Frequently Asked Questions - Healthcare Practitioners – Inagene Diagnostics Inc.

Frequently Asked Questions - Healthcare Practitioners

1. Who should consider taking the Inagene Personalized Insights™ test?

Inagene Personalized Insights™ is designed for anyone who is interested in understanding which drugs will work best for their pain or mental health condition. Personalized Insights™ may also be useful for people interested in knowing how best to incorporate cannabis into their pain treatment regimen.

Physicians may consider offering the test to any patients who are currently being treated/are about to receive treatment for pain or mood disorders using any of the medications affected by at least 1 of the 55 genes tested by our panel (including OTC and many commonly-used prescription medications)

The test may be particularly valuable for anyone who has experienced/is experiencing any of the following clinical problems:

History of ‘sensitivity’ to drugs

Unusual side effects

Poor response to pain/mental health drugs

Requiring doses outside of typical ranges

Taking multiple medications (polypharmacy)

2. Where do the recommendations in the report come from? How strong is the evidence? How reliable are the recommendations in your report?

Pharmacogenomic studies over the last three decades have generated an overwhelming amount of evidence that genetic variation plays a major role in drug response variability. The recommendations in our report are taken directly from published pharmacogenetic recommendations (publicly available) from several well-recognized, government – funded governing bodies that have been established over the past two decades in the USA, Europe, and Asia. These include CPIC and PharmGKB, the FDA, and Dutch Pharmacogenetics Working Group (DPWG).

Pharmacogenetic recommendations are based on peer-reviewed reports providing high levels of evidence of the link between specific genetic variations and drug responses. Since 2000, government funded governing bodies (in the USA, Europe, Asia) have been established to 1) review and grade the available pharmacogenetic evidence 2) develop peer reviewed recommendations to guide incorporation of pharmacogenetics profiles into healthcare. In some countries (e.g. the USA), many of these recommendations are now incorporated into drug labels. For example, to date, the FDA has re-labeled >380 commonly used drugs with pharmacogenetic guidance.

Main evidence sources for Pharmacogenetics recommendations typically include observational studies (e.g. cross-sectional, case-control studies, case reports) and pharmacokinetic/pharmacodynamic studies (in vivo /vitro). Randomized controlled trials (RCTs) can be difficult to run and are not ideal in measuring the benefit of pharmacogenetic testing for several reasons:

Some clinically significant variants are present in only a small percentage of patients

RCTs in patients with specific genetic polymorphisms may be precluded on ethical grounds (e.g. failing to adapt treatment of a patient based on presence of a gene variant known to impact expected metabolism of a prescription drug carries ethical concerns).

Compared with RCTs, observational studies enable comparisons of larger numbers of subjects to be conducted at a lower cost with less ethical concerns.

The reliability of the recommendations contained within our report is further enhanced by the unparalleled comprehensiveness of the Inagene genetic panel (testing more genes and variants linked to the metabolism of common medications in pain and mental health than any other commercial pharmacogenetic assay), as well as our commitment to rigor and stringency in quality control (we are the only CLIA – certified commercial pharmacogenetic lab in Canada). Other methods Inagene employs to assure quality and accuracy of results include:

Comparison with known controls

Second method validation

Allele frequency recording

Testing all samples in duplicate

Comparison of results with competitor tests results

CAP validated

3. What kind of results should I expect from “green” medications vs. yellow or red medications? (How likely is it that treatment with a “red” medication will be successful?)

The goal of prescribing according to pharmacogenetic insights is to increase the likelihood that an individual will find treatment success faster (i.e. avoid multiple cycles of trial and error) while minimizing the chance of side effects. Drugs may be categorized as “red” (not recommended) for a variety of different reasons. Depending on how a gene variant impacts a specific drug’s metabolism, the individual may experience various combinations of increased or decreased efficacy or side effects (see table below). In general, if a drug is categorized as “red”, it is unlikely to produce the expected efficacy and/or tolerability and hence the overall net effect is expected to be negative (and in some cases, may be hazardous) for the patient versus using an alternative option.

