Leaders in Pharmaceutical Business Intelligence (LPBI) Group

MENSANA THERAPEUTICS POWERPOINT PRESENTATION (adapted for post)

A Novel, Science-based Approach in
Treating Alzheimer’s disease

Michael V Ward, DVM

CEO/CSO

Mensana Therapeutics

 

ABOUT MICHAEL WARD, DVM

• Canadian-born and educated.
• 20+ years of senior leadership in the design, development and testing of medical devices.
• Scope of experience includes pre-clinical, clinical, regulatory, medical affairs,and business development – USA, Europe, and Asia Pacific.
• >6 years of neurological business development and clinical programs in China.

CHINA HISTORY – July 29 2008

• National Summer School for top 100 Postgraduate Medical Students in China.
• Co-hosted by China’s Ministry of National Education, National Science Foundation of China, and the Second Military Medical University, Shanghai.
• Plenary lecture on establishing a career in clinical research.

PRESENTATION – INTRODUCTION

• This presentation describes a science-based, unique approach to the treatment of Alzheimer’s disease (AD), which compensates for an overt failure of the brain to manage inflammatory processes and the kinetics of beta amyloid(Aβ).

A MULTITUDE OF THERAPEUTIC DISAPPOINTMENTS

• Approximately 90 drug companies have assessed >300 compounds for the treatment of AD,with no success.
• Drugs developed to block Aβ production.
• The medical community now forced to seek a fresh approach.
• Current search for additional mediators and pathways. 

RECENT HIGHLIGHTS OF FAILED DRUG THERAPY

• Pharmaceutical companies targeted Aβ production, a possible error in strategy or at least not the whole picture.
• Sample pharmaceutical losers: Eli Lilly’s “Semagacestat gamma secretase inhibitor” in which all 2,600 subjects had worsened symptoms (2010); J&J/Pfizer blamed flawed patient selection criteria that resulted in failed clinical trials (2012).
• Baxter Healthcare Announcement: Intravenous immunoglobulin (IVIG), treatment failed to slow down cognitive decline and failed to preserve functional abilities; in studying patients with mild to moderate AD (May 2013).

KEY FACTORS COMPROMISING DRUG TRIALS

 

1.Not affecting the principal cause of Alzheimer’s disease.

2.Difficulty of drugs to cross blood-brain barrier.

3.Drug-related serious side effects.

4.>40% non-adherence to prescribed regimen: sub-standard drug exposure.

5.Targeted patient populations have much too advanced disease and brain parenchyma damage.

 

.New Ideas & Alternate Pathways Starting to Emerge…..

 

WHAT IS THE COMPLETE PATHOGENESIS OF ALZHEIMER’S DISEASE?

 

• This is a “work in progress” as we continue to learn more about immunological mechanisms and the biochemical events involving certain proteins, inflammatory mediators, and complex pathways in neurodegenerative diseases.

ONE NEW FOCUS IN AD

• Failure to clear amyloid beta (Aβ) into the vascular system
• Stockpiling of beta amyloid in the brain parenchyma, creating plaques that destroy brain tissue.
• Is Aβ a cause of the neurodegeneration or an “innocent bystander” caught up in the fibrils associated with AD lesions.

[Reference:O’Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer’s disease. AnnuRevNeurosci (2011),Vol 34, pg185-204]

ROLE OF NEUROINFLAMMATION IN AD

• Microglial activation, with excessive expression of immune cytokines, acquiring the status of “principal culprit” in the unresolved connection between an elevated risk for the development of sporadic Alzheimer’s disease and traumatic brain injury, systemic infections, normal aging, and several neurologic disorders.

[Reference: Sue T & Griffin T. “Neuroinflammatory Cytokine Signaling and Alzheimer’s Disease.” NEJM (Feb 21, 2013) Vol 368 (8), pg 770 – 771]

Biomarkers in CSF to Consider in Addition to Beta Amyloid…..

TAU PROTEIN 

• Increased CSF tau protein (CSF-tau) found in AD patients. 
• Primarily within neurons; but, in CSF, after brain parenchymal damage.

[Reference: Zetterberg H, David Wilson, et. al. “Plasma tau levels in Alzheimer’s disease.” Alzheimer’s Research & Therapy (2013), Vol 5:9.]

