NEW YORK (GenomeWeb) – Myriad Genetics is hoping that data from a large randomized controlled study published last week on GeneSight will change the reimbursement prospects for the pharmacogenetic test, as well as shift the standard of care for treating depression.
Myriad CEO Mark Capone told analysts last week following publication of the study that the company has been discussing this data with commercial payors. Data from the Genomics Used to Improve Depression Decisions (GUIDED) study, published in the Journal of Psychiatric Research, will also be part of an evidence package that Myriad will use to request expansion of its Medicare local coverage decision for the test when ordered by primary care docs.
Although the study failed to meet its primary endpoint, and symptom improvement at eight weeks was not statistically significant for patients in the pharmacogenetic testing arm compared to the treatment-as-usual arm, the study did show that patients receiving GeneSight-guided treatment had significant improvements in remission and response rates.
Researchers also presented additional analysis in the publication that Myriad executives said have intrigued payors. "When supported by reimbursement, we will begin our launch into the primary care market, which represents more than 60 percent of the depression market," Capone said. "[This] will also included a significant direct-to-patient awareness campaign."
Last year, before Myriad presented top-line data from GUIDED at a psychiatry conference, a task force of the American Psychiatric Association's research council evaluated the evidence underlying several pharmacogenetic tests for personalizing antidepressant treatment, including GeneSight, and found the data wanting. "At present, there are insufficient data to support the widespread use of combinatorial pharmacogenetic testing in clinical practice, although there are clinical situations in which the technology may be informative, particularly in predicting side effects," the authors wrote in the American Journal of Psychiatry last April.
Charles Nemeroff, head of the APA task force and chair of the University of Miami's psychiatry and behavioral sciences department, remains unmoved by the latest published data, because the GUIDED study failed to show statistically significant improvements in symptoms in the GeneSight arm. "Definitely no change in our statement [which is] now supported by the US Food and Drug Administration," he said.
Last year, the FDA issued a statement cautioning patients and healthcare providers against changing treatments based on results from pharmacogenetic tests with unproven indications that the agency hasn't approved for marketing. In particular, the agency called out companies offering non-FDA approved or cleared PGx tests that claim to help physicians identify which antidepressants patients will best respond to or experience side effects from. "The relationship between DNA variations and the effectiveness of antidepressant medication has never been established," the agency said.
Myriad told analysts that it believes the FDA's statement was directed at direct-to-consumer testing companies, which is not the space in which Myriad operates because GeneSight is a lab-developed test ordered by a physician. The company also doesn't seem to be waiting for the APA task force to change its mind. Capone pointed out to analysts that the APA's own guidelines say that the goal of treatment is remission, which is an endpoint that GUIDED met.
Myriad executives also noted that the APA task force's publication is separate from the association's guidelines on the treatment of depression, which haven't been updated since 2010. In any case, Myriad is concerned about increasing reimbursement of its test, and in its discussions with payors, they seem to care most about the remission endpoint, according to Capone, and haven't been too concerned about missing the symptom improvement endpoint in the GUIDED study.
"One of the differences we face in the neuroscience area is that guidelines are generally updated maybe every decade or longer," and as a result, payors have had to make coverage decisions that aren't supported by guidelines, Capone said. He noted that the company is in discussions with groups to try to update pharmacogenetic testing guidelines supportive of the GeneSight test.
Following publication of the GUIDED data, Cowen and Co. analyst Doug Schenkel upgraded Myriad's stock to an Outperform rating from a previous Market Perform rating. Even without broader GeneSight reimbursement, the company has a path to low-single digit to mid-single digit growth, Schenkel wrote in a note to investors on Friday, and put a price target on Myriad's stock of $37 per share, which is 26 percent above its closing price of $29.29 on Thursday but lower than a previous target of $40 per share.
Analyst William Quirk from Piper Jaffray reiterated an overweight rating and a $47 price target for Myriad's stock. "We believe the published manuscript should drive longer-term private payor coverage," Quirk wrote in a note to investors.
GeneSight employs a proprietary algorithm to analyze 12 genes and assess how they impact patients' ability to process dozens of psychotropic medications. The test report buckets depression treatments as red (significant gene-drug interaction), yellow (moderate gene-drug interaction), or green (use as directed.) When the test report shows that patients are on red or yellow medications, their doctors should consider changing the drug or dose, while patients on green medications don't require a medication change.
Myriad executives highlighted GUIDED as the largest prospective, randomized-controlled pharmacogenetic study in depression that the company designed specifically to answer questions insurers are interested in. The study randomized 1,200 patients with major depression who failed at least one previous treatment to either getting treatment guided by GeneSight or treatment as usual. Patients were evaluated from baseline to eight weeks to assess changes in the Hamilton Depression Scale (HAM-D 17) scores, a subjective questionnaire used to measure the impact interventions are having on patients' outcome. Patients and centralized raters who assessed HAM-D 17 scores in the GUIDED study were blinded to GeneSight results.
A HAM-D 17 score between zero and 7 is normal, eight to 14 is mildly depressed, 14 to 18 is moderately depressed, 19 to 22 is severely depressed, and above 22 is very severely depressed. Between baseline and the eight week follow up visit, the percent change in HAM-D 17 scores indicated symptom improvement, the primary outcome of the study. Secondary endpoints included response rate, defined as the percentage of patients whose HAM-D 17 scores decrease by greater than 50 percent, and remission rate, which was the percentage of patients whose HAM-D 17 scores decrease to 7 or below.
