Update in Biological Therapies and New Developments in · PDF fileSteering the Course of IBD Webcast David T. Rubin, MD Professor of Medicine Co-Director, Inflammatory Bowel Disease

Steering the Course of IBD Webcast

David T. Rubin, MD Professor of Medicine

Co-Director, Inflammatory Bowel Disease Center

Associate Section Chief for Education

The University of Chicago Medicine

Update in Biological Therapies and New Developments in IBDIncluding the latest abstracts from DDW 2013 and newly FDA-approved therapies

Learning Objectives

At the conclusion of this presentation, learners will:

1. Implement newly FDA-approved drugs into clinical practice.

2. Have a better perspective of the latest ongoing research and new drug developments presented at DDW 2013.


Question #1

Which of the following agents has NOT shown efficacy in ulcerative colitis?

1. MMX budesonide

2. Adalimumab

3. Laquinimod

4. Golimumab

5. Tofacitinib

Question #2

Which of the following agents has NOT shown clinical trial efficacy in Crohn’s disease?

1. Adalimumab

2. Dims0150 (TLR-9 agonist)

3. Vedolizumab

4. Laquinimod

5. Natalizumab


FDA Approved and Newly Available

• Adalimumab (Humira®) (September 28th 2012)– Indication: Moderate-to-severe ulcerative colitis

• Budesonide MMX™ (UCERIS™) (January 14th 2013)– Indication: Induction of remission in mild-to-moderate UC

• Golimumab (Simponi®) (May 15th 2013)– Indication: Moderate-to-severe UC

• Drug level / anti-drug antibodies assay for:– IFX levels/ATI (Prometheus ®Anser™ IFX)– ADA levels/ATA (Prometheus ®Anser™ ADA)

Adalimumab for Induction and Maintenance of Remission in UC

Sandborn, et al. Gastroenterology. 2012;142(2):257-65.e1-3.


Budesonide MMX(Approved January 14th 2013)

• Budesonide extended release tablets.

• MMX - Multi-matrix system colonic delivery technology.

• Approved dosing system: 9mg qd for 8 weeks.

Budesonide MMX for active ulcerative colitis:Remission at week 8 (US trial)

*Statistically significant (p<0.025)

Remission (%)*

7.4

17.9

13.212.1

0

20Placebo

MMX 9 mg

MMX 6 mg

Mesalamine DR 2.4 g

Mesalamine DR = Asacol® Sandborn, et al. Gastroenterology. 2012;143(5):1218-26.e1-2.


Golimumab(Approved May 15th 2013)

• Fully human monoclonal IgG1 antibody acting on both soluble and membrane bound TNF-.

• Previously approved by the FDA for: RA, PsA and AS.

• Monthly SC administration.– Load: 200 mg week 0, 100 mg week 2

– Maintain: 100 mg q4w

Imman RD, et al. Arthritis Rheum 2008;58(11):3402-12.

Golimumab Phase 2/3 PURSUIT trial

29.7

6.3

28.5

51.8

18.7

43.2

55

17.8

45.3

0

20

40

60

80

100

ClinicalResponse

ClinicalRemission

MucosalHealing

Outcomes at 6 weeksPlacebo(n=256)200/100mg(n=257)

* +

*

*

*

*

Response = decrease from baseline in the Mayo score by ≥ 30% and ≥ 3 points, with either a decrease from baseline in the rectal bleeding subscoreof ≥ 1 or a rectal bleeding subscore of 0 or 1. *P<0.0001 +P=0.0005

Rutgeerts P et al. United European Gastroenterology: Week, 2012. Abstract.

Pro

po

rtio

n o

f p

atie

nts

(%

)


Golimumab Phase 3 PURSUIT trial

31.4

15.4

26.9

47.1

23.5

41.8

50.6

28.6

43.5

0

20

40

60

80

100

ClinicalResponse

ClinicalRemission

MucosalHealing

Outcomes through week 54Placebo(n=156)50mg (n=153)

p=0.01P=0.001

p<0.001

P=0.003

NS

P=0.011

Response = decrease from baseline in the Mayo score by ≥ 30% and ≥ 3 points, with either a decrease from baseline in the rectal bleeding subscoreof ≥ 1 or a rectal bleeding subscore of 0 or 1.

Pro

po

rtio

n o

f p

atie

nts

(%

)

Rutgeerts P et al. United European Gastroenterology: Week, 2012. Abstract.

Golimumab (GLM) Safety through week 54 PURSUIT trial

• GLM antibodies (at any time): Thirty two patients (32; 2.9%)

• Four active TB cases on GLM

• Three deaths (GLM 100mg) due to:– Malnutrition and sepsis– Disseminated TB– Cardiac failure

• Malignancy rates:– 0.4% (Placebo), 0.0% (GLM 50mg) and 0.3% (GLM 100mg).– Breast cancer (placebo only); 3 GLM 100 mg: thyroid cancer*; rectal cancer *; lung

adenocarcinoma

* Symptoms leading to diagnosis first presented while patients were receiving placebo induction therapy

Rutgeerts P et al. United European Gastroenterology: Week, 2012. Abstract. (Additional data from Colombel,

Advances in IBD 2012).