Multiple other factors (for instance age, overall health and concomitant medical conditions, organ function, drug- drug interactions) may either decrease or increase the overall impact of a given gene variant for a given individual. Drugs categorized as “yellow” may be appropriate treatment options in some cases in which the specific prescribing guidance is followed. It is therefore important to read the associated recommendations (e.g. an alternate dose may be required to produce the desired response).

4. How much of a difference does it REALLY make in terms of treatment success when you prescribe based on pharmacogenetic insights vs. not?

Multiple studies have shown that leveraging pharmacogenetic insights to guide treatment results in better drug efficacy, tolerability, and safety. In the area of Pain and Mental Health, for example:

In a 2019 study by Smith et al, 24% of patients receiving pharmacogenetic - guided treatment had >30% reduction in pain versus 0% of patients receiving standard treatment. (4)

In a 2019 study in major depression, Gredin et al demonstrated that pharmacogenetics – guided treatment resulted in 30% increased treatment response and 50% increased remission over 8 weeks. Negative side effects were reduced by 60%. Patients taking pharmacogenetically-incongruent medications prior to baseline who switched to congruent medications by week 8 experienced a 5-fold increased response rate and 2.5-fold increased remission rate as compared to those remaining incongruent. (5)

A study by Hall-Flavin et al. (2012) demonstrated a > 4-fold greater improvement in symptoms of depression and a shorter time to achieve symptom relief. (6)

Cycling through one drug after another is frustrating, time-consuming, costly and discouraging. Lack of efficacy and side effects lead to poor adherence, which can be further exacerbated by depression. In fact, up to one third of prescriptions provided in the context of chronic disease are never filled, and 50% of patients do not take their medications as prescribed. Most nonadherence is intentional, with fear of side effects, lack of perceived effect, mounting cost of drugs, and concomitant depression being among the top reasons for non-adherence. Better efficacy and reduced side effects enabled by pharmacogenetic guidance may also lead to better treatment adherence, further enhancing positive effect over time. (8, 9, 10)

Ref: Kaye, A et al. Update on the pharmacogenomics of pain management; Pharmacogenomics and Personalized Medicine 2019:12 125–143 (table 3)

5. Why did you focus the Inagene test specifically on pain and mental health?

Pain and mental health issues are the top causes of disability in Canada. Pharmacogenetics supports/enables information-based decision making to achieve the most efficacious and safe treatment sooner. Pain and associated mental health conditions are notoriously DIFFICULT to treat, with multiple complex biological, psychological and social factors contributing to etiology and outcomes. There is typically no “one-size-fits-all” solution, with existing therapies often being only partially effective or ineffective in individual patients.

Chronic pain & major depression overlap genetically. People with chronic pain have three times the average risk of developing psychiatric symptoms — usually mood or anxiety disorders — and depressed patients have three times the average risk of developing chronic pain. Negative mental health effects can also amplify pain. (11)

Medications used to treat mental health conditions and pain often overlap. Common pain/mood drugs are estimated to be ineffective in up to 50% of patients due to gene variations that influence drug responses. Typical “numbers needed to treat” (NNTs) for pain/mental health drugs can range between 2 – 6. As a result, patients suffer through the “trial and error” approach, cycling through multiple medications seeking relief. (11)

Pain is also closely linked to other areas of key medical importance (the opioid epidemic, cannabis usage) for which additional support and information are currently being sought by patients and health care providers. The opioid epidemic is integrally tied to pain management and has left many physicians hesitant to prescribe opioids or increase doses in response to patient complaints of insufficient analgesia. Patients who truly require higher doses but are not able to get them are at risk of turning to street sources. For both opioids and cannabis, there is great variability in response and side effects between individuals, much of which may be explained by genetics and aided by pharmacogenetics. (12)

Focusing specifically on chronic pain and mental health allows Inagene to offer the most comprehensive test panel available and to help deliver the most accurate and complete insights possible for people suffering from pain and associated mental health – related conditions.

6. What is the likelihood that investing in this test will provide my patients with insights that are valuable to them?

Over 95% of us carry at least one genetic variant that will impact our predicted response to many common medications; most of us carry several such variants. The presence of genetic variants impacting the efficacy or tolerability of common medications for pain and mental health is therefore common.

One study showed that >60% of us have been exposed to a drug with a pharmacogenomic recommendation, and >35% have been prescribed a “high risk drug” based on pharmacogenetic predictions (2).

