This article has been updated to include comments from Genomadix.
NEW YORK — The UK National Institute for Health and Care Excellence (NICE) has embarked on an assessment of different CYP2C19 genotyping approaches that can be used to gauge how well a patient suffering from ischemic stroke or a transient ischemic attack might respond to clopidogrel, an antiplatelet therapy.
NICE is evaluating different genotyping platforms through its Diagnostics Assessment Program (DAP). As part of the program, point-of-care tests sold by Genedrive and Genomadix will be assessed, as well as laboratory-developed tests used within the UK National Health Service.
Clopidogrel — sold under the brand names Plavix, Iscover, and others — is often administered to patients with ischemic stroke or transient ischemic attack to prevent an additional stroke. The CYP2C19 gene encodes a protein that is necessary to metabolize the drug, but some patients carry variants of the gene that render clopidogrel less effective. As such, if identified as a carrier of such variants, a different antiplatelet therapy might be more beneficial.
NICE is part of the UK Department of Health and Social Care and publishes guidance for healthcare professionals. As noted in a document describing the DAP published this month, the current standard of care for treating stroke patients in the UK relies on administering both aspirin and clopidogrel as a first-line therapy.
Earlier this year, the Clinical Pharmacogenomics Implementation Consortium suggested that CYP2C19 genotyping could speed the selection of alternative, more impactful antiplatelet therapies. NICE also noted that the French National Network of Pharmacogenetics and Royal Dutch Pharmacists Association Pharmacogenetics Working Group have made similar recommendations.
The stated goal of NICE's assessment is to determine if clopidogrel genotype testing after ischemic stroke or a transient ischemic attack would represent a cost-effective use of NHS resources. The institute aims to assess the use of Genedrive's and Genomadix's tests, as well as NHS LDTs, for accuracy, turnaround time, impact on healthcare decisions, ease of use, and cost, as well as any associated healthcare costs, such as a reduction in hospital stays. If NICE does deem these tests to be cost effective by the end of the assessment in August 2023, then CYP2C19 genotyping could become the new standard of care for treatment of stroke patients in the UK.
"Our guidance sends a signal to the NHS system that the tests we recommend are clinically and cost effective," said a NICE spokesperson about the DAP. "We work to develop tools, in association with relevant stakeholders, to help organizations put this guidance into practice."
To produce a diagnostic guidance, NICE follows an internal timeline, one that involves a diagnostics advisory committee consisting of experts in the subject under consideration. This committee formulates a draft guidance, which is then reviewed during a consultation period. Any comments from stakeholders are taken into account, and then the guidance can be approved.
According to the NICE spokesperson, technologies that are endorsed by NICE typically serve an unmet clinical need and are likely to lead to a "stepwise change to a care pathway in the UK." The spokesperson said that NICE relies on evidence, such as data from randomized controlled trials, marketing and cohort studies, and accuracy studies, to make its decision. Advice from patients and clinicians is also factored in.
In the case of the CYP2C19 DAP, the spokesperson confirmed that NICE will be assessing Genedrive's CYP2C19 ID Kit, Genomadix's Cube CYP2C19 System, and laboratory-based genotype testing approaches, including gene-sequencing-based tests.
Genomadix, based in Ottawa, Canada, offers a portable analyzer called the Genomadix Cube CYP2C19 System that provides on-site PCR-based testing, including CYP2C19 genotyping, in about an hour. The test carries a CE-IVD mark and the company plans to obtain a UKCA mark by the end of this year.
CEO Steve Edgett said in an email that the firm is "hopeful that the NICE DAP will conclude point-of-care genetic tests, like the Genomadix Cube CYP2C19 System, are a clinically meaningful and cost effective use of NHS resources for the management of UK stroke patients."
According to Genedrive CEO David Budd, the Manchester, UK-based company's CYP2C19 kit is currently in a prototype stage, and the firm intends to launch it as a product in the first quarter of 2023. Its regulatory path is less certain, as the EU's In Vitro Diagnostic Regulation came into effect in May, and given shortages in regulatory capacity, it is difficult for European diagnostics firms to forecast when their tests might be certified under the IVDR.
"We can look at what we can control, but the time period between that and when we can actually sell the test is unknown," commented Budd.
He said that a point-of-care test fits well with recommendations about genotyping patients prior to administering clopidogrel, as genetics laboratories remain distant from patients, and may have up to two-week turnaround times whereas according to the CPIC, therapies should be prescribed within 12 hours. Genedrive's CYP2C19 kit in contrast has a turnaround time of less than an hour.
"If you want to have a genetic result within a day, you need a device near a patient," he said.
Creating discrete tests that can be run more or less at the point of care is Genedrive's ambition. Established in 2000, the firm has also sought to distinguish itself in the molecular diagnostics market by going after opportunities where there is an unmet need that is underserved by entrenched players. "If Roche, Abbott, and Beckman Coulter are doing something, that isn't where we are going to go," said Budd of this strategy. "We are going to go places they don't go."
One such opportunity has been in neonatal testing, where the company has developed and launched an assay to prevent hearing loss in infants caused inadvertently by the prescription of broad-spectrum antibiotics. The test relies on a reverse-transcription loop mediated isothermal amplification approach to screen patients for MT-RNR1 m.1555A>G, a variant that predisposes carriers to hearing loss when prescribed gentamicin, a first-line antibiotic given to newborns admitted to intensive care units. The assay runs on the company's portable Genedrive System.
Genedrive gained a CE-IVD mark for its MT-RNR1 ID Kit in 2019, and the pharmacogenomic assay was at the center of a UK study that published its results earlier this year. The test was also mentioned in a NICE Medtech Innovation Briefing in March, and the institute soon after embarked on a DAP of Genedrive's test, which is scheduled to result in a guidance by September 2023.
Like the MT-RNR1 ID Kit, Genedrive's CYP2C19 kit will run on its Genedrive System, but relies on real-time PCR instead of RT-LAMP, Sarah Barnett, Genedrive's marketing director, said. The company has developed a new cartridge that will be run on the same system.
According to Barnett, the ideal outcome of the NICE assessment of CYP2C19 genotyping approaches would be the recommendation that Genedrive's test be used in routine care in the UK.
Budd affirmed that this is a possible outcome. "When NICE recommends that hospitals do something, they should do it," he said. "The fallback position is that hospitals say they don't have the money so they are not going to do it," he added. "But while you will not get universal uptake, you will get a certain level of adoption with a NICE recommendation."
He noted that the market for such a test is not solely within the UK. Budd pointed to a new paper in the Expert Review of Clinical Pharmacology that found that individuals of Han Chinese descent were more likely to experience vascular events when prescribed clopidogrel. But the company's initial regulatory strategy remains to obtain a CE-IVD mark, as well as a UKCA mark, under the UK's new regulation on IVDs.
There are also opportunities for Genedrive's test beyond genotyping stroke patients. Budd said that CYP2C19 variants are involved in other drug metabolite interactions. A 2019 study published in Psychiatry Research, for example, found that CYP2C19 genotyping improved the prescription of antidepressant and antipsychotic therapies and thus better patient outcomes.
"This is the type of test that allows you to expand into lots of indications," remarked Budd. "It's quite a cool technology to be working on."