In the GUIDED study, 15.3 percent of patients getting treatment based on GeneSight achieved remission, 26 percent had a response, and 27.2 percent saw their symptoms improve. In the placebo arm, comparatively, 10.1 percent achieved remission, 19.9 percent had a response, and 24.4 percent saw symptom improvement. The 50 percent improvement in remission rates in in the GeneSight arm compared to placebo and the 30 percent improvement response rates were statistically significant, though the 11 percent symptom improvement was not.
"Payors have been very responsive to this data," particularly on remission, Capone told analysts, because that suggests they can save thousands of dollars per patient per year. Insurers are paying attention to GUIDED data, he explained, because other depression studies tend not to enroll more challenging treatment-resistant patients, and don't compare the investigational treatments against an active agent. In contrast, GUIDED had a higher bar, Myriad execs suggested, enrolling treatment-resistant patients and evaluating GeneSight's ability to improve outcomes compared to those receiving treatments based on trial-and-error prescribing.
During the call with analysts, Capone also tried to provide context regarding the evidence regulators use to evaluate depression treatments. An evaluation Myriad conducted of 40 registration studies for depression drugs submitted to the FDA over the last 20 years showed that no drugs were approved based on a comparison against an active drug and most studies enrolled treatment-naive patients instead of more challenging treatment-resistant patients. In only 13 percent of the registration studies the investigational drug had statistical significant improvements in remission compared to placebo, 30 percent significantly improved response, and 70 percent significantly improved symptoms.
"Remission is particularly difficult to achieve for treatment-resistant depressed patients who have failed previous medications," Capone said, adding that prior studies have shown that in treatment resistant patients, achieving symptom improvement without remission can result in relapse back into depression.
In GUIDED, after the eight-week blinded period, patients in the GeneSight arm continued to improve in terms of remission, response, and symptom improvement over a six-month follow-up period. Remission rates more than doubled between week eight and 24 during the open-label phase. "These result has been well received by payors that want assurance that the GeneSight benefits are enduring," said Bryan Dechairo, executive VP of clinical development at Myriad and the last author of the GUIDED study.
Researchers further evaluated patients who entered the study on red medications and either remained on red medications or were switched to yellow or green drugs. Remission rates were 153 percent higher, response rates were 71 percent higher, and symptom improvement rates were 59 percent higher when patients were switched from red to yellow or green meds — all statistically significant changes.
This analysis "establishes a new standard of care" for physicians by demonstrating that patients on red medications must be identified and have their medications modified, said Dechairo. "This switching analysis has also been an important point in our payor discussions, as utilization management programs can focus on switching patients from red medications, which would deliver results even better than those in the GUIDED study," he said.
Researchers also analyzed the data excluding the 30 percent of patients who entered the study on green medications and were already expected to be doing well. In this subset, patients in the GeneSight-guided arm who entered on yellow or red medications had statistically significant improvements in all three outcome measures. Myriad intends to publish this analysis in an upcoming publication.
"We believe this reflects the real-world reality in the US," said Dechairo. "Having a tool that can improve outcomes for some of the 70 percent of treatment-resistant depressed patients is a major advance in the growing mental health crisis."
The data from GUIDED is the latest addition to Myriad's growing dossier of evidence demonstrating the impact of GeneSight on patient outcomes and healthcare costs. And the company plans to use it to push ahead with marketing to increase reimbursement and adoption.
One prior cost-effectiveness study using drug claims data showed that using GeneSight can increase treatment adherence and save an average of $1,036 per year per patient, while another study using commercial claims data showed GeneSight's potential to save $1,556 per patient by reducing disability claims, medical utilization, workplace absence.
Additionally, for the Medicare-eligible population, Myriad was asked to conduct the IMPACT study and evaluate whether primary care physicians would be able to use GeneSight results. The study showed no clinically meaningful differences in outcomes between patients treated by psychiatrists or primary care docs, though since primary care docs were more likely to follow GeneSight's recommendations, patients in this arm had better remission, response, and symptom improvement rates compared to those treated by psychiatrists.
Myriad is hoping this data will support expansion of its local coverage decision for GeneSight when it is ordered by primary care doctors, who see 60 percent of treatment-resistant patients in the US and represent a significant untapped market opportunity for the test. Currently, the more than 300,000 GeneSight tests Myriad sells per year are largely ordered by psychiatrists. Once there is greater reimbursement traction, Myriad is planning a significant marketing push into the primary care market, including direct-to-patient advertising for the test, according to Capone.
During the call, Myriad executives also tried to mitigate regulatory concerns and confusion fueled by FDA's cautionary statement on PGx testing. The company has interpreted this as being directed at direct-to-consumer testing companies. GeneSight, which is a lab-developed test (LDT) performed in a CLIA-certified lab, must be ordered by physicians.
Capone noted that the FDA has publicly stated that it will continue to practice enforcement discretion for LDTs, and leave it up to legislators to reform diagnostic regulations that may or may not bring LDTs under the agency's oversight. In December, legislators in the House of Representatives and the Senate incorporated the FDA's ideas for diagnostics regulatory reform into a draft bill that features a pre-certification program that labs could use to bring the majority of new diagnostics to market, while having to submit around 10 percent of tests for premarket review.
Capone acknowledged support for the bill that's working its way through Congress. "When legislation is passed we will comply with that," he said, noting that the draft bill language thus far suggests that tests already on the market, such as GeneSight, would be grandfathered.