Από τη θεωρία στη πράξη: Συζήτηση κλινικών περιστατικών. Κωνσταντίνος Κατσάνος Επίκουρος Καθηγητής Γαστρεντερολογίας Πανεπιστήμιο Ιωαννίνων

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Toby Clement Hall
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1 Από τη θεωρία στη πράξη: Συζήτηση κλινικών περιστατικών Κωνσταντίνος Κατσάνος Επίκουρος Καθηγητής Γαστρεντερολογίας Πανεπιστήμιο Ιωαννίνων

2 Conflict of interest By means of this, the speaker confirms that he receives honoraria for consulting services (educational services, scientific articles, participation in Advisory Boards, clinical trials, other) from the companies as follows AbbVie, ENORASIS,Ferring,Genesis, JANNSEN, MSD, Shire and Takeda.

3 Patient-case-based discussion: Katsanos K.

4 CASE 1

5 Female patient, age 30 years old 2010: mild Crohn s ileo-colitis Budesonide 2012: started smoking. 2014: relapse of abdominal pain and diarrhoea 20 cm terminal ileum and extensive colitis Aphthous and superficial ulcers and diffuse terminal ileitis on endoscopy Oral prednisolone (P) 40mg/day and azathioprine (AZA) 2.5mg/kg body weight MP: Gradual tapering to zero over the next of 3 months She remained relatively well for 3 years on AZA 2mg/kg. CT, computed tomography.

6 Female patient, age 30 years old 3 years later (2017) Progressive deterioration Hospitalized 15 liquid/bloody bowel motions per day and fever (38.5oC); no peri-anal disease Anorectic; lost 7 kg of body weight Arthralgias; erythema nodosum CBC: wbc, platelets , ESR 55 mm/h; CRP mg/l (ULN=5) Stools for CD toxins A & B (-); stool culture (-) CT scan: Terminal ileitis, extensive colitis, No abcsess Ileocolonoscopy: Aphthous, superficial and deep ulcers; diffuse terminal ileitis Histology: CMV inclusion bodies not detected CT, computed tomography.

7 Female patient, age 30 years old, Erythema Nodosum

8 Female patient, age 30 years old, Terminal ileum ulcers

9 What is the preferred therapeutic option? 1. Course of IV steroids and continue azathioprine 2. Start anti-tnf 3. Start IL12/23 inhibitor (ustekinumab) 4. Start α4β7 integrin binding antibody (vedolizumab) 5. Other? TNF, tumour necrosis factor.

10 Female patient, age 30 years old iv hydrocortisone (100mg qid) for 5 days AZA was continued. Followed by oral steroids (40 mg prednisolone/day Two weeks later 4-6 BO with visible blood T: 37.5oC Leukocytosis, elevated platelets CRP: 25 mg/l (ULN=5) CT, computed tomography.

11 Now, what next? 1. Start anti-tnf 2. Start IL12/23 inhibitor (ustekinumab) 3. Start α4β7 integrin binding antibody (vedolizumab) 4. Other? TNF, tumour necrosis factor.

12 What are the treatment goals for this patient? 1. Fast and sustained relief of symptoms 2. Achieve and maintain clinical remission w/o steroids 3. Achieve mucosal healing prevention of complications 4. Few (or even better, negligible) side effects of treatment 5. Steroid withdrawal 6. All of the above

13 Female patient, age 30 years old UST induction therapy Patient BW at the Recommended Number of 130 mg time of dosing dose a ustekinumab vials 55 kg 260 mg 2 > 55 kg to 85 kg 390 mg 3 > 85 kg 520 mg 4 Single IV infusion (~6 mg/kg), in 1 hr Followed by SC maintenance. First maintenance dose 8 weeks after the IV induction dose Subsequently every 8 or 12 weeks, based on the physician s judgement a Dose corresponding to approximately 6 mg/kg. BW, body weight. SmPC Stelara

