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Geneticure Launches PGx Test Via Consumer-Facing Model; Pursuing Randomized Trial


NEW YORK (GenomeWeb) – Pharmacogenetics firm Geneticure last week began selling a test for personalizing treatments for high blood pressure via a consumer-facing online model.

However, the company is also pursuing a prospective, randomized controlled trial to demonstrate the safety and efficacy of its test compared to the standard methods of prescribing blood pressure medications. Geneticure plans to submit data from this study to the US Food and Drug Administration for regulatory approval of its test.

For a number of years, Geneticure has been keeping a low profile in order to build the evidence base for the test, which uses an algorithm to analyze 17 variants in 11 genes known in the literature to play a role in how the heart, kidney, and blood vessels maintain blood pressure. In a retrospective analysis published in the Journal of Clinical Medicine in February, researchers from the company and the Minneapolis-based healthcare system Fairview showed the multi-gene algorithm's potential to identify the hypertension drugs that patients are most likely to benefit from.

Geneticure has also been working on clinically validating the test in a prospective, randomized-controlled trial since 2017, but ran in to recruitment difficulties and since has decided to redesign the trial with the FDA's feedback. Along the way, Geneticure CEO Scott Snyder said the company noted significant interest from patients who, despite not meeting the enrollment criteria for the randomized controlled trial, still wanted access to this test to see if it could help get them to the right drug and their blood pressure under control.

"It was just hard to ignore the market in the short term," he said. "In a small, scrappy startup, we have to pursue revenue channels where they exist, and [in] parallel, path the longer tail of getting reimbursement and [having] FDA discussions."

High blood pressure, or hypertension, affects 80 million people in the US and can lead to myocardial infarction, stroke, and renal failure, racking up $93.5 billion in healthcare costs per year. Around 360,000 people die annually from having high blood pressure. Although the majority of patients take drugs to try to control it, only around half achieve this, even when they are adherent to their prescriptions.

One's proclivity to develop hypertension can be inherited, and studies have shown that variants in certain genes also play a role in how patients respond to drugs for managing high blood pressure. Instead of studying the impact of individual genetic variants on drug response, however, in the present study, researchers retrospectively evaluated a multi-gene algorithm in a cohort of 384 non-smokers with a family history of hypertension. Patients had to have their blood pressure under control for six months, and be receiving diuretics, ACE inhibitors, angiotensin receptor blockers, beta blockers, or calcium channel blockers.

When researchers, co-led by Geneticure COO and the CEO's brother Eric Snyder, looked in this cohort from diagnosis to the conclusion of the study, patients who received a drug that the genetic algorithm predicted as their best option saw a significant drop in blood pressure compared to those who didn't receive a matched drug — 7.1 mm Hg lower systolic blood pressure and 5.4 mm Hg lower diastolic blood pressure.

This much of a reduction in blood pressure has been reported in the literature to be associated with a 40 percent reduction in the risk of strokes and a 25 percent reduction in the risk of heart attacks. "A [blood pressure] drop of 5 mm Hg is generally considered clinically meaningful in the hypertension world," said Eric Snyder.

Patients who matched to the first drug recommended by the algorithm and only received one therapy were 50 percent more likely than those who didn't match to have their blood pressure under control, defined as systolic blood pressure less than 120 mm Hg (a newer, more stringent goal than the older target at 140 mm Hg). The study didn't show a significant difference in the drop in blood pressure between patients who were on the top-ranked drug and those on the second-best ranked therapy, but overall, the study suggested that these patients were "slightly more likely" to have their blood pressure under control compared to those who didn't have an algorithm-recommended drug.

These insights from the study are important, according to Eric Snyder, since Geneticure's test ranks the drugs patients are likely to respond to based on genetics alone, but there are other factors, such as patients' overall health status, that can also impact blood pressure and that doctors must consider when prescribing treatments. "The physician may see that the genetic test is recommending a non-selective beta blocker as number one," he offered as an example. "But the patient has [chronic obstructive pulmonary disease,] which is a comorbidity or contraindication, so [the doctor] moves onto drug number two."

This study is a retrospective analysis, which introduces the potential for bias, and leaves some questions unanswered. For example, there will have undoubtedly been some proportion of patients in the present study who received an algorithm-ranked drug but didn't experience a drop in blood pressure compared to controls, but the present paper doesn't address this.

Eric Snyder acknowledged that another limitation is the lack of racial diversity in Minnesota, where patients seen by Fairview Health Services were enrolled as study subjects. However, Geneticure has partnered with institutions in Texas and Maryland to study the algorithm in non-European populations.

The positive and negative predictive value for the algorithm is also not locked down, which, according to Eric Snyder, will be defined in the randomized-controlled trial, the biggest test of Geneticure's algorithm. The study, previously described as an 800-patient trial, has taken some effort to get off the ground, however.

In the meantime, the company has done a small, pilot randomized-controlled trial and will publish some early insights gleaned from the study comparing the PGx-guided method with the standard of care. Scott Snyder highlighted that both groups in this pilot had meaningful reductions in blood pressure and similar withdrawal rates due to lack of control, though seven out of the 11 serious adverse events occurred in the control group, not the genetically guided group.

