Inflammatory Bowel Disease Drug Therapy...

David T. Rubin, MD, FACG

Inflammatory Bowel Disease Drug Therapy 2016

David T. Rubin, MD, FACGJoseph B. Kirsner Professor of Medicine

Chief, Section of Gastroenterology, Hepatology and Nutrition

Objectives

• Emphasize more recent changes in the approach to medical management of IBD

• Discuss basic principles of each class of therapy in IBD

• Provide optimization tips for each type of therapy

ACG 2016 Annual Postgraduate Course Copyright 2016 American College of Gastroenterology

of 17


General Principles of IBD Management• We are treating the result of the IBD, not the cause (as far as

we know)- immune-based therapy

• Earlier is better

• Induction therapy usually dictates maintenance needs

• Severity of disease and burden of inflammation require more intensive therapy

• We are not curing IBDRubin DT, et al. Am J Gastroenterol. 2016; [Epub ahead of print].

Evolving Principles of IBD c.2016• Incorporate elements of prognosis into diagnosis and medical

decision making

• Moving beyond “one size fits all” to “smart therapy for the right patient”

• Precision medicine- optimization of treatments instead of “guesswork”

• Monitoring disease activity to achieve deeper remission and to anticipate flares

Rubin DT, et al. Am J Gastroenterol. 2016; [Epub ahead of print].


of 17


Drug Classes in IBD 2016

• Aminosalicylates– Oral– Rectal

• Corticosteroids– Systemic– Non-systemic– Rectal– Oral

• Immunomodulators– Thiopurines– Methotrexate

• Antibiotics

• Biologics– Anti-cytokines (Anti-TNF, Anti-IL12/23/6) – Anti-integrin (adhesion molecule

inhibitors)

• Investigational molecules– Janus kinase inhibitors– Anti-SMAD7 antisense oligonucleotide– Sphingosine-1-phosphate receptor

modulator

Aminosalicylates


of 17


General Principles of Aminosalicylates

• Effective for induction of mild to moderate UC (15-40%)

• Effective for maintenance of mild to moderate UC (58%-78%)

• Delivery-response relationship- get the drug to the location of the disease

• Very safe, but not completely safe (renal)1,2

• Affected by payers now- substitution required that is not bioequivalent

Hanauer SB, et al. Am J Gastroenterol. 1993;88:1188.Hanauer SB, et al. Am J Gastroenterol. 2005;100:2478.

Levine DS, et al. Am J Gastroenterol. 2002;97:1398.Sninsky CA, et al. Ann Intern Med. 1991;115:350.

1Van Staa TP, et al. Gastroenterology. 2004;126(7):1733–9.2Gisbert JP, et al. Inflamm Bowel Dis. 2007;13(5):629–38.

Ham M, Moss AC. Expert Rev Clin Pharmacol. 2012;5(2):113-23.Hanauer SB, et al. Ann Intern Med. 1996;124(2):204-11.

Pearls for Optimization of Aminosalicylates

• Don’t forget 3% of patients intolerant/allergic1

• Get the drug to the disease location

• Delivery systems may matter! If not responding, add or substitute a different delivery system2

• Dose reduction when deep remission obtained is usually safe3

1Kornbluth A, Sachar DB. Am J Gastroenterol. 2004;99(7):1371–85.2Harris MS, Lichtenstein GR. Aliment Pharamcol Ther. 2011;33(9):996-1009.

3Rubin DT, et al. J Crohns Colitis.2016;10(8):925-33.


of 17


Dose Reduction after Induction is Safe if there is Mucosal HealingMOMENTUM Trial

Rubin DT, et al. J Crohns Colitis.2016;10(8):925-33.

Induction (8 weeks)MMX mesalazine 4.8g/day

Maintenance (12 months)MMX mesalazine 2.4g/day

UC patients (n=717)

Corticosteroids


of 17


Corticosteroids

• Revolutionary discovery in IBD1

• Not sustainable

• Worst outcomes

• Prognostic- need for steroids dictates subsequent outcomes2

• Understand steroid-dependence

1Edwards FC, Truelove SC. Gut. 1963;4:299-215.2Faubion WA, et al. Gastroenterology. 2001;121(2):255-60.

