Therapy for Inflammatory Bowel Disease

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Dinah Harper
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1 Therapy for Inflammatory Bowel Disease Jonathan P. Terdiman, MD Professor of Clinical Medicine Clinical Director, Center for Colitis and Crohn s Disease University of California San Francisco, CA UC: Current Treatment Mesalamine (5-ASA)/sulfasalazine) Corticosteroids Azathioprine (AZA)/ 6-mercaptopurine (6-MP) Infliximab Cyclosporine (CsA) Surgery 1

2 5-ASA Delivery Systems Stomach Jejunum Ileum Colon Sulfasalazine 5ASA+sulfapyridine Dipentum (olsalazine) 2 5-ASAs Colazal balsalazide 5-ASA + 4ABA Asacol (mesalamine) Delayed-Release Tablets Pentasa (mesalamine) Controlled-Release Capsules Delayed-Release Oral 5-ASA (Asacol): Active UC Treatment Success* at Week 6 Mild UC 1 Moderate UC 2 Percent of Patients P=NS Response Remission P= g 4.8 g 2.4 g 4.8 g Daily 5-ASA Dose Daily 5-ASA Dose N=254 *Treatment success=response + remission. Response defined as improvement in PGA and 1 other clinical assessment with no worsening in any other clinical assessment. Remission defined as PGA and all clinical assessments=. 1 Data on file, Procter & Gamble Pharmaceuticals Inc. 2 Sandborn WJ et al. Am J Gastroenterol. 24;99:S251. Abstract

3 Efficacy of a new formulation of MMX mesalamine (Lialda) for mild-moderate UC 517 pts PBO 2.4 gm daily Compare % of patients in remission at wk gm daily % Pts in Remission Wk % % 1 Treatment Group Details: Pooled results from 2 RCT using 1.2 and 2.4 gm tablets 35.1% PBO (n=171) 2.4 gm (n=172) 4.8 gm (n=174) Sandborn WJ et. al. DDW 26 #813 Cessation of Rectal Bleeding(Wk 6) Distal Colitis Therapy 46 Asacol 5-ASA Enema Combined 69 (2.4 g/d) (4 g/d) More distal 5-ASA delivery Safdi, M, et al. Am J Gastroenterol 1997;92(1): P=.5 vs.. Asacol 3

4 Oral Cortisone: Mild-to-Severe Active UC, Clinical Response and Clinical Remission at 6 Weeks Percent of Patients P<.1 69 P< Clinical Response* Clinical Remission Placebo (n=11) Cortisone (n=19) # *Clinical response defined as improved or clinical remission Clinical remission defined as 1 or 2 stools/d without blood #Cortisone dosing: 1 mg/day for 6 weeks (N=38) 1 mg/day for 2-3 weeks followed by 5-75 mg/day until 6 weeks (N=38) >1 mg/day for 6 weeks (N=17) Truelove SC. Br Med J. 1954;4884:375. Immediate and Prolonged Outcomes of Corticosteroid Therapy in UC 1-Month Responses (n=63) Complete 54% (n=34) Partial 3% (n=19) None 16% (n=1) 1-Year Responses (n=63) Steroid- Dependent 22% (n=14) Prolonged Response 49% (n=31) Surgery 29% (n=18) Faubion WA et al. Gastroenterology. 21;1121:255. 4

5 AZA/6-MP in Steroid Resistant UC % Patients Complete Response 24 Partial Response 11 Treatment Failure (n=68) (n=25) (n=12) George J, et al. Am J Gastroenterol. 1996;91: Infliximab in UC: Clinical Response* ACT 1 ACT 2 Percent of Patients Placebo IFX 5 mg/kg IFX 1 mg/kg Weeks 3 Weeks Percent of Patients Placebo IFX 5 mg/kg IFX 1 mg/kg Weeks 3 Weeks *Preliminary data P.2 vs placebo P<.1 vs placebo Rutgeerts P et al. Presented at: Digestive Disease Week; May 17, 25; Chicago, IL. Abstract 689. Sandborn WJ et al. Presented at: Digestive Disease Week; May 18, 25; Chicago, IL. Abstract

6 CsA in Severe UC Lichtiger RCT, n = 2 steroid refractory patients 4mg/kg/d IV for up to 14 days 9/11 versus /9 with response to Rx, mean time = 7 days 36% require colectomy within 6 months Additional data 6-8% response mg/kg as good as 4mg/kg IV in RCT? Role of blood levels (HPLC level of about 3) Why not oral therapy (Neoral or Prograf)? Avoidance of Colectomy After CYSA Induction 1% 8% Probability 6% of 4% Avoiding Colectomy2% CSA + 6MP/aza* (n=27) All Patients (n=42) CSA alone (n=15) 66% 58% 4% % Months Since Initiation of Cyclosporin Cohen, Stein, Hanauer. Am J Gastroenterol 1999;94(6):

