Accurate Pgx Testing: the Gateway to Personalized Medicine
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Accurate PGx Testing: The Gateway To IPI Supergraphic 2 Personalized Medicine For use as a graphic overlay on the edge of photos, at the given angle. Should act as a bridge between the photo and adjacent background. Please do not change the color or the angle of the supergraphic. POWERED BY CITELINE & IN VIVO SPONSORED BY Accurate PGx Testing: The Gateway To Personalized Medicine Pharmacogenetic testing is critical to the implementation of personalized medicine. Researchers continue to uncover the multiple genetic influences on drug response, and the considerable variations across populations and regions. Hence the urgent need for accurate, comprehensive and accessible tests, in order to ensure that patients receive the most effective and safest treatments. Personalized trials continue to grow The proportion of clinical trials that incorporate PGx biomarkers to target specific patients continues Pharmacogenomics’ potential to transform drug to increase. Data from Informa’s Trialtrove shows discovery and development is becoming clearer. Over that well over half (55%) of all trials initiated in 2018 half of all trials initiated in 2018 included the use of included PGx biomarkers for patient selection into a selective pharmacogenomic and/or pharmacogenetic trial or cohort, up from 40% in 2014. The trend-line (PGx) biomarkers, according to data from Informa’s looks set to continue rising. (See Exhibit 1) Trialtrove. These trials are more likely to succeed than those without – and that advantage has grown This growth could be explained by the fact that trials several-fold in the last two years. which include a PGx biomarker for patient selection 2 / October 2019 © Informa UK Ltd 2019 (Unauthorized photocopying prohibited.) Exhibit 1. Phase I–IV Trials Using Biomarkers By Trial Start Year, 2003–2018 2500 60% 50% 2000 40% ) n 1500 ( t n u o 30% c l a i r T 1000 Proportion (%) 20% 500 10% 0 0% 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 Trials using PGx biomarkers for patient selection (n) Trials testing biomarkers only (n) % biomarker trials using PGx for patient selection Source: Trialtrove, July 2019 Definition: Clinical trials with PGx biomarkers are trials which incorporate analysis of pharmacogenomics (genome-level variations) and/or pharmacogenetics (single-gene or DNA sequence-level variations) for patient selection or stratification. Individuals are invited to participate in the study, or in a particular study arm, based on genetic or molecular profiling that can help predict their response to a therapy. Trials testing biomarkers only are those using biomarkers for efficacy or toxicity, and NOT for patient selection or stratification. are more likely to succeed than those that do not – drug pricing translate into an urgent need and the relative advantage is growing, according to among biopharma companies to transform trial Trialtrove data. An analysis of trial outcomes from success rates and efficiency. PGx are making that studies initiated between 2003 and 2018 showed transformation possible. By using genetic fingerprints that over 58% of PGx trials had a positive outcome, to predict individual responses to drugs – around versus just 50% for those without. (See Exhibit 2) safety, efficacy, and/or pharmacokinetics – they allow That 8% difference represents a four-fold increase sponsors to optimally select the patients most likely over that found just two years ago, from the same to benefit from a particular treatment. This increases analysis on trial data from 2003-2016.1 the chances of a positive trial outcome. The challenges of rising R&D costs, declining Indeed, an earlier BIO Industry Analysis using productivity and growing payer pressure on Informa Pharma Intelligence’s Biomedtracker © Informa UK Ltd 2019 (Unauthorized photocopying prohibited.) October 2019 / 3 Exhibit 2. Effect Of Biomarker Use On Completed Trial Outcomes 70.0 PGx biomarkers for patient selection Biomarkers only Non-biomarker trials 60.0 50.0 40.0 30.0 20.0 Proportion (%) 10.0 58.4 51.2 50.4 15.6 16.0 25.9 32.8 40.5 52.8 49.4 47.9 14.1 17.0 11.1 33.1 33.5 41.0 55.1 53.0 50.8 15.1 15.0 29.9 32.0 40.4 9.1 8.7 0.0 Positive Negative Unknown* Positive Negative Unknown* Positive Negative Unknown* All Therapeutic Areas Oncology Non-Oncology Source: Trialtrove, July 2019 *Unknown category includes trials that have not yet reported full results for the primary endpoint(s) or reporting indeterminate outcomes (reported outcome(s) are neither clearly positive nor clearly negative) and Amplion Inc.’s BiomarkerBase suggested that (pembrolizumab) for non-small cell lung cancer are drug candidates tested in trials that used selection first tested for levels of a protein found on cancer biomarkers to inform patient recruitment were cells called programmed death ligand-1 (PD-L1). three times more likely to be approved than those According to the Personalized