Precision Medicine · Cancer Genetics and Prevention Program at Mount Zion, Cardiovascular Genetics Program, Memory and Aging Center, andMedical Genetics and …

Precision Medicine Current and Future Applications

Tim Remus, PhD Senior Director

2 Confidential and Proprietary © 2018 Sg2

Different Name, Same Definition

Aka; DNA-Based, Genomic or Molecular Medicine

Personalized Medicine: An emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.

-National Institutes of Health

Precision Medicine: An emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.

-National Institutes of Health


Before Symptoms (Prospective) After Symptoms (Retrospective)

Service Line/Disease Area Screening: Everyone Screening: Targeted Diagnostic Therapeutic Prenatal Testing NOW NOW NOW NOW Cancer SOON NOW NOW NOW Pharmacogenomics SOON NOW NOW NOW Rare Disease SOON NOW NOW NOW Neonatal Screening SOON NOW NOW NOW Cardiovascular LATER NOW NOW NOW Pulmonary LATER SOON NOW NOW Infectious Disease LATER SOON NOW NOW Diabetes LATER SOON NOW NOW Obesity LATER SOON NOW NOW Hematology LATER NOW NOW SOON Transplant LATER SOON NOW SOON Neurosciences LATER SOON NOW SOON Psychiatry LATER LATER SOON SOON Surgery LATER LATER LATER SOON Orthopedics and Spine LATER LATER LATER LATER Trauma LATER LATER LATER LATER “Scientific Wellness” LATER LATER LATER LATER

Note: “NOW” indicates genetic testing and/or therapeutic clinical availability today; “SOON” indicates availability likely within the next 3 years; “LATER” indicates some sort of precision medicine offering might become possible within the next 10 years; therapeutic indicates a gene therapy or altered care pathway; “Genetic testing” is defined broadly and includes single gene testing via PCR, Sanger sequencing, classic cytogenetic karyotyping, chromosomal microarrays (CMA), single nucleotide polymorphism (SNP) genotyping, targeted gene panels, mitochondrial panels, pathogen sequencing, whole exome sequencing (WES) and whole genome sequencing (WGS); “Prenatal testing” wraps up many invasive (amniocentesis and chorionic villus sampling) and noninvasive (cell-free fetal DNA [cffDNA]) services including family planning, carrier testing and preimplantation diagnosis. Sources: Sg2 Analysis 2017 (determined by clinical availability of genetic testing in indicated service lines).

Availability by Service Line/Disease Area

Sg2’s Precision Medicine Status Snapshot

Confidential and Proprietary © 2018 Sg2 4

Precision Medicine: Fast Forward to Today Precision Medicine: The Future The Next Dimension


Adoption Two Years Ago…

Is Your System Currently Practicing Precision Medicine? Health Care Leader Surveys, Summer 2016

HIMSS = Healthcare Information and Management Systems Society. Sources: Sg2. Medicine forecast and landscape 2016 [webinar]. Sg2 client survey, slide 20. June 29th, 2016; HIMSS Analytics. Precision medicine: a market snapshot—results of August 16 survey. Presentation at HIMSS17 conference; Sg2 Analysis, 2017.

