Emerging Therapies in IBD 2006

Transcription

1 Overview Emerging Therapies in IBD 26 David T. Rubin, MD Assistant Professor of Medicine Inflammatory Bowel Disease Center University of Chicago Describe the unmet needs of therapy in IBD Emerging biologic therapy in IBD Adalimumab Natalizumab Discussion of potential strategies for the future New aminosalicylate formulation for UC: MMX Early phase development of other agents Why do we need new therapies in IBD? Substantial unmet needs Primary non-responders to standard therapies Unproven ability to change long-term outcomes Loss of response/intolerance due to immunogenicity or disease modification Dirty drugs We don t know how to predict response Systemic therapies probably not needed for local disease Emerging concerns about safety of existing therapies Infections Malignancies Cost! Surgery isn t what we d like it to be Recurrence rate in CD Pouch outcomes in UC What Pathways Are Important in IBD? Secretion of cytokines and other products from activated immune cells injury to the colon Activation of lymphocytes results in increased immune response Failure to downregulate Trafficking to the intestine of inflammatory leukocyte populations Judge et al. Inflammatory Bowel Disease. In Friedman et al, eds. Current Diagnosis & Treatment in Gastroenterology. 23;18. 1

2 Therapeutic Targets for IBD Antigens Activated macrophages IL-18 IL-12 Repair & Restitution Bacteria -Heparin -IL-11 -Nicotine Sargramostim (GM-CSF) Ag processing & presentation, Activation of macrophages: Inflammation and injury -Aminosalicylates -Sargramostim (GM-CSF) -Corticosteroids Ag recognition & activation of CD4+T Cells: Activated neutrophils IL-2 -AZA/6MP -CyA, Tacrolimus -Sargramostim (GM-CSF) -MTX, Cyclophosphamide IL-4 Second messenger systems: -MAPK inhibitors Crohn s Disease TNFα IFNγ ICAM-1 -Fontolizumab Generation of Th1/Th2 response: -Infliximab -IL-1 -IL-12, IL-18 IL-1 Recruitment, migration and adhesion: -Antisense, oligonucleotides to ICAM-1 -Anti-α4 integrin antibody Sands B. Gastroenterology 2;118:S68-S82. Key Actions Attributed to TNF Construct of the Anti-TNF Biologic Agents Macrophages Proinflammatory cytokines Chemokines Increased inflammation Cκ VL VH CH1 Endothelium Adhesion molecules Increased cell infiltration TNF Fibroblasts Epithelium Acute phase response Metalloproteinase synthesis Collagen production Ion transport Permeability Increased CRP in serum Tissue remodeling Compromised barrier function Infliximab Chimeric 75% human IgG 1 isotype PEG PEG pegol Pegylated Humanized 95% human Adalimumab Human 1% human IgG 1 isotype 2

3 Anti-TNF Biologic Agents Indications, Route of Administration, and Dosing Infliximab (infusion) Indicated for reducing the signs & symptoms and inducing & maintaining remission in adult & pediatric patients with CD and an inadequate response to conventional therapy Indicated for reducing the number of fistulas and for maintaining fistual closure in adults with CD dose: 5 mg/kg IV at, 2, and 6 weeks dose: 5 mg/kg IV q 8 weeks Adalimumab (subcutaneous, pre-filled syringe, injectable pen) In development; has demonstrated significant efficacy in phase III studies in CD Loading dose: 16 mg at week ; 8 mg at week 2 dose: mg SC weekly vs mg SC every other week pegol (subcutaneous) In development; has demonstrated significant efficacy in phase III studies in CD Loading dose: mg SC at weeks, 2, 4 dose: mg SC q 4 weeks Clinical Trials with TNF Antagonists in Crohn s Disease Agent Infliximab Adalimumab F = fistulas; P = pediatric. Study Name ACCENT I ACCENT II REACH CLASSIC I CLASSIC II CHARM GAIN PRECiSE 1 PRECiSE 2 Reference Targan et al. N Engl J Med 1997 Present et al. N Engl J Med 1999 Rutgeerts et al. Gastroenterology 1999 Hanauer et al. Lancet 22 Aim of Study (F) Sands et al. N Engl J Med 24 Lichtenstein et al. Gastroenterology 25 (F) Hyams et al. DDW 26 & (P) Hanauer et al. Gastroenterology 26 Sandborn et al. UEGW 25 Colombel et al. DDW 26 Sandborn et al. ACG 26 2 o Infx failures Schreiber et al. Gastroenterology 25 Sandborn et al. DDW 26 & Schreiber et al. UEGW 25 CLASSIC I: Therapy With Adalimumab N = 299 anti-tnf naive Wk (n = 74) Hanauer S, et al. Gastroenterology. 26;13: Wk 2 Adalimumab mg wk 2 mg wk 2 (n = 74) Adalimumab 8 mg wk mg wk 2 (n = 75) Adalimumab 16 mg wk 8 mg wk 2 (n = 76) Wk 4 Remission (CDAI < 15) CLASSIC I: Results at Week 4 18 Adalimumab /2 Adalimumab 8/ Adalimumab 16/8 24 Clinical Remission Clinical Response Δ7 p <.5 vs placebo; p =.1 vs placebo; p =.7 vs placebo. Clinical remission = CDAI < 15; Clinical response = Δ7 or Δ1 is a 7 or 1 point decrease in CDAI from baseline. Hanauer S, et al. Gastroenterology. 26;13: Clinical Response Δ1 3

