cases in biologic therapeutic drug monitoring › labcorp-d8 › 2020-03 › 56e...3. ordas, et al....

Cases in Biologic Therapeutic Drug MonitoringPresented by: Jane Yang, MD LabCorp Medical Science Director

June, 2019

2©2019 Laboratory Corporation of America® Holdings All rights reserved. 20942-0619

• 65 y/o female with 15-year history of seropositive RA. Treated for several years with DMARDs.

• Presented with persistent active inflammatory arthritis after failing traditional DMARDs.

• 3 years ago, started on adalimumab (40 mg q2 weeks). Disease activity responded favorably

• One a year ago, dosage reduced to 40 mg/3 weeks.

• Now, flaring again for last 6 months. DAS 5.8. Elevated ESR, positive CRP.

Case Study 1


Low drug, Intermediate Anti-Drug Antibodies (ADAbs)

Early Immunogenicity


No drug, Very high titer ADAbs

Late, refractory Immunogenicity


• 48 y/o male with 3-year history of RA. Treated with methotrexate and NSAIDs

• Now presents persistent bilateral symmetric pain in wrists, knees, ankles.

• Was started on adalimumab(40 mg q2 weeks)

• Now 6 months later, no change in DAS, still positive CRP, ESR, polyarthritis

Case Study 2


Low drug, No anti-drug antibodies

Pharmacokinetic Insufficiency


Pharmacokinetic Variability of Biologics

One Size Fits All does not work

Up to one third of patients may be subtherapeutic.

Male genderLarger body size (BMI)Low serum albuminHigh CRP High TNF or inflammatory burden Absence of immunomodulatorPresence of ADAbs

Standard dose or dosing by weight

1. Mulleman D, et al. Infliximab concentration monitoring improves the control of disease activity in RA Arthritis Research & Therapy 2009, 11:R1782. Pouw MR et al. Adalimumab trough level in blood corresponding with clinical response Ann Rheum Dis 2013 71: 3593. Laine J et al Cost-effectiveness of routine measuring of serum drug concentrations and anti-drug antibodies in treatment of rheumatoid arthritis patients with TnF-α blockers Biologics: Targets and Therapy 2016:10 67–73

• Multiple patient-specific factors determine optimal dose• Same patient’s need may change over time


High drug, No ADAbs

Pharmacodynamic Mismatch, non-TNF-driven disease


TDM is Key to Right Decision-Making

1. Mulleman D, et al. Infliximab concentration monitoring improves the control of disease activity in RA Arthritis Research & Therapy 2009, 11:R1782. Pouw MR et al. Adalimumab trough level in blood corresponding with clinical response Ann Rheum Dis 2013 71: 3593. Laine J et al Cost-effectiveness of routine measuring of serum drug concentrations and anti-drug antibodies in treatment of rheumatoid arthritis patients with TnF-α blockers Biologics: Targets and Therapy 2016:10 67–73

What is the drug level?

Low

Therapeutic

What is the anti-drug

antibody titer?

Undetected

Low to Intermediate

High

No ADAbs

Increase Drug

Increase DrugMaybe add

MTx

Switch biologicIn class

Switch biologicOut of Class

Inadequate Response

10©2019 Laboratory Corporation of America® Holdings All rights reserved. 20942-0619©2019 Laboratory Corporation of America® Holdings All rights reserved. 18768-0418/20550-0319

Detect total antibody not hindered by presence of drug

Anti-Drug Antibody (ADAb)

Detect free drug

Biologic Drug Concentration

Biologic Therapeutic Drug Monitoring (TDM) … Precision Medicine

• Titrate Doses for Personalized therapy1

• Identify & Prevent #1 cause of failure2-3

• Reduce drug waste3

• Manage co-therapies & drug switches 4

• Support Proactive management5

• Improve outcomes & durability of treatment5

Informs & expedites clinical decision making

1.Vande Casteele N, et al. Trough Concentrations of Infliximab Guide Dosing for Patients With Inflammatory Bowel Disease. Gastroenter 2015;148:1320-1329. 2.Ungar B, et al. The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with ifliximab. Gut 2014;63:1258-1264. 3.Steenholdt C, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut 2014;63:919-927. 4. American Gastroenterological Association. Guidelines for the Identification, Assessment and Initial Medical Treatment in Crohn’s Disease. https://www.gastro.org/IBDcarepathway 5. Papamichael et al. Improved Long-term Outcomes of Patients With Inflammatory Bowel Disease Receiving Proactive Compared With Reactive Monitoring of Serum Concentrations of Infliximab. Clinical Gastroenterology and Hepatology 2017;15:1580–1588 .

