By Emma Kampouraki
Differences in the genetic material we carry make us who we are. Individual variability is important when prescribing drugs, as we can now genotype a person in less than a few hours. We can then use this information to inform drug prescription. Genotype-informed prescription is more than virtual reality nowadays. Both FDA (US Food and Drug Administration) and EMA (European Medicines Agency) recommend the use of genetic information to drive the decision of treatment and prevent patients from serious mistakes in the prescription of “useless” drugs. Although ethical concerns don’t facilitate the establishment of genotyping in clinical practice, it is common sense that it is also unethical not to use all the existing data for a more informed and safe process of drug therapy. Trial and error is still in place in most drug schemes, however moving on to a more individualised approach has the advantages of costing less and resulting in more effective treatments, increasing patient satisfaction and compliance at the same time.
The first FDA-approved genetically-guided therapy was for the treatment of HER2 (human epidermal growth factor) positive metastatic breast cancers in 1998. The case of trastuzumab (Herceptin®) paved the way for the co-development of gene-based therapies with tests to detect the drug targets, in order to identify the right therapies for the right patients. Simultaneously with the approval of trastuzumab, a laboratory technique for detection of HER2 protein overexpression in breast cancer cells (Dako North America, Inc. for HercepTest).
Later, the cases of olaparib (Lynparza®) and rucaparib (Rubraca®) prove the increasing need for more targeted therapies and the outstanding interest of medicines regulatory agencies to cover this need as soon as possible. Recent findings show that tumours rely on poly (ADP-ribose) polymerase (PARP)-mediated DNA repair for their survival. Both olaparib and rucaparib are inhibitors of the PARP enzymes responsible for DNA damage repair. In 2014, olaparib was the first drug in its category to be approved for ovarian cancer with mutations in BRCA gene, with only mild to moderate adverse effects to date. In fact, the clinical trial data that convinced the EMA in 2014 for the efficacy of olaparib were not as convincing for the FDA for various reasons. A few months later, olaparib was granted approval in the US. Further testing on humans confirmed the increased progression-free survival for patients with BRCA mutations on olaparib. Two years later, in 2016, rucaparib became the second drug with accelerated approval for treatment of patients with BRCA mutations. In addition, the need for a reliable genetic test to identify patients eligible to receive the treatment was also covered by the FDA. The FoundationFocus CDxBRCA test is the first FDA-approved next-generation sequencing (NGS)-based companion diagnostic, which detects alterations in BRCA genes in the tumour tissue of ovarian cancer patients.
Between the two decades of cancer treatment genotype-based approvals, the first oral anticoagulant warfarin, used for the prevention and treatment of strokes, thrombosis and atrial fibrillation among others, was shown to be influenced by genetic variation, as well. Genetic testing prior to prescription along with genotype-guided dosing of warfarin was recommended, changing the way we perceive drug dosing. Warfarin is one of the most commonly prescribed drugs, with more than 2 million people are treated with warfarin every year in the US, hence the importance of such advancement is great, as it affects the clinical management of millions of people worldwide.
The list of drugs that receive approval and are specifically designed for variant genotypic characteristics is fast growing. It is our responsibility to educate health professionals and most of all patients. Now, more than ever, we need to find the best way to use and protect genetic information, while at the same time proving its power to change clinical practice forever.