7 Infliximab for Severe UC RCT #1 (Probert et al. Gut, 23) 5 mg/kg at, 2 weeks Remission in 6 weeks: 9/23 (39%) vs. 6/2 (3%), NS RCT #2 (Jarnerot et al. Gastroenterology, 25) 5 mg/kg at time 7/24 IFX patients need colectomy vs. 14/21, p =.2 CD: Conventional Treatment Aminosalicylates (5-ASA, sulfasalazine) Steroids (prednisone, budesonide) Immunomodulators (AZA, 6-MP, methotrexate [MTX]) Infliximab Surgery 7

8 5-ASA for Active CD Change From Baseline in CDAI Score P=.5 CD I N=155 Placebo P=.7 CD II N=15 5-ASA 4 g P=.5 CD III N=31 P=.4 Overall N=615 Percent Difference in Remission Rates CD I N=155 5-ASA 4 g Minus Placebo 3 CD II N=15 4 CD III N=31 9 Overall N=615 Change in CDAI scores and difference in remission rates in 3 placebo-controlled trials Hanauer SB et al. Clin Gastroenterol Hepatol. 24;2: ASA for Maintenance of Medically Induced Remission in CD Study Thomson Prantera Brignola Gendre Bresci Thomson Arber Modigliani Sutherland De Franchis Overall Year No. Pt % Favors Treatment Favors Control Risk Difference 95% CI Camma C et al. Gastroenterology. 1997;113:

9 NCCDS: Response to Therapy for Active CD Percent of Patients Prednisone.25 mg/kg to.75 mg/kg (6 mg) Sulfasalazine 1 g/15 kg (5 g) AZA 2.5 mg/kg (25 mg) Placebo N=569 Weeks After Randomization Summers RW et al. Gastroenterology. 1979;77:847. Less than a Third Show Endoscopic Healing With Steroids at 7 Weeks in CD % Patients* (%) % 93/ /131 *Among patients with clinical remission, n=131 9% 12/131 Remission No Remission Endoscopic Status Worsened Modigliani R et al. Gastroenterology. 199;98:811. 9

10 NCCDS: Maintaining Remission in CD Percent of Patients Prednisone.25 mg/kg (2 mg*) Sulfasalazine.5 g/15 kg (2.5 g*) AZA 1 mg/kg (75 mg*) Placebo N=569 *Maximum daily dose Months After Randomization Summers RW et al. Gastroenterology. 1979;77:847. Outcome of Steroid Therapy* for Patients With Crohn s Disease 3-days from start (n=19) Remission 48% Improved 32% No response 2% 3 days from stop (n=87) Remission 54% Relapse 46% Improved 57% Relapse 43% Summary Outcomes (n=19) Steroid Dependent 36% (n=39) Prolonged Response 44% (n=48) Steroid Resistant 2% (n=22) *Prednisone 1 mg/kg for 1 month. Munkholm P et al. Gut. 1994;35:36. 1

11 Budesonide Bioavailability Systemic circulation 1% Liver 9% First-Pass Metabolism Edsbäcker. Drugs Today. 2;36(suppl G):9-23. Patients in Remission (%) (CDAI 15) Budesonide vs Prednisolone: Induction of Remission for Active CD *p=.22; p<.1; p=.12. Rutgeerts et al. N Engl J Med. 1994;331: * Prednisolone 4 mg qd (n=88) Budesonide 9 mg qd (n=88) Treatment (weeks) 11

12 Side Effect (1 weeks) Budesonide Prednisolone Moon face 19% 36% Acne 7% 23% Swollen ankles 3% 13% Easy bruising 5% 8% Hirsutism 3% 2% Buffalo hump 1% 3% Skin striae 1% % Rutgeerts et al. N Engl J Med. 1994;331: Budesonide vs Prednisolone: Side Effects in Active CD Efficacy of Oral Budesonide as Maintenance Therapy Cumulative Probability of Remission 1..5 Placebo Budesonide 6 mg Budesonide 3 mg P =NS * N=15 Days * The rate of relapse in the 6 mg budesonide group was not significantly different from rates in the 3 mg and placebo groups. Adapted from Greenberg GR et al. Gastroenterology. 1996;11:45. 12

Odds Ratio of Response and Maintenance in Controlled Studies

experience In 6MP group: Duration of steroid use shorter (p<.

