So Long Needles!

What Pills are Here and What’s Coming

MICHAEL CHIOREAN, MD DIRECTOR – IBD CENTER OF EXCELLENCE VIRGINIA MASON MEDICAL CENTER SEATTLE, WA @mchiorean4 Disclosures

• Janssen • AbbVie • UCB • Takeda • Pfizer • Celgene • Arena • Medtronic Discussion Points

• Why are small molecules important • Advantages and disadvantages • How they work • What’s in the pipeline • How will we use them The Next Big Thing is Small (Molecules) Why are Small Molecules a Hot Topic?

• We have used them for decades ◦ 5-ASA ◦ Steroids ◦ Immunomodulators ◦ Azathioprine + 6MP ◦ Methotrexate ◦ Tacrolimus • They come in the form of pills • Hypersensitivity is very uncommon • Easy to manufacture ◦ Generics ◦ Inexpensive Cost of IBD Care

Van der Walk et al. – Gut ‘14 Biologics Manufacturing Process

Biosimilar production costs: Fill and finish - $ 100M – $ 250MCell culture production Seed train bioreactor

seed Patient

Cell culture Purification Small Molecules are Much Less Complex than Biologicals Small Molecule Drug Manufacturing Process

Generic drug production costs: - $ 1M – $ 4M Functional Differences between Biologics and Small Molecules

• Biologics: • Old small molecules ◦ Targeted (focused) (Aza, 6MP, Mtx) • The benefit and side- ◦ Diffuse (multi-target) ◦ “happenstance” drugs effects are the result of ◦ Non-specific blocking the target… ◦ Low-efficacy ◦ Beneficial (inflammation) ◦ Myriad side-effects ◦ Harmful (defense) ◦ Target-related • Or the molecule itself ◦ Molecule-related ◦ hypersensitivity Functional Differences between Biologics and Small Molecules

• Biologics: • “New” small molecules ◦ Targeted (focused) ◦ Targeted (selective) ◦ Designer drugs ◦ Designer drugs • The benefit and side- ◦ Can be easily “tweaked” effects are the result of ◦ Efficacy = biologics blocking the target… ◦ Less side-effects ◦ Beneficial (inflammation) ◦ Target-related ◦ Safer than old SM ◦ Harmful (defense) ◦ Molecule-related • Or the molecule itself ◦ Safer ◦ Hypersensitivity uncommon ◦ hypersensitivity Current IBD Therapies

Standard Anti- Anti- JAK Steroids Anti-TNF IMM integrin interleukin inhibitors

Prednisone Azathioprine Infliximab Vedolizumab Ustekinumab Tofacitinib

Solumedrol 6-MP Adalimumab

Prednisolone Methotrexate Golimumab Budesonide Certolizumab- PEG This is the only new small Small molecules Biologics molecule in 30 years! What’s New and What’s In the Pipeline

JAK S1-PR inhibitors modulators

Tofacitinib Ozanimod

Upadacitinib Etrasimod

Filgotinib Amiselimod

Baricitinib Siponimod

TD-1473 Ponesimod

Peficitinib Ceralifimod

Ruxolitinib

Lestaurtinib Mechanism of Action of JAK Inhibitors

Jakinibs

Adapted from Hodge JA et al. – Clin Exper Rheumatol ‘16 Consequences of JAK Inhibition on Signaling by Key Cytokines

• JAK-inhibitors also known as “Jakinibs”

O’Shea, Plenge – Immunity ‘12 The Importance of JAK-STAT Pathways in Autoimmune Diseases

O’Shea, Plenge – Immunity ‘12 Tofacitinib for Induction and Maintenance of Remission in UC

Remission = Total Mayo score ≤ 2, no score >1 and bleeding =0

100% 100% Remission wk 8 Remission wk 52

80% 80% p<0.001

60% 60% p<0.001 40.6% p<0.001 % patients % 40% p<0.001 40% % patients % 34.3%

18.5% 20% 16.6% 20% 8.2% 11.1% 3.6% 0% 0% Placebo Tofacitinib Placebo Tofacitinib Placebo Tofa 5 mg Tofa 10 mg OCTAVE Induction 1 OCTAVE Induction 2 OCTAVE Sustain

Sandborn et al. – NEJM ‘17 Time Course of Clinical Response in OCTAVE 1 – Tofacitinib

Reduction from baseline in stool frequency Reduction from baseline in rectal bleeding

Hanauer et al. – CGH ‘19 Tofacitinib for Crohn’s disease

• Phase 2 trial – negative results • Program abandoned JAKinibs in Development

• Upadacitinib • Filgotinib • Baricitinib • Peficitinib • Lestaurtinib • Ruxolitinib • TD-1473 Filgotinib in Crohn’s Disease The FITZROY Study

Vermeire et al. – Lancet ‘17 Upadacitinib for Ulcerative Colitis

• JAK1-selective inhibitor

Outcomes at week 8 Remission PMS 100% Endoscopic Improvement *p<0.05 Remission FMS 80% **p<0.01 ***p<0.001 Response

