FPWR Canada National Conference. May 13, 2017

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1 FPWR Canada National Conference May 13, 2017

2 Theresa Strong FPWR Research Team Nathalie Kayadjanian Jessica Bohonowych Priya Balasubramanian

3 Genetic Mechanisms Resulting in PWS: Lack of active genetic material on the paternal 15q11-q13 Paternal Maternal Imprinting defect Deletion Uniparental disomy ~70% 25-30% 1-4% In all cases, the full complement of PWS genes are present, but not active (maternal allele)

4 PWS region: 15q11-13 SYS Cassidy et al, Genetics Med 2012 ~6Mb 2 common deletion breakpoints

5 How does PWS occur? I. Deletion Low-copy repeats at Break Points > misalignment of chromosomes

6 Deletion Expect ~ 40 per 1,000,000 sperm will have chromosome 15 deletion

7 How does PWS occur? II. Uniparental disomy Nondisjunction Trisomy Rescue Not compatible with life

8 PWS Mechanisms III Imprinting Mutations Mutation or epi-mutation All of us carry 7-10 disease causing mutations; >25 deleterious gene variants

9 Mission The mission of FPWR is to eliminate the challenges of PWS through the advancement of research

Our Research Portfolio FPWR supports a broad portfolio of

basis of the PWS characteristics, to the development of novel

10 Our Research Portfolio FPWR supports a broad portfolio of research, from fundamental studies to understand the molecular basis of the PWS characteristics, to the development of novel therapeutics, through early phase clinical trials to evaluate new drugs and devices in PWS. We prioritize innovative research that will lead to new therapies to alleviate the symptoms associated with PWS. 10

11 Drug Discovery Pathway 11

12 Our Approach FPWR can de-risk therapeutic development across the drug development pathway. We can build translational programs that are more directive in advancing the research along the pathway. Review the current state of PWS research, identify gaps in knowledge, identify points where FPWR could significantly impact therapeutic development Develop a 5 year Research Plan 12

13 Five Year Research Plan Clinical Care Research Creating Critical Knowledge Therapeutic Approaches for PWS Research Tools Grant Program

Funding Strategy Discovery and Translational Research Programs Focuses on identifying the underlying causes of PWS symptoms, discovering drug targets, and efficiently transforming the most promising

14 Funding Strategy Discovery and Translational Research Programs Focuses on identifying the underlying causes of PWS symptoms, discovering drug targets, and efficiently transforming the most promising approaches to new therapies. Shorter-term goals of evaluating existing approaches are balanced with support of longer-term, potentially transformative therapeutic development Grant Program Supports innovative PWS research through a competitive, investigatorinitiated grant program. Grants are selected based on the collaborative input of expert scientists and parent advocates, to ensure that funded research is both scientifically meritorious and relevant to our community. Research Tools Strategic investments support the development of critical research resources that will de-risk and accelerate drug development. 14

15 Five Year Research Plan Balance: Short & long term goals Directed research & investigator-initiated Fundamental knowledge & therapeutics development Knowledge building & targeted studies At all stages: Improve efficiencies Involve stakeholders from academics, industry, regulatory agencies, our PWS community Leverage our resources and experience Overarching goal: Discover and develop new treatments that will improve the health and well being of our loved ones with PWS.

16 Clinical Care Research: Rationale New drug / therapeutic development is great, but we need to improve the lives of our loved ones with PWS in the near term. Are available drugs, devices and techniques being used optimally to support the health and quality of life for people with PWS?

