August 10, 2019

IBD Treatments on the Horizon

DR. VIYAN UDAWATTA ASSISTANT PROFESSOR DIVISION OF GASTROENTEROLOGY, HEPATOLOGY & NUTRITION THE OHIO STATE UNIVERSITY WEXNER MEDICAL CENTER

Confidential. For internal use only. Disclosures • None History of in IBD 1955: Corticosteroids shown to be 1989: MTX shown to be effective in CD effective in UC 1974: Azathioprine shown to be effective in UC 1948: Sulfasalazine discovered to 1997: anti-TNF biologic data published be effective in UC 1977: 5-ASA compounds in general shown to be showing effectiveness in inducing 1962: 6-MP shown to be effective in UC effective in UC remission in CD

1948 1953 1958 1963 1968 1973 1978 1983 1988 1993

2013: FDA approves Simponi for UC

2014: FDA approves Entyvio for UC and CD

2016: FDA approves Stelara for CD

2016: FDA approves biosimilar (of Humira) AMJEVITA for UC and CD (not yet available)

2017: FDA approves biosimilar (of Remicade) RENFLEXIS for UC and CD

2017: FDA approves biosimilar (of Remicade) IXIFI for 2005: FDA approves Remicade for UC UC and CD

2007: FDA approves Humira for CD 2017: FDA approves biosimilar (of Humira) CYLTEZO for UC and CD (not yet available) 1998: FDA approves Remicade for CD 2008: FDA approves Tysabri for CD 2018: FDA approves Xeljanz for UC 2008: FDA approves Cimzia for CD 2019: FDA accepts application for subcutaneous 1997: anti-TNF biologic data 2012: FDA approves Humira for UC administration of Enyvio for UC published showing effectiveness in inducing remission in CD 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2017 2019

Today 3 Advances in our Understanding of IBD: Natural History • • Only 1/3 of patients will sustain remission for 10 years • 20-30% colectomy within 25 years of diagnosis

• Crohn’s Disease • Most: periods of flares and remission, 10-15%: chronic disease progression • Average time to surgery 15-20 years • Most (60-80%) will require surgery • Third of patients will require a 2nd surgery within 10 years

4 Advances in our Understanding of IBD

• Historically, symptoms have driven therapy decisions • Nearly 50% of adult patients with IBD in endoscopic remission have symptoms typical of IBD • Nearly 50% of adult patients with active IBD do not have typical symptoms

• Symptoms improvement/resolution absolutely important!

• Objective measures also extremely important

5 Advances in our Understanding of IBD • Severe inflammation predicts outcomes in both CD and UC

Mild to moderate inflammation

Severe inflammation

6 Allez et al, AJG 2002 Advances in our Understanding of IBD Symptoms • Tissue healing leads to: • better symptoms • fewer hospitalizations • fewer surgeries Healing

• Tissue healing reduces colon No cancer rates in UC healing

Abdominal Surgery

No healing 7 Schnitzler et al 2009 Healed Partial healing Anti-TNF medications: a few observations • Tissue improvement and remission in 75% and 45%, respectively • ~1/3 of patients have no response; another ~1/3 with partial response

• Almost 50% of patients lose response by year 1 • ~10% of those patients lose response each year after • Strategies like therapeutic drug monitoring helps get every last drop, but new therapies are needed

8 Beyond anti-TNF

MEDICATIONS ALREADY AVAILABLE

9 Real-world outcomes of Entyvio® in UC Entyvio® () • Approved for UC and CD in 2014 • “Gut specific” antibody against α4β7 integrin • Blocks inflammatory cells from migrating from blood circulation to intestines • IV infusions (similar to Remicade) given at weeks 0, 2, 6, then every 8 weeks Real-world outcomes of Entyvio® in CD • May work better in UC than CD • Longer duration of therapy needed in CD

10 Kotze PG et al APT 2018 Entyvio® (Vedolizumab) • One of the safest biologics on the market (4 year safety data of 2830 patients) • no increased risk of serious infection compared to placebo

• ≤5% infusion reaction

• <1% malignancy rate

• No heart failure or demyelinating complications

• 1 case of PML (in HIV positive patient)

• Drug may cross placenta

11 Clinical remission of CD at week 44 on Stelara compared to placebo

p=0.005 Stelara® () Δ17.2% 60.00% 53.10% • Blocks cell signaling molecules IL-12 50.00% and IL-23 40.00% 35.90% • Currently only approved for CD, but 30.00% expecting approval for UC in Fall 2019 20.00%