Mor

talit

y (%

)

1938 –1952

1953–1962

1963–1972

1973–1982

1983–1987

40 Corticosteroids introduced in 1952

30

20

10

0

Ulcerative Colitis

Pearls for Optimization of Steroids

• Use non-systemic steroids first (also protects bones)1

• Have an exit strategy

• Don’t lose the forest for the trees (“what’s the harm of one more course of steroids?”)

• Don’t forget vitamin D, bone density1

1Schoon EJ, et al. Clin Gastroenterol Hepatol. 2005;3(2):113–21.


of 17


Why Do We Taper Steroids? Is There Evidence For It?

• Prevention of adrenal crisis or adrenal insufficiency– This is rare!– 5 mg or less does not seem to cause adrenal insufficiency– Higher doses are variable – 2 weeks of steroids unlikely to cause this

• Concern for disease relapse or “rebound”- no evidence

• Practical approach: taper over duration of induction period OR duration of time for maintenance therapy to work

LaRochelle GE Jr., et al. Am J Med. 1993;95(3):258-64.Streck WF, Lockwood DH. Am J Med. 1979;66(6):910-4.

Becker KB. Principles and Practice of Endocrinology and Metabolism. 3rd ed. Philadelphia, PA: J.B. Lippincott; 2001.Melmed S, et al. Williams Textbook of Endocrinology. 11th ed. Philadelphia, PA: Sauders;2007.

Immunomodulators


of 17


Thiopurines

• Genetically determined metabolism

• Steroid sparing

• Lymphoma risk well known (Schwartz)– HR 5.28 (95% CI, 2.0-13.9)1

– Back to baseline after stopping2

– Consider EBV testing for patients <20 yo 1Beaugerie L, et al. Lancet. 2009;374(9701):1617-1625.

2Khan N, et al. Gastroenterology. 2013;145(5):1007-1015.

AZA 6-MP HPRT

TPMT

6-TImP

DNARNA

Purinesynthesis

6-MMP

6-TU

XO

TPMT

Circulation Intracellular

6-MMPN

6-TGN

Early AZA Therapy is Not More Effective Than Placebo or Conventional Therapy for CD

Cosnes J, et al. Gastroenterology. 2013;145(4):758-65.

Actuarial probability of survival free relapse. Defined as CDAI >175 in patients treated with azathioprine and placebo.

n=63

Proportion of patients in corticosteroid-free remission per trimester over time. Concomitant proportions were significantly different only at trimester 3 (P<.05).

n=67

Panes J, et al. Gastroenterology. 2013;145(4):776-74.


of 17


Pearls for Optimization of Thiopurines

• No prospective data on optimization• Intermediate metabolizers do better!• Metabolites can be helpful1 (Siegel)

– Remember allopurinol2

• Bedtime or split dosing if nausea predominant• Pancreatitis is genetically determined too3

1Dubinsky MC. Curr Gastroenterol Rep. 2003;5(6):506-11.2Sparrow MP, et al. Clin Gastroenterol Hepatol. 2007;5(2):209-14.

3Ledder O, et al. Expert Rev Gastroenterol Hepatol. 2015;9(4):399-403.

Methotrexate

• Our colleagues are not as comfortable using it

• Effective for induction and maintenance of Crohn’s disease1

• Limited by toxicity/side effects2

• Relatively contraindicated in menstruating females

• No data for its use as salvage therapy after failing anti-TNF therapy

1Feagan BG, et al. N Engl J Med. 1995;332:292-297.2Patel V, et al. Cochrane Database Syst Rev. 2014;(8).


of 17


Pearls for Methotrexate

• Equal bioavailability PO up to 15 mg– ≥12.5 mg/w gives preferred outcomes in combination with anti-TNF

• Use ondansetron as a pre-med (30 minutes before MTX)

• Take it on weekends

• Don’t forget folic acid! (1-2 mg/day)

• Monitor liver enzymes every 6 months (but safe)1,2

1Te HS, et al. Am J Gastroenterol. 2000;95(11):3150-6.2Khan N, et al. Inflamm Bowel Dis. 2012;18(2):359-67.

