Translational Strategies in CNS

The CNS industry has experienced its fair share of ups and downs in recent years. However, a greater understanding of the underlying disease, particularly neurodegenerative, and the emergence of new, improved targets and technologies is bringing renewed interest, excitement and investment into this potentially lucrative industry.

Cambridge Healthtech Institute’s Translational Strategies in CNS conference focuses on one of the key issues of CNS drug development – early stage development. Key session topics include developing and validating CNS targets and biomarkers, cross-integration of existing targets, bridging the preclinical/clinical translation gap, evaluating the strengths and weaknesses of current preclinical models, challenging “gold-standards”, understanding mechanism of action, dose selection, neuroimaging, neuroinflamation, neuroimmunology, and more.

Final Agenda

Wednesday, June 14

11:00 am Registration

Genervon Biopharmaceuticals12:00 pm Bridging Luncheon Presentation: Disruptive and Novel Regulatory Therapeutic Strategy for Treatment of Neurodegenerative Diseases by Neuronal Peptide GM6

Winston Ko, CEO, Genervon Biopharmaceuticals, LLC

GM6 showed neuroprotection in neurodegenerative disease rodent models. Using DNA microarrays, Genervon identified 1259 genes altered ≥ 2-fold in SH-5YSY cells, including 89, 48, 46 and 9 genes associated with ALS, AD, PD and MS, respectively, suggesting repression of apoptotic pathway and stimulation of mitotic/proliferation pathways. Phase 1 and 2A trials demonstrated safety of GM6 and observed favorable shifts in biomarkers and improved functional measures. Planning Phase 3 trials.

12:30 Session Break

1:00 Coffee and Dessert in the Exhibit Hall with Poster Viewing


3:30 Refreshment Break in the Exhibit Hall with Poster Viewing


4:15 Chairperson’s Opening Remarks

Murali Gopalakrishnan, Ph.D., Senior Director, Head Search & Evaluation Neuroscience, AbbVie

4:25 Current Challenges and Opportunities in CNS Drug Development

Murali_GopalakrishnanMurali Gopalakrishnan, Ph.D., Senior Director, Head Search & Evaluation Neuroscience, AbbVie

CNS drug development represents an exciting area, particularly for neurodegenerative indications. This presentation details current understanding of CNS-related disease biology, emerging targets, new technologies and the major hurdles facing developers bringing CNS therapies to market.

4:55 Developing Novel CNS Therapies at Yumanity

Kenneth_RhodesKenneth Rhodes, Ph.D., CSO, Yumanity Therapeutics

Yumanity Therapeutics is working to fill a critical need in drug discovery by identifying novel targets, pathways and drug candidate molecules for diseases caused by protein misfolding. This presentation will cover Yumanity’s three integrated discovery platforms and their productivity in the context of target and molecule discovery for neurodegenerative diseases including Parkinson’s disease, Alzheimer’s disease and ALS.

Neucyte5:25 Addressing Relevant Physiological Readouts for CNS Drug Discovery

Daniel_HaagDaniel Haag, Ph.D., CSO, NeuCyte

High attrition rates of novel CNS drugs indicate that current preclinical testing fail to meet the unmet needs of patients. NeuCyte supports the early phases of CNS drug discovery programs for Lead Compound Optimization. Based on our SynFireTM technology, NeuCyte's human neural in vitro platforms are uniquely suited for assessing relevant higher order electrophysiology readouts allowing for a more reliable predictor of drug efficacy and potential CNS Safety/Toxicology.

5:40 Sponsored Presentation (Sponsorship Opportunity Available)

5:55 CT-526: A Peptide Targeting CDK5 in Neurodegenerative Disease

Kent_WernerKent Werner, M.D., Ph.D., Co-Founder and CEO, Cogentis Therapeutics; Johns Hopkins Neurology Adjunct Faculty

In Alzheimer’s disease, CDK-5 is one of the two major kinases to phosphorylate tau and is found to be 10x more active than in cognitively normal controls - largely due to p25. Previous efforts to target CDK5 were toxic and unsuccessful. CT-526 is a peptide targeting p25 and exhibiting zero toxicity at 100x the effective dose. In multiple models, CT-526 reduces tau hyperphosphorylation, amyloid plaque formation, neuroinflammation and rescues phenotype.

6:25 Close of Day

6:30 Dinner Short Course Registration

Thursday, June 15

7:00 am Registration Open and Morning Coffee

7:30 Interactive Breakout Discussion Groups with Continental Breakfast

This session features various discussion groups that are led by a moderator/s who ensures focused conversations around the key issues listed. Attendees choose to join a specific group and the small, informal setting facilitates sharing of ideas and active networking. Continental breakfast is available for all participants.

