Neurodegenerative Disorders: Are We Finally Scaling the Wall?tau/α-syn . correlation with severity...

Page 1 © Defined Health

Neurodegenerative Disorders: Are We Finally Scaling the Wall?

Moderator: Ginger S. Johnson – VP, Defined Health Panelists: Anders Hinsby – CEO, Orphazyme ApS

Christer Nordstedt – VP, Neuroscience Discovery Research and Clinical Investigation, Eli Lilly and Company

Per Svenningsson - Professor, Department of Clinical Neuroscience, Karolinska Institute

Page 2 BioEurope Spring 2016 © Defined Health

The information in this presentation has been obtained from what are believed to be reliable sources and has been verified whenever possible. Nevertheless, we cannot guarantee the information contained herein as to accuracy or completeness. All expressions of opinion are the responsibility of Defined Health, and though current as of the date of this report, are subject to change. The opinions and information set forth herein are expressed solely for the benefit of the addressee and only for the purpose(s) for which the report was produced. Without the prior written consent of Defined Health, this report may not be relied on in whole or in part for any other purpose or by any other person or entity, provided that this report may be disclosed where disclosure is required by law. This report may contain information provided by third parties such as Thomson Reuters, Springer, EvaluatePharma, Datamonitor, Informa Healthcare, IMS Health and others with a proprietary interest in the data provided herein. Please note that you are not permitted to redistribute any such third party information without consent from the originator company. © Defined Health, 2016


Defined Health will be participating in the following events:

Therapeutic Insight by Defined Health at BioEurope Spring | April 4 - 6, 2016 Stockholm, Sweden | http://www.therapeuticinsight.com AACR Annual Meeting 2016 | April 16 - 20, 2016 New Orleans, LA | http://dfndhlth.com/AACR-2016

ASGCT | May 4 - 7, 2016 Washington, DC | http://dfndhlth.com/ASGCT-2016 ASCO | May 29 - June 2, 2016 Chicago IL | http://dfndhlth.com/ASCO-2016

BIO International Convention | June 6 - 9, 2016 San Francisco, CA | http://dfndhlth.com/BIO-2016 Pharma CI USA Conference | September 13 - 14, 2016 Parsippany, NJ | http://dfndhlth.com/PharmaCIUSA

The International Cancer Immunotherapy Conference | September 25 - 28, 2016 New York City | http://dfndhlth.com/ICIC-2016 LES Annual Conference | October 23 - 2 6, 2016 Vancouver, BC | http://dfndhlth.com/LES-2016 Bio-Europe | November 7 – 9, 2016 Cologne, Germany | http://dfndhlth.com/Bio-Europe2016

SITC 2016 | November 9 – 13, 2016 National Harbor, MD | http://dfndhlth.com/SITC-2016 ASH Annual Meeting | December 3 - 6, 2016 San Diego, CA | http://dfndhlth.com/ASH-2016


Are We Finally Scaling the Wall in Neurodegenerative Disease?

♦ Recent groundbreaking scientific insights into the genetic causes and biological processes underlying neurodegenerative disease offer an unprecedented opportunity for the discovery and development of effective medicines for Alzheimer’s disease, Parkinson’s disease, ALS and other neurodegenerative disease.

Denali Therapeutics website


Fueling the Future of Neurodegenerative Disease with Novel Approaches

http://labcentral.org/resident-companies/yumanity-31015/�

http://www.danforthadvisors.com/whoweserve.html�

http://www.oxfordbiomedica.co.uk/�

http://www.brainstorm-cell.com/index.php�

http://www.neuralstem.com/�

http://www.voyagertherapeutics.com/index.php�

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=0ahUKEwjV18fYivDLAhXFGB4KHYCHCSgQjRwIBw&url=http://www.aescap.com/index.php?p=portfolio_detail&portfolio_id=30&bvm=bv.118443451,d.dmo&psig=AFQjCNFs10LkQvJWOlt8ka1LpeFlkK18mA&ust=1459690922367952�


Investors and Partners are Jumping In

Company Websites, Press releases

Novem

http://www.flagshipventures.com/�


http://atlasventure-ls.com/�


Investors and Partners are Jumping In

Company Websites, Press releases

2015 2016

Jan, 2016 - Alector raised $2 9.5M in a Series D lead by Dementia Discovery Fund, with new investors

Amgen Ventures and AbbVie

Feb, 2016 - Yumanity announced a $45M Series A led by Fidelity, also

including Biogen amd Sanofi-Genzyme BioVentures

Oct, 2015 -The Dementia Discovery Fund launched to support discovery and development of novel dementia treatments, raising $100M from investors including the UK Government’s Department of Health and Alzheimer’s Research UK with major pharma including Biogen, GSK, J&J, Lilly, Pfizer and Takeda

Jan, 2016 – Acorda buys Biotie for $363M to complement its emerging Parkinson’s pipeline

March, 2015 0 Teva acquires Auspex for $3.2B to strengthen the CNS franchise with addition of Austedo for treatment of HD, Tardive dyskinesia and Tourette’s

http://breakingfinancenews.com/business/auspex-pharmaceuticals-stock-jumps-successful-trial/4774/�



http://atlasventure-ls.com/�

http://seekingalpha.com/article/3902856-35-percent-annualized-return-acquisition-biotie�

http://www.printed-promotional-lanyards.com/customers/teva/�


We Still Need That Big Hit

Measures of Success

Continued advancement √

Disruptive tool/technologies √

High impact clinical success Not Yet

♦ A lot of excitement around novel approaches and science, but we still need that one big clinical hit.


