Lessons Learned from Biologic Agents in Rheumatology – Immunogenicity
Vibeke Strand, MD, MACR, FACPBiopharmaceutical Consultant
Adjunct Clinical Professor, Division Immunology/RheumatologyStanford University, Palo Alto CA
Disclosures: Consultant
AbbvieAmgenAstraZenecaBMSBoehringer IngelheimCelltrionCORRONACrescendoEMD SeronoGenentech/RocheGlenmarkGSKHorizonInmedix
JanssenKyphaLillyMerckNovartisPfizerRegeneronSamsungSandozSanofiSelectaServierSetpointUCB
2
Agenda
Many pathways influence the bioavailability of biologics – immunogenicity is a part of the picture
All TNF inhibitors are immunogenic
How does MTX impact the bioavailability of TNFis?
Most tests for ADAbs only capture a fraction of the “truth”
Immunogenicity and Treatment Survival – clinical practice implications
Biologic Agents Have Complex Pharmacokinetics [PK]
• IgG antibodies are recycled and salvaged by Fcϒ receptors [FcRn] on vascular endothelial cells or by reticuloendothelial system
• Fcϒ receptors are also present on monocytes, tissue macrophages and dendritic cells
• Proteolytic catabolism occurs: exact location not known
• Receptor-mediated clearance
• Formation of anti-drug antibodies: ADAbs
Mould DR & Green B. BioDrugs. 2010;24:23–39. Buss N, et al. Curr Opin Pharmacol. 2012;12:615–622. Ordas I, et al. Clin Pharmacol Ther. 2012;91(4):635–646.
Several Factors May Impact Clearance of Biologic Agents
FDA. Guidance for industry assay development for immunogenicity testing of therapeutic proteins. Available at: http://www.fda.gov/downloads/Drugs/.../Guidances/UCM192750.pdf.; Kapel N, et al. Eur J Clin Chem Clin Biochem. 1992;30:197–202., Ordas I, et al. Clin Pharmacol Ther. 2012;9:635–646.
Antibody Salvage
• Brambell (FcRn) protects IgG
Metabolism • Breakdown by proteolysis
Target Binding
• Nearly irreversible binding to antigen
• TNF inhibitors w/ IgG Fc’s bind FcγRs
• Usually relates to clearance (half-life)
Cellular Uptake• Phagocytosis
• Pinocytosis (not receptor mediated)
Anti-biologic Agent Antibodies
[ADAbs]
• Extent of “humanization”
• Route of administration
• Dose regimen and duration
Atypical Clearance Mechanisms
• Low albumin
• High BMI
• High baseline TNFα
Concomitant medication
• Concomitant MTX [otherantiproliferatives] reduce FcγRmediated clearance rates – elevate drug levels
All Biologic Agents Have a Distinct Immunogenic Profile
Product related:• Protein structure• Manufacturing processes • Impurities• Host-cell proteins or contaminants • Aggregate formation• Denatured proteins
Disease related:• Underlying disease; eg RA v SpA• Disease severity (degree of inflammation)
Treatment related:• Dose schedule, frequency, route of administration and duration
• Repeated administration is more immunogenic than a single dose• Induction regimens decrease immunogenicity• SQ vs IV administration
• Concomitant medication• Increase serum concentrations of anti-cytokine mAbs by down-regulating FcgR mediated clearance mechanisms• Decrease ADAb formation
Patient related:• TNF burden • Immune status of patients• Serum albumin concentration • Body mass index
Immunogenicity of biologic agents
Schellekens H. Nat Rev Drug Discov 2002;1:457-462, Strand V et al Nat Drug Disc 2007; 6:75-92 .
Do Neutralizing ADAbs matter?
• The term «neutralizing» describes the bindingsite of an ADAb: for most mAbs the epitopebinding region is the target [anti-ID]
• Neutralizing ADAbs block the binding site of a respective TNFi mAb and thus limit its activity
• All ADAbs form immune complexes [ICs]
• ICs can accelerate clearance mechanismsaffecting bioavailability of TNFis/biologics
Potential Consequences of Immunogenicity on PK/PD
Brinks V, et al. Pharm Res. 2011;28:2379–2385. Ordás I, et al. Clin Pharmacol Ther. 2012;91:635–646. van SchouwenburgPA, et al. Nat Rev Rheumatol. 2013 Feb 12. doi:10.1038/nrrheum.2013.4. Vincent FB et al. Ann Rheum Dis. 2013;72:165-78.
No Effect
Reduced Efficacy• Immune complexes – accelerated drug clearance• Neutralizing antibodies blocking binding site of biologics
Effects on Safety• Hypersensitivity reactions: infusion reactions, ISRs, serum sickness• Rare thromboembolic events
Formation of immune complexes• Alter clearance by RES and/or impaired binding to target• Accelerated clearance of mAb–ADAb complexes can result in reduced serum concentrations and activity
What have we Learned from Enzyme Replacement Therapy?
9
Lessons from Enzyme Replacement Therapy [ERT]
Factors VIII and IX deficiency: “cross reactive immunologic material” [CRIM] determines degree of immunogenicity
Most patients make some factor VIII protein, although non-functional, presumably known to immune system; thus self-tolerance established
Wang et al: Nature Biotech 2008; 26:901--8
Lessons from Enzyme Replacement Therapy [ERT]
• Immunologic tolerance to an endogenous enzyme more strongly associated with level of protein, whether mutated and/or non-functional than bioactivity
• Protocols designed to induce “tolerance”
– CRIM positive factor VIII deficiency or Gaucher’s Ds:
• High doses [Bonn protocol]: induction of tolerance? May be 2°to epitope spreading
• Use of concomitant immunosuppressives: cyclophosphamide, IVIg, extracoporealimmunoadsorption [Malmo protocol]; MTX, MMF
– CRIM negative severe factor IX deficiency or Pompe’s Ds:
• Such protocols have been shown to induce nephrotic syndrome resulting from renal deposition of Ag-ADAb immune complexes
• Concomitant administration of rituximab, aBAFF mAbs, bortezomib [targeting long lived plasma cells] or ipilimumab [aCTLA-4] also tried
Wang et al: Nature Biotech 2008; 26:901–8; Bali et al: Am J Med Genetics 2012; 160C:40–49
Use of Immunosuppressives to Facilitate ERT: murine models
Fabry [agalactosidase KO] mice: MTX reduced r-haGAL-specific serum Ab levels; not effective in dampening robust ongoing Ab responses 1
Pompe [acid aglucosidase KO] mice: evaluated MMF, MTX, CsA/AZA 2
• MTX only antiproliferative that reduced specific Ab responses
• Required administration of MTX within 1st 24 hours of ERT Rx
• Inhibited expansion of peritoneal B1 B cells within 1st 24 hours of Rx
Use of rabbit anti thymocyte globulin [ATG] to Rx transplant rejection 3
– Induces anti-rabbit Ab responses which limit readministration
– mATG in murine cardiac allotransplantation model
– Single course of MTX at time of 1st ATG Rx most effective
– >99% reduction in anti-ATG Ab titers; Reduced alloAbs
– Improved allograft survival: >100 days vs either alone: <30 days
121. Garman et al: Clin Exp Immunol 2004; 137:496–502; 2. Joseph A et al: Clin Exp Immunol 2008; 152:138–146; 3. Joseph A et al: J Immunol 2012; 189:734-43
What About Pegloticase: Pegylated Uricase?
