Disease heterogeneity and interpatient variability contribute to differences in drug efficacy and safety. This variability initiates a cycle of trial and error that continues until a suitably safe and effective drug is identified for each individual patient. Personalized medicine promises to eliminate the trial-and-error method by incorporating predictive biomarkers into therapeutic decision making.
A cumulative understanding of disease mechanisms and advances in molecular diagnostics in recent years have spurred a rise in the number of predictive biomarker assays being developed. These assays may be categorized as companion or complementary diagnostics, and a number of them are currently approved by the US Food and Drug Administration (FDA). While most are used in conjunction with oncology therapies, other therapeutic areas can also benefit from these predictive assays.
Companion and complementary diagnostics in oncology
Oncology has spearheaded the development and growth of the companion and complementary diagnostics industry. Predictive biomarker assays were first developed in the 1970s when the efficacy of tamoxifen was found to correlate with estrogen receptor status in patients with advanced-stage breast cancer.1 Subsequently, when Genentech developed the HER2 receptor antagonist trastuzumab, it collaborated with Dako to develop an in vitro diagnostic assay to screen breast cancer patients for HER2 overexpression. In 1998, this immunohistochemistry (IHC) assay, known as the HercepTest, became the first companion diagnostic to be approved by the FDA. Since then, several oncology products have adopted the drug-diagnostic co-development model, although the FDA also permits companion diagnostics and their corresponding drugs to be approved at different times.
Companion Versus Complementary Diagnostics
The FDA defines a companion diagnostic as “a medical device, often an in vitro device, which provides information that is essential for the safe and effective use of a corresponding drug or biological product.” Companion diagnostics are meant to identify patients most likely to benefit from a particular therapeutic product or, conversely, those most likely to suffer serious adverse effects due to the product. Notably, the companion diagnostic assay is identified on the corresponding drug or biological product’s label under Indications and Usage or Patient Selection.
Although there is not yet an official definition of complementary diagnostics, the FDA has presented a draft definition. It states that complementary diagnostics “identify a biomarker-defined subset of patients that respond particularly well to a drug and aid risk/benefit assessments for individual patients, but that are not pre-requisites for receiving the drug.”
Currently, 32 drugs are linked to 33 oncology companion diagnostics that have been cleared or approved for use by the FDA. These assays help identify relevant patient populations based on the drug’s mechanism of action. For instance, in vitro diagnostics such as the EGFR pharmDx Kit (Dako), cobas KRAS Mutation Test (Roche Molecular Systems), Praxis Extended RAS panel (Illumina), and FoundationOne CDx (Foundation Medicine) help identify colorectal cancer patients eligible for treatment with the EGFR inhibitors cetuximab and panitumumab based on EGFR receptor expression or absence of KRAS mutations. Similarly, IHC, fluorescence in situ hybridization, and next-generation sequencing assays have been developed by Ventana Medical Systems, Abbott Molecular, and Foundation Medicine, respectively, to identify non-small cell lung cancer patients who can undergo treatment with ALK inhibitors (ceritinib, crizotinib, and alectinib). These assays qualitatively determine ALK expression and gene rearrangement. Companion diagnostics have also been approved for ovarian, gastric, urothelial, and cervical cancers, as well as melanomas.
In 2015, the FDA approved Dako’s PD-L1 IHC 28-8 pharmDx as the first complementary diagnostic for the oncology drug nivolumab in patients with non-small cell lung cancer. Currently, two oncology drugs (nivolumab and atezolizumab) have complementary diagnostics whose indications are expanded to include melanoma and urothelial carcinoma.2 The IHC assays by Dako and Ventana measure PD-L1 protein expression to identify patients who may demonstrate a better response to the PD-1 receptor inhibitors, but the assays are not prerequisites for receiving the drug.
Oncology comprises approximately 87 percent of the companion diagnostics market in North America and 95 percent in Europe. With nearly 60 percent of drugs in late-stage clinical development relying on biomarker data,3 oncology is expected to continue to lead the field of personalized medicine.
Companion and complementary diagnostics beyond oncology
Taking a cue from oncology, biopharmaceutical companies are also developing companion and complementary diagnostics in other disease areas. Some estimates suggest that nearly half the therapies currently in Phase 3 clinical trials are associated with a non-oncology biomarker assay.4 Major therapeutic areas for companion and complementary diagnostic development are discussed below.