Leveraging pharmacogenetic insights in pain management has been shown to result in:

A change in medication (for >45%) or dosage (for >30%) (13)

Improved understanding of prior pain experiences - side effects, degree of pain relief (68%) (13)

Reductions in pain intensity (4)

Reduced overall utilization of narcotics (up to 50%) (14)

Significantly improved response and remission rates (mental health) (5,6)

7. If a drug is labelled “Red” (for example, due to predicted lack of efficacy or side effects), but a patient has been taking the drug and doing well, should I stop the medication?

This depends on the reason why the medication has been categorized as a “do not use”. If it is due to risk of serious adverse events and alternatives exist, it is advisable to discontinue the medication in favor of other drug options.

Some genetic variations can cause serious or even fatal effects. Adverse drug reactions account for up to 30% of hospitalizations and are the #4 cause of death in Canada, implicated in 20% of hospital patients’ illness or deaths. Many gene variants can cause or exacerbate drug-drug interactions. In response, the US-based FDA has re-labelled 380 common drugs with genomic information/guidance to date. Compared with others, individuals with “high-risk” gene variants have been shown to have 69% higher total healthcare costs, 67% more medical visits, 3 X more absence days and 4 X more disability claims. (15)

If a medication has been labelled “red” due to predicted lack of response, but the patient feels they are responding to the medication it is possible/likely that the response to a medication labelled as “green” would be greater. Responses to medications are influenced by multiple factors and while 40% - 60% of such responses may be attributed to genetics, it is not impossible that a medication categorized as “do not use” may produce some response. The “placebo effect” may also be a factor in perceived efficacy. Whether or not to switch medications is ultimately at the discretion of the physician, taking all factors into consideration.

8. If a drug is labelled “Green”, what are the chances that it will work well with minimal side effects?

When a drug is categorized as “green” (use as directed) for a given patient, then no variants have been identified in the patient’s genetic profile that correspond with a known gene-drug interaction. This finding indicates that there is no known reason that this individual would respond to the medication differently than expected. Using a medication that is categorized as “green” for an individual increases the likelihood of success, but does not guarantee success, as other factors also influence drug responses (age, overall health/organ function/comorbid conditions, drug-drug interactions, organ function etc). In other words, taking pharmacogenetic insights into consideration when choosing a treatment plan increases the probability but does not guarantee achieving a good outcome.

9. Can some medications be considered “ultra green”? (i.e. do some patients have genetic variants that will cause them to respond exceptionally well to certain medications?)

This possibility has been suggested for certain gene variants and, if this is the case, will be reflected in the individual recommendation for the drug.

10. Do you test for injectable anesthetic agents, steroids, or topical creams?

Injectables (locally acting) medications are not susceptible to first pass metabolism so gene variations that impact metabolizing enzymes have a much less profound effect as compared to oral medications. Some pharmacodynamic interactions are still relevant, however, and we test for genetic variants impacting BOTH pharmacokinetic and pharmacodynamic aspects of drug metabolism. For instance, some topical analgesics interact with TRPV1 and this variant is studied by our test.

11. Why do you include gene variants that are supported only by preliminary data in your test?

The science of pharmacogenetics is evolving rapidly, and we therefore update our test when new data and recommendations become available. However, our test does include preliminary data that we believe has a high chance of graduating to an actionable recommendation. We clearly delineate what recommendations are based on preliminary data vs. higher levels of evidence/actionable recommendations. As your DNA results are for life, being tested for these gene variants provides the opportunity to receive valuable insights based on these findings in the future as new information becomes available.

12. Is the test covered by insurers?

Although the integration of pharmacogenetics into clinical practice is only at the early stages, insurers recognize the clear benefits of pharmacogenetics in increasing effectiveness of treatment, reducing side effects, unfilled prescriptions, and lack of compliance, and as a result, providing cost savings. Most private insurers will reimburse for pharmacogenetic tests through health care expense accounts, and some private insurers/employers are now reimbursing costs of these tests on their general benefits.