Lost in translation? Asking the right questions in the right language

Dario Doller, PhD., CCO, Alcyoneus/ScienceWorks

  • CNS disease etiology understanding: who owns it?
  • What are the major disconnects between lab experimentation and clinical research?
  • Are differences in physiology between preclinical species and human affecting the translational gap?
  • Patient segmentation: strategies and outcomes
  • Correlation or causation? Importance of genetic links for different CNS diseases
  • What are the attributes that have real impact minimizing risk during novel target selection?
  • Human as a model for human – what is the future of experimental medicine in CNS drug discovery?

Criteria for Selection of Translational Tools for Target Validation

Kent Werner, M.D., Ph.D., Co-Founder and CEO, Cogentis Therapeutics; Johns Hopkins Neurology Adjunct Faculty


Problem: In vitro/animal models are crucial, but in CNS, they frequently do not predict clinical success, wasting millions and stifling pipelines.

  • What criteria for human-animal parallelism should be realistically required when selecting a preclinical readout/outcome measure? 
  • Are some readouts/outcome measures only valid in humans and should not required in preclinical models?
  • Should functional imaging such as PET receptor occupancy always be a part of target validation effort? Target engagement effort? 
  • Can we rigorously evaluate and standardize CNS preclinical models for a given disease? Who should do it?
  • Phase I early target engagement: Is translation of markers from normal human subjects valid? What criteria should be used in choosing downstream changes from a drug? - Ability to show consistent directional change across normal human subjects? - Necessary to show quantitative correlation in functional measure at every dose from zero to MTD?



8:35 Chairperson’s Remarks

Antti Nurmi, Ph.D., Managing Director, Discovery, Charles River

8:45 Translatability of Early Development Proof of Principle Trials in Neurology

Johan_LuthmanJohan Luthman, Ph.D., Vice President, Neuroscience Clinical Development, Neurology Business Group, Eisai, Inc.

Biomarkers are gaining importance as predictive biomarkers to supplement clinical outcome measures, although validation of biomarkers as surrogate outcome measures still remains a high hurdle. Alzheimer’s disease (AD) is a clear illustration of the introduction of biomarkers has entirely changed the way drug R&D is executed, but also shows the challenges of addressing remaining hurdles.

9:15 Incorporating Biomarker Endpoints in Early Clinical Development to Enable the Successful Development of Novel Neurodegenerative Therapies

Danielle_GrahamDanielle Graham, Ph.D., Director, Neurodegenerative Disease, Biomarker Discovery and Development, Biogen

This presentation will focus on preclinical discovery biomarker strategies designed to increase the successful transition of biomarkers from preclinical discovery to clinical development. As one example, the presentation will highlight studies conducted in cynomolgus monkey with BIIB076, a pan tau antibody, and the CSF pharmacokinetic and pharmacodynamic biomarker data generated. These data were critical for dose selection and sampling times in our ongoing Phase I with BIIB076.

9:45 Translational Validation of Preclinical Models of Neurological Disease

Antti Nurmi, Ph.D., Managing Director, Discovery, Charles River

Charles River offers early discovery phase efficacy testing for novel therapies aimed at neurological and psychiatric conditions. Using a full range of different animal models, we use translational methods including in vitro assays, behavioral and cognitive testing and imaging to accelerate the development of novel CNS and neurological disease related therapies. Multi-modal study designs are essential for robust preclinical data that translate to success in the clinic.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing

 11:00 Translational Strategies in Psychiatry 

Gopi Shanker, Ph.D., Head of Psychiatry, Neuroscience Department, Novartis Institutes for Biomedical Research (NIBR)

Recent advances in the genetics of psychiatric disorders have led to a renewed focus on development of effective therapies in this area. However, the lack of predictive animal models continues to be a challenge for drug discovery. New advances in biomarker development through case-control as well as longitudinal studies in patients are paving the way for the development of new translational strategies in Psychiatry.

11:30 Preclinical Development of NPT088: Translation of a Novel Finding into an Alzheimer’s Drug Candidate

Jonathan_LevensonJonathan Levenson, Ph.D., Senior Director, Preclinical Research and Development, Proclara Biosciences

An unexpected discovery revealed that a minor capsid protein from filamentous bacteriophage M13 selectively binds to and remodels misfolded proteins with an amyloid conformation, such as those found in AD. Here we describe the preclinical development of NPT088, a novel Ig fusion protein and therapeutic approach, for the treatment of AD and other neurodegenerative disorders.

