New IBD Therapies Promise and Pitfalls. Frederick L. Makrauer, MD Center for Crohn s and Colitis Brigham and Women s Hospital March 12, 2016

Transcription

1 New IBD Therapies Promise and Pitfalls Frederick L. Makrauer, MD Center for Crohn s and Colitis Brigham and Women s Hospital March 12, 2016

2 None Conflicts of Interest and Disclosures

3 Treatments we will discuss Antibiotics, prebiotics, probiotics Corticosteroids Azulfidine, 5-ASA s Immunomodulators (AZT/6-MP, cyclosporine, tacrolimus) CAM (complementary and alternative therapy) Today - anti- TNF s (IFX, adlimumab, certolimumab, golimumab) anti-adhesion molecules (natalizumab, vedolizumab) Cytokine inhibitors (ustekinumab) Step-Up vs Step Down Rx Combination, Cessation and Resumption of Therapy Experimental therapies: fecal transplant, nutrients

4 I. Patient Susan S y teacher, L-sided UC x 2002, Mayo Score 0 FHx: F- CRC, M-UC PMHx: Colonic adenoma ASA 2.5 g/d, AZA 50 mg (metabolites good) Colonoscopy - L-sided mild scarring, inactive Is there anything else we should do?

5 The Challenges to Proper IBD Rx Worldwide - increasing incidence/prevalence U.S. - UC 1:400, Crohn s 1:500 Proper study endpoint deep remission No drug > 70 % effective Toxicity Insurance coverage

6 Good IBD Care is Patient - Centered

7 Individualized Rx Decisions Clinical Factors ( phenotype and activity ) Fertility, Pregnancy, Delivery and Lactation Genetic Factors ( genotype ) Past Rxs & Response Drug Metabolism (assay) Insurance Coverage Goal of Therapy (patient vs provider) Siegel, 2014

8

9 Monitoring The Patient Symptoms (activity indices) Labs: calprotectin, drug levels and antibodies Imaging (monitor radiation exposure) IBD Conference Support (patient & family)

10 Supportive Care Oral/perineal hygiene and comfort Anti-diarrheals Pain control Nutrition Counseling, support, advocacy (CCFA) Gerson and Triadafilopoulos 2000

11 IBD in Pregnancy and Delivery A dedicated Ob/Gyn Service is recommended Sweden 1209 UC and 787 CD, with 10,773 controls DVT in UC OR 3.78 Antepartum hemorrhage in CD OR 1.66 Emergency C section in UC OR 1.39; in CD OR 1.50 Broms G et al. 2012

12 Pregnancy Outcomes on Anti-TNF Therapy Case-control study following 124 pregnant women over 133 pregnancies on anti-tnf therapy Seirafi et. al. APT. 2014; 40(4):

13 II. Susan S Rapid onset of cramps, diarrhea and urgency What questions need to be answered?

14 Complications of Therapy Infection (disease activity, narcotic, CS, IFX) Hematologic Cancer skin (melanoma), cervical, lymphoma Bone marrow, liver/pancreas, skin, hair, nerve, heart TREAT Registry

15 Why does IBD happen? Genetics + innate immunity + environment Genes - NOD2, ATG16L1, Arg381Gln, and > 150 others Innate Immunity - inappropriate response to invader Environment - Microbiome dysbiosis (diet, antibio., hygiene) Abreu 2015, Serban, 2015

16 An Imbalanced Host-Microbiome Interaction Kahng, 2009

17 Gene Impact on Disease expression Only in % patients NOD2/CARD15 complicated CD course ATG16L1, JAK2 stenosis CD IRGM, TNFS15 need for surgery CD IL23R, CDPRDM1 fistulizing CD TLR4 pancolitis UC, colitis CD IKBL severity of UC Serban, 2015 from H.U.

18 Foods alter the activity of IBD Ant-inflam: fresh fruit & veggie s, SCFA, S. boulardii, VSL-3, curcumin Eg., curcumin - UC mild to moderate Inflam: fat, refined sugars, alcohol. Gluten? Eg., emulsifiers, carrageenan, metals

19 The westernized diet s impact on the microbiome from breast milk to Burger King Herbivore to carnivore Shift to hostile bacterial populations Less fruit fiber, more refined CHO, fat, sulfur Less intra-luminal SCFA*, and more H2S N-6 FA s > N-3 = more inflammation! * short-chain fatty acids = n-3 PUFA (poly-unsaturated fatty acid)

