On the 26th of June 2000, President Clinton and Prime Minister Blair announced amid much fanfare that the first draft of the human genome had been completed. This led to extraordinarily optimistic claims about the ways in which genomics research would immediately impact diagnosis, treatment and prevention of disease, but also reduce drug development time lines and increase the likelihood of R&D success rates.
Of 132 new molecular entities and biologics identified as approved precision medicines by the Personalized Medicine Coalition (PMC) in their 2017 report, an impressive number, 85, are non-oncology products. PMC broadly categorizes personalized medicines as therapeutics for which the label includes reference to specific biomarkers identified by diagnostic tools, which can “help guide decisions regarding the use of therapeutics in individual patients.”
Recently approved non-oncology drugs with pharmacogenomic information on the label include Orkambi (lumacaftor/ivacaftor) to treat cystic fibrosis, Repatha (evolocumab) for hyperlipidemia in the familial form, and Nucala (mepolizumab) indicated for severe asthma.
Breaking down the numbers, however, it becomes clear that a gap exists between degrees of personalization of cancer versus non-cancer drugs. Thirty-six of the 132 precision medicines are reliant on a companion or complementary diagnostic for therapy selection; 26 of which are oncology, and 10 non-oncology drugs. Twenty of the 26 oncology drugs have Food and Drug Administration (FDA) approved companion diagnostics. The 36 drugs generated approximately $25 billion in revenue in 2016. Ninety percent of this revenue was attributed to oncology drugs.
Examining the drug development pipeline, researchers at M.I.T. identified what they termed “Likely Precision Medicines” (LPMs) in development. Narrowing LPMs to those which in clinical trials specifically employ biomarkers for selection of therapy and prediction of treatment efficacy and toxicity - a much narrower definition of precision medicine than the one PMC employs – researchers found that, for the years 2015 and 2016, approximately 25% of all cancer drug trials were "LPM" trials, but only 1-2% of trials for non-cancer indications were "LPM" trials. This suggests that most non-oncology trials which make use of biomarkers are employing them for diagnosis and screening, and not selection of therapy, or prediction of treatment efficacy and toxicity.
In oncology, companion diagnostics measure genetic mutations of a therapeutic target in tumor tissue, linking the biomarker identified by the diagnostic test to the drug’s mechanism of action. At present, in most non-oncology indications, this is usually not clinically feasible given the difficulties in obtaining diseased tissue for sampling.
Furthermore, there are many unapproved Laboratory Development Test (LDT) tests being used to monitor patients for therapy response and disease recurrence in the non-oncology space. Many of these LDT tests may aid physicians in benefit-risk decision-making about the use of a drug, but such information is not considered “essential for the safe and effective use of a therapeutic,” as would be the case with an FDA-approved companion diagnostic.
In cardiology, precision medicine has resulted in the ability to measure gene variants associated with increases in risk for diseases. For example, Roche is in the early stages of developing complementary diagnostic tests to help select the appropriate medicines to be used for acute coronary syndrome. But thus far, in cardiology, pharmacogenomic measurements are not meaningful in most instances, because relative risks associated with given gene variants are quite small and therefore not actionable.
Drug companies are also identifying biomarkers across neurological conditions that have genetic ties to disease, such as depression, schizophrenia, Parkinson’s and Alzheimer’s diseases. For example, several companies have drugs in the pipeline targeting deposits of amyloid β-peptide in plaques in brain tissue, which is hypothesized to cause neuro-degeneration in Alzheimer’s. Late-phase failure has been the norm recently, however, as Lilly’s solanezumab and Merck & Co’s verubecestat bowed out in phase III. Two phase III amyloid targets remain in clinical trials - Biogen’s aducanumab and Roche‘s crenezumab.
Amyloid imaging has been established as a robust biomarker of the presence of abnormal amyloid deposition in the brain. The use of positron emission tomography (PET) with florbetapir F18 identifies abnormal deposits of amyloid. Florbetapir may accelerate research by helping to identify people at high risk of developing Alzheimer’s and to enroll them in clinical drug trials. But, to date florbetapir has done little to impact treatment decisions. It is a validated biomarker test without a companion therapy. It appears that this has prevented many payers from reimbursing the diagnostic.
In spite of significant challenges, drug and diagnostic companies have been increasing their investment in discovery of exploratory biomarkers that focus on non-oncology areas such as infectious diseases (eg, hepatitis), rheumatology, and cardiovascular diseases.
In rheumatology, precision medicine is gradually emerging as scientists begin to employ genetic profiling of joint tissue to assess which drugs will work for which rheumatoid arthritis patients.
Notably, several rare diseases outside of oncology are heavily reliant on pharmacogenomics, including cystic fibrosis, for which several precision medicines have been launched.
And, a promising sign of progress in precision non-oncology is reflected by the fact that as of March of this year 18 of 52 (35%) companion diagnostics in the pipeline are intended for use in non-oncology indications. As more companion diagnostics are being developed close to or in conjunction with precision therapies, a concomitant higher degree of personalization in the non-oncology space will likely be achieved.