Percent Percent ofSubjects 10.00% • Infusion → subcutaneous injection 0.00% • Week 8 symptom improvement and Placebo 90 mcg SC q8wk resolution, ~50% and ~30%, Stelara respectively 6 month endoscopic response and remission rates on Stelara • Very safe • no association with opportunistic infections like tuberculosis • Safe in heart failure, multiple sclerosis • Safe in pregnancy and breastfeeding, but long-term data lacking

Adapted from Feagan et al. New England J Med 2016; Battat R et al. CGH 12 2017 Stelara®: Anticipated approval for Ulcerative Colitis

Week 44 outcomes on Stelara in patients with UC

Placebo SC Ustekinumab 90 mg SC q8w

80.00 71.02 70.00 p<0.05 for all outcomes

60.00 51.14 50.00 43.75 44.57

40.00 28.57 30.00 24.00

20.00

10.00

0.00 Proportion Proportion of patients (%) Patients in clinical remission Patients maintained clinical Patients achieved endoscopic response healing

Outcomes

Unpublished industry data. Courtesy of Janssen Pharmaceutical/Janssen 13 Scientific Affairs, LLC Mucosal Healing Rates with Xeljanz 50.0% Xeljanz® (Tofactinib) 45.7% 45.0%

• Approved only for UC 40.0% 37.4% • Blocks JAK1 and JAK3>JAK2 in 35.0% order to block multiple pro- 30.0% 28.4% inflammatory cytokines 25.0% 20.0% • Oral , 10mg twice 15.0% 13.1% daily →5mg twice daily (typically 11.6% after 8 weeks) 10.0% 5.0% • Prior anti-TNF exposure doesn’t 0.0% hinder effectiveness Placebo Xeljanz 5mg BID Xeljanz 10mg BID • Symptom improvement can be Week 8 1 Year seen in as little as 3 days

14 Adapted from Sandborn WJ et al NEJM 2017 Xeljanz®: Safety

• Most common side effects: nasopharyngitis, arthralgias, headache

• Rates nearly the same in placebo arm

• Herpes zoster (shingles) risk 5% with 10mg twice daily dosing

• Recommend Shingrix® vaccine

• Risk of non-melanoma skin cancer

• LDL and HDL Cholesterols may increase within first 1-2 months • Rare lab abnormalities: low white cell counts, high serum creatine kinase (muscle turnover byproduct), elevated liver enzymes • Should not be combined with Imuran (azathioprine), 6-MP, Methotrexate, biologics

15 New Drug Discovery

CLINICAL RESEARCH

16 Clinical Research Process

Pre- • Lab studies Clinical Research • Animal research

• Phase 1 - Safety Clinical • Phase 2 - Efficacy Trials • Phase 3 – Effectiveness • Open label extension

Drug • Phase 4 Approval • FDA monitoring

17 New Drug Discovery

• Process can take more than 10 years

• According to the Deloitte Center for Health Solutions, the cost to bring a new drug from discovery to market is $2,168 million*

• Additional $312 million is spent after the drug is approved

Tufts Center for the Study of Drug Development. Published March 10, 2016. www.marketwired.com/press-release/tufts-center-study-drug- development-assessment-cost-develop-win-marketing-approval-new-2104802.htm. Accessed July 31, 2018.

*Deloitte Center for Health Solutions. Published December 2018. https://www2.deloitte.com/us/en/pages/life-sciences-and-health- care/articles/measuring-return-from-pharmaceutical-innovation.html. Accessed January 2019

18 How Are New Drugs Found?

• Identifying active ingredient or mechanism of traditional drugs and using this knowledge to find new IBD drugs

• Unexpected side effects from existing drugs can yield potential new drugs

• Understanding how IBD affects the body on a cellular and physiological level and targeting drugs to stop or reverse IBD

19 What Questions Need to Be Answered

• What is the mechanism of action?

• What potential benefits does the compound have?

• What are the potential risks of the compound?

• How is it absorbed in the body?

• How does the body metabolize it?

• How does the body excrete it?

• How is it disturbed in the body?

20 How are these questions answered?

• Computer models

• Perform laboratory tests using animal and human cells

• Test compounds in animals to determine safety of compounds

21 What Happens Next?

A few of the compounds (5 to 10) will be tested in humans

Must have FDA approval before test in people

• Submit application to FDA with all scientific research (called an investigational new drug application or IND)

• Medical and scientific experts review application

• If preliminary research and safety profile look promising, then begin clinical trials

22 Purpose of Clinical Trials

• Each clinical trial phase is designed to advance the knowledge of new treatment

• Gain better understanding of treatment

• Learn risks of new treatment

• Demonstrate effectiveness and safety in treating IBD

23 Phase 1 Trial: Safety

• Goal is to show that short-term use of the product is safe in people (usually healthy volunteers)