13
Immunogenicity with Pegloticase [PEGL]
169 patients in 2 combined 6 month phase 3 RCTs: 1
• 58% developed high titer aPEG Abs; 40% aPEGL Abs; 14% auricase Abs
• In those w/ persistent responses ≈ 42%: mean aPEGL titers: 1:837 ± 1687 vs non-responders: 1:34,528 ± 42,228
• Loss of sUA response preceded infusion reactions in 56 [79%]
• Pre-infusion sUA can be used as a surrogate for presence of aPEGL Abs with recommended dosing interval every 2 weeks
30 patients receiving up to 5 infusions q 3 weeks: 2
• 17 persistent responders [PR]; 12 transient [TR] and 1 no response [NR}
• All TR and NR: loss of response accompanied by aPEGL Abs; 50% pre-existing
• 11 of 12 TR: plasma uricase activity fell rapidly, sUA ≥6.0 before dose 2
• All PR and 6/7 organ Tx recipients: no sustained aPEGL Ab responses
OLE in 8 pts: rec’d MTX 15mg/wk 1 month prior to and continued w/ PEGL; 3 rec’d 12; 4 rec’d 8 infusions: 3
100% maintained sUA <6.0 >80% determinations141. Lipsky P et al: ART 2014: 16:R60 doi:10.1186/ar4497; 2. Hershfield MS et al: ART 2014, 16:R63 doi:10.1186/ar4500 3. Botson J & Peterson J: ACR2018 #1286
Agenda
Many pathways influence the bioavailability of biologics – immunogenicity is a part of the picture
All TNF inhibitors are immunogenic
How does MTX impact the bioavailability of TNFis?
Most tests for ADAbs only capture a fraction of the “truth”
Immunogenicity and Treatment Survival – clinical practice implications
Infliximab (INF): a Chimeric Monoclonal Antibody – Summary of Literature
• Presence of ADAbs to INF generally associated with1
– Reduced serum INF concentrations
– Decreased clinical responses to INF
– Greater risk of infusion reactions
• Identified patient factors that impact INF exposure2,3
– BMI
– Albumin levels – esp in IBD
– ADAbs: vs. murine portion: cdrs of mAbs
• IgG, IgA, IgM;
• IgE NOT assoc with infusion Rxnsbased on recombinant IgE aINF mAb4
– Disease activity/severity
– Less in SpA even in absence of background Rx5
1. Vincent FB, et al. Ann Rheum Dis. 2013;72:165–178. 2. Fasanmade AA, et al. Eur J Clin Pharmacol. 2009;65:1211. 3. Xu Z, et al. American College of Clinical Pharmacology; September 23-25, 2012; San Diego, CA 4. van Schie KA et al ARD 2017 doi:10.1136/annrheumdis-2016-211035; 5. Braun J, et al. ACR 2014, #L21
These observations were similar across indications; less ADAb+ in SpA
ADAbs
Decrease in drug levels
or binding capacity
Decrease in efficacy
Atypical clearance
mechanisms
Infusion reactions
Frequency of ADAbs to Infliximab Across Disease Indications
•
• ADAb formation is lower in RA patients receiving higher dosages of infliximab– 10 mg/kg dose associated with less antibody formation vs. 3 or 1 mg/kg– Induction regimens commonly utilized
• Concomitant methotrexate (MTX), AZA, 6-MP, LEF reduce risk of ADAb formation
Disease EMA SmPCFrequency of
ADAb Formation (%)Association w/
Serum Drug Levels Clinical Relevance
RAMean: 14%Mono: 24%Combo: 8%
10–50 Inversely correlated ADAb associated with lower clinical responses and
infusion reactions
AS/PsA
PsA Mean: 15%Mono: 26%Combo: 4%
15.4–29 Inversely correlated Decreased clinical responses and infusion rxns
CDMean: 3.3%
Mono: 13.3%5.9–61 Inversely correlated Loss of initial responses; Infusion rxns
Ps0 Mono: 28% 19.7–51.5 Not reported Decreased clinical responses; infusion rxns
RASpA
w/ MTXMono
40-48% v CT-P13 1
21-25% v CT-P13 2Inversely correlated Decreased clinical responses; infusion rxns
Remicade Package insert. Vincent FB, et al. ARD 2013;72:165–178; 1. Park ARD 2013; 2013 72: 1605-1612; ARD 2015; doi:10.1136/annrheumdis- 2015-2087832. Yoo ARD 2013;72:1613-1620; ARD 2015; doi:10.1136/annrheumdis-2015-208786; Ruiz-Arguello et al: ARD 2015; doi:10.1136/annrheumdis-2015-208684
Patients with Lower INF levels had Lower Clinical Responses in RA Associated with ADAbs
Mean serum trough levels of INF at 8 weeks after administration of 3 mg/kg INF were significantly lower in ADAb+ patients than AdAb- (0.2 mg/l vs. 1.5 mg/l, p<0.001)
Wolbink GJ, et al. A+R. 2006;54:711–715
EULAR Response in Presence/Absence of ADAbs
ADAb Titres in Responders vs. Non-responders to INF Therapy
No ADAbs ADAb+
Nu
mb
er o
f p
atie
nts
5
15
20
10
25
30 Non-responder
Responder
Responders Non-responders
An
ti-i
nfl
ixim
ab a
u/m
l
10
100
1000
10000
100000
1
Fewer ADAb+ patients were responders
INF Trough Concentrations Correlate with Mucosal Healing in CD
5.77
3.89
0.95
p=0.013
Moerkercke WV, et al DDW 2010. Oral 405
Lines represent median;Bars represent interquartile range
N=210 subjects with INF trough levels measured 2-6 weeks after dosing
ADAbs to Infliximab can Result in Infusion Reactions in RA and SpA
Pascual-Salcedo D et al. Rheumatology 2011;50:1445-52Plasencia C, et al. Ann Rheum Dis. 2012;71:1955-60; ibid EULAR 2014: SAT0331 20
• Patients with infusion reactions:
• 9 (10.5%) in RA and 100% had ADAbs to INF
• 11 (12%) in SpA and 73% had ADAbs to INF
10000
80000
0
60000
40000
