therapeutic landscape of parkinson’s disease · 1990 2015 2040 millions. 6 the causes of...

THERAPEUTIC LANDSCAPE OF PARKINSON’S DISEASE

Kuldip Dave, Ph.D.

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Our MissionThe Michael J. Fox Foundation is dedicated to finding a cure for Parkinson’s disease through an aggressively funded research agenda and to ensuring the development of improved therapies for those living with Parkinson’s today.

Vital Stats» Founded in 2000 by actor Michael J. Fox» Public Charity» More than 100,000 donors in 2018

supporting our mission to speed a cure» No chapters: team of 140+ based in NYC» Community advocates contacted

lawmakers 52000+ times about critical Parkinson’s issues in 2018.

» Nearly $900 million in research programs funded to date

» Nearly $108 million in research programs funded in 2018

» More than 3,200 projects funded to date» More than 600 active grants in portfolio» 31% of funded projects are led by

researchers outside the United States» Fund academics, biotech and pharma

MJFF IS THE WORLD’S LARGEST NONPROFIT FUNDER OF PD RESEARCH

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We prioritize and pursue research in these areas, providing financial and intellectual support for projects from discovery through the clinic to ensure progress toward new therapies for PD patients.

MJFF RESEARCH PRIORITIES

LRRK2 Alpha-synuclein

EmergingTargets

GBA1Parkin/PINK1

SLOWPROGRESSION

EmergingTargets

MotorSymptoms

Non-MotorSymptoms

SYMPTOMATIC

Clinical TrialRecruitmentBiomarkers

ResearchTools

FIELD-WIDECHALLENGES

Public Policy &

Advocacy

WHAT IS PARKINSON’S DISEASE?» More than 6 million people worldwide live with Parkinson’s .» Parkinson’s is the second most common brain disease

after Alzheimer’s.» One in 100 people over age 60 have PD, though some are

diagnosed at 40 or younger.» About 8-10% of all PD is tied to a genetic or familial factor.

Parkinson’s is a neurodegenerative disease with loss of dopamine neurons and Lewy body pathology.» Motor symptoms of PD include:

– resting tremor– slowness of movement– rigidity– issues with balance and gait

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» Non-motor symptoms include:– cognitive dysfunction– pain, depression and anxiety– constipation and digestion issues– sleep and smell dysfunction

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o Estimated 6.2 million worldwide currently live with Parkinson’s

o Doubled since 1990

o Expect nearly 13 million by 2040

o Rates could grow even more quickly due to:

o People living longer

o Declining smoking rates

o Underreporting

PARKINSON’S IS THE FASTEST GROWING NEUROLOGICAL DISORDERParkinson’s Pandemic

Data from the Global Burden of Disease Study

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12.9

1990 2015 2040M

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The causes of Parkinson’s may fall on a continuum, with some due more to genetics, others from environmental factors and most a mix. Environmental factors may push or protect one from developing PD.

WHAT CAUSES PARKINSON’S?

Head Trauma Heavy Metals Pesticides Toxins

SNCA LRRK2 GBA

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IDENTIFYING THERAPEUTIC TARGETS THROUGH GENETICS & PATHWAYS

GENETIC MUTATIONS

INFLAMMATION

PROTEIN HANDLING

MITOCHONDRIAL DYSFUNCTION

OXIDATIVE STRESS

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GENES DRIVE NORMAL (OR ABNORMAL) FUNCTION OF PROTEINS

• Millions of genetic differences make us who we are: from eye color to risk for disease

• So far scientists have linked ~80 genetic regions to Parkinson’s

• Ten years ago, we knew only about ~10

• Some genes linked to Parkinson’s are pointing to ways we may stop the disease: SNCA, LRRK2, GBA1

• Cells use the recipes in our genes to make proteins, which do many jobs such as carry oxygen and aid in digestion

• Rare variations in a gene are called mutations; These mutations cause protein dysfunction, which can play a role in disease

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WHAT ABOUT PEOPLE WITHOUT GENETIC PARKINSON’S?Studying the causes of Parkinson’s – genetic and environmental –can identify pathways that lead to disease shared by others.

Targeting those pathways may stop PD in larger subsets of the population

Parkinson’s disease

Genetics

Pesticides

Unknown

Unknown

Unknown

Unknown

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GENETICS AND PARKINSON’S

» SNCA: Encodes alpha-synuclein, extremely rare, nearly 100% penetrance

» LRRK2: Accounts for around 2% of PD cases, 25% penetrance– Promising results from first LRRK2 inhibitor trials; Denali Therapeutics moving

to test in people with Parkinson’s disease

» GBA1: Accounts for around 5-10% of PD cases, produces GCase protein (“garbage disposal” of cells), 30% penetrance– First drug trial recruiting with genetic eligibility began in February 2017 from

Sanofi Genzyme; a step toward personalized medicine

» Pink1 and PRKN: Recessive mutation, linked to young-onset PD, extremely rare– Druggable (crystal structure solved), genetic and biology well understood

(affects mitochondria)

About 10 percent of Parkinson's cases have been linked to a genetic correlation. Most cases are idiopathic.

ALPHA-SYNUCLEIN

MJFF Research Priority Area

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IN 1997, FIRST GENETIC MUTATION IN PARKINSON’S DISCOVERED

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Spillantini 1997 NatureSpillantini 1998 Proc Natl Acad Sci

ALPHA-SYNUCLEIN FOUND TO BE MAJOR COMPONENT OF LEWY BODIES

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Monomers are good. Oligomers and fibrils are bad/toxic and lead to Lewy bodies, clumps of protein that scientists believe are harmful to cells.

THE GOOD AND BAD OF ALPHA-SYNUCLEIN

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WE’RE SUPPORTING VARIED APPROACHES TO STOP THE DISEASE PROCESS

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aHashed bars represent programs that are new to MJFF monitoring or have made advances since the last report.bRoles include direct funding at any stage of development ($) or additional support (Other) such as specific trial recruitment and study protocol advice. MJFF continuously identifies and engages with companies to understand challenges and opportunities.cDates of expected results are estimates derived from publicly available press releases or estimated study completion dates

ALPHA-SYNUCLEIN CLINICAL PROGRAMSSponsor Therapeutic Mechanism

StageaMJFF Roleb

Status orResults

ExpectedcI II III Reg.

AFFiRiS AFFITOPE PD01A Vaccine against alpha-synuclein $ Phase II trial

pending 2019

AstraZeneca/Takeda MEDI-1341 Antibody therapy targeting alpha-synuclein - H2 2019

Lundbeck Lu-AF82422 Antibody therapy targeting alpha-synuclein - Q1 2020

Biogen BIIB054 Antibody therapy targeting alpha-synuclein Other Q2 2022

Prothena/RochePrasinezumab

PRX002RO7046015

Antibody therapy targeting alpha-synuclein Other 2020

AbbVie ABBV-0805 Antibody therapy targeting alpha-synuclein - Phase I trial

pending in 2019

Neuropore/UCB NPT200-11UCB0599

Small molecule alpha-synuclein disaggregator

$Other

Pending next trial

Prana Bio PBT434 Small molecule alpha-synuclein disaggregator $ H2 2019

Proclara NPT088Small molecule amyloid protein disaggregator (including alpha

synuclein)$

Alzheimer’s disease trial

results expected Q2 2019

Yumanity YTX-7739 Small molecule inhibitor of alpha-synuclein toxicity - Phase I trial

pending in 2019

LEUCINE-RICH REPEAT KINASE 2 (LRRK2)MJFF Research Priority Area

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Mutation causes and increase in protein kinase activity. Current leading therapeutic strategy against LRRK2 is reducing kinase activity.

LRRK2 GENE VS. LRRK2 KINASELRRK2 Gene (LRRK2)

LRRK2 RNA

LRRK2 kinase (formerly called Dardarin)

GLUCOCEREBROSIDASE (GBA1)

MJFF Research Priority Area

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» Ceramide is an important building block for many fat (lipid) molecules in the cell.

» Glucosylceramide is important for stability of cell membranes and signaling.

» Glucosylceramide normally recycled by Glucocerebrosidase (GBA1)

» Mutations in GBA1 reduce GBA1 function and lead to abnormal accumulation of glucosylceramide resulting in Gaucher disease and increased risk for Parkinson’s.

» Risk of PD if you carry a GBA1 genetic mutation is reported to be 20-30 percent.

Given strong genetic links to PD and insight from Gaucher disease, there is strong interest in targeting GBA1 pathway to treat PD.

GBA1 IS PART OF A COMPLEX AND ESSENTIAL CELLULAR PATHWAY

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» Major focus has been to:

– Enhance glucosylceramide degradation by stimulating, stabilizing and/or replacing GBA1 enzyme activity

– Reduce formation of glucosylceramide through inhibition of synthase

» Other therapeutic approaches targeting downstream toxic effects of GBA1 dysfunction, including those being developed for idiopathic PD, may also be beneficial to people with GBA1-PD

Approved therapies in Gaucher disease provide some proof-of-concept but lack of brain penetration limits value to PD and requires optimization and novel drug development.

DRUG DEVELOPMENT LEVERAGES GAUCHER DISEASE STRATEGIES

InhibitSynthesis

EnhanceDegradation

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LRRK2 CLINICAL PROGRAMSSponsor Therapeutic Mechanism

StageaMJFF Roleb

Status orResults


Denali DNL201 LRRK2 kinase inhibitor Other Q4 2019

Denali DNL151 LRRK2 kinase inhibitor Other Results pending

GBA1 CLINICAL PROGRAMSSponsor Therapeutic Mechanism

StageaMJFF Roleb

Status orResults

ExpectedcI II III Reg.Lysosomal Therapeutics/

Allergan LTI-291 Glucocerebrosidase enhancer$

Other Results pending

Lawson Health Research Institute Ambroxol Glucocerebrosidase enhancer - 2019

University College London Ambroxol Glucocerebrosidase enhancer - Results pending

Sanofi Genzyme GZ/SAR402671 Ceramide glycosyltransferase inhibitor Other H2 2021

resTORbio RTB-101 + sirolimus

TORC1 inhibitor(autophagy enhancer) - Trial pending

Q1 2019

REPURPOSINGDRUGS FOR PARKINSON’SMJFF Research Priority Area

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Famous examples of drug repurposing include Viagra and Rogaine.

REPURPOSING DRUGS:OLD DOGS, NEW TRICKS

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WHY IS GLP-1 A GOOD TARGET IN PD?

These findings give rationale to test GLP1 agonists such as exenatide in people with Parkinson’s disease.

Exenatide is a drug approved for type 2 diabetes.

o Brand names: Byetta, Bydureon

o Exenatide stimulates insulin release from the pancreas by binding to the GLP1 receptor.

o Increased risk of PD seen in people with diabetes:

– Possibly PD and diabetes share genetic abnormalities that may predispose to both and/or share abnormal cellular processes and pathways in the brain.

o Introducing exenatide and activating GLP1 showed improvements in lab models and showed modest effects in two small clinical trials.

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WHY IS C-ABL A GOOD TARGET IN PD?Nilotinib is a drug approved for chronic myelogenous leukemia, a cancer of the white blood cells.

o Brand name: Tasigna

o Tasigna has a black box warning for possible life-threatening heart problems

o Nilotinib inhibits a certain class of proteins, including one called c-Abl.

o Higher levels of c-Abl are associated with Parkinson’s disease and may:

Allow proteins (such as alpha-synuclein) and damaged mitochondria to build

up and harm the cell

Disrupt dopamine-signaling pathways

o Inhibiting c-Abl and giving nilotinib showed protective effects in PD models

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While it’s difficult to make conclusions from an open-label study, current findings are supportive of continued, more rigorous research in this area.

WHAT HAS THE RESEARCH SHOWN?The first nilotinib clinical trial results published in 2016.

• 12 participants with PD, PD dementia, or dementia with Lewy bodies enrolled• 1 participant withdrew after heart attack; 1 withdrew voluntarily• 10 completed 24-week study

• Open-label (all knew getting the drug)

• Evaluated safety and tolerability• Participants experienced pneumonia, urinary tract infections and other side effects

• Evaluated spinal fluid measures of alpha-synuclein and brain concentration of the drug

• Participants noted improvements in motor skills and cognitive function

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Sponsor Therapeutic MechanismStagea

MJFF Roleb

Status orResults

ExpectedcI II III Reg.GLP1

University College London Exenatide GLP-1 agonist $ Trial Pending

Neuraly NLY-01 GLP-1 agonist - Q2 2019

Peptron PT320 GLP-1 agonist - Trial Pending

Cedars-Sinai Medical Center Liraglutide GLP-1 agonist - Q3 2019

University Hospital, Toulouse Lixisenatide GLP-1 agonist - Q4 2021

Oslo University Semaglutide GLP-1 agonist - Trial Pending

c-AblSPARC K0706 c-Abl kinase inhibitor Other Q1 2021

Inhibikase ikT-148009 c-Abl kinase inhibitor $ Trial pending in 2019

Northwestern University nilotinib c-Abl kinase inhibitor$

Other Q4 2019

Georgetown University nilotinib c-Abl kinase inhibitor - Q3 2019

OTHER THERAPIES IN CLINICAL TRIALS

LEVERAGING OTHER CELLULAR PATHWAYS FOR THERAPIESMJFF Research Priority Area

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IDENTIFYING THERAPEUTIC TARGETS THROUGH GENETICS & PATHWAYS

GENETIC MUTATIONS

INFLAMMATION

PROTEIN HANDLING

MITOCHONDRIAL DYSFUNCTION

OXIDATIVE STRESS

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MJFF Roleb

Status orResults


Other Neuroprotective Approaches

ApoPharma Deferiprone Iron chelator - Q4 2019

University of Plymouth Simvastatin Anti-inflammatory - Q2 2020

University of Nebraska Sargramostim Anti-inflammatory - Trial Pending

Sheffield Teaching Hospital Ursodiol (UDCA) Mitochondrial enhancer - Q3 2020

BioElectron EPI-589 Mitochondria enhancer - Results pending

Kainos Medicine KM-819 Cell death inhibitor - Trial pending

Io Therapeutics IRX-4204 RXR agonist $ Trial pending

Parkinson Study Group Nicotine patch Acetylcholine receptor agonist $Results negative;

pending publication

Parkinson Study Group Isradipine Calcium channel blocker$

Other

Trial completed; results expected

Q1 2019

Parkinson Study Group Inosine Urate precursor$

Other

Results negative; pending

publication

OTHER THERAPIES IN CLINICAL TRIALS

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CELL REPLACEMENT AND REPAIR CLINICAL PROGRAMS


MJFF Roleb

Status orResults


Growth Factors

Herantis CDNF CDNF protein infusion Other H2 2019

NIH/NINDS AAV2-GDNF GDNF gene therapy $ Q1 2025

MedGenesis GDNF GDNF protein infusion $Negative;

Publication pending

Stem Cell and Tissue TherapiesInternational Stem Cell

Corporation ISC-hpNSC Dopamine cell replacement - Pending next trial

Kyoto University Hospital iPSC-DA Transplants Dopamine cell replacement $ H2 2019

Celavie Biosciences OK99 Dopamine cell replacement - Q4 2018

Living Cell Technologies NTCell Pig choroid plexus cells (cell-derived protective factors) - Results under

review

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A robust, diverse and rapidly advancing pipeline of therapies being tested in clinical trials is a key metric of progress toward our vision of new treatments and cures for people with PD.

TODAY’S PARKINSON’S THERAPY PIPELINE IS THE MOST ROBUST EVER

WHAT CAN YOU DO TODAY?

We Need Your Help

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Disease measures – biomarkers – could diagnose and track Parkinson’s and speed clinical trials. MJFF’s Parkinson’s Progression Markers Initiative study is collecting data on 1,400 people with and without PD to look for a biomarker.

HELP RESEARCHERS LEARN MORE ABOUT PARKINSON’S

BRAIN IMAGING

SWEAT

TISSUE(E.G. SKIN)

SPINAL FLUID

BLOOD

BREATH

EYE TRACKING

WEARABLE DEVICES

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• Contribute data on the lived experience of Parkinson’s through online surveys and questionnaires

• Open to people with and without Parkinson’s

• Participants with PD can contribute genetic data to Fox Insight through a collaboration with consumer genetics company 23andMe

www.foxinsight.org

FOX INSIGHT: YOUR EXPERIENCE FUELING RESEARCH

JOIN OUR COMMUNITY Visit www.michaeljfox.org for the latest on Parkinson’s research and care.

Webinars: Live panel discussions monthly; available on-demand www.michaeljfox.org/webinars

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Ask the MD: Blogs and videos on Parkinson’s research and care by a movement disorder specialistwww.michaeljfox.org/ask-the-md

Podcasts: Expert interviews on life with Parkinson’s and the latest sciencewww.michaeljfox.org/podcasts

Advocate for Parkinson’s Policieswww.Michaeljfox.org/congress

Join Grassroots Fundraising Effortswww.teamfox.org

WE THANK THE PARKINSON’S COMMUNITY FOR THEIR TREMENDOUS SUPPORT AND ENDLESS OPTIMISM!

www.michaeljfox.org

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Take control of your journey