Poster #Sa1203 - Pharmacokinetics and Exposure-Response Relationship of Golimumab in Patients With Moderately to Severely Active Ulcerative Colitis: Results From Phase2/3 Induction and Maintenance StudiesOmoniyi J. Adedokun1, Zhenhua Xu1, Colleen W. Marano1, Richard Strauss1, Hongyan Zhang1, Jewel Johanns1, Joyce A. Ford1, Honghui Zhou1, Hugh M. Davis1, Jean-Frederic Colombel2, Walter Reinisch3, Brian G. Feagan4, Paul J. Rutgeerts5, William Sandborn6

Abstract:Background & Aims: Pharmacokinetics (PK) and exposure-response (ER) relationship data of golimumab (GLM) from the PURSUIT-SC induction and maintenance studies in UC are evaluated.Methods: PURSUIT-SC induction was an integrated Phase 2 dose-finding/ Phase 3 confirmatory study. UC patients with Mayo scores of 6-12 inclusive, including endoscopic subscore >2, were randomized to placebo (PBO)/PBO (n=331); GLM 100 mg/50 mg (before Ph3 dose selection only, n=72); GLM 200 mg/100 mg (n=331); GLM 400 mg/200 mg (n=331) at wks0&2. The Phase 3 maintenance study enrolled 1228 patients from PURSUIT-IV & PURSUIT-SC induction studies. The primary analysis population consisted of patients (n=464) who responded to GLM induction & were randomized to receive PBO, GLM 50 mg, or GLM 100 mg at baseline (wk0) & q4wks through wk52. Serum GLM concentrations (SGC) were measured from blood samples collected at scheduled visits through wk6 during induction and through wk54 during maintenance.Results: Median SGC peaked at wk2 of induction in all dose groups with concentrations of 2.34 μg/mL, 6.27 μg/mL and 11.95 μg/mL for the 100 mg/50 mg, 200 mg /100 mg, 400 mg/200 mg grps, respectively. At wk6, median SGC were 0.78 μg/mL, 1.78 μg/mL, and 4.01 μg/mL respectively. SGC were approximately dose-proportional during induction and maintenance. SGC were sustained reaching steady-state approximately 8wks after start of GLM maintenance (or a total of 14wks after initiation of GLM therapy) regardless of induction dose. Median preadministration (trough) SGC from Week 8 through Week 44 of the maintenance study, ranged from 0.69 to 0.83 µg/mL in the 50 mg GLM group and 1.33 to 1.58 µg/mL in the GLM 100 mg group. Immunomodulators use had no apparent impact on median SGC in the GLM 100 mg group; median SGC were slightly higher in the GLM 50 mg in combination with immunomodulator vs without immunomodulator. A trend towards lower SGC with increasing body weight was observed; however, there were no differences in clinical response during maintenance across body weight quartiles for GLM 100 mg. Median SGC were lower for subjects who were positive for antibodies to golimumab compared with levels in subjects who were negative; overall incidence of antibodies to golimumab from induction through maintenance was low (approximately 3%). Higher SGC were associated with higher proportions of patients achieving efficacy endpoints during induction and maintenance (Figure 1). There was no apparent relationship between SGC and the occurrence of infections.Conclusion: Serum golimumab concentrations were approximately dose-proportional and a positive E-R relationship was demonstrated during induction and maintenance treatment of adult UC patients with golimumab.

Adedokun O, et al. DDW 2013, Orlando. Abstract.

Serum golimumab concentrations were approximately dose-proportional and a positive exposure/response relationship

was demonstrated during induction and maintenance treatment of adult UC patients with golimumab.

Measurement of IFX and antibody levels• Loss of response is due to failure to achieve and maintain

adequate drug levels or due to formation of anti-drug antibodies.

• Different methods of measuring anti-drug antibody levels. (ELISA, Radioimmunoassay(RIA) or homogenous mobility shift assay (HMSA)).

• ELISA has cross interference with circulating drug.

• RIA less practical due to safety.

Miheller P at al. Expert Opin Biol Ther. 2012;12(2):179-92.

Wang SL, Hauenstein S, Ohrmund L et al. J Immunol Methods. 2012;382(1-2):177-88.


Trough Levels and Antidrug Antibodies Predict Safety and Success of Restarting Infliximab After a Long Drug Holiday

Baert FJ, Hauenstein S, Drobne D et al. DDW 2013, Orlando. Abstract 492.

Restarting infliximab after a long drug holiday is highly successful short and long term. Higher TL and undetectable ATI titers early after restart

predict the outcome very significantly. Immunomodulators at restart clearly attenuate ATI formation responsible for infusions reactions.

