Inflammatory Bowel Disease Drug Therapy 2016

Transcription

1 Inflammatory Bowel Disease Drug Therapy 206 David T. Rubin, MD, FACG Joseph B. Kirsner Professor of Medicine Chief, Section of Gastroenterology, Hepatology and Nutrition Objectives Outline the goals of management in IBD Emphasize more recent changes in the approach to management Discuss basic principles of each class of therapy in IBD Provide optimization tips for each type of therapy Page of 20

2 Goals of Management of IBD Make the diagnosis quickly and accurately Include elements of prognosis Induce remission rapidly Achieve normal bowel function (improve QoL) Inflammatory symptoms no longer present Laboratory signs of inflammation normalized Growth and development restored Maintain sustained and durable steroid-free remission over time Modify long-term outcomes of the disease Avoid hospitalization and surgery Avoidance of drug-related and disease-related complications Reduce costs of care Rubin DT, et al. Am J Gastroenterol. 206; [Epub ahead of print]. Peyrin-Biroulet L, et al. Am J Gastroenterol. 205;0(9): General Principles of IBD Management We are treating the result of the IBD, not the cause (as far as we know)- immune-based therapy Earlier is better Induction therapy usually dictates maintenance needs Severity of disease and burden of inflammation require more intensive therapy We are not curing IBD Rubin DT, et al. Am J Gastroenterol. 206; [Epub ahead of print]. Page 2 of 20

3 Evolving Principles of IBD c.206 Incorporate elements of prognosis into diagnosis and medical decision making Moving beyond one size fits all to smart therapy for the right patient Precision medicine- optimization of treatments instead of guesswork Monitoring disease activity to achieve deeper remission and to anticipate flares Rubin DT, et al. Am J Gastroenterol. 206; [Epub ahead of print]. Drug Classes in IBD 206 Aminosalicylates Oral Rectal Corticosteroids Systemic Non-systemic Rectal Oral Immunomodulators Thiopurines Methotrexate Antibiotics Biologics Anti-cytokines (Anti-TNF, Anti- IL2/23/6) Anti-integrin (adhesion molecule inhibitors) Investigational molecules Janus kinase inhibitors Anti-SMAD7 antisense oligonucleotide Sphingosine--phosphate Page 3 of 20

4 Aminosalicylates General Principles of Aminosalicylates Effective for induction of mild to moderate UC (5-40%) Effective for maintenance of mild to moderate UC (58%-78%) Delivery-response relationship- get the drug to the location of the disease Very safe, but not completely safe (renal),2 Affected by payers now- substitution required that is not bioequivalent Van Staa TP, et al. Gastroenterology. 2004;26(7): Gisbert JP, et al. Inflamm Bowel Dis. 2007;3(5): Ham M, Moss AC. Expert Rev Clin Pharmacol. 202;5(2):3-23. Hanauer SB, et al. Ann Intern Med. 996;24(2):204-. Hanauer SB, et al. Am J Gastroenterol. 993;88:88. Hanauer SB, et al. Am J Gastroenterol. 2005;00:2478. Levine DS, et al. Am J Gastroenterol. 2002;97:398. Sninsky CA, et al. Ann Intern Med. 99;5:350. Page 4 of 20

5 Pearls for Optimization of Aminosalicylates Don t forget 3% of patients intolerant/allergic Get the drug to the disease location Delivery systems may matter! If not responding, add or substitute a different delivery system 2 Dose reduction when deep remission obtained is usually safe 3 Kornbluth A, Sachar DB. Am J Gastroenterol. 2004;99(7): Harris MS, Lichtenstein GR. Aliment Pharamcol Ther. 20;33(9): Rubin DT, et al. J Crohns Colitis.206;0(8): Ulcerative Colitis Remission Status After Induction With Mesalazine Predicts Maintenance Outcomes: the MOMENTUM Trial UC patients (n=77) Induction (8 weeks) MMX mesalazine 4.8g/day Maintenance (2 months) MMX mesalazine 2.4g/day Rubin DT, et al. J Crohns Colitis.206;0(8): Page 5 of 20

6 Corticosteroids Corticosteroids Revolutionary discovery in IBD Not sustainable Worst outcomes Prognostic- need for steroids dictates subsequent outcomes 2 Understand steroid-dependence Mortality (%) 40 Corticosteroids introduced in Ulcerative Colitis Edwards FC, Truelove SC. Gut. 963;4: Faubion WA, et al. Gastroenterology. 200;2(2): Page 6 of 20