14 Patients (%) Rapid induction of response to ustekinumab in bio-naive and bio-refractory patients UNITI-2 Failed prior conventional therapy (primarily anti-tnf naive) UNITI-1 100% anti-tnf a refractory patients 60 Placebo (n = 247) UST ~ 6 mg/kg (n = 249) 55.5% 57.9% Placebo (n = 209) UST ~ 6 mg/kg (n = 209) % 38.8% 28.7% 32.1% 17.8% 30.1% 21.5% 33.7% 20.2% 37.8% 0 Week 3 Week 6 Week 8 Week 3 Week 6 Week 8 a 41% failed 2 anti-tnfs; 10% failed 3 anti-tnfs. All p values for ustekinumab versus placebo. CRP, C reactive protein; UST, ustekinumab. Feagan BG, et al. N Engl J Med. 2016;375:

15 Patients (%) Patients (%) Durable maintenance of remission with ustekinumab in Crohn s disease IM-UNITI a Patients in clinical remission at 1 year IM-UNITI a Clinical remission at 2 years in patients in remission at 1 year IV induction only (n = 131) UST 90 mg SC q12w (n = 129) 48.8% UST 90 mg SC q8w (n = 128) 53.1% UST 90 mg SC q12w (n = 63) 79.4% UST 90 mg SC q8w (n = 68) 82.4% 35.9% a Mixed population, from UNITI-1 and UNITI-2 trails IV, intravenous; q8w, every 8 weeks; q12w, every 12 weeks; SC, subcutaneous. Feagan BG, et al. N Engl J Med. 2016;375:

16 Clinical remission with ustekinumab over time of randomized subjects entering LTE of IM-UNITI Subject in clinical remission (%) ITT population 84.1% 77.4% 74.4% 72.6% 20 UST 90 mg q12w (n = 84) UST 90 mg q8w (n = 82) Time (weeks) LTE, long-term extension; UST, ustekinumab. Sandborn WJ, et al. Poster presented at ECCO Poster OP010.

17 Subjects (%) Endoscopic endpoints with ustekinumab at Week 44 in the pooled maintenance population % (p < 0.05) 48.6 Placebo (n = 51) UST q12w (n = 47) UST q8w (n = 74) % (p < 0.05) % SES-CD 3-pt reduction Endoscopic response Mucosal healing Mucosal healing (all ulceration resolved), endoscopic response (50% SES-CD improvement) Subjects with eligible SES-CD and ulcerations at baseline SES-CD, simple endoscopic score for Crohn s Disease. Rutgeerts P, et al. Presented at UEGW Abstract 2820.