Biologics


of 17


Anti-TNF Therapies for IBD

Modified from van Schouwenburg PA, et al. Nat Rev Rhematol. 2013;9(3):164-72.

CD CDUC

UCCDUC

Anti-TNF Biological Therapies

• Revolutionary in IBD

• Loading and maintenance needed

• Known risks of non-response or loss of response

• Important role for therapeutic drug monitoring (Siegel)


of 17


Pearls for Optimization of Anti-TNFs

• Routine assessment of stability between doses

• Understanding difference between class effect non-response and individual drug effect (swapping vs. cycling)

• Combination therapy mostly accepted as superior1,2

1Colombel JF, et al. N Engl J Med. 2010;362(15):1383-95.2Panaccione R, et al. Gastroenterology. 2014;146(2):392-400.

Higher Response and Remission Rates with Anti-TNFs in Patients with Shorter Disease Duration

• Infliximab for CD:– Pediatric response/remission = 90%/60%1

– Adult response/remission = 66%/39%2

• Adalimumab/certolizumab pegol for CD3,4:– Post-hoc– Shorter dz duration = better response

• Adalimumab maintenance3

– Less with shorter dz duration

• Claims data5

– Shorter time to anti-TNF = less time to surgery, steroids

1Hyams J, et al. Gastroenterology. 2007;132(3):863-73.2Hanauer S, et al. Lancet. 2002;359(9317):1541-9.

3Schreiber S, et al. J Crohns Colitis. 2013;7(3):213-21.4Sandborn W, et al. ACG. 2007.

5Rubin DT, et al. Inflamm Bowel Dis. 2012 Dec;18(12):2225-31.

0

20

40

60

100

58 80 104 140 164

80

Weeks from CHARM Baseline

Perc

ento

f Pat

ient

sin

Clin

ical

Rem

issi

on

<2 years, n=36≥2 to <5 years, n=63≥5 years, n=229


of 17


Biosimilars

• Inflectra, biosimilar to infliximab (Remicade), approved by the FDA on April 5th, 20161

• Amjevita, biosimilar to adalimumab (Humira) approved by the FDA on September 28th, 20162

• Infliximab biosimilar available in EU since 20133

1Food and Drug Administration. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm494227.htm. Accessed July 29 2016.2Food and Drug Administration. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm522243.htm. Accessed September 28 2016.

3European Medicines Agency. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/06/news_detail_001837.jsp&mid=WC0b01ac058004d5c1. Accessed July 29 2016.

• Several ongoing studies in Europe and Asia

• Evidence that unidirectional switches are safe1-7

• Still not available in the USA

• “Biosimilars are Here! What Every Gastroenterologist Needs to Know”– Tuesday, October 18th 11:30-11:50AM– Annual Scientific Meeting – 3B

1Park SH, et al. Expert Rev Gastroenterol Hepatol. 2015;9(Suppl1):35-44.2Kang YS, et al. Dig Dis Sci. 2015;60(4)951-6.

3Jung YS, et al. J Gastroenterol Hepatol. 2015;30(12):1705-12.4Gesce KB, et al. J Crohns Colitis. 2016;10(2):133-40.

5Smits LJ, et al. J Crohns Colitis. 2016. [Epub ahead of print].6Kolar M, et al. ECCO 2016. Abstract DOP032.

7Sieczkowska J, et al. J Crohns Colitis. 2016;10(2):127-32.

Biosimilars


of 17


Anti-integrins

Natalizumab Vedolizumab

Modified from van Schouwenburg PA, et al. Nat Rev Rheumatol. 2013;9(3):164-72.Rutgeerts P, et al. Gastroenterology. 2009;136(4):1182–97.

NatalizumabVedolizumab

300mg IV q4W 300mg IV at weeks 0, 2, and 6then 300 mg IV q8W

CD CDUC

Pearls for Anti-integrins• You still need to check for TB and HBV prior to insurance approval! (not because

of risk but because insurance companies are ignorant and require it)

• There are some patients who develop joint pain after starting therapy, unclear if this is:

– Side effect of medication– “uncovering” parallel joint problems in IBD patients that were otherwise treated with systemic

therapy– Withdrawal from steroids

• We have not had much difficulty getting dose escalation to monthly infusions– I have usually tried monthly infusions for 3-4 months before making a decision to stop trying this

mechanism


of 17


No Additional Benefit to Combination Therapy in Pivotal Trial of Vedolizumab

Colombel JF, et al. Gastroenterology. 2015;148(4):S277-8.

