and Safety of Vedolizumab Subcutaneous Formulation in a Randomized Trial of

Patients with Ulcerative Colitis

Sandborn W et al. Gastroenterology, August 2019

Adverse Effects are Uncommon with Vedolizumab

*(One case in HIV patient)

Safety in Special Populations

Elderly

Similar safety profile across all ages

Pregnancy

Compatible with pregnancy and lactation

Perioperative

Conflicting data re: post-operative infection

Shim H et al. JGHF 2018; 2: 223-234Mahadevan U et al. Gastroenterology 2019; 156: 1508-1524

• Slower in CD than UC; may need steroid bridge

• Anti-TNF >> Anti-cytokine >> Anti-integrinInduction of Remission

• Efficacy/durability = anti-TNF, anti-cytokine

• Better efficacy in anti-TNF naïve – start first?

Maintenance of Remission

• Anti-TNF contraindications: MS, CHF, lymphoma

• Favorable profile: elderly, prior malignancy, transplant

Patient Factors/

Safety

• Severe hospitalized UC→ favor infliximab

• Severe outpt IBD (on verge of hospitalization)

• EIMs not coinciding with gut activity (spondyloarthritis, PG, AS)

Special Scenarios

Not to Use

• Currently infusion is only option but injectable formulation may be available in the future

• Savings programCost/Convenience

Engel T et al. Dig Liv Dis 2019; 51: 1232-1240

Considerations in Positioning Vedolizumab for IBD

Case

• Your patient responds well to vedolizumab Q8 weeks for 12 months but develops hematochezia and diarrhea. VDZ level is > 20 without antibodies. Colonoscopy demonstrates moderate to severe pancolitis. What would you offer next?

- Increase frequency of vedolizumab to Q4 weeks

- Continue vedolizumab Q8 weeks + immunomodulator

- Start tofacitinib

- Refer to surgery for colectomy

Case

• Your patient responds well to vedolizumab Q8 weeks for 12 months but develops hematochezia and diarrhea. VDZ level is > 20 without antibodies. Colonoscopy demonstrates moderate to severe pancolitis. What would you offer next?

- Increase frequency of vedolizumab to Q4 weeks

- Continue vedolizumab Q8 weeks + immunomodulator

- Start tofacitinib

- Refer to surgery for colectomy

Tofacitinib

Sabino J et al. Ther Adv Gastroenterol 2019; 12:1-14

Blocks lymphocyte proliferation, T-cell differentiation, innate defense

• 58 pts (53 UC, 4 CD, 1 pouchitis)

• Disease extent, previous medical therapy and steroid exposure were not predictive of response

• 20% systemic infections – most with concomitant steroids

Weisshof E et al. Dig Dis Sci 2019; 64:1945-1951

33%33%

27%

51% of patientsremained on drug at 1 year

Improvement in stool frequency Improvement in rectal bleeding

Tofacitinib Safety: Bone Marrow Suppression,Liver Toxicity, Hyperlipidemia

• 1613 patient-years of exposure (median 1.4 years, 84% were on 10mg BID dose)

• Most common adverse effects: nasopharyngitis, headache

Sandborn WJ, Clin Gastroenterol Hepatol 2019

Placebo (incidence rate) Tofacitinib (incidence rate)

Serious infections 1.9 2.0

Herpes Zoster 1.0 4.1

Opportunistic infections (excluding zoster)

0.0 0.2

Malignancy 1.0 0.7

NMSC 1.0 0.7

MACE (cardiovascular events) 0.0 0.2

• Mortality“Rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular (CV) risk factor treated with XELJANZ 10 mg twice a day had a higher rate of all-cause mortality, including sudden CV death, compared to those treated with XELJANZ 5 mg given twice daily or TNF blockers in a large, ongoing, postmarketing safety study.”

• Thrombosis“Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, has been observed at an increased incidence in rheumatoid arthritis patients who were 50 years of age and older with at least one CV risk factor treated with XELJANZ 10 mg twice daily compared to XELJANZ 5 mg twice daily or TNF blockers in a large, ongoing postmarketing safety study. “

• IndicationThe ulcerative colitis (UC) indication has been modified to state that it is for the treatment of adult patients with moderately to severely active ulcerative colitis, who have an inadequate response or who are intolerant to TNF blockers. There are also modifications to the dosing section for UC, including that the maintenance dose is XELJANZ 5 mg twice daily, and limit use of 10 mg twice daily beyond induction to those with loss of response.

FDA approves Boxed Warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib- July 26, 2019

• Rapid induction of remissionInduction of Remission

• Efficacy/durability = biologics

• Anti-TNF agnostic

• No immunogenicity – can start and stop if needed

Maintenance of Remission

• Anti-TNF contraindications: MS, CHF, lymphoma

• Safe perioperatively – short ½ life

• Avoid in pregnancy for now

Patient Factors/

Safety

• Oral administration

• Savings program Cost/Convenience

Engel T et al. Dig Liv Dis 2019; 51: 1232-1240

Considerations in Positioning Tofacitinib for UC

Considerations for Positioning Therapies in IBD

Drug Factors

Rapid induction of remission

Durable maintenance of remission

Steroid sparing

Immunogenicity (need for combo tx)

Favorable safety profile

Patient Preference Factors

Mode of administration

Cost-effectiveness

Convenience

Patient Clinical Factors

Phenotype: strictures, fistulas

Extra-intestinal manifestations

Age/ co-morbidities

Tolerance of IS

Steroid refractory

Provider Factors

Market time/Comfort

Ease of use

Personal experience

Afif W. CAG Symposium 2018

Putting It All Together: Crohn’s DiseaseAnti-TNF Ustekinumab Vedolizumab

Induction of Remission ++ ++ +Maintenance of Remission + + +Fistulizing Disease ++ ++ +Immunogenicity + ++ +ExtraintestinalManifestations

++ ++ +

Safety + ++ +++Convenience ++ ++ +Cost + + +

Putting It All Together: Ulcerative Colitis

Anti-TNF Vedolizumab Tofacitinib

Induction of Remission ++ + ++Maintenance of Remission + + +Immunogenicity + + +++ExtraintestinalManifestations

++ + +

Safety + +++ +Convenience + + ++Cost + + +

Thank You for Your Time and Attention

Predictors of Favorable Response

Fewer previous anti-TNF α agents

Cessation of anti-TNF α agent for intolerance vs. efficacy

Lower endoscopic severity at initiation

Adverse Events 12%

Dermatologic

Infections: Respiratory and GI

Iborra M et al. AP&T 2019; 50:278-288

Tofacitinib is Effective for Clinical Remission

Sandborn WJ, NEJM 2017

Tofacitinib is effective for mucosal healing

Sandborn WJ, NEJM 2017

D’Amico F et al. Ther Adv Gastroenterol 2019; 12: 1-10