https://www.gastro.org/IBDcarepathway

11©2019 Laboratory Corporation of America® Holdings All rights reserved. 20942-0619©2019 Laboratory Corporation of America® Holdings All rights reserved. 18768-0418/20550-0319

• Vedolizumab and Anti-Vedolizumab Antibody, DoseASSURE™ VDZ

• Infliximab and Anti-Infliximab Antibody, DoseASSURE™ IFX

• Adalimumab and Anti-Adalimumab Antibody, DoseASSURE™ ADL

• Golimumab and Anti-Golimumab Antibody, DoseASSURE™ GOL

• Certolizumab and Anti-Certolizumab Antibody, DoseASSURE™ CTZ

• Ustekinumab and Anti-Ustekinumab Antibody, DoseASSURE™ UST

• Etanercept and Anti-Etanercept Antibody, DoseASSURE™ ETN

• Rituximab and Anti-Rituximab Antibody, DoseASSURE™ RTX

Biologic TDM…Precision Medicine

LabCorp’s DoseASSURE™is the most comprehensive biologic drug monitoring portfolio available

Inflammatory Bowel Disease

RA, Psoriasis, other related


Rationale for Biologic TDM

1. Vaughn BP, et al. Proactive Therapeutic Concentration Monitoring of Infliximab May Improve Outcomes for Patients with Inflammatory Bowel Disease: Results from a Pilot Observational Study. Inflamm Bowel Dis 2014;20:1996-2003. 2. Steenholdt C, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut 2014;63:919-927. 3. Ordas, et al. Therapeutic Drug Monitoring of Tumor Necrosis Factor Antagonists in Inflammatory Bowel Disease. Clin Gastroenterol Hepatol 2012;10:1079-1087.

Not everyone responds. ~30%Long-term efficacy could be better.~ 50% fail at 1-2 years+ 10% every year thereafter

Clinical assessment of efficacy is

imperfect

Drug failure looks alike

despite different

underlying causes.

TDM Informs & expedites important changes in medication

The drug is expensive.

Drug failure is expensive.

The cost of the drug

>>> cost of TDM


Biologic TDM discerns causes of failure to

1..American Gastroenterological Association. Guidelines for the Identification, Assessment and Initial Medical Treatment in Crohn’s Disease. https://www.gastro.org/IBDcarepathway

Inform & Expedite Right Action

Increase dose or shorten interval Consider switch out-of-class Evaluate Anti-Drug Antibody Titer

Low drug Positive Anti-Drug AntibodiesHigh drugLow drug

PharmacokineticNot enough drug

PharmacodynamicWrong drug

ImmunogenicAnti-drug antibodies

https://www.gastro.org/IBDcarepathway


What is Immunogenicity?

Anti-Drug Antibodies

1. Papamichael et al. Long-term outcome of infliximab optimization for overcoming immunogenicity in patients with inflammatory bowel disease. Dig Dis Sciences 2018;63:761-7. 2. Steenholdt C, et al. Clinical Implications of Variations in Anti-Infliximab Antibody levels in Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis 2012 Vol 18 (12): 2209-2217. 3. Strik AS, van den Brink GR, Ponsioen C, et al. Suppression of anti-drug antibodies to infliximab or adalimumab with the addition of an immunomodulator in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2017;45:1128–1134. 4. Ungar B, Kopylov U, Engel T, et al. Addition of an immunomodulator can reverse antibody formation and loss of response in patients treated with adalimumab. Aliment Pharmacol Ther. 2017;45:276–282.

• All therapeutic proteins have the potential of inducing an antibody-mediated immune response at any time

• Anti-Drug Antibodies are inversely related to drug

• ADAbs diminish drug levels, efficacy and longevity of treatment.

• ADAbs can only be diagnosed with the lab test. 30-50% of patients may develop Anti-Drug Antibodies to TNF inhibitors1


Low titers may have little or no effect on drug levels or clinical efficacy.3

Or they may progress to higher

titers.3

High titers are likely to be more

consequential leading to loss of

drug efficacy.3

Clinicians need excellentanti-drug antibody

Tests.

Immunogenicity is #1 Reason for Loss of Response1,2

It is possible to prevent progression of immunogenicity.It is also possible to “treat away” low to intermediate titers.