20000
RA SpA
HA
CA
Lev
els
(A
U/m
L)
300000
200000
100000
0
Infusion reactionsNo Yes
HA
CA
Lev
els
(A
U/m
L)
Infusion reactionsNo Yes
*
******
*
O O19
O11
Retrospective observational study in 162 SpA patients; 85 [52.5%] on INF• 21 [24.7%] ADAb+; 3 [1.8%] on MTX; 28 [24.7%] without MTX• No difference by MTX dose
Anti-ID ADAb Complexes have Restricted Immune Activation Capacity
• Large, irregularly shaped complexes only form at high concentrations of drug and ADAbs, such as IV infusions of INF
HP-SECTEM
aINF ADAbs mixed w/ INF: HP-SEC• % dimers (red box) and complexes bigger than tetramers (blue box)
determined by dividing AUC of these complexes by total AUC• % specified complexes correlated to aINF IgG titer for each patient
(n=41) • Spearman’s r for >tetramers: r=0.687, p<0.0001
and for dimers: r=−0.6676, p<0.0001• Pt w/ highest ADAb titer had no infusion reaction
van Schie KA,et al. ARD doi:10.1136/annrheumdis-2018-213299
Anti-ID ADAb Complexes have Restricted Immune Activation Capacity
• Large, irregularly shaped complexes only form at high concentrations of drug and ADAbs, such as IV infusions of INF
– After infusion, high peak concentrations in serum approx. 100–150 μg/mL achieved, corresponding to roughly 1% total serum IgG leading to rapid formation of soluble IgG complexes
– Different propensities of each ADAb clone to form dimers, tetramers, hexamers and larger complexes, highly dependent on ADAb/drug concentrations
– Large ICs preferentially, rapidly cleared in vivo; binding to FcγRs increases with complex size; ICs >dimers efficiently internalized by macrophages, leaving only dimers circulating
– aID Abs don’t activate immune cells; little proinflammatory capacity
– Large disorganized complexes >hexamers activate complement; IRs represent type III rather than type I IgE hypersensitivity RxnsICs >1000 kDa (>6 Abs) were detected in 1 patient who developed a severe IR, tentatively relating IC size to an AE
van Schie KA,et al. ARD doi:10.1136/annrheumdis-2018-213299
ADAbs and Fully Human mAb [Phage substitution]: Adalimumab: Summary of Literature
• Presence of ADAbs against adalimumab can be associated with: 1
– Low or undetectable serum trough drug levels
– Reduced clinical response
– ? Relationship to rare thromboembolic events
• Identified patient factors that impact adalimumab exposure 3,4
– BMI
– Albumin levels – esp in IBD
– ADAbs: bind to 3 aa’s adjacent to epitope binding site
• Predominantly IgG1 and IgG4
• Neutralizing
• Predominantly monomers, dimers
– Disease activity/severity
1. Vincent FB et al. ARD. 2013;72:165–178. 2. Korswagen LA, et al. A+R. 2011; 63:877–883. 3. Noertersheuser P et al. P493 Presented at ECCO 2012. 4. Jani M et al: A+R 2015; DOI 10.1002/art.39169
These observations were similar across indications
ADAbs
Decrease in drug levels or binding capacity
Decrease in efficacy
Atypical clearance mechanisms
Presence and Impact of ADAbs to Adalimumab Across Indications
• Concomitant MTX increases ADA bioavailability and lower ADAbs in RA and CD• ADAbs not associated with AEs, with exception of single publication reporting rare thromboembolic events
Vincent FB, et al. ARD. 2013 Feb;72:165–178. HUMIRA package insert. Korswagen LA, et al. A+R. 2011;63:877–83. 1. Cohen SB, et al. ACR 2015 #2054; 2.Matsumoto A, et al. ACR 2015 #2757; 3. Strober B, et al. AAD2016; #2957; 4. Gooderham M et al. AAD2016; #2961
Disease SmPCFrequency of
ADAb Formation (%)Association with Serum Drug
Levels Clinical Relevance
RAMean: 5.5%
Mono: 12.4%/Combo: 0.6%
0.72–87 Negatively associated Lower clinical response
AS/PsA
PsA Mean: 10%Mono: 13.5%/Combo: 7%
AS: Mean: 8.3%Mono: 8.6%/Combo: 5.3%
18–31 Negatively associated Lower clinical response
CD 2.6% 0.04–17 Negatively associated Lower clinical response
PsOMono Rx: 8.4%;
ReRx 2.3%6–45 Negatively associated Lower clinical response
RAPs
w/ MTXMono Rx
38.2% v ABP-501 1,2
61.9% v ABP-501 3,4
NAbs: 11.1%NAbs: 13.1%
Lower clinical response
ADAbs to ADA and ADA Biosimilar [ABP-501] in RA vs Psoriasis
• Based on RCTs in RA and PsO w/ADA Biosimilar ABP-501; Post-hoc analysis of ADAbs
• Background MTX in RA, none in PsO
ABP-501 RA
(n=264)
ADA RA
(n=262)
ABP-501 PsO
(n=174)
ADA PsO
(n=173)
Week 16 55.2 63.6
Week 26 31.8 35.1
Week 32 50 57
Week 52 68.4 74.7
ADAb+ ever 38.3 38.2 64 75
Neutralizing Abs 9.1 11.1 13.8 20.3
Percentage of patients with ADAbs
1. Cohen SB, et al. ACR 2015 #2054 2. Matsumoto A, et al. ACR 2015 #2757; 3. Strober B, et al. AAD2016; #2957; 4. Gooderham M et al. AAD2016; #2961
More ADAbs evident in PsO than RA, without use of background MTX in PsO
Clinical Relevance of Measured Anti ADA ADAbs
• Prospective cohort: 272 consecutive RA patients Rxed with ADA over 2004–2008; follow-up thru 2010, 3 years; Dutch rheum centers, Amsterdam
– ADAbs by RIA; trough ADA levels by ELISA; 76 [28%] became ADAb+ after 3 years
– ADAb levels may fall but increase again later; indicating “tolerance”?