Prevalence of Antibodies to Adalimumab (ATA) and Correlation Between ATA and Low Serum Drug Concentration on CRP and Clinical Symptoms in a Prospective Sample of IBD Patients

Methods:

• Cross-sectional study (54 IBD pts; 2 UC)

Results:

• Prevalence of detectable ATA( 1 mcg/ml): 22.2% (n=12/54)

• Detectable ADA 90.7% (n=49/54):

• Serum <5mcg/ml associated with elevated CRP (p=0.001)\

• Detectable ATA was associated with elevated CRP.

• Low drug conc (<5mcg/ml)or detectable ATA demonstrated more

active disease (P=0.01).

Velayos F, Sheibani S, Lockton S et al. DDW 2013, Orlando. Abstract 490.


Prediction of Clinical Response and Mucosal Healing At One Year by Faecal Calprotectin Assay After Induction With Anti-TNF Alpha Agents in IBD Patients

Faecal calprotectin (FC) is a protein present in the cytosol of neutrophil granulocytes and of macrophages that is released in the biological fluids under inflammatory conditions. FC levels seem to be correlated with active inflammation in inflammatory bowel diseases (IBD), Crohn’s Disease (CD) and Ulcerative Colitis (UC). Non-invasive markers of response to biological therapy in IBD are needed to limit current routine investigations that are expensive and invasive. The aim of our study is to evaluate the role of FC as a non invasive marker of inflammation in order to monitor and predict the effect of therapy with TNFα-antagonists in IBD.63 IBD patients (44 CD, 19 UC) provided samples for FC assay, before and after the induction course of anti-TNFα therapy (Infliximab n=42, Adalimumab n=18, Certolizumab Pegol n=3). Clinical activity, measured by clinical indexes (CDAI, CAI), was assessed in all patients before and after induction treatment. For mucosal healing assessment (defined as CDEIS <3 or Mayo Endoscopic Score ≤1) all patients performed colonscopy before and after 1-year of anti-TNFα treatment.Clinical response at 1-year was obtained in 36/63 (57%, 12 UC and 24 CD) of the patients with a median FC value of 106 μg/g after induction therapy, while the 27 patients not in clinical response at 1-year had a post-induction median FC value of 300 μg/g(p=0.0002). The ROC curve analyses showed that FC levels after anti-TNFα induction have a sensitivity of 83% and a specificity of 74%, with a cut-off of 168 μg/g, for predicting clinical response at 1-year (p=0.0001). In CD we detected a sensitivity of 83% and a specificity of 75%, with a cut-off of 125 μg/g, for predicting clinical response at 1-year (p=0.0001), while in UC we detected a sensitivity of 100% and a specificity of 79%, with a cut-off of 121 μg/g, for predicting mucosal healing at 1-year (p=0.0001). Survival analysis showed for patients with FC above 168 μg/g after anti-TNFα induction course a probability of being in clinical response at 1-year significantly lower than for patients with FC less than 168 μg/g (HR 0.20, p=0.0001). The same analysis conducted in the UC patients showed a HR of 0.16 (p=0.037), while for CD patients with FC above 125 μg/g after anti-TNFα induction course the HR was 0.22 (p=0.0008).Our preliminary results suggest that faecal calprotectin can be used as a marker to estimate anti-TNFα agents’ efficacy in IBD and to predict clinical response and mucosal healing at 1-year.

Guidi L, Marzo M, Andrisani G et al. DDW 2013, Orlando. Abstract 491

Faecal calprotectin can be used as a marker to estimate anti-TNFα agents’ efficacy in IBD and to predict clinical response and mucosal healing at 1-year.

Emerging Agents

• Ustekinumab (anti-IL12/23)

• Vedolizumab (anti-integrin therapy)– DDW2013: #91 GEMINI-II CD & #643 Safety analysis in CD &UC

• Tofacitinib (JAK inhibitor)

• Etrolizumab (Rhumab Beta7)– DDW2013: #159 Eucalyptus Phase II in UC

• Dims0150 (TLR-9 agonist) – DDW 2013: #89 DIMS0150 for UC

• Laquinimod– DDW2013: #90 IMM for CD Phase IIa

*Numbers correspond to abstracts at DDW 2013.


Ustekinumab – a monoclonal antibody against IL-12 and IL-23

Sandborn WJ, et al. N Engl J Med. 2012;367(16):1519-28.

Vedolizumab -integrin antibody

• An -integrin antibody with high specificity for gut-homing lymphocytes.

• IgG1, anti-human integrin LPAM-1 (lymphocyte Peyer’spatch adhesion molecule 1).

• No effects on central nervous system in contrast to natalizumab.

• GEMINI - I1: ulcerative colitis

• GEMINI - II2: Crohn’s disease

1. Feagan BG, Rutgeerts PJ, Sands BE et al. Gastroenterology 2012; 142: S160–1.2. Rutgeerts PJ, Sandborn W, Reinisch W et al. DDW 2013.


Vedomizumab in UCGEMINI - I

25.5

5.4

24.8

47.1

16.9

40.9

0

5

10

15

20

25

30

35

40

45

50

Clinical Response Clinical Remission Mucosal Healing

Placebo

Vedolizumab

%

P<0.0001

P=0.0009

P=0.0012

Outcomes at week 6

Feagan BG, et al. Presentation at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract 943b.

