Latest Meds Approved for IBD: What are they and how do they work?

Transcription

1 Latest Meds Approved for IBD: What are they and how do they work? JAMES LORD, MD PHD BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON MEDICAL CENTER SEPT 30, 2018

2 Brief history of IBD Dr. Burrill Crohn JAMA 1932, vol. 99(16) Surgery Steroids Thiopurines ulcerative colitis Crohn s disease Methotrexate Certolizumab (Cimzia) Adalimumab (Humira) Infliximab (Remicaide) Golimumab (Simponi) Vedolizumab (Entyvio) Natalizumab (Tysabri) Tofacitinib (Xeljanz)

3 IBD Drugs: Timeline Small Molecules Biologicals Steroids 5 ASA s Other Anti-TNF s Anti-Integrins Anti-IL-12/23 Sulfasalazine 1950 s Azathioprine 1970 s 6-MP Methotrexate 1980 s Mesalamine 1990 s Balsalazide 1998 Infliximab Adalimumab 2008 Certolizumab Natalizumab 2013 Golimumab 2014 Vedolizumab 2016 Ustekinumab Tofacitinib 2018 Prednisone Budesonide

4 How New IBD Drugs Generally Work Block immune cell communication Biologicals: Block signals (cytokines) outside cells from interacting with receptors on cell surface Small Molecules (Jakinibs): Block cell surface receptor signals (kinases) inside cells Block immune cell migration Biologicals: Block receptors (integrins) on circulating cells from recruiting them from blood to tissue

5 Cytokines: how immune cells talk to each other Infliximab (Remicade) Adalimumab (Humira) Certolizumab (Cimzia) Golimumab (Simponi)

6 Different cytokines work at different points in the immune system Differentiation Survival Function Immature Immune Cell IL-12 Mature IL-23 Mature TNF-a Immune Immune Cell Cell Target Ustekinumab (Stelara) Infliximab (Remicade) Adalimumab (Humira) Certolizumab (Cimzia) Golimumab (Simponi)

7 Different cytokines work at different points in the immune army Differentiation Survival Function Immature Army Boot camp Mature Army Provisions Mature Army Bullets Target Infliximab (Remicade) Adalimumab (Humira) Certolizumab (Cimzia) Golimumab (Simponi)

8 Different cytokines work at different points in the immune army Differentiation Survival Function Immature Army Boot camp Mature Army Provisions Mature Army Bullets Target Ustekinumab (Stelara)

9 Different cytokines work at different points in the immune army Differentiation Survival Function Immature Army Boot camp Mature Army Provisions Mature Army Bullets Target

10 Blocking immune cell migration: Anti-integrins (biologicals)

11 Anti-integrins block immune cell traffic, not function

12 Anti-integrins block immune cell traffic, not function

13 fistula closure response (Mayo drop of >2) response (CDAI drop of >70) remission (CDAI <150) Dugs that block TNF ( anti-tnf s ) do work in up to 2/3 of IBD patients 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 70% 60% 50% Crohn s: 4 wk initial response treated placebo Infliximab adalimimab certolizumab Targan 1997 CLASSIC I 2006 PRECISE I 2007 Crohn's: Fistula Closure by 18-26wks treated placebo 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 80.0% 70.0% 60.0% Crohn s: 4 wk initial remission treated placebo Infliximab adalimimab certolizumab certolizumab Targan '97 CLASSIC I PRECISE I Schreiber '05 UC: 6-8 wk initial response treated placebo 40% 30% 20% 50.0% 40.0% 30.0% 20.0% 10% 0% Present '99 CHARM PRECISE I PRECISE II 10.0% 0.0% ACT ACT ULTRA ULTRA PURSUIT- SC 2014 Feagan et. al GEMINI 2013 Infliximab adalimumab certolizumab infliximab adalimimab golimumab vedolizumab

14 % of Patients with Benefit (DCDAI>70) % of Patients with Benefit (DCDAI>70) Anti-TNF benefit wanes over time 100% Loss Of Response to Infliximab (ACCENT-I trial, Hanauer, S., Lancet 2002, 359:1541.) 100% Loss Of Response to Adalimumab (CHARM trial, Colombel, J.F., Gastro 2007, 132:52.) 90% 90% 80% 70% Infliximab Dose: 80% 70% Adalimumab Dose: 60% 50% 40% 30% 20% 10% 10 mg/kg (n=112) 5 mg/kg (n=113) 0 mg/kg (n=110) 60% 50% 40% 30% 20% 10% 40 mg weekly (n=157) 40 mg every 2 wks (n=172) none (n=170) 0% 0% Weeks Weeks Crohn s Disease Clinical Trials