• 53 of 99 [55%] patients produced ADAbs over 2–3 years treatment
– 94% within 1st 28 weeks of therapy: IgG1 and IgG4
– ADAb responses highly restricted; bind to overlapping epitopes of TNF binding site; all are neutralizing
– Only high levels lead to ADA levels and clinical responses
– Many have complexed ADAbs, present as small IC’s: IgG dimers
– ? Link to rare occurrence of thromboembolic events ?3 patients: 2 w/ RA, 1 PsA 2
• In 76/252 with ADAbs 4 such events: HR 7.6 [1.3 – 45.1] p=0.025
Clinical relevance of measuring ADAbs limited; of questionable predictive value; ADAb+ patients more commonly discontinued Rx due to lack of efficacy
1. Bartelds GM, et al. ARD. 2010;69:817–821. 2. Korswagen. A+R. 2011;63:877–883. 3. Van Schouwenburg, et al. ARD. 2013;72:104–109. 4. ARD. 2013;72:1680–6.
ADAbs Can Impact Clinical Responses in RA
Not all patients who developed ADAbs had loss of response
• 11.4% of all treated patients discontinued adalimumab due to ADAbs
• 81% on MTX +/- other DMARDs
• 38% ADAb+ patients discontinued treatment due to treatment failure
• 14% ADAb- patients discontinued treatment due to treatment failure
• Median ADA levels: 4.1 ug/ml w/ monotherapy; 7.4 ug/ml w/ MTX
Bartelds GM, et al. JAMA. 2011;305:1460–1468; Pouw MF et al: ARD 2015; 74:513–18
Dropout Due to Treatment Failure
18%21%
23%26%
Adalimumab Levels and ADAbs Impact Clinical Responses in RA
• ADAb− patients had higher response rates; higher adalimumab concentrations vs. ADAb+
• However, some ADAb+ patients retained clinical responses with measurable drug levels
N=272
1964531
No. at riskWithout ADAb
ADAb 13-100 AU/mlADAb >100 AU/ml
1513623
1352716
1181910
Sustained Minimal Disease Activity(DAS28 <3.2)
Pro
po
rtio
n o
f p
atie
nts
0
0.6
0.2
0
0.4
0.8
50 100 150
Weeks
ADAb titre 13-100 AU/mL
Without ADAb
ADAb titre >100 AU/mL
Bartelds GM, et al. JAMA. 2011;305:1460–8.
WeekNo. of patientsWithout ADAb
ADAb 13-100 AU/mlADAb >100 AU/ml
4
1874331
Med
ian
ad
alim
um
abco
nce
ntr
atio
n, m
g/L
0
10
12
2
480
4
6
84 150
Weeks
12 24 96 108726036 156144120
6
14
0
1964531
16
1774228
28
1643727
40
1453422
52
1393419
78
1312816
104
1182414
130
1071911
156
9317
8
Without ADAbsADAb titre 13-100 AU/mLADAb titre >100 AU/mL
High ADAb titers correlate with low clinical responses and ADA levels
Concentration, Immunogenicity of Adalimumab in PsA
• Objectives: Correlate trough serum ADA concentrations, clinical response in PsA, effect of background MTX
• Methods: – 103 consecutive PsA pts, ADA 40 mg sc qow– 28 wk trough ADA levels measured by ELISA– Clinical response: ΔDAS28
• Results: – 28 wk median serum trough concentration: 7.2
(range 0.0–18.8) mg/L– ADA concentrations 5–8 mg/L optimal, as in RA
• 36 (35%) w/ concentrations <5 mg/L; 58% ADAb+• 48 (47%) >8 mg/L; some low titer or intermittently ADAb+
– ADAb+: 23 (22%); 12 on MTX, 11 on monoRx– 1.3 mg/L [0-3.2 IQR] v ADAb- 8.7 mg/L [5.7-11.1]– 0.7 mg/L [0-2.9] monoRx v 8.4 mg/L [5.7-12.1] MTX– ADAb- pts had lower DAS scores at wks 28, 52
ADA concentrations of 5–8 mg/L achieve optimal clinical benefit in RA and PsA
Vogelzang E,et al. ARD 2014; 0:1–5. doi:10.1136-annrheumdis-2014-eular.3618; Pouw MF et al: ARD 2015; 74:513–18
-0.5
1.0
04 8 1612
-1.0
-1.5
0.5
1.5
2 6 10 14
ADA concentration mg/L
ΔD
AS
28
-2.0
-2.5
-3.0
-3.5
-4.0
DAS28 over time ADAb-ADAb+
4.5
00 4
DA
S2
8
Time (weeks)
4.03.53.0
2.5
2.01.51.00.5
16 28 40 52
2.95
2.16
2.95
2.19
Effect of MTX/DMARDs on ADAb Formation in RA vs PsA
2 series of consecutively treated RA [n=272] 1 and PsA pts [n=103] 2 receiving ADA in Dutch rheumatology centers
• Monotherapy: RA: 51, PsA: 16
• Conc MTX: 202 /77
• MTX+other DMARDs: 55 /3
• Other DMARDs: 19 /7
ADAb+: RA: 76/272 (28%) / PsA: 23/103 (22%)
• MonoRx: 28 (37%) /11 (48%)
• Conc MTX: 49 (63%) /10 (50%) [MTX+other DMARD: 8 (11%) /0]
• Other DMARDs: 7 (9%) /2 (2%)
RA: 41/202 [20%] vs 28/51 [55%] monoRxPsA: 12/80 [15%] rec’g MTX vs 11/16 [69%] monoRx
1. Bartelds et al. JAMA 2011;305:1460–8; 2. Vogelzang et al. ARD 2014; 0:1–5. doi:10.1136 ARD 2015; 74:474; 3. Behrens F et al Rheumatol doi:10.1093/rheumatology/keu415
.
