Clinical Trails In Parkinson’s Disease.

Dr. Alon Yaar (DVM, MBA)

24.4.2018

Parkinson’s Disease

• Progressive, neurodegenerative disease, characterized by non motor, and

motor symptoms. The motor symptoms include, involuntary tremor, muscle

rigidity, bradykinesia and impaired balance and coordination.

•Pathologically it is characterized by death of dopaminergic cells in the

Substantia Nigra (SNc) Dopamine (DA) deficiency in the striatum. Initial

symptoms develop when striatal DA is reduced by 60-80%.

• The second most common neurodegenerative disorder in elderly, affecting 1%–

2% of individuals aged ≥65 years worldwide.

Instead of steady levodopa levels – oral levodopa creates fluctuations.

Almost all patients develop fluctuations within 5 years.

The brain needs steady levels of dopamine.

Oral levodopa quickly disintegrates in the blood and loses its effect.

Oral Dopaminergic Therapy Causes Fluctuations & Severe Side Effects

Continuousdelivery

The greatest challenge of levodopatherapy

Blo

od L

evel

s o

fLevodopa

Levodopa Administration

“Off”state

“On”Time

Dyskinesia

Flu

ctu

atio

ns

SevereModerateMild

ND0612

Levodopa, the Gold Standard, has a major drawback: short half life

Adopted from web available NeuroDerm ppt

Because it was thought impossible;

previous attempts to formulate LD into

liquid forms havefailed

Why has LD not been developed

to enable alternative routes of

administration that provide

better continuity?

NeuroDerm is the 1st to formulate LDinto a liquidformulation

Efforts to improve continuous LD therapy – Limitedsuccess

Attempts to achievecontinuity…

…but no Game Changers: Why?

LD has only existed to date in solid form that

must be administered through the GItract

Adopted from web available NeuroDerm ppt

The 1st liquid LD/CD

alternative to surgical

treatments

Device CE approved in EU

>350,000 patients US and EU

2nd generationdeliveredthrough a patch pump

“One and done” operation

Device in development

The 1st liquid LD/CDdrug

Device CE approved EU

> 900,000 patients US and EU

SeverePD ModeratePD

ND0612H ND0612LModeratePD

ND0612L

| 9|

ND0612A subcutaneous alternative to continuous LD infusion

Adopted from web available NeuroDerm ppt

10

100

1000

10000

-2 3 8

Pla

sma

LD

(ng

/ml)

Phase II – first period pharmacokineticsND0612L stabilizes LD plasma concentration above an average of ~800ng/ml

ND0612L transforms levodopa PK in PD patients

Peak to trough 53.7 59.4 4.8

Fluctuation index 2.4 2.9 1.4

n=30

Baseline(Best Current Oral Therapy)

Day0

Best Current Oral Therapy(Placebo)

Day14

ND0612L(Adjunct to OralTherapy)

Day14

-2 3 8-2

Time(h)

3 8

Adopted from web available NeuroDerm ppt

Efforts to improve continuous LD therapy – Limitedsuccess

Attempts to achievecontinuity…

…but no Game Changers: Why?

LD has only existed to date in solid form that must be administered through the GI tract

Adopted from web available Neuroderm ppt

Parkinson’s Disease (PD) is a multi-system motor disorder with central, peripheral and non-motor manifestations, many of which center in the Gastrointestinal system.

“npj Parkinson’s Disease (2017) 3:3 ; doi:10.1038/s41531-016-0002-0”

CONSTIPATION IS A PRIMARY MANIFESTAION OF PARKINSON’S DISEASE

Confidential

CHRONIC CONSTIPATION IS A KEY DISORDER IN PARKINSON’S DISEASE

• Chronic Constipation is one of the most devastating and frequent non-motor

symptoms in Parkinson’s Disease (PD).

• Chronic constipation severely impacts the daily living activities and quality of life of

PD patients.

• Almost all PD patients suffer from chronic constipation.

• Constipation precedes motor symptoms by as much as 20 years.

• People with constipation are at higher risk of developing PD.

“Parkinson disease with constipation: clinical features and relevant factors. Scientific reports, Jan 12 2018”

Confidential

CONSTIPATION IS A KEY SYMPTOM IN PARKINSON’S DISEASE PATIENTS

• Constipation negatively effects absorption of levodopa, and other

dopaminergic drugs, and halts their therapeutic effect.

• Chronic Constipation is a neglected medical unmet need in PD.

• The current constipation drugs negatively affect PD drug absorption, and

provide compromised efficacy and significant SE.

Eur J Neurol. 2016 Nov;23(11):1606-1613. Epub 2016 Jul 22

Confidential

• VIBRANT pill was tested on more than 350 human

volunteers, with no side effects and proved efficacy.

• Potential Improvement of PD drugs absorption.

• Improved management of PD symptoms.

• Improved Patients Quality of Life.