18 Adverse events in UNITI-1, UNITI-2, and IM-UNITI Event UNITI-1 UNITI-2 IM-UNITI Any AE Common AEs a Placebo Ustekinumab Placebo Ustekinumab Placebo Ustekinumab (n = 245) 159 (64.9) 130 mg (n = 246) 159 (64.6) 6 mg/kg (n = 249) 164 (65.9) (n = 208) 113 (54.3) 130 mg (n = 212) n (%) 106 (50.0) 6 mg/kg (n = 207) 115 (55.6) (n = 133) 111 (83.5) 90 mg/ q12w (n = 132) 106 (80.3) 90 mg/ q8w (n = 131) 107 (81.7) Arthralgia 18 (7.3) 26 (10.6) 15 (6.0) 4 (1.9) 8 (3.8) 9 (4.3) 19 (14.3) 22 (16.7) 18 (13.7) Headache 22 (9.0) 20 (8.1) 20 (8.0) 14 (6.7) 20 (9.4) 10 (4.8) 15 (11.3) 15 (11.4) 16 (12.2) Nausea 18 (7.3) 20 (8.1) 13 (5.2) 5 (2.4) 7 (3.3) 11 (5.3) 9 (6.8) 10 (7.6) 4 (3.1) Pyrexia 15 (6.1) 14 (5.7) 15 (6.0) 10 (4.8) 6 (2.8) 11 (5.3) 10 (7.5) 11 (8.3) 8 (6.1) Nasopharyngitis 13 (5.3) 12 (4.9) 11 (4.4) 10 (4.8) 10 (4.7) 14 (6.8) 10 (7.5) 17 (12.9) 14 (10.7) Abdominal pain 13 (5.3) 9 (3.7) 13 (5.2) 7 (3.4) 5 (2.4) 10 (4.8) 16 (12.0) 13 (9.8) 11 (8.4) CD event 24 (9.8) 13 (5.3) 6 (2.4) 10 (4.8) 8 (3.8) 7 (3.4) 19 (14.3) 16 (12.1) 16 (12.2) Fatigue 13 (5.3) 6 (2.4) 9 (3.6) 4 (1.9) 3 (1.4) 4 (1.9) 6 (4.5) 8 (6.1) 6 (4.6) Infections b Any 58 (23.7) 57 (23.2) 64 (25.7) 48 (23.1) 31 (14.6) 45 (21.7) 66 (49.6) 61 (46.2) 63 (48.1) Serious 3 (1.2) 3 (1.2) 7 (2.8) 3 (1.4) 3 (1.4) 1 (0.5) 3 (2.3) 7 (5.3) 3 (2.3) Serious AEs 15 (6.1) 12 (4.9) 18 (7.2) 12 (5.8) 10 (4.7) 6 (2.9) 20 (15.0) 16 (12.1) 13 (9.9) AEs associated with infusion or injection-site reactions c 5 (2.0) 11 (4.5) 9 (3.6) 6 (2.9) 5 (2.4) 3 (1.4) 1 (0.8) 3 (2.3) 9 (6.9) a The listed adverse events were reported by at least 5% of the patients in any group. b Infections were assessed by the investigator. c AEs associated with infusions in UNITI-1 and UNITI-2 refer to events that occurred within 1 hour after infusion. AEs summarized for IM-UNITI refer to injection-site reactions. AE, adverse event; CD, Crohn s disease.

Corticosteroid-Free Remission and Response at 44 Weeks Patients Receiving Corticosteroids at Baseline Abbreviations: CS=corticosteroid(s);

19 Corticosteroid-Free Remission and Response at 44 Weeks Patients Receiving Corticosteroids at Baseline Abbreviations: CS=corticosteroid(s); N=number of patients in treatment group; q8w=every 8 weeks; q12w=every 12 weeks; UST=ustekinumab *Versus placebo Feagan BG. Poster presented at DDW 2017.

20 Female patient, age 30 years old 8 weeks later: Still unwell some abdominal pain BO 3-4/day, semi-formed, no blood CRP 15 mg/l (ULN=5 mg/l) What next? CT, computed tomography.

21 What would you do if there is little response 8 weeks after the IV infusion? 1. Discontinue ustekinumab 2. Another course of oral steroids 3. Increase the dose of AZA 4. Administer the 1 st SC dose of 90mg UST

22 Week 44 Efficacy assessments (primary randomized population) Ustekinumab delayed responders: non-responders to 130 mg a or ~ 6 mg/kg IV induction Induction phase UNITI-1 & -2 Week 0 8 Maintenance Phase IM-UNITI Week 0 44 PBO SC (n = 133) Yes n = 397 R UST 90 mg SC q12w (n = 132) IV ustekinumab Week 8 responder? b UST 90 mg SC q8w (n = 132) Corticosteroid tapering No N=467 UST 90 mg SC at Week 0 (IM-UNITI) Wk 8: responder? b Yes No UST 90 mg SC q8w (n = 251) Discontinue study agent (n = 216) a 130 mg dose is not approved in Europe. b Based on 100-point decrease in CDAI. R, randomizaton; SC, subcutaneous. Adapted from: Feagan BG, et al. N Engl J Med 2016;375: (Supplementary data pp )