20

21 Pro-inflammatory Anti-inflammatory TNF II-1b IL-12/IL-18 IFN IL-10 TGF IL-4/IL-13 IL-1Ra PGE 2 Tolerance Loss of Tolerance Chronic inflammation vs mediator balance in IBD

22 Crohn s disease

23 Crohn s - Esophagus

24 Crohn s - Rectum

25 Crohn s - Perineum 1 o clock: incision site with a silk seton in place; drainage of pus. 3 o clock: sinus tract with fistula opening

26 Crohn s - Perianal Abscess

27 Ulcerative Colitis

28 Ulcerative Colitis Endoscopic Spectrum of Severity Normal Mild Moderate Severe

29 U.C. - Colonic Wall Thickening

30 Be sure it is IBD Infection Mesenteric Ischemia IBS ( Irritable Pouch ) Medication (NSAID, Cellcept, etc.) Diverticulitis Endometriosis Radiation therapy Lymphoma, leukemia, GVHD, cancer Microscopic colitis Diversion colitis

31 III. Susan S. 10/2009 Flared with urgency, bleeding on prednisone + + imuran + 5-ASA Should we check any additional studies? Are there other treatment options?

32 Treatments We Will Discuss Antibiotics, prebiotics, probiotics Corticosteroids Azulfidine, 5-ASA s Immunomodulators (AZT/6-MP, cyclosporine, tacrolimus) CAM (complementary and alternative therapy) Today - anti- TNF s (IFX, adlimumab, certolimumab, golimumab) anti-adhesion molecules (natalizumab, vedolizumab) Cytokine inhibitors (ustekinumab) Step-Up vs Step Down Rx Combination, Cessation and Resumption of Therapy Experimental therapies: fecal transplant, nutrition

33 Targeted Drug Therapy Korzenik 2006; Sands 2002

34 Currently Approved Biologics For IBD CD Infliximab approved for Crohn s disease (1998) Initial ca2 (Infliximab) NEJM (1997) Adalimumab approved for Crohn s disease (2007) Certolizumab Pegol approved for Crohn s disease (2008) Natalizumab approved for Crohn s disease (2008) Vedolizumab approved for Crohn s disease (2014) UC Infliximab approved for ulcerative colitis (2005) Adalimumab approved for ulcerative colitis (2012) Golimumab approved for ulcerative colitis (2013) Vedolizumab approved for ulcerative colitis (2014)

35 TNF Alpha First described in 1975 Synthesized by activated macrophages and T cells as a transmembrane precursor protein Binds to one of two receptors-tnfr1 and TNFR2 Stimulation of release of inflammatory cytokines (IL- 1beta, IL-6, IL-8, and GM-CSF) Upregulation of endothelial adhesion molecules (ICAM-1, VCAM-1, E-selectin) and chemokines 35 35

36 anti-tnf s Infliximab CD and UC Adalimumab CD and UC Certlizumab - CD Golimumab - UC

37 Anti-TNF Therapy in Crohn s Disease Infliximab, adalimumab, and certolizumab are approved for use in CD Indications for Early Treatment: Complex fistula Deep ulceration on endoscopy Young age Steroid dependence/resistance High risk anatomy Severe disease activity (wt loss, low albumin, Hgb) 37

38 % Patients Clinical Response and Remission with Infliximab P< % 60 P< % Placebo (n=25) 40 REMICADE 5 mg/kg (n=27) % 4-week Clinical Response 4% 4-week Clinical Remission 38 Targan SR, et al. N Engl J Med

39 Long-term endoscopic remission 5 year follow up data Regueiro M, et al. Clin Gastro Hep

40 Infliximab Prevents CD Recurrence After Ileal Resection 40 Regueiro M, et al. Gastroenterology

41 CD: Primary Non-Responder Individuals who fail induction within 12 weeks Approximately 35-40% of patients in anti-tnf clinical trials are primary non-responders For primary non-responders Add an antimetabolite (6MP/AZA/methotrexate) for patients not previously on these agents Switch to second anti-tnf Switch to natalizumab/vedolizumab Surgery may be an option to consider in patients with limited disease 41 Lichtenstein G, et al. Am J Gastroenterol Yanai H et al. Am J Gastroenterol

42 SONIC: Mucosal Healing at Week 26 secondary endpoint 42 Colombel JF, et al. NEJM

43 Median Serum Trough Levels (mg/ml) SONIC: IFX Trough Levels Wk 30 Higher with Concomitant AZA (N=97) IFX + placebo 3.5 (N=109) IFX + AZA 43 Sandborn W, et al. NEJM

