Biologics in IBD: Optimizing Therapies and Emerging Agents

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1 Optimizing Therapies and Emerging Agents Peter Mannon, MD Professor of Medicine and Microbiology UAB AGS Annual Conference July 1, 2017 Hilton Sandestin Optimizing Therapies and Emerging Agents Optimizing Biologics for Effectiveness and Endurance Emerging Agents on the Horizon Biosimilars in IBD: They re Here Biologics in Use in IBD, JUL2017 Drug Description Crohn s UC Infiximab (Remicade) chimeric IgG1κ MAb (composed of human constant and murine variable regions), IV + + Adalimimab (Humira) recombinant human IgG1 MAb, SC + + Certolizumab pegol (Cimzia) recombinant, humanized antibody Fab' _ + fragment, conjugated 40kDa PEG, SC Golimumab (Simponi) Human IgG1κ MAb, SC _ + Vedolizumab (Entyvio) Humanized IgG1 MAb to α4β7 integrin, IV + + Natalizumab (Tysabri) Humanized IgG4κ MAb to α4 integrins, IV + _ Ustekinumab (Stelara) Human IgG4κ MAb to IL-12/23 p40 subunit

2 The Promised Impact of Enhanced Control, Steroid-sparing and Altering the Natural History of Complications Cumulative probability % inflammatory penetrating strictures Number of patients at risk: Cosnes J et al. Inflamm Bowel Dis. 2002;8: The Impact of Enhanced Control, Steroid-sparing and Altering the Natural History of Complications Feagan et al., Gastroenterology 2008, 135:1493 Many RCTs document the effectiveness of biologics at steroid-sparing and reducing hospitalizations (and need for surgery) in the short term Biologics are effective at inducing mucosal healing which is a treatto-target goal associated with long term remission Robust data on longer-term effects on the natural history of IBD are needed The Gaps in Therapy Primary Non-Response Secondary Non-Response Anti-drug antibodies Increased drug clearance Needs to be attributed to recurrent inflammatory disease 2

3 Strategies to Optimize Therapy Ensure scheduled (vs episodic) treatment Earlier introduction of biologics Accelerated dosing in severe colitic disease Concomitant use of immunosuppressive drugs Drug monitoring to guide decision making Optimization Through Early Use Aloi, M. et al. (2013) Nat. Rev. Gastroenterol. Hepatol. Rationale for use SONIC trial results Various post-hoc trial data suggest increased response and remission rates when used closer to data of diagnosis Certain risk factors identify patients at higher risk of complicated course Early onset disease Perianal, early penetrating or stricturing disease Severe endoscopic lesions >3 anti-microbial antigen Abs (Crohn s) Tobacco use (Crohn s) Downside: avoiding early/combined use in patients who will not need this level of intensified therapy Optimization Through Accelerated Dosing Hospitalized, severe UC patients have lower response rates to IFX than predicted by trial results (Sands, IBD 2001, 7:83) Intact infliximab excreted in the stool in active colitis and is associated with lack of response (Brandse et al., Gastroenterology 2015, 149:350) In RCTs, serum concentrations of anti-tnf biologics generally are higher in responders, remitters, and in those with mucosal healing There are many factors associated with the increased clearance of biologics: Higher circulating TNF levels Higher CRP Hypoalbuminemia 3

4 Monitoring Drug Levels and Anti-drug Antibodies Patients with lower trough drug levels have lower rates of response and mucosal healing Trough levels ADA >4.5 µg/ml and IFX >3.8 µg/ml seem adequate as they predicted no further clinical improvement with increased dosing (Yanni et al. CGH 2014) High trough levels early in IFX treatment (>3.5 µg/ml) (Cornillie et al., Gut 2014) and (>4.7µg/mL at week 14 in pediatric IBD pts) (Casteele et al. Gut 2015, 64:1539) associated with sustained clinical response Proactive drug monitoring that informs drug dosing helps to optimize dose and limit overuse of medication early in treatment but the robust improvement in clinical outcomes is lacking (especially beyond conventional assessment) Anti-drug Abs >4 µg/ml-eq (ATAs) or >9 (ATIs) by the Prometheus assay predict poor response to increase drug dosing So there are data that suggest how early drug levels can guide therapy but the downsides include expense, turnaround time, lack of convincing data for the beneficial effects on long-term outcomes. Monitoring Drug Levels and Anti-drug Antibodies Anti-drug Antibodies No Yes Good Drug Trough Levels Yes No For loss of response: 1: Optimal parameters but ineffective response, consider different anti-tnf agent or change of drug class 2: Consider temporary increase in drug dosage to overcome ADAs, (if <4 µg/ml-eq (ATAs) or <9 (ATIs) by the Prometheus assay) 3: Increase dose of drug 4: Consider new anti-tnf (with addition of IS) or change drug class Effects of Immunosuppressants on Biologic Drug Levels and Anti-drug Antibodies Observed that anti-drug Abs are associated with secondary loss of response Anti-drug Abs occur less often in pts also taking AZA or MTX Early combined IS/biologic therapy has also been associated with improved response/remission, mucosal healing and reduced risk for hospitalization and surgery (within the first year) compared to biologic monotherapy Combined use of IS/biologics was associated with higher IFX trough levels and lower rates of anti-drug Abs (22 vs 38%) (Drobne et al. CGH 2014) Emerging data that low-dose AZA associated with lower rates of Anti-drug Abs induction 4

