Precision medicines, defined as a medical approach that proposes to prevent and treat disease based upon a person's unique genetic makeup and lifestyle habits, is touted as the next wave in drug development. So has the promise of precision medicines been realized or are they still a work in progress?
As of 2016, more than 230 therapies across the US, Canada, Europe, and Japan include pharmacogenetics information on their labels and the FDA's list of therapies with pharmacogenomic biomarkers in drug labeling totals more than 200 medicines, according to a recent analysis by QuintilesIMS. So what is the verdict thus far on precision medicines?
Precision medicines and drug approvals
Personalized medicine, which is also called precision or individualized medicine, is an evolving field in which physicians use diagnostic tests to determine which medical treatments will work best for each patient, according to a definition provided by the Personalized Medicines Coalition (PMC), an industry advocacy group for personalized medicines. By combining the data from diagnostic tests with an individual’s medical history, circumstances and values, the goal of personalized medicines is to develop targeted treatment and prevention plans.
In evaluating the new molecular entities (NMEs) approved by the US Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research, PMC defined personalized medicines as those therapeutic products for which the label includes reference to specific biological markers, identified by diagnostic tools, that help guide decisions and/or procedures for their use in individual patients. Using that as a definition, PMC identified that six of the 22 new molecular entities (NMEs) approved in 2016 (see Table I ) may be classified as personalized medicines, which continues a trend in personalized medicine approvals. More than 20% of NMEs approved by the FDA in each of the past three years were personalized medicines: 2014 (21%), 2015 (28%), and 2016 (27%). In 2016, 50% of the NME personalized medicines approved were oncology drugs: Roche’s Tecentriq (atezolizumab) for treating bladder cancer and non-small-cell lung cancer; AbbVie’s and Roche’s Venclexta (venetoclax) for treating chronic lymphocytic leukemia; and Clovis Oncology’s Rubraca (rucaparib) for treating advanced ovarian cancer. In 2015, 13 of the 45 NMEs approved by the FDA were personalized medicines.
|Table I: Personalized Medicines Approved as New Molecular Entities in 2016 (New Drug Applications (NDAs) and Original Biologics License Applications (BLAs) by the US Food and Drug Administration’s Center for Drug Evaluation and Research.
||Proprietary name (active ingredient); application type
|AbbVie and Roche*
||Venclexta (venetoclax); NDA
||Chronic lymphocytic leukemia in patients with a specific chromosomal abnormality
||Rubraca (rucaparib); NDA
||Certain types of ovarian cancer
||Epclusa (sofosbuvir and velpatasvir); NDA
||All six major forms of hepatitis C virus
|Merck & Co.
||Zepatier (elbasvir and grazoprevir); NDA
||Chronic hepatitis C virus, genotypes 1 and 4
||Tecentriq (atezolizumab); NDA
||Advanced or metastatic urothelial cancer and metastatic non-small cell lung cancer. Iinformed by PD-L1 expression levels in the tumors of patients.
||Exondys 51 (eteplirsen); NDA
||Duchenne muscular dystrophy
* Venclexta (venetoclax) is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the US and commercialized by AbbVie outside of the US.
Source: US Food and Drug Administration's Center for Drug Evaluation and Research, company information, and Personalized Medicine at FDA: 2016 Progress Report (Personalized Medicines Coalition).
Roche scored two personalized medicine NME approvals in 2016. The first was for Tecentriq (atezolizumab), an anti-bladder-cancer drug, and Venclexta (venetoclax), a drug for treating chronic lymphocytic leukemia. Tecentriq, a programmed death (PD)-1/PD-L1 inhibitor, is the first (PD)-1/PD-L1 inhibitor approved for urothelial carcinoma, the most common type of bladder cancer, according to the FDA. The decision to use this product is informed by PD-L1 expression levels in the tumors of patients. Tecentriq represents Roche’s first commercial entry for a (PD)-1/PD-L1 inhibitor, an important new class of immuno-oncology drugs and is forecast by some analysts to reach blockbuster status.
The other NME approval for personalized medicines by Roche in 2016 was Venclexta, which is pegged by some analysts for blockbuster status. The drug is manufactured by AbbVie and jointly commercialized in the US by AbbVie and Roche, through its Genentech subsidiary. AbbVie is commercializing the drug outside the US. The decision to use this product is informed by the chromosome 17p deletion biomarker status in patients.
Merck & Co. gained a NME approval for one personalized medicine in 2016 with Zepatier (elbasvir and grazoprevir), a small-molecule combination drug regimen for treating hepatitis C. The decision to use this product is informed by the hepatitis C virus genotype 1 and 4 biomarker status of the viral infection.
