mapping the genomic landscape to accelerate precision drug development · 2020-03-11 · prioritize...
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Mapping the Genomic Landscape to Accelerate Precision Drug Development
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Mark Kiel, M.D. PhDFounder & Chief Science OfficerGenomenon
www.genomenon.com
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Alastair Garfield, PhDVice President, Translational Research & Development (TRAD) Rhythm Pharmaceuticals
www.rhythmtx.com
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Sign up for Mastermindbit.ly/mm-rhythm
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30M Titles/Abstracts6M+ Full-text Articles
50K+ Suppl. Files
10K+ Diseases30K+ Genes3M+ Variants
100+ Keywords
WHAT IS GENOMENON?
Organizing the World’s Genomic Information
www.genomenon.com
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For a given indication, produce a list of annotated and
evidence-supported variants for any gene associated with that
indication
EVIDENCE-BASED GENOMIC LANDSCAPE
www.genomenon.com
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Data Required to Interpret Genomic Variants
1. Population Data
2. Predictive Models
3. Published Literature
EVIDENCE-BASED GENOMIC LANDSCAPE
www.genomenon.com
PUBLISHED LITERATURE
PREDICTIVEMODELS
POPULATIONDATA
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1. Genomic Landscape for Drug Discovery
2. Clinical Trial Target Identification
3. New Indications – Repurposing
GENOMENON SERVICES FOR PHARMA
www.genomenon.com
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Example Use Cases
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• DNA Damage Repair Genes
• Hematopoietic Malignancies
• Cancer-Related Fusions
USE CASE #1: GENE LEVEL
www.genomenon.com
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• AML Variants
• Functional Variant Landscape for 500 known cancer-causing genes
USE CASE #2: VARIANT LEVEL
www.genomenon.com
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Prioritize and Rank by Number and
Strength of Associations
Auto-Curate with Machine Learning
Manual Review
We have indexed 6M full-text genomic articles to exhaustively catalogue biomarker candidates
Annotate, Filter, Rank and Curate for Pathogenicity or Actionability
1. ----2. ----3. ----
Collate a Comprehensive
Body of Evidence
1
4
Filter by Client-Specific Clinical or
Research Goals
3
5 6
GENOMIC LANDSCAPINGGenomenon’s Approach
Identify all the Disease-Gene and
Disease-Variant Associations
2
www.genomenon.com
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Understanding Rare Genetic Disorders
of Obesity
RHYTHM PHARMACEUTICALS
www.genomenon.com
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Alastair Garfield, PhDVice President, Translational Research & Development (TRAD) Rhythm Pharmaceuticals
www.rhythmtx.com
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Rare Genetic Disorders of Obesity
Alastair Garfield, PhDVice President, Translational Research & Development
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2 © Rhythm Pharmaceuticals, Inc. All rights reserved. MC4R-XXXX
Overview of Rhythm Pharmaceuticals
Rhythm is a biopharmaceutical company focused on deepening an understanding of the genetics underlying rare disorders of obesity.
RhythmTX.com
NASDAQ: RYTM
@RhythmPharma
LinkedIn.com/company/rhythm-pharmaceuticals-inc-/
50+Employees
Foundedin 2008
Located inBoston, MA
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3 © Rhythm Pharmaceuticals, Inc. All rights reserved. MC4R-XXXX
Genetic Factors Play a Significant Role in Determining BMI
BMI
Obesity is thought to be a consequence
of poor lifestyle choices, leading to
substantial social stigma2
Genetics1Environment1
(eg, leisure activity, food choice)
BMI, body mass index.References: 1. van der Klaauw AA, Farooqi IS. Cell. 2015;161(1):119-132. 2. Hilbert A et al. Obesity (Silver Spring). 2008;16(7):1529-1534. 3. Maes HH et al. Behav Genet. 1997;27(4):325-351.
Approximately 50% to 90% of variance
in BMI can be attributed to genetic
causes3
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4 © Rhythm Pharmaceuticals, Inc. All rights reserved. MC4R-XXXX
Genetic Contributions to Obesity and Rare Genetic Disorders of Obesity
Rare genetic disorders of obesityMultiple gene variants – not rare
Types of obesity1-3
(pie chart not drawn to scale for prevalence of the types of obesity)
MC4R, melanocortin-4 receptor.References: 1. Huvenne H et al. Obes Facts. 2016;9(3):158-173. 2. Hinney A et al. Eur Child Adolesc Psychiatry. 2010;19(3):297-310. 3. Kostovski M et al. Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2017;38(3):121-133.
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CONFIDENTIAL5 © Rhythm Pharmaceuticals, Inc. All rights reserved. MC4R-C0131
Hallmark features of rare genetic disorders of obesity
There are several different rare genetic disorders of obesity, but those caused by variants in the MC4R pathway have a few things in common.
Feelings of insatiable hunger
Severe obesity that may begin early in life, known as early-onset obesity
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6 © Rhythm Pharmaceuticals, Inc. All rights reserved. MC4R-XXXX
Eating Behavior is Highly Regulated to Maintain Body Weight
The hypothalamus regulates appetite and energy expenditure
Figure adapted from: Morton GJ et al. Nat Rev Neurosci. 2014;15(6):367-378. Reference: van der Klaauw AA, Farooqi IS. Cell. 2015;161(1):119-132.
Weight maintained
Energy intake
Energy output
Feeding
Circulating Hormones
Circulating Hormones
Satiety
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7 © Rhythm Pharmaceuticals, Inc. All rights reserved. MC4R-XXXX
Eating Behavior is Highly Regulated to Maintain Body Weight
The hypothalamus regulates appetite and energy expenditure
.Figure adapted from: Morton GJ et al. Nat Rev Neurosci. 2014;15(6):367-378. Reference: van der Klaauw AA, Farooqi IS. Cell. 2015;161(1):119-132.