5 Optimizing Summary Better short term outcomes linked to higher serum levels of anti-tnf agents Primary non-response not always a drug class-effect (low drug levels, early anti-drug Ab induction) Accelerated drug dosing can improve severe colitis response Anti-TNF trough levels and anti-drug Abs can help clarify mechanisms of secondary non-response Concomitant use of IS (mostly AZA) and anti-tnf drugs can improve drug levels, clinical outcomes, and reduce anti-drug Ab formation Gaps in knowledge about optimizing biologics include Chosing patients for targeted biologics (anti-tnf vs anti-integrin vs anti-il12/23 p40, e.g.) how precise use of pro-active monitoring can improve outcomes superior to conventional treatment how biologic optimization can change the trajectory of IBD natural history Emerging Therapies in IBD: Aims State of the Art The Changing Look of Success Gaps in Effectiveness (Opportunity Knocks) What are the New Targets? Therapies Being Tested Now A Look To the Future Danese, S. et al.(2015) 5

6 Anti-TNF Updates Biosimilars CT-P13, Inflectra (infliximab biosimilar) Immunogenicity concerns (changes in manufacturing vs originator) TNF-Kinoid htnf-klh vaccine to produce anti-tnf Ab AVX-470 Oral antibody to TNF from colostrum of TNFimmunized cows Emerging Anti-cytokine Agents Antibodies against specific cytokines Inhibition of cytokine signaling Enhancement of suppressor cytokines (IL- 10, TGFβ) Agents against specific cytokines HMPL-004 (Andrographis paniculata extract) can reduce TNFα, IL-1β, IFNγ, IL-22 Ustekinumab anti-p40 IL12/23 (Stelara) Sandborn et al., NEJM CERTIFI study 6

7 Anti-cytokine agents Anti-IL-13 Tralokinumab Anrukinumab Lebrikinumab (asthma) Anti-IL-6/R Tocalizumab (anti-il-6r approved for RA) PF (anti-il-6 in early stage CD studies) Anti-cytokine Agents JAK inhibitors JAK isoforms 1,2,3,5 BM toxicity (JAK2), infections esp. zoster (JAK3), dyslipidemia Tofacitinib (Xeljanz) JAK 1,3>2 inhibition UC Trial, PO BID 8wks, 4 dose groups Sandborn et al., NEJM Enhancing Suppressor Cytokine Activity IL-10 TGFβ SMAD7 levels increased in CD Mongersen (21 base antisense oligo) Primary end point remission at day 15 with maintenance for 2 more weeks Caveats No significant change in CRP No robust objective measures Long term effects of TGFβ unknown (esp. fibrosis) Monteleone et al., NEJM

8 Update on Cell Trafficking Based Drugs Natalizumab anti-α4 (Tysabri) Vedolizumab anti-α4β7 (Entyvio) Etrolizumab anti-β7 Anti-MadCAM-1 Update on Anti-Trafficking Strategies Vedolizumab as Induction and Maintenance Therapy for Crohn s Disease 6 Week Response and Remission Rates 52 Week Results Among Those Patients in Remission at Week 6 (includes induction trial and open-label trial subjects) Sandborn et al., NEJM 2013 Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis Feagan et al., NEJM

9 Additional Pipeline Agents MERIT-UC study Trichuris suis oocysts Masitinib (TKI targeting c-kit receptor) Curcumin in UC Mesenchymal stem cells Fecal microbiota transplant 9