Vedolizumab (VDZ) is more effective than placebo as induction and maintenance therapy in patients with moderate to severely active ulcerative colitis (anti-TNF exposed and naïve patients)

GEMINI I – Vedolizumab for the Maintenance of UC

15.9

23.819.8

8.7

13.9

41.8

56.651.6

20.5

31.4

44.8

52.056.0

24.0

45.2

0

10

20

30

40

50

60

70

Pe

rce

nt

Primary and Secondary Outcomes Through 52 Weeks

Placebo

VDZ Q8 weeks

VDZ Q4 weeks

*P<0.05, **P<0.01,***P<0.0001

ClinicalRemission

Durable ClinicalResponse

MucosalHealing

Durable ClinicalRemission

Corticosteroid-FreeRemissions

Maintenance ITT Population

******

*

***

****** ***

***

****



GEMINI I – Safety of Vedolizumab for the Treatment of UC

Maintenance ITT Population Safety Population

PlaceboN=126

VDZQ8WksN=122

VDZQ4WksN=125

PlaceboN=275

VDZN=620

Any Adverse Event (AE), % 84 82 81 80 80

Drug-related AE, % 32 30 30 28 32

AE resulting in discontinuation, % 12 6 5 11 6

Serious AEs, % 16 8 9 13 12

Serious infection AEs, % 3 2 2 3 2

Deaths, n (%) 0 0 0 0 1 (<1%)

VDZ, vedolizumab


GEMINI-II: Crohn’s diseaseVedolizumab

15.9

28.8 31.7

0

20

40

60

80

100

Placebo VDZ Q4W VDZ Q8W

Corticosteroid-free clinical remission at week 52

P=0.0450

P=0.0154

Rutgeerts PJ, Sandborn W, Reinisch W et al. DDW 2013. Abstract 91.


Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis.

Sandborn WJ, Ghosh S, Panes K et al. N Engl J Med. 2012;367(7):616-24.

Tofacitinib blocks phosphorylation of STAT and downstream activation by blocking JAK 1-3, inhibits multiple cytokine related functions and T-cell differentiation.

Dose-dependent increase in LDL and HDL.

Differentiation Between Etrolizumab (Rhumab Beta7) and Placebo in a Randomized Double-Blind Placebo-Controlled Induction Study to Evaluate Efficacy and Safety in Patients With Refractory Moderate-to-Severely Active Ulcerative Colitis (Phase 2)

Introduction: Selective inhibition of leucocyte trafficking is a promising treatment for IBD. We evaluated a humanized monoclonal antibody to the β7 subunit of the heterodimeric integrins α4β7 and αEβ7 in patients with moderate-to-severely active UC. Methods: This parallel, randomized, double-blind, placebo-controlled study enrolled outpatients with a total Mayo Clinic Score (MCS) ≥ 5, an endoscopy subscore ≥ 2 by central reading and a rectal bleeding subscore ≥ 1. The primary efficacy endpoint was the proportion of patients in clinical remission at Wk 10 (defined as a total MCS of ≤ 2 with no individual subscore > 1). The secondary endpoint at Wk 10 of endoscopic remission was defined as an endoscopy score of 0. Patients (n=124) were randomized in a 1:1:1 ratio to either 2 dose levels of etrolizumab (100mg monthly SC or 300mg monthly SC + loading dose [LD] of 420mg SC between Wk 0 & 2) or placebo for 3 doses. Concomitant therapy for UC remained stable through to the primary endpoint at Wk 10. MCS was evaluated at Wks 0, 6 & 10. Five patients were excluded from the primary efficacy analysis due to a screening endoscopy subscore of < 2 by central read. Results: Patient demographics and baseline characteristics are outlined in Table 1. Primary and secondary efficacy endpoints are summarized in Table 2. Etrolizumab showed significantly higher rates of clinical remission vs Pbo at Wk 10: 100mg dose 20.5% and 300mg + LD dose 10.3% versus Pbo 0% (p=0.004 and 0.049 respectively). In the anti-TNF naïve subgroup, the rates of clinical remission at Wk 10 were significantly higher in the 100mg dose group compared with Pbo (43.8% vs 0%, p=0.007). Etrolizumab achieved endoscopic remission in the 100mg dose of 10.3% and in the 300mg + LD dose of 7.7% vs Pbo of 0%. In the anti-TNF naïve subgroup, endoscopic remission was 25% and 16.7% vs 0% respectively (p=0.058 vs Pbo for the 100mg dose group). Etrolizumabdemonstrated apparent full occupancy of beta7 receptors on CD4 and CD8 T cells in both colonic tissue (α4β7 and αEβ7) and peripheral blood (α4β7), and of the α4β7 receptor on B cells in peripheral blood, in both etrolizumab dose groups. Rates of AEs were comparable for the 3 groups. One etrolizumab treated patient suffered a rash & headache after the first dose and was admitted to hospital for observation. This patient was negative for ATAs. There were a total of 4 actively treated patients with mild (Grade 1) injection site reactions all of whom were in the 300mg + LD dose group. Conclusion: Etrolizumab administered SC is well tolerated and has shown clinically meaningful efficacy compared with Pbo in patients with moderate-to-severely active UC. These promising results warrant further Phase III studies.

