Precision Medicine: Dx leads to Rx

by Mridula Iyer, PhD and Yuri Fesko, MD, Quest Diagnostics, Secaucus, NJ

The right medicine for the right patient, that’s the principle behind the Precision Medicine Initiative, originally focused on leveraging global investments in cancer and genome sequencing (superseded by All of US). More recently, the approach has grown to encompass the concept of a more individualized (n of 1) care strategy for cardiovascular diseases, autoimmune diseases, cancers, and gene‑centered maladies, as seen in Figure 1.1

An example of this “n of 1” treatment is the emerging chimeric antigen receptors T-cell (CAR-T) therapies, which are designed specifically for each patient. Each CAR-T therapy is best designed to attack the unique disease of a single patient, thereby improving survival rates. While these therapies are a more expensive treatment option, the higher likelihood for patient response and better outcomes would result in net overall improved benefits – e.g., fewer return trips for treatments, extended lifetime, improved quality of life for the patient and his/her family.

                                  Figure 1: The growth of precision medicine

Precision in prevention: Going further to identify the right patients
To date, the biggest investment of precision medicine has been in oncology, with significant funding committed to validate biomarkers that test for patients who can benefit from the most appropriate treatment.2 However, there is growing interest in applying precision medicine to neuromuscular diseases and some rare diseases, which gives hope to patients who have typically been underserved.

In addition to identifying affected individuals, a shift is underway towards a three-fold treatment strategy that includes early diagnosis, the application of preventive medicine, and targeted therapy for precise treatment options. Deeper understanding of biomarkers and better understanding of disease causation is anticipated to improve the ability to identify populations of at-risk patients who could benefit from the new therapy3 prior to full disease onset, and hence evolve into ‘precision in prevention.’4 Using robust diagnostic testing strategies for the detection of eligible, at-risk patients for preventive care has enormous benefits and the potential to reduce overall healthcare costs.

The crucial role of diagnostics, informatics, and data in a centralized model
As the focus shifts towards this three-fold treatment strategy, national reference labs such as Quest Diagnostics bring a depth of data, medical and scientific expertise, and analytics capabilities by centralizing resources that can:

1. Enable the correlation between diagnostic insights with other data sets:
2. Bring together physicians, patients, and Principal Investigators (PIs) to drive more effective and efficient clinical trials.

Quest leverages its expertise in informatics and data to deliver the powerful benefits of precision medicine to compile and track patterns for interpreting real-world results that determine inclusion-exclusion criteria, patient engagement, and foster patient education and awareness.

Technology factors critical to a centralized model utilizing the three‑fold treatment strategy

1. Access to critical patient and physician data

◆ Quest has access to hundreds of thousands of patients through nationwide Patient Service Centers (PSC, now expanded into Walmart locations and grocery stores) and mobile Phlebotomy services that support patients who prefer home or office draws.
◆ Quest also has decades of real-world experience with physicians: their ordering behavior, testing practices, barriers, and typical preferences in treating patients. Ensuring that tests are integrated into these patterns is often critical for success and serve as guidance for assay design.
◆ Broad access to patients and physicians allows Quest to commercialize tests effectively, utilizing a sales team with expertise in all therapeutic areas to drive maximum awareness to practices, hospitals, patients, and communities.

2. High-quality tests

◆ Diagnostic tests and related data and information provide a quantitative measure of a patient’s status of sufficient quality for healthcare providers to make decisions for treatment. Qualified reference labs will validate tests under CAP/CLIA laboratory guidelines using the best‑available technology and methodology. The data should be of such quality that patients are confident in they will receive the most appropriate treatment protocols.
◆ Physician decisions are based on combination of clinical observation, patient history, and related tests that serve as guidance for treatment. For example, other relevant tests for biomarkers based on, e.g., guidelines for cancer patients, cholesterol, potassium levels for cardiac CDx tests, biomarker testing, may need to be considered as part of a patient’s history from prior tests.

3. Technology expertise and knowledge across all therapeutic areas

◆ In general, qualified diagnostics companies employ the best-available technology for assay design across therapeutic areas.
◆ In addition to sensitivity and specificity, robustness of the technology is instrumental in bringing effective treatments to market, especially for genetically inherited rare diseases.
◆ Company subject matter experts and users (e.g., MDs and Lab Directors) are consulted for input on new assay targets, new assay designs, and applying their collective clinical and medical expertise in interpreting tests. These experienced experts add a personalized component to this precision approach.
◆ Diagnostics companies with global reach (like Quest) offer end-to-end services to pharmaceutical companies including the development of new assays, securing FDA approval, and launching tests commercially. Quest, as a covered entity under HIPAA, can reach out globally to partners and to patients for clinical trial purposes as a care option.