13. Why are some common pain/mental health medications not included?

Although Inagene Personalized Insights™ reports on more pain and mental health medications than any other panel, some medications have not been found to be influenced by specific genetic variants. We only report on medications for which a gene-drug interaction has been identified and is supported by a high enough level of evidence to provide true health benefit.

14. Can your test predict an individual’s risk of addiction?

As part of our research program, we test for specific gene variants that have been identified as potentially “protective” (i.e. tend to occur in those who have not developed use disorders) or “risk” (i.e. tend to occur in those who have developed use disorders). This research is still in the early stages and while factors have been identified, the information is too preliminary for use in guiding healthcare decisions. Thus while the available evidence indicates that the genetic contribution is significant (possibly accounting for up to 70% of risk for addiction) (16, 17), it is currently not possible to reliably predict risk based on genetics alone. This is an area of keen interest for Inagene and we are committed to advancing the research in this area.

15. How is this test different from other pharmacogenetic tests on the market?

Unlike other genetic tests, Inagene Personalized Insights™ is uniquely focused on providing the most comprehensive test to support decisions related to pain management and related treatments. Personalized Insights™ also includes evaluation of cannabis treatment options. Inagene uses its own CLIA certified lab to produce and deliver all results and does not subcontract to other labs, allowing us to adhere to the highest standards of stringency, reliability and quality control.

16. Which Medications for Pain and Mental Health Conditions are Included in Your Report?

Inagene Personalized Insight reports on the majority of medications used in the treatment of pain and mental health conditions. If a medication is NOT included in our report, it is because no gene variants have been identified that are known to affect individual response to that drug.

See following page for list of references

References

1.Caudle, K et al. Evidence and resources to implement Pharmacogenetic Knowledge for Precision Medicine. Am J Health Syst Pharm. 2016; 73(23): 1977–1985
2. Krebs, K; Milani, L. Translating pharmacogenomics into clinical decisions: do not let the perfect be the enemy of the good. Human Genomics (2019) 13:39
3. Huddart, Rachel et al. Are Randomized Controlled Trials Necessary to Establish the Value of Implementing Pharmacogenomics in the Clinic? Clin Pharmacol Ther. 2019; 106 (2): 284 – 286
4. Smith et al. CYP2D6-guided opioid therapy improves pain control in CYP2D6 intermediate and poor metabolizers: a pragmatic clinical trial. Genetics in medicine. 2019; 21 (8): 1842 – 1850
5. Gredin, John et al. Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled study. Journal of Psychiatric Research. 2019; 111: 59-67
6. Hall – Flavin et al. Using a pharmacogenomic algorithm to guide the treatment of depression. Transl Psychiatry. 2012; Oct; 2 (10)
7. Kaye, Alan D et al. Update on the pharmacogenomics of pain management; Pharmacogenomics and Personalized Medicine 2019:12 125–143
8. Tamblyn, Robyn et al. The Incidence and Determinants of Primary Nonadherence with Prescribed Medication in Primary Care: A Cohort Study. Ann Intern Med. 2014;160(7):441-450
9. Brown, Marie T. et al. Medication Adherence: WHO Cares? Mayo Clin Proc. 2011 Apr; 86(4): 304–314
10. American Medical Association.org: https://www.ama-assn.org/delivering-care/patient-support-advocacy/8-reasons-patients-dont-take-their-medications
11. https://www.health.harvard.edu/mind-and-mood/depression-and-pain: Hurting bodies and suffering minds often require the same treatment (March 2007)
12. Hryhorowicz, S et al. Pharmacogenetics of Cannabinoids. Eur J Drug Metab Pharmacokinet (2018) 43:1–12
13. Kirsh, K et al. Using Pharmacogenetic Testing in a Pain Practice. Practical Pain management; 2015:l14 (10)
14. Senagore.A. et al. Pharmacogenetics-guided analgesics in major abdominal surgery: Further benefits within an enhanced recovery protocol. Am J of Surg 213 (2017)
15. Gardner KR, Brennan FX, Scott R, Lombard J. The potential utility of pharmacogenetic testing in psychiatry. Psychiatry J. 2014;2014:730956. doi:10.1155/2014/730956
16. https://www.apa.org/monitor/2008/06/genes-addict
17. https://www.drugabuse.gov/publications/drugfacts/genetics-epigenetics-addiction