Sg2 Client Survey HIMSS Survey

35%

26%

15%

24%

37%

18% 16%

29%

Unsure No No, but Planning It Yes


Institutions With Precision Medicine Programs Continue to Grow

Albert Einstein Hospital | American Association for Cancer Research | American Medical Association | Association for Molecular Pathology (AMP) | Baylor Health Care System Precision Medicine Institute | Brigham and Women’s Hospital, Genomes2People Research Program | Brown University | Business Finland | Cancer Treatment Centers of America | Center for Medical Technology Policy | College of American Pathologists | Colorado Center for Personalized Medicine | Coriell Institute for Medical Research | CREATE Health Translational Cancer Centre, Lund University | Duke Center for Research on Personalized Health Care | Essentia Institute of Rural Health | Geisinger Health | Genome British Columbia | Genome Canada | Georgetown Lombardi Comprehensive Cancer Center | Harvard Business School | H Lee Moffitt Cancer Center & Research Institute | Helmholtz Zentrum München | The Hugh Kaul Personalized Medicine Institute, University of Alabama, Birmingham | Inova Health System | Instituto de Salud Carlos III | Intermountain Healthcare | International Society of Personalized Medicine | The Jackson Laboratory | Johns Hopkins Individualized Health Initiative | King Faisal Specialist Hospital and Research Centre | Manchester University School of Pharmacy | Marshfield Clinic | Mayo Clinic | MD Anderson—Institute for Personalized Cancer Therapy | Mission Health, Fullerton Genetics Center | Moffitt Cancer Center | National Pharmaceutical Council | Nicklaus Children’s Hospital Research Institute | NorthShore University HealthSystem | North Carolina Biotechnology Center | Ontario Genomics Institute | Partners HealthCare Personalized Medicine | Poliambulatorio Euganea Medica | Precision Health Initiative at Cedars-Sinai | Precision Medicine Alliance, LLC | Qatar Biobank | Rutgers Cancer Institute of New Jersey | Sanford Imagenetics, Sanford Health | Stanford University School of Medicine | Swedish Cancer Institute | Sylvester Comprehensive Cancer Center | The Christ Hospital Health Network | The Mouse Biology Program | The Quebec Network for Personalized Health Care (QNPHC) | University of Arizona Health Sciences | University of California, San Francisco (UCSF) | University of Florida | University of Maryland School of Pharmacy | University of Pennsylvania Health System | University of Pittsburgh Medical Center (UPMC) | University of Rochester | University of South Florida Morsani College of Medicine | Vanderbilt University Medical Center | Wake Forest Baptist Health | West Cancer Center |

In 2018, 57% of hospitals

are using genomic testing to provide personalized care to patients.

Sources: Personalized Medicine Coalition (PMC). Current members (ie, research, education and clinical care institutions). Accessed June 2018. Sg2 Analysis 2018.


Happening as We Speak: 75,000 tests available now 10 new genetic tests each day Unclear which tests hold clinical utility? CPT coding for molecular diagnostics is a mess. Reimbursement challenges remain; payer uncertainty Trend of gene panel genome has increased ambiguity of results.

Number of Tests on the Market Poised to Explode—Leadership Deficit Emerges

Sources: Health Affairs. Precision Medicine. May 2018; Sg2 Analysis 2018.

>70% of providers consider genetic testing useful and expect it to improve clinical outcomes and have formal education in genetics but…

Only 14% felt confident interpreting genetic test results.


Precision Medicine’s Inflection Point: Are You Ready to Deliver?

Precision Care Delivery

DNA Sequencing

2018

DIF

FER

EN

TIAT

ION

PO

TEN

TIA

L

Note: This is an Sg2 provocative depiction of what could come to pass if the landscape continues its current progression. ROI = return on investment. Sources: Health Affairs. Precision Medicine. May 2018; Sg2 Analysis 2018.

Who is the workforce?

What is the next innovation?

How to bridge? $$ Who PAYS? $$ ROI? $$ Will precision medicine

add or cut costs?




Definitions Omit Specific Technology

Sources: Ginsburg GS and Phillips KA. Health Aff. 2018;37(5):694–701; National Research Council website; National Institutes of Health (NIH) website; Sg2 Analysis, 2018. All websites accessed October 2018.

Precision/Personalized Medicine Individual patient characteristics classify individuals into subpopulations that differ in their disease susceptibility or treatment response.

Concentrates preventive or therapeutic interventions only on those who will benefit, sparing expense and side effects.

EQUAL PARTS:

Technology

Approach

Vision POINT:

Patients live longer and live better


Precision Medicine Encompasses 3 Domains

E&M = evaluation and management; VH = virtual health; VBC = value-based care. Source: Impact of Change®, 2018; HCUP National Inpatient Sample (NIS). Healthcare Cost and Utilization Project (HCUP) 2015. Agency for Healthcare Research and Quality, Rockville, MD; OptumInsight, 2016; The following 2016 CMS Limited Data Sets (LDS): Carrier, Denominator, Home Health Agency, Hospice, Outpatient, Skilled Nursing Facility; Claritas Pop-Facts®, 2018; Sg2 Analysis, 2018.