Median ADA concentration (LOCF) and DMARD use
2
4
6
8
00 4 16 28
Me
dia
n A
DA
co
nc
(mg
/L)
weeks
MTX + other DMARDs (n=58) p<0.001
Other DMARDs (n=26) p=0.011 Monotherapy (n=67)
MTX (n=224) p<0.001
Apparent benefit of MTX maintaining ADA blood levels and decreasing ADAb formation in PsA as in RA
Adalimumab Trough Levels and Induction Regimens in CD
• Median serum concentrations significantly higher in patients in remission vs those not in remission (p <0.05) at week 4 of CLASSIC I / II, week 24 of CLASSIC II, but not week 56 of CLASSIC II (p=0.34) 1
• Considerable overlap of serum concentrations at all time points.
• A threshold serum adalimumab concentration that discriminated between remission status could not be identified.
• Comparison of 160/80mg induction regimen in EXTEND [n=70] vs 80/40mg in CHARM [n=336]: 2
• Greater % time in remission, wks 0 – 52: 36 vs 25%, p<.05 [NRI]
• After multivariate adjustment, OR: 4.8, p<.001 for remission wks 0 – 52
• Fewer CD related hospitalizations per patient: 0.7 vs 0.18, p<.05 [NRI]
• Comparable safety profile
• In a US specialty pharmacy study. Pts receiving 160/80mg induction regimen half as likely to move to weeklytherapy: 9.9 vs 19.6% over 12 months 3
1. Chiu et al. Inflamm Bowel Dis. 2013; 19:1112-22; 2. Colombel et al: ECCO Dublin 2011; P182 3. Loftus EV et al: J Crohns and Colitis 2011; 5: 550–4;
ADAbs and Fully Human mAb [Homologous Recombination]: Golimumab: Summary of Literature
• GOL produced using homologous recombination: FULLY human
• Presence of ADAbs against golimumab can be associated with1-7
– Low or undetectable serum trough drug levels
– Reduced clinical responses
• Data available from a single small prospective observational study 8
• Lower trough GOL levels associated with 8
– Lower clinical responses
1. Kay J et al: A+R 2008; 58:964-75; 2.Inman R et al A+R 2008; 58:3402-12; 3. Kavanaugh A et al A+R 2009; 60:976-86; 4. Kremer J et al: A+R 2010; 62: 917-28; 5. Kavanaugh A et al A+R 2012; 64:2504-17; 6. Emery P et al AC&R 2013; 65:1732-42; 7. Weinblatt ME et al ARD 2012). doi:10.1136/annrheumdis-2012-201411 8.
Kneepkens E et al ARD 2014; 0:1–3. doi:10.1136/annrheumdis-2014-205983
These observations were similar across indications
ADAbs
Decrease in drug levels or binding capacity
Decrease in efficacy
Atypical clearance mechanisms
Frequency and Impact of ADAbs to GOL in Various Diseases
• Immunogenicity less with IV than SQ administration
• Serum levels of GOL are affected by concomitant MTX
• ADAbs to GOL appear not to be associated with adverse events other than ISRs
Kay J et al: A+R 2008; 58:964-75; Inman R et al A+R 2008; 58:3402-12; Kavanaugh A et al A+R 2009; 60:976-86; Kremer J et al: A+R 2010; 62: 917-28; Kavanaugh A et al A+R 2012; 64:2504-17; Emery P et al AC&R 2013; 65:1732-42; Weinblatt ME et al ARD 2012). doi:10.1136/annrheumdis-2012-201411; Kneepkens E et al
ARD 2014;0:1–3. doi:10.1136/annrheumdis-2014-205983.
Disease SmPCFrequency of
ADAb Formation (%)Association with
Serum Drug Levels Clinical Relevance
RA4%
SQ: Mono: 9.2%/Combo: 5.5%IV: Mono: 9%/Combo: 3%
4%Negative
AssociationLow drug levels associated with lower
clinical responses
AS/PsAPsA 4.9%
AS 2.2 – 4.6%2.2 – 4.9%
Negative Association
Low drug levels associated with lower clinical responses in PsA
ADAbs and Soluble Receptor Construct: Etanercept: Summary of Literature
• ETN ADAbs are non-neutralising and generally associated with: 1
– Impact on trough serum drug levels
– Impact on clinical responses 1,2
– Injection site reactions; rarely serum sickness due to anti-Fc Abs [Example: Lenercept]
• Low trough ETN levels associated with ADAbs 2-4,8
– Lower clinical response
• Identified patient factors that impact ETN exposure 5-7
– BMI
– Age
– Gender
1. Zeltzer et al. Arch Derm. 2001;137:893–9. 2. Vincent FB et al. ARD 2013;72:165–78. 3. Dore RK et al. Clin Exp Rheum 2007; 25:40–6. 4. Jamnitski A et al. ARD 2012; 71:88–91. 5. Daien CI et al. J Rheum 2012; 39:1533–8. 6. Lee H et al Clin Pharm Ther 2003; 73:348–65 7. Zhou SY et al. J Clin Pharm. 2011; 51:864–75. 8. Jani
M et al: A+R 2015; DOI10.1002/art.39169
These observations were similar across indications
ADAbs
Decrease in drug levels or binding capacity
Decrease in efficacy
Atypical clearance mechanisms
Frequency and Impact of ADAbs to ETN in Various Diseases
• Lower drug levels associated with higher disease activity in RA, SpA and PsA
• Serum levels of etanercept appear to be affected by concomitant use of MTX
– No effect of MTX dose in TEMPO and COMET 7
• ADAbs to ETN not associated with adverse events other than ISRs – although at least 1 case of serum sickness reported as well as many reports of vasculitis
1.Vincent FB et al. ARD 2013 Feb;72:165–178; 2. Jamnitski A et al. ARD 2012;71:88–91; 3. Daien CI et al. J Rheum 2012; 39:1533–8; 4. Plascencia C et al. EULAR FRI0168; 5. Kneepkens E et al. ARD 2015;74:1825–9; 6. Gallo G et al: RMD Open 2016;2: e000186. doi:10.1136/rmdopen-2015-000186; 7. Emery P at al: ARD
2017; 76:51-7; 8. Emery P et al: ARD 2017; doi:10.1136/annrheumdis-2017-211591
Disease SmPCFrequency of
