Which Initial Therapy to Choose in

Crohn’s and UC?

What for who and when?

Monday June 12, 2023

Joshua Korzenik, MD
Director, Resnek Family Center for PSC Research
Founding Director, BWH Crohn’s and Colitis Center
Brigham and Women’s Hospital
Boston, MA
 Disclosures
• Consultant:
– Thetis, ClostraBio, Corevitas, Promakhos

• Research support:
– Pfizer

• Co-Founder:
– ColonaryConcepts
– Bilayer Therapeutics
 What options?
• Infliximab (Remicade)
– Crohn’s (1998), fistula (2002), UC (2005), pediatric CD (2006), UC (2011)
• Adalimimab (Humira)
– Crohn’s (2007), UC (2012), pediatric Crohn’s (2014)
• Certolizumab (Cimzia)
– Crohn’s (2008) Mesalamine
Prednisone/budesonide
• Golimumab (Simponi) Azathioprine/6-MP
– UC (2013) Antibiotics
Methotrexate
• Vedolizumab (Entyvio) Nutrition
– UC (2014), Crohn’s (2014) Alternative Therapies
• Ustekinumab (Stelara) - Crohn’s (2016)
• Infliximab-dyyb (Inflectra) - Same indications as infliximab (2016)
• Tofacitinib (Xeljanz) UC (2019)
• Ozanimod (Zeposia)- UC (2021)
• Upadacitinib (Rinvoq) - UC (2022) Crohn’s (2023)
• Risankizumab (Skyrizi) – Crohn’s (2022)
Sequential Therapies for IBD: how should
this be updated?
Tofacitinib
Disease severity Ustekinumab
at presentation?
Vedolizumab
Anti-TNF (UC)/
Severe Anti-TNF Thiopurine/MTX (CD)

Budesonide Aminosalicylate (UC)/

Corticosteroids
Thiopurine/MTX (CD)
Moderate (CD, UC)

Aminosalicylate Aminosalicylate
Induction
Maintenance
Mild

Step-up according to severity at presentation or failure at prior step

time
 Personalized Medicine
• A hope with promise- but nothing on the
horizon
• No genetic, cytokine, clinical profile clearly defines a
subset of patients more or less likely to respond to a
particular medication.

• What data can guide a particular medication

in a particular subset of patients?
Considerations for positioning biologic therapy
• Disease severity
• Extent of disease
• Prior and current therapies
• Safety
• Cost
Kornbluth A, Sachar DB, et al. Am J Gastroenterol 2010; 105:501–523
 Criteria
• Patient age • Efficacy
• Patients history – Remission
– Complications – Healing
– Prevention of
• Extra-intestinal hospitalization
manifestations – Healthcare utilization
• Infectious risk – Timing
• Cancer history – Concomitant
• Pregnancy medications
• Safety
• Patient preference
• Durability/Immunogenicity
• Cost – Loss of response
– Antibody development
– Persistence of benefit
 Everyone wants to be first
• Tofacitinib/upadacitinib
– Small molecule;
– quick response;
– durability;
– ease of administration,
– no immunogenicity issues
– Safety concerns
• Ustekinumab/rizankizumab
– Effective, durable,
– good safety profile,
– low immunogenicity
• Vedolizumab
– Safety, effective in UC, low immunogenicity
• TNFi
– Tried and true
WHICH? WHO? WHEN?
 First line Choices
UC CD

• mesalamine • TNFi
• TNFi • vedolizumab
• vedolizumab • ustekinumab
• ustekinumab • 6-MP/aza
• tofacitinib • MTX
• upadacitinib • steroids
• 6-MP/aza
• steroids
 Selection of therapy in US is not guided
by best data
63% of patients initiated on a corticosteroid were only
managed by this agent; some were on a corticosteroid
for up to 10 cycles
Corticosteroids 42%

Crohn’s Diagnosis 5-ASA+Corticosteroids 5-ASA

N=16,260

5-ASA 35% Corticosteroids Corticosteroids

5-ASA+Corticosteroids
5-ASA
Other_Combo_NonBio
5-ASA+Corticosteroids 7%
Other_Combo_NonBio IST
IST
IST Biologic
Surgery Other_Combo_Bio
Other_Combo_Bio
Biologic Surgery
Biologic
Biologic+IST
Other_Combo_NonBio Surgery
Other_Combo_Bio Biologic+IST
Biologic+IST

