Future Directions in IBD: Treatments & Approaches

JAMES LORD, MD PHD BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON MEDICAL CENTER APRIL 29, 2018 Why do pharmaceuticals dominate IBD therapy discussions?

 “Evidence-Based Medicine”

 Strongest evidence is large, blinded, randomized, placebo-controlled clinical trial

 Hard to blind, randomize, or make placebo for non- pharmaceutical interventions (eg: surgery, diet, THC…)

 Safety mechanisms make such clinical trials expensive

 Money

 Global biopharmaceuticals market to exceed $340 billion by 2023

 Improving technology

 Safety and efficacy of pharmaceuticals rapidly improving

IBD Drugs: Current

Small Molecules Biologicals

Steroids 5’ASA’s IMM’s Anti-TNF’s Anti-Integrins Anti-IL-12/23 Prednisone Sulfasalazine Azathioprine Infliximab Natalizumab Ustekinumab Solu Medrol Mesalamine 6-MP Adalimumab Vedolizumab Briakinumab Budesonide Balsalazide Methotrexate Certolizumab Etrolizumab Brazikumab Golimumab PF-00547659 Guselkumab Risankizumab Mirikizumab Jakinibs S1P1 Agonists Tofacitinib Ozanimod Filgotinib Etrasimod Upadacitinib How New IBD Drugs Generally Work

Block immune cell Block immune cell communication migration  Biologicals:  Biologicals:

 Block signals (cytokines)  Block receptors (integrins) outside cells from on circulating cells from interacting with receptors recruiting them from blood on cell surface to tissue

 Small Molecules (Jakinibs):  Small molecules (S1P1’s):

 Block cell surface receptor  Trap immune cells in lymph signals (kinases) inside cells nodes Blocking immune cell communication (cytokines)

Biologicals: Outside immune cell Anti-TNF, anti-IL (infliximab, ustekinumab…)

Inside immune cell Small Molecules: Jakinib (tofacitinib…)

Olivera P, et al. Gut February 2017 Vol 66 No 2 Blocking immune cell migration: Anti-integrins (biologicals) Blocking immune cell migration: S1P1 agonists (small molecules)

 Activate the S1P1 Receptor, used by lymphocytes to “smell” their way out of a lymph node Blocking immune cell migration: S1P1 agonists (small molecules)

 S1P1 receptor gets down-regulated, and lymphocytes get trapped in lymph nodes, so they cannot go to inflamed tissues

S1P1 agonist

S1P1 agonist Small Molecules versus Biologics

Small Molecules Biologicals

Pros: Cons: Pros: Cons: Cheap Nonspecific Specific Expensive

Fast Short half life Long half life Slow Oral IV or shots Allergies rare Immunogenic

Small molecules are much less complex than biologicals Small molecules can be pills Biologicals are proteins. If you eat them, they are food. Small molecules are much cheaper than biologicals

$120,000 IBD drugs by price $100,000

$80,000

$60,000

$40,000

$20,000

Lialda

Apriso

Asacol

Delzicol

Pentasa

MTX (SQ) MTX

MTX (PO) MTX

Infliximab*

prednisone

balsalazide

Golimumab

budesonide

azathioprine

sulfasalazine

Ustekinumab

Adalimumab

Certolizumab

Natalizumab*

Vedolizumab* Estimated Annual Cost for 70 kg Patient kg70 forCost Annual Estimated Steroids Immunomodulators 5'ASA's Biologicals

Walgreens CVS Target Kmart Costco Kroger Safeway Rite-Aid Walmart HealthWarehouse Blink Health

All prices per GoodRx.com or WellRx.com, 9/3/17, and *exclude infusion center costs* Biologic drugs require complex staged culture in sterile bioreactors Small molecules do not Current small molecules are less effective than biologics

Crohn’s: SONIC Colombel et. al., N Engl J Med 2010;362:1383-95

c. 15% Biologic drug efficacy wanes over time

Loss Of Response to Infliximab Loss Of Response to Adalimumab (ACCENT-I trial, Hanauer, S., Lancet 2002, (CHARM trial, Colombel, J.F., Gastro 2007, 359:1541.) 132:52.)