Vermeire S, O’Byrne S, Williams M et al. Presentation at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract 159.

Etrolizumab administered SC is well tolerated and has shown clinically meaningful efficacy compared with Pbo in patients with moderate-to-severely active UC. These promising results warrant further Phase III

studies.


Sustained Clinical Response and Remission Achieved in Moderately Severe Ulcerative Colitis Patients by Local Application of the TLR-9 Agonist Dims0150

BACKGROUND: DIMS0150 is an oligonucleotide that acts as a Toll like receptor 9 (TLR-9) agonist and elicits its immunomodulating effects through specific target cells resulting in the induction of anti-inflammatory cytokines such as interleukin 10 and interferons. As a previous clinical study has shown positive effects of DIMS0150 in ulcerative colitis patients the aim of the present study was to evaluate the efficacy and safety in moderately severe ulcerative colitis patients.METHODS: A randomized, double-blind, multicenter trial was conducted in steroid refractory patients with ulcerative colitis of moderate degree. 34 patients were randomized to a single rectal administration of either of 30 mg of DIMS0150 or placebo at 2:1, respectively. Clinical response was defined as DAI score decrease of at least 3 points from baseline and clinical remission as total DAI score of 2 points or lower, with no individual subscore exceeding 1 point.RESULTS: Clinical response at week 1 was 41.2% (7/17) in the DIMS1050 group and 9.1% (1/11) in the placebo group. Clinical response at week 4 was 52.9% (9/17) in the DIMS1050 group and 36.4% (4/11) in the placebo group (p=0.46). 31% (5/16) in the DIMS1050 treated group showed sustained clinical response at 3 months, whereas no sustained clinical response was observed in the placebo group (0/8).In DIMS1050 treated patients, clinical remission was 11.8% at week 1 (2/17) and 17.7% at week 4 (3/17). None of the patients receiving placebo were in clinical remission at week 1 or 4. At 3 months, 37.5% (6/16) in the DIMS1050 treated group and 25.0% (2/8) in the placebo group were in remission. Sustained clinical remission at 3 months was observed in 12.5% of the DIMS1050 treated patients (2/16) with no case of sustained clinical remission in the placebo group.Histological response at week 1 was 17.7% (3/17) in the DIMS1050 treated group and 18.2% (2/11) in the placebo group. At week 4, 35.3% (6/17) in the DIMS1050 treated group and 0 of 11 patients in the placebo group showed histological response (p=0.05).Histological remission at week 1 was 11.8% (2/17) in the DIMS1050 treated group and 9.1% (1/11) in the placebo group. At week 4, 35.3% (6/17) in the DIMS1050 treated group and 0 of 11 patients in the placebo group were in histological remission (p=0.05). At 3 months, 25.0% (4/16) in the DIMS1050 treated group and 12.5% (1/8) in the placebo group were in histological remission. DIMS1050 was safe and well tolerated in the study population.CONCLUSION: The efficacy results in patients with moderately severe ulcerative colitis were encouraging, with clinical response one week after single dose administration. Within this small study population sustained clinical response and remission was only observed in DIMS1050 treated patients suggesting that DIMS1050 may offer a substantial benefit for this target group.

Knittel T et al. Presentation at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract 89.

Early phase: The efficacy results in patients with moderately severe ulcerative colitis were encouraging, with clinical response one week after single dose administration.

Safety and Efficacy of Laquinimod in Inducing Clinical and Biochemical Improvement in Active Crohn's Disease: Results of an Exploratory Trial (Phase 2a)

