Transcript Pro: Patients losing response to their first anti

What to Do When Biological Therapy
Doesn’t Work in IBD Patients?
Gary R. Lichtenstein, MD
Professor of Medicine
Director, Center for IBD
University of PA School of Medicine
Philadelphia, PA
DISCLOSURES
Grants/Research Support: Celgene, Ferring, Janssen Biotech, Prometheus
Laboratories, Inc., Salix Pharmaceuticals, Santarus, Shire Pharmaceuticals,
UCB, Warner Chilcott
Consultant: Abbott Corporation/AbbVie, Actavis, Alaven, Celgene,Ferring,
Hospira, Janssen Biotech, Luitpold/American Regent, Pfizer
Pharmaceuticals, Prometheus Laboratories, Inc., Romark, Salix
Pharmaceuticals / Valeant, Santarus / Receptos, Shire Pharmaceuticals,
Takeda, UCB, Warner Chilcott
Honorarium Recipient: Ironwood, Luitpold/American Regent (CME
programs), Merck (CME Program).
Editorial Board Involvement: Gastroenterology and Hepatology
Other Financial Material Support: SLACK, Inc. (book royalty)
Janssen BIotech (IBD Fellowship Funding), McMahon Publishing – Author
(Honorarium), Takeda (grant), Up To Date (Author).
Overview
•
•
•
•
•
Etiologies for Loss of Response
Contraindications and safety
Optimization
Therapeutic Drug Monitoring
Therapeutic Treatment Options
Loss of Response to the First Biologic
• I. Evaluate for Disease Complications
• II. Evaluate for Enteric Infections
• III. Miscellaneous
• NonAdherence
• NSAIDs
• Cigarettes
• IV. Use Optimal Medication Doses
I. Identify Disease Related
Complications
 Fibrostenotic Disease –Inappropriately Treated




as Inflammatory Disease
Intraabdominal Abscesses
Pelvic Abscesses
Toxic Megacolon
Mesenteric Venous Thrombosis
Identify Disease Related
Complications
 Fibrostenotic Disease –Inappropriately Treated
as Inflammatory Disease
• Assess Inflammatory Markers
o ESR
o CRP
o Fecal Calprotectin / Lactoferrin
 Bowel Imaging
 CT enterography or MRI enterography
• Hyperenhancement
• Mural Thickening
 Plain Abdominal Radiography
 Megacolon
Disease Complications
 Abdominal / Pelvic Abscess
 CT abdomen and pelvis with oral and iv
contrast
 MRI pelvis with gadolinium
 Mesenteric Venous Thrombosis
 CT abdomen and pelvis with oral and iv
contrast
 MRI pelvis with gadolinium
II. Enteric Infections
 Bacterial Infections
 CMV
 Clostridium Difficile
 Parasitic Diseases
III. Miscellaneous
 NonAdherence
 NSAIDs
 Cigarette
• Cessation in UC
• Use in CD
IV. Use of Optimal Medication Doses
 Use Appropriate Loading Doses
 Dose Escalation
Optimal Therapy with Biologics:
Maximizing Efficacy and Avoiding Loss of Response
 Give a loading dose
• Infliximab 5 mg/kg IV at weeks 0, 2 and 6
• Adalimumab 160 mg, 80 mg, then 40 mg SC EOW
• Certolizumab pegol 400 mg SC EOW x3
• Golimumab Load: 200 mg week 0, 100 mg week 2 then 100
mg q4w
• Vedolizumab 300 mg iv mg/kg IV at weeks 0, 2 and 6
• Natalizumab 300 mg iv every 4 weeks
• Ustekinumab (Initial iv loading)
Weight Range (kilogram)
Up to 55 kg
Greater than 55 kg to 85 kg
Greater than 85 kg
Then 90 mg sq every 8 weeks
Recommended Dosage
260 mg (2 vials)
390 mg (3 vials)
520 mg (4 vials)
Optimal Therapy with Biologics:
Maximizing Efficacy and Avoiding Loss of Response
 Give in combination with an immune modulator
(6-mercaptopurine, azathioprine, or methotrexate)
 Unclear if high drug levels (monotherapy) with biologic agent
similar to combination therapy (biologic + IMM)
 If not given in combination with immune modulator, give
infliximab with hydrocortisone pretreatment ?
 Avoid episodic dosing
 Dose optimize early to avoid unintentional episodic dosing?