• Usually 10-30 participants

• About 70% of drugs move to Phase 2 trials

24 Phase 2 Trial: Efficacy

• Questions the trial answers

o Does it treat IBD?

o Effective dose and dosing frequency

o Best route for drug delivery (ie, iv, oral, etc.)

o Reconfirm safety in longer studies and in patients

• Most drugs fail during Phase 2 trials • 33% of drugs move onto phase 3

25 Phase 3 Trial: Effectiveness

• Goals of the trial

o Collect enough data to show overall risk-benefit is worth approving the drug for IBD

o Show effectiveness of drug on large scale and the appropriate dose for patients

o If data shows that the benefits outweigh the risks, then submit an application for approval to the FDA

• Approximately 25-33% of drugs succeed and reach the general public

26 FDA Approval

• If phase 3 data is positive, then submit application to FDA, FDA requires two, large, well-controlled trials to approve most drugs.

• Scientific and medical experts review all data

• Potential FDA actions

o Drug can be approved for use

o More studies may be required

o Application can be rejected

27 Post-Market Monitoring Phase 4 Trials

• Done after a drug is approved to monitor long-term safety

• Not all drugs complete this phase

• “Real life” study of treatment

28 FDA Monitoring

Continues to monitor safety of new drug

Monitors manufacturing of the product

Responds to complaints from the public and medical field

29 Targets for IBD Drug Development

Fecal microbiota alteration Janus Kinase (JAK) Inhibitors: Xeljanz Upadacitinib Filgotinib

Anti-TNF Inhibitors: Remicade Humira Cimzia Simponi

Phosphodiesterase Sphingosine-1 inhibitor-4: phosphate Apremilast Anti-IL 12/23: receptor (S1PR): Stelara Ozanimod Anti-IL 23: Etrasimod Anti-adhesion/anti-trafficking: Tysabri® Entyvio® Etrolizumab Anti-MAdCAM Modified from Ungaro R et al, Lancet 2017 Medications in the Pipeline

BIOLOGICS Etrolizumab Clinical Response and Remission Rates in Moderate-to-Severe UC Clinical Response 70% Clinical Remission Etrolizumab 60% • against 50% 40% 33% α4β7 and αEβ7 49% 30% • Treatment for UC and CD 38% 31% 20% 34% 29% • Similar mechanism of action to 21% Proportion Proportion Patients of(%) 10% 10% 10% 5% 8% Entyvio® 0% 0% Placebo Etrolizumab Etrolizumab Placebo Etrolizumab Etrolizumab • “Gut specific” 100mg 300mg+LD 100mg 300mg+LD • Blocks inflammatory cells attaching Week 6 Week 10 to walls of blood vessels and Endoscopic Remission Rates in UC migrating to GI tract 12% 10% • Subcutaneous injection 10% 8% 8% 8%

6%

4% 3% 3% Percent Percent ofPatients 2% 0% 0% Week 6 Week 10

Placebo Etrolizumab 100mg Etrolizumab 300mg+LD Vermeire S et al. Lancet 2014 Week 12 Outcomes for Risankizumab in Moderate-to-Severe Crohn's Disease 45.0% 41.5% Risankizumab 40.0% 36.6% 36.6% 37.0% 35.0% 30.0% 27.0% • Moderate-to-severe CD 24.4% 25.0% 20.5% 20.0% 20.0% • Targets cell signaling molecule 15.4% 15.0% 15.0% 13.0% IL-23 (p19 subunit) only (Stelara 10.0% 5.0% 3.0% targets both IL-12 and IL-23) Proportion Patients (%) of 0.0% Clinical Clinical Endoscopic Endoscopic • Infusion → subcutaneous Remission Response Remission Response injection Placebo 200mg Risankizumab 600mg Risankizumab • Promising short- and long-term Risankizumab Open-Label outcomes Extension to 52 weeks of PhasePlacebo 2 200mg • No increased adverse side Trial Risankizumab 600mg effects compared to placebo in 90.0% 84.0% 81.0% Risankizumab 77.0% 80.0% 71.0% short term 70.0% 60.0% 53.0% 50.0% 41.0% 40.0% 30.0% 20.0% 10.0%

0.0% Proportion Proportion Patients of(%) Clinical Response or Remission Endoscopic Response or Remission