1) Overall remission induction: 89% of both groups By 548

13 Odds Ratio of Response and Maintenance in Controlled Studies of AZA/6-MP for Active CD 3.9 Pearson DC et al. Ann Intern Med. 1995;123:132. Early Treatment with Immunomodulators the Pediatric experience In 6MP group: Duration of steroid use shorter (p<.1) Cumulative dose of steroids lower at 6, 12, 18 months (p<.1) Overall remission induction: 89% of both groups By 548 days after remission: 47% controls relapsed 9% 6MP group relapsed (p=.7) Markowitz et al, Gastroenterology 2;119:

14 Long-Term Efficacy of AZA Percentage of Patients in Remission Patients in clinical remission with AZA for at least 3.5 years before randomisation Azathioprine Placebo Months after randomisation Lemann et al. Gastroenterol. 25 Jun;128(7): Remission (months) mean ± SE 17.3 ± ± % relapse 21.3 MTX Induction in Steroid-Dependant CD Multicenter, randomized, controlled trial 141 steroid-dependent patients Active disease despite treatment with prednisone 1 mg/d to 4 mg/d Randomized to MTX 25 mg IM or placebo x 16 wk Percent of Patients Placebo P=.3 19 MTX 25 mg/wk Week In Remission and Complete Steroid Withdrawal Feagan BG et al. N Engl J Med. 1995;332:

15 MTX Maintenance in Steroid-Dependant CD 76 patients in remission following MTX 25 mg IM x 16 wk Patients steroiddependent Randomized to maintenance MTX 15 mg IM (N=36) or placebo (N=4) x 4 wk Percent Remaining in Remission Placebo 65% P=.44 39% MTX Weeks Since Randomization Feagan BG, et al. N Engl J Med. 2;342: Infliximab Mechanism of Action 15

Clinical Response and Remission in Infliximab-Treated Patients % Patients 1 75 5 25 P=.1 17% 81% P=.

score from baseline Clinical remission defined as a CDAI score <15 4-Week Clinical Remission Targan SR et al. N Engl J Med.

16 Clinical Response and Remission in Infliximab-Treated Patients % Patients P=.1 17% 81% P=.1 48% Placebo (n=25) Infliximab 5 mg/kg (n=27) 4% 4-Week Clinical Response Clinical response defined as a 7-point decrease in CDAI score from baseline Clinical remission defined as a CDAI score <15 4-Week Clinical Remission Targan SR et al. N Engl J Med. 1997;337:129. Healing of Colonic Ulceration With Infliximab Pretreatment 4 Weeks Posttreatment Reprinted with permission of van Dullemen HM et al. Gastroenterology. 1995;19:

17 Endoscopic Healing With Infliximab 1 95% 96% % Resolution of Ulceration % 79% 77% Ileum Ascending Colon Transverse Colon Descending Colon Rectum D Haens G et al. Gastroenterology. 1999;116:129. ACCENT I: Clinical Response and Remission at Week 54* Single Dose (n=12) 5 mg/kg q 8 wk (n=14) 1 mg/kg q 8 wk (n=15) Proportion of Patients P<.1 P= % 5 P<.1 P= % 38 Clinical Response Clinical Remission *Among patients responding at Week 2 Hanauer SB et al. Lancet. 22;359:

18 Scheduled Infliximab Reduces Subsequent Rates of Hospitalization, Surgery, and Disability % 5 39% % 48% 16% 64% 3% Hospitalized Surgery Hospitalized Required Surgery 48% 3% Permanent Disability SCHEDULED EPISODIC 25% Before starting infliximab After starting infliximab Williams JB et. al. DDW 26 #926 Treatment of steroid dependent CD with IFX plus AZA Lemann et al, Gastro 26;13:154-61). 18

19 If you start a biological do you need the immune modulator? Trial Endpoint With IM No IM OR (95% CI) Act 1 Rem-wk 54 34% 36%.92 ( ) Hosp wk % 5.1% Accent 1 Rem-wk 54 37% 32% 1.24 ( ) Hosp wk % 5.3% ATI Formation No Immunomodulators With Immunomodulators Proportion of Patients (%) p= Episodic Strategy 11 p=.42 7 Maintenance q8w 5 mg/kg p= Maintenance q8w 1 mg/kg Proportion of Patients with ATI* through Week 54 * 442 patients with evaluable samples were assessed for ATI s 19