ADAb Formation (%)Association w/
Serum Drug Levels Clinical Relevance
RA 6%–7% 0–5.6 Not reported Low drug levels associated with lower clinical response
AS/PsAPsA 7.5%
AS 2%0 Not reported Low drug levels associated with lower clinical response in AS
RA w/MTX
Wk 52: 14.3% v 2.4% SB47
Wk 100: 15.1% v 3.2% SB48 ISRs; no cases of anaphylaxis; no ISRs wks 52—100
Summary
• All TNFis are associated with certain immunogenicity profiles
• Differences in immunogenicity profiles are based on structure, frequency of ADAb formation and observed associations with efficacy
• Patients treated with all TNFIs show variable serum drug levels, in part influenced by immunogenicity but also other factors
– IV administration and immunogenicity dominate PK of INF
– SQ administration: can sort out differing effects of background Rx and ADAbs on serum levels
• Serum drug levels can be associated with observed efficacy
Agenda
Many pathways influence the bioavailability of biologics – immunogenicity is a part of the picture
All TNF inhibitors are immunogenic
How does MTX impact the bioavailability of TNFis?
Most tests for ADAbs only capture a fraction of the “truth”
Immunogenicity and Treatment Survival – clinical practice implications
What Explains the Effect Between MTX and Biologic Agents?
• Exact mechanism MTX impacts PK of biologics is not fully known, evidence for:
– Antiproliferative effects: Prevention of ADAbs
– Impact on clearance of biologic agents
• e.g., via expression of FcϒR on monocytes
• Modulation of interaction between mAb and FcϒR
Inhibition of DHFR
Induction of apoptosis of in vitro activated T lymphocytes
IgG, IgA, IgM production
Circulating RF levels in vitro
AICAR adenosineIn vitro prostaglandin E2 release and peroxide productionNeutrophil chemotaxisAngiogenesisLevels of metalloproteinases
IL-1 activityIL-6, IL-8 levelsIL-4 i IL-10 gene expression in vitro IL-1ra and sTNFrproduction
Anti-inflammatoryImmunomodulatory
Cytostatic Apoptosis
Cytokines
Bunescu A, et al. J Rheum. 2004;31:2347–2355. Joseph A. Clin Exp Immunol. 2008;152:138–146. Mould DR & Green B.BioDrugs. 2010;24:23–39. Tabrizi MA, et al Drug Discov Today. 2006;11:81–88. Swierkot J, et al. Pharmacol Rep 2006;58:473–492.
Background Therapy and Development of ADAbs
Patients on combination therapy had less immunogenicity than those who received monotherapy (68% less chance, 69% for MTX)
• Analysis not done for AZA due to limited data• 18 studies included, most with INF, only 2 each with ADA and CZP
Concomitant treatment influence in development of ADAbs
• A higher chance was observed in RA (85%), less with SpA(48%)
• No difference observed with concomitant use of steroids.
Maneiro JR et al. JAMA Intern Med. 2013;():1-13. doi:10.1001/jamainternmed.2013.7430
MTX Reduces Formation of ADAbs in a Dose-dependent Manner
• Observed in patients with RA, PsA, Ps and CD
• Reported with INF, ADA, GOL and CZP
• Associations between use of MTX and ETN ADAbs are unclear in RA
• Patients who produce ADAbs have higher disease activity at baseline
Percentages of RA patients developing ADAbs per baseline MTX dose group
Krieckaert CL et al. ARD 2012;71:1914–15. Van Schouwenburg et al: ARD 2013;72:104–9; ARD 2013;72:1680-6
%
0
40
10
560
20
84 140Time (weeks)
14 28 112847043 154126
30
60
No MTX50
Low dose MTX (5-10 mg/week)
Intermediate dose MTX (12.5-20 mg/week)
High dose MTX (≥22.5 mg/week)
Impact of Loading Dose and MTX on Immunogenicity to F(ab’) PEG construct: Certolizumab Pegol
• 2 RCTs: J-RAPID: CZP+MTX and HIKARI: CZP monotherapy
• Comparison of active Rx pts receiving loading dose [LD] vs placebo pts rescued at 16 or 24 wks without LD
• LD → rapid onset of efficacy, sustained responses, less immunogenicity
• BRAGGS [UK]: ADAbs 42/112 (37%) at 12 mos: lower drug levels but not efficacy2
Additional benefit of loading dose as well as background therapy in mitigating immunogenicity; but no effect of MTX dose on efficacy in Phase 3 RCTs 3
Pts w/ anti-CZP Abs at any time during 24 weeks: 1
1. Takeuichi T, et al. ACR 2013, San Diego, #2322; 2. Jani M et al. ARD 2016;0:1–6. doi:10.1136/annrheumdis-2015-208849; 3. Combe B et al: AC&R 2016: 68: 299–307
J-RAPID HIKARI
All patients Anti-CZP Ab+ patients All patients Anti-CZP Ab+ patients
N N % N N %
Loading Dose 82 1 1.2 116 18 15.5
No Loading Dose
61 3 4.9 99 27 27.3
Summary
• Concomitant MTX [and other antiproliferative agents] have been shown associated with higherbioavailability (serum levels) of TNFis and other anti-cytokine mAbs with Fcg portions
− Due to inhibition of FcgR mediated clearance mechanisms
• Higher biologic serum concentrations are associated with better efficacy
• Concomitant MTX [and other anti-proliferative agents] are associated with lower rates of ADAbformation− Presumably due to their reversible effects on proliferation of activated lymphocytes− This effect is evident even with low doses
Agenda
Many pathways influence the bioavailability of biologics – immunogenicity is a part of the picture
All TNF inhibitors are immunogenic
How does MTX impact the bioavailability of TNFis?