Successful applications of the precision medicine-focused model

Supported by program managers assigned to handle day-to-day activities, projects are custom designed to meet the company’s unique goals. Two studies highlight the distinctive way Quest advances the benefits of precision medicine, customizing each case aligned with a general format:

◆ Develop a new test → FDA approval → commercialization
◆ Develop a new test → commercialization
◆ Existing LDT on menu → FDA approval → commercialization
◆ Existing LDT on menu → commercialization

Case study #1: STRATIFY JCV test for Tysabri

Overall process followed for this case: Develop a new test → seek FDA approval → go to commercialization

Quest Diagnostics was granted a de novo classification petition to its STRATIFY JCV™ Antibody ELISA testing service.5 Developed under exclusive collaboration with Biogen Idec and offered only through Quest Diagnostics, STRATIFY JCV is the first blood test to receive FDA marketing authorization for the qualitative detection of antibodies against the John Cunningham virus (JCV). STRATIFY JCV provides a surrogate measure of the load of this polyomavirus for stratifying risk for progressive multifocal leukoencephalopathy (PML), an infrequent but serious brain infection. TYSABRI® (natalizumab*) is a highly effective therapy for patients at-risk for relapsing forms of MS.

Quest Diagnostics supported the Tysabri project by:

◆ Developing the assay;
◆ Performing clinical trial testing;
◆ Developing IVD kit;
◆ Conducting regulatory clearance;
◆ Supporting patients and physicians;
◆ Commercializing the test.

The standardized testing at a centralized laboratory has proven to be a valuable tool that enhances PML risk assessment.

The approach:

◆ eliminates inter-lab variability for patients;
◆ simplifies test ordering for physicians;
◆ provides medical informatics that improve utilization of the test to identify the right patients.

                          Figure 2: The growth of precision medicine

This approach marks a significant step forward in the personalization of clinical management of MS patients who may benefit from natalizumab, and Quest Diagnostics has successfully scaled up the testing capability to meet the demand. The STRATIFY JCV program demonstrates the benefits of collaboration between pharmaceutical and diagnostic companies to bring important medical innovations to market in an efficient way.

Case study #2: Rare disease – HDV program for Eiger Pharmaceuticals for Lonofarnib
Overall process followed for this case: Develop a new test → dentify patients utilizing the data → support clinical recruitment → go to commercialization

Quest Diagnostics worked with Eiger Biopharmaceuticals on a complex phase 3 Hepatitis Delta Virus (HDV) trial. Knowing that patient identification and pre‑screening is the most challenging (and costly) step in clinical trials, Quest developed a patient‑centric Quantitative D Virus RNA6 to identify the right patients. Since HDV is underdiagnosed with no current treatments available, many patients with HBV also have HDV but are unaware/ untested. Bearing this in mind, Quest took a multi‑pronged approach to identifying HDV+ patients to enroll in the trial:

1. Provided a national mapping of HBV, HDV patients and care teams
2. Identified >400 HDV+ patients for patient outreach proximal to sites
3. Implemented a sponsored testing program to known HBV+ patients for HDV screening

Our tailored approach to patient recruitment includes doing more upfront work to preprofile patients based on relevant lab tests/ results and ICD‑10 codes, and then using the most cost‑effective methods to reach out to highly motivated patients. This approach, along with careful consideration of patient convenience (e.g., through Patient Service Centers and mobile healthcare options), allows us to maximize trial enrollment, as shown in Figure 2. Quest’s highly effective, tailored outreach to patients and providers is committed to building clinical trial awareness to address many of the industry challenges with clinical trial involvement.

Conclusion: Dx to Rx – the key to advancing precision medicine
Early phase clinical development for precision medicine starts by combining a data‑driven stratification of patient sub‑groups (by, e.g., well‑defined exclusion/inclusion criteria) with the ability to reach into a diverse community to facilitate trial planning, recruitment, and enrollment. As diagnostic companies take on more challenging cases (as described in the cited Case Studies), identification of these patient subgroups has become increasingly complicated.