Introduction: Laquinimod (LAQ) is a novel oral immunomodulator in development for the treatment of Crohn’s disease (CD). LAQ has an immune modulatory effect on antigen presenting cells (mainly M2 monocytes), directing T cells towards an antiinflammatory phenotype & resulting in down regulation of proinflammatory cytokines. This study evaluated the safety & efficacy of LAQ in patients with active moderate-severe CD and also assessed the impact of the drug on fecal calprotectin as an objective biomarker of intestinal inflammation.Methods: Phase IIa, multicenter, sequential-cohorts RCT with LAQ doses of 0.5, 1, 1.5, or 2 mg/day or placebo (45 patients per cohort randomized 2:1) for 8 weeks with 4-weeks follow-up. CD patients with a CD Activity Index (CDAI) of 220-450 & serum CRP >5mg/L or mucosal ulcerations evident on endoscopy were included. Stable concomitant therapies (corticosteroids, immunosuppressive drugs [AZT, 6MP, MTX], 5-ASA, antibiotics) & prior anti-TNF use were allowed. Elevated fecal calprotectin was not required. Comprehensive safety monitoring and assessments were performed. Efficacy analyses included the proportions of patients in remission (CDAI <150 & no treatment failure [TF]), those with a response 100 (i.e. 100 point CDAI reduction & no TF) and those who had a reduction in fecal calprotectin defined as a decrease from ≥250 μg/g to below 250 μg/g & ≥50% reduction. This study was exploratory & no hypothesis testing was planned.Results: Overall 117 patients received LAQ & 63 pts received placebo. AEs occurred in 86-97% of LAQ groups vs. 83% in pooled placebo group; most common AEs were headache, abdominal pain, nausea & vomiting, and musculoskeletal pain. For pooled LAQ and placebo groups, mean (SD) baseline CDAI were 298(58) & 311(75), and median (IQR) fecal calprotectin levels were 389(749) & 475(802) μg/g, respectively. At week 8, effects on remission and response were observed with the 0.5 mg LAQ dose; 1mg dose showed lower magnitude effects and higher LAQ doses showed similar effects to placebo (Table). All doses reduced fecal calprotectin.Conclusions: This study indicates that treatment with LAQ is well tolerated and the 0.5 and 1 mg doses may have clinically relevant effects on remission & response. All doses (LAQ 0.5-2 mg) were found to reduce objective measures of intestinal inflammation in active CD.

D’Haens GR et al. Presentation at Digestive Disease Week; May 19–22, 2012; San Diego, California. Abstract 90.

Treatment with LAQ is well tolerated and the 0.5 and 1 mg doses may have clinically relevant effects on remission & response. All doses

(LAQ 0.5-2 mg) were found to reduce objective measures of intestinal inflammation in active CD.


Near-term pipeline drugs in IBDMonday 2pm-3:30pm. AGA clinical symposium

• Vedolizumab and Lymphocyte Homing Sp471

Brian G. Feagan

• Tofacitinib and JAK Antagonists Sp472

William Sandborn

• Ustekinumab and IL-12/23 and IL-17 Antagonists

Stephan R. Targan

Summary: New Therapies in IBD and Updates in Management

• More therapies means we need to be smarter about using them.

• Strategize:– What therapy do you use first? – What will you do next?– When is surgery the right option? (Is “medically refractory” a moving target?)

• Optimize:– Use the best treatment available for your patient– Choose objective time points and endpoints of your treatments– Prevent complications (screen, vaccinate)– Educate about adherence and safety

• Maximize:– Use the right dose!– Minimize immunogenicity (load, combine, maintain)– Monitor for relapse


Challenges for IBD Surgery in the “Biological Era”

Feza H. Remzi, MD, FACS,FASCRS, FTSS ( Hon) Chairman, Department of Colorectal Surgery

Rupert B. Turnbull Jr MD,. Chair Professor of Surgery

Digestive Disease Institute Cleveland Clinic, Ohio

Disclosures

None


Operative Options• Subtotal colectomy (STC) and end ileostomy

• Total abdominal colectomy (TAC) and ileal-rectal anastomosis (IRA)

• Total proctocolectomy (TPC) and end ileostomy

• Total proctocolectomy (TPC) and continent ileostomy

• Total proctocolectomy and ileal pouch-anal anastomosis(IPAA)

TPC and IPAA


STC and End Ileostomy

Indications

• Significant co-morbidity

• Obesity

• Immune-modulating agents

• High-dose prednisone (>20 mg/day)

• Severe hypoalbuminemia

• Severe anemia








Results over 4000 Patients

• 97% patients said that they would undergo surgery again

• 97.4% patients stated that they would be willing to recommend surgery to other patients


Department of Colorectal Surgery,

Digestive Disease Institute, Cleveland Clinic, Ohio

Operative Strategy Modifies Risk of Pouch Related Outcomes in Patients with Ulcerative Colitis on Preoperative Anti-TNF Therapy

Jinyu Gu, MD, Feza H. Remzi, MD, Bo Shen, MD

Jon D. Vogel, MD, Ravi P. Kiran, MD

TNF: tumor necrosis factor; UC: ulcerative colitis; IC: indeterminate colitis; IFX: infliximab * mixed surgical procedures

Does Anti-TNF therapy increase postoperative complications after abdominal surgeries for UC/IC?

Author Period Biologics(definition)

Biologics users/ none

users

Risk factor

Selvasekar 2002 - 2005 IFX (None) 47/254 Yes

Mor 2000 - 2006 IFX (None) 46/46 Yes

Eshuis 2006 - 2009 IFX (None) 38/34 Yes

Schluender 2000 - 2005 IFX (None) 17/134 No

Ferrante 1998 - 2008 IFX (< 12 wk) 22/119 No

Coquet-Reinier

1999 - 2008 IFX (None) 13/13 No

Gainsbury 2005 - 2009 IFX (< 12 wk) 29/52 No

Bregnbak 2005 - 2010 IFX (< 12 wk) 20/51 No

Nørgård * 2003 - 2010 IFX (< 12 wk) 199/1027 No


TNF: tumor necrosis factor; UC: ulcerative colitis; IC: indeterminate colitis; IFX: infliximab * mixed surgical procedures

Does Anti-TNF therapy increase postoperative complications after abdominal surgeries for UC/IC?