Clinical remission in Crohn’s Disease patients at week 6 by week 0 concomitant medication use: ITT Population

Where Should We Position Anti-Integrin Therapies?

• In patients unresponsive or intolerant to conventional therapies and anti-TNF agents

• In patients with unusual or other immune conditions such that additional systemic immune modification may be relatively contraindicated– Organ transplant patients– Hereditary or acquired immune deficiencies

• Other possibilities:– The older patient– Before systemic therapies?– Combination with calcineurin inhibitors

Christensen B, et al. Gastroenterology. 2015;148(4):S866.


of 17


• Approved by the FDA for moderate to severe Crohn’s disease on Sept 26, 2016

• Dose– Initial weight-based IV dose:

• ≤55 kg: 260 mg IV• >55 kg to 85 kg: 390 mg IV• >85 kg: 520 mg IV

– Maintenance dose:• 8 weeks after initial, 90mg SC q8w

Anti-IL 12/23 (Ustekinumab)

Brooks M. Medscape. http://www.medscape.com/viewarticle/869259. Accessed September 28, 2016.Medscape. http://reference.medscape.com/drug/stelara-ustekinumab-345050. Accessed September 29, 2016.

35.9%44.3%

29.8% 26.2%

49.0%*48.8%

*58.1%

*42.6% 38.6%

56.6%*53.1%

*59.4% *

46.9% 41.1%

*65.4%

0%

20%

40%

60%

80%

100%

Clinical Remission Clinical Response Steroid-Free Remission Remission in anti-TNF Failure Remission in anti-TNF Naïve

Week 44 Outcomes

Placebo (n=131) 90 mg Q12 weeks (n=129) 90 mg Q8 weeks (n=128)

1Sandborn W, et al. N Engl J Med. 2012;367(16):1519-28.2Sandborn W, et al. Presented at DDW, May 2016. Oral Presentation 768.

Phase 3 Maintenance Study in CD2

Ustekinumab (anti-IL12/23) for Moderate to Severe CD

• Effective for induction with clinical response rates at week 6 compared to placebo (23.5%)1

– 36.6% (1mg/kg)– 34.1% (3mg/kg)– 39.7% (6mg/kg)


of 17


Safety of Ustekinumab Through 44 WeeksIM-UNITI

• No notable new safety issues identified• No deaths or serious opportunistic infections• 2.3% of patients developed antibodies, but these did not preclude drug efficacy

Subjects With (%) Placebo 90 mg SC Q12w 90 mg SC Q8w

Death 0% 0% 0%

AEs 83.5% 80.3% 81.7%

Serious AEs 15.0% 12.1% 9.9%

Serious Infections 2.3% 5.3% 2.3%

Discontinuation due to AE 6.0% 7.6% 3.1%

Malignancies 0.8% 0% 0.8%AE, adverse event; Q8w, every 8 weeks; Q12w, every 12 weeks

Sandborn W, et al. Presented at DDW May 2016. Oral Presentation 768.

Summary: IBD Drug Therapy 2016• Goals of management are evolving: use prognosis, target deep remission.

• For 5-ASAs understand delivery and possible dose-reduction in maintenance.

• You don’t need to taper steroids as much as you think.

• Lymphoma is from thiopurines, goes away when these drugs are stopped.

• Pro-active anti-TNF drug monitoring is coming soon.

• Biosimilars are coming soon… Interchangeability is uncertain.

• Anti-integrin therapies are safe and probably should be used earlier, at least in UC.

• Anti-IL12/23 is shown to be effective in induction and maintenance of moderate-to-severe CD as maintenance therapy.


of 17

Inflammatory Bowel Disease Drug Therapy...

Documents

Transcript of Inflammatory Bowel Disease Drug Therapy...