Dose Optimisation: Clinical Evidence
• In ACCENT I1 & II2 patients with disease reoccurrence regained response
with a dose increase from 5 mg/kg to 10 mg/kg in scheduled treatment
89.3
ACCENT I
29
57.1
ACCENT II
23.7
0
20
40
60
80
100
Proportion of patients (%)
Regained treatment response
Lost treatment response
Patients can regain clinical response with dose optimization
1-Hanauer SB et al. Lancet. 2002;359:1541.
2- Sands BE et al N Engl J Med 2004;350(9):876-885
CHARM: Benefit of Weekly Dosing with
Adalimumab for Flare
78%
58%
69%
63%
47%
37%
Sandborn WJ., et al., Inflamm Bowel Dis. 2011; 17: 141-151.
PRECISE 4: Study Design
PRECISE 4: Re-induction of Certolizumab Pegol in
Patients Losing Initial Response After Induction
Optimal Therapy with Biologics:
Maximizing Maintenance Dosing
 Maintenance dose:
• Infliximab: 10 mg/kg IV every 4 weeks maximal dose
• Adalimumab: 40 mg SC weekly (?80 mg sq weekly)
• Certolizumab pegol: 400 mg SC additional dose (? 400 mg
sq every 2 weeks)
• Golimumab: 100 mg q4w
• Vedolizumab: 300 mg iv every 4 weeks
• Ustekinumab: 90 mg sq every 8 weeks
Among IBD Experts, No Unanimity
on IFX Rescue Dosing for Severe UC
Herfarth HH, et al. Clin Gastroenterol Hepatol. 2015;13(2):336-8.
Biologic Therapy Limitations
• One Size Does Not “Fit All”
• Need to dose adjust and consider
combination therapy (IMM + Biologic)
• Therapeutic Drug Monitoring
– Should be performed
• Pharmacodynamic
– Evolution of resistance to anti-TNF
mechanism
ACCENT I, CHARM and PRECISE 2
Clinical Remission in UC: ACT (Infliximab), ULTRA-2
(Adalimumab) and PURSUIT (Golimumab)
Patients failing 5-ASA/Steroids/IS
1
Adalimumab 8 Weeks
Infliximab 8 Weeks
**
**
40%
30%
40%
30%
30%
*
20%
10%
10%
Infliximab 5
mg/kg
**
Golimumab
400/200 mg
Golimumab
200/100 mg
0%
Adalimumab
Placebo
**
10%
0%
0%
Golimumab 6 Weeks
40%
20%
20%
Infliximab 10
mg/kg
3
2
Placebo
Placebo
4
1
Infliximab 54 Weeks
40%
Adalimumab 52 Weeks
Golimumab 54 Weeks
40%
40%
30%
30%
30%
20%
20%
10%
10%
**
**
0%
Infliximab 10
mg/kg
1.)
2.)
3.)
4.)
Infliximab 5
mg/kg
Placebo
**
**
20%
10%
0%
0%
Adalimumab
Placebo
Rutgeerts P, et al. N Engl J Med. 2005;353:2462-2476;
Sandborn WJ, et al. Gastroenterology. 2012;142:257-265;
Sandborn WJ, et al. Gastroenterology. 2014;146:85-95;
Sandborn WJ, et al. Gastroenterology. 2014;146:96-109;
Golimumab Golimumab 50
100 mg
mg
Placebo
* P<.05 versus placebo;
** P<.01 versus placebo
Optimizing AntiTNF Therapy
Approaches
• Treat Early Disease
– But, not in all patients: attempt to prognosticate - fistula, early steroid
users, smokers, severe endoscopic lesions, age < 40, high risk anatomy- rectum,
foregut, extensive disease.