ALPHA-SYNUCLEIN

• Associated with plaque formation in Alzheimer’s disease.
• New evidence – potential role of α-synuclein in synaptic damage and neurotoxicity involving fibril formation and mitochondrial dysfunction.
• Levels of soluble α-synuclein are about twofold higher in AD brains than in control brains.
• Measurable levels in CSF.

 [Reference: Marques O &  Outeiro TF. “Alpha-synuclein: from secretion to dysfunction and death.” Cell Death and Disease (2012) 3, e350]

LATEST RECOMMENDATION IN NEW ENGLAND JOURNAL OF MEDICINE

• “Given the mounting sociological, economic, and personal costs of Alzheimer’s disease, the lack of a perfect understanding of its mechanisms should not stop researchers from conducting clinical studies of a variety of strategies intended to reduce the risk of development of the disease and of experimental approaches to expedite its treatment.”

[Reference: Sue W & Griffin T.  Neuroinflammatory Cytokine Signaling and Alzheimer’s Disease.  N Engl J Med (2013), Vol 368, pp 770-771]

ALTERNATIVE PATHOGENESIS

 

• Exact cause and full pathogenic pathways of Alzheimer’s disease are unknown.
• Is Aβ an “innocent bystander,” trapped within another pathologic process?
• ‘Sticky’ Aβ complexes created entrapped in brain parenchyma among fibrils part of the histopathology observation. 
• AD patients have less circulating Aβ in CSF than normal human subjects in spite of diminished Aβ clearance into the vascular system.
• High probability that at least part of AD progression involves inflammatory mediators (e.g., cytokines) and/or immune complexes, both of which may be found in CSF.

MENSANA’S WORKING HYPOTHESIS

• CSF pheresis will disrupt the overall dynamics that lead to the pathological accumulation and damaging distribution of inflammatory mediators, antibodies, immune complexes, and Aβ in the parenchyma of the brain and result in arrested  disease progression.

U.S. PATENT 7887.503.B2

• Patent issued 2/15/11.
• Method and Apparatus for removing “harmful proteins” from ventricular CSF.
• Organizations with previously expressed interest in this IP include: J&J, Medtronic, Integra Life Sciences. Shire, & Alfred Mann Foundation. 

 Historical Precedence: CSF Pheresis……

WOLLINSKY’S MEDICAL TREATMENT FOR GUILLAIN-BARRE SYNDROME (GBS)

• Goal to eliminate inflammatory mediators associated with GBS by repeated extracorporeal filtration of CSF to remove proteins, cells and      polypeptides. 
• Removed soluble mediators included tumor necrosis factor, interleukin-6,12 antiganglioside antibodies, and C3a/C5a (indicates complement activation) – found in high concentrations in the CSF of GBS patients.
• Disease pathogenesis: immune-mediated attack of the myelin sheath of peripheral nerves is the primary cause of the neurologic deficits.

 WOLLINSKY’S TREATMENT RESULTS

• Significant clinical improvement of GBS signs & symptoms.
• No serious side-effects for up to 70+ days of in-hospital therapy.

[Reference: Wollinsky KH, Hulser PJ, Brinkmeier H, et.al.  “CSF filtration is an effective treatment of Guillain-Barre syndrome: A randomized clinical trial.”  Neurology (2001), Vol 57, pp 774-780.]

First Medical Device to Treat Alzheimer’s Disease…….

EUNOE CORPORATION

• Gerald Silverberg, M.D., a neurosurgeon from Stanford University, co-founded Eunoe Corporation, in Northern California, to develop a medical device to treat Alzheimer’s disease.
• Phase I/Pilot studies “encouraging”, leading to an IDE trial (PMA), assessing effectiveness of a simple implantable ventriculoperitoneal shunt.
• Phase II study failed to meet study objectives; sold company assets and technology to Integra Life Sciences.

RETROSPECTIVE ANALYSIS OF EUNOE

• Two key considerations:

1. There was too slow ventricular drainage (flow) of CSF through the shunt, leading to minimal or no impact on CSF concentrations and dynamics of beta amyloid and other possible AD mediators in the brain.
2. Possibly flawed patient selection criteria – enrolling subjects with too advanced clinical signs of dementia: disease process too advanced and the treatment too minimal to create any impact on the dynamics of disease mediators.