|BRACAnalysis CDx||BRACAnalysis CDx Myriad Genetic Laboratories|
|therascreen EGFR RGQ PCR Kit||Qiagen Manchester|
|cobas EGFR Mutation Test v2||Roche Molecular Systems|
|PD-L1 IHC 22C3 pharmDx||Dako North America|
|Abbott RealTime IDH1||Abbott Molecular|
|MRDx BCR-ABL Test||MolecularMD Corporation|
|FoundationOne CDx||Foundation Medicine|
|VENTANA ALK (D5F3) CDx Assay||Ventana Medical Systems|
|Abbott RealTime IDH2||Abbott Molecular|
|Praxis Extended RAS Panel||Illumina|
|Oncomine Dx Target Test||Life Technologies Corporation|
|LeukoStrat CDx FLT3 Mutation Assay||Invivoscribe Technologies|
|FoundationFocus CDxBRCA Assay||Foundation Medicine|
|Vysis CLL FISH Probe Kit||Abbott Molecular|
|KIT D816V Mutation Detection by PCR for Gleevec Eligibility in Aggressive Systemic Mastocytosis (ASM)||ARUP Laboratories|
|PDGFRB FISH for Gleevec Eligibility in Myelodysplastic Syndrome / Myeloproliferative Disease (MDS/MPD)||ARUP Laboratories|
|cobas KRAS Mutation Test||Roche Molecular Systems|
|therascreen KRAS RGQ PCR Kit||Qiagen Manchester|
|Dako EGFR pharmDx Kit||Dako North America|
|FerriScan||Resonance Health Analysis Services|
|Dako c-KIT pharmDx||Dako North America|
|INFORM HER-2/neu||Ventana Medical Systems|
|PathVysion HER-2 DNA Probe Kit||Abbott Molecular|
|PATHWAY antiHer2/neu (4B5) Rabbit Monoclonal Primary Antibody||Ventana Medical Systems|
|InSite Her-2/neu KIT||Biogenex Laboratories|
|SPOT-LIGHT HER2 CISH Kit||Life Technologies Corporation|
|Bond Oracle HER2 IHC System||Leica Biosystems|
|HER2 CISH pharmDx Kit||Dako Denmark A/S|
|INFORM HER2 Dual ISH DNA Probe Cocktail||Ventana Medical Systems|
|HercepTest||Dako Denmark A/S|
|HER2 FISH pharmDx Kit||Dako Denmark A/S|
|THXID BRAF Kit||bioMérieux|
|Vysis ALK Break Apart FISH Probe Kit||Abbott Molecular|
|cobas 4800 BRAF V600 Mutation Test||Roche Molecular Systems|
|VENTANA PD-L1 (SP142) Assay||Ventana Medical Systems|
|therascreen FGFR RGQ RT-PCR Kit||Qiagen Manchester|
|therascreen PIK3CA RGQ PCR Kit||Qiagen GmbH B|
In 2012, the FDA approved Quest Diagnostics’ Stratify JCV—an immunoassay to aid risk stratification in multiple sclerosis patients receiving natalizumab. The companion diagnostic detects anti-JC virus antibodies that are associated with an increased risk of development of a rare but serious brain infection in patients undergoing prolonged natalizumab therapy.
Of the 261 FDA-approved drugs with pharmacogenomic labeling information, 54 are used in the treatment of psychiatric or neurological disorders. This therapeutic area is therefore a viable candidate for the development of companion and complementary diagnostics. Although there are currently no FDA-approved pharmacogenomics-based companion or complementary diagnostics for neurological disorders, several CLIA-certified laboratory-developed tests are available. For instance, Assurex Health’s GeneSight Psychotropic test and Admera Health’s PGxPsych test evaluate the influence of several individual gene variants to predict patient response to 38 to 60 neuropsychiatric medications. Recently, Adial Pharmaceuticals announced plans to begin Phase 3 studies of their alcohol use disorder drug AD04 in subjects with target genotypes. The company has partnered with Eurofins Scientific to develop a quantitative polymerase chain reaction-based companion diagnostic to help identify the appropriate patient population.
As the global population of individuals aged 65 years and older continues to grow, it is essential to develop drugs and companion diagnostics for age-related neurodegenerative disorders such as Alzheimer’s disease (AD). CSF levels of Aβ or tau and positron emission tomography (PET) neuroimaging biomarkers are being evaluated as potential companion diagnostics in a Phase 3 clinical trial of Roche’s gantenerumab in patients with prodromal AD.5 Other clinical trials that contemporaneously evaluated AD drugs (Merck’s verubecestat and Eli Lilly’s solanezumab) and diagnostics failed to show significant benefits.
Over the past two decades, biologics such as anti-TNF-α drugs have revolutionized the management of inflammatory disorders, including rheumatoid arthritis. However, with a third of the patients failing to respond adequately to these agents, relying on trial and error alone to identify the appropriate biologic can become expensive. Therefore, single nucleotide polymorphisms in TNF-α or its receptor and other gene variants may be used as predictive biomarkers in the development of companion and complementary diagnostics to stratify patients into potential responders and nonresponders. Additionally, other protein biomarkers involved in immune regulation have been incorporated into the Vectra DA test panel by Crescendo Bioscience to classify patients based on disease severity and to measure changes in response to drug treatment.6
Inflammatory molecules are also being evaluated as potential biomarkers for asthma. An assay to measure serum levels of periostin was used as a companion diagnostic in Phase 3 trials of two IL13 inhibitors (Genentech’s lebrikizumab and AstraZeneca’s tralokinumab).