4 CHARM: of Clinical Response in Crohn s Disease With Adalimumab N = 854 Included patients with prior exposure to anti-tnf agents Wk Wk 2 8 mg mg Wk (58%) responders randomized EOW = every other week. Colombel JF, et al. DDW 26, Abstract 686d. Wk 26 (n = 17) mg EOW (n = 172) mg weekly (n = 157) Remission (CDAI < 15) Wk 56 Remission (CDAI < 15) CHARM: Clinical Remission at Weeks 26 and 56 With Adalimumab Randomized Responders (n = 499) Adalimumab mg EOW Adalimumab mg Weekly /17 68/172 73/157 2/17 62/172 65/157 N = Week 26 Week 56 p <.1 vs placebo. EOW = every other week. No statistically significant difference between mg EOW and mg weekly groups. Colombel JF, et al. DDW 26, Abstract 686d. 12 CHARM: Clinical Remission of CD Over Time With Adalimumab Randomized Responders (n = 499) Adalimumab mg EOW Adalimumab mg weekly p <.1 vs placebo; p =.5 vs placebo. EOW = every other week; remission = CDAI < 15. Colombel JF, et al. DDW 26, Abstract 686d. Weeks CHARM: Additional results Response (CR7) Week 26 Week 56 Steroid-free remission Weeks 26 Weeks 56 Remission (prior anti-tnf use) Weeks 26 Weeks 56 Remission (no prior anti-tnf use) Weeks 26 Weeks 56 Fistula healing Week 26 Weeks 26 and 56 # # includes all treated patients, randomized responders and randomized non-responders p<.1; p=.8; ^^p<.5; ^p<.1 vs placebo p=.43 both ADA groups combined vs placebo Colombel JF, et al. DDW 26, Abstract 686d ADA mg QOW ^^ 31^ ADA mg QW

5 CHARM: Serious Adverse Events All Patients Incidence of Anti-Adalimumab Antibodies (AAA) Adverse Event Infections (n[%]) Abscess Tuberculosis Other opportunistic infections Wound infection/ septicemia Pneumonia, chest infection Cancer (n[%]) Multiple sclerosis (n[%]) Serum sickness (n[%]) Death (n[%]) 4-Week OL (n = 854) 11 (1.3) 5 (.6) 3 (.4) 1 (.1) 1 (.1) 1 (.1) a (n = 261) 9 (3.4) 3 (1.1) 1 (.4) 1 (.4) 1 (.4) Post Randomization (Weeks 4 56) mg EOW (n = 535) 19 (3.6) 3 (.6) 1 (.2) 1 (.2) 1 (.2) 1 (.2) mg Weekly (n = 41) 11 (2.7) 4 (1.) 1 (.2) 2 (.5) RA Clinical Trials 1 Overall, approximately 5% of patients receiving adalimumab developed low-titer AAA at least once during treatment There was no apparent correlation between the development of AAA and the occurrence of adverse events CD Clinical Trials 2,3 CLASSIC I: 2 patients (.7%) positive for AAA (1 in the placebo group) CLASSIC II: 7 patients (2.6%) positive for AAA (1 in the placebo group) a Pulmonary embolus. EOW = every other week; OL = open label. Colombel JF, et al. DDW 26, Abstract 686d. 1. Data on file, Abbott Laboratories; 2. Hanauer SB, et al. Gastroenterology. 26;13: ; 3. Peng JZ, et al. DDW 26, Abstract T1133. PRECiSE 1: Safety and Efficacy of Pegol in Patients With Moderately to Severely Active CD N = 659 Included patients with prior exposure to anti-tnf agents Wk Sandborn WJ, et al. DDW 26. Abstract 745. Wk 2 Wk 4 Wk 6 Wk 26 Response q 4 wks ( n = 328 ) Stratified for CRP (< 1 mg/l vs 1 mg/l) Stratified for baseline steroids and immunosuppressants Response: Improvement in CDAI score 1 points Co-primary endpoints were assessed in patients with CRP 1 mg/l pegol mg q 4 wks (n = 331 ) Response (Weeks 6 & 26) PRECiSE 1: Clinical Response (CDAI 1) and Remission (CDAI < 15) Intent-to-Treat Population Clinical Response Clinical Remission p <.5 vs placebo; p <.1 vs placebo. Sandborn WJ, et al. DDW 26, Abstract Week 4 Week 6 Weeks 6 & Week 4 Week 6 Weeks 6 & 26 (n = 328) pegol mg (n = 331) 5