Author Period Biologics(definition)

Biologics users/ none

users

Risk factor

Selvasekar 2002 - 2005 IFX (None) 47/254 Yes

Mor 2000 - 2006 IFX (None) 46/46 Yes

Eshuis 2006 - 2009 IFX (None) 38/34 Yes

Schluender 2000 - 2005 IFX (None) 17/134 No

Ferrante 1998 - 2008 IFX (< 12 wk) 22/119 No

Coquet-Reinier

1999 - 2008 IFX (None) 13/13 No

Gainsbury 2005 - 2009 IFX (< 12 wk) 29/52 No

Bregnbak 2005 - 2010 IFX (< 12 wk) 20/51 No

Nørgård * 2003 - 2010 IFX (< 12 wk) 199/1027 No

Study Design

• Patient groups: biologics vs. no biologics

• Index Surgeries

• TPC/IPAA

• STC/EI• after STC/EI

• after subsequent CP/IPAA


PatientsBiologics No Biologics Total


25 156 181



25 156 181

142 265 407


25 156 181

142 265 407



25 156 181

142 265 407

CP/IPAA

(N=88)

CP/IPAA

(N=164)252

* Kaplan-Meier estimated 1-year cumulative rate

EPSBO: early post operative small bowel obstruction

Biologics (N = 25)

No Biologics (N = 156)

Pvalue

30 day complications

Pelvic sepsis, N (%) 4 (16) 11 (7) 0.13

Wound infection, N (%) 2 (8) 10 (6) 0.67

EPSBO, N (%) 1 (4) 6 (4) 1

Postoperative hemorrhage, N (%) 0 5 (3) 1

Cumulative 1-year complications *

Pelvic sepsis (%) 8 (32) 25 (16) 0.012

Anastomotic Stricture (%) 2 (8) 21 (13) 0.55

Fistula (%) 2 (8) 9 (6) 0.14

Pouch Failure (%) 0 7 (4) 0.55

TPC + IPAA at Index Surgery: Postoperative Complications


* Kaplan-Meier estimated 1-year cumulative rate

EPSBO: early post operative small bowel obstruction

Biologics (N = 25)

No Biologics (N = 156)

Pvalue

30 day complications

Pelvic sepsis, N (%) 4 (16) 11 (7) 0.13


EPSBO, N (%) 1 (4) 6 (4) 1

Postoperative hemorrhage, N (%) 0 5 (3) 1


Pelvic sepsis (%) 8 (32) 25 (16) 0.012


Fistula (%) 2 (8) 9 (6) 0.14


TPC + IPAA at Index Surgery: Postoperative Complications

Hazard Ratio95% Confidence Interval

P value

Age at colectomy (per 10 years increase) 0.96 (0.69 - 1.33) 0.81

Preoperative leukocytosis (WBC > 10.8 x 103/µl) 1.27 (0.51 - 3.19) 0.61

Preoperative use of anti-TNF biologics 2.62 (1.11 - 6.15) 0.027

Preoperative use of corticosteroids (> 20 mg) 1.88 (0.73 - 4.83) 0.19

Preoperative azathiopurine /6-mercaptopurine use

0.84 (0.34 - 2.05) 0.7

Omission of proximal ileostomy 1.10 (0.25 - 4.84) 0.9

TPC: total proctocolectomy; IPAA: ileal pouch-anal anastomosis; TNF: anti-necrosis factor; WBC: white blood count

Pelvic Sepsis After TPC + IPAA: Cox Proportional Hazard Model


Hazard Ratio95% Confidence Interval

P value

Age at colectomy (per 10 years increase) 0.96 (0.69 - 1.33) 0.81

Preoperative leukocytosis (WBC > 10.8 x 103/µl) 1.27 (0.51 - 3.19) 0.61

Preoperative use of anti-TNF biologics 2.62 (1.11 - 6.15) 0.027

Preoperative use of corticosteroids (> 20 mg) 1.88 (0.73 - 4.83) 0.19

Preoperative azathiopurine /6-mercaptopurine use

0.84 (0.34 - 2.05) 0.7

Omission of proximal ileostomy 1.10 (0.25 - 4.84) 0.9

TPC: total proctocolectomy; IPAA: ileal pouch-anal anastomosis; TNF: anti-necrosis factor; WBC: white blood count

Pelvic Sepsis After TPC + IPAA: Cox Proportional Hazard Model

Initial STC/EI: Features at Index Surgery

Biologics(N = 142)

No biologics (N = 265)