Most tests for ADAbs only capture a fraction of the “truth”
Immunogenicity and Treatment Survival – clinical practice implications
Issues Regarding ADAb Testing and Measurement of Serum Levels
• Assays vary in capacity to detect specific idiotypes and subclasses of ADAbs
• Results cannot be compared across assays, trials or labs
• Lack of evidence supporting current decision trees according to the presence of ADAbs in routine care w/ exception of IBD
• Cost of assays
• Central lab
• High variability across assays as well as individual patients
• No established therapeutic window for biologic agents for use in routine practice
• Feasibility in clinical practice for timing collection at trough serum levels
FDA. Guidance for industry assay development for immunogenicity testing of therapeutic proteins. Available at: http://www.fda.gov/downloads/Drugs/.../Guidances/UCM192750.pdf. Krieckaert C, et al. Curr Opin Rheum.2012;24:306-11
Most Commercially Available Assays are Limited in their Measurement Capabilities and thus not Comparable
• Bridging ELISA
• Radioimmunoassay (RIA)
• Antigen Binding Test
• Electro-chemiluminescence Immunoassay (ECLIA)
Only measure ADAbs at trough levels
–Lower sensitivity
assays
• pH-shift anti-idiotype antigen binding (PIA) followed by ECLIA
• Fluid-phase mobility shift followed by ECLIA
Measure ADAbs in presence of biologic
agents [mAbs] in serum – higher
sensitivity assays
Antidrug antibodies (ADAbs): Results with different assays
• Measured ADAbs to ADA in 84 AS pts
• Assays: Sandwich ELISAABT – radioimmunoassayARIA – acid-dissociation-radioimmunoassay
• Drug levels [ADA] measured
– Pts negative by ADAb or + only by ARIA
• [ADA] ~9.5 mg/L (5.3–13.3); not different
– Patients ADAb+ on both ARIA and ABT
• [ADA] ~2.8 mg/L (0.9–4.3)
– Patients ADAb+ by all 3 assays
• [ADA] – undetectable
– Different assays detect ADAbs differently – likely due to sensitivity differences
Ruward J, et al. EULAR 2017, Madrid, OP0025.
Cumulative % ADAb+ by assay type at 4, 12, 24 weeks
Cu
mu
lati
ve %
AD
Ab
+
Weeks of treatment
Sandwich ELISA ABT ARIA
80
12
100
0
60
20
4 24
40
Assays: Electrochemiluminescence is the Current Industry Standard, Particularly After Acid Dissociation
Acidic washAcid
neutralized
Ru-labeled antibody
Therapeutic mAb
Y ADAb
Soluble IL-6R
Acidic washAcid
neutralized
Wadhwa M et al. Biologicals. 2015;43:298-306
Monoclonal Antibody Evolution1,2
1. Catapuno AL and Papadopoulos N. Atherosclerosis. 2013;228:18-28. 2. Foltz I et al. Circulation. 2013;127:2222-30.
Imm
un
og
en
icit
y
Fully Mouse
1st generation
Chimeric
2nd generation
Humanized
3rd generation
“Fully” Human
4th generation
Highly immunogenic
Still immunogenic
Can be time-consuming to create
Least immunogenic
eg,infliximab and rituximab
eg, tocilizumab
eg, golimumab, sarilumab, secukinumab
eg, ibritumomabMouse variable
Mouse constant
Human variable
Human constant
Sarilumab Was Developed Using VelocImmune® Technology1,2
1. Data on file. Sanofi-Genzyme and Regeneron Pharmaceuticals; 2015. 2. Sanofi and Regeneron Press Release. May 15, 2013.
MONARCH: ADAb Seropositivity of Sarilumab Monotherapy
n (%) patientsSarilumab 200 mg Q2W
n=184
Treatment-emergent ADAb* 13 (7.1%)
Median titer (range) 30 (30, 120)
Neutralizing 0
Persistent† 5 (2.7%)
ADAb +n=13
ADAb −n=171
Change from baseline in DAS -3.49 -3.34Patients with DAS remission 23% 27%Discontinued for lack of efficacy 0 1.2%
Hypersensitivity reactions 3Dermatitis x2, rash
7Allergic dermatitis, hypersensitivity, pruritic rash, allergic rhinitis, urticaria
*Reduced ADAb analysis time points: BL, Week 12, Week 24, EOT/EOS samples. If positive at Wk12 also test Wk2 and 4 For AE of interest, test ADAb sample prior to event: 2 or more consecutive timepoints over 16 weeks or last value positive. All persistent ADAbs in MONARCH were positive only at the last time point.
Data on file. Sanofi-Genzyme.
Agenda
Many pathways influence the bioavailability of biologics – immunogenicity is a part of the picture
All TNF inhibitors are immunogenic
How does MTX impact the bioavailability of TNFis?
Most tests for ADAbs only capture a fraction of the “truth”
Immunogenicity and Treatment Survival – clinical practice implications
TNF Inhibitor Switching Studies
3 open label series:
• RESTART: 203 pts failing ETN or adalimumab switched to INF: 1
• Of 40% and 47% w/ ADAbs, 12 developed ADAbs to INF; not cross-reactive
• 235 pts failing INF switched to adalimumab: 2
• ADAb+ switchers developed ADAbs to ADA (27 versus 18%, p=0.039)
• Δ DAS28 for ADAb+ switchers did not significantly differ from TNFi naïve
• Δ DAS28 greater for TNFi naive than for switchers without ADAbs
• 89 switched from ADA or INF to ETN vs 203 TNFi naïve: 3
• Responses did not differ between TNFi naive and 53% ADAb+ switchers
• Responses greater for TNFi naïve than for ADAb- switchers
SUMMARY:
– More ADAb+ patients will develop ADAbs to 2nd or 3rd TNFi; but they are NOT cross reactive
– Many non-responders have no evidence of immunogenicity
1. Pool C et al. ACR 2012 Poster #1286; 2. Bartelds GM et al. Ann Rheum Dis 2010; 69:817–21; 3. Jamnitski A et al ARD 2011; 70:284–8; 4. Vincent FB et al ARD 2013: 72:165-782.