• Treat Actual Active Disease
• Benefit of Concomitant Immunomodulator Use with anti- TNF Therapy
• Higher Drug Levels
• Fewer Acute AE’s
 Infusion Reactions
 Serious Infections
• Better Efficacy
• Evaluate Secondary Nonresponse
• CMV, C diff, Fibrotic Stricture, Fistula…
• Dose Escalation
• Switch Drug Mechanisms
Defining Primary and Secondary
Failure of Biologic Therapy
Defining Anti-TNF Failure:
Secondary Non-response (Loss of Response)
• “Pseudo-failure” for symptoms unrelated to active
inflammation
• Pharmacokinetic
– Inadequate drug levels because of anti-drug antibody
– Inadequate drug levels because of rapid drug clearance
for other reasons
– Inadequate dose
• Pharmacodynamic
– Evolution of resistance to anti-TNF mechanism
• Dose-limiting adverse event
Secondary Loss Of Response:
Reactive Testing Algorithm
Secondary Loss of Response
(disease activity confirmed)
Therapeutic
Biologic
Concentration
Change drug class
(Biologic: Anti-TNF,
Anti-Integrin, Anti-IL12/23) or surgery
Sub-therapeutic
concentration
ADA positive
ADA negative
Dose escalate
Low level
High level
Consider dose
escalation, addition of
immunomodulator, or
change Biologic: AntiTNF, Anti-Integrin,
Anti-IL-12/23
Change to different
Biologic: Anti-TNF,
Anti-Integrin, Anti-IL12/23
Modified from Khanna R, et al. Aliment Pharmacol Ther. 2013;38(5):447-59.
Commercially Available Drug Assays
•
•
•
•
•
•
•
•
•
•
Prometheus(1) – IFX, ADA, CZP, VEDO, UST
ARUP Labs (2)- IFX
Mayo Medical Laboratories(3)- IFX, ADA, CZP, VEDO
Miraca Laboratories(4)- IFX, ADA, CZP, VEDO, UST
Esoterix (Labcorp) (5)- IFX
1-https://www.anserifx.com/
2- http://www.aruplab.com/immunology/IFX
3- http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/63437
4- http://www.miracalifesciences.com/
5- http://www.esoterix.com/test-menu/infliximab-concentration-and-anti-infliximabantibody/a1948211-4072-4432-8b80-43eea8d3e682
AGENT
Therapeutic
Level
Mucosal
Healing
IFX
3-7
? 5-10
> 7.1
ADA
5-10
CZP
VEDO
?
UST
?
Critical Component
Presence of Inflammation
The key patient selection factor for
treatment with Anti-TNF therapy
and Anti-Integrin therapy
SONIC
Corticosteroid-Free Clinical Remission
at Week 26 in Patients With Crohn’s
Disease by Baseline Endoscopy Status
AZA + placebo (n=170)
Proportion of Patients (%)
100
IFX + placebo (n=169)
IFX + AZA (n=169)
P<0.001
P=0.93
P=0.003
P=0.002 P=0.12
P=0.37 P=0.69
P=0.14 P=0.07
80
61.3
60
57.1
50.5
40.7
40
40.0
38.2
33.3
29.6
21.4
20
35/115
0
50/99
Lesions
(n=325)
AZA, azathioprine; IFX, infliximab;
UTD, unable to determine
68/111
11/27
12/36
12/30
No Lesions
(n=93)
6/28
13/34
16/28
No Endoscopy
or UTD
(n=90)
Colombel JF et al. N Engl J Med. 2010;362:1383.
AGA Clinical Pathway for Crohn’s Disease:
Assessing Inflammatory Status
Assess inflammatory status
Assess symptoms/signs
• Fever
• Abdominal pain
• GI bleeding
• Localized tenderness
• Weight loss
• Joint pain
• Cutaneous signs
Perform clinical lab testing
• CBC
• CRP
• CMP
• Fecal calprotectin
• ESR
Select imaging modalities
(if indicated)
Perform endoscopy
Identify symptoms
without inflammatory
markers
Identify symptoms
with inflammatory
markers*
Perform CTE or MRE
Consider whether treatment decisions to be based on inflammatory markers vs confirming with colonoscopy.
This may depend on whether there was historically good correlation between the biomarker selected and colonoscpy in the specific patient.
CMP, complete metabolic panel; CTE, computed tomography enterography; ESR, erythrocyte sedimentation rate; MRE, magnetic resonance enterography.
Sandborn WJ. Gastroenterology. 2014;147:702-705.
The Role of Mucosal Healing in Clinical Practice in 2016:
Treating to Achieve a Target
• Don’t settle for symptoms alone
• Pay attention to labs
– WBC, CRP, Calprotectin and Lactoferrin
• Plan scheduled follow-up
• Adjustments to Therapy
(Treat To Target)
– Confirm adherence
– Optimize therapy dosing and therapeutic drug monitoring
– Incremental step up based on best evidence and
comparative effectiveness
• Patient buy-in is very important
Treat-to-Target Algorithm
)
CRP, C-reactive protein.