Siegel CA, et al. ECCO, Barcelona, February 2017

Overall use of biologics at any time point
(“ever use”)
CD Pathways-Based UC Pathways-Based
Patient Counts (N=16,260) Patient Counts (N=28,119)

Crohn’s Disease Ulcerative Colitis

100 94
81
80
Patients (%)

60

40
19
20
6
0
With Without Without
biologics biologics With biologics biologics

Siegel CA, et al. ECCO, Barcelona, February 2017

 How to decide?
• Direct Head-to-head trials?
– Very limited in IBD
– Unlike other fields- psoriasis
• Comparative efficacy trials
– Difficult to compare across trials
• Comparing RCT results
• Network Meta-analysis
 Does everyone need a biologic?
• No
• Ulcerative colitis:
– mesalamine remains first line for mild to
moderate disease
• Crohn’s disease:
– Mesalamine not effective:
• For small bowel disease,
• For post-op prevention of recurrence
• Maybe a subset of colonic disease
 Very Few Direct Comparative
Effectiveness Trials

• Sonic (CD): azathioprine vs. infliximab vs.

both

• Varsity (UC): adalimumab vs. vedolizumab

• Seavue (CD): ustekinumab vs adalimumab

WHICH IS BETTER FOR FIRST LINE (UC)?
ANTI-TNF VS VEDOLIZUMAB
VARSITY: VEDOLIZUMAB VS ADALIMUMAB FOR UC

Sands, NEJM, 2019

 Is it a fair comparison? Serene Study
 Double-blind, multicenter study of high-dose (160 mg weekly for
4 wks followed by 40 mg weekly for 2 wks) vs standard-dose
adalimumab in patients with moderate to severe UC
High-Dose Standard-Dose
Patients With Outcome at P
Adalimumab Adalimumab
Wk 8, % Value
(n = 512) (n = 340)
Clinical remission 13.3 10.9 .273
Endoscopic improvement 31.1 27.1 .182
Fecal calprotectin < 150 22.5 19.8 .283
mg/kg
IBDQ response 66.8 60.9 .063
Clinical response per full 47.1 40.0 .034
Mayo Score*
Endoscopic remission 13.1 10.0 .162

Panes. United European Gastroenterology Week 2019. Abstr OP216.

?
 TNFi vs Vedolizumab
Anti-TNF vedolizumab

• Fast onset (2 weeks) • Slow onset (4 weeks)

• Better efficacy (CD) • Better efficacy (UC)
• Antibody risk • Low antibody risk
• As safe? • Safer?
• Lymphoma risk • Unknown but none
evident
Best Evidence for Combination Therapy is in Biologic- and
Immunosuppressive-Naïve Patients with Moderate to
Severe Crohn’s (SONIC)
Primary End Point AZA + placebo
Corticosteroid-free clinical remission IFX + placebo
100 IFX + AZA
P<.001
Proportion of Patients (%)

80
P=.006 P=.022

60 57
44
40
30

20

51/17 75/16 96/16

0 0 9 9

AZA = azathioprine.
Colombel JF, et al. N Engl J Med.
2010;362(15):1383-1395.
 Advantages of ustekinumab

• Durable; Low risk of antibody development 3% at week 52

• Low infection risk

Sandborn, NEJM, Nov 2017

ANTI-TNF FOR ALL?
WHO?
Which group responds best for TNFi?

• Disease characteristics
– Severe disease/poor prognosis (how defined)?
• Perianal disease, young age at dx (< 40), need for steroids at first flare
• Deep ulcerations at colonoscopy in > 10% of colon
• Location- extensive or proximal disease
– Montreal classification
• Penetrating disease: more aggressive disease
• Stricturing disease: less responsive
• Inflammatory disease- more responsive
• Earlier in disease
– Shorter duration of disease
– Pediatrics
– Faster loss of response in elderly
Factors associated with initial response
• Smoking: reduced response
• Age: pediatric response > adult
• Vitamin D: low levels reduced response
• Disease duration: conflicting data
• Disease location: no difference
• Durability less in elderly
• Concomitant Immune modulators
– Possibly for infliximab, unclear for others
IS TIMING IMPORTANT IN
SELECTION? IS EARLIER BETTER?
 Are biologics administered late, when
structural damage has already occurred?
High Potential Low Potential
Cumulative Probability (%)