7 Corticosteroid Pharmacokinetics Clearance (L/h) Oral bioavailability (%) Systemic glucocorticoids Topical glucocorticoids Derendorf H. Respir Med. 997;9(Suppl.): A22 8. Budesonide MMX for Active Ulcerative Colitis Odds Ratios for Different Endpoints Placebo better MMX 9 mg better US trial: 9mg vs. placebo OR (95% CI) Remission 2.7 (.9, 6.6) Clinical improvement.52 (0.87, 2.65) Endoscopic improvement.43 (0.85, 2.42) 0. 0 Symptom resolution Histologic healing EU trial: 9mg vs. placebo Remission Clinical improvement Endoscopic improvement Symptom resolution Histologic healing 2.0 (.08, 3.73) 0.60 (0.9,.88) OR (95% CI) 4.49 (.47, 3.72).44 (0.80, 2.57).59 (0.88, 2.86) 2.47 (.2, 5.46) 2.74 (.04, 7.22) Sandborn WJ, et al. Gastroenterology. 202;43(5): Page 7 of 20

8 Pearls for Optimization of Steroids Use non-systemic steroids first (also protects bones) Have an exit strategy Don t lose the forest for the trees ( what s the harm of one more course of steroids? ) Don t forget vitamin D, bone density Schoon EJ, et al. Clin Gastroenterol Hepatol. 2005;3(2):3 2. Why Do We Taper Steroids? Is There Evidence For It? Fear of adrenal crisis or adrenal insufficiency This is rare! 5 mg or less does not seem to cause adrenal insufficiency Higher doses are variable 2 weeks of steroids unlikely to cause this Fear of disease relapse or rebound - no evidence Practical approach: taper over duration of induction period OR duration of time for maintenance therapy to work LaRochelle GE Jr., et al. Am J Med. 993;95(3): Streck WF, Lockwood DH. Am J Med. 979;66(6):90-4. Becker KB. Principles and Practice of Endocrinology and Metabolism. 3rd ed. Philadelphia, PA: J.B. Lippincott; 200. Melmed S, et al. Williams Textbook of Endocrinology. th ed. Philadelphia, PA: Sauders;2007. Page 8 of 20

9 Immunomodulators Thiopurines Genetically determined metabolism 6-TU 6-TGN DNA RNA Steroid sparing Lymphoma risk well known AZA XO 6-MP TPMT HPRT TPMT 6-TImP HR 5.28 (95% CI, ) Back to baseline after stopping 2 6-MMP 6-MMPN Purine synthesis Consider EBV testing for patients <20 yo Circulation Intracellular Beaugerie L, et al. Lancet. 2009;374(970): Khan N, et al. Gastroenterology. 203;45(5): Page 9 of 20

10 AZA/6-MP as Maintenance Therapy in Crohn s Disease after Steroid Induction % Patients Not Failing Trial Adults AZA 2.5 mg/kg/d (n=33) Placebo (n=30) P= Fractional Survival Children 6MP.5 mg/kg/d (n=55) Control Duration of Trial (months) Remission Duration (days) *Remission induced by prednisolone tapered over 2 wk. Candy S, et al. Gut. 995;37(5): Markowitz J, et al. Gastroenterology. 2000;9(4): Early AZA Therapy is Not More Effective Than Placebo or Conventional Therapy for CD n=63 n=67 Actuarial probability of survival free relapse. Defined as CDAI >75 in patients treated with azathioprine and placebo. Panes J, et al. Gastroenterology. 203;45(4): Proportion of patients in corticosteroid-free remission per trimester over time. Concomitant proportions were significantly different only at trimester 3 (P<.05). Cosnes J, et al. Gastroenterology. 203;45(4): Page 0 of 20