60% *** *** *** 50.0% 44.9% 44.2% *** 40% * *** 35.7% 29.8% 30.6% *** 26.9% 19.6%** 19.6%** Proportion of patients (%) patients of Proportion 20% 14.9% 14.3%* * * * 13.0% 13.5% 11.5% 8.5% 8.5% 10.2% 0.0%2.2%0.0% 0% Placebo Upa 7.5 mg Upa 15 mg Upa 30 mg Upa 45 mg

Sandborn et al. – UEGW ‘18 Common Features of Jakinibs

• Pros: • Cons: ◦ Work fast (days) ◦ Systemic ◦ Work well immunosuppression ◦ Sustained response ◦ Serious infections ◦ Well tolerated ◦ Shingles ◦ Easy to use ◦ Skin cancer ◦ No immunogenicity ◦ Lipids ◦ Low hypersensitivity risk ◦ Dose adjustments S1P Receptor Modulators Result in the Sequestration of Lymphocytes in the LN

• S1P promotes the exit of activated lymphocytes from lymph nodes into Lymph node the circulation trafficking • If the S1P inhibitorsreceptor is blocked, T- cells are trapped in the lymph

Ozanimod nodes

Rivera-Nieves – Curr Opin Gastroenterol ’15; Cohen et al. – Lancet Neurol ‘16 S1P-Receptor Modulators in Development

• Fingolimod* • Ozanimod • Etrasimod • Amiselimod • Siponimod • Ponesimod • Ceralifimod

*approved for treatment of MS S1P-Receptor Modulators in Development

Etrasimod

Comi et al. – Drugs ‘17 Ozanimod for Moderate UC Week 8 Outcomes

Remission n=197 Response

p=0.048 p=0.01

Placebo 0.5 mg/kg 1 mg/kg Placebo 0.5 mg/kg 1 mg/kg

Sandborn et al. – DDW ‘15:S93 Etrasimod in UC: Primary End Point: 3-Component MCS Improvement at Week 12 (RB, SF, and Endoscopy)

3 Δ = −0.99 (P = 0.009) 2.49 Δ = −0.43 (P = 0.146)

2 1.94 1.50

Component MCS Component 1

- in 3 in

LSM Improvement From Baseline From Improvement LSM n = 54 n = 52 n = 50 0 Placebo Etrasimod 1 mg Etrasimod 2 mg

Sandborn et al. – ACG ‘18 Common Features of S1P-Receptor Modulators

• Pros: • Cons: ◦ Work well ◦ Slower onset ◦ Safe (newer generations ◦ Non-selective drugs may are even safer) have more side-effects ◦ Easy to use ◦ Systemic infections ◦ Will probably work for both UC and Crohn’s ◦ No malignancy signal ◦ No immunogenicity Small Molecules vs. Biologics Small Molecules vs. Biologics

Small Molecules Biologics Efficacy Safety Immunogenicity Combination MOA Convenience Interchangeability (biosimilars, generics) Cost (5 year horizon) The Gartner Hype Cycle of Innovation

Santoso, Alex (September 5, 2012). "Four Geeky Laws That Rule Our World". Neatorama. Retrieved April 26, 2017. The Gartner Hype Cycle of Fashion The Gartner Hype Cycle of Innovation in IBD

Microbiome science Peak of Inflated expectations

Diet Surgery Plateau of productivity

Current biologics, small molecules Slope of Enlightenment

Anti-oxidants, vitamins Trough of Disillusionment Personalized medicine Technology trigger Approach to Treatment of UC (circa 2019)

Severity-based IFX, Tofacitinib, Cys A Severe individualized therapy

Maintain with the Vedolizumab agent effective for ADA/GOL induction Moderate

Azathioprine, 6-MP Monitor Optimize Corticosteroids Risk mitigation

5-ASA, Budesonide Mild Approach to Treatment of UC (circa 2023)

1st Line Agents 2nd Line Agents

Induction of JAK inhibitors Anti-TNF Severe remission

Maintenance Anti-integrin S1P-modulators Moderate of remission Anti-IL-23

Corticosteroids Diseaseseverity

• Individualized Mild UC • Staged Rx 5-ASA, Budesonide • Combo Rx Unsolved Issues in the Management of UC

• Identifying the ideal goal of therapy ◦ Symptoms, endoscopy (healing) • Personalized therapy (which drug) • Becoming smarter about figuring out when a drug works • Which combination ◦ Current therapeutics have ceilings of 50% response and 30% remission ◦ Surpassing this ceiling will require combining MOA • Transitions from one drug to another Conclusions

• The pipeline of small molecules is very rich • Completely new mechanisms of action will become available • The gain will extend from simple convenience to efficacy, safety • Combination or sequential therapy will be the new paradigm • We will finally have enough competition to drive the prices down