 

 MENSANA’S CSF PHERESIS SYSTEM TO TREAT ALZHEIMER’S DISEASE

 

1. Long-term implantable medical device.
2. COMPONENTS: circuit of outflowing and inflowing separate catheters with a filtration system and pump; filter and pump adjusted by remote control device.
3. Filters CSF draining from the ventricle: Aβ, α-synuclein, tau, and other proteins; inflammatory mediators;  &immunoglobulins/complexes – returns “clean CSF” to the ventricular system.
4. High flow rates from/to the brain minimizes side effects related to fluctuations in ventricular pressures and volumes.
5. CSF pheresis eliminates CSF-containing mediators of AD by compensating for the inherent deficiencies of the choroid plexus to clear Aβ and other elements associated with AD.

MERITS OF MENSANA’S APPROACH

1. Historical precedence of both CSF filtration and a medical device designed to treat AD – both very safe and former effective.
2. Well-established commercial technology and methods: combines features, concepts, and surgical methods of well-established safe and effective approved devices used in ventricular shunting of CSF, percutaneous intrathecal drug delivery, and plasmapheresis (blood filtration); accessing the subarachnoid space with a catheter is well established as a common and safe procedure; percutaneously-implanted devices, with access ports and hand-held device controllers, are commonly used for  intrathecal drug delivery.

    3.  Balanced & rapid CSF flow rate:

a) Exceeds outflow rates in shunting therapies for hydrocephalus.

b) Exceeds inflow rates of intrathecal drug delivery.

    4.  Clinical Risk low – infection management well developed in current clinical practice.

    5.  Filtration process will not generate ‘residuals’ in returning CSF.

    6.  Regulatory timelines for devices significantly faster than those for drugs.

DEMONSTRATE PROOF OF PRINCIPLE – EXTRACORPOREAL DEVICE

1. In animal studies and early clinical studies (China).
2. In the early period of clinical application to evaluate patient response.
3. In addressing key therapeutic  questions, there may be a need to externalize some of the drainage & filtration components.

 QUESTIONS TO ADDRESS IN INITIAL STUDIES

– CONVENIENCE VERSUS CURE VERSUS RISK

1. Most efficient filtration system – physical, margination, immunological? (cost,practicality, patient risk, complexity of procedure).
2. Filtrate content: beta amyloid (AB), Tau, α-synuclein (proteins); other proteins; immunoglobulins/immune complexes; and cells.
3. Optimum frequency and duration of filtration therapy – continuous, once/day, every 3 days, longer interval?
4. The longer the therapeutic interval, the more it favors an extracorporeal procedure under aseptic conditions (akin to renal dialysis).

REGULATORY PATHWAY – STRATEGY

1. Clinical studies and first approvals in China.
2. CE Mark to enter European market and increase revenue.
3. United States/FDA – PMA, including IDE Clinical Trial to demonstrate safety and effectiveness.
4. As long as no filtration residuals or leachable(s) returned to the subarachnoid space, FDA should have limited safety concerns.
5. FDA very well versed in assessing device components in other applications – catheters, pumps, and other long-term implantables, which minimizes the regulatory timelines.

PROJECTED ALZHEIMER’S MARKET

• Readily recognized, on a world-wide basis, as a devastating and overwhelming unmet medical need by: World Health Organization; NIH and other government agencies; Physicians and multiple medical associations; biomedical companies; patients and their families.
• AD prevalence: @ 5 million in US & @ 38 million WW;

            >  Population dynamics – many countries projecting an increasingly top-heavy population (elderly), particularly in China.

            >  Number of U.S. residents >65 years suffering with Alzheimer’s disease projected to reach 13.8 million by 2050.

 

PROJECTED EARLY MARKET SHARE FOR MENSANA

MANAGEMENT TEAM

 

Michael Ward, DVM, Co-founder, CEO, & CSO

• Dr Ward has a rich and diverse experience in medical device development and assessment, principally in neurosciences and cardiovascular domains and at senior executive levels.  Areas of focus have included pre-clinical assessments, clinical research, medical affairs and regulatory affairs.  His career has included 3 start-up organizations as well as 18 combined years with Baxter Healthcare and Johnson & Johnson.  

Mark Geiger, Co-founder

• Mark has a 22-year career in medical device development, marketing, and sales of OR-based medical equipment, instruments, and implants, in the Neuro, Ortho, ENT, and Spine markets.  He has been a member of 3 senior teams, leading medical device companies, such as the Neurosurgery Division of Medtronic.  Mark authored Mensana’s US Patent 7,887,503, already noted in this presentation. 

Michael Williams, MD, Neurologist & Board Member

• Dr. Williams was on faculty at Johns Hopkins for 16 years before becoming the Medical Director of the Sandra and Malcolm Berman Brain & Spine Institute. He is internationally recognized for expertise in neurocritical care, hydrocephalus and disorders of CSF circulation, and the diagnosis and treatment of dementia. He helped to found and is the current President of the International Society for Hydrocephalus and CSF Disorders. He currently receives funding from the National Space Biomedical Research Institute to validate noninvasive methods of measuring intracranial pressure.

Jo Battacharya, MD – Neuroradiologist & Board Member

• Dr. Bhattacharya was born, raised and educated in the United Kingdom. He received his medical degree from the University of London and is specialized in Neuroradiology, with a focused interest in interventional therapies. For the past 15 years, Jo has served as Consultant Neuroradiologist and Interventional Neuroradiologist at the Institute of Neurological Sciences, Southern General Hospital, Glasgow Scotland. He is also a Senior Lecturer at the University of Glasgow and heads the UK National Service for vein of Galen malformations in children.

Collaborative Partners in Research and Medical Device Development

Professor Jongoon Han, PhD

• Associate Professor of Electrical and Biological Engineering, Massachusetts Institute of Technology, Cambridge, Mass, USA.
• Co-author of a patent with a novel electrokinetic filtration method for body fluids.
• Considerable expertise on other filtration methods for body fluids.
• Key for medical device concept and development.

Professor Edward H Koo, MD. PhD

• Professor of Neurosciences at University of California, San Diego, California, USA.
• Primary research focus: cellular and molecular biology of Alzheimer’s disease(AD) and neurodegeneration.
• Major research focus includes the normal and pathologic functions of presenilin-1 (PS1), a protein linked to early onset familial AD.

Petra Klinge, MD

• Currently Head of Neurosurgery at Rhode Island Hospital Providence, Rhode Island, USA.
• Early career at International Neuroscience Institute, Hannover, Germany.
• Recognized international expert in the treatment and research of Hydrocephalus and Normal Pressure Hydrocephalus.
• Extensive experience in animal models of Alzheimer’s disease.
• July 2008 – completed a 9-city lecture tour of China, giving presentations, surgical advice, and attending several neurosurgeries.

 Thomas Brinker, MD

• Born and educated in Germany and much of career at the International Neuroscience Institute, Hannover Germany, in clinical practice as a neurosurgeon and extensive investigator in animal models, particularly for Alzheimer’s disease.
• Collaborator on the development and evaluation of a VP Shunt to treat AD patients (Eunoe Corporation).
• Will work extensively as a principal investigator in Mensana Therapeutic’s early proof of principle studies in animal models and human subjects.

SELECTED REFERENCES

1. Mawuenyegal KG et. al. Decreased Clearance of CNS β-Amyloid in Alzheimer’s Disease,  Departments of Neurology, Alzheimer’s Disease Research Center, Hope Center for Neurological Disorders, Pathology and Immunology, Medicine, Washington University School of Medicine, St. Louis, MO.
2. Yarasheski, RJ. The Choroid Plexus Removes β-Amyloid from Brain Cerebrospinal Fluid, Experimental Biology and Medicine (2005),230 (10), 771-776. 
3. Redzic ZB, et al. The choroid plexus-cerebrospinal fluid system: from development to aging, Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD United Kingdom.
4. Chodobski A, et al. Choroid plexus: target for polypeptides and site of their synthesis,  Department of Clinical Neurosciences, Brown University Medical School, Providence, Rhode Island 02903, USA.
5. Alvira-Botero X and Carro EM. Clearance of Amyloid-Beta Peptide Across the Choroid Plexus in Alzheimer’s Disease, Current Aging Science (2010) 3, 219-229.
6. Reference about new focus on early stage AD and Hopkins medical device trial:  http://articles.baltimoresun.com/2012-12-24/health/bs-hs-pacemaker-alzheimers-20121223_1_amyloid-pacemaker-cass-naugle.
7. Wollinsky      KH, Hülser PJ, Westarp ME, et al. Cerebrospinal fluid pheresis in Guillain      Barré syndrome. Med Hypotheses. (1992) 38 (2), 155 – 165.

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