23 Subjects (%) IM-UNITI delayed responders: clinical response & remission 8 weeks after first ustekinumab SC dose Non-responders to 130 mg a or ~ 6mg/kg IV induction 100 N = Response 50.5 Remission Note: only maintenance Week 8 responders continued to receive UST (n = 251) a 130 mg dose is not approved in Europe. Adapted from: Feagan BG, et al. N Engl J Med 2016;375: (Supplementary data pp )

24 Patients in clinical remission (%) a Of 467 subjects given induction treatment at Week 0, 251 were in clinical response and continued to receive 90 mg SC q8w in the maintenance study. Adapted from: Feagan BG, et al. N Engl J Med 2016;375: (Supplementary data pp ) Ustekinumab clinical remission (CDAI score < 150) at Week 44 Delayed responders group (90 mg SC q8w) a vs randomized subjects (90 mg SC q8w) % Ustekinumab 90 mg SC q8w randomized patients (n = 128) 50.2% Ustekinumab 90 mg SC q8w delayed responders (n = 251)

25 CASE 2

26 Young female, age 21 years, non - smoker, unemployed 2014: Diagnosis of Crohn s disease, (phenotype: A2L3B1p0) Ileopancolitis with ulcerations; started on azathioprine May 2015 Persistent mild symptoms, active disease Anti-TNF and AZA clinical and biological remission 2016 Progressive loss of response, leading to stepby-step optimization of the anti-tnf dose Hb, haemoglobin; MRI, magnetic resonance imaging.

27 Young female, age 21 years, non - smoker, unemployed - Terminal ileum ulcers

28 Young female, age 21 years, non-smoker, unemployed MRI enterography

29 Young female, age 21 years, non-smoker, unemployed 2017 Mild symptoms over the past 4 months CRP 9 mg/dl; Hb 12.1 g/dl; faecal calprotectin 1,024 g/g ; Clostridium difficile negative Ileitis/extensive colitis with large superficial ulcerations (> 2 cm) and a few non-extensive deep ulcerations in the left colon and transverse colon Wall thickness of the terminal ileum of 5 cm on MRI enterography, no complications The patient also complained for joint manifestations over the past months [type I or II arthritis and arthralgias] What would you do????? Hb, haemoglobin; MRI, magnetic resonance imaging.

30 Young female, age 21 years, non-smoker, unemployed Reactive Therapeutic Drug Monitoring Hb, haemoglobin; MRI, magnetic resonance imaging.

31 Young female, age 21 years, non-smoker, unemployed Optimal anti-tnf levels and no Anti-Drug Antibodies Hb, haemoglobin; MRI, magnetic resonance imaging.

32 What would your next step be? 1. Continue the same anti-tnf but switch from azathioprine to methotrexate 2. Switch to another anti-tnf 3. Switch to IL12/23 inhibitor 4. Switch to α4β7 integrin binding antibody

33 Back to the case Young female, age 21 years, non-smoker Diagnosis of Crohn s disease in 2014, L3 (ileopancolitis), B1, azathioprine antitnf and azathioprine started in 2015, but progressive loss of response leading to step-by-step optimization Active disease (ileopancolitis) with intestinal symptoms and joint manifestations despite optimal dose of anti-tnf and azathioprine; Extra-intestinal manifestations (arthritis) Optimal anti-tnf levels and no ADA Treatment with a biologic with alternative MoA to anti-tnfs Ustekinumab treatment is proposed to the patient

34 How quick is the onset of action of ustekinumab in anti-tnf refractory patients? 1. Within days 2. Within 2 4 weeks 3. Maximal efficacy only after 8 weeks