100% 100%

90% 90%

80% Infliximab 80% Adalimumab

Dose: Dose: CDAI>70)

CDAI>70) 70% 70%

D D

60% 10 mg/kg 60% 40 mg (n=112) weekly 50% 50% (n=157) 5 mg/kg 40% (n=113) 40% 40 mg 30% 30% every 2 wks 0 mg/kg (n=172) 20% (n=110) 20%

none % of Patients with Benefit ( Benefit with Patientsof % % of Patients with Benefit ( Benefit with Patientsof % 10% 10% (n=170)

0% 0% 0 30 54 0 26 56 Weeks Weeks Crohn’s Disease Clinical Trials: Biologic drug efficacy wanes over time: Why?

 Rapid protein drug clearance?

 Inflammation gobbles up proteins?

 Protein is lost in diarrhea?

 Immune reaction (antibodies) to protein drug?

 Immune system recognizes protein as foreign

 Antibodies block or clear drug?

 Drug target is too specific?

 Disease mechanism “escapes” blockade by using a different mechanism? “Life finds a way”

Ustekinumab Tofacitinib Tofacitinib safety profile

100% 90% 80% 70% 60% 50% 40% 30% Placebo 20% 10% Tofa, 5 mg 0% Tofa, 10 mg

Sandborn WJ et. al, N Engl J Med. 2017 May 4;376(18):1723-1736 Tofacitinib is effective induction therapy for UC

Remission at week 8 Mucosal Healing at week 8

Independent but identical Sandborn WJ et. al, N Engl J Med. 2017 May 4;376(18):1723-1736 phase III induction trials Tofacitinib is effective maintenance therapy for UC

Remission at week 52 Mucosal Healing at week 52

Coming this June for UC?

Sandborn WJ et. al, N Engl J Med. 2017 May 4;376(18):1723-1736 Tofacitinib week 4 benefit in Crohn’s (phase II) less impressive

100% 90% 80% 70% 60% Placebo 50% Tofa, 1mg 40% Tofa, 5mg 30% Tofa 15mg 20% 10% 0% Response Remission

Sandborn WJ et. al., Clinical Gastroenterology and Hepatology 2014;12:1485–1493 Filgotinib benefit in Crohn’s induction phase II was more impressive

100% Week 10 90%

80%

70%

60%

50% Placebo 40% Filgotinib 30% 20% Now 10% recruiting

0% phase III Response Remission Endoscopic for UC & (DCDAI of 100) (CDAI < 150) Response Crohn’s (DSES-CD of 50%)

Vermeire S et. al., Lancet Vol 389 January 21, 2017 Upadacitinib also worked in Crohn’s induction phase II (CELEST)

100% Week 16 90%

80%

70% Placebo 60% Upa, 3mg Bid 50% Upa, 6mg BID 40% Upa, 12 mg BID 30% Upa,Now 24 mg BID 20% Upa,recruiting 24mg QD phase III for 10% Crohn’s, 0% Response Remission Endoscopic Phase II for (CDAI < 150) Response UC (DSES-CD of 50%)

Sandborn, WB, DDW 2017, abstract 874h, in Gastroenterology, Vol 152 (5), Suppl 1, pp S1308-S1309 Ozanimod showed efficacy for UC induction in phase II (TOUCHSTONE)

Sandborn WJ et. al., NEJM 2016 May 5;374(18):1754-62. Ozanimod showed efficacy for UC maintenance in phase II (TOUCHSTONE)

Now recruiting phase III for UC, Phase II for Crohn’s

Sandborn WJ et. al., NEJM 2016 May 5;374(18):1754-62. Etrasimod showed efficacy for UC induction in phase II (OASIS)

Week 12, UC 100% 90% 80% 70% 60% p=0.003 50% p=0.004 P<0.001 40% 30% 20% 10% 0% Clinial + Clinical Endoscopic Endoscopic remission improvement remission Placebo Etrasimod 2 mg Arena Pharmaceuticals press release, March 19, 2018 Entirely new pills for IBD are coming

Jakinibs S1P1 Agonists  Tofacitinib (Xeljanz)  Ozanimod

 UC only, June 2018  UC phase III

 Filgotinib  Crohn’s phase II

 UC & Crohn’s, phase III  Etrasimod

 Upadacitinib  UC phase II data just out

 Crohn’s phase III  Not yet recruiting phase III

 UC phase II Newer versions of current biologics are coming

Anti-integrins Anti-IL-23 Similar to vedolizumab: Similar to ustekinumab:

 Etrolizumab  Brazikumab  Anti-integrin b7  Briakinumab  Blocks a4b7 (like vedolizumab) plus aEb7  Guselkumab

 PF-00547659  Risankizumab

 Anti-addressin MADCAM1  Mirikizumab  Receptor for integrin a4b7

Clinical decision making: needs predictive biomarkers for guidance Patients with high baseline integrin alpha E expression in colon biopsies responded better to integrin beta 7 blockade than those without. Efficacy and Safety of MEDI2070, an Antibody Against Interleukin 23, in Patients With Moderate to Severe Crohn's Disease: A Phase 2a Study. Sands et. al., Gastroenterology. 2017 Jul;153(1):77-86.

aka Brazikumab, AMG139

Only people with a high blood level of IL-22 responded more to brazikumab than to placebo What is not coming:

 Mongersen (SMAD7 antisense RNA pill)

 Phase III trials failed to show anything like phase II successes

 IL-6 therapies (tocilizumab, etc)

 Trials canceled due to bowel perforations

 IL-17 therapies (sekukinumab, brodalumab)

 Actually made Crohn’s worse than placebo did

 CTLA4 therapy (abatacept)

 Actually made UC worse than placebo

What is new besides drugs?

 Diet:

 Autoimmune Protocol (AIP: basically Paleo) diet

 Specific Carbohydrate Diet (SCD)

 Partial Enteral Nutrition (PEN)

 Curcumin  Fecal transplant

 Colonoscopic vs enema vs feeding tube delivery

 Single vs multiple (pooled) donor(s)

 Single vs multiple treatments 9 Calprotectin CRP Albumin

8 700 25 5 7 4.5 600 6 20 4 500 3.5 5 15 3 400 4 HBI (Crohn's: n=7) 2.5 300 10 2 3 pMayo (UC: n=6) 1.5 200 2 5 1

SymptomSeverity Score 0.5 100 1 0 0 0 0 0 6 0 6 0 6 11 0 6 Weeks on AIP Weeks on AIP Weeks on AIP Diet Weeks on AIP Diet Diet Diet

“The AIP dietary intervention consisted of a 6-week elimination phase (staged elimination of grains, legumes, nightshades, dairy, eggs, coffee, alcohol, nuts and seeds, refined/processed sugars, oils, and food additives) followed by a 5-week maintenance phase (during which no food group reintroduction was allowed)”

n e

i 6

e 4

a e

r 2

0 P r e P o s t

S C D

3 0

s p

i 2 0

n o

r 1 0

m i

S 0 P r e P o s t

m S C D “The patients entered 45 clinical remission on 4–12 40 weeks of EEN and were subsequently maintained 35 on PEN (50% of total

30 calories as polymeric diet, 25 usually Modulen IBD) as a EEN/PEN (n=42)

supplementary diet. “ 20 wPCDAI 15 Conventional “The route of (n=45) administration was oral, 10 but if not tolerated, 5 nasogastric feeding was 0 used instead” 0 2 5 12 24 36

“Children with CD who Months refused EN served as the control group” exclusive enteral Partial enteral nutrition (EEN) nutrition (PEN) Curcumin: extract of Turmeric

 Augments mesalamine benefit in mild to moderate UC

 3 grams curcumin/day for 1 month

 Enough to turn stool yellow, alter body odor

 Blinding thus in question 8

7 6

5 Curcumin, 4 150mg, 3x/day (n=29) 3 Placebo (n=33) 2

UC Disease Activity Index ActivityDisease UC 1 0 0 4 8 Weeks

Conclusions:

 New oral agents for IBS are promising:  Jakinibs (tofacitinib, etc.)

 S1P1 agonists (ozanimod, etc.)  New biologic (not oral) agents may have predictive biomarkers:  Colon (biopsy) integrin alpha E for etrolizumab

 Serum (blood) IL-22 for brazikumab  Diet remains hard to study  Small studies, subjective outcomes

 No placebo groups/blinding  Growing interest in fecal transplant/microbiome  Unclear if pooled or single donor is better

 Need for frequent, repeated transplants—how?

 Colonoscopy unfeasible for frequent use

 Enemas? Encapsulated “stool pills”?