17 Plan Develop an panel of experts and parents to identify and prioritize available therapies Support the evaluation of those therapies Examples: Characterize clinical complications: seizures, central adrenal insufficiency, hypoglycemia Evaluate existing medications to optimize treatment of PWS symptoms: GI motility problems, sleep problems, hypotonia Investigate behavioral interventions for behavioral problems including OCD, anxiety, autistic symptomology, depression, and temper outbursts for PWS Systematically investigate existing pharmacological interventions for obesity, mental health and behavioral problems Develop and evaluate methods (or pharmacological interventions) to overcome ID / learning disabilities common in PWS Develop methods and approaches to help reduce high levels of parental/caregiver stress, family stress

18 Clinical Care Progress Detailed list of PWS symptoms and potential existing drugs and therapies in development to be prioritized Exploring a large international study of growth hormone for adults with PWS FPWR Canada will support a A MINDFULNESS-BASED INTERVENTION FOR TEMPER OUTBURSTS IN PRADER WILLI SYNDROME

19 How does loss of PWS genes lead to the characteristics of PWS, and how do genes outside the PWS region influence severity of disease symptoms? Rationale: We do not yet understand how loss of genes in the PWS region leads to the changes at the cellular, organ, and system level. Neither do we understand the how genes outside the PWS region impact disease severity, including the likelihood of medical complications and patient response to interventions/medications. Approach and Programs: Critical Knowledge PWS: Genotype to Phenotype 1. Understanding the genetics of the PWS region. Use advanced informatics, genomic, proteomic, cellular approaches to fill in gaps of knowledge on how loss of PWS genes impacts protein expression and cellular function 2. PWS Genome Project: Generate genome sequencing data on 100 individuals with PWS (pilot), linked to PWS Global Registry data. Goal: Identify gene variants that modify clinical aspects of PWS, response to medication (pharmacogenomics), impact drug safety parameters. Provide families and their physicians with information to guide clinical care, including medication selection.

20 Critical Knowledge: Neurobiology of Feeding behavior and Mental Health What is the basis of hyperphagiain PWS? What is the basis of susceptibility to mental illness? Rationale: We need to better understand the brain circuitry of feeding behavior in PWS, and why children switch from apparently having little appetite and failure to thrive to having an overwhelming drive to eat in late childhood/adulthood. The underlying basis of mental health problems in PWS is also poorly understood and has a tremendous impact on quality of lift Approach: Fund longer, larger, multidisciplinary teams (clinician/basic scientists) and studies in humans and PWS models to: Understand the neurobiological mechanisms of hyperphagiaat the molecular, cellular, structural and functional level Understand the neurological basis for behavioral challenges and susceptibility to mental illness in PWS failure to thrive reduced energy use increased fat storage increased appetite severe hyperphagia fetus neonate toddler child adolescent adult

21 Therapeutic Approaches: Genetic Therapy for PWS Can PWS gene activation or replacementcompensate for lost function and reverse the symptoms of PWS? Rationale: All individuals with PWS (deletion, UPD, imprinting mutation) have one copy of the PWS region genes present, but in an inactive form. PWS Gene Activation will explore methods to specificallyactivate the PWS genes and determine whether this can compensate for loss of function. PWS Gene Replacement will examine the feasibility of replacing PWS region gene function. Approach: Develop a collaborative approach to investigate the feasibility of genetic therapies to correct the PWS phenotype. FPWR will support of proof of concept studies, coordinate studies to address go/no go decisions, help prioritize technical approaches, and facilitate advancement towards human clinical trials.

Therapeutic Development: Pharmaceutical Development Can we find or develop drugs that can meaningfully reduce some of the most severe features of PWS? Rationale: 1.

22 Therapeutic Development: Pharmaceutical Development Can we find or develop drugs that can meaningfully reduce some of the most severe features of PWS? Rationale: 1. Support the development of novel pharmacological therapeutics for PWS from high throughput screening of drug libraries, including drugs developed for other purposes 2 Facilitate clinical trials for industries developing drugs for PWS Approach: Small molecule drug development Drug Repurposing Program Facilitating Clinical Trials through industry interactions Drug developed by industry for symptoms of interest for PWS HTS using PWS cell models and assays

23 PWS Research Plan Tools for Research Preclinical Animal Network PWS Cellular models network New animal models of PWS International PWS Clinical Trials Consortium Global PWS Registry PWS Biobank(feasibility) Data Sharing Platform

24 Preclinical Animal Network International PWS Experts Rachel Wevrick, Jim Resnick, Anthony Isles, Valter Tucci, Francoise Muscatelli Standardize animal models Standardize methods for evaluating PWS symptoms in the animals Attractive for drug development

25 International Consortium to Advance Clinical Trials for Prader-Willi Syndrome (PWS-CTC)

26 FPWR Grant Program Goals of the Investigator-Initiated Grant Program o o o o Support research that will significantly advance the understanding of PWS and/or develop and evaluate new therapeutic interventions Support innovative, early stage and high risk / high reward research Expand the base of PWS researchers: o o Draw scientists with expertise in relevant areas of study into the PWS field Support promising young investigators who wish to become established in PWS research Involve parents in the process of identifying relevant areas of research and selecting the most deserving research proposals

FPWR supported research has made significant contributions to the understanding and treatment of PWS, with more than 120

27 Grant Program Accomplishments Since its inception, FPWR has invested more than $9 million in PWS research, supporting over 130 research projects in 12 countries. FPWR supported research has made significant contributions to the understanding and treatment of PWS, with more than 120 publications in high impact medical journals. FPWR supported investigators have received >$8 million in additional funding from gov t programs New resources (cells, animal models), new investigators, new collaborations 27

drug target in PWS Drs. Cole-Burnett and Leibel: http://research.fpwr.

28 Fundamental Research How does loss of genes in the PWS critical region result in the PWS characteristics? Insufficient proconvertase1 (PC1) may be responsible for multiple hormone deficiencies in PWS PC1 is a new drug target in PWS Drs. Cole-Burnett and Leibel: Good fundamental research sometimes lets you jump ahead towards new potential therapies

29 Genetic Therapy: Gene Activation Normal Deletion UPD, imprinting Gene activation using a small molecule (UNC0642) PWS genes expressed from maternal allele First demonstration that epigenetic therapy is possible in PWS Dr. Yong-Hui Jiang, Duke University Puzzle Project 2012, 2014 PWS mice + drug Normal mice 2016: PRECLINICAL STUDIES OF A NOVEL EPIGENETIC THERAPY FOR PRADER-WILLI SYNDROME

30 Genetic Therapy: Gene Activation Normal Deletion UPD, imprinting Feasibility Questions for Gene Activation Does activation/replacement of PWS genes reverse symptoms in animal models of PWS? What level of expression needs to be achieved? When will gene activation need to occur to have an effect? What organs and cell types need to be targeted? What are the possible side effects? What is the best approach to deliver the drug/vector?

31 2017 Grants PROOF OF CONCEPT STUDY OF VAGUSNERVE STIMULATION FROM AN EXTERNAL DEVICE IN PWS (YEAR 2). Tony Holland, MRCP, University of Cambridge ($71,585) TRANSCRANIALDIRECT CURRENT STIMULATION, STARTLE MODULATION AND EVENT-RELATED POTENTIALS OF THE BRAIN (YEAR 2). Merlin Butler, PhD, University of Kansas Medical Center ($106,177). ROLE OF THE ENDOCANNABINOIDSYSTEM IN PWS-INDUCED OSTEOPOROSIS AND SKELETAL GROWTH. Yossi Tam, DMD, PhD, Hebrew University of Jerusalem ($108,000). PREVALENCE AND AETIOLOGYOF PWS LOW LEVEL MOSAICISMIN UPD UNDETECTED BY STANDARD TESTING.David Godler, PhD, Murdoch Children s Research Institute ($107,942). DEVELOPING OBJECTIVE BIOMARKERS OF HYPERPHAGIAIN CHILDREN WITH PWS. Alexandra Key, PhD, Vanderbilt University ($95,278). A POST-MORTEM STUDY OF VON ECONOMONEURONS IN THE FRONTAL CORTEX OF BRAINS OF PERSONS WITH PWS (YEAR 2).Patrick Hof, MD, Icahn School of Medicine at Mount Sinai. ($100,000). GENE EXPRESSION ANALYSIS IN PWS SUBJECT DERIVED DENTAL PULP STEMCELL NEURONS (YEAR 2). Lawrence Reiter, PhD, University of Tennessee Health Sciences ($75,600).

2017 Grants EVALUATING FACTORS THAT MAY AFFECT THE EFFICACY OF INTRANASAL OXYTOCIN TREATMENT IN PWS.Daniel Driscoll, MD, PhD, University of Florida ($130,639).

32 2017 Grants EVALUATING FACTORS THAT MAY AFFECT THE EFFICACY OF INTRANASAL OXYTOCIN TREATMENT IN PWS.Daniel Driscoll, MD, PhD, University of Florida ($130,639). IDENTIFING PROTEOME-WIDE DIFFERENCES IN PRADER-WILLI SYNDROME SUBJECTS VERSUS CONTROL DPSC-DERIVED NEURONS. Reiter ($10,755). GENE ACTIVATION STUDY. Marc Lalande, PhD, University of Connecticut ($54,000). *Funded by FPWR-Canada PIG MODELS OF PRADER-WILLISYNDROME FOR PATHOPHYSIOLOGIC AND THERAPEUTIC INTERVENTIONS.Rob Nicholls, PhD, University of Pittsburg (~$125,000 TBD).

33 Plan: Grant Program Stay the course: Continue to support excellent science that is important to families Focus on the most innovative, cutting edge science high risk / high reward Maintain a robust and competitive farm team that can spin into bigger projects in the directed research program

34 Encouraging Collaboration FPWR has supported a number of collaborative, workshop-style meetings, engaging experts on priority areas (eg, mental health, appetite, genetics) to define research questions, identify opportunities, and guide the development of targeted initiatives. We work with other PWS and rare disease organizations around the world to support our goal: eliminating the challenges of PWS through RESEARCH. 34

36 What is the PWS Registry? The purpose of the registry is to develop a comprehensive database of individuals with PWS to better understand the full spectrum of PWS characteristics to expedite the completion of clinical trials to determine areas of needed research and treatments guide standards of care to improve the lives of those affected by PWS

37 Privacy and Safety IRB approved protocol and consent/assent The registry collects patient data through a series of surveys De-identifieddata can be mined to find trends and answer questions De-identified data may be used for research and publications

38 The Registry is composed of surveys which cover topics including: Comprehensive clinical/medical history Developmental milestones Therapies Behavior/Mental health/quality of Life Supplements Medications Surveys can be completed individually Opportunity to login/out, update information, complete new surveys, explore aggregate data Store all of your medical information in one place

39 Representation of the full spectrum of PWS will strengthen the Registry Traditional demographics Age Socio-economic status International Ethnically diverse Spectrum of the PWS experience Participants that are doing well and not as well Diversity in living conditions Diversity in access to current standards of aid/care

40 Global PWS Registry - Current Status 1000 participants registered ~150 participants have completed all surveys ~450 participants have completed some surveys ~400 participants have created accounts Collaborating on recruitment, education, completion PWS organizations globally clinicians, PWS homes, etc... Launch tools getting started video and PDF registry Facebook help group informational webinar

41 Sleep apnea 70% of participants who have had a sleep study have been diagnosed with some form of sleep apnea 12% 30% Normal Obstructive 23% Central Combination (Central/Obs) Apnea (don't know type) N=296 15% 20%

42 Prevalence of Seizures in PWS PWS Subtype of participants reporting seizures Prevalence of seizures by PWS subtype 19% 3% 3% 3% Deletion UPD All PWS 9% Deletion 12% UPD 4% Don't Know 72% Imprinting N=32 Translocation N=352

43 C-Pap Compliance ~50% of those prescribed C-Pap use it less than prescribed or not at all 25% 5% 5% Do not use Use less than prescribed Use as prescribed 37% Use more than prescribed Don't know N=43 28%

44 IQ of Participants 75% of participants who have had IQ testing score below 85 Did not differentiate among IQ test types 6% 2% 9% 36% 14% > <49 - < avg intelligence -mild ID - moderate/severe ID N=266 33%

46 Age of Diagnosis

47 Opportunities for developing therapeutics for PWS Good molecular genetic testing Strong PWS and rare diseases communities Strong clinical community Tools in place : Global PWS Registry, standards of care, several animal and cellular models Interest from pharmain PWS with several undergoing trials Trials testing different targets

48 Growth hormone use

49 Global PWS Registry - Future Directions Develop/launch longitudinal surveys Data curation NORD continuing to expand functionality comprehensive query feature clinical portal support multiple languages Ability to develop and send surveys to targeted groups Country specific Potential for endpoint development, Research studies, PROs, Patient preferences

50 Orphan Drug Development Benefits (for pharmaceutical companies) to work in our population: Some level of homogeneity Compelling unmet medical need Potential for a less expensive route to approval Motivated, active population (!)

51 Orphan Drug Development Risks/challenges companies face in our population: Limited patient population Intellectual disability Decreased pain perception Medications, lots of meds in adults (interactions) Behavioral and psychiatric vulnerabilities Underlying medical risks that could be exacerbated Expensive on a per patient basis

52 Research Ready Community Robust diagnostic test Understanding of natural history of disorder Defined unmet medical need Families have an understanding of the clinical trial process Awareness of ongoing clinical trials Patient registry

53 Clinical Trials for PWS Drug Sponsor Proposed target Phase Status Age Oxytocin Various OXTR Appetite/behavior 1, 2 various All Carbetocin FerringLevo OXTR Appetite/behavior 2 Completed, planning AZP-531 Alize Ghrelin, Appetite / weight 2/3 Completed,pl anning Children Adults Tesomet Saniona tesofensine and metoprolol 2 ongoing Adult Setmelanotid e Diazoxide- CCR Rhythm MC4R, Weight / appetite 2 Completed 16 & up Essentialis/ Capnia Long acting diazoxide, K ATP, appetite behavior Cannabidiol INSYS Endocannabinoid system, Appetite/ weight Diet Intervention FPWR-C/Dr. Scheimann Reducehunger, improve behavior 2/3 Completed, planning Planning 8-65 Pilot ongoing Children VNS FPWR/Holland Vagus nerve behavior Pilot Ongoing Adults tdcs FPWR/Butler Electric stimulation - appetite Pilot Ongoing Adults

54 Our Approach FPWR de-risks therapeutic development throughout the drug development pathway. Discovery and Translational programs generate critical knowledge and identify drug targets and compounds The Preclinical Animal Model Network(PCAN) ensures models accuratelymeasure efficacy and safety The PWS Registry provides longitudinal data of the many characteristics of PWS and expedites enrollment and the completion of clinical trials The PWS Consortium brings together stakeholders to collaboratively address the challenges of PWS clinical trials. We work with the FDA to define unmet medical needs and assess benefit risk to facilitate the drug approval process 54

55 Leadership activities

56 What to expect in st Round of Grants has just been announced, new project received. Outcomes of clinical studies (oxytocin, carbetocin, Rhythm s setmelanotide, Dr. Scheimann s diet study) Start of new clinical studies DCCR, CBD oil, oxytocin/carbetocin, others Continued progress advancing our basic knowledge of PWS, with the goal of identifying new targets for therapeutics development Continued development of early stage drugs Continued engagement and leadership in the Rare Disease Community

Thank you!! Stay up to date: https://www.fpwr.org/fpwr-funded-projects/ https://www.fpwr.org/fpwr-research-outcomes/ http://research.

57 Thank you!! Stay up to date: Webinars, blogs.or /call Theresa!

Run for Prader-Willi Information Sponsoring 2017

1 Run for Prader-Willi Information Sponsoring 2017 1 Introduction Do you know the expression it takes a village to raise a child? In our case it takes a whole community to advance research into Prader-Willi