Medicine Coalition, which did not. PGx programs were also more likely the number of personalized medicines on the to progress from one development phase to the market rose to over 130 in 2016 from just 5 in 2008.3 next. Phase III programs incorporating PGx were Of the 59 new drugs approved by the US FDA in tagged with a 76.5% success rate, versus 55% for the 2018, 12 (20%) were based on predictive biomarkers. non-selective trials. This difference is meaningful, given the high cost of Phase III studies – comprising Phase II is the PGx sweet spot, but this is shifting by far the largest chunk of overall R&D spend.2 Phase II accounts for the largest share of PGx trials The use of PGx testing is not limited to trials: –over 40% of the total. (See Exhibit 3) Phase II trials a growing number of approved drugs are are generally large enough to be able to associate ‘personalized’, meaning they are indicated a pharmacogenomic marker with a given clinical specifically for patients with particular genetic phenotype or endpoint, and are able to inform more or molecular biomarkers. For example, almost effective Phase III trial design.4 half of patients with advanced melanoma have mutations in the BRAF gene, and are thus suitable Furthermore, in oncology – which dominates the for treatment with a targeted BRAF inhibitor, such PGx trial landscape - Phase I studies are often as Zelboraf (vemorafenib). Patients taking Keytruda combined with Phase II for ethical reasons and to 4 / October 2019 © Informa UK Ltd 2019 (Unauthorized photocopying prohibited.) accelerate a therapy’s route to market where there is a significant unmet need. In this analysis, mixed The Genomics Revolution phase trials were rolled into accounts for the more advanced phase, meaning Phase I/II trials were Scientists’ understanding of health – and included in Phase II trial counts. disease – has deepened exponentially since Yet the use of PGx has nevertheless steadily shifted the sequencing of the Human Genome at upstream since 2005, with an increasingly large the turn of the century. That achievement share taken by Phase I studies. Over a quarter of unlocked a treasure trove of new drug all Phase I trials initiated in 2018 were PGx trials, according to Trialtrove, versus just over 10% in 2005. targets, and led to the development of (See Exhibit 3) more efficient, accessible and accurate gene sequencing and editing tools, including The blue segments of the horizontal lines represent the share of PGx trials that were Phase I. This share CRISPR-Cas9, for example. has steadily increased since 2005, illustrated by But this was just the start. Researchers lengthening blue segments in later years. have since uncovered and begun to This trend suggests that drug developers analyse the multiple intermediary ‘-omics’ recognize the need to begin early – including in layers that sit between the genome and pre-clinical work – in order to take full advantage of PGx approaches. Early-phase trials provide actual disease symptoms. They are also an opportunity to generate hypotheses about starting to determine the various influences the various pharmacogenomic signals that may (environmental, behavioural, molecular, be relevant to drug response – signals that can be tested and confirmed in later-stage trials. For genetic) on these intermediary pathways example, in Phase I studies, toxicity parameters may and molecules. Pharmacogenomic and be studied at varying dosages, as well as drug-drug pharmacogenetic tools and tests are a interactions, and in some cases (oncology), drug core component of this work, helping pin- efficacy or proxy-biomarkers. All this can inform Phase II design, doses, patient stratification and point and measure the many genetic and choice of diagnostic. molecular players in health and disease, and use them to develop better treatments. Oncology still dominates, but other indications are catching up Indeed, the result of this scientific Oncology remains the runaway leader in PGx trials, flourishing include targeted immuno- accounting for over 90% of the 11,000 trials initiated therapy drugs for cancer, potentially between 2003-2018, according to Trialtrove. curative gene therapies for certain inherited That dominance has not changed over last two disorders, and the first engineered cell years, and is unlikely to in the near-term: cancer is therapies, Yescarta and Kymriah. The a very heterogenous set of conditions, caused by foundations are being laid for a new era of genetic mutations that are now understood to often be specific to particular patient sub-populations. personalized medicines and drug R&D. Data from the Personalized Medicine Coalition © Informa UK Ltd 2019 (Unauthorized photocopying prohibited.) October 2019 / 5 Exhibit 3. Trial Phase Distribution By Year - PGx Trials 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 I II III IV Source: Trialtrove, July 2019 The pink segments of the horizontal lines represent the share of PGx trials that were Phase I.