Feeding
Satiety
Weight Gain
Energy intake
Energy output
Circulating Hormones
Circulating Hormones
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8 © Rhythm Pharmaceuticals, Inc. All rights reserved. MC4R-XXXX
The melanocortin-4 receptor pathway - physiology
The melanocortin-4 receptor (MC4R) signaling pathway regulates appetite and energy expenditure
Mutations in this pathway can result in rare genetic disorders of obesity
POMC NEURON
Upstream
LEPR
LEPTIN
Downstream
SATIETYSIGNALS(LEPTIN)
PCSK1
α-MSHβ-MSHγ-MSH ACTH
POMCα-MSHβ-MSH
PVH
ADIPOSETISSUE
POMC Neuron
MC4R-Expressing Neuron
£ FOOD INTAKE£ WEIGHT
AgRPPOMC
α-MSHPCSK1
AgRP/NPY
Neuron
LEPTIN
¤ FOOD INTAKE¤ WEIGHT
MC4RECEPTOR
ACTIVATION¤APPETITE¤BODY WEIGHT£EXPENDITURE
MC4R-EXPRESSING NEURON
MC4R
RHYTHM FOCUS
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9 © Rhythm Pharmaceuticals, Inc. All rights reserved. MC4R-XXXX
ACTH, adrenocorticotropic hormone; AgRP, agouti-related protein; ARH, arcuate nucleus; BBS, Bardet-Biedl syndrome; LEPR, leptin receptor; MC4R, melanocortin-4 receptor; MSH, melanocyte stimulating hormone; NPY, neuropeptide Y; PCSK1, pro-protein convertase subtilisin/kexin type 1; POMC, pro-opiomelanocortin; PVH, paraventricular nucleus of hypothalamus.Figure adapted from: Yazdi FT et al. PeerJ. 2015;3:e856.References: 1. Yazdi FT et al. PeerJ. 2015;3:e856. 2. Krashes MJ et al. Nat Neurosci. 2016;19(2):206-219. 3. Cone RD. Endocr Rev. 2006;27(7):736-749. 4. Sohn JW et al. Trends Neurosci. 2013;36(9):504-512. 5. van der Klaauw AA, Farooqi IS. Cell. 2015;161(1):119-132.
BBS and Alström syndrome
POMC NEURON
Upstream
LEPR
LEPTIN
Downstream
SATIETYSIGNALS(LEPTIN)
PCSK1
α-MSHβ-MSHγ-MSH ACTH
POMCα-MSHβ-MSH
PVH
ADIPOSETISSUE
POMC Neuron
MC4R-Expressing Neuron
£ FOOD INTAKE£ WEIGHT
AgRPPOMC
α-MSHPCSK1
AgRP/NPY
Neuron
LEPTIN
¤ FOOD INTAKE¤ WEIGHT
MC4RECEPTOR
ACTIVATION
MC4R-EXPRESSING NEURON
MC4R
Mutations in this pathway can result in rare genetic disorders of obesity1-5
The melanocortin-4 receptor pathway - pathology
OBESITY£ APPETITE£ BODY WEIGHT¤ EXPENDITURE
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10 © Rhythm Pharmaceuticals, Inc. All rights reserved. MC4R-XXXX
The Challenge and Our Approach
Two specific needs
� Generate a searchable compendium of all genetic variants associated with MC4R-pathway deficiency obesity documented in published literature.
� Surface variant specific biological data to inform the pathogenic status of each variant and its potential contribution to obesity.
Rhythm brings a deep internal knowledge of the
MC4R-pathway
• Manual review and collation of published literature.
• Focused on expanding this groundbreaking work by scaling up our efforts.
Special considerations
• Ensure the completeness of the literature review.
• Ensure the accurate assimilation of all relevant data across multiple publications.
• Overcome the semantic inconsistencies.
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11 © Rhythm Pharmaceuticals, Inc. All rights reserved. MC4R-XXXX
Partnering with Genomenon: Database Assembly
• All mentions of a given variant, regardless of format or location within a manuscript, are captured.
• Context of the discussion is documented.
Genomenon’s methodology improved the efficiency and completeness of our literature review process.
• Rhythm compiled a list of 120 obesity related genes for which we sought a catalogue of clinically relevant published variants.
• Mastermind Genomic Search Engine was used a develop a database of variants across all these genes and a list of relevant citations.
Within 60 days Mastermind identified and collated a database of over 10,000 variants.
Centralizing these data in a searchable resource has facilitated our ability to rapidly locate and review published literature on any variant of interest.
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12 © Rhythm Pharmaceuticals, Inc. All rights reserved. MC4R-XXXX
Partnering with Genomenon: Database Assembly
• Building an association between a given genetic variant and the clinical presentation in which it is observed.
Next we focused on developing an understanding of the pathogenicity of individual variants in a prioritized subset of those genes.
• Not readily surfaced by the algorithms behind public search tools.
• Genomenon’s custom curation service was used to mine the previously compiled list of literature for data relevant to the ACMGs criteria for pathogenicity and benignness.
Rhythm utilizes this resource as a means for building an understanding of the genetics that underlie MC4R-pathway deficiency obesity.
Much of this evidence is buried within the published data.
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13 © Rhythm Pharmaceuticals, Inc. All rights reserved. MC4R-XXXX
Partnering with Genomenon: Database Assembly
We are using this evidence-based view of the genetic factors contributing to obesity to help inform our understanding of
rare genetic disorders of obesity.
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[email protected] | www.genomenon.com |1-734-794-3075
Thank You
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