John F. Valentine, MD Inflammatory Bowel Disease Program University of Utah

Transcription

1 John F. Valentine, MD Inflammatory Bowel Disease Program University of Utah Hawaii 1/20/2017

2 DISCLOSURES Research Support: NIH, Pfizer, Celgene, AbbVie, Roche/Genentech, Takeda, CCFA

3 OBJECTIVES Review non-biologic drug monitoring. Update on biologic drug monitoring Explore reactive vs proactive therapeutic drug monitoring Discuss treat to target concept

4 37 yo WF seen in consultation 9/2010 dx Crohn's colitis involving the rectum and transverse colon 2010 Lialda 4.8 gm/d 11/2010 Prednisone, intermittent use since then, 90% on past 2 yrs 2/2011 Started 6MP 75 mg/d 3/20/2011 stopped 6MP due to side effects - nausea, lower back pain, hives 4/2011 started Infliximab with response, held in the third trimester of her pregnancy fall /2013 Infliximab dose escalated to every 6 weeks due to a flare 8/2013 stopped Infliximab due to loss of response and started Adalimumab 40 mg every other week 10/2014 Stopped Adalimumab due to ongoing active disease, started Certolizumab 2/2015 Stopped Certolizumab due to ongoing active disease 2/2015 Started Vedolizumab, no benefit, caused tremor/migraine HA, 6/9/2015 Stopped Vedolizumab 7/6/2015 restarted 6MP caused severe lower back pain, worsening diarrhea, fever, hives 7/22/2015 restarted Infliximab at 10 mg/kg every 8 weeks

5 QUESTIONS TO ASK IN IBD PTS FAILING THIOPURINE TREATMENT 1) Is the IBD active? R/O Infection, C diff, CMV Check fecal calprotectin, CRP, Endoscopy or imaging if needed 2) Is the patient compliant with the medication regimen? 3) Is the patient metabolizing the drug preferentially to 6MMP? Is the 6TG in range?

6 Weinshilboum RM, Sladek SL Am J Hum Genet 32: , 1980 Should not take 6MP with dairy products due to high levels of XO. No data on Aza Coskun et al. Clin Pharmacokinet. 2016;55(3):257-74

7 ASSOCIATION OF 6-THIOGUANINE NUCLEOTIDE LEVELS AND IBD ACTIVITY: A META-ANALYSIS N=382 6-TGN levels above threshold values of pmol x 10 8 RBCs were significantly more likely to be in clinical remission with an OR of Osterman MT. Gastroenterology 2006;130:

8 6TGN level between 235 and 450 pmol/8x10 8 RBCs are 5-times more likely to be in clinical remission than those with lower 6TGN levels while 6MMP levels >5,700 pmol/8x10 8 RBCs are associated with a threefold risk of hepatotoxicity* Dewit et. al. Eur J Clin Invest 2010;40: *Kopylov et al. Ann Gastroenterol 2014; 27:

9 29-year-old with ileocolonic Crohn's disease. He was started on 6MP at a dose of 100 mg/d. Pt remains symptomatic and has active disease. WBC 8.3, LFTs normal, metabolites obtained. Do you increase the dose? YES

10 29-year-old with ileocolonic Crohn's disease. He was started on 6MP at a dose of 100 mg/d. Pt in clinical remission. WBC 4.5, LFTs normal, metabolites obtained. Do you decrease the dose? 7945 NO

11 29-year-old with ileocolonic Crohn's disease and had a perirectal abscess. He was started on 6MP at a dose of 100 mg/d. On this dose he is in remission but developed abnormal liver test: AST 133, ALT MP metabolites were obtained.