6 N = 668 Included patients with prior exposure to anti-tnf agents PRECiSE 2: of Remission in CD With Pegol Wk Wk 2 Wk 4 certolizumab pegol mg Wk 6 Wk (64.1%) responders randomized q 4 wks (n = 212) pegol mg q 4 wks (n = 216) Response (reduction in CDAI of 1 pts) PRECiSE 2: Clinical Response and Remission at Week 26 in Patients With CD Randomized Responders (N = 428) Clinical Response (decrease in CDAI 1 points) 63 q 4 wk (N = 212) pegol mg q 4 wk (N = 216) Clinical Remission (CDAI < 15 points) Schreiber S, et al. Gut. 25;54(Suppl VII):A82. p <.1 vs placebo. Schreiber S, et al. Gut. 25;54(Suppl VII):A82. PRECiSE 1 & 2: Safety and Tolerability of Pegol in CD PRECiSE 1 PRECiSE 2 Adverse Event (n[%]) (n = 329) (n = 331) (n = 668) (n = 212) (n = 216) Headache 54 (16.4) 6 (18.1) 84 (12.6) 14 (6.6) 15 (6.9) Abdominal pain 37 (11.2) 37 (11.2) 27 (4.) 1 (4.7) 1 (4.6) Crohn s disease 37 (11.2) 33 (1.) 36 (5.4) 25 (11.8) 9 (4.2) Nasopharyngitis 27 (8.2) 44 (13.3) 25 (3.7) 8 (3.8) 12 (5.6) Cough 8 (2.4) 9 (2.7) 5 (.7) 2 (.9) 12 (5.6) Nausea 27 (8.2) 26 (7.9) 24 (3.63) 6 (2.8) 6 (2.8) UTI 17 (5.2) 25 (7.6) 27 (4.) 5 (2.4) 8 (3.7) Pyrexia 22 (6.7) 21 (6.3) 16 (2.4) 7 (3.3) 1 (4.6) Arthralgia 16 (4.9) 22 (6.6) 16 (2.4) 6 (2.8) 1 (4.6) Injection site pain 23 (7.) 4 (1.2) 8 (1.2) 11 (5.2) 1 (.5) Back pain 17 (5.2) 9 (2.7) 11 (1.6) 9 (4.2) 1 (.5) Vomiting 11 (3.3) 18 (5.4) 14 (2.1) 3 (1.4) 1 (.5) PRECiSE 1 malignancies reported in 4 patients: 1 cervical cancer and 1 Hodgkin s lymphoma in the placebo group, 1 lung cancer and 1 rectal cancer in the certolizumab group. PRECiSE 2 no study-related malignancies were reported. Schreiber S, et al. DDW 26, Abstract T1126. Incidence of Antibodies to Pegol in Patients With CD 12.3% (9 of 73) of patients receiving certolizumab pegol mg had a least 1 positive result for anticertolizumab antibodies The plasma concentrations of certolizumab pegol were lower in the antibody-positive patients The proportions of patients who responded to treatment by week 12 were similar between antibody-positive and antibody-negative patients Schreiber S, et al. Gastroenterology. 25;129:

7 Construct and Mechanism of Action of Natalizumab Complementarity-Determining Regions (CDRs) Human IgG 4 Framework Natalizumab Humanized mab against α4-integrins Human IgG 4 framework with CDRs grafted from murine antibodies Mechanism of Action Binds to the α4 subunit of α4β1 and α4β7 integrins expressed on all leukocytes except neutrophils Prevents the interaction of leukocytes with vascular endothelial cells Inhibits transmigration of leukocytes across the endothelium into inflamed parenchymal tissue ENACT-1: Natalizumab for of Clinical Response in Patients With Moderately to Severely Active CD N = 95 Included patients with prior exposure to anti-tnf agents Wk ( n = 181) Stratified for CRP ( or > 2.87 mg/l) Concomitant immunosuppressants Prior use of anti-tnf agents Sandborn WJ, et al. N Engl J Med. 25;353: Wk 4 Wk 8 Wk 1 Wk 12 Natalizumab 3 mg (n = 724) Response (reduction in CDAI of 7 pts) ENACT-2: of Clinical Response With Natalizumab Response or Remission at Weeks 36 and Wk 36 Wk 6 Wk 36 Wk 6 Response Remission p <.5 vs placebo; p =.3 vs placebo; p <.1 vs placebo. Sandborn WJ, et al. N Engl J Med. 25;353: Withdrawal of Oral Corticosteroids During Sustained Remission Natalizumab 8 6 Natalizumab (n = 67) (n = 76) Weeks ENCORE: and of Response With Natalizumab in Patients With CD N = 59 Included only patients with elevated levels of CRP (> 2.87 mg/l) Wk Targan SR, et al. DDW 26, Abstract 747. ( n = 181) Wk 4 Wk 8 Wk 12 Natalizumab 3 mg (n = 724) Sustained Response at Weeks 8 & 12 (reduction in CDAI of 7 pts) 7

8 ENCORE: Clinical Response and Remission of CD in Patients Receiving Natalizumab p <.1 vs placebo; p <.2 vs placebo. Targan SR, et al. DDW 26, Abstract 747. Response ( 7) Remission (CDAI < 15) Wk 8 Wk 12 Wks Wk 8 Wk 12 Wks Natalizumab (n = 259) (n = 25) Natalizumab: Safety Most common AEs ( 1% of patients) were headache, nausea, and nasopharyngitis 8 14% of patients discontinued treatment due to AEs 3 cases of progressive multifocal leukoencephalopathy (PML) have been reported Patients in all clinical trials have been re-evaluated for PML 2,3 89% of eligible clinical trial patients participated (N = 3389) No additional, confirmed cases of PML were identified in > 3 patients PML was excluded in all but 1 patient, where repeat MRI and CSF were not available Estimated risk of PML in this population: 1 per 1 patients (.1%; 95% CI: per 1) 3 Incidence in CD: 1 in 1275 Incidence in MS: 2 in Sandborn WJ, et al. N Engl J Med. 25;353: ; 2. Sandborn WJ, et al. DDW 26, Abstract 492; 3. Yousry T A, et al. N Engl J Med. 26; 354: Natalizumab: Immunogenicity 8 9% of patients in ENACT-1 and ENACT-2 developed anti-natalizumab antibodies 1 therapy with natalizumab does not require concomitant administration of immunosuppressants for sustained efficacy in CD 2 Unanswered Questions About Biologic Therapy in IBD Do biologics change long-term outcomes in IBD? Where should biologic therapy fit in our treatment algorithm? Top down approach? Are concommitant immunosuppressives beneficial indefinitely or just early? Will Immunosuppressive therapy need to be used with newer biologic therapies? 1. Sandborn WJ, et al. N Engl J Med. 25;353: ; 2. Sandborn WJ, et al. DDW 26, Abstract T

9 Assessment of Top-Down Versus Step-Up Strategies in CD Newly diagnosed CD of < 4 CDAI < 15 Points years duration (N = 129) AND No Steroids Naive to immunomodulators AND No Surgery 1 and biologics IFX + AZA + (episodic) IFX Top-down (n = 65) Steroids IFX (Wk, 2, 6) + AZA +IFX +AZA MTX Steroids Step-up (n = 64) Steroids Steroids Hommes D, et al. DDW 26, Abstract Co-primary endpoints 6 & 12 months Weeks Top-down Step-up P <.1; P <.5 Top-Down Versus Step-Up Trial Clinical Results at 2 Years Reduction and Disappearance of Ulcers Top-down 1 p <.1 Step-up 88 5 p < Patients Receiving Immunosuppressants Reduction Disappearance Weeks Hommes D, et al. DDW 26, Abstract 749.; D Haens GR, et al. DDW 26. Abstract Top-down Step-up Patients Receiving Infliximab Continuation of Immunomodulators (IMMs) Is Not Required to Maintain Efficacy With Biologic Agents Infliximab Adalimumab (CLASSIC II) Natalizumab (ENACT-2) With concomitant IMMs Without concomitant IMMs n = n = n = Success CDAI CDAI CDAI CDAI (No CDAI 7) 1 <15 7 <15 mg EOW or weekly. van Assche G, et al. Panaccione, et al. Sandborn, et al. DDW 26, Abstract 923. DDW 26, Abstract T1124. DDW 26, Abstract T Crohn s s Disease: The Future Anti-TNF: 3 FDA approved agents likely in 27 What will guide choice? Patient convenience, cost, immunogenicity? Top down therapy Patient selection Natalizumab Safety monitoring plan Anti-IL-12/23 CTLA4 Ig (abatacept) Sargramostim Pheresis Other targets 9