Bouguen G, et al. Clin Gastroenterol Hepatol. 2015 Jun;13(6):1042-50
Therapeutic Treatment Options
 Anti-TNF: to Different Anti-TNF
 Anti-TNF: to Anti-Integrin
 Anti-TNF: to Anti-Il-12/23
Secondary Nonresponder
Switch from Infliximab to Adalimumab
• GAIN trial, 325 adults 18-75 years of age with
moderate to severe Crohn disease (CDAI score, 220450 points) and who had lost response to infliximab
or had adverse events were randomly assigned to
receive induction doses of adalimumab, 160 mg/80
mg, or placebo at weeks 0 and 2; 301 completers
• Twenty-one percent (34 of 159) of patients in the
adalimumab group vs 7% (12 of 166) in placebo
group achieved remission at week 4
• 70-point response at week 4 in 52% (82 of 159)
of patients in adalimumab group vs 34% (56 of 166)
of patients in placebo group
Sandborn WJ, et al. Ann Intern Med. 2007;146(12):829-38.
4-Week Remission Rates With
Adalimumab by Prior Anti-TNF Exposure
Clinical
Remissionb(%)
100
TNF-blocker Naïve vs Previous Infliximab
80
Placebo
60
Adalimumab 160 mg (wk 0)/80 mg
(wk 2)
36%a
40
21%a
20
0
12%
n=74
7%
n=76
TNF-blocker Naïve Patients
(CLASSIC-I)1
aP<.001
n=166
Infliximab Failure/
Intolerance
(GAIN)2
vs placebo
remission was defined as a decrease in the
Crohn’s Disease Activity Index score to <150 points at week 4
bClinical
n=159
1- Hanauer SB et al. Gastroenterology. 2006;130:323-33.
2- Sandborn WJ et al. Ann Intern Med. 2007;146(12):829-838
Secondary Nonresponder: Switching
from Infliximab to Certolizumab
• WELCOME: 26 week study; 539 patients with active
Crohn's disease and secondary failure to infliximab
received open-label induction with subcutaneous
certolizumab 400 mg at weeks 0, 2, and 4
• Responders were then randomized to certolizumab
400 mg every 2 or every 4 weeks through week 24
• The primary end point was response at week 6
• Secondary end points included remission at week
6 and response and remission at week 26
Sandborn WJ, et al. Clin Gastroenterol Hepatol. 2010 Aug;8(8):688-695.e2. Epub 2010 May 6.
Secondary Nonresponder: Switching
from Infliximab to Certolizumab
• At week 6, 334 of 539 patients (62.0%) achieved
response and 212 of 539 (39.3%) achieved remission
• A total of 329 patients were randomized and
received maintenance therapy
– At week 26, 39.9% (67 of 168) and 36.6% (59 of
161) of patients in the every 4 weeks and every
2 weeks groups were in clinical response,
respectively (P = .55)
– Corresponding remission rates at week 26 were
29.2% and 30.4%, respectively (P = .81)
Sandborn WJ, et al. Clin Gastroenterol Hepatol. 2010 Aug;8(8):688-695.e2. Epub 2010 May 6.
Certolizumab in Patients with Moderate to Severe CD
and Secondary Failure to Infliximab
Response and Remission Rates
Response and remission rates
(A) over the open-label induction phase (n = 539)
(B) at week 26 (n = 329)
Sandborn WJ, Abreu MT, D'Haens G, et al. Clin Gastroenterol Hepatol; 2010; 8(8):688-695.
GEMINI I Week 6 Results: Clinical Response
and Remission in TNF Failure and TNF-Naïve
Patients (Exploratory Endpoints)
TNF Failure
Placebo, n=63
VDZ, n=82
Patients (%)
80
60
(3.9, 32.9)*
39.0
40
20
100
20.6
(-9.8, 22.8)*
9.8
TNF-Naive
Placebo, n=76
VDZ, n=130
80
Patients (%)
100
(13.7, 39.9)*
60
53.1
40
26.3
23.1
20
6.6
3.2
0
(2.4, 30.2)*
0
Clinical
response
Clinical
remission
Clinical
response
Clinical
remission
*95% CI for difference from placebo.
Clinical response was defined as reduction in complete Mayo score of ≥3 points and ≥30% from baseline with an accompanying decrease in
rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point.