Gilead Sciences received FDA approval for one personalized therapy in 2016, a new combination hepatitis C drug, Epclusa (sofosbuvir and velpatasvir), an all-oral, pan-genotypic, single tablet regimen for treating a broad genotype range of chronic HCV infection. Epclusa uses the active ingredient, sofosbuvir, also the active ingredient in Gilead’s blockbuster HCV drug, Sovaldi. The decision to use this product is informed by the HCV genotype status of the viral infection in patients.
Other personalized medicines approved in 2016 were Clovis Oncology’s Rubraca (rucaparib), a poly ADP-ribose polymerase (PARP) inhibitor for treating ovarian cancer, and Sarepta Therapeutics’ Exondys 51 (eteplirsen) for treating Duchenne muscular dystrophy (DMD), a rare genetic disorder. For Rubraca, the decision to use this product is informed by the BRCA1/2 biomarker status in patients. For Exondys, the decision to use this product is informed by the DMD mutation biomarker status in patients.
Precision medicines and drug development and market penetration
In addition to drug approvals, another important measure of the success of precision or personalized medicines is the level of new drug development for these products. In an article in The Journal for Precision Medicine, “Towards Targeted Therapeutics: The Pharmaceutical Industry and Personalized Medicine,” (2015), PMC President Edward Abrahams and PMC Board Chair Stephen Eck, Vice President, Oncology Medical Sciences, Astellas Pharma Global Development, cite data from the Tufts Center for the Study of Drug Development showing that personalized medicines account for more than 40% of all drugs in development. A 2017 report by QuintilesIMS, Upholding the Clinical Promise of Precision Medicine: Current Position and Outlook, says that as of 2016, more than 230 therapies across the US, Canada, Europe, and Japan include pharmacogenetics information on their labels and the FDA's list of therapies with pharmacogenomic biomarkers in drug labeling totals more than 200 medicines.
For purposes of its analysis, QuintileIMS first defines “systems therapeutics” as interventions that are: personalized with respect to the selection of medicines and dosing; directly or indirectly impact disease progression; and are complex (incorporating patient status, comorbidities). It then breaks down “system therapeutics” into two broad categories: stratified and personalized. Both stratification and personalization are components of precision medicines. Stratified medicines provide differential treatments tailored to specific groups of patients with individuals within the group receiving identical treatment. Personalized medicine takes stratified medicine one step further as differential treatments tailored to individual patients based on their specific genome as well as their status (e.g., pediatric, elderly, gender).
Using these definitions, the QuintilesIMS report notes that overall a total of 80 therapies have been approved with labeling that requires or recommends pharmacogenomic testing. Since 2011, 30 of the stratified medicines in its analysis contained a pharmacogenomic biomarker that directed patient stratification post-approval, and 40 received regulatory approval. Oncology contributed the greatest number of molecules and represented 58% of the total number of stratified therapies. Sixteen percent of the stratified molecules consist of antiviral therapies from the HIV and hepatitis C drug classes. Central nervous system (CNS) therapies made up 9% of stratified medicines, according to the analysis. On a molecule basis, the QunitilesIMS report points out that 80% of stratified medicines are small molecules. Within stratified medicines, older small molecules, particularly those in CNS and breast cancer, account for over 75% of the volume. Also, although the greatest number of stratified therapies have been approved or received biomarker designation postapproval since 2006, 31% of stratified therapies were approved before 2005.
The report further points out total use of stratified medicines in the developed markets, measured in standard units, has remained relatively flat since 2006. This is primarily due to the higher representation of small-molecule therapies within the group, many of which experienced generic competition within the study period, balanced against the launch of new oncology and antiviral therapies with low volumes. Overall, spending on stratified therapies in the 10 developed markets totaled over $62.8 billion in 2016, according to the QuintilesIMS report. Spending across the developed markets increased at a compound annual growth rate (CAGR) of 20.5% from 2011–2016, driven primarily from growth outside of the United States and the EU5 (Italy, Germany, Spain, France, and the UK) however, growth slowed to 3% in 2016. This change in growth rate is largely driven by a reversal in hepatitis C-driven therapy growth seen during the 2013-2015 period. In the US, spending on stratified therapies was $38.2B billion in 2016. Spending on stratified medicines in the EU5 reached $14.4 billion in 2016. EU5 countries experienced significant growth in the past five years, with a CAGR of 11.3% over the period of 2011 through 2016. However, growth declined from 2015–2016 by -8.1%. This decline was due in part to the end of hepatitis C therapy uptake, as well as policymaker responses to unexpectedly high new drug spending in 2014 and 2015, according to the QuintilesIMS report.