10 MMX mesalamine (SPD476): induction of remission in patients with mild and moderate UC Ulcerative Colitis MMX = Multi Matrix System TM mesalamine, a novel once-daily, high-strength formulation of 5-ASA (mesalamine 1.2 g tablet) designed to release 5-ASA throughout the colon Mild-to-moderate UC (score of 4 1 on UC-DAI) with: Sigmoidoscopy score 1 PGA score 2 Relapse 6 weeks prior to baseline MMX mesalamine 2.4 g/day Randomization MMX mesalamine 4.8 g/day give QD 8-week treatment period Primary endpoint: remission after 8 weeks treatment Remission = UC-DAI 1 with score of for rectal bleeding and stool frequency, and 1-point reduction from baseline in sigmoidoscopy score NB: Study SPD476-2 also included a reference arm (Asacol [US formulation, Procter & Gamble Pharmaceuticals, Cincinnati, OH, USA] 2.4 g/day given in three divided doses) MMX mesalamine2.4 g/day was give in two divided doses in study SPD476-31, and once daily in SPD UC = ulcerative colitis; UC-DAI ulcerative colitis-disease activity index; PGA = Physician s Global Assessment; QD = once daily 1. Sandborn WJ, et al. DDW 26, #T1139; 2. Lichtenstein GR, et al. ibid, #T1147; 3. Kamm MA, et al. ibid, #T1148; 4. Sandborn, WJ et al. ibid, #813 MMX mesalamine (SPD476) in mild-to-moderate UC: subgroup analyses (remission rates) MMX mesalamine 2.4 g/d MMX mesalamine 4.8 g/d Mild Moderate Left-sided Extensive ASA naïve Failing 2 gm/d 5-ASA p<.1 vs placebo p.1 vs placebo p<.1 vs placebo p<.5 post-hoc analysis Curcumin for long-term maintenance therapy in patients with UC Background Pharmacologically active phytochemical derived from turmeric Suppresses NF-kB Study design Multicenter, double-blinded, placebo-controlled trial Patients with quiescent UC (CAI 4 for 4 weeks) randomized to curcumin 2g/day (n=45) or placebo (n=44) Continued on sulfasalazine or 5-ASA Primary analysis: Relapse rates by 6 months 1. Sandborn WJ, et al. DDW 26, #T1139; 2. Lichtenstein GR, et al. ibid, #T1147; 3. Kamm MA, et al. ibid, #T1148; 4. Sandborn WJ, et al. ibid, #813 Hanai H, et al. DDW 26, #572 1

11 Curcumin for long-term maintenance therapy in patients with UC Ulcerative Colitis: The Future Patients in remission (%) cases relapsed Curcumin 2 cases relapsed 4.6% 2.5% 3 months 6 months p<.49 Where will infliximab be positioned? Moderate, steroid refractory outpatients. Efficacy in severe disease? Other TNF inhibitors Visilizumab (anti-cd3) Severe IV steroid refractory inpatients? Retreatment, safety, immunogenicity, durability? MLN-2 (anti-α4β7) CTLA4 Ig (abatacept) Pheresis Other targets Hanai H, et al. DDW 26, #572 Conclusions There is substantial unmet need for therapy of IBD New biologic agents and a host of other pipeline therapies are being developed for CD Need to understand which ones to use and when to use them Need to communicate safety issues effectively to our colleagues and patients Need long-term outcome data! New aminosalicylate may offer convenient on-label dosing in UC, but is likely not superior to other therapies Need to understand who and how to use New patients? All patients? Cost and access to care will be an issue for all new therapies It s time we faced reality, my friends.. There s plenty of room for improvement. 11