Penetrating

Stricturing

Inflammatory

0 1 2 3 4 6 7 8 9 1 1 1 1 1 1 1 1 2 2 2 2
2 4 6 8 0 2 4 6 0 2 3 4 5 6 8 9 0 1 2 4
Patients at risk: Months 8 0 2 4 6 8 0 2 4 6 8 0

N= 2002 552 229 95 37

Cosnes J et al. Inflamm Bowel Dis. 2002;8:244-250.
 WHEN?
Remission in CD at week 26 by disease duration
Patients (%)
100
Placebo
All adalimumab
*
59
*
40 41
*
25
17 14

0
n= 23 39 36 57 111 233
<2 years 2 to <5 years ≥5 years
*p=0.002, **p<0.001, all vs placebo

Schreiber et al, Gastroenterology 2007; 132(4 Suppl. 2): A-147

 Early TNFi administration:
Pediatric RISK
• 913 children with Crohn’s disease
– 36 months’ prospective follow-up.
– 78 patients (9%) had disease complications;
• Risk for disease complications:
– older age at diagnosis,
– African American race
– anti-Saccharomyces cerevisiae antibodies (ASCA)
– CBir1 seropositivity;

• Early anti-TNFα therapy was associated with a

reduction in penetrating disease;
• No reduction in stricturing disease
Kugathasan et al. Lancet, April, 2017
Do TNFi change the natural history of CD?
Not effective for stricturing disease
Effective for fistulizing disease

Kugathasan et al, Lancet, 2017

WHICH ANTI-TNF FIRST?
 CD: Overview of Long-Term TNFi Trials
100 Week 26–30

ACCENT 1 CHARM PRECiSE 2

n = 113 n = 172 n = 215
80
Certolizumab pegol
Infliximab 5 mg/kg Adalimumab 40 mg EOW
400 mg every 4 weeks
Placebo Placebo Placebo
60 **
62.8
*

* **
52.0
*
40 51.0 **
47.9
*
**
* *
* 40.0
39.0 36.2
20 27.0
28.6
26.0
21.0
17.0
0

Response† Remission Response‡ Remission Response‡ Remission

Hanauer SB et al. Lancet. 2002;359:1541–1549. *P = .0002; **P = .003; ***P < .001
Colombel J et al. Gastroenterology. 2006;131:950. Remission = CDAI score < 150
† Decrease in CDAI score of ≥ 70 points and ≥ 25%
Schreiber S et al. NEJM. 2007;357:239-50. ‡ Decrease in CDAI score of ≥ 100 points
 CD: Which to start?
Comparative Efficacy
Relative risk 95% credible interval
infliximab 6.11 2.49-18.29
adalimumab 2.98 1.12-8.18
certolizumab 1.48 0.76-2.93
vedolizumab 1.40 0.63-3.28

Insurance mandating adalimumab

UC: infliximab > adalimumab
Continued Use at 6 months: each for first exposure to anti-TNF2
Infliximab adalimumab certolizumab
CD 37% (2039) 30% (1666) 11% (625)
UC 61% (1470) 14% (399)

Singh et al. Mayo Clin Proc. 2014;89(12):1621-35; Loftus, DDW, 2015

 Infliximab vs adalimumab
• First-line TNFi agent, 487 patients with CD
– Mean duration 3.6 yrs IFX and 2.5 years ADA (P = 0.219).
– Lower persistence in women (P = 0.0005) and stricturing behavior (P = 0.008)

• For second-line TNFi agent,134 patients.

• Mean duration: 2.4 yrs IFX and 2.6 years in ADA (P = 0.488).
– Age under 37 was only factor associated with lower persistence (P = 0.016)

• Compared with adalimumab patients, infliximab-treated

patients had a lower risk of:
– CD-related hospitalization ( [aHR], 0.80; 95% con [CI], 0.66-0.98),
– Abdominal surgery (aHR, 0.76; 95% CI, 0.58-0.99), and
– Corticosteroid use (aHR, 0.85; 95% CI, 0.75-0.96).

