Future Directions in IBD: Treatments & Approaches JAMES LORD, MD PHD BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON MEDICAL CENTER APRIL 29, 2018

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1 Future Directions in IBD: Treatments & Approaches JAMES LORD, MD PHD BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON MEDICAL CENTER APRIL 29, 2018

2 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 nonpharmaceutical 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

3 IBD Drugs: Current Small Molecules Biologicals Steroids 5 ASA s IMM s Anti-TNF s Anti-Integrins Anti-IL-12/23 Prednisone Solu Medrol Budesonide Sulfasalazine Mesalamine Balsalazide Azathioprine 6-MP Methotrexate Infliximab Adalimumab Certolizumab Golimumab Natalizumab Vedolizumab Ustekinumab

4 IBD Drugs: Current & Future Small Molecules Biologicals Steroids 5 ASA s IMM s Anti-TNF s Anti-Integrins Anti-IL-12/23 Prednisone Solu Medrol Budesonide Jakinibs Tofacitinib Filgotinib Upadacitinib Sulfasalazine Mesalamine Balsalazide Azathioprine 6-MP Methotrexate S1P1 Agonists Ozanimod Etrasimod Infliximab Adalimumab Certolizumab Golimumab Natalizumab Vedolizumab Etrolizumab PF Ustekinumab Briakinumab Brazikumab Guselkumab Risankizumab Mirikizumab

5 How New IBD Drugs Generally Work Block immune cell communication Biologicals: Block signals (cytokines) outside cells from interacting with receptors on cell surface Small Molecules (Jakinibs): Block cell surface receptor signals (kinases) inside cells Block immune cell migration Biologicals: Block receptors (integrins) on circulating cells from recruiting them from blood to tissue Small molecules (S1P1 s): Trap immune cells in lymph nodes

6 Blocking immune cell communication (cytokines) Outside immune cell Biologicals: Anti-TNF, anti-il (infliximab, ustekinumab ) Inside immune cell Small Molecules: Jakinib (tofacitinib ) Olivera P, et al. Gut February 2017 Vol 66 No 2

7 Blocking immune cell migration: Anti-integrins (biologicals)

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

9 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

10 Small Molecules versus Biologics Small Molecules Biologicals Pros: Cons: Pros: Cons: Cheap Fast Oral Allergies rare Nonspecific Short half life Specific Long half life Expensive Slow IV or shots Immunogenic

11 Small molecules are much less complex than biologicals

12 Small molecules can be pills

13 Biologicals are proteins. If you eat them, they are food.

14 Estimated Annual Cost for 70 kg Patient prednisone budesonide azathioprine 6-MP MTX (PO) MTX (SQ) sulfasalazine balsalazide Lialda Asacol Delzicol Apriso Pentasa Infliximab* Adalimumab Certolizumab Golimumab Natalizumab* Vedolizumab* Ustekinumab Small molecules are much cheaper than biologicals $120,000 $100,000 $80,000 $60,000 $40,000 $20,000 IBD drugs by price $0 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*

15 Biologic drugs require complex staged culture in sterile bioreactors

16 Small molecules do not

17 Current small molecules are less effective than biologics Crohn s: SONIC Colombel et. al., N Engl J Med 2010;362: c. 15%

18 % of Patients with Benefit (DCDAI>70) % of Patients with Benefit (DCDAI>70) Biologic drug efficacy wanes over time 100% Loss Of Response to Infliximab (ACCENT-I trial, Hanauer, S., Lancet 2002, 359:1541.) 100% Loss Of Response to Adalimumab (CHARM trial, Colombel, J.F., Gastro 2007, 132:52.) 90% 90% 80% 70% Infliximab Dose: 80% 70% Adalimumab Dose: 60% 50% 40% 30% 20% 10% 10 mg/kg (n=112) 5 mg/kg (n=113) 0 mg/kg (n=110) 60% 50% 40% 30% 20% 10% 40 mg weekly (n=157) 40 mg every 2 wks (n=172) none (n=170) 0% 0% Weeks Weeks Crohn s Disease Clinical Trials:

19 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?

