Why so few companion diagnostics? The difficulty of translating biological data into predictive biomarkers

Nicholas C. Dracopoli, Ph.D.Vice President, Head Oncology BiomarkersJanssen R&DJohnson & Johnson

CADTHSt Johns, NF, CanadaMay 6, 2013

The Biomarker Paradox

There are 21,748 biomarkers listed in GOBIOM database on 02/19/2013

-BUT -

only 32 valid genomic biomarkers in FDA approved drug labels

- AND -0 are multiplex IVD’s based on proteomic or

genomic profiles that predict response to therapy

Biomarkers in Drug Development

Marker Function Test

PD/MOA • Determine whether a drug hits the target and has impact on the biological pathway

• Evaluate mechanism of action (MOA)

• PK/PD correlations and determine dose and schedule

• Determine biologically effective dose

• Research test used during drug development

• Not developed as companion diagnostic

Predictive • Identify patients most likely to respond, or are least likely to suffer an adverse event when treated with a drug.

• Companion diagnostic test (e.g. herceptin, EGFR)

Resistance • Identify mechanisms driving acquired drug resistance

• Mutation analyses (e.g. Bcr-Abl mutation in imatinib treated CML)

Prognostic • Predicts course of disease independent of any specific treatment modality

• Approved tests (e.g. CellSearch, Mammaprint)

Surrogate • Approved registrational endpoints • Commercial diagnostic tests (e.g. LDL, HbA1c, viral load, blood pressure)

Biomarkers for Oncology Targeted Therapies

Ph+, KRAS, EGFR, KIT, HER2, BRAF, ALK

Predictive Biomarkers

CD3, CD4, CD5, CD8, CD19,CD20, CD41, IgA, IgM, IgG, Estradiol, Estrone, Estrone sulfate, soluble HER2, PET tratsuzumab, Testosterone, Androstenedione, SHBG, plasma HDL, Albumin, Treg, CD8, CBC, CD4+, Caspase 3-9, Bcl2, PDGFR, cKIT, ER, PR, Ki67, pS2, IgA, IgG, IgM, IgG, IgA, IgM, 20S proteasome, EGFR, pEGFR, Ki67,p27, pMAPK, AKT, pAKT , keratin 1, STAT3, VEGF, FDG-PET, CT, DCE-MRI, plasma PLG, CECs, EGFR, pEGFR, Ki67,p27, TGFalpha , amphiregulin, epiregulin, EGFRvIII, MEK, ERK1, pERK1, ERK2, pERK2, actin, Acetylated H3, H4, HDAC2-6, TopoIIa, HP1, KRAS, SRC, pSRC, pBCR/ABL, pCRKL, IGFR1, pS6, TGF-alpha, p95, 4EBP1, p4E-BP1, eIF-4G, S6, pS6, IDO, TNFalpha, ……………..

PD/MOA Biomarkers

Oncology CoDx: Twelve Drugs Against Seven Targets

5

Date Drug Markers

1998 trastuzumab HER2

2007 lapatinib HER2, EGFR

2001 imatinib BCR-ABL, KIT

2006 dasatinib BCR-ABL

2007 nilotinib BCR-ABL

2004 cetuximab KRAS

2006 panitumumab KRAS

2011 crizotinib EML4-ALK

2011 vemurafenib BRAF

2012 pertuzumab HER2

2012 bosutinib BCR-ABL

2012 ponatinib BCR-ABL

0

2

4

6

8

10

12

No CoDx With CoDx

Minimal Requirements for Predictive Markers

Patient samples:Training set (n > 100)

Validation set(s) (n > 500)

Candidate markers:Drug target statusMolecular profile

Stable endpoints:Response (ORR)

Survival (PFS, OS)

Algorithm:Biological rationalePredefined cutoffs“Black box” model

PredictiveBiomarker

6

Predictive Biomarker Discovery for a 1st in Class Drug

Pre-ClinicalPhase IDose

Escalation

Phase IExtension at

MTDPhase II Phase III Post-Launch

N: # patients treated at or above biological effective dose

in vivo &in vitromodels

1st

Training1st

Validation

2nd

Validation&

Registration

SimpleBiomarker(e.g. BRAF V600E)

in vivo &in vitromodels

1st

Training1st

Training1st

Validation

2nd

Validation&

Registration

MolecularProfile

>30 >80 >200N 0 0 >1,000

Clinical Endpoints CR/PR PFS/OS

7

Training Set (n = 62) Validation Set (n = 138)

Ross, R.W., et al. Lancet, 2012http://dx.doi.org/10.1016/s1470-2045(12)70263-2

Biomarker Discovery and Validation

6-gene expression model in blood to predict survival in CRPC

8

Approved Oncology Companion Dx

Markers Direct Markers Secondary Markers

Molecular Profiles*

Readout Drug target status Downstream pathway

Consolidated profiles

Examples HER2+

ER+

CD20+

BCR-ABL (Ph+)

KIT+

EGFR+

BRAF

EML4-ALK

KRAS wt

9

No IVDMIA Tests Approved as Companion Diagnostics

Test Company FDA Approval CompanionDiagnostic

Prognostic Test

Mammaprint Agendia 2007 No Yes

Tumor of Unknown Origin

PathworkDiagnostics

2008 No Yes

Allomap XDx 2008 No Yes

OVA1 Vermillion 2009 No Yes

An IVDMIA is a device that combines the values of multiple variables using an interpretation function to yield a single, patient-specific result that is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment or prevention of disease and provides a result whose derivation is non-transparent and cannot be independently derived or verified by the end user.Draft Guidance for Industry, Clinical Laboratories, and FDA staff – Multivariate Index Assays (Rockville, MD: FDA, Center for Devices and Radiologic Health, 2007)

10

Conclusions

• All approved oncology companion diagnostic tests evaluate status of the drug target:

– Complex profiles have only been approved as prognostic markers

– Signal transduction pathways defined by “driver mutations”

• Developing companion diagnostics for other drug classes (e.g. epigenetic modulators, immuno-oncology agents) because they do not inhibit classic “driver mutations”

• Developing complex molecular profiles as companion diagnostics for 1st in class drugs is not feasible prior to approval:

– Too few samples exposed to an efficacious dose

– Response is not always correlated with survival

11