» Exercise regularly » Eat a healthy, balanced diet » Form a support system of family,

friends and people with Parkinson’s» See a Parkinson’s specialist » Get involved in the community

or research studies

WHAT CAN YOU DO TODAY?Partner to help speed a cure

» Fox Trial Finder matches you to recruiting studies in your area and online www.foxtrialfinder.org

» Fox Insight collects data on life with Parkinson’s through online surveys and remote genetic testingwww.foxinsight.org

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NEW TREATMENTS PROVIDE MORE OPTIONS

Motor symptoms and “off” time

Xadago(safinamide)

Dyskinesia

Gocovri(extended-

release amantadine)

“Off” time and dyskinesia

VerciseDeep Brain Stimulation

Rytary(levodopa/carbidopa)

Duopa(levodopa/carbidopa)

Infinity Deep Brain Stimulation

Osmolex ER (amantadine

extended release)

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MJFF Roleb

Status orResults

ExpectedcI II III Reg.Motor Impairment

Lundbeck Lu-AF28996 Dopamine receptor agonist - Q1 2019

AbbVie ABBV-951 Dopamine receptor agonist - Pending trial launch

Cerevance CVN-424 Dopamine signaling modulator - Q2 2019

Intra-Cellular Therapies ITI-214 Phosphodiesterase 1 inhibitor $ Pending nexttrial

Axovant AXO-Lenti-PD Dopamine synthesis gene therapy - H1 2019

Voyager VY-AADC Dopamine synthesis gene therapy $, Other Q4 2020

Intec Pharma AP09004‘Accordion Pill’

Gastric-retentive levodopa formulation $, Other Mid-2019

MT Pharma ND0612 Levodopa pump $, Other Q3 2021

Neurocrine/Bial OpicaponeOngentyx COMT inhibitor - Pending FDA

submission

Acorda CVT-301Inbrija Inhaled levodopa formulation $ Recently

Approved!

Sunovion APL-130277 Sublingual apomorphine strips $ Pending FDA resubmission

KyowaKW-6002

IstradefyllineNouriast

Adenosine receptor antagonist - Pending FDA resubmission

Kyowa KW-6356 Adenosine receptor antagonist - Q2 2020

MeiraGTx AAV-GAD GAD gene therapy $ Pending next trial

Lundbeck/Prexton Foliglurax Glutamate receptor agonist $ Q2 2019

MOTOR SYMPTOM CLINICAL PROGRAMS

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MJFF Roleb

Status orResults


Dyskinesia

Amarantus Eltoprazine Serotonin receptor agonist $ Pending next trial

Addex Therapeutics ADX48621Dipraglurant Glutamate receptor agonist $ Pending next

trial

Trevi Therapeutics Nalbuphine Opioid receptor antagonist - Pending trial launch

Gait

Arizona State University DroxidopaNorthera Norepinephrin precursor - Q3 2019

University of Arkansas Modafinil Norepinephrin receptor agonist - Q2 2019Oregon Health and Science University Donepezil Acetylcholinesterase inhibitor $ Results

pending

MOTOR SYMPTOM CLINICAL PROGRAMS

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MJFF Roleb

Status orResults

ExpectedcI II III Reg.Cognitive Impairment/Dementia

Acorda SYN120Landipirdine Serotonin receptor agonist $, Other

Negative; publication

pending

Eli Lilly LY-3154207 Dopamine receptor agonist Other Q4 2019

BrainX Corporation Ceftriaxone Cell wall synthesis inhibitor - Q4 2020

Anavex ANAVEX 2-73 Acetylcholine receptor antagonist $, Other Q4 2019

Alkahest GRF6021 Blood plasma fraction $, Other Q4 2020

Rodin Therapeutics RDN-929 Histone deacetylase inhibitor $ Q3 2019

Sleep Issues

BenevolentAI Bio BEN-2001Bavisant Histamine receptor antagonist - Pending

updatesConstipation/Incontinence

Enterin ENT-01Kenterin

Small molecule alpha-synuclein disaggregator - Q4 2019

Sialorrhea/Dysphagia

Balto Therapeutics BAL-001Glycopyrrolate Acetylcholine receptor antagonist - Pending

updates

NON-MOTOR SYMPTOMS CLINICAL PROGRAMS

QUESTIONS?

therapeutic landscape of parkinson’s disease · 1990 2015 2040 millions. 6 the causes of...

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