Prevention Diagnostic Therapeutic

Healthy Population and/or At-Risk Screening

After Patient Starts Showing Clinical Symptoms

Target Therapy to Patient’s Unique Profile

Precision Health

Integrated Diagnostics

Precision “Medicines”

Preventive genetic clinics Consumer–generated data mHealth DNA



PAST

Medical Bracelet Pro: concise

Con: limited data

Personalized Care Abounds With Shiny Objects; Providers Ignore at Their Peril

PRESENT

Mobile Phone Pro: entire EHR

Con: actionability

FUTURE

Under-Skin Chip Pro: responsive

Con: creepy


Big Data Just Got Much Bigger: Patient-Generated Health Data

Patient-Generated Health Data

Every patient has become a big data problem. —Thomas Lee, MD, MSc

DTC = direct to consumer; ECG = electrocardiogram; T1D = type 1 diabetes. Sources: Lee T. Health care teams with grit [video]. NEJM Catal. October 2018; Sg2 Analysis, 2018.

Activity monitors: 150B hours of heart data

Sleep trackers: >6B nights of sleep data from activity trackers

Continuous glucose monitors: 803 donors, 479 years of insulin pump use

Mood monitors: >80M crisis text messages

EHR: >9M for Kaiser Permanente, >14M for University of California Health

DTC genomics: >10M have low-resolution DNA tests for genealogy

ECG: >30M new recordings, with more already offered on smart watches

” “


Emerging Clinics Integrate Genetics Into Part of Primary Medical Care

UCSF HEALTH’S PREVENTIVE GENOMICS CLINIC

PCP = primary care physician. Sources: Marks R. As genetic testing goes mainstream, clinics emerge to guide patients through information. UCSF News Center. November 20, 2017; UCSF Health. Cancer Genetics and Prevention Program at Mount Zion, Cardiovascular Genetics Program, Memory and Aging Center, and Medical Genetics and Genomics Clinic websites. Sg2 Analysis, 2018. All websites accessed October 2018.

Opened in late 2017 with focus on healthy adults Appointments allow patients to discuss their health questions.

Provide professional outlet for asking questions and getting answers Walk through DTC testing results

Offers medically valid tests Carrier screening (family planning) Risk screening (CV) DNA-drug contraindication tests Broad genome screening

Integrated care is future focused, provides relevant, advanced tools via collaborations: Clinical geneticists/counselors Basic biomedical scientists PCPs, frontline providers

Additional UCSF clinics for patients with strong family background of genetic disease: Cancer Heart disease Neurodegenerative disease Rare conditions







Target Therapy to Patient’s Unique Biometric Profile


Subtype diseases Value-based care strategy Halt diagnostic odysseys


Precision Health




Prevent Healthy People From Becoming Patients

Precision Health and Integrated Diagnostics Center (PHIND) Stanford Medicine

Develop, test and disseminate next-gen precision health strategies. >19 multidisciplinary initiatives designed to detect and prevent:

Diabetes, IBD, cardiovascular disease, cancer, neurological, & mental health

In healthy and at-risk individuals, use wearables, implantables and biomolecules to measure transitions from health to disease.

Sources: Stop it: The new Precision Health and Integrated Diagnostics Center searches for ways to prevent disease entirely. Stanford Medicine, Vol. 34, Issue 3, Summer 2018 (link); Gambhir S, et al. Toward achieving precision health. Science Translational Medicine, Vol. 10, Issue 430 February 28th 2018 (link); Sg2 Analysis 2018.

“Integrate repetitive, precise measurements of individual’s health to make diagnoses earlier and ultimately stop disease before it causes real damage.” Monitor based on YOUR risk. BUT NO SPECIFIC DISEASE FOCUS!!! Bring all disease together to enable all practitioners of all types. Not an easy fight and will not be clear for (several) decades.

Philosophy: Predict. Prevent. Diagnose. Cure. Precisely. Not focused on therapeutics.