20 Serious Infections in All Completed Clinical Trials Placebo All Infliximab Patients treated Avg weeks of follow-up Pts with 1 serious infection 3.9% 5.9% Abscess.2% 1.% Pneumonia.2% 1.2% Cellulitis.4%.5% Sepsis.4%.5% Lymphomas Observed During Infliximab Clinical Trials PtYrs followup Observed Lymphomas Expected Lymphomas vs Non-RA Population* SIR 95% CI All Studies RA Studies *SEER Database Data on file. Centocor, Inc. 2

21 Hepatosplenic T Cell Lymphoma Mackey et al, J Pediatr Gastroenterol Nutr 27;44: Anti-TNF-α Protein-engineered Antibodies Chimeric monoclonal antibody Humanized Fab fragment VL VH Human recombinant antibody Fab Cκ CH1 Infliximab PEG PEG Adalimumab Mouse Human Certolizumab pegol CDR = Complementarity-determining region PEG = Polyethylene glycol Hanauer, Rev Gastroenterol Disord 24; 4 (supp 3): S

22 Adalimumab: CLASSIC Results at Week 4* Percent of Patients Placebo/placebo 4 mg/2 mg 8 mg/4 mg 16 mg/8 mg Clinical Remission *Preliminary data Remission=CDAI 15; response=drop in CDAI of 7 or 1 points from baseline Clinical Response Clinical Response Δ 1 Δ 7 Hanauer S et al. Presented at: Digestive Disease Week; May 24; New Orleans, LA. Optimal maintenance dose of adalimumab for active CD: CHARM trial 854 pts Humira 8/4 wk /2 499 responded PBO 4 qowk 4 qwk Thru wk 56 Compare % of patients in remission at wk 26 and 56 % pts in remission 5% 4% 3% 2% 1% % * 46% * 4% 41% 36% 17% 12% Wk 26 Wk 56 * * PBO (n=17) 4 qowk (n=172) 4 qwk (n=157) *p<.1 vs. PBO Colombel JF et. al. DDW 26 #686d 22

23 Use of Certolizumab Pegol in active CD: PRECiSE I trial 659 pts PBO 4 mg sc /2/4 then every 4 wks Thru wk 24 Compare % of patients with response at wk 6 and both wk6/26 (in CRP >1) % pts with response 4% 3% 2% 1% % * 35% 27% * 23% 16% Wk 6 Wk 6+26 PBO (n=328) 4 mg sc (n=321) *p<.5 vs. PBO Sandborn WJ et. al. Gastro, 28 Adhesion and Recruitment Mucosal and Inflammatory Zip Codes α4 Integrins α4β1 α4β7 Leukocyte VCAM-1 Chemokines Vascular Endothelium MAdCAM-1 23

24 Natalizumab (Anti-α4 Integrin) Humanized IgG 4 monoclonal antibody (anti-α4 integrin) Half-life 4 to 11 days Approved for use in multiple sclerosis Voluntarily removed from the market in February 25 because of 3 cases of progressive multifocal leukoencephalopathy (PML) from the human JC polyoma virus Ghosh S et al. N Engl J Med. 23;348:24. Natalizumab [prescribing information]. 24. Use of Natalizumab in active CD: ENCORE trial PBO 59 pts 3 mg IV /4/8 wks No maintenance Compare % of patients with combined response at wk 8 AND wk 12 % pts with response 6% 5% 4% 3% 2% 1% % 32% * 48% PBO (n=259) 3 mg IV (n=25) *p<.5 vs. PBO Wk 8+12 Details: Response: 7 point decrease in baseline CDAI Sandborn WJ et. al. Gastro, 28 24

25 Natalizumab for CD: Phase III Maintenance Trial (ENACT-2)* 339 patients from ENACT-1 Either mild disease (CDAI 15 to 22) or remission (CDAI <15) Concomitant 5-ASA, steroids, AZA/6-MP, antibiotics allowed Randomized to receive 12 monthly infusions of placebo or natalizumab 3 mg Percent of Patients P=.3 61 P< Response 6 Months Remission 6 months *Preliminary data Response and remission evaluated monthly; patients needed to maintain response or remission through month 6 to be counted Placebo Natalizumab Sandborn W et al. NEJM, 25 Safety Evaluation for PML in >35 Patients with CD, RA, and MS Treated with Natalizumab in Clinical Trials Natalizumab-monoclonal antibody vs. a4 integrin adhesion molecule Clinial trials suspended Feb 25 due to 3 cases progressive multifocal leukoencephalopathy (JC virus) Safety evaluation-neuro evaluation, brain MRI, CSF evaluation 4 potential PML cases (postmarketing) evaluated as well Independent analysis of studies by experts to determine if pts had PML Participating Neuro exams and MRIs CSF tested Plasma tested CD 87% >97% 6% 88% RA 91% >97% 4% 95% Bottom line: 1) No new cases of PML identified 2) No good way to screen for PML MS 92% >97% 16% 56% Sandborn WJ et. al. Nejm, 28 25