VIBRANT PILL - A UNIQUE & NOVEL TREATMENT FOR A MEDICAL UNMET NEED IN PARKINSON’S DISEASE PATIENTS

Confidential

H2H EFFICACY OF VIBRANT PILL VS.LINZESS - GOLD STANDARD TREATMENT

Confidential

VIBRANT PILL - STRONG COMPETITIVE EDGE

Low Efficacy

Side effects

LINZESS

AMITIZA

OTC LAXATIVES

VIBRANT

High Efficacy

No Side effects

SYNERGY

Confidential

KOLS SUPPORT THE VIBRANT TREATMENT INPARKINSON’S DISEASE PATIENTS

Prof. Nir Giladi MD FAAN FEAN, Chairman Neurological InstituteTel Aviv Medical CenterSlacker School of medicineTel Aviv University

Confidential

Prof. Weidong Le, MD, PhD.Adjunct Professor of Neuroscience Research Program, Houston Methodist Research Institute and Weill Cornell Medical College of Cornell University, USA

Prof. Peter LeWitt, MD. A movement disorders specialist. World known KOL in Parkinson’s disease

Parkinson disease with constipation: clinical features and relevant factors Qiu-Jin Yu1, Shu-Yang Yu2, Li-Jun Zuo1, Teng-Hong Lian1, Yang Hu2, Rui-Dan Wang1, YingShan Piao2, Peng Guo2, Li

Liu2, Zhao Jin1, Li-Xia Li2, Piu Chan7,5,6, Sheng-Di Chen8, Xiao-Min Wang4,5,6,9 & Wei Zhang1,2,3,4,5,6

Constipation is one of the most frequent non-motor symptoms of Parkinson disease (PD) and it may be ignored by PD patients, leading to this problem not to be reported in time. The relationships between constipation and demographic variables, motor symptoms and other non-motor symptoms of PD are still unknown. PD patients were evaluated by diagnostic criteria of functional constipation in Rome III and divided into PD with constipation (PD-C) and PD with no constipation (PD-NC) groups. PD patients were assessed by rating scales of motor symptoms and other non-motor symptoms, activity of daily living and quality of life. The frequency of constipation in PD patients was 61.4%, and 24.5% of PD patients had constipation before the onset of motor symptoms. PD-C group had older age and age of onset, longer disease duration, more advanced disease stage, and more severe motor symptoms and non-motor symptoms, including worse cognition and emotion, poorer sleep quality, severer autonomic symptoms, fatigue and apathy. Binary Logistic regression analysis showed that the age, H-Y stage, depression, anxiety and autonomic dysfunction increased the risk of constipation in PD patients. Constipation exerted serious impact on the activity of daily living and quality of life in PD patients.

Confidential

A prospective, multicenter, randomized, open label, 3- Arm Clinical Study to Assess the Safety and Efficacy of the Vibrant pill given up to 5 Times per Week vs. Standard of care in Idiopathic PD Patients Positively Responding to Dopaminergic Therapy, in the Treatment of Chronic Constipation.Objective: Vibrant pill vs. SOC to treat chronic constipation in PD patients. End Points: Safety and efficacy in treating constipation in PD patients.Improved management of motor symptoms due to increased PD drug absorption

VIBRANT CLINICAL STUDY V-400

Confidential

.

Randomization will be done at a ratio of 1:1:1 (Vibrant capsule : Laxative)

Patient will be randomized to one of three arms: Arm A. Vibrant Capsule: administered after onset, 2-5 times per week, (adaptive administration, per investigator's decision) for 8 weeks.

Arm B. Vibrant Capsule: administered in the afternoon 2-5 times per week, (adaptive administration, per investigator's decision) for 8 weeks.

Arm C. Laxative : administered 2 pills, twice a week (adaptive administration, per investigator's decision) for 8 weeks.

Administration of either Vibrant capsule or Laxative will be prior to levodopa and other antiparkinsonian medications administration.

VIBRANT CLINICAL STUDY V-400 -Study Design

INVESTMENT HIGHLIGHTS

Pharmaceutical market potential Medical device regulatory path. FDA clearance expected in 2020.

Drug-free and side-effect free treatment multiple customization options

Multi billion dollar marketsOne product for multiple indications

Strong IPBoth as novel pill and as treatment method

Clinical experience350 patients. High responder rates. No related adverse effects

Confidential

REGULATORY PATH

FDA – 510K DE NOVO. Classified as NSR (Non-significant-Risk

device)

Study design for achieving FDA expedited clearance, against

standard of care for PD constipation (Open IDE)

Confidential

2018 2019 2020

Apply for IRB Q2 2018

PII Study Q3-Q4 2018

FDA discussion Q4- 2018

Q1-Q4 2019 H2H pivotal study

PARKINSON DISEASE V-400 STUDY TIMELINE

Confidential

FDA Submission for Clearance for CIC – end of 2019

FDA Submission for Clearance for

PD Q1-2020