What About Switching Class of Therapy? – Abatacept
• Ph 3b RCTs: Immunogenicity w/ SQ administration
– ACQUIRE: SQ v IV: 8/725 (1.1%) v 16/710 (2.3%)
– ACCOMPANY: SQ ABA+MTX v ABA MonoRx:
• RCT: 2/51 (3.9%) v 2/49 (4.1%)
• LTE: 1/47 (2.1%) v 0/43
– ALLOW: Withdrawn: non-significant, transient increases in ADAbs that did not persist on Rx reintroduction
– ATTUNE: switch IV to SQ: 8 ADAb+ but continued Rx w/no sequelae; 6 ADAb+ before switch
– AMPLE: ABA v ADA: fewer ISRs, no D/Cs v 3 w/ ADA
Presence of ADAbs not associated w/ safety, infusion/ISRs nor loss of efficacy
Genovese MC et al A+R 2011; 63:2854-64; Nash P et al AC&R 2013; 65; 718-28; Schiff M: Rheumatol 2013:doi:10.1093/rheumatology/ket018
What About Switching Class of Therapy? – Tocilizumab
1. G jones, C Ding: Clin Med Ins: Arth MSK Dis 2010; 2:81–9; 2. Burmester et al ARD doi:10. 1136 annrheumdis -2013-203523; 3. Dougados M et al ARD 2013; 72:43-50; 4. Burmester G et al; ARD 2016; 0:1–8. doi:10.1136/annrheumdis-2016-210297
Conclusions: IV infusion reactions; 5 anaphylaxis events reported; 1 fatalSQ low incidence ADAbs even after interruption in dosing
n/% TCZ SQ (n=3099) TCZ IV (n=5875)
Anaphylaxis 0 10 (0.2)
Leading to withdrawal 31 (1.0) 91 (1.5)
Hypersensitivity Rxns -SAEs 10 (0.3) 51 (0.9)
ISRs / Infusion Rxns 2,3 310 (10.0) 24 (4.0) 2,3
ADAb+ Pts 47 (1.5) 69 (1.2)
+NAb 40 (1.3) 54 (0.9)
Anaphylaxis 9 (0.3) 5 (0.1)
Hypersensitivity Rxns -SAEs 0 6 (0.1)
ISRs 4 (0.1) N/A
DRESS Syndrome in a Pt w/ Adult Still’s Syndrome post TCZ
• DRESS: Drug Reaction with Eosinophilia and Systemic Sx
- 10 days p admin TCZ 8mg /kg monoRx: diffuse maculopapular rash
- Bx: lymphocytic and eosinophil infiltration perivascularly
- Eosinophil count: 2.3 x109 cells/L
- LFTs up to 6xULN
- Excluded infections and parasitic ds
- Resolved 5 wks p D/C TCZ
• Rash different than when Stills presented;no prior LFT ; sx had remitted prior to new rash
Zuelgaray E et al. Letter Ann Int Med 2017; doi:10.7326/L16-0592
What About Switching Class of Therapy? – Secukinumab
1. Deodar A et al: J Rheumatol 2019; DOI: 10.3899/jrheum.190116
PsA: FUTURE 1 ⎯ 3n=14145 (0.35%) ADAb+
AS: MEASURE 1 ⎯ 4n=11648 (0.69%) ADAb+
Immunogenic Portions of mAbs / Soluble Receptors
Summary 1
• ALL biologic products are immunogenic, including TNFi’s
– INF: chimeric; murine portions of F(ab’)2; IgG, IgA, IgM and IgE associated with IRs
– ADA: restricted to epitopes of TNF binding site; IgG1 and IgG4
– ETN: to linker portion, may include Fc portion; not neutralizaing
– No cross reactivity between ADAbs to different products
– Immunogenicity affected by: product, patient, treatment schedule
• Assays for immunogenicity/drug levels variable
– Methodology including detection of binding epitopes, Ig subclasses
– Lack of comparability/cost
– Commercial assays require trough levels of drug; feasibility in practice?
– No accepted therapeutic drug levels for routine practice
• Induction regimens decrease immunogenicity
• Intermittent Rx, extended drug free intervals increase immunogenicity
Clinical Relevance of PK and ADAbs:Should We Use for Monitoring Therapy in IBD?
• Loss of response to TNFi’s at 12 months – when judged by:
– Dose intensification occurs in 23–46% of patients
– Drug discontinuation, in 5–13% of patients 1
• Intermittent Rx or extended drug free intervals increase ADAbs 2
• Concomitant use of immunosuppressive agents reduce frequency of ADAbs
• More patients with sustained remission received background therapy
• IV Hydrocortisone reduced ADAb levels but did not eliminate them or infusion reactions 3
• Regular practice in Crohn’s Ds and Ulcerative Colitis:
– Induction regimens; regular not intermittent therapy
– Now adoption of background therapy
– Assays of ADAbs and drug levels when query loss of response
1. Ben-Horin&Chowers. Aliment Pharmacol Ther. 2011;33:987–995 2. Molnar, et al: J Gastroin Liver Dis. 2012;21:265–9. 3. Farrell, et al. Gastroent. 2003;124:917–24
IBD: Treatment Algorithm in Setting of “Loss of Response”
Recommendations to avoid immunogenicity:• Regular not intermittent Rx• Induction regimen• Use of background therapy Ordas I, et al. Clin Pharmacol Ther. 2012;91:635–46.
Summary 2
• Background therapy is beneficial for treatment survival
– Decreases immunogenicity
– Prolongs T ½ thru FcgR mediated clearance of cytokine binding mAbs
• Yet there are many non-responders for whom no evidence of immunogenicity demonstrated
• Dose intensification a matter of debate; RCTs have not demonstrated efficacy
• Standard of care in rheumatology today is based on assessment of disease activity, function and markers of disease progression
– Role for routine assessment of immunogenicity, drug levels in rheumatology clinical practice requires further assessment/confirmation
– However GI practice in IBD now includes use of all 3:
• Induction regimens,
• Background therapy and
• Routine monitoring of TDM