12 Allopurinol Alters Thiopurine Metabolism Must reduce the 6MP or Aza dose to 25-30% of the hepatoxic dose Sparrow et al. Aliment Pharmacol Ther 2005; 22:

13 Split Thiopurine Dosing to Alter Metabolism? Retrospective review of patients with 6MMP levels greater than 7000 that were treated with split dosing (N = 20) Dividing the total daily thiopurine dose reduced 6- MMP levels (11785 vs pmol/8x10 8 RBCs; P < ) without negatively affecting clinical disease activity or 6- TGN levels (239 vs. 216 pmol / 8x10 8 RBCs; P = NS). Shih DQ et al. Aliment Pharmacol Ther. 2012;36:

14 QUESTIONS TO ASK IN IBD PTS FAILING ANTI-TNF TREATMENT 1) Is the IBD active? R/O Infection, C diff, CMV Check Fecal calprotectin, CRP, Endoscopy or imaging if needed 2) Is this a primary or secondary failure? 3) If secondary, is the drug level low or high? Are there antibodies to the anti-tnf?

15 CDAI Score 250 Defining Primary and Secondary Failure Primary Failure: a patient that never responded. Secondary Failure: a patient who initially responds to the biologic but loses response over time. 200 Primary Failure (~30%*) 150 Remission Secondary Failure (40-50%*) 4 weeks 8 weeks 12 weeks 1 Year *Peyrin-Biroulet L, et al. Clin Gastroenterol Hepatol 2008;6:

16 FACTORS AFFECTING THE PHARMACOKINETICS OF MONOCLONAL ANTIBODIES High Disease Activity Presence of anti-drug Abs (ADAs) Concomitant use of Thiopurines or MTX High baseline TNFα Low albumin High baseline CRP Body size Gender Impact on Pharmacokinetics Decreases serum mabs Threefold-increased clearance Worse clinical outcomes Reduces formation Increases serum mabs Decreases mab clearance Better clinical outcomes May decrease mabs by increasing clearance Increases clearance Worse clinical outcomes Increases clearance High BMI may increase clearance Males have higher clearance mab, monoclonal antibody; ADA, antidrug antibody Ordas et al. Clin Gastroenterol Hepatol 2012;10:

17 Primary Failure/Non-Response Occurs in about 30% Low Drug levels or Mechanistic Resistance? Primary non response, defined as no response to the first two doses of infliximab leading to discontinuation of treatment. Ainsworth et al. Am J Gastroenterol 2008;103:

18 PT WITH INITIAL RESPONSE BUT LOSS OF EFFECT (SECONDARY FAILURE) Assess for Inflammation Exclude infection Inflammation present No inflammation Assess Trough Drug level/anti-drug antibodies Treat underlying causes: IBS, SBBO, stricture etc...

19 ASSESSING LOSS OF RESPONSE TO MONOCLONAL ANTIBODY THERAPY Anti-drug Ab Trough Drug level (+) Anti-drug Ab No or low drug ( ) Anti-drug Ab No or low Drug ( ) Anti-drug Ab Drug present at appropriate level Alternative anti-tnf Increase dose Change to drug with different mechanism Assays commercially available for IFX, ADA, Certoliz, Vedo and Ustekinumab.

20 DRUG (-), ADA (+) Switching anti-tnf agent will regain response in the majority of patients

21 Complete / partial response (%) CLINICAL UTILITY OF MEASURING IFX AND ATI LEVELS IN PATIENTS WITH IBD Clinical outcomes in patients with detectable ATI (n=35)* P< Anti-TNF changed (11/12) 17 Infliximab increased (1/6) * 6 discontinued IFX, 3 continued same dose, 3 proceeded to surgery, 5 patients could not be assessed Afif, et al. Am J Gastroenterol 2010;105:

22 Patients (%) Patients (%) GAIN: WEEK 4 CLINICAL REMISSION BY BASELINE ANTIBODIES TO INFLIXIMAB Placebo n=166 Adalimumab 160/80 mg n= * * * /58 10/48 10/101 21/105 (+) antibody (-) antibody Clinical Response 70 pt CDAI decrease *p<0.001 vs placebo; (Full analysis population) Sandborn et al. Ann Intern Med 2007;146:829-38