12:00 pm Validation of Animal Models and Understanding Animal Model MOA

Manuela_PolydoroManuela Polydoro, Ph.D., Investigator II, Neuroscience, Novartis Institutes for BioMedical Research, Inc.

Despite large financial investment in drug development, the clinical development success rate of most programs remains low. One explanation is imperfect preclinical research, in which the use and outcome of animal models is pivotal to bridge the translational gap to the clinic. The selection of validated and predictive models is essential to address clinical questions. The translational value of animal models could be further enhanced when combined with novel translational approaches.

12:30 Luncheon Presentation: Accelerating Drug Discovery and Development for Huntington’s Disease

Larry Park, Ph.D., Director, In Vivo Research, CHDI

CHDI Foundation is a nonprofit biomedical research organization focused on developing therapies for Huntington’s disease. CHDI’s activities extend from exploratory biology to the identification and validation of therapeutic targets, and from drug discovery to clinical studies and trials. CHDI manages a diverse portfolio of research projects through a novel virtual model that encourages scientific collaboration to more directly connect academic research, drug discovery and clinical development.

1:00 Session Break


1:30 Chairperson’s Remarks

Tricia A. Thornton-Wells, Ph.D., Investigator III / Clinical Genetics Expert, Neuroscience Disease Area Portfolio Leader, Novartis Institutes for BioMedical Research

1:35 Non-Invasive Epigenetic Neuroimaging

Changning Wang, Ph. D., Instructor, Martinos Center, Massachusetts General Hospital

The epigenetic neuroimaging is expected to usher in a new area of human epigenetic research. Brain imaging studies will provide valuable information to study the causes and epigenetic mechanisms of human disease, especially on neurodegenerative diseases and substance use disorders.

 2:05 Translational Studies with Abeta Lowering Agents

Michael_AhlijanianMichael K. Ahlijanian, Ph.D., Director, Discovery Biology and Head, Clinical Biomarkers, Bristol-Myers Squibb

Halting the progression of tau pathology is an important therapeutic target in neurodegenerative diseases. This talk will review different therapeutic modalities that target tau and the preclinical data sets that can be generated to inform dose selection and provide target engagement and proof of pharmacology endpoints in clinical studies. Specific case studies will be used as examples.

2:35 Refreshment Break in the Exhibit Hall (Last Chance for Poster Viewing)

3:20 Using MRI to Identify Sex Differences in the APOE4 Rat

Craig_FerrisCraig Ferris, Ph.D., Professor, Psychology and Pharmaceutical Sciences, Director, Center for Translational NeuroImaging, Northeastern University

With MRI, we characterized the brain and cognitive development of young male and female APOE Ɛ4 knock-in rats, a preclinical model of Alzheimer’s disease. Male APOE4 rats show a deficit in cognitive function, altered microarchitecture and functional connectivity with elevated oxidative stress. Female APOE4 rats show normal cognitive function, functional connectivity and microarchitecture. Does the APOE4 isoform confer some benefit to healthy adult females while they are still reproductively active?

3:50 Developing Biomarkers for the Frontotemporal Disorders

Nadine_TattonNadine Tatton, Ph.D., Scientific Director, The Association for Frontotemporal Degeneration

Biomarkers that enable clinicians and researchers to accurately diagnose FTD and monitor disease progression are critical to both clinical practice and drug development. However, such biomarkers are currently unavailable, resulting in diagnostic delays or errors and impeding the search for effective treatments. In 2016, the AFTD launched a global request for proposals that would accelerate the discovery of biomarkers across the spectrum of frontotemporal disorders.

4:20 Functional Brain Measures (fMRI and EEG) to Characterize an Awake Individual Using Either Resting or Task Based Data

Bill_PotterWilliam Z. Potter, M.D., Ph.D., Senior Advisor, National Institute of Mental Health

NIMH follows a target validation approach whereby studies of any putative drug include direct evidence of a functional brain effect related to its primary biochemical action(s). Such evidence includes both exposure/response studies on degree of receptor occupancy and downstream functional consequences measured by fMRI, EEG and/or MRS. Data from efforts to validate or reject therapeutic hypotheses about mGluR2/3 agonists, Kappa selective opiate antagonists and GABA subtype selective agonists utilizing agents developed at Lilly and AstraZeneca will be presented.

4:20 Presentation to be Confirmed

4:50 Close of Conference

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