Vision:

http://stanmed.stanford.edu/2018summer/phind-center-detect-prevent-disease.html

http://dx.doi.org/10.1126/scitranslmed.aao3612


Bedrooms with sleep monitors

Economic analyses of impact and cost of prevention medicine

Glucotyping with continuous glucose monitors and

prescribing precision diets for prediabetes prevention

Automobiles equipped with stress sensors

Breath analysis of chemicals for diabetes, lung cancer detection

Blood-based inflammatory biomarkers to measure

onset of depression/suicide

PHIND’s First Set of Initiatives Among Those That Will Necessitate a Digital Health Strategy

Implantables to sense movement, glucose, vital signs

Electronic skin to measure UV exposure, and sweat

chemistry changes

What does a healthy individual

look like?

Smart clothing to analyze motion, sweat, heart rhythms,

detect breast cancer

Ultrasound powering of under-skin chips for chemotherapeutic

dosing during infusions

Wristbands with vital signs and movement monitoring

Shoes with balance, contact distribution,

cadence, force sensors

Smart bathrooms with toilets and toothbrushes to analyze weight, urine, stool, saliva

Smart kitchens to assess dietary habits

and food quality

Contact lens based sensing of glucose and intraocular pressure

Sources: Stop it: The new Precision Health and Integrated Diagnostics Center searches for ways to prevent disease entirely. Stanford Medicine, Vol. 34, Issue 3, Summer 2018 (link); Gambhir S, et al. Toward achieving precision health. Science Translational Medicine, Vol. 10, Issue 430 February 28th 2018 (link); Sg2 Analysis 2018.

http://stanmed.stanford.edu/2018summer/phind-center-detect-prevent-disease.html

http://dx.doi.org/10.1126/scitranslmed.aao3612







Target Therapy to Patient’s Unique Biometric Profile




Drugs targeted to DNA Tumor DNA care redesign Clinical trial recruitment

“Living” Drugs Targeting DNA DNA redesign

Precision Health




Select Areas Provide Near-Term Applications

AVAILABLE DEVELOPING RESEARCH

Notes: This list is not meant to be exhaustive—see appendix for a more complete account; Trials Forbidden = ethically/officially forbidden to use public funds to research. DIY = do it yourself. Sources: Alliance for Regenerative Medicine (ARM). ARM Q3 2017 Quarterly Data Report; Sg2 Analysis, 2018.

> 550 Clinical Trials

INHERITED CONDITIONS

Hemophilia Congenital blindness ACQUIRED CONDITIONS

Cancer/CAR T therapy Chronic diseases AUGMENTATIVE THERAPIES

“Biohacking,” DIY science Trials Forbidden


Description Enable the immune systems ability to attack B-cell malignant tumors by infusing genetically engineered T-cells back into the patient

What Is the Current Impact? Novartis, Kite (Gilead) – FDA approved ALL, NHL Next indications – lymphoma, adult leukemia, MM Future – replace some BMT volume, expand into the community

Novartis and Kite Break Ground with FDA Approved CAR T-cell Therapies

ALL = acute lymphoblastic leukemia; NHL = non-Hodgkin lymphomas; MM = multiple myeloma. Source: American Cancer Society. 2017 Facts and Figures; Sg2 Impact of Change Forecast, 2018.

Activated T Cell

Tumor Cell

AVAILABLE

On the Horizon FDA releases guidance reports for gene therapy 40 gene therapies could be approved by 2022 “Off-the-Shelf” third-party CAR T-cells Additional


Gene Therapy Involves DNA: Designed, Packaged and Delivered

HEMOPHILIA GENE THERAPY PROCESS

1 Precision medicine identifies patients. 2 DNA is designed.

3 DNA is packaged into virus. 4 Virus is injected intravenously.

DNA is delivered to liver cells.

5 Cells make DNA into protein.

6 Protein is secreted into blood.

Sources: Lillicrap D. Cell. 2017;171:1478–1480; Chen SL. Am J Manag Care. 2016;22:S126–S133; Sg2 Analysis, 2018.