15 % of Patients with Benefit (DCDAI>70) % of Patients in Remission (CDAI<150) Is secondary loss of response less of a problem for newer biologics? 100% Loss Of Response to Infliximab (ACCENT-I trial, Hanauer, S., Lancet 2002, 359:1541.) 100% Loss of Response to Ustekinumab (IM-UNITI Trial, Feagan, BG, NEJM 2016, 375:20.) 90% 80% 70% 60% 50% 40% 30% 20% 10% Infliximab Dose: 10 mg/kg (n=112) 5 mg/kg (n=113) 0 mg/kg (n=110) 90% 80% 70% 60% 50% 40% 30% 20% 10% Ustekinumab Dose: 90 mg every 8 wks 90 mg every 12 weeks placebo 0% 0% Weeks Weeks Crohn s Disease Clinical Trials

16 Newer biologics do a good job maintaining benefit

17 Biologic drugs are made of proteins the immune system can make antibodies to reject drug Protein drug Protein fragment (peptide) Anti-drug antibodies (ADA s)

18 Antibodies to Infliximab Increase Risk of an Infusion Reaction Baert F, NEJM 2003, 348;7

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20 % of Patients with antibodies to drug Immunomodulators (IMM) reduce anti-drug antibody formation 25% 20% c. 15% c. 15% 15% c. 15% 10% 5% biological alone biological + IMM 0% IMM = Azathioprine (SONIC) IMM = Methotrexate (COMMIT) IMM = Azathioprine (SUCCESS) Crohn's UC

21 Two drugs are better than one Crohn s: SONIC Colombel et. al., N Engl J Med 2010;362: UC: SUCCESS Panaccione et. al., Gastroenterology 2014;146: c. 15% c. 15%

22 Immunomodulators carry risks Symptoms Nausea/vomiting, headache, rash Bone marrow suppression (anemia, immunodeficiency) Infection Liver toxicity Pancreatitis Cancer Skin (not melanoma) Cervix Lymphoma Virus

23 Do I have to take azathioprine with my biologic forever? Maybe not!

24 Immunomodulators (IMM) could be safely stopped after 6-12 mos deep remission in patients with a high infliximab (IFX) trough level (TL) Drobne et. al., Clin Gastro & Hep 2015; 13:

25 Do I have to take azathioprine with my biologic at all? Maybe not!

26 Rates of immunogenicity are lower with newer biologics Vermeire S et al, Therap Adv Gastroenterol Jan 21;11: X

27 % of patients Anti-Drug Antibodies (ADA) to new biologics are usually only transient 4.50% 4.00% 3.50% 3.00% 2.50% 2.00% 1.50% 1.00% 0.50% 0.00% Antibodies to Vedolizumab GEMINI 1 (n=620, UC) GEMINI 2 (n=814, CD) GEMINI 3 (n=209, CD) Any ADA ADA > once In all UNITI (ustekinumab) trials (n=1154, CD), 2.3% were positive for antibodies to ustekinumab during at least one timepoint through one year. Many of these patients were only positive at a single timepoint and then had subsequent negative antibody results. - Adedokun OJ et. al., Gastro 2018, epub ahead of print

28 Antibodies to newer biologics do not decrease their safety Vedolizumab (GEMINI 1, UC): Clinically important infusion reactions were few; three cases (two with detectable anti-vedolizumab antibodies) resulted in drug discontinuation. No cases of anaphylaxis or serum sickness were observed. Feagan BG et. al, NEJM 2013, 269(8): Ustekinumab (UNITI trials, CD): None of the patients who were positive for antibodies to ustekinumab had injection-site, serum-sickness-like, or anaphylaxis reactions. -Adedokun OJ et. al., Gastro 2018, epub ahead of print

29 % of Patients with antivedolizumab antobodies Antibodies to new biologics do not decrease their benefit 25% Vedolizumab antibodies vs efficacy P= % 15% 10% P=1.0 5% 0% responders Induction 1ry nonresponders responders maintenance 2ry loss of response Ungar et. al., Clin Gastro & Hep, Nov 2017, epub ahead of print

30 Azathioprine (AZA) cotherapy increases infliximab (IFX) levels

31 Combination therapy does not increase levels of ustekinumab -Adedokun OJ et. al., Gastro 2018, epub ahead of print

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33 Unadjusted rate per 1000 patient-years Long-term safety data on anti-tnf agents in Crohn s: USA TREAT Registry: 6,273 Crohn s patients with an average of 5.2 years follow-up Infliximab Other treatments only c. 10 serious infections per 1000 patient/ years 5 0 any neoplasia any malignancy lymphoma solid tumor mortality serious infection Lichtenstein et. al., Am J Gastroenterol 2012; 107: Lichtenstein et. al., Am J Gastroenterol 2014;109:

34 Incidence /1000 pt/yrs Long-term safety data on anti-tnf agents in Crohn s: Europe ENCORE Registry: 2,960 IBD patients, followed for 5 yrs p= ND c. 10 serious infections per 1000 patient/ years serious infection infusion reaction CHF hematological condition ND IFX exposure p< p=0.023 Non-exposure p= p= fatalities demyeliniation malignancies