Elevated serum periostin levels are indicative of severe asthma. Despite promising Phase 2 data, neither drug caused significant improvements in patient subgroups with high periostin levels.
Companion diagnostics that test HIV tropism identify patients suitable for treatment with the antiretroviral drug maraviroc. Maraviroc specifically inhibits the entry of the CCR5 receptor-dependent HIV virus but not the CXCR4 receptor-dependent or dual tropic viruses. Therefore, HIV tropism testing is a prerequisite for use of the drug.
Pharmacogenomic studies suggest that individuals with specific gene variants may be at an increased risk of adverse effects in response to two antiretroviral drugs—abacavir and efavirenz. Although there is no FDA-approved test to confirm this, several laboratory-developed test panels are available. Additionally, hepatitis C-infected patients carrying specific gene variants may be resistant to the antiviral agents mericitabine and danoprevir.
Growing antimicrobial resistance presents considerable challenges in the treatment of infectious diseases. In 2012, Cempra Pharmaceuticals collaborated with Curetis to use the latter’s PCR-based molecular diagnostics platform to aid pathogen diagnosis during the Phase 3 trial of its pneumonia drug. Although the drug was not approved by the FDA, the trial paved the way for drug-diagnostic co-development in the field of infectious diseases. Earlier this year, the FDA issued a guidance document to promote the coordinated development of antimicrobial drugs and antimicrobial susceptibility test devices.
Cystic fibrosis is an autosomal recessive disease characterized by mutations in the CFTR gene that encodes an ion channel. Nearly 2,000 disease-causing mutations have been identified and classified based on the nature of the defect they cause. Cystic fibrosis drugs currently available on the market are effective against specific CFTR mutations. For instance, ivacaftor is not effective in patients who are homozygous for the F508del mutation; however, combinations of lumacaftor and ivacaftor or tezacaftor and ivacaftor are beneficial in such patients. Therefore, a CFTR mutation test is recommended prior to treatment initiation.
Several nucleic acid-based CFTR mutation detection tests have been cleared for use by the FDA. These include the Cystic Fibrosis Genotyping Assay (Celera Diagnostics), InPlex CF Molecular Test (Third Wave Technology), Verigene CFTR and Verigene PolyT (Nanosphere Inc.), and xTAG Cystic Fibrosis 39/60 Kit (Luminex Molecular Diagnostics), among others. The most recently approved test is Illumina’s MiSeqDx Cystic Fibrosis 139-Variant Assay based on nextgeneration sequencing technology.
Challenges and future directions
Although oncology currently dominates the field of companion and complementary diagnostics, discovery of predictive biomarkers and technological advances are enabling progress in other therapeutic areas. While infectious diseases and cystic fibrosis may be amenable to rapid progress given their fairly uncomplicated pathogenesis, heterogeneous disease states such as asthma, Alzheimer’s disease, and psychiatric disorders are far more challenging. Gaps in knowledge about disease progression and lack of predictive biomarkers limit the development of companion and complementary diagnostics for these polygenic diseases. Additional challenges are the difficulty in sample collection and the paucity of blood biomarkers.
Despite these challenges, the companion and complementary diagnostics market is estimated to exceed $7 billion by 2024. The industry is witnessing a shift away from the “one drug, one test” paradigm, with companies now formulating high-throughput systems and multibiomarker panels to test for several drugs at once. This flux calls for regulatory bodies to formulate policies for complementary diagnostics and laboratory-developed tests to ensure patient safety.
- Lerner, HJ, et al. "Phase II study of tamoxifen: report of 74 patients with stage IV breast cancer." Cancer Treatment Reports 60.10 (1976): 1431-1435.
- Scheerens, H., et al. "Current status of companion and complementary diagnostics: strategic considerations for development and launch." Clinical and Translational Science (2017): 84-92.
- Milne, Christopher-Paul, Joshua P. Cohen, and Ranjana Chakravarthy. "Market watch: where is personalized medicine in industry heading?" Nature Reviews Drug Discovery (2015): 812-813.
- Lee, Jessica, Ravi Patel, and David Ruch. “Companion diagnostics: the expanding reach of personalized medicine.” In Vivo (2017).
- Ostrowitzki, Susanne, et al. "A phase III randomized trial of gantenerumab in prodromal Alzheimer's disease." Alzheimer's Research & Therapy (2017): 95.
- Roodenrijs, Nadia MT, et al. "The multi-biomarker disease activity score tracks response to rituximab treatment in rheumatoid arthritis patients: a post hoc analysis of three cohort studies." Arthritis Research & Therapy (2018): 256.