Clinical remission was defined as a complete Mayo score of ≤2 points and no individual subscore >1 point.
Feagan BG, et al. N Engl J Med. 2013;369:699-710.
GEMINI I Week 52 Results: Clinical Remission
and Durable Clinical Response
Patients with prior anti-TNF failure (%)
Anti-TNF Failure
100
80
(11.8, 49.6)*
(10.3, 51.4)*
(7.5, 45.9)*
(7.4, 49.4)*
60
46.5
37.2
42.5
35.0
40
15.8
20
5.3
0
Clinical remission
Placebo, n=38
Vedolizumab Q4W, n=40
Durable clinical response
Vedolizumab Q8W, n=43
*95% CI for difference from placebo. All patients were responders at Week 6 Durable clinical response =response at Weeks 6 and 52.
Durable clinical remission=remission at Weeks 6 and 52.
Feagan BG, et al. N Engl J Med. 2013;369:699-710
Ustekinumab in CD:
Clinical Response (≥100-point CDAI Reduction) at Week 6
UNITI-1
Patients Failing Anti-TNF Therapy
UNITI-2
Anti-TNF Naïve Patients
100
100
P=0.003
80
P<0.001
60
34.3
40
33.7
21.5
n=247
Placebo
80
P=0.002
51.7
55.5
n=209
n=209
n=249
Placebo
130 mg
~6 mg/kg*
60
40
28.7
20
20
0
Patients, %
Patients, %
P<0.001
n=245
n=209
130 mg
~6 mg/kg*
Ustekinumab
0
Ustekinumab
*Weight-range based UST doses approximating 6 mg/kg: 260 mg (weight ≤55 kg), 390 mg (weight >55 mg and ≤85 kg), 520 mg (weight >85 kg).
Subjects who had a prohibited Crohn's disease-related surgery or had prohibited concomitant medication changes prior to designated analysis time point are
considered not to be in clinical response, regardless of their CDAI score. Subjects who had insufficient data to calculate the CDAI score at designated
analysis endpoint are considered not to be in clinical response.
Feagan BG, Sandborn WJ, et al. New Engl J Med. 2016 17;375(20):1946-1960..
41
Ustekinumab in CD:
Clinical Remission* (CDAI<150) at Week 8
UNITI-2
Anti-TNF Naïve Patients
100
100
80
80
P<0.001
60
P=0.003
40
20
0
7.3
15.9
n=247
n=245
Placebo
130 mg
20.9
n=249
~6 mg/kg†
Ustekinumab
Patients, %
Patients, %
UNITI-1
Patients Failing Anti-TNF Therapy
P<0.001
P=0.009
60
30.6
40
20
0
40.2
19.6
n=209
n=209
Placebo
n=209
n=209
130 mg
~6 mg/kg†
Ustekinumab
*Subjects who had a prohibited Crohn's disease-related surgery or had prohibited concomitant medication changes prior to Week 8 are considered
not to be in clinical remission, regardless of their CDAI score. Subjects who had insufficient data to calculate the CDAI score at Week 8 are considered
not to be in clinical remission
†Weight-range based UST doses approximating 6 mg/kg: 260 mg (weight <55 kg), 390 mg (weight >55 mg and <85 kg), 520 mg (weight >85 kg).
Feagan BG, Sandborn WJ, et al. New Engl J Med. 2016 17;375(20):1946-1960.
42
Don’t Forget
 NonAdherence
 Paradoxical Response to Mesalamine
 NSAIDs
 Cigarettes
Conclusions
Optimize Biologic Therapy
Approaches
• Treat Actual Active Disease
• Benefit of Concomitant Immunomodulator Use
with Biologic Therapy
• Higher Drug Levels
• Fewer Acute AE’s
 Infusion Reactions
 Serious Infections
• Better Efficacy
• Evaluate Secondary Nonresponse
• CMV, C diff, Fibrotic Stricture, Fistula…
• Dose Escalation
• Switch Drug Mechanisms
Conclusions
• Always consider combination therapy
– Assess Risk versus Benefit
– Avoid AZA / 6-MP in males < 30 or >50- especially
– Avoid MTX in women of childbearing age
• Avoid episodic dosing
• Load biologic appropriately
• Treat active infection before starting Biologic
Therapy
• Prevent preventable infections with vaccination
• Initiate TDM in Secondary LOR