35 Infection Risks of Biologics Anti-TNF s double annual risk of serious infections However, this only means 1%/yr 2%/yr Many of these infections are influenza and pneumonia Preventable with vaccination Annual Flu shot (not intranasal mist) Pneumococcal vaccine series (2 shots, >1 yr apart) No clear risk of infection with other/newer biologics

36 Patients per 1000 patient/yrs Incidence per 1000 pt/yrs Safety data on newer biologics looks even safer than anti-tnf s Vedolizumab safety and tolerability Ustekinumab safety and tolerability (psoriasis) 45mg/day 90mg/day vedolizumab placebo Meta analysis of 2 phase II & 4 phase III trials Colombel et. al., Gut 2017 May;66(5): year safety data on ustekinumab in psoriasis Papp et. al., Brit J. Derm. 2013;68:

37 Downsides to newer biologics Vedolizumab (Entyvio): Slow (especially for Crohn s): 3-4 mos Might not work as well in small bowel No benefit for fistulas No benefit to prevent recurrence after surgery Crohn s Ustekinumab (Stelara): Not (yet) approved for UC Expensive!

38 Estimated Annual Cost for 70 kg Patient List Price for IBD Biologicals $140,000 Bio $120,000 $100,000 $80,000 $60,000 $40,000 Biosimilars of Infliximab $20,000 $0 Walgreens CVS Target Kmart Costco Kroger Safeway Rite-Aid Walmart HealthWarehouse Blink Health All prices per GoodRx.com or WellRx.com, 9/3/17, and *exclude infusion center costs*

39 Step Therapy (or fail first ) policies Insurance requirement that therapies be tried in a particular order, in an effort to reduce cost Typical: Newer biologics cannot be tried until at least two anti-tnf agents (usually adalimumab and some version of infliximab) have been failed first, possibly as well as steroids and/or immunomodulators. May not make the most biomedical sense Hence can sometimes paradoxically increase cost Can be appealed with enough time/effort

40 Trying a second anti-tnf might help here but probably not here and definitely not here

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43 Blocking immune cell communication (cytokines) Outside immune cell Biologicals: Anti-TNF, anti-il (infliximab, ustekinumab ) Inside immune cell Small Molecules: Jakinib (tofacitinib ) Olivera P, et al. Gut February 2017 Vol 66 No 2

44 Small Molecules versus Biologics Small Molecules Biologicals Pros: Cons: Pros: Cons: Cheap Fast Oral Allergies rare Nonspecific Short half life Specific Long half life Expensive Slow IV or shots Immunogenic

45 Small molecules are much less complex than biologicals

46 Small molecules can be pills

47 Biologicals are proteins. If you eat them, they are food.

48 Ustekinumab

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50 Life finds a way

51 Tofacitinib

52 Tofacitinib is effective induction therapy for UC Remission at week 8 Mucosal Healing at week 8 Sandborn WJ et. al, N Engl J Med May 4;376(18): Independent but identical phase III induction trials

53 Tofacitinib is effective maintenance therapy for UC Remission at week 52 Mucosal Healing at week 52 Sandborn WJ et. al, N Engl J Med May 4;376(18): FDA approved in UC

54 Tofacitinib safety profile 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Placebo Tofa, 5 mg Tofa, 10 mg Sandborn WJ et. al, N Engl J Med May 4;376(18):

55 New vaccine for zoster (shingles)

56 Tofacitinib safety profile 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Placebo Tofa, 5 mg Tofa, 10 mg May require statin therapy Sandborn WJ et. al, N Engl J Med May 4;376(18):

57 Benefits of Tofacitinib (Xeljanz): Fast: Benefit usually <3 wks (vs <3 mos w/ biologics) Rapidly cleared if any toxicity/side effects Less expensive to try briefly: Annual cost similar to biologics BUT: annual = c. 6 doses of a biologic annual > 700 doses of Tofacitinib Thus per dose cost MUCH lower, so brief trial cheaper No anti-drug antibodies to Tofacitinib: Intermittent use (like brief trial, above) will not prevent it from working in the future

58 Janus Kinase Inhibitors (Jakinibs) Tofacitinib in now FDA-approved for UC Less impressive for Crohn s in phase II trial Other Jakinibs (Filgotinib, Upadacitinib) worked well in trials for Crohn s Similar drugs for Crohn s will be here soon Cheaper to manufacture than biologics Free market competition can lower cost

59 Other drugs coming Biologics Anti-integrin/addressins Etrolizumab, PF Anti-IL-23 Rizankizumab, Brazikumab, Briakinumab, Guselkumab, Mirakizumab Small Molecules Jakinibs S1P1 Agonists: Ozanimod, Etrasimod

60 Conclusions: New Biologics may have advantages over older anti-tnf s New & different mechanisms of action No significant anti-drug antibodies No infusion reactions No clear increased infection risk New, improved oral agents are coming Easier/more forgiving to try Faster (thus cheaper) to declare success/failure OK to interrupt therapy for cost/side effects Some increased health risks Infection (shingles) Cholesterol Ultimately cheaper