11 Lymphoproliferative Disorders with Thiopurines and anti-tnfs T-Cell Non-Hodgkin s Lymphomas with anti-tnfs Malignancies in Children Receiving IBD Therapies DEVELOP Registry (n=4343) Medication use Standardized Incidence Ratio (95% CI) Anti-TNF + immunomodulator combo 5.73 ( ) Immunomodulator mono 7.2 ( ) Anti-TNF monotherapy 0 (0-2.40) Neither Anti-TNF nor immunomodulator 0 (0-7.90) FDA Administration Adverse event Reporting System Data from Deepak P, et al. Am J Gastroenterol. 203; 08: Colletti RB, et al. Presented at DDW; May 20, 203. Pearls for Optimization of Thiopurines No prospective data on optimization Intermediate metabolizers do better! Metabolites can be helpful (Siegel) Remember shunters (6-MMP:6-TG >20:) can be treated with allopurinol 2 Bedtime or split dosing if nausea predominant Pancreatitis is genetically determined too 3 Dubinsky MC. Curr Gastroenterol Rep. 2003;5(6): Sparrow MP, et al. Clin Gastroenterol Hepatol. 2007;5(2): Ledder O, et al. Expert Rev Gastroenterol Hepatol. 205;9(4): Page of 20

12 Methotrexate Our colleagues are not as comfortable using it Effective for induction and maintenance of Crohn s disease Limited by toxicity/side effects 2 Relatively contraindicated in menstruating females No data for its use as salvage therapy after failing anti-tnf therapy Feagan BG, et al. N Engl J Med. 995;332: Patel V, et al. Cochrane Database Syst Rev. 204;(8). Pearls for Methotrexate Equal bioavailability PO up to 5 mg Use ondansetron as a pre-med (30 minutes before MTX) Take it on weekends Don t forget folic acid! (-2 mg/day) Monitor liver enzymes every 6 months (but safe),2 Te HS, et al. Am J Gastroenterol. 2000;95(): Khan N, et al. Inflamm Bowel Dis. 202;8(2): Page 2 of 20

13 Biologics Anti-TNF Therapies for IBD CD CD UC UC CD UC Modified from van Schouwenburg PA, et al. Nat Rev Rhematol. 203;9(3): Page 3 of 20

14 Anti-TNF Biological Therapies Revolutionary in IBD Loading and maintenance needed Known risks of non-response or loss of response Important role for therapeutic drug monitoring (Siegel) Pearls for Optimization of Anti-TNFs Routine assessment of stability between doses Understanding difference between class effect non-response and individual drug effect (swapping vs. cycling) Combination therapy mostly accepted as superior,2 Colombel JF, et al. N Engl J Med. 200;362(5): Panaccione R, et al. Gastroenterology. 204;46(2): Page 4 of 20

15 Higher Response and Remission Rates with Anti-TNFs in Patients with Shorter Disease Duration Infliximab for CD: Pediatric response/remission = 90%/60% Adult response/remission = 66%/39% 2 Adalimumab/certolizumab pegol for CD 3,4 : Post-hoc Shorter duration = better response Adalimumab lost of response 3 Less in disease duration Claims data 5 Shorter time to anti-tnf = less time to surgery, steroids Percent of Patients in Clinical Remission <2 years, n=36 2 to <5 years, n=63 5 years, n= Weeks from CHARM Baseline Hyams J, et al. Gastroenterology. 2007;32(3): Hanauer S, et al. Lancet. 2002;359(937): Schreiber S, et al. J Crohns Colitis. 203;7(3): Sandborn W, et al. ACG Rubin DT, et al. Inflamm Bowel Dis. 202 Dec;8(2): Biosimilars Inflectra, biosimilar to infliximab (Remicade), approved by the FDA on April 5 th, 206 Amjevita, biosimilar to adalimumab (Humira) approved by the FDA on September 28 th, Infliximab biosimilar available in EU since Food and Drug Administration. Accessed July Food and Drug Administration. Accessed September European Medicines Agency. Accessed July Page 5 of 20

16 Biosimilars Several ongoing studies in Europe and Asia Evidence that unidirectional switches are safe -7 Still not available in the USA Biosimilars are Here! What Every Gastroenterologist Needs to Know Tuesday, October 8 th :30-:50AM Annual Scientific Meeting 3B Park SH, et al. Expert Rev Gastroenterol Hepatol. 205;9(Suppl): Kang YS, et al. Dig Dis Sci. 205;60(4) Jung YS, et al. J Gastroenterol Hepatol. 205;30(2): Gesce KB, et al. J Crohns Colitis. 206;0(2): Smits LJ, et al. J Crohns Colitis [Epub ahead of print]. 6 Kolar M, et al. ECCO 206. Abstract DOP Sieczkowska J, et al. J Crohns Colitis. 206;0(2): Anti-integrins Natalizumab Vedolizumab Natalizumab Vedolizumab 300mg IV q4w 300mg IV at weeks 0, 2, and 6 then 300 mg IV q8w Modified from van Schouwenburg PA, et al. Nat Rev Rheumatol. 203;9(3): Rutgeerts P, et al. Gastroenterology. 2009;36(4): Page 6 of 20

