About OneOme

MINNEAPOLIS, MN – Minneapolis based pharmacogenomics precision medicine company, OneOme, is pleased to announce the appointment of Jason Walker, PhD as Lab Director.

Dr. Walker is an accomplished molecular biologist and clinical lab director with more than 10 years of experience in the clinical laboratory. He is certified to direct high complexity molecular genetics testing by the American Board of Bioanalysis and holds degrees in Biology and Genetics from Louisiana State University and Yale University. Dr. Walker is thrilled to see molecular genetics being used to inform healthcare and wellness both in the clinic, and in our everyday lives.

Jason Walker, PhD Named Lab Director at OneOme

James Kelley, MD, PhD has accepted the role of Chief Medical Officer (CMO) of OneOme. In this role, he will lead OneOme’s Medical functions including Medical Affairs and Laboratory. As CMO, James will also serve as OneOme’s overall executive in charge of all medical and clinical policies and procedures as well as all external affairs with federal, state and international regulatory agencies as it relates to all medical matters. Dr Julie England will resume her role as Medical Director of Medical Affairs. Co-founded by Mayo Clinic, OneOme is a Minneapolis, Minnesota-based precision medicine company focused on bringing high-quality pharmacogenomics (PGx) into patient care.

The RightMed Test offers Alliance Healthcare employees a path to more personalized prescriptions.

Minneapolis, MN and 's-Hertogenbosch, Netherlands (November 13 2020) – OneOme, LLC today announced a new agreement with Alliance Healthcare Netherlands (a subsidiary of Walgreens Boots Alliance) to provide pharmacogenomic testing via the RightMed Test to Alliance Healthcare employees and immediate family members. This agreement builds on the pilot program announced last year that brought the RightMed Test to Boots and Alphega Pharmacy locations throughout the Netherlands.

Alliance Healthcare Netherlands decided to start a pilot in order to gain a better understanding of the crucial role that pharmacogenetic tests can play in advising appropriate medication for different conditions. Alliance Healthcare is excited to extend the test, as part of the pilot, to the company's own employees.

Pharmacogenomics (PGx) is the study of how DNA may affect individual response to medications. PGx testing analyzes a patient's DNA to give doctors and pharmacists information that may help them optimize medication selection for that patient, minimize trial and error in the prescribing process, reduce potential healthcare costs and decrease the likelihood of adverse drug reactions.

The first analysis of the test carried out by Dutch Alphega and Boots pharmacies, showed that one in three patients who had the pharmacogenetics test carried out in consultation with the doctor had their medication adjusted.

“We see this as an opportunity to bring the vast benefits of pharmacogenomic testing to our employees, as well as offering a unique and valuable benefit to aid in talent acquisition and retention,” said Manuel Voll, Commercial Director. “We’ve already seen how well we work with OneOme, so they were the obvious choice for this program.”

As part of the program, the RightMed Test will be available to more than 1,500 Netherlands-based Alliance Healthcare employees. Employees will provide a DNA sample using a simple cheek swab, which will be processed in OneOme’s CLIA-regulated lab in Minnesota, United States. Within seven days, they will receive their results via OneOme’s secure portal.

“Alliance Healthcare is a forward-thinking organization, and we are excited to embark on this next step in our relationship with them,” said Patrick McIntyre, CEO at OneOme. “Genomic benefits are the next frontier in employee benefit offerings, and I expect that organizations across the globe will soon follow in Alliance Healthcare’s footsteps."

About OneOme

OneOme offers stakeholders across the healthcare industry high-quality, end-to-end solutions for implementing pharmacogenomics in patient care. Central to OneOme’s portfolio of solutions is the RightMed Test, which analyzes 27 genes to provide valuable information doctors and pharmacists can use in prescribing or medication management. Co-founded by Mayo Clinic, OneOme combines leading-edge laboratory testing with advanced analytics designed to help reduce the total cost of care and improve patient outcomes. OneOme serves customers across the globe from its Minneapolis, MN headquarters. For more information, visit oneome.com.

About Alliance Healthcare

Alliance Healthcare Netherlands is a versatile company in the entire pharmaceutical care chain from producer to consumer. This unique position enables Alliance Healthcare to integrate the various needs of stakeholders within the chain and thus arrive at innovative solutions. The health and well-being of customers is the companies connecting factor. By forming strategic partnerships, Alliance Healthcare guarantees the quality of the care and the optimal support of the customer. Cooperation is the companies key to success.

Internationally leading brand Alliance Healthcare Nederland is part of the Walgreens Boots Alliance. Walgreens Boots Alliance is present in more than 25* countries, employs more than 450,000 people and has more than 21,000 stores, delivering to more than 250,000** pharmacies, doctors, health centers and hospitals each year in more than 20* countries. Alliance Healthcare is the market leader in Europe.

* As of Aug. 31, 2020, including equity method investments.

**For 12 months ended Aug. 31, 2020, including equity method investments

On February 20, FDA released a Table of Pharmacogenetic Associations (updated February 25) and opened a docket for gathering feedback and comments.

As a leader in the pharmacogenetics (PGx) space, OneOme believes this is a positive step toward achieving consensus evidentiary standards for PGx testing. Our intent in providing the following comments was to help move toward this consensus by offering constructive feedback using our team’s extensive experience in evaluation of PGx evidence and our practical knowledge of how clinicians use PGx testing in patient care.*

Introduction

OneOme appreciates FDA's move to further precision medicine as well as the opportunity to review and provide feedback on the Table of Pharmacogenetic Associations. The following comments are intended to promote development and consensus around evidentiary standards and best practices in pharmacogenomics ("PGx").