Improving the Probability of Clinical Success

♦ A combination of genetics, genomics and pathology deepen the understanding of disease pathophysiology and etiology.

♦ While the fundamental questions and issues don’t change, the probability of clinical success does (should). • Right target?

• Right model?

• Right patient?

• Right time?

• Right measure?

• Right value?

v


The Right Target

Clin Pharmacol Ther. 2015

♦ Improved molecular, genetic and neuropathological techniques (e.g., GWAS)

♦ Identification of molecular determinants of neurodegenerative diseases

♦ Enhanced pace of unraveling implicated pathways

♦ Promising leads for drug discovery

v Disease

AD

PD

ALS

FTD

HD


The Right Model

♦ iPSCs have potential to model and treat (e.g., cell therapy) neurodegenerative disease.

http://issuu.com/alsassociation/docs/rat_spring15; Neurol Sci (2015) 36:21–27

• ~20 % of familial ALS linked to dominant mutations in

SOD1 gene. VAPB and TDP-43 also implicated. • iPSC lines generated with mutations for each of these

genes (alone and in combination); show disease relevant pathology and phenotypes (e.g., neurofilament inclusions, reduced cell survival).

• These models are being used to elucidate ALS disease mechanisms and for screening candidate drugs.

Amyotrophic lateral sclerosis


The Right Patient

♦ No such thing as AD, PD, HD, ALS, FTD, etc. ♦ Umbrella terms for a diverse set of diseases, all marked by some

symptomatic or pathological similarities. ♦ Beyond that, heterogeneous at every level: clinical presentation, underlying

neuropathology, dysfunctional neural networks, and associated genes.

http://www.alzforum.org/news/conference-coverage/vancouver-frontotemporal-dementia-conference-shows-awakening-field

For example: Frontotemporal dementia (FTD) represents a spectrum of diseases that stretches toward ALS on one end and parkinsonian symptoms on the other.


The Right Time, The Right Measure

♦ Biomarkers - combination strategy of clinical, laboratory, imaging and genetic data to: • Confirm target engagement • Identify at risk population

Aging and Disease Vol. 5, No.1 Feb 2014

Candidate Biochemical Markers of Parkinson’s Disease SOURCE BIOMARKER VALUE CSF α-syn Helpful in diagnosis of PD even at early stages; no clear

correlation with severity of PD tau/α-syn DJ-1 [HVA]/[xanthine]

BLOOD α-syn Helpful in diagnosis of PD even at early stages; poor sensitivity and/or specificity DJ-1

GST protein ROS Uric acid

OTHERS SAMPLES Salivary α-syn and DJ-1 More accessible biological samples; further evidences needed Urinary 8-OHDG

“OMICS” TECHNIQUES Proteomics Helpful in diagnosis of PD even at early stages; further evidences needed Metabolomics

Transcriptomics

• Track disease progression • Monitor response to therapy

“…there is a world of validation work to be done regarding the relationship of marker to pathway to target…” NeuroPerspective Sept/Oct 2015


The Right Value

♦ Does the required regulatory statistical significance translate to clinical relevance?

♦ Does the magnitude of effect and the benefit/risk ratio justify the cost to the patient/family and the healthcare system?

Barnett et al. BMC Neurology 2014, 14:101

Hypothetical Alzheimer’s Disease Modifying Therapy


We Still Need That Big Hit

♦ The amyloid hypothesis of Alzheimer’s Disease is 25 Years Old. Where are we now?

Sequence of major pathogenic events leading to AD proposed by the amyloid cascade hypothesis.

EMBO Molecular Medicine, March 2016


Will the Nearest-Term Clinical Hit in Neurodegenerative Disease be a Symptomatic Therapy?

Acadia Pharmaceuticals press release

March 30, 2016 FDA Panel Warily Votes In Favor of Novel Parkinson's Psychosis Drug

The FDA's Psychopharmacologic Drugs Advisory Committee voted 12 to 2 that the benefits of Acadia Pharmaceuticals' pimavanserin (Nuplazid) outweigh the risks in treatment of Parkinson's disease psychosis.

The drug was previously granted priority review and breakthrough therapy status, with an action date of May 1, 2016.

While the vote does not directly recommend approval, it does suggest that the committee felt the drug was efficacious and the safety profile was well-characterized.


Topics for Discussion

♦ Are we entering a new era in neurodegenerative disease drug development? What is driving the forward momentum? Where are the speed bumps?

♦ What are the emerging tools/approaches to improve potential for clinical success?

♦ How can common targets/approaches that may address multiple neurodegenerative disease types be best advanced?

♦ What are the important collaborative efforts/partnerships to advance the field and absorb risk?

♦ What symptoms/domains are not adequately addressed? Which particular programs that promise to address these needs are most promising?

♦ What is your advice for early-stage companies looking for a partner?

♦ What do you see as the next significant advancement/clinical success in neurodegenerative disease?

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Neurodegenerative Disorders: Are We Finally Scaling the Wall?tau/α-syn . correlation with severity...

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