23 % of patients WELCOME: EFFICACY OUTCOMES AT WEEKS 2, 4, 6 FOR PATIENTS ON CERTOLIZUMAB AFTER IFX FAILURE Clinical Response 100-point reduction in CDAI 62 Clinical Remission CDAI <150 points Weeks N=539 Sandborn et al. Clin Gastroenterol Hepatol. 2010; 8:

24 DRUG (-), ADA (-) Dose intensification before switching is most appropriate

25 Complete / partial response (%) CLINICAL UTILITY OF MEASURING IFX AND ADA LEVELS IN PATIENTS WITH IBD Clinical outcomes in patients with sub-therapeutic concentrations (n=69)* P< Anti-TNF changed (2/6) Infliximab increased (25/29) * 10 continued same dose, 9 discontinued IFX, 8 proceeded to surgery and 7 patients could not be assessed Afif, et al. Am J Gastroenterol 2010;105:

26 Individualised therapy is more cost-effective than dose intensification in patients with Crohn's disease who lose response to anti-tnf treatment: a randomised, controlled trial. 69 patients with secondary IFX failure were randomized to IFX dose intensification (5 mg/kg every 4 weeks) (n=36) or interventions based on serum IFX and IFX antibody levels Steenholdt et al. Gut. 2014;63:919-27

27 HOW TO MINIMIZE SECONDARY FAILURE TO ANTI-TNF THERAPY? Biologic therapy is optimized with induction and scheduled maintenance therapy Concomitant immunomodulators or iv hydrocortisone pre-treatment 1 can reduce (but not eliminate) immunogenicity Patients thought to be secondary failures to anti-tnf therapy should be re-evaluated to confirm active inflammation as source of symptoms Patients found to be secondary failures to one anti-tnf agent may be treated successfully with dose intensification or other anti-tnf agents based on drug levels and ADA If a patient develops ADA, Aza/6MP or MTX should be added with the next biologic Ferrell et al. Gastroenterol 2003;124: Frederiksen MT et al. Inflamm Bowel Dis. 2014;20:

28 Proportion of Patients (%) SONIC Corticosteroid-Free Clinical Remission at Week 26 Primary Endpoint p=0.009 p<0.001 p= /170 75/169 96/169 AZA + placebo IFX + placebo IFX+ AZA Colombel JF et al. N Eng J Med. 2010;362:

29 SONIC Colombel JF et al. N Eng J Med. 2010;362:

30 Cross-sectional study of 72 patients receiving maintenance therapy with infliximab and a thiopurine for IBD Those with 6-TGN levels <125 pmol/8x10 8 RBCs had a significantly higher likelihood of having detectable ATI (OR, 13; 95% CI, ; P <.01). Yarur AJ et al. Clin Gastroenterol Hepatol. 2015;13(6):

31 Biologic and MTX-naive RA patients (N=395) with mean disease duration of less than 4 months and high disease activity, were evenly randomised to open-label adalimumab (40 mg every other week) plus weekly blinded 2.5, 5, 10 or 20 mg MTX for 26 weeks. The % of patients with at least one AAA+ sample were 21%, 13%, 6% and 6% for the 2.5, 5, 10 and 20 mg MTX dose groups, respectively. Burmester G-R, et al. Ann Rheum Dis 2014

32 Data from 9 clinical trials of CZP for moderate to severe Crohn s were pooled for this analysis. Patients who were treated concurrently with CZP and either MTX or AZA/6MP for at least 90 days (N=700) versus no concurrent immunomodulators (N=1315) were analyzed for ADA. CONCLUSIONS: In these analyses, AZA/6MP and MTX were similarly effective at reducing formation of ADAs to CZP. An MTX dose of at least 15 mg/week was most effective in preventing formation of ADAs to CZP, but no such threshold was seen for AZA/6MP. Dubinsky et al. Inflamm Bowel Dis 2014 Supplement (Abst P-096)

33 Should we check a trough level on all patients on biologics? At the first maintenance dose? At time of failure? What is the right level? IFX trough level of 5-10 mg/ml ADA trough level >5 mg/ml Papamichael K et al. Clin Gastroenterol Hepatol. 2016;14:543-9 Vande Casteele N et al. Gastroenterology. 2015;148: Vande Casteele N et al. Gut. 2015;64:

34 Vaughn BP, et al. Inflamm Bowel Dis. 2015;21:

35 Proactive therapeutic concentration monitoring (TCM) of infliximab may improve outcomes 48 pts had proactive TCM. 78 pt control group 15% had an initial undetectable trough concentration. 25% (12 of 48) escalated IFX after the first proactive TCM. 15% (7 of 48) de-escalated IFX therapy over the study period. Fewer pts in the proactive group stopped IFX (10% vs 31%, P = 0.009). Trough concentration >5 μg/ml more likely to remain on IFX (P < vs trough <5 μg/ml Vaughn BP. Inflamm Bowel Dis. 2014;20:

36 TAXIT Study: A consecutive cohort of 275 IBD patients (186 CD and 89 UC) receiving maintenance infliximab were screened 8.7% 21.1% 44% 22.6% Trough >7 Trough 3-7 Trough <3 Trough Zero Those with TCs >7 μg/ml, 93% achieved TCs of 3-7 μg/ml after dose reduction. This resulted in a 28% reduction in drug cost Once optimized, there was no difference in the % achieving remission when dose adjustments were based on clinical parameters vs trough concentrations. Relapses were more frequently with clinically based dosing (17%) vs concentration-based dosing (7%) (P=.018). Casteele et al. Gastroenterology Jun;148(7):1320-9]

37 Do we know a level for Certolizumab? Data were available from 2,157 adults with moderate to severe CD who were treated with CZP in 1 of 9 trials. ACG 2016 Abstract: 31 Vande Casteele et al.

38 Do we know a level for Vedolizumab? Longitudinal sera from 16 Crohn s; 19 UC at baseline before VDZ and at trough during induction. Clinical response was determined using physician s global assessment and steroid-free status. A response to VDZ was seen in 80% (n=28) with complete resolution of symptoms in 37% (n=13). Median week 14 serum VDZ concentrations o higher in responders vs non-responders (NR) (12.3 vs. 7.1 μg/ml, p=0.02), o higher among patients who were steroid-free vs steroid dependent (12.5 vs. 7.8 μg/ml, p=0.03). ACG 2016 P375 Boland et al.

39 Drug Trough Assay Infliximab 5-10 ARUP, Labcorp, Mayo, Miraca, Prometheus Adalimumab 5-10 ARUP, Labcorp, Mayo, Miraca, Prometheus Certolizumab 15* Miraca Golimumab unknown Labcorp in 2017? Vedolizumab >12* Miraca, Prometheus, Labcorp in 2017? Ustekinumab unknown Miraca *More Data Needed

40 Biologic Drug Monitoring - Not all tests are the same: Covered by insurance? Cost to patient? Drug tolerant assay? Prometheus, Labcorp - Yes Mayo, Arup, Miraca - No Know what to do with the results Test reactively: trough or time of failure Proactive testing makes sense - more data is needed o Check prior to first maintenance dose o Follow during maintenance? How often?

41 The TREAT to TARGET concept 1,2 Multiple studies in UC and Crohn s have shown better longterm outcomes when mucosal healing is achieved 3,4. Multiple studies have shown that colonoscopy is better at determining mucosal healing than CRP and calprotectin 5,6 1. Peyrin-Biroulet L et al. Am J Gastroenterol. 2015;110: Bouguen G et al. Clin Gastroenterol Hepatol. 2015;13: Baert F, et al. Gastroenterology Colombel JF, et al. Gastroenterology Peyrin-Biroulet L et al. Gut. 2014;63: Falvey DB et al. Inflamm Bowel Dis 2015;21:

42 Proposed Timing of Monitoring in Crohn s 12 weeks Adequate drug levels Need a prospective study treating to symptoms, biomarkers vs mucosal healing Bouguen G et al. Clin Gastroenterol Hepatol. 2015;13:

43 Questions?