Olivera et al. Inflamm Bowel Dis. 2017.

Singh et al. Clin Gastroenterol Hepatol. 2016
UC: Comparative Efficacy

Vickers, PLOS One, 2016

Tofacitinib

Sandborn et al. CGH 2022

Upadacitinib

Danese et al, Lancet, 2022

Comparative Efficacy: Real World Data
Tofacitinib vs Upadacitinib- UC

Tofa = 119; Upa = 35

Boneschansker, Ananthakrishnan, Clin

Gastro Hep, 2023
 Loss of Response by 6 Months With all
TNFis Fixed Dose Maintenance

ACCENT I1 CHARM2 PRECiSE 23

Patients (%) Patients (%) Patients (%)
100 100 100
37%
48% 46%

0 0 0
(CDAI ≥70 or 25%) (CDAI >70) (CDAI ≥100)

1 Hanauer et al. Lancet 2002;359:1541

2Colombel et al, Gastroenterology 2007;132:52
3 Schreiber et al. Gut 2006;55(Suppl V):A131
4 Sandborn et al. Gastroenterology 2007;132:A 505 (T1274)

5 Loftus et al, DDW, 2015

 Seavue: ustekinumab vs adalimumab

Sands et al. Lancet, 2022

SAFETY
 Infections and Mortality in the TREAT Registry:
15,000 Patient-Years of Experience
Multivariate Analysis
4.5

4.0 Mortality Serious infections

Adjusted Odds Ratio

3.5
Steroids
3.0

2.5
AZA
2.0
AZA IFX 6-MP Steroids
6-MP MTX
1.5 IFX MTX

1.0
P<.001 P=.006 P=.002
0.5

0.0

AZA = azathioprine; IFX = infliximab; MTX = methotrexate. 4

Lichtenstein GR et al. Am J Gastroenterol. 2012;107:1409-1422.. 2
Adverse Events Associated with
TNFi Treatment

43
Safety of TNFi in the Elderly
 Safety of TNFi agents in a pediatric
population
5 deaths in 5528 patients
Serious infection 352/10,000 patient years
Similar to immune modulator
Less than glucocorticoids

Dulai et al, CGH, 2014

 Comparative Safety
• Monotherapy with immunosuppressive agent
associated with lower risk of serious infections
than monotherapy with a TNF antagonist (7
cohorts; RR, 0.61; 95% CI 0.44- 0.84)
• Infliximab associated with lower risk of serious
infections compared to adalimumab in UC (4
cohorts; RR, 0.57; 95% CI, 0.33–0.97), but not
Crohn’s disease (4 cohorts; RR, 0.91; 95% CI,
0.49–1.70).

Singh, CGH, In press

Comparative safety

Holmer & Singh, Expert Review of Clinic Immun, 2019

IMMUNOGENICITY
 Immunogenicity of Biologics with and without
Concomitant Immune Modulators (IMS)
Patients, %

Episodic Maintenance Scheduled Maintenance

IMS- IMS+ IMS- IMS+
(CD 5 mg/kg) 11% 7%
Infliximab1 38% 16%
(CD 10 mg/kg) 8% 4%
(UC 5 mg/kg) 19% 2%
Infliximab2
(UC 10 mg/kg)
No data 9% 4%
Certolizumab3 (PRECiSE I) 10% 4%
Certolizumab4 (PRECiSE II) 24% 8% 12% 2%
Adalimumab5 (RA, all doses) 12% 1%
No data
Adalimumab6 (CLASSIC II) 4% 0%
Golimumab7 (PURSUIT) No data 4% 2%
Natalizumab8a,b (ENACT-1a & 2b) No data 11%8a ; 8%8b 3%8a ; 0%8b
v/p:* 18% v/p: 3%
Vedolizumab9,10 (GEMINI) No data
v/v:* 3.0% v/v: 3%
Ustekinumab11 (CERTIFI) No data 0.7% 3%
1Hanauer et al. Clin Gastroenterol Hepatol. 2004; 2Sandborn et al. DDW 2007 Poster and abstract T1273;
3Sandborn WJ, et al. N Engl J Med. 2007; 4Schreiber S, et al. N Engl J Med. 2007; 5Summary of Product Characteristics for adalimumab. Abbott