44 CD: Secondary Non-Responder Improve after initial induction but lose response Between 10-15% lose response annually For secondary non-responders Measure drug levels and antibodies Escalate the dose Switch to another anti-tnf Switch to natalizumab/vedolizumab Work up for infections or other pathological processes 44

45 Clinical Utility of Measuring Anti-TNF Trough and Antibody Levels 45 Afif W, et al. Am J Gastroenterol. 2010; Brandse, J et al. Clin Gastro and Hep 2016

46 Anti-TNF Therapy in Ulcerative Colitis Indications: Moderate to severe UC Steroid-dependent UC Refractory pouchitis Maintenance of disease in remission Infliximab, adalimumab, and golimumab are approved for use in UC 46

47 Patients (%) Patients (%) Rates of Sustained Clinical Remission in ACT 1 and 2 Sustained Clinical Remission ACT 1 ACT P<0.001 P= P< P=0.001 P= P< Week 8 and 30 Week 8, 30, and 54 Remission Remission at Week 8 and 30 Placebo Infliximab 5 mg/kg Infliximab 10 mg/kg 47 Rutgeerts P, et al. NEJM

48 UC: Non-Responder Enhanced clearance with High BMI Male Lack of concomitant immunosuppression Low albumin Severe Inflammation Loss of proteins, lytes, minerals via ulcerated mucosa 48

49 ULTRA 1 and ULTRA 2 49 Sandborn WJ, et al. Gastroenterology

50

51

52 IV. Susan S. -11/2009 Hair loss! Mayo Score 0, colonic mucosa healed. What might be causing her hair loss? What should we do next?

53 Neutropenia Infections Anti-TNF Adverse Effects Demyelinating disease Heart failure Cutaneous reactions, including psoriasis Malignancy Induction of autoimmunity 53

54 Anti-TNF Opportunistic Infections Most Frequently Reported Organisms: Herpes Zoster Candida albicans Herpes simplex Cytomegalovirus Epstein-Barr virus Histoplasma capsulatum 54 Toruner M, et al. Gastroenterology. 2008

55 Association of Immunosuppressive Medication Combinations with Opportunistic Infection Number of Immunosuppressive Medication Combinations None OR (95% CI) 1.0 (reference) (1.5 to 5.3) 2 or (4.9 to 43) 55 Toruner M, et al. Gastroenterology

56 Advanced Age and Anti-TNF Side Effects Italian study of patients over 65 with IBD receiving infliximab or adalimumab Two control groups: < 65 with anti-tnf and > 65 with IBD but no biologics Outcome of interest: serious infection, neoplasm or death Age/Years Infection (%) Neoplasm (%) Death (%) > < 65 Control (anti-tnf) > 65 Control (no biologics) Cottone M, et al. Clin Gastroenterol and Hepatol

57 Skin Cancer Among Patients with IBD 57 Long MD, et al. Gastroenterology

58 Hepatosplenic T-Cell Lymphoma Rare and usually fatal lymphoma, that primarily affects men <35 years old As of 2013, 37 reported cases of HSTCL among patients with IBD In a systematic review of the first 36 cases, no cases were associated with anti-tnf therapy alone 20 occurred with combination therapy with infliximab and a thiopurine 16 occurred with thiopurine monotherapy 58 Kotylar DS, et al. Clin Gastro Hep Selvaraj, et al. Systematic Reviews

59 Stopping Anti-TNF Alpha Therapy One study 1 : 115 CD patients in remission IFX & AZA > 1 yr, remission for 6 mo IFX stopped; followed for 1 yr; 39% relapsed Similar study 2 : 84% CD relapsed in 5 yr In Crohn s, relapse after stopping IFX > 6MP/AZA Louis E et al. Gastroenterology Schnitzler F et al. Gut

60 Summary anti-tnf Points Anti-TNF - CD perianal fistulas, post-op prevention Combo therapy (IFX + IM) better for CD and UC Lymphoma: Imm only 4/10 3pt-yr ; Imm + IFX 6/10 3pt-yr Combination therapy = higher IFX levels 60

61 Leucocyte Adhesion Molecule Inhibitors Natalizumab - CD, anti-alpha 4 integrin (gut and CNS) Vedolizumab CD + UC, anti-alpha4b7 integrin (gut only) FDA-approved after failure of AZT, CS, anti- TNF s Future: Etrolizumab UC anti beta7 integrin (gut only) AJM300 anti-alpha-4 integrin antibody.

