Translating a Trillion Points of Data into Therapies and New Insights in Health and Disease

atul.butte@ucsf.edu

@atulbutteAtul Butte, MD, PhD

Director, Institute for Computational Health Sciences

University of California, San Francisco

Conflicts of Interest• Scientific founder and

advisory board membership

– Genstruct

– NuMedii

– Personalis

– Carmenta

• Honoraria for talks

– Lilly

– Pfizer

– Siemens

– Bristol Myers Squibb

– AstraZeneca

– Roche

– Genentech

– Warburg Pincus

• Past or present consultancy

– Lilly

– Johnson and Johnson

– Roche

– NuMedii

– Genstruct

– Tercica

– Ecoeos

– Ansh Labs

– Prevendia

– Samsung

– Assay Depot

– Regeneron

– Verinata

– Pathway Diagnostics

– Geisinger Health

– Covance

– Wilson Sonsini Goodrich & Rosati

– 10X Genomics

– Medgenics

– GNS Healthcare

– Gerson Lehman Group

– Coatue Management

• Corporate Relationships

– Northrop Grumman

– Aptalis

– Thomson Reuters

– Intel

– SAP

– SV Angel

– Progenity

• Speakers’ bureau

– None

• Companies started by students

– Carmenta

– Serendipity

– NuMedii

– Stimulomics

– NunaHealth

– Praedicat

– MyTime

– Flipora

bit.ly/genedata

5,178 compounds· 1,300 off-patent FDA-approved drugs· 700 bioactive tool compounds· 2,000+ screening hits (MLPCN and others)3,712 genes (shRNA + cDNA)· targets/pathways of FDA-approved drugs (n=900)· candidate disease genes (n=600)· community nominations (n=500+)15 cell types· Banked primary cell types· Cancer cell lines· Primary hTERT immortalized· Patient derived iPS cells· 5 community nominated

@AssayDepot

Validation methods are increasingly commoditized

Rat colonoscopy Rat with Inflammatory Bowel Disease

Inflammatory Bowel Disease

After Anti-seizure Drug

bit.ly/scitmtop

Anti-seizure drug works against a rat model of inflammatory bowel disease

Joel DudleyMarina Sirota

Psychiatric Drug Imipramine Shows Significant Activity Against Small Cell Lung Cancer

Vehicle control Imipramine

p53/Rb/p130triple knockoutmodel of SCLC

Mice dosed after tumor formation

Joel DudleyNadine Jahchan

Julien SageAlejandro Sweet-Cordero

Joel Neal@NuMedii

Need more drugs for more diseases

Public big data available

NIH fundingData analyzed,

method designed

Company launched, ARRA, StartX,

Stanford license, first deal

Claremont Creek, Lightspeed ($3.5

million)

@NuMedii

bit.ly/immport

The next big open data: clinical trialsDownload 100+ studies today

Jeff WiserPatrick Dunn

Sanchita Bhattacharya

Reanalyzing RAVE

• Rituximab in ANCA-Associated Vasculitis (RAVE) trial of new approach to the induction of remission

– randomized

– double-blind

– double-dummy

– active-controlled

– non-inferiority

RAVE re-analysis

• 63 of the 99 patients in the rituximab group (64%) reached the primary end point, as compared with 52 of 98 in the control group (53%).

• The treatment difference of 11% points between the groups met the criterion for non-inferiority (P<0.001).

In retrospect, do any measured factors predict response?

Mazen Nasrallah

Nasrallah M, …, Butte AJ. Arthritis Research & Therapy (2015) 17:262.

Nasrallah M, …, Butte AJ. Arthritis Research & Therapy (2015) 17:262.

Targeted_therapy_graph

ANCA-

associated

Vasculitis

Profiled

Therapy

~ 54% of patients

Non-profiled

Therapy

~46% of patients

Treat with

Rituximab

~ 30% of patients

Remission Rate ~ 83%

Treat with

Cyclophosphamide

~24% of patients

Remission Rate ~ 66%

Do not treat with

Cyclophosphamide

Failure rate ~ 67%

Do not treat with

Rituximab

Failure rate ~ 70%

GI ≤ -9.25%

OR

GI ≥ 47.6%

GI ≤ -9.25% GI ≥ 47.6%

Treat with either Rituximab or

Cyclophosphamide

according to best clinical judgement

Average Remission Rate ~ 60%

Non-profiled

Therapy

100% of patients

NO

Proposed

Method

Current

Method

Measure the Granularity Index

(GI)

YES

Mazen Nasrallah

Institute for Computational Health Sciences

Collaborators• Jeff Wiser, Patrick Dunn, Mary Shaffran / Northrop Grumman

• Ashley Xia and Quan Chen / NIAID

• Takashi Kadowaki, Momoko Horikoshi, Kazuo Hara, Hiroshi Ohtsu / U Tokyo

• Kyoko Toda, Satoru Yamada, Junichiro Irie / Kitasato Univ and Hospital

• Shiro Maeda / RIKEN

• Alejandro Sweet-Cordero, Julien Sage / Pediatric Oncology

• Mark Davis, C. Garrison Fathman / Immunology

• Russ Altman, Steve Quake / Bioengineering

• Euan Ashley, Joseph Wu, Tom Quertermous / Cardiology

• Mike Snyder, Carlos Bustamante, Anne Brunet / Genetics

• Jay Pasricha / Gastroenterology

• Rob Tibshirani, Brad Efron / Statistics

• Hannah Valantine, Kiran Khush/ Cardiology

• Ken Weinberg / Pediatric Stem Cell Therapeutics

• Mark Musen, Nigam Shah / National Center for Biomedical Ontology

• Minnie Sarwal / Nephrology

• David Miklos / Oncology

Support• University of California, San Francisco

• National Institutes of Health

• March of Dimes

• Juvenile Diabetes Research Foundation

• Hewlett Packard

• Howard Hughes Medical Institute

• California Institute for Regenerative Medicine

• Luke Evnin and Deann Wright (Scleroderma Research Foundation)

• Clayville Research Fund

• PhRMA Foundation

• Stanford Cancer Center, Bio-X, SPARK

• Tarangini Deshpande

• Sam Hawgood

• Keith Yamamoto

• Isaac Kohane

Admin and Tech Staff

• Mary Lyall

• Mounira Kenaani

• Kevin Kaier

• Boris Oskotsky