1. Vincent et al. Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective Ann Rheum Dis 2013;72:165–178.2. Vermeire et al. Immunogenicity of biologics in inflammatory bowel disease Ther Adv Gastroenterol 2018, Vol. 11: 1–13. 3. Ungar et al. The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab. Gut 2014;63:1258–1264

How should we think of Anti-Drug Antibodies?

Presenter

Presentation Notes

Extend successful treatment


Preventing drug failure & avoiding drug waste

High Performing ADAb Assay is Key

200 1000ng/mL

22 10,000+LOW HIGHINTERMEDIATE

Reversible Immunogenicity Late Refractory Immunogenicity

We designate Low, Intermediate, High

We can detect early and reliably monitor changes

Increase dose +/-Consider adding

MTX or Thiopurine

Consider switching biologics within class

(or to a different mechanism)


Reactive TDM Proactive TDM

TDM is Key to Right Decision-Making

Determine cause of lack or loss of response Early Optimization


Biologic TDM Informs Medication

Responder? No No No No Yes Yes YesDrug low high low - mid low low high midADAb no no low - mid high no no low

Medicationchange

Increase dose

Switch to different class

Increase dose +/- MTX or TP

Switch (in or out of class)

Optimize to target range

Prolong dosing interval

Monitor closely

Will the patientbenefit frommore drug?

YesAdd MTX?

or Thiopurine

NoDoes the patient need to switch

biologic?

Should that switch be in class?

Should it be out of class to a different

mechanism?


Potential Checkpoints

Enables personalized dosing to achieve Early Optimization With new prescriptions Whenever re-starting biologic Before discontinuing or de-escalating biologic

Should inform & expedite medication changes in setting of failure Before switching biologic Before & after dose changes When adding second immunomodulator

Reactive TDM

Proactive TDM

Opportunity to extend duration before symptoms


“The measurement of infliximab trough concentration modifies the therapeutic decision for RA patients and helps improve control of disease activity.”

Visit 1 Preliminary therapeutic decision • based on clinical (DAS & global)• trough collection for IFX level

24 patients on stable IFX dosage

Mulleman D, et al. Infliximab concentration monitoring improves the control of disease activity in RA Arthritis Research & Therapy 2009, 11:R178

• 7/24 (29%) were subtherapeutic.• Serum infliximab & DAS28 were inversely related.• The final therapeutic decision at Visit 2 , taking into account serum infliximab,

differed from the preliminary therapeutic decision for 50% of patients.

Two subsequent visitsVisit 2Final therapeutic decision • based on clinical plus trough IFX• 5 mcg/mL; < 2 is low; > 8 is high

Use of TDM enhanced therapeutic decisions & improved disease control


Can TDM guide safe de-escalation of Biologic?

• L’Ami et al. Prospective 28 week Dutch study. n=147 with RA on adalimumab 40 mg q2week

• Identified 55 with serum adalimumab trough levels greater than 8 ug/mL randomized

l'Ami MJ, et al. Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial Ann Rheum Dis 2018;77:484–487. doi:10.1136/annrheumdis-2017-211781

Tapered group (n = 27) q 3 week dosing

∆DAS28 –0.14±SD 0.61 at 28 wk10.6±2.5 μg/mL to 6.6±2.0 μg/mL

Control group (n = 27) q 2 week dosing

∆DAS28 0.30±0.52 at 28 wk10.4±2.4 μg/mL to 9.3±3.0 μg/mL

Patients with adalimumab > 8 can safely prolong their dosing interval to every 3 weeks without loss of disease control (at 28 weeks)• This study demonstrates the potential benefit of TDM.• Potential cost savings of ~34%

• Tapered group did slightly better in ∆DAS28 at 28 wk, 0.44 in favor (p=0.01) • 7 (26%) versus 10 (37% control) had an increase in DAS28 ≥0.6 points after 28

weeks (p=0.56). 2 of 7 opted to return to q2wk dosing.


How Biologic TDM optimizes Treatment

Proactive TDM may1. Improve longevity 2. Improve disease control3. Reduce complications4. Enable safe tapering

Not everyone responds.~30%

Long-term efficacy could be better.~ 50% fail at 1-2 years+ 10% every year thereafter

Reactive TDM informs when1. To continue or increase drug2. To add co-therapy3. To switch biologic4. Whether to switch biologic in- or out-of-class


I have no actual or potential conflict of interest in relation to this program/presentation.

• Grant/Research Support: N/A• Speaker’s Bureau: N/A• Consultant: N/A• Major Shareholder: N/A• Other: N/A


Target ranges for trough concentrations in RA


Cost savings ranging from 28 to 34%

Cost effectiveness of Biologic TDM

Martell et al. Cost-effectiveness of drug monitoring of anti-TNF therapy in inflammatory bowel disease and rheumatoid arthritis: a systematic review J Gastroenterol (2017) 52:19–25

• Individualized therapy using an algorithm with drug and anti-drug antibody measurements leads to major cost savings related to anti-TNF therapy in both IBD and RA patients with no negative impact on efficacy.

• Sum of healthcare costs related to Crohn’s disease was substantially lower (31 %) for patients randomized to algorithm- based interventions: $11,940 versus $17,236.

• At 5 years, cost savings among the 10,000 CD patients using a test-based strategy were $152,932,672, and the mean cost saving per patient was $15,292.

• Three modeling approaches in CD demonstrated savings of $5396+ over a 1 year period.

Martelli 2017 Review : Cost Effectiveness of Biologic TDM in IBD and RA

Presenter

Presentation Notes

In a French modeling approach- At 5 years, cost savings among the 10,000 CD patients using a test-based strategy were €131,300,293, and the mean cost saving per patient was €13,130. Interestingly, even when including the costs of both postoperative anti-TNF treatment and surgery, dramatic cost savings were still observed: €106,437,792 for a cohort of 10,000 patients at 5 years. The direct cost of the test had no impact on the results until the cost per test reached €2000.


Infliximab• In rheumatoid arthritis, EULAR responders had higher trough levels (median

3.6 ug/mL) than non-responders (0.5 ug/mL). Wolbink et al. Relationship between serum trough infliximab levels, pretreatment C reactive protein levels, and clinical response to infliximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis 2005;64:704–707.

Adalimumab• In rheumatoid arthritis, trough levels of 5 to 8 ug/mL are associated with

clinical response (EULAR).• Patients with higher levels did better, up to about 12.

Pouw et al. Key findings towards optimising adalimumab treatment: the concentration–effect curve. Ann Rheum Dis 2015;74:513–518.Pouw et al. Adalimumab trough level in blood corresponding with clinical response. Ann Rheum Dis 2013 71: 359

Target Ranges & Maximally Beneficial Concentrations


Etanercept• In rheumatoid arthritis (RA), good responders had higher trough levels

(median 3.8 ug/mL, 2.5 – 5.2) than non-responders (2.8 ug/mL, 1.3 - 3.9).

• Trough concentrations > 3.1 ug/mL at 3 months predict EULAR response to etanercept at 6 months.

Jamnitski et al. Patients non-responding to etanercept obtain lower etanercept concentrations compared with responding patients. Ann Rheum Dis 2012;71:88–91. Daien et al. Etanercept Concentration in Patients with Rheumatoid Arthritis and Its Potential Influence on Treatment Decisions: A Pilot Study. J Rheumatol 2012;39;1533-1538

Certolizumab• In rheumatoid arthritis, higher drug levels (> 23 ug/mL) are associated

with better 12 month EULAR response.• 37% incidence of anti-certolizumab antibodies in RA over 12 months.

Jani M et al. AnnRheum Dis 2017;76:208-213

Threshold concentrations may predict response


Ustekinumab• In plaque psoriasis, median trough ustekinumab concentrations were 0.4 ug/mL

at weeks 14 and 28 (ranging from undetectable to 3.6 ug/mL).• Responders (PASI 50) had higher trough concentrations (median 0.3 ug/mL)

than non-responders (0.07 ug/mL, p= 0.03) in a study of 76 patients• A definitive therapeutic target range for psoriasis has yet to be established.

Golimumab• In rheumatoid arthritis, higher trough levels (median 3.4 ug/mL)

correspond to a greater rate of clinical responseKay et al. Golimumab in Patients with Active Rheumatoid Arthritis Despite Treatment with Methotrexate. Arthritis Rheum 2008;58(4):964975.

Efficacy is Concentration-Dependent

Menting SP, Coussens E, Pouw MF, et al. Developing a therapeutic range of adalimumab serum concentrations in management of psoriasis: a step toward personalized treatment. JAMA Dermatol. 2015;151(6):616–622.

cases in biologic therapeutic drug monitoring › labcorp-d8 › 2020-03 › 56e...3. ordas, et al....

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