When can we use combination therapy for our pediatric IBD

patients?

Athos Bousvaros MD, MPHAdvances in IBD Dec 2014

Disclosures (last 12 months)

• Consultant– Takeda/Millennium– Dyax– Cubist– Peabody Arnold (litigation)

• Research support– Prometheus

Questions

• Should we use combination therapy in our pediatric IBD patients?

• If so, what kind?– Thiopurines and infliximab– Methotrexate and infliximab

• How does monitoring of biologic levels (therapeutic drug monitoring) impact on our decision?

• Is adalimumab different from infliximab?• How long do we continue combination therapy?

The “Balancing Act”

Our options with biologicsPros Cons

Infliximab Works Antibodiesmonotherapy Loss of response

IFX with levels May work better Antibodies

Adalimumab Works Antibodiesmonotherapy

Combination Works best Lymphoma Therapy – AZA/IFX

Combination Works No better than IFXMTX/IFX Decreased antibody monotherapy?

Reading the literature on biologics, antibodies, loss of response, and drug levels

Adult studies

Combination therapy in both CD and UC (adult data – remission rates)

• SONIC (Crohn disease) – Remission 26 weeks– AZA plus infliximab – 57%– Infliximab alone – 44%– Antibodies to IFX – 1% (combination) vs. 15% (mono)

• UC SUCCESS (Ulcerative colitis)* – Remission 16 wks – AZA plus infliximab – 40%– Infliximab alone – 22%– Azathioprine alone – 23%– Ab to IFX – 3% (combination) vs. 19 % (mono)

*Panaccione et al, Gastro 2014;146:392

UC SUCCESS trial

• 239 adult patients randomized to:– AZA alone – 2.5 mg/kg/day– IFX alone (5mg/kg) – 0,2,6, 14– AZA and IFX together– Double blind, double dummy design

• Inclusion criteria– Moderate to severe disease (Mayo score >= 6)– Stable dose of steroids allowed– No prior rx with MTX, CyA, Tacro, or rectal therapy– AZA naïve for 3 months or more

Panaccione, Gastro 2014; 146:392

UC SUCCESS in close up

Panaccione, Gastro 2014; 146:392

US SUCCESS results• Week 16• Remission rates

– 23 % AZA and IFX– 39% combination

• Drops in Mayo score – AZA - 3.00– IFX - 4.3– AZA/IFX - 5.2

• Calprotectin levels lower in combination group– 170 combination– Around 400 other 2 groups

• SAE’s more common in the two azathioprine groups (pancreatitis, anemia, nausea, vomiting)– NO 6MP levels or TPMT assayed

Loss of response – natural history(Oussalah et al; AJGastro 2010)

• 88 patients treated with combination AZA and infliximab for at least 6 months

• Azathioprine withdrawn in 48 patients• Probability of infliximab failure

– Increasing dose, shortening interval, surgery, or hypersensitivity

– 15% at 12 months– 41% between 24 and 32 months

• Withdrawal of AZA strongly associated with infliximab failure (hazard ratio of 7 in patients that received combination for less than 800 days)

COMMIT trial (MTX and IFX in Crohn)

• 50 week trial in adults with CD• 126 patients randomized to:

– IFX monotherapy– IFX and MTX (SQ, up to 25 mg/week)

• Primary endpoint – lack of steroid free remission at week 14, or at 50 weeks– 30 % failure in both groups

• However, antibodies lower in IFX + MTX– 4% (combo) vs. 20% (mono) at 1 year

remission

Low CRPFeagan et al Gastro 2014; 146:681-8

Development of antibodies to adalimumab

• 247 adult and pediatric patients– 205 Crohn, 42 UC

• 330 “loss of response events”– Suspected worsening by physician– “Definite inflammatory LOR” (identification of inflammation by

labs, stool markers, or endoscopy)• Of 142 “LOR events”, 38% were associated with antibodies.

– Concomitant immunomodulators in about 30%– No clear impact of IM on outcome– AAA antibodies > 4 mcg/ml predicted patients who did not

respond to increased dosage of IM.

Yanal et al, CGH 2014, in press

Pediatric studies

Infliximab in pediatric Crohn’s(REACH trial)

• Children with active CD – Infliximab 5mg/kg

• 0,2, 6 weeks then q 2 months• 88% response rate after 3 infusions• 56% remission rate after 12 months

• However:– Concomitant immunomodulators used for

duration of study • REACH describes efficacy of

combination therapy (mostly thiopurine)

Hyams et al Gastro 2007;132:863

Prevalence of antibodies to infliximab in children with IBD

• Boston Children’s Hospital– Cross-sectional cohort of 133

children– All still receiving infliximab as per

their primary physician’s dictates.– 20% had antibodies to infliximab– ATI correlated with lower IFX

levels, but not (as of yet) with loss of response or infusion reactions.

– ? Latency period between development of antibodies, drop in levels, and loss of response. Zitomersky et al, in press, IBD

Long term outcomes of pediatric infliximab therapy

• 259 patients – CD and UC• 188 on IFX for at least 1 year

– Median duration 29 months– 84% CD, 16% UC

• Results– Half of CD patients underwent dose

intensification to maintain or recapture remission

• Most patients stayed on IFX (about 70% in both groups).

• No effect of low dose oral MTX

Vahabnezhad et al, IBD 2014; 20:606

IFX level at week 14 may determine clinical outcome in children

• Prospective study of 58 IBD patients (81% CD)

• 13% primary nonresponse• 58% in persistent remission at 1

year of therapy• Median IFX level at week 14

correlated with remission (4.7 mcg/ml for patients in remission at 1 year, vs. 2.6 mcg/ml).

• Immunomodulators correlated with higher level, but this was not statistically significant.

• 26% had detectable antibodies to infliximab by week 54

Singh et al, IBD 2014; 20: 1708

Adalimumab in pediatric CD(Hyams et al, Gastro 2012; 143:365-74)

• 192 CD patients with active PCDAI (>30)– Approximately 60% on ‘immunosuppressants”– Standard induction, then hi vs. low dose

• Results (clinical remission, high dose)– Week 26

• 57% infliximab naïve, 17% if prior infliximab

– Week 52• 45% infliximab naïve, 19% if prior infliximab

Infection rate about 5%, antibody rate only 3%

Summarizing

• Good evidence that using combination treatment with thiopurines in patients starting on infliximab– Improves clinical remission rates in CD and UC– Reduces the likelihood of antibody formation

• Data on combination therapy with methotrexate and infliximab is lacking– Perhaps reduction in antibody formation– More studies needed

• Unclear if combination treatment impacts antibody development and clinical outcomes in patients treated with adalimumab

• More studies are needed

How I like to practice

• Moderate Crohn’s disease treated with an immunomodulator first, then biologic if poor response.– Continuation of combination treatment (eg. AZA and

inflximab) for at least 6 months– Replacement of the thiopurine with low dose MTX

• High risk or severe Crohn’s treated with combination therapy– Extensive disease (especially mid-small bowel disease)– Severe rectal or perianal disease– Steroid-unresponsive disease– Growth failure in mid to late puberty

• Patient preference is important in making the decisions.

Age < 18 yearsBeginning anti-TNF therapyNo contraindication to MTX use

RANDOMIZE

Anti-TNF plus methotrexate

Anti –TNF plus placebo

Week 104 assessment

Steroid free remission (primary endpoint)

Adverse eventsPatient reported outcomesAntibodies to anti-TNF

Week 104 assessment

Steroid free remission (primary)Adverse eventsPatient reported outcomesAntibodies to anti-TNF

Proposed clinical trial(Kappelman, PI)