26 CD: Current Treatment Paradigm Bottom Up SEVERE MODERATE MILD AZA 6-MP Surgery Bowel Rest Immunomodulators (AZA/6-MP/MTX) Systemic Corticosteroids Nonsystemic Corticosteroids Aminosalicylates Infliximab Natural Course of Disease Behavior 1 9 Cumulative Probability (%) Inflammatory Penetrating Stricturing Months Cosnes J, et al. Inflamm Bowel Dis. 22;8:

27 Up to 8% of CD Patients will Require Surgical Intervention 1 8 Probability (%) Mean ± 2 SD D Years Number of events Munkholm P, et al. Gastroenterology. 1993;15: Summary of Post-operative Recurrence Rates Endoscopic Clinical Operation 1 year 5 years 1 years 27

28 No Impact of Increasing Use of Immunomodulators When Used in Sequential Therapeutic Pyramid on Surgery Rates in CD Annual Surgery Rates for CD Number of Intestiona Resections per 1 Patients Surgery >3 mo After Diagnosis Surgery <3 mo After Diagnosis patients followed over 25 years; 17 patients underwent 1426 resections. Except for 1978, the operative rate has remained steady despite recent widespread use of immunomodulators. Cosnes J et al. Gut. 25;54:237. REACH: Response and Remission Rates to Infliximab in Pediatric Patients With Moderate-to-Severe CD Response* Remission % of Patients p = p <.1 n = 99 n = 66 n = 33 n = 29 n = 17 n = 12 Week 1 Week 54 q8 Week 54 q12 *Reduction from baseline of 15 points in PCDAI score and a PCDAI score 3. PCDAI score 1. Hyams et al, Gastroenterology 26,doi:1.153/j.gastro

29 Humira 4 mg EOW at Week Remission Rates (%) * * < 2 years 2-5 years > 5 years Disease Duration Remission The ideal management of CD: Step-up vs. Top-down strategies 129 pts Step-up (65) Top-down (64) Compare % of patients in remission after 2 years (off steroids and without surgery) +AZA MTX +IFX Top-down IFX (/2/6) + AZA (2-2.5 mg/kg) IFX + AZA Steroids + (episodic) IFX Steroids Steroids Step-up Budesonide or steroids Details: Newly diagnosed CD; open label; 26 centers in Belgium; never treated GCS/immuno/IFX Hommess D et. al. Lancet, 28 29

30 Patients (%) Top down versus step up: Results CDAI <15 AND no steroids AND no surgery * ** 2 1 *p<.1 **p< Weeks Step up Top down Hommes D, et al. Lancet, 28 * Patients (%) Proportion of pts on immunosuppressants Weeks Step up Top down 2-Year Outcomes Step-up vs. Top-Down 2 year outcomes In remission AND no steroids AND no surgery Surgery Relapse** Steroid days** Proportion pts on immunosuppression Mucosal healing** Step-Up (n=64) 5% 12.5% 42% 79.7 days 77.1% 6/2 (3%) Top-Down (n=65) 57% 9.2% 14% 5.6 days 94.2% 17/24(71%) * Significant month 6 and 12; **p<.5 Hommess D et. al. Lancet, 28 3

31 5-Year Follow-Up of Patients With Nondisabling and Disabling CD According to Characteristics at Baseline Variable Male Age < 4 yr Disease location Small bowel only Small bowel & colon Colon only Smoker Systemic findings Perianal lesions Steroids for first flare Percent of Patients Nondisabling (n = 166) Beaugerie L, et al. Gastroenterology. 26;13: Disabling (n = 957) Independent Risk Factors Odds Ratio (95% CI) 2.1 (P =.4) 1.8 (P =.1) 3.1 (P =.1)

Ali Keshavarzian MD Rush University Medical Center

Treatment: Step Up or Top Down? Ali Keshavarzian MD Rush University Medical Center Questions What medication should IBD be treated with? Can we predict which patients with IBD are high risk? Is starting