20 Life finds a way

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22 Ustekinumab

23 Tofacitinib

24 Tofacitinib safety profile 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Placebo Tofa, 5 mg Tofa, 10 mg Sandborn WJ et. al, N Engl J Med May 4;376(18):

25 Tofacitinib is effective induction therapy for UC Remission at week 8 Mucosal Healing at week 8 Sandborn WJ et. al, N Engl J Med May 4;376(18): Independent but identical phase III induction trials

26 Tofacitinib is effective maintenance therapy for UC Remission at week 52 Mucosal Healing at week 52 Sandborn WJ et. al, N Engl J Med May 4;376(18): Coming this June for UC?

27 Tofacitinib week 4 benefit in Crohn s (phase II) less impressive 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Response Remission Placebo Tofa, 1mg Tofa, 5mg Tofa 15mg Sandborn WJ et. al., Clinical Gastroenterology and Hepatology 2014;12:

28 Filgotinib benefit in Crohn s induction phase II was more impressive 100% 90% Week 10 80% 70% 60% 50% 40% 30% 20% 10% 0% Response (DCDAI of 100) Remission (CDAI < 150) Endoscopic Response (DSES-CD of 50%) Placebo Filgotinib Now recruiting phase III for UC & Crohn s Vermeire S et. al., Lancet Vol 389 January 21, 2017

29 Upadacitinib also worked in Crohn s induction phase II (CELEST) 100% 90% Week 16 80% 70% 60% 50% 40% 30% 20% 10% 0% Response Remission (CDAI < 150) Endoscopic Response (DSES-CD of 50%) Placebo Upa, 3mg Bid Upa, 6mg BID Upa, 12 mg BID Now recruiting phase III for Crohn s, Phase II for UC Upa, 24 mg BID Upa, 24mg QD Sandborn, WB, DDW 2017, abstract 874h, in Gastroenterology, Vol 152 (5), Suppl 1, pp S1308-S1309

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

31 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):

32 Etrasimod showed efficacy for UC induction in phase II (OASIS) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% p=0.004 Clinial + Endoscopic remission Placebo Week 12, UC P<0.001 Clinical remission Etrasimod 2 mg p=0.003 Endoscopic improvement Arena Pharmaceuticals press release, March 19, 2018

33 Entirely new pills for IBD are coming Jakinibs Tofacitinib (Xeljanz) UC only, June 2018 Filgotinib UC & Crohn s, phase III Upadacitinib Crohn s phase III UC phase II S1P1 Agonists Ozanimod UC phase III Crohn s phase II Etrasimod UC phase II data just out Not yet recruiting phase III

34 Newer versions of current biologics are coming Anti-integrins Similar to vedolizumab: Etrolizumab Anti-integrin b7 Blocks a4b7 (like vedolizumab) plus aeb7 PF Anti-addressin MADCAM1 Receptor for integrin a4b7 Anti-IL-23 Similar to ustekinumab: Brazikumab Briakinumab Guselkumab Risankizumab Mirikizumab

35 Clinical decision making: needs predictive biomarkers for guidance

36 Patients with high baseline integrin alpha E expression in colon biopsies responded better to integrin beta 7 blockade than those without.

37 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 Jul;153(1): aka Brazikumab, AMG139 Only people with a high blood level of IL-22 responded more to brazikumab than to placebo

38 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

39 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

40 Symptom Severity Score Weeks on AIP Diet HBI (Crohn's: n=7) pmayo (UC: n=6) Calprotectin Weeks on AIP Diet CRP 0 6 Weeks on AIP Diet Albumin 0 6 Weeks on AIP 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)

41 C re a c tiv e p r o tie n P r e P o s t S C D

42 S im p le E n d o s c o p ic S c o re fo r C ro h n 's d is e a s e P r e P o s t m S C D

43 wpcdai The patients entered clinical remission on 4 12 weeks of EEN and were subsequently maintained on PEN (50% of total calories as polymeric diet, usually Modulen IBD) as a supplementary diet. The route of administration was oral, but if not tolerated, nasogastric feeding was used instead Children with CD who refused EN served as the control group exclusive enteral nutrition (EEN) Months Partial enteral nutrition (PEN) EEN/PEN (n=42) Conventional (n=45)

44 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

45 UC Disease Activity Index Curcumin, 150mg, 3x/day (n=29) Placebo (n=33) Weeks

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48 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?