CDx Opportunities in Rare and Orphan Diseases
Rare and orphan diseases represent another area where the genetically defined disease and, likewise, genetically defined patient populations allow for potential CDx opportunities. Cystic fibrosis (CF) is one example. CF is one of the more common rare diseases that affects 1 in every 3,000 live births, however, 1 in 25 individuals is a carrier.
The gene associated with CF, which is part of the ABC superfamily of transporters, encompasses a very large locus with more than 2,000 types of genetic variants and mutations described and categorized within this large gene. The challenge here is developing assays that can characterize the wide variety of genetic changes, such as splice variants, point mutations, insertions and deletions, and then creating targeted treatments specific to these various mutations.
Different types of genetic mutations can be classified into functional groups within the CF gene, such as mutations that block the action of the CFTR protein, or its ability to be integrated into the right cellular location, all mechanisms that can lead to CF. Genetic tests can evaluate the gene and characterize any existing mutations, and is critical to support drug development activities focused on therapies that can counter the action of these mutations, potentially yielding therapies that could slow the progress of CF or even provide a long-term cure.
A few Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator therapies have been approved for CF patients, and while none require the use of a specific CDx, the labels of these therapies recommend using an FDA-cleared CF mutation test
Understanding Alzheimer’s Biomarkers and CDx
Usually taking decades to manifest, and often mimicking the symptoms of other conditions including the normal effects of aging, Alzheimer’s disease (AD) is an insidious and complex disease that is extremely difficult to diagnose and treat. Several candidate biomarkers have been identified and are being evaluated in AD patients. Selection of appropriate AD biomarkers could help identify pre-symptomatic populations with prodromal, or mild, AD. Late onset AD is driven primarily by variations within the ApoE gene. Those with an ApoE4 variant, especially with a homozygous gene status, have a higher risk for developing the disease. The early-onset form is thought to be driven by the APP gene that generates amyloid-beta (Aβ42), associated with amyloid plaques in AD. Two forms of the tau protein, phosphorylated tau (p-Tau) and total tau (t-Tau), also serve as key biomarkers.
Examining the ratios and abundance of these different proteins as well as the ApoE genotype can help create stratification markers to identify and potentially understand the subset of people who have may have early-onset, prodromal or moderate cognitive impairment in the first stages of AD.
In terms of developing a CDx assay, ApoE4 is a relatively easy genotypic assay. But developing useful diagnostic markers for Aβ42, t-Tau or p-Tau has proven to be quite challenging. Many companies have attempted to develop an assay to understand the quantitative response to therapy and assess the safety of a potential treatment. After extended efforts, one company finally was able to develop a robust assay that measures three critical proteins for AD using cerebrospinal fluid biomarkers. Covance was asked to participate in the verification of that assay and was cited in a subsequent publication. (Alzheimer’s & Dementia 12 (2016) 517-526) Clinical trials using these markers are underway.
Although treatment options for AD are still very limited, tests like this provide important knowledge that can help individuals and their families monitor and prepare for the onset of AD symptoms. Importantly, this exciting development will help advance research and can spur development of new treatments for Alzheimer's in the years to come.
Looking Ahead to Advance CDx
As precision medicine is expanding beyond oncology, we are witnessing how CDx can potentially make a similar impact across a broader spectrum of therapeutic areas. Coupled with the intersection of greater knowledge of the human genome and our growing understanding of the molecular basis of specific diseases, it's inspiring to see how our industry is creating practical applications to identify patient groups and the most appropriate treatment.
For sponsors considering a companion, complementary or in vitro diagnostic (IVD) as part of their drug development process, there are many strategies and partnership options to consider. Whether leveraging the scientific and technical expertise of a central lab, CRO provider or an IVD manufacturer, it’s essential to have a partner that is experienced with wide array of technology platforms, has expertise to navigate through the complexities of a specific therapeutic areas, can handle diverse regulatory challenges and offers a global reach to implement specific assays and generate crucial clinical data from around the world.