62 Natalizumab Humanized IgG4 monoclonal antibody that blocks the adhesion and subsequent migration of leukocytes into the gut Antibody is directed towards alpha 4 integrin α4β1 and α4β7 antibody Natalizumab is approved for the treatment of moderate to severe CD. 62

63 Progressive Multifocal Leukoencephalopathy 63 Wenning W, 2009

64 Natalizumab-Associated PML Factors Associated with Increased Risk Positive status anti-jc virus antibodies Increased duration of natalizumab treatment: greatest risk occurred after 2 years of therapy (25-48 months in this study) Prior use of immunosuppressants 64 Bloomgren G, et al. NEJM. May 2012.

65 Vedolizumab Vedolizumab - humanized, monoclonal α4β7 antibody blocks lymphocyte trafficking to gut, but not CNS The α4β7 integrin is variably expressed on circulating B and T lymphocytes interacts with addressin-cell adhesion molecule 19 (MAdCAM-1) on intestinal vasculature 65

66 Vedolizumab for Crohn s GEMINI 2 66 Maintenance phase Sandborn W, 2013.

67 New Orphan Biologics Ulcerative Colitis Tofacitinib JAK inhibitor (rheumatoid arthritis) Crohn s Disease Ustekinumab - ab to p40 unit IL s -12, -23 (psoriasis) Wils, 2016 retrospective, 122 pts , 20 centers, steroid-free. 3 mo 65% responders; with immunosuppressive OR mo 68% responders. 67

68 Janus Kinase (JAK) Inhibitors Tofacitinib Oral inhibitor of JAK kinases 1-3 Reduced cytokine production FDA-approved only for rheumatoid arthritis UC (off-label) Elevates of LDL

69 Tofacitinib 69 Sandborn W, et al.,2012.

70 IL-12 & IL-23 Receptor Inhibitors Ustekinumab Blocks IL-12 & IL-23 rec on T lymph, Ag-presenting cells FDA-approved only for psoriatic arthritis. CD (off label) after failure of anti-tnf agents 6 wk (6 mg/kg iv), U 39.7 % vs placebo 23.5 % (p =.005) 22 wk (90 mg sc q 8wks) - clinical response U 41.7 % vs placebo 27.4 % p < mucosal healing - equal - clinical remission U 69.4 % vs placebo 42.5 % p < Serious induction maintenance 4/11 Cancer - basal cell 1

71 V. Susan S. 04/ flares respond to 5 ASA boosts But, multiple skin ca s, hematuria and, Low bone density, increased glucose Urology transitional cell ca of renal pelvis What are our treatment options?

72 A. Non-targeted (today) Oral Therapies Present and future i. induction: CS, 5-ASA, CSA, tacrolimus ii. maintenance: thiopurines, MTX, 5-ASA, tacrolimus B. Targeted (breakthrough agents) i. Anti-TNF s, anti-integrins, IL 12/23 inhibitors (Stelara off label) ii. Synthetic 1. jakinibs: reduce inflammatory CK production (Tofacitinib off label) 2. anti-integrins: block circ lymphocyte entry into mucosa (AJM300) 3. sphingosine-1-phos (S1P): blocks nodal lymphocytes (Ozanimod) 4. anti-sense nucleotide: normalizes TGF B1 signaling (Mongersen)

73 The Promise Bio-engineered E. coli Nissl (IL-10) - anti-inflammatory n-3 PUFA, curcumin Fecal Transplant - under investigation Oral Therapies Pre-Rx tissue signatures - personalized care

74 The Pitfalls Is it really an IBD flare? (infection, IBS) Underestimating disease activity Under-treating (bottom-up, mono Rx) Non-responders Drug toxicity

75 Good IBD Care is Collaborative

76 Acknowledgements Our patients Our professional organizations: SGNA, CCFA Our Colleagues: Crohn s & Colitis Center Our Trainees: Edward L. Barnes, Rachel W. Winter Our Teachers: Dr. Peter A. Banks.

77 Bibliography Genetics and Environmental Interactions Shape the Intestinal Microbiome to Promote Inflammatory bowel Disease Versus Mucosal Homeostasis Gastroenterology 2010;139: Inflammatory Bowel Disease: Role of Diet, Microbiota, Lifestyle Translational Research 2012;160:29-44 Combinatorial Effects of Diet and Genetics on IBD Pathogenesis Inflamm Bowel Dis 2015; 21: Mechanism of Probiotic Action: Implications for Therapeutic Applications in IBD Inflamm Bowel Dis 2008;14: Guidelines for Management of Growth Failure in Childhood IBD Inflamm Bowel Dis 2008;14: DNA-driven Nutritional Therapy of IBD Nutrition 2009;25:885-91