35 Daily score change (mean) Daily score change (mean) Daily score change (mean) Crohn s disease symptom improvement within the first week of UST in anti-tnf refractory patients Mean change of soft/liquid stool (SF) from baseline per day Time (days) Mean change of abdominal pain (AP) from baseline (rated 0-3) Time (days) ** ** * ** * ** ** * * * * * * * ** -0.4 ** ** * ** ** ** ** ** * ** ** ** -0.6 Mean change of general wellbeing (GWB) from baseline (rated 0-4) Time (days) ** ** ** * * * * * * * ** ** ** ** ** PBO (n = 191) UST 130 mg (n = 188) UST ~6 mg/kg (n = 184) *p<0.05 for UST 130 mg vs placebo; **p<0.05 for UDT ~6mg/kg vs placebo PBO, placebo; UST, ustekinumab Sandborn WJ et al. Late Breaking Abstract LB07. Presented at UEGW 2017.

36 Case continued started ustekinumab 6 mg/kg IV Infusion given over 1 hour; no prophylaxis When starting ustekinumab, what would you do with immunomodulators? 1. Give ustekinumab as monotherapy 2. Give concomitant azathioprine or methotrexate 3. I don t know

37 Concomitant immunomodulators: UNITI-1 for ustekinumab 6 mg/kg group Oral corticosteroids Odds ratio and 95% CI Ustekinumab vs placebo Proportion of patients in clinical response at week 6 Ustekinumab Placebo 6 mg/kg* Odds n (%) n (%) ratio (95% CI) p-value Receiving 111 (24.3) 108 (37.0) 1.9 (1.0, 3.4) Not receiving 136 (19.1) 141 (31.2) 1.9 (1.1, 3.3) Oral 5-ASA compounds Receiving 54 (24.1) 50 (36.0) 1.8 (0.8, 4.3) Not receiving 193 (20.7) 199 (33.2) 1.9 (1.2, 3.0) MP/AZA/MTX Receiving 81 (23.5) 78 (28.2) 1.3 (0.6, 2.7) Not receiving 166 (20.5) 171 (36.3) 2.2 (1.3, 3.6) Oral corticosteroids and 6-MP/AZA/MTX Receiving 35 (31.4) 33 (30.3) 1.0 (0.3, 3.0) Not receiving 212 (19.8) 216 (34.3) 2.1 (1.3, 3.2) < Oral corticosteroids or 6-MP/AZA/MTX Receiving 157 (22.3) 153 (34.0) 1.8 (1.1, 3.0) Not receiving 90 (20.0) 96 (33.3) 2.0 (1.0, 4.0) All patients 247 (21.5) 249 (33.7) 1.9 (1.2, 2.8) Placebo better 1 10 Ustekinumab better *Weight-range based ustekinumab doeses approximating 6 mg/kg: 260 mg (weight < 55 kg), 390 mg (weight > 55 kg and < 85 kg), 520 mg (weight > 85 kg). p < 0.05, but only nominally significant, as the endpoint is not among the Type 1 error-controlled endpoints (therefor interpret with caution).

38 Concomitant immunomodulators: UNITI-2 for ustekinumab 6 mg/kg group Oral corticosteroids Odds ratio and 95% CI Ustekinumab vs placebo Proportion of patients in clinical response at week 6 Ustekinumab Placebo 6 mg/kg* Odds n (%) n (%) ratio (95% CI) p-value Receiving 75 (34.7) 92 (56.5) 2.4 (1.3, 4.6) Not receiving 134 (25.4) 117 (54.7) 3.7 (2.1, 6.3) < Oral 5-ASA compounds Receiving 89 (29.2) 93 (60.2) 3.8 (2.0, 7.2) < Not receiving 120 (28.3) 116 (51.7) 3.1 (1.7, 5.4) < MP/AZA/MTX Receiving 73 (28.8) 72 (65.3) 6.0 (2.8, 13.1) < Not receiving 136 (28.7) 137 (50.4) 2.5 (1.5, 4.2) < Oral corticosteroids and 6-MP/AZA/MTX Receiving 22 (45.5) 23 (56.5) 2.4 (0.6, 9.2) Not receiving 187 (26.7) 186 (55.4) 3.4 (2.2, 5.3) < Oral corticosteroids or 6-MP/AZA/MTX Receiving 126 (29.4) 141 (61.0) 3.9 (2.3, 6.6) < Not receiving 83 (27.7) 68 (44.1) 2.0 (1.0, 4.0) All patients 209 (28.7) 209 (55.5) 3.2 (2.1, 4.9) < Placebo better 1 10 Ustekinumab better *Weight-range based ustekinumab doeses approximating 6 mg/kg: 260 mg (weight < 55 kg), 390 mg (weight > 55 kg and < 85 kg), 520 mg (weight > 85 kg). p < 0.05, but only nominally significant, as the endpoint is not among the Type 1 error-controlled endpoints (therefor interpret with caution).