33 Feagan BG et al, Lancet 2017; Feagan BG et al, Lancet 2018 MIRIKIZUMAB WEEKS 12 AND 52 RESULTS FOR UC

Mirikizumab Clinical Remission Endoscopic Response (Mayo 0-1) 57.4%

• Moderate-to-severe UC and CD *

*

47.8%

*

46.8% 37.0%

• Targets IL-23 (p19 subunit) 30.6%

23.8%

22.6% 15.9%

• IVF → subcutaneous 6.3% 4.8%

• Most effective dose and PBO MIRI 50MG MIRI MIRI MIRI frequency of maintenance doses 200MG 200MG 200MG Q4W K Q12W K not yet certain (%) PATIENTS OF PROPORTION W EEK 12 W EEK 52 • Similar rates of response for CD and UC MIRIKIZUMAB 12 WEEK INDUCTION RESULTS FOR CROHN'S DISEASE • Side effects similar to placebo PBO

* 600mg Miri *

1000mg Miri

*

43.8%

*

37.5%

*

*

28.1%

21.9%

(%)

20.3%

15.6%

10.9%

6.3% 1.6%

ENDOSCOPIC ENDOSCOPIC CLINICAL PROPORTION OF PATIENTS PATIENTS OF PROPORTION RESPONSE REMISSION REMISSION

Data from abstracts presented at DDW May 2018; Geert G et al. ECCO 34 Congress 2019. Abstract OP038 Medications in the Pipeline

ORAL MEDICATIONS – SMALL MOLECULE DRUGS Filgotinib

• JAK1-selective inhibitor for Filgotinib Week 10 Clinical Remission moderate-to-severe Crohn’s Rates for Moderate-to-Severe Crohn's disease Disease 70.0% 60.0% • Once daily medication 60.0%

• Phase 2 study showed clinical 50.0% 47.0%

benefit but not endoscopic 40.0% 37.0% 29.0% • Serious infections may be more 30.0% common compared to placebo 23.0% 20.0% 13.0% Proportion Proportion Patients of(%) 10.0%

0.0% PBO Filgotinib PBO Filgotinib PBO Filgotinib 200mg 200mg 200mg Anti-TNF Naïve Anti-TNF exposed Overall

Vermiere S et al. Lancet 2017 Week 16 Induction Results for Upadacitinib in Moderate-to-Severe CD 35% Upadacitinib 30% 25% • JAK1-selective inhibitor for 20% 15% moderate-to-severe UC and CD 10%

• Once or twice daily medication Proportion Patients of 5% 0% • Clinical and endoscopic benefit PBO 3mg BID 6mg BID 12mg BID 24mg BID 24mg daily seen early on and continue to Clinical Remission Endoscopic Response progress with time

• Serious side effects may be Week 52 Outcomes of CD Patients on greater with higher doses Upadacitinib who showed a clinical response with induction 50.0%

40.0%

30.0%

20.0%

10.0%

0.0%

3mg BID 6mg BID 12mg BID 24mg daily Proportion Proportion Patients of(%) Clinical Remission Endoscopic Remission Endoscopic Response

Sandborn WJ et al. Gastroenterology 2017 Abstract; Sandborn WJ et al. UEQ 37 Week 2018 Abstract Ozanimod

• S1P receptor agonist Ozanimod UC Outcomes at week 8 • Prevents T-cells (an inflammatory 40% cell) from leaving lymph node 35% 34% • Treatment for moderate-to-severe UC and CD 30%

• Oral daily medication 25% • Long term safety uncertain 20%

• Similar drugs associated with 16% • Cardiac arrhythmias 15% 12% • Hepatic dysfunction Proportion Patients of(%) 10%

6% 5%

0% Clinical Remission Endoscopic Remission

PBO 1mg daily

38 Sandborn et al. NEJM 2016 Etrasimod • S1P Agonist • Treatment for moderate-to-severe UC and CD • Once daily medication • By week 12, ~42% of moderate to severe UC patients on 2mg daily dosing had endoscopic improvement vs 17% on placebo

39 Sandborn et al. ACG 2018 Abstract AJM-300

• Blocks inflammatory cell Week 8 Outcomes with AMJ-300 in migration from circulation to Moderate-to-Severe UC 70.0% intestinal tissue (anti-α4 integrin) 62.7% 58.8% • Treatment of moderate-to-severe 60.0%

UC 50.0%

• Similar to Entyvio and Tysabri 40.0%

• Three times/day dosing 29.4% 30.0% 25.5% • Side effects similar to placebo 23.5%

Proportion Proportion Patients of 20.0%

10.0% 3.9%

0.0% Clinical Response Clinical Remission Endoscopic Remission

PBO AMJ-300

40 Challenges and Future Considerations • Greatest challenge is personalizing these medications • Finding the right medication for the right patient

• Need diagnostic tools to identify inflammatory pathway in patients • Cheap and quick

• Multimodal treatment algorithms

• Better understanding of development of IBD • Microbiome’s role • Host factors (genetics, diet) • Environmental factors

• Holy Grail = a cure

41 Thank you

Questions?

42