Presentation on theme: "Emerging treatments in Crohn’s disease and ulcerative colitis"— Presentation transcript:
1 Emerging treatments in Crohn’s disease and ulcerative colitis Athos Bousvaros MD MPHBoston Children’s Hospital
2 Disclosures Consulting: Millennium, Dyax, Cubist, Nutricia Research support: Prometheus, MerckEvery medication I discuss in this talk is not approved in adult or pediatric IBDAll the data I give in this talk will be from adult studiesThis data should NOT be extrapolated to very young children with IBD, especially those with suspected immune deficiencies.
3 When anti-TNF really doesn’t work, options are very limited Weigh benefit to risk ratioIs surgery preferable?Ulcerative colitis – colectomy with/without pouchCrohn’s – limited resection, diversion, colectomyIs long term nutritional therapy an option?Pediatric rescue medication data is limitedNatalizumab for Crohn diseaseThalidomide for Crohn diseaseTacrolimus, cyclosporine for ulcerative colitis
4 Help is on the way - maybe UstekinumabCrohn’sTofacitinibUlcerative colitisVedolizumabUC and maybe Crohn’s
6 Ustekinumab in Crohn’s Antibody to IL12 and IL23 (p40 subunit)Approved for use in psoriasis526 patients from 153 centersFour arm study – 3 different doses and placeboInclusion criteriaCrohn’s for at least 3 monthsActive CDAI ( )Failure of anti-TNF therapyloss of response or serious adverse eventStable doses of ASA, 6MP, MTX, or prednisone allowedSandborn et al, Gastro :1130
8 Ustekinumab Adverse events Serious infections7 patients (6 ustekinumab) during induction11 patients (4 ustekinumab) during maintenanceAntibodies rare1 basal cell CA in an ustekinumab ptInfusion reactions 5% across the board (including in the placebo group)Psoriasis trials suggest overall good safety profile, with no significant increase in infections or cardiovascular events.
10 Tofacitinib Small molecule JAK kinase inhibitor Affinity for JAK 1 and 3Inhibits cytokine signalingApproved for RA that has not responded to MTXMetabolized by liver(CYP3A4)Phase 2 clinical trial suggests efficacy in ulcerative colitis
11 Tofacitinib in active ulcerative colitis Phase 2 placebo RCT194 adults active UC assigned to 4 different doses of tofacitinib or placeboMayo score of 6-12, and active score on endoscopy (Mayo score of 2-3)Prior meds40% immunomodulator failure30% prior anti-TNF exposureShort term trial – only 2 monthsSandborn et al NEJM 2012; 367:616
12 Tofacitinib results Clinical remission at 2 months 48% at tofacitinib, 10 mg bid vs. 10% on placeboEndoscopic remission30% on tofacitinib 10 mg bid vs. 2% on placebo
13 Tofacitinib adverse events MyelosuppressionLipid abnormalitiesIncrease in both LDL and HDLSome patients need statins to controlSerious infectionsPneumonia, cellulitis, zoster, UTILiver function abnormalitiesMalignancies (including lymphoma)Scott, Drugs 2013; 73; 857
14 VedolizumabHumanized IgG 1 monoclonal antibody to alpha4 beta7 integrinModulates gut, but NOT brain lymphocyte traffickingLess risk of PML compared to natalizumabTakeda website
15 Vedolizumab as induction and maintenance therapy for UC Combination placebo controlled and open-label trial374 patients – vedolizumab or placebo521 patients – open label vedolizumabInclusion – active UCMayo score 6-12, endoscopy subscore of 2.Induction – two doses – week 0 and 2MaintenanceResponders continued on active drug, or randomized to placeboFeagan et al NEJM 2013; 369:699
16 Vedolizumab - results Week 6 Week 52 Response – 47% vedolizumab vs. 25% placeboRemission – 17% vedolizumab vs. 8% placeboWeek 52Remission (in the responders)45% of patients getting vedolizumab monthly42% of patients getting it every other month16% of patients randomized to placebo
17 “Off label” does not necessarily mean “experimental” – FDA statement The FD&C Act does not, however, limit the manner in which a physician may use an approved drug. Once a product has been approved for marketing, a physician may prescribe it for uses or in treatment regimens or patient populations that are not included in approved labeling. Such “unapproved” or, more precisely, “unlabeled” uses may be appropriate and rational in certain circumstances, and may, in fact, reflect approaches to drug therapy that have been extensively reported in medical literature.
18 ConclusionsOptions for our patients with IBD who respond poorly to biologics are limitedThree new drugs with potential in IBD, but limited data, especially in children, are:UstekinumabTofacitinibVedolizumabThe first two are FDA approved for other indications besides IBD.