P value

Age at surgery (years) 37 (18-77) 41 (18-84) 0.04

Body mass index (kg/m2) 24 (16-45) 25 (15-52) 0.04

Active smoker, N (%) 13 (9) 9 (3) 0.02

Age-adjusted CCI (mean ± SD) 1.5 ± 0.8 2.0 ± 1.4 0.001

Steroids use, N (%) 100 (70) 212 (80) 0.03

Estimated blood loss (ml) 100 (20-1000) 150 (10-1500) 0.04

CCI: Charlson Comorbidity Index


Complications Biologics(N = 142)


P value

Pelvic sepsis, N (%) 3 (2) 12 (5) 0.23

(Colo)rectal stump leak, N (%) 16 (11) 24 (9) 0.48


Postoperative hemorrhage, N (%) 3 (2) 9 (3) 0.55

Thromboembolism, N (%) 7 (5) 22 (8) 0.21

Urinary tract infection, N (%) 2 (1) 8 (3) 0.61

Pneumonia, N (%) 2 (1) 2 (1) 0.61

30-day Complications After Index STC/EI

Complications Biologics(N = 142)


P value

Pelvic sepsis, N (%) 3 (2) 12 (5) 0.23

(Colo)rectal stump leak, N (%) 16 (11) 24 (9) 0.48



Thromboembolism, N (%) 7 (5) 22 (8) 0.21

Urinary tract infection, N (%) 2 (1) 8 (3) 0.61

Pneumonia, N (%) 2 (1) 2 (1) 0.61

30-day Complications After Index STC/EI


Index surgery and risk of pelvic sepsis for patients treated with and without anti-

TNF agents prior to surgery

P = 0.012 P = 0.23

Biologics(N = 88)


Pvalue

30-day complications

Pelvic sepsis, N (%) 6 (7) 13 (8) 0.75


EPSBO, N (%) 2 (2) 0 0.12



Pelvic sepsis (%) 5 (6) 16 (10) 0.27


Fistula (%) 2 (2) 8 (5) 0.5


* Kaplan-Meier estimated 1-year cumulative rate EPSBO: early post operative small bowel obstruction

Complications After Subsequent CP/IPAA


Conclusions

• Preoperative exposure to biologics is associated with an increased risk of pelvic sepsis after TPC/IPAA

• This risk can be mitigated by the performance of an initial STC

Author (year of ublication)

Ref.Study period

Study design

Diagnosis

Biologics(cut-off value)

Impact on initial surgery

Patient Number

(user/non-user)

End point Risk factor

Selvasekar ( 2007)

52002-2005

RC UC IFX (None) TPC/IPAA 301 (47/254)30-day

complicationYes

Schluender (2007)

62000-2005

RC UC IFX (None) TPC/IPAA 151(17/134)30-day

complicationNo

Mor (2008) 72000-2006

RCM UC/IC IFX (None) TPC/IPAA 92 (46/46)30-day

complicationYes

Ferrante (2009)

81998-2008

RC UC/IC IFX (< 12 weeks) TPC/IPAA 144 (22/119)30-day

complicationNo

Coquet-Reinier (2010) 9

1999-2008

RCM UC IFX (None)Laparoscopic

TPC/IPAA26 (13/13)

30-day complication

No

Gainsbury (2011)

102005-2009

RC UC IFX (< 12 weeks) TPC/IPAA 81(29/52)30-day

complicationNo

Bregnbak (2012)

112005-2010

RC UC IFX (< 12 weeks) Colectomy 71 (20/51)30-day

complicationNo

Nørgård (2012)

122003-2010

RC UC IFX (< 12 weeks) Colectomy1200

(199/1027)

30- and 60-day

complicationNo

Eshuis (2012)

132006-2009

RC UC IFX (None) TPC/IPAA 72 (38/34)30-day

complicationYes *

Present study

2006-2010

RC UC/IC

IFX (<12 weeks); adalimumab or certolizumab

pegol (<4 weeks)

STC/EI or TPC/IPAA

588 (167/421)Long-term f/u,

pouch function, QOL

Yes *


Operative Options

Bypass

• Internal with/without exclusion

• External

Resection with/without anastomosis

Strictureplasty

Internal Bypass

Generally avoided

• Infected mucocele and reactivated disease

• Cancer risk in excluded segment

Occasionally acceptable

• Gastroduodenal disease

• Complicated ileocecal phlegmon


Resection

Procedure of choice

Operative principles

• Adequate mobilization

• Minimal contamination

• Suture ligation of mesenteric pedicles

• Conservative resection margins (~2 cm)

Resection Margins

Extended (~12 cm) versus limited (~2 cm) margin

• Randomized, controlled trial

• Small bowel disease

• N=131; follow-up: 56 months

• Recurrence: 18% versus 25%

Fazio 1996


Anastomosis

Configuration and technique unrelated to recurrence

• Side-to-end versus end-to-end

• End-to-end versus side-to-side

• Side-to-side versus end-to-side

• Stapled versus handsewn

Cameron 1992, Scott 1995, Munoz-Juarez 2001, Mc Leod 2009


Documents

Update in Biological Therapies and New Developments in · PDF fileSteering the Course of IBD Webcast David T. Rubin, MD Professor of Medicine Co-Director, Inflammatory Bowel Disease