Furthermore, devising novel diagnostic tests takes a new way of looking at diagnostics and pharmaceutical development. To get that new perspective, Quest utilizes a team approach to understand the medical ecosystem for the successful, planning, reach, and understanding of the information provided in an increasingly crowded and complicated landscape. Quest’s team approach integrates perspectives from its clinical partners; Ameripath pathology luminaries; Information Ventures (data analytics); regulatory groups; and disease specific clinical franchises to customize a plan created for clients. We at Quest have learned to achieve the promise of precision medicine by soliciting the input of these groups to launch successful diagnostics for precision medicine applications. We point to our success in the cited Case Studies as a model to motivate others to realize the promise of precision medicine for better patient management.

Acknowledgements
The authors would like to acknowledge the work and support by the Quest Diagnostics team. Special thanks to Dr Jay Wohlgemuth, Senior Vice President, R&D, Medical and Chief Medical Officer; Richard Heichemer, Senior Director, Precision Medicine; Dr Nicholas Conti, Executive Director, Business Development; Pamela Wong, Assistant General Counsel; Andrea Luker, Director of Marketing; and the Quest Diagnostics Healthcare Analytics Solutions team.

Mridula Iyer, Ph.D., currently serves as the General Manager, Precision Medicine at Quest Diagnostics leading the Precision Medicine business for all therapeutic areas. Dr. Iyer’s professional experience spans the academic Pharma and biotechnology industry. At Quest Diagnostics, she is responsible for leading the Pharma Services business including providing strategic direction to the Precision Medicine/Companion Dx business, working closely with other teams to align with the market needs. Dr Iyer leads Programs with Pharma companies that include Custom Testing, Commercialization of CDx tests, REMS and End -End services including ssPMA projects. Prior to joining Quest Diagnostics, Dr Iyer was at AZ as Director, Commercial for Companion Diagnostics, at Molecular Health as Director of Product Marketing and with Qiagen Inc. leading their North American Molecular Diagnostics marketing and Global Product Management teams.

 

Yuri Fesko, M.D., is Medical Director of Oncology at Quest Diagnostics. As a leading oncologist, Dr. Fesko plays a key role in helping Quest advance the fi eld of precision medicine and give new hope to people with cancer. Prior to joining Quest in 2017, Dr. Fesko was Director of Medical Oncology at the Duke Cancer Institute in Raleigh, North Carolina, where he was responsible for the oncology service line and development of inpatient oncology, multiple network sites and infusion centers. He also was responsible for strategies including the determination of appropriate clinical trials for population and resource utilization. Dr. Fesko received his bachelor’s degree and medical degree from Case Western Reserve University School of Medicine. He is certified by the American Board of Internal Medicine in hematology and medical oncology.

 

 

References

1. Diaceutics. Pharma Precision Medicine Readiness Report 2019 Supplemental Update: Analysis of FDA 2019 Test-Dependent Therapy Approvals.

https://www.diaceutics.com/pharma-precisionmedicine-readiness-report-2019-supplemental-update-analysis-offda-2019-test-dependent-therapy-approvals/

2. Fortune. Precision Medicine Has Transformed Cancer Treatment. Here’s How to Move It Beyond Oncology. Published November 12, 2018

https://fortune.com/2018/11/12/precision-medicine-cancertreatment- data/

3. National Library of Medicine. Creating a common language: defining individualized, personalized and precision prevention in public health. Published Dec 1, 2018;40(4):e552-e559. doi: 10.1093/pubmed/fdy066.

https://pubmed.ncbi.nlm.nih.gov/29897560/

4. U.S. News. What’s All the Fuss About Precision Medicine? Published August 25, 2017.

https://health.usnews.com/health-care/for-better/ articles/2017-08-25/whats-all-the-fuss-about-precision-medicine

5. Quest Diagnostics. Quest Diagnostics STRATIFY JCV™ First FDA Market Authorized Antibody-based Blood Test to Help Stratify PML Risk in Multiple Sclerosis Patients. Published January 20, 2012.

https://ir.questdiagnostics.com/press-releases/press-releasedetails/2012/Quest-Diagnostics-STRATIFY-JCV-First-FDA-Market-Authorized-Antibody-based-Blood-Test-to-Help-Stratify-PMLRisk-in-Multiple-Sclerosis-Patients/default.aspx

6. Internal Quest test data. https://testdirectory.questdiagnostics.com/test/test-detail/37889/hepatitis-d-virus-rna-quantitative-real-timepcr? p=r&q=HepatitisDVirus(HDV)Antibody,Total&cc=MASTER * TYSABRI is a trademark of Biogen Idec Inc. and Elan Corporation, plc. STRATIFY JCV is a trademark of Biogen Idec.