This story is a continuation of Part 1. Click here for theother half of the story.
It's not a tumor
Cancer is not the only therapeutic area receiving attentionfrom the companion diagnostics industry, although the predominant approach isstill genomics.
In January, the FDA approved Vertex Pharmaceuticals'Kalydeco, a new drug for the treatment cystic fibrosis (CF), but only inpatients with a specific mutation (G551D) of the CFTR protein, which is muchrarer than the F508 mutation commonly seen in CF patients. As part of thedrug's label, the drug cannot be given to a patient until the presence of theG551D mutation is known using either existing knowledge or the use of anFDA-cleared CF mutation test, such as Luminex's xTAG Cystic Fibrosis Assay.By July, the drug was also approved for use in Europe, andongoing studies are showing efficacy in patients with the F508 deletionmutation when used in combination with the company's investigational compoundVX-809.
Infectious disease is also seeing an increasing interest fromthe companion diagnostics market. In February, Erlangen, Germany's SiemensHealthcare Diagnostics announced a partnership with ViiV Healthcare ofBrentford, U.K., to focus on clinical trials related to Selzentry (maraviroc),the latter's CCR5 co-receptor antagonist for use in select HIV patients. Aspart of ViiV's Phase III trial, Siemens will provide genotyping expertise thatit hopes will lead to an FDA-approved test.
Similarly, in June, San Diego's Millennium Laboratoriesannounced its introduction of Millennium Pharmacogenetic Testing (PGT), asaliva-based test targeted at genetic variations in enzymes associated withmedications commonly used in patients with chronic pain. The goal is to ensurepatients not only receive drugs that effectively ameliorate their pain, butalso help identify patients who could experience unpleasant side effects.
Whether PGT becomes a true companion diagnostics or justanother tool in the clinical arsenal remains to be seen.
Of course, as noted, companion diagnostics aren't just aboutputting the right patient on the right drug, they can also be about making surethe right patient gets the right amount of a drug or that specific patientpopulations are monitored for undesirable side effects that may occur morefrequently.
The granddaddy in this category is warfarin. Recognizing theimpact of genetic profile on how patients metabolized warfarin, the FDA issuednew guidance in 2007 on the use of genetic testing to help determine theappropriate dose of warfarin, allowing for efficacy while limiting the risk ofexcessive bleeding. The forms of the CYP2C9 and VKORC1 genes a patient carrieshave significant impact how he or she responds to a given dose, so the drug'slabeling was updated to reflect the importance of genotype information inpatient dose selection.
What's true for warfarin may also be true for Plavix. LastNovember, Jessica Mega and colleagues at Brigham and Women's Hospital in Bostonpresented their findings on the possible role of patient genetics in their responseto treatment with Plavix. Looking strictly at platelet function (rather thanclinical outcomes), the researchers found that patients carrying one mutantversion of the CYP2C19 gene required up to threefold as much daily Plavix (225mg) to show the same effect as other patients showed with the standard dose (75mg). Furthermore, patients carrying two mutant versions of the gene did notshow the same response at the highest dose tested.
"It appears that it is only patients who are homozygousCYP2C19*2 carriers—and these make up only 2 percent of the population—who arereally difficult to treat with clopidogrel (Plavix), and they probably do needto be treated with one of the other agents—prasugrel (Effient) or ticagrelor(Brilinta)," explains Mega.
Whether this information might lead to any labeling changesfor Plavix or changes in clinical practice by physicians is hard to say. Megaacknowledges that at the time, testing required sending samples off, which mayput physicians off, but she strongly believed that this was an importantconsideration in dosing decisions, alongside the more typical clinicalcharacterizations.
The University of Florida-Gainesville's Lawrence Lesko addedhis voice to the conversation, stating: "I've been both a patient and a scientist.There is a clinical utility that is generally speaking to the populationbenefit of doing the test. And then there is the personal utility: what thistest means to me. If I were a patient, I'd very much want this genetic test ifI were going on Plavix today."
Already, companies like Santa Fe, N.M.-based Matrix Genomicsare offering consumers the chance to have their CYP2C19 status tested, as wellas markers for response to warfarin and tamoxifen and a variety of medicalconditions such as depression, Alzheimer's and Parkinson's.
Tomorrow never knows
How rapidly companion diagnostics become the norm for drugapproval and eventually for patient prescribing is an open question, but itseems to be inevitable in one form or another.
"Looking at flow of diagnostics tests performed in apathology lab today I could also foresee a significant change in favor ofcompanion diagnostics," offers Dako's Winther. "In my opinion, I could easilyforesee that in seven to eight years' time, you will see no oncology drug beingprescribed without having a companion diagnostics attached to it."
Whether for oncology or to simply ensure the safest dosesare being prescribed, the advent of companion diagnostics should be asignificant comfort to patients like Dorothy, who, by the way, recovered fullyfrom her mishap and lived another decade or so, thanks to her healthcare teamand therapeutics.