DEVELOPING


Future Applications For CRISPR Gene-editing Tool Are Now Underway

Description CRISPR (pronounced “crisper”) stands for Clustered Regularly Interspaced

Short Palindromic Repeats. Molecular “spell check” to treat inherited diseases (eg, sickle cells anemia)

What Is the Current Impact? Low cost, ‘fairly’ reliable, very easy to program, fast and easy to use FDA lifts clinical hold; first trials in sickle cell to begin

Where Will CRISPR Be Used in the Future? Advances in basic biomedical research and drug discovery Correction of heritable conditions and germline mutations ‘Humanization’ of organs for xenotransplantation Future Impact: Advancement will initially disrupt

health care in non-obvious ways

RESEARCH


RESEARCH BOUNDARIES TRADITIONAL

BENCH BEDSIDE

RESEARCH TREND EMERGING

PERSONAL PRECISION THERAPY


Redefine Applicability in Research Studies With N = 1

Sources: Torkamani A et al. Cell. 2017;170:828–843; Collins F. Creative minds: designing personalized clinical trials. National Institutes of Health Director’s Blog. December 14, 2017; Sg2 Analysis, 2018.

Solution: Use “1-person

studies” to compare

patients to themselves.

Problem: No patient is actually “average.”


Redefine Applicability in Research Studies With N = 1

Source: Torkamani A et al. Cell. 2017;170:828–843; Collins F. Creative minds: designing personalized clinical trials. National Institutes of Health Director’s Blog. December 14, 2017; Sg2 Analysis, 2018.

Develop Deep Disease

Characterization (Using Continuous

Measurement Process)

Detect Early Deviation From Personal Baseline

(Intervention Here Can Be Most Effective) Monitor Normal Variation

PRECISION THERAPY

TREATMENT

Synthesize and Set a Personal Baseline

DISEASE

Continuous Measurements

COMPARE

PREVENT

Kaitlyn’s Digital Twin




WHAT IF… We could cure inherited and acquired conditions?


WHAT IF… We could eliminate systemic organ failure?


WHAT IF… We could prevent and cure Alzheimer disease and dementia?


Adapted From: Kvedar JC et al. The New Mobile Age: How Technology Will Extend the Healthspan and Optimize the Lifespan. Partners Connected Health: October 2017.

Increase the Health Span AND Extend the Life Span

LIFE SPAN

HEA

LTH

SPA

N


Progress is being made today by… Google Calico project and Human Longevity, Inc.

—The Guardian. January 2015

Sources: Corbyn Z. Live for ever: scientists say they’ll soon extend life “well beyond 120.” The Guardian. January 11, 2015; De Lange C. Interview: Cynthia Kenyon: “The idea that ageing was subject to control was completely unexpected.” The Guardian. March 16, 2013; Corbyn Z. Interview: Craig Venter: “This isn't a fantasy look at the future. We are doing the future.” The Guardian. October 12, 2013; Peter H Diamandis, MD. XPRIZE website; Calico website; Human Longevity Inc, website. All websites accessed March 2018.

Live for ever: scientists say they’ll soon extend life well beyond 120.


Meet Kaitlyn…


…Kaitlyn’s Life Journey Will Be Shaped by Innovations

WGS = whole-genome sequencing. Sources: Parent’s Guide to Cord Blood Foundation. Cord Blood Banking web page. Updated May 2, 2018; Fliesler N. BabySeq: Early results of newborn genomic sequencing are mixed. Vector. Boston Children’s Hospital: October 26, 2016; Buhr S. A 3D printed cast that can heal your bones 40%–80% faster. TechCrunch.com. May 29, 2014; American Pregnancy Association. Genetic Counseling web page. Updated March 28, 2017; Tarantola A. Robot caregivers are saving the elderly from lives of loneliness. Engadget. August 29, 2017; Sg2 Analysis, 2018.

Currently Possible Future Possibilities

BIRTH

Cord Blood and Placenta in Biobank

WGS Performed After Birth





BIRTH

Cord Blood and Placenta in Biobank

WGS Performed After Birth





3D-Printed Cast for Sports Injury

Genetic Services During Childbirth

Bioprinted-Ligaments Repair

Injury





Cognitive Decline Cured With Vaccine

Kidney Replaced Using Stem Cells and 3D Bioprinting

Complement Inhibitors Cure Macular Degeneration


QUESTIONS

Documents

Precision Medicine · Cancer Genetics and Prevention Program at Mount Zion, Cardiovascular Genetics Program, Memory and Aging Center, andMedical Genetics and …