Laboratories. July 2007; 6Sandborn WJ, et al. Gut. 2007; 7Golimumab package insert. Janssen Biotech Inc., Horsham PA. 2012; 8Sandborn WJ, et
al. N Engl J Med. 2005 ; 9Sandborn WJ, et al. N Engl J Med. 2013; 10Feagan B, et al. N Engl J Med. 2013. 11Sandborn WJ, et al. N Engl J Med. 2012
SPECIAL CASES
 TNFi Provoked Autoimmune Diseases (?)
• Rheumatoid Arthritis
• Psoriasis
• Autoimmune hepatitis
• Demyelinating disease/Multiple Sclerosis
• Alopecia
• Vasculitis
• Drug-induced lupus

• Crohn’s disease
• Ulcerative colitis
51
PREGNANCY
 Anti-TNF biologics:
Fusion protein, antibodies and PEGylated
Fab' fragment
Certolizumab
Etanercept Infliximab Adalimumab pegol
Golimumab
Fab′
Receptor Fab

IgG1 IgG1 PEG

Fc Fc

Chimeric Human
PEGylated
Human humanized
recombinant Monoclonal Fab′ fragment
receptor/Fc fusion antibody
2 × 20 kDa
protein PEG
 Cases with more certainty?
• Pregnancy: certolizumab
• TNFi induced psoriasis: ustekinumab
• Recurrent skin cancers: vedolizumab
• Recurrent infections: vedolizumab (?)
Should we change how we position biologics for
their use in UC and Crohn’s disease?
YES- in a subgroup
• The earlier the better (probably)
• Patient selection is paramount
– Fistulizing disease
– Smokers
– Young patients
– Stricturing disease may need alternate first line agent
• Should TNFis be first?
– Reassess in light of safety
– Reassess in elderly
– Those at higher risk of infection
 TNFi agents: For whom?
• Not for:
• - Mild disease (how defined?)
• - CHF
• - Abscess
• - Active infection
• - Stricturing disease
• Reasonable candidates:
– Steroid dependent
– Inflammatory disease
• Uncertain
– Elderly (how defined?)
– Post-op prevention of recurrence
 What group that responds best for TNFi?

• Disease characteristics
– Severe disease/poor prognosis (how defined)?
• Perianal disease, young age at dx (< 40), need for steroids at
first flare
• Location- extensive or proximal disease
– Montreal classification
• Penetrating disease: more aggressive disease
• Inflammatory disease- more responsive
 WHO-(2)?
• Genetic profile:
• Weak association:
– Nothing that is clinically actionable
• Earlier in disease?
– Shorter duration of disease
– Pediatrics
– Faster loss of response in elderly
• Steroid dependent
– How defined
 Vedolizumab
• Older
• Multiple co-morbidities
• Concomitant steroids and/or narcotics
• Long-standing disease
• Young “healthy” patients are not in the clear,
but probably much less at risk
• ? Prior malignancy UC>CD
 Ozanimod
• Sphingosine 1 phosphate interaction
– Different mechanism of action
• UC
• Not for prior MI/CVA in previous 6 months
• check EKG for arrhythmia
– Type II/III AV block
• Reasonable safety and efficacy
• At end of the line or beginning?
 Tofacitinib/upadacitinib
• Quick acting
• Durable response
• No immunogenicity issues
• Safety concerns
– Thrombosis in elderly RA; Not in UC database
• Oral agent
• Close monitoring- lipids, lymphocytes
• A role in severe, acute inpatient UC?
• Upadacitinib more effective?
• Safety appears dose dependent
 Ustekinumab
• First line?
• Low immunogenicity
• Good durability of response
• Low infection risk (vs placebo)
• Low risk of SAE (vs placebo)
 Are we able to choose-?
Or will the insurance companies tell us
• FDA indication:
– prior to anti-TNFs
– After anti-TNFs
• Insurance limiting ustekinumab after TNFis
– AWP $110,000
• Some insurance companies limiting vedolizumab
• Ideal subset not clear
• Biosimilars will shake up insurance algorithms
• Legislative landscape changing in terms of “fail
first” laws