General feedback

• OneOme requests FDA publish the level of evidence criteria that was required for inclusion in each of Tables 1, 2 and 3, including requirements around demographics and in vitro and in vivo data, as well as how FDA assessed and reconciled limitations of the studies reviewed. Clarifying how FDA defines "sufficient scientific evidence" will help healthcare practitioners evaluate lab-developed PGx tests and laboratories assure their gene-drug associations meet FDA's standards.
• OneOme recognizes the challenges large organizations and regulatory agencies have in maintaining updates to their publications every time new, impactful research is published. However, citations are important to help providers understand what information was considered by FDA and therefore reconcile any differences between new or other existing data that may be applicable to patient care and the practice of medicine.
• OneOme has concerns that the lack of transparency around criteria for inclusion and absence of specific guidance from FDA related to PGx abrogates the clinical utility of this table. Moreover, it is likely that this will be misinterpreted by patients and providers as FDA's official guidance on PGx testing.

Specific feedback

Critical omissions: Phenytoin and HLA-B*15:02 and CYP2C9

Phenytoin (PHT) is metabolized by CYP2C9. Studies have associated the *3 allele with increased risk of severe cutaneous adverse reactions, particularly in patients of Chinese and Thai descent. Poor CYP2C9 metabolism of phenytoin is associated with increased plasma concentrations and probability of toxicity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group (DPWG) have published specific guidelines regarding this association.^1,2 In addition, CPIC, FDA, and the Canadian Pharmacogenomics Network for Drug Safety (CPND) noted that presence of the HLA-B*15:02 allele is associated with the risk of developing Stevens-Johnson Syndrome (SJS)/Toxic epidermal necrolysis (TEN).^1,3,4 The high frequency of HLA-B*15:02 in Chinese, Thai, Taiwanese, and Indonesian populations (4%-36%) means it is important to note the risk of PHT-associated SJS/TEN in patients carrying this allele.

Confusing category assignments

FDA presented three tables, describing only the first as being supportive of therapeutic management recommendations. The rationale and practical implications of FDA's categorical divisions are unclear at the outset and become more so when, for example, citalopram and escitalopram are categorized separately, in Tables 1 and 3, respectively.

Citalopram is a racemic mixture in which the S-enantiomer, escitalopram, is the active component (167x more active than the R-enantiomer⁴) and favored target of CYP-mediated metabolism (CYP2C19, -3A4, and -2D6).^5,6 Given the adverse drug event (ADE) and efficacy data available for citalopram, the pharmacokinetic data alone, which FDA acknowledges by inclusion of escitalopram in Table 3, should be sufficient to support the use of CYP2C19 PGx in therapeutic management with escitalopram and thus its inclusion in Table 1. The FDA tables also note only the likelihood of increased systemic drug concentrations in poor metabolizers but ignore the substantial data available indicating the likelihood of reduced systemic drug concentrations and lack of efficacy in rapid and ultrarapid metabolizers (carriers of CYP2C19*17).^2,7-9

The confusion lies with the implication that the contents of Table 3 have less supporting evidence than those in Table 1. The case of citalopram/escitalopram belies this demarcation, because the racemic mixture of R and S citalopram is comprised of 50% escitalopram. Given the level of data supporting increased ADE risk with the racemic mixture demonstrated by FDA's inclusion of citalopram in Table 1, additional in vivo studies of escitalopram would unnecessarily expose human subjects to increased risk without demonstrable benefit.

Recommendations

As FDA works on future drafts of the Table of Pharmacogenetic Associations, OneOme offers the following recommendations:

• Collaborate with PGx experts in academia, industry, pharmacy, and clinical practice to achieve consensus on criteria and level of evidence for documented PGx associations.
• Develop and share information on the timelines for reviewing new evidence and schedule for updating the Table.
• Publish draft guidance for PGx testing to clarify how this table fits into FDA’s future plans regarding PGx.

References

1. CPIC®. Guideline for Phenytoin and CYP2C9 and HLA-B. https://cpicpgx.org/guidelines/guideline-for-phenytoin-and-cyp2c9-and-hla-b/ Accessed 2/27/2020.
2. Dutch Pharmacogenomic Working Group. Dutch guidelines, November 2018 update. https://api.pharmgkb.org/v1/download/file/attachment/DPWG_November_2018.pdf Accessed 2/27/2020.
3. FDA. Dilantin (phenytoin sodium) package insert: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/084349s060lbl.pdf Accessed 2/27/2020.
4. FDA. Celexa (citalopram) package insert: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020822s038s040,021046s016s017lbl.pdf Accessed 2/27/2020.
5. von Moltke, Lisa L., et al. "Citalopram and desmethylcitalopram in vitro: human cytochromes mediating transformation, and cytochrome inhibitory effects." Biological psychiatry 46.6 (1999): 839-849.
6. Olesen, Ole V., and Kristian Linnet. "Studies on the stereoselective metabolism of citalopram by human liver microsomes and cDNA-expressed cytochrome P450 enzymes." Pharmacology 59.6 (1999): 298-309.
7. CPIC®. Guideline for Selective Serotonin Reuptake Inhibitors and CYP2D6 and CYP2C19. https://cpicpgx.org/guidelines/guideline-for-selective-serotonin-reuptake-inhibitors-and-cyp2d6-and-cyp2c19/ Accessed 2/27/2020.
8. Rudberg, I., et al. "Impact of the ultrarapid CYP2C19* 17 allele on serum concentration of escitalopram in psychiatric patients." Clinical Pharmacology & Therapeutics 83.2 (2008): 322-327.
9. Mrazek, David A., et al. "CYP2C19 variation and citalopram response." Pharmacogenetics and genomics 21.1 (2011): 1.

*Note: Due to commenting platform constraints, the comments presented here include minor changes to formatting. References have also been included as part of the comments rather than listed in a separate reference sheet as they are on the docket.