csf presentation 2009

CSFDynamics

CSFDynamics

Company Presentation

CSFDynamics

Introduction

Key persons behind CSFDynamics A/S

MD, Dr.med.sci., University of Aarhus (1976), Specialist in Neurosurgery (1979). Currently employed as Chief Surgeon and Medical Director at PrivatHospitalet Danmark (1992-). Previously Dr. Børgesen was employed as chief neurosurgeon at the University Clinic of Neurosurgery at Rigshospitalet (1988-02), consultant at Arbejdsskadestyrelsen (1987-99), assistant neurologist at Sikringsstyrelsen (1986-87), consultant at the department of neurosurgery at KAS Glostrup (1984-87), consultant at the department of neurosurgery at Borgaspitalin in Iceland (1982-82). Dr. Børgesen is author and co-author of 86 scientific articles

Svend Erik Børgesen Niels Agerlin

MD from the University of Copenhagen (1986), Ph.D. from the University of Copenhagen (1993). Currently employed as Chief Neurosurgeon at the Neurosurgical dept. at KAS Glostrup (2002-). Previously employed as senior resident physician at the Neurosurgical dept. at KAS Glostrup (1997-01), resident physician and senior resident physician at the Neurosurgical dept. and Neurological dept. at Rigshospitalet (1988-96)

CSFDynamics

Introduction

History of the SinuShuntYear Event

1993 The first animal experiment on dogs took place.

1994-95 Dr. Børgesen finished the first technical development of the SinuShunt and prepared the shunt ready for patenting.

26 Sep. 1996 An APCT application was filed for the USA, all of Europe, Japan, Hong Kong, Canada and Australia.

1997 The first SinuShunts were implanted.

1997-99 Clinical development and testing of the SinuShunt.

2000 The SinuShunt and the first results were presented at a neurosurgery world congress in Sydney. The interest was overwhelming. At that congress, the first contacts were made with university hospitals in Europe which wanted to participate in the future testing. The development started of a new shunt for treatment of hydrocