PML development:Risk factors and predictive biomarkers

- limitations and perspective -

Heinz Wiendl

University of Münster, Germany

PML workshop 07_2011

1) Biomarkers for Mab therapy: what do we have?2) „The german pharmacovigilance natalizumab study“: an

academic approach by the KKNMS3) Immunological consequences of long-term Efalizumab and

Natalizumab therapy: insights from our cohorts4) Summary and outlook

Hypothesis: PML is Caused By A Convergence of Multiple Risk Factors

Candidates for additive risk factors

Duration of therapy

Biomarker – identifying the risk group

© Kompetenznetz Multiple Sklerose

2-Step Assay Demonstrates Anti-JCV Antibody Prevalence of 54% in MS Patients in STRATA Study1

Gorelik L et al. Ann Neurol. 2010;69:295-303.

450

Step 1: ELISA

40% Positive

30% Negative

30% Indeterminate

48% Confirm Positive

52% Confirm Negative

Step 2: Confirmation test

54% Positive

46% Negative

Overall Result:

negative

JCV-Antibody status

positive

Prior immune suppression

No Yes

Natalizumab therapy duration

JCV-seronegative JCV-seropositive

No prior immune suppression

Prior Immune suppression

0-2 years

0,11/1000(95% CI: 0-0,59)

~1:9000

0,35/1000(95% CI: 0,19-0,60)

~1:2900

1,2/1000(95% CI: 0,58-2,2)

~1:800

>2 years 2,8/1000(95% CI: 2,0-3,8)

~1:350

8,1/1000(95% CI: 5,4-11,6)

~1:120

Sandrock A et al. AAN 2011; Poster P03.248.

PML incidence / 1000

A possible risk calculation algorithm?

What should a “biomarker” for Mab-associated PML be like?

1) Biomarkers for Mab therapy: what do we have?2) „The german pharmacovigilance natalizumab study“: an

academic approach by the KKNMS3) Immunological consequences of long-term Efalizumab and

Natalizumab therapy: insights from our cohorts4) Summary and outlook

German “Natalizumab Pharmakovigilance Study”

© Kompetenznetz Multiple Sklerose

• Aim 1: To identify risk factors that predispose to the development of PML during long-term therapy with Natalizumab

• Aim 2: To better understand the immunomodulatory and immunosuppressive effects of Natalizumab.

Approach: multiparametric, multicentric (Münster, Bochum, Düsseldorf, Munich), crossectional + longitudinal

1.Thera py history: previous immunosuppressive/modulatory conditions,

2.Genetics: individual genetic predisposition

3.Pathogen-host interaction: preexisting JC-virus specific antibodies

4.Virology: presence of JCV in biofluids

5.Bioenergetics: altered bioenergetic values and

6.Immunephenotyping

7.Functional assessments of immune components (e.g. migration, TCR repertoire etc.)

Objectives

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PML risk assessment

• !"#$#%&'(#!)'%*+!+,*-!'(!.+, , -/!!0#%1&/!234!*(-!1%'(#!5"67!

• !"#$#%&'(#!*($'. , -?!$'$#%!*<*'(0$!8*$@,<#(0!5A67!

• !"#$#%&'(#!0#%,8,0'$')'$?!5"67!

• !D($'<#(!08#9'E'9!FG9#++!8%,+':#%*$', (!5A37!

• !HID!$?8'(<!5A37!

• !D(*+?;#!F2J!%#8#%$, '%#!5"67!

• !D(*+?;#!. ',#(#%<#$'9!8*%*&#$#%0!5=>7!

Natalizumab mechanism of action

• !"#$#%&'(#!8%#0#(9#!, :!(#1$%*+';'(<!*($'. , -'#0!'(!.+, , -!5=>/!"67!

• !2,&8+#$#!8@#(,$?8'(<!, :!'&&1(#!9#++!8,81+*$', (0!'(!.+, , -!*(-!234!5A6/!A3/!"67!

• !B#%:,%&!C*$*+';1&*. !. '(-'(<!*00*?!*(-!0'<(*+'(<!0$1-'#0!5A37!

• !2*%%?!,1$!:1(9$', (*+!*00*?0!, (!(#1$%,8@'+!<%*(1+,9?$#0!5A37!

• !"#$#%&'(#!*($'. , -?!8%,E'+#0!10'(<!8%,$#,&'9!&'9%,*%%*?!*88%,*9@#0!5=>7!

• !"#$#%&'(#!&'$,9@,(-%'*+!3CB0K@*8+,<%,180!5=>7!

0 126Months Longitudinal studies

CSF

Blood

X

X

Urine

XX

Project phase

MS: Nat. therapy 0. point

MS: Nat. therapy ≥

18 months

MS: Interferon therapy

Healthy donorMS: Nat therapy 6 months follow-

up

MS: No therapy

MS: Nat. therapy 12 months follow-

up

X X

X

X

X

X

X

Patient groups

© Kompetenznetz Multiple Sklerose

30-50 Natalizumab patients/center (total appr. 120-200 patients)

1) Biomarkers for Mab therapy: what do we have?2) „The german pharmacovigilance natalizumab study“: an

academic approach by the KKNMS3) Immunological consequences of long-term Efalizumab and

Natalizumab therapy: insights from our cohorts4) Summary and outlook

PML associated with Efalizumab (anti-LFA-1/CD11a)

• 4 confirmed cases of PML associated with Efalizumab (Raptiva®) (Major et al., 2010)

• incidence ca. 1 in 500• withdrawn from the market 2009

Serial „immunological“ assessments of one Efalizumab-PML patient:

Schwab et al., Neurology in pres

- Serial analysis of peripheral blood and parallel CS- Functional analysis of immune cells (e.g. migration- Detailed CNS tissue analysis- Immune repertoire and antigen-specific T cell ana

LFA1-blockade blunts T cell activation and maturation development of effector/memory populations over time

What should a “biomarker” for Mab-associated PML be like?

And how can one get there?- Currently 3 risk parameters are available:

1) duration of treatment, 2) prior immune suppression, 3) JC antibody status

- Due to the multifactorial nature of the rare event (PML), a „dynamic“ biomarker ofPML risk is probably needed

- A „biosignature“, including „functional components“ is probably more likely to reflethe complex nature of disease pathogenesis

- Partly, these are highly difficult to standardize (e.g. migration, flow cytometry)

- Biological plausibility is important! (e.g. dynamic aspects, reversibility)

- Larger consortia have be established, that cooperate and independently validatedifferent aspects of Mab-associated changes and PML pathogenesis

- The KKNMS has already established a structure, IT platform, different biorepositorieand common SOPs for sampling of different biospecimens

Wiendl-Lab

Stephan BittnerNicole BobakJohanna BreuerAngela DreykluftPetra EhlingKerstin GöbelCatharina GroßAlexander HerrmannNico MelzerSven Meuth Suse PankratzVilmos PosevitzTobias RuckOle SimonTilman SchneiderMichael SchumannNicholas SchwabMax-Philipp Stenner

Collaborators

Laura Airas (Turku)Amit Bar-Or, Jack Antel (Montreal)Christian Bien, Christian Elger (Bethel/Bonn)Wolfgang Brück, Christine Stadelmann (Göttingen)Thomas Budde, Christian Pape (Münster)Lieping Chen (Baltimore) Ralf Gold (Bochum)Bernhard Hemmer (München)Reinhard Hohlfeld, Klaus Dornmair (München) Thomas Hünig (Würzburg)Helmut Jonuleit, Ari Waisman (Mainz)Bernd Kieseier, Hans-Peter Hartung (Düsseldorf)Monique Lafon (Paris)Joel Le-Maoult, Edgardo Carosella (Paris)Rudolf Martini (Würzburg)

Funding:DFG, SFB 581, KFO421, IZKF Münster, IMF MünsterBMBF, Hertie-Foundation, Thyssen, DMSG, American Myositis Association, Industry

Alumni

Ute FegerYu-Hwa HuangSonja OrtlerAlla ZozulyaChristoph LederAnne Waschbisch

Klinik für Neurologie – Abtl. Entzündliche Erkrankungen

und Neuroonkologie

Westfälische Wilhelms Universität Münster

heinz.wiendl@ukmuenster.de