By Dr. Georg Lautscham, chief business officer (CBO), and Dr. Stefan Müllner, CEO and cofounder, Protagen
Precision medicine (also known as personalized medicine) offers a more efficient mode of drug development for the pharmaceutical industry, as well as promising more-effective therapeutic tools for physicians and better outcomes for patients.
While it has been reasonably well-applied in the field of oncology, the ongoing development of novel technologies and changes in the regulatory landscape are essential if the approach is to be effectively applied to other important therapeutic areas.
THE NEED FOR PRECISION MEDICINE
Drug development is a risky and expensive process; an analysis published in 2016 by the Tufts Center for the Study of Drug Development cited an estimated cost of $2.5 billion to take a drug to market. In addition, most of the drugs that do make it to market only work on a fraction of patients, which is causing regulators and payers to reconsider which drugs should be approved for clinical use and reimbursed by the healthcare system. For example, the 10 highest-grossing drugs prescribed today in the U.S. are effective on just 25% of recipients. This suggests that our ability to match the right patient with the right treatment is poor and that improvements need to be made.
One promising approach for overcoming this challenge is precision medicine. At its core, it uses specific molecular diagnostics and biomarkers to stratify patients into more discrete disease subsets. This knowledge can enable researchers to identify exclusive molecular drug targets likely to be important within a given disease subset, so that they can develop new compounds against them. The idea is that the more tailored the treatment is toward a certain subset of patients, the more effective it will be.
Molecular biomarker data also can support the development of new companion diagnostic (CDx) tools designed to profile patients based on the molecular characteristics of their specific disease subset. These can then be used to predict whether a patient will respond favorably to a treatment and anticipate any potential adverse reactions before it is administered.
A HISTORICAL FOCUS ON CANCER
To date, oncology has been the field to benefit most from precision medicine. The textbook example is Herceptin, which targets human epidermal growth factor 2 (HER2) receptors and is only administered to patients who overexpress the receptor. The drug’s success came to embody the notion that better characterizing a particular disease phenotype at the molecular level, and subsequently developing therapies and diagnostic tools that exploit this knowledge, is an effective way of boosting treatment response rate. In fact, the overwhelming majority of cancer drug development programs today are based on patient stratification guided by biomarker analysis.
So why has most of the focus been on cancer? First, for many years, if not decades, cancer research has received significant financial investment compared to other diseases, both within academia and the pharmaceutical industry. This is mainly because a cancer diagnosis was formally considered a death sentence, and U.S. President John F. Kennedy initiated a research campaign to identify a cure for cancer. This initiative was the start of a global research effort, which has since increased our understanding of the genetic complexity underpinning the wide range of disease subsets we classify as cancer and opened our eyes to the true molecular diversity of the disease. In turn, researchers have been able to use information from genome sequencing and genomics technologies to better stratify patients into subgroups (as well as develop new drugs and diagnostic tools to treat them). Secondly, at a time when treatment responses for cancer therapies were very low (5 to 20 percent), regulatory bodies encouraged pharmaceutical companies to invest in biomarker-driven approaches to enhance patient stratification and improve patient outcomes.
While there has clearly been significant progress in applying precision medicine to cancer, other disease areas have lagged behind. For example, autoimmune diseases have significant economic and social impacts and represent the second-most important market for pharmaceutical companies, which is unsurprising when you consider that, while 1 in 33 Americans will suffer from cancer, 1 in 6 will suffer from an autoimmune disease, costing the U.S. over $100 billion a year. However, the uptake of precision medicine in this area has been slow at best, even though it can be extremely difficult to accurately diagnose and treat patients effectively using the tools that are currently available.
APPLYING PRECISION MEDICINE TO AUTOIMMUNE DISEASES
There are three main factors that can drive the widespread adoption of precision medicine for treating autoimmune diseases: increased research funding, greater regulatory pressure, and the development of new technologies to enable better patient stratification.
The first two mirror what has happened in oncology over the last few decades and will rely upon a shift in mindset among stakeholders such as policy makers, funding bodies, healthcare providers, and the pharmaceutical industry as a whole. Promisingly, the wheels may already be in motion, with the FDA having released a guidance paper in July 2016 recommending the codevelopment of novel therapies and corresponding CDx in all disease areas.
Autoimmune diseases also require different technology platforms for molecular characterization, as they are fundamentally dissimilar in nature to cancer. For example, many cancers can be attributed to specific changes in a patient’s DNA that can be detected using techniques such as PCR (polymerase chain reaction) and DNA sequencing, which themselves have been the source of concerted research efforts to increase their sensitivity and specificity. These methods are now so sophisticated that they can be used to detect and analyze circulating tumor DNA molecules that have been shed into a patient’s bloodstream, even when only a few copies of the mutant DNA are present. Furthermore, they are now considered relatively cheap, easy-to-perform, and highly reliable, making them a regular feature of cancer drug research and clinical trials.
Sadly, the pathology of autoimmune diseases is usually much more intricate, and the onset of these diseases is rarely triggered by a series of genetic mutations. Instead, the term encompasses a wide variety of related maladies, all characterized by a complex, maladaptive response of the immune system (which begins to target the body’s own tissues and organs through the generation of autoantibodies). It is this underlying process that provides us with a window of opportunity; the autoantibodies produced can often provide insights into how the disease will manifest and progress, making them viable candidates as biomarkers for the differential diagnosis of patients. In many cases, these autoantibodies are intrinsic to the disease itself and are often highly detectable (even in the early stages), while their ongoing expression patterns can give a strong indication of disease stage and severity.
If autoantibodies are excellent candidates for biomarkers in patients with autoimmune diseases, how can we account for their lack of adoption within clinical research and diagnostic development? The answer to this question may revolve around the technologies currently available for the systematic identification of novel biomarkers, many of which cannot offer the necessary sensitivity and specificity. In addition to this, the detection of multiple autoantibodies (sometimes as many as 10 to 15 as part of a multiplex panel) is required for the proper stratification of patients into meaningful disease subgroups.
If the adoption of precision medicine is to truly gather pace among diseases outside of cancer, there are still a number of regulatory, technological, and funding-related hurdles to be overcome. Taking lessons learned from within the field of oncology and systematically applying them to areas such as autoimmune disease will enable the development of more effective drugs across a wider range of illnesses. Most importantly, this will lead to a better outcome for patients.