Geneticure has ambitions to take its test through the FDA and met with the agency last November for a pre-submission meeting. Based on the agency's feedback, the company decided to redesign the randomized controlled trial by involving other academic medical centers that specialize in hypertension trials and track more standard measures of blood pressure. "We are in the process of setting this up now," Scott Snyder said. 

Meanwhile, the data from the retrospective analysis, gave Geneticure the confidence to commercialize the test. Individuals can order the test online for $249 and provide a cheek swab sample from home. Third-party doctors from PWNHealth review the test orders and customers' answers to a health history questionnaire, which asks about patients' blood pressure history and family history of hypertension, the treatments they're on to assess drug/drug interactions, as well as if they've received stem cell, liver or heart transplantation. 

After reviewing this information, if physicians deem it appropriate, they can approve the test order. Alternatively, they might reach out with questions or decide that testing is not right for a patient. The "frequently asked questions" section of Geneticure's website informs customers that "if for some reason our test is not a fit for you after physician review, the cost of your test will be fully refunded, without limitation." 

Genetic counseling, also provided by PWNHealth, is available to customers and included in the cost of the service. Before reporting the results to the customer, a genetic counselor schedules a call to review the results. 

The launch of Geneticure's test, however, coincided with an FDA warning letter to Inova's genomics laboratory for marketing PGx tests without the agency's approval. In the letter, the agency seemed to be asserting that labs could only market PGx tests for "established" drug/gene relationships in FDA-approved drug labeling.

According to FDA's website, it has updated the labels of a number of hypertension drugs with PGx information. However, Geneticure is not marketing tests for specific genetic variants, but a multi-gene algorithm, and only CYP2D6 genotypes gauged by Geneticure's panel are listed in FDA-approved drug labeling. 

Scott Snyder noted that the other variants on the panel have been confirmed in multiple studies as having "a much more dramatic effect on blood pressure." As an example, he noted that two sites of the beta-1 adrenergic receptor have been shown to significantly impact people's ability to respond to beta blockers.  

Geneticure, of course, is not the only lab marketing a PGx test that gauge variants not in FDA labeling. There are other commercial labs in the psychiatric pharmacogenetics space, for example, that are also marketing tests that gauge variants that have support in expert guidelines or in the published literature, but not in FDA labeling. Additionally, the consumer-facing model that Geneticure is using, which can involve either the patient's own doctor or a third-party network doctor, mirrors many labs' strategy, including Color, Invitae, and most recently, PerkinElmer

Although Inova decided this week to entirely stop offering its PGx tests, the FDA warning letter has been criticized by legal and pharmacogenetics experts as an overreach into the practice of medicine. Scott and Eric Snyder said that they've been scrutinizing the letter closely to figure out what it might mean for their test, which is performed as a lab-developed test (LDT) in a CLIA-certified lab.

"It's been an intense week reading all this stuff," said Eric Snyder, noting that FDA's warning letter once again creates uncertainty for labs that were under the impression that the agency was practicing enforcement discretion over LDTs. In the letter to Inova, the agency asserts that while it has practiced enforcement discretion over LDTs, it can change its mind when it deems necessary to protect the public health.

Given the agency's concerns in this regard, the company believes it has taken the right approach by involving doctors and genetic counselors as part of its service. While Geneticure has a consumer-facing channel, Scott Snyder highlighted that the company is also marketing its test to doctors who may be interested in ordering testing for their patients and to healthcare systems.

"We make it clear to the clinician ... that they should make the best recommendation based on labeling, their experience, and other comorbidities of the patient," Scott Snyder said. "While important, genetics is only one piece of clinical care."

Ultimately, the company is betting that the randomized study will generate the kind of evidence the FDA and payors want to see. "Our goal is to eventually seek FDA approval, even though we currently operate as an LDT under CLIA," said Scott Snyder. "While we do think that LDTs do need some freedom in development and commercialization, we believe it is important for PGx companies and academic centers to demonstrate that their panels are effective through peer-review, rather than simply relying on existing peer-reviewed literature."

Reimbursement may be a tougher challenge since most insurers currently deem pharmacogenetic testing investigational and medically unnecessary for the most part, and aren't reimbursing for such testing. As such, the company will also have to convince payors that its test is clinically useful and cost effectiveness.

Toward this end, Geneticure published a cost-effectiveness analysis in the Journal of Medical Economics in October 2018, in which researchers modeled the impact of its multi-gene pharmacogenetics panel in a population of 10 million insured patients over a three-year period. The authors projected that taking a genetically guided approach to treating hypertension could reduce costs by 47 percent and result in savings of more than $42.3 billion, most of which are generated by avoiding adverse events.

However, Scott Snyder is realistic about the fact that achieving meaningful reimbursement will be a longer road, and as the company works on growing the evidence underlying its test,  Geneticure will also seek to raise more money. When the Minnesota-based company was founded in 2014, it received $1.1 million from angel investors, including contributions from Mayo Clinic Business Accelerator, Stanford University, and the University of St. Thomas. The company is planning a Series A funding round later this year.