17 Pearls for Anti-integrins You still need to check for TB and HBV prior to insurance approval! (not because of risk but because insurance companies are ignorant and require it- see There are some patients who develop joint pain after starting therapy, unclear if this is: Side effect of medication uncovering parallel joint problems in IBD patients that were otherwise treated with systemic therapy Withdrawal from steroids When joint pain develops, it can be treated with steroids, and is usually not limiting to therapy We have not had much difficulty getting dose escalation to monthly infusions I have usually tried monthly infusions for 3-4 months before making a decision to stop trying this mechanism Should You Use Combination Therapy with Vedolizumab? Clinical remission in Crohn s Disease patients at week 6 by week 0 concomitant medication use: ITT Population Colombel JF, et al. Gastroenterology. 205;48(4):S Page 7 of 20

18 Where Should We Position Anti-Integrin Therapies? In patients unresponsive to conventional therapies and anti-tnf agents Caveat is optimization of other therapies first In patients intolerant to anti-tnf therapies Class effect problems like myelitis and neuritis Intolerable side effects In patients with unusual or other immune conditions such that additional systemic immune modification may be relatively contraindicated Organ transplant patients Hereditary or acquired immune deficiencies Other possibilities: The older patient Before systemic therapies Combination with calcineurin inhibitors Natalizumab is still an effective therapy and an important option Christensen B, et al. Gastroenterology. 205;48(4):S866. Anti-IL 2/23 (Ustekinumab) Approved by the FDA for moderate to severely active Crohn s disease on September 26 th, 206 Dose Initial weight-based IV dose: 55 kg: 260 mg IV >55 kg to 85 kg: 390 mg IV >85 kg: 520 mg IV Maintenance dose: 8 weeks after initial, 90mg SC q8w Brooks M. Medscape. Accessed September 28, 206. Medscape. Accessed September 29, 206. Page 8 of 20

19 Ustekinumab (anti-il2/23) for Moderate to Severe CD Effective for induction with clinical response rates at week 6 compared to placebo (23.5%) 36.6% (mg/kg) 34.% (3mg/kg) 39.7% (6mg/kg) 00% 80% 60% 40% 35.9% * * 53.% 48.8% 44.3% Phase 3 Maintenance Study in CD 2 * 58.% * 59.4% Week 44 Outcomes * * 46.9% 42.6% 38.6% 4.% 29.8% 26.2% 49.0% * 65.4% 56.6% 20% 0% Clinical Remission Clinical Response Steroid-Free Remission Remission in anti-tnf Failure Remission in anti-tnf Naïve Placebo (n=3) 90 mg Q2 weeks (n=29) 90 mg Q8 weeks (n=28) Sandborn W, et al. N Engl J Med. 202;367(6): Sandborn W, et al. Presented at DDW, May 206. Oral Presentation 768. Ustekinumab Has a Favorable Safety Profile Through 44 Weeks: Results from IM-UNITI Results: No notable new safety issues identified No deaths or serious opportunistic infections 2.3% of patients developed antibodies, but these did not preclude drug efficacy Subjects With (%) Placebo 90 mg SC Q2w 90 mg SC Q8w Death 0% 0% 0% AEs 83.5% 80.3% 8.7% Serious AEs 5.0% 2.% 9.9% Serious Infections 2.3% 5.3% 2.3% Discontinuation due to AE 6.0% 7.6% 3.% Malignancies 0.8% 0% 0.8% AE, adverse event; Q8w, every 8 weeks; Q2w, every 2 weeks Sandborn W, et al. Presented at DDW May 206. Oral Presentation 768. Page 9 of 20

20 Summary: IBD Drug Therapy 206 Goals of management are evolving: use prognosis, target deep remission. For 5-ASAs understand delivery and possible dose-reduction in maintenance. You don t need to taper steroids as much as you think. Lymphoma is from thiopurines, goes away when these drugs are stopped. Pro-active anti-tnf drug monitoring is coming soon. Biosimilars are coming soon Interchangeability is uncertain. Anti-integrin therapies are safe and probably should be used earlier, at least in UC. Anti-IL2/23 is shown to be effective in induction and maintenance of moderate-tosevere CD as maintenance therapy. Page 20 of 20