39 Median serum UST concentration (μg/l) Exposure response to SC ustekinumab in IM-UNITI maintenance study Median serum UST concentrations over time through the maintenance study IM-UNITI in those receiving or not receiving concomitant immunomodulators a 1000 UST 6 mg/kg IV 90 mg SC q8w Receiving AZA, 6-MP, or MTX Not receiving AZA, 6-MP, or MTX Time (weeks) a Mixed population, from UNITI-1 and UNITI-2 trails 6-MP, 6-mercaptopurine; AZA, azathioprine; MTX, methotrexate. Adapted from: Adedokun OJ, et al. Gastroenterology Jan 31. Epub ahead of print.

40 Back to the case Young female, age 21 years, non-smoker Ustekinumab IV 6mg/kg Week 8: clinical improvement; SC 90 mg Week 16: clinical remission; SC 90 mg; azathioprine is stopped How would you continue with the maintenance? 1. continue with ustekinumab sc every 12 weeks 2. continue with ustekinumab sc every 8 weeks

41 Patients (%) IM-UNITI primary endpoint: clinical remission with ustekinumab at Week p = p = p = n = 47 n = 63 n = 68 n = UST IV responder a PBO SC* (n=131) UST 90 mg SC q12w (n=129) UST 90 mg SC q8w (n=128) Combined (n=257) a Subjects were in clinical response to ustekinumab IV induction dosing and were randomized to placebo SC on entry to this maintenance study. Subjects who had insufficient data to calculate the CDAI score at the designated analysis time points are considered not to be in clinical remission. Feagan BG, et al. N Engl J Med. 2016;375:

42 Randomized Patients in Clinical Remission through Week 44 Gosh S. Poster presented at ECCO P186

43 Clinical Endpoints at Week 44 of IM-UNITI, Stratified by Fecal Calprotectin at Maintenance Baseline *All comparisons versus placebo Gosh S. Poster presented at ECCO P186

44 Clinical Remission Over Time By Induction Study: ITT of Randomized Patients Entering LTE UNITI - 1: TNF antagonist failure UNITI - 2: Conventional therapy failure ITT, intent to treat population; LTE, long-term extension; q8w, every 8 weeks; q12w, every 12 weeks; TNF, tumor necrosis factor; UST, ustekinumab Adapted from: Sandborn WJ et al. Presented at DDW 2017.Su1889

45 Summary Active management of patients on biological therapy can improve outcomes Our choices for biologic therapy have increased anti-tnf antibodies Anti-integrins (currently: vedolizumab) ustekinumab Need to tailor choice first- and second-line therapies to patient profile Ustekinumab Good short and long term clinical efficacy IV followed by SC dosing results in rapid onset of symptom relief plus a convenient long term maintenance regime Excellent safety profile

2nd Nottingham IBD Masterclass, 2017

2nd Nottingham IBD Masterclass, 217 Positioning IL12/IL23 blockade in the Crohn s disease treatment algorithm Prof James Lindsay, Consultant Gastroenterologist, Barts Health NHS Trust Professor in Inflammatory