MONITORING BIOLOGICALS

Biological drugs

A great alternative for the treatment of chronic inflammatory diseases (rheumatology and gastroenterology).

Most common drugs used:o Infliximab (Remicade®)o Adalimumab (Humira ®)o Etanercept (Enbrel ®)

Structural differences with different immunogenicity grades

+ Immunogenicity -

Immunogenicity and bioavailability

• The development of antibodies against biologicals leads to a lack of efficiency of the therapy.

• Low levels of biologicals in serum is correlated to a lack of efficiency of the drug**

*“Guidelines on the Clinical Investigation of the Pharmacokinetics of Therapeutic Proteins of 31 July 2007”**Clinical validation with 1400 samples of 70 RA patients

“All therapeutic proteins are potentially immunogenic”*

Time after beginning treatment (weeks)

Fre

e In

flix

imab

(u

g/m

l)10

xan

ti-I

nfl

ixim

ab

(UA

/ml)

DA

S28

References…“Several studies have shown that immunogenicity is associated with allergic reactions and loss of response in a significant number of patients treated with chimeric or human therapeutic antibodies. Monitoring of drug levels as well as of antibodies against therapeutic antibodies may lead to more rational treatment strategies.” Wolbink et al. Curr Op Rheum 2009.

“Secondary response failure is associated with low trough levels of anti-TNF-alpha biologicals and development of antibodies against these drugs. Indeed, trough level assessments of anti-TNF-alpha drugs and measurements of antibodies against these biologicals are among the parameters that best predict the response of individual RA patients” Radstake et al. Ann.Rheum.Dis 2009

“Assesments of bioavailability and immunogenicity of infliximab may be used to optimize dose regimens and prevent prolonged use of inadequate therapy.” Svenson et al. Rheum 2007.

“We show that determining the immunogenic status of a non responding patient may be important for further decision making and could assist in developing an optimised treatment for the individual patient.” Bartelds et al. Ann.Rheum.Dis 2009

Nowadays…

Clinicians monitor patients under biological treatment based on subjective or unspecific parameters:

o DAS28 (disease activity score): measurement of swollen and tender joints

o HAQ (health assessment questionnaire): functional capability questionnaire

o Intensity of pain: based on a scale from 0 to 10o Unspecific analytical markers: RCP, RF, ESR

Monitoring biological drugs is a regulatory requirement, to increase uniformity and consistency of measurement methods of patient´s response

Monitoring biological drugs is a regulatory requirement, to increase uniformity and consistency of measurement methods of patient´s response

Double test to determine:o Serum levels of biological.o Antibodies against drugs.

Therapeutic parameterization of biological treatment.

Early prediction of infusion reactions.

Accurately predicts patient´s response to treatment.

Optimizes treatment, assuring the correct therapy.

Cost-effective of biological therapies.

PROMONITOR

“Early prediction of treatment failure”

Results of the clinical validation

>1.5 g/ml

<15 UA/ml

*Clinical validation with 1400 samples of 70 RA patients

PROMONITOR

Interpretation guidelines in RA, based on the clinical validation performed in Proteomika*

Analysis of infliximab and antibodies against infliximab Analysis of infliximab and antibodies against infliximab

IFX > 1.5 ug/ml andAntibodies negativeIFX > 1.5 ug/ml andAntibodies negative

IFX < 1.5 ug/ml andAntibodies positiveIFX < 1.5 ug/ml andAntibodies positive

Good clinical responseGood clinical response Bad respondersBad responders

Adequate treatmentAdequate treatment

Treatment maybe is not efficient.

Surveillance and monitoring required.

Treatment maybe is not efficient.

Surveillance and monitoring required.

*Clinical validation with 1400 samples of 70 RA patients

< 0.8 ug/ml

< 8 AU/ml

Results of the clinical validation

*Clinical study with samples from Hospital universitario La Paz

PROMONITOR

Interpretation guidelines for Adalimumab in RA, based on the clinical validation performed in Proteomika*

Analisys of adalimumab and antibodies against adalimumabAnalisys of adalimumab and antibodies against adalimumab

ADA > 0.8 ug/ml andAntibodies negativeADA > 0.8 ug/ml andAntibodies negative

ADA < 0.8 ug/ml andAntibodies positiveADA < 0.8 ug/ml andAntibodies positive

Good clinical responseGood clinical response Bad responderBad responder

Adequate treatmentAdequate treatment

Treatment maybe is not efficient.

Surveillance and monitoring required.

Treatment maybe is not efficient.

Surveillance and monitoring required.

*Clinical validation with 180 samples of RA patients

PROMONITORPROMONITOR

Optimizes each patient´s therapy

Adequate drug level+ no antibody

response

Decreased drug level + antibody

response

Low drug level+ significant antibody

production

Treatment OK Consider increasing dosage or frequency

of dosage

Consider switching to another drug

PROMONITOR

ELISA immunoassay in serum samples, easily reproducible with high specificity and sensitivity.

Extended menu for a wide variety of biologicals :

– Infliximab (Remicade ® )– Adalimumab (Humira ® )– Etanercept (Enbrel ® )*– Rituximab (MabThera ® )*

Sample volume required: 40µl of serum for each assay.

Sample extraction must be immediately before drug administration.

*Launch 2010

PROMONITOR ELISA KIT

48 test (24 immunogenicity assays and 24 bioavailability assays)

4 batches of 6 samples can be performed

Sample type: serumVolume required: 40µl each assay.High specificity (100%) and

sensitivity (>90%)Total assay time: 6hHands-on-time: 1.5h

PROMONITOR KIT Cat. No.

Promonitor IFX PG-PIFX-10200

Promonitor ADA PG-PADA-10700

MARKET

Patients undergoing these biological therapies are affected by chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease.

¹ WHO. Disease and injury regional estimates for 2004

² Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004 May;126(6):1504-17.

20% of the total affected population are treated with biological drugs.

Pathology Prevalence Europe

Rheumatoid Arthritis 0.5-1 % 6.200.000 ¹

Inflammatory Bowel Disease

0.3 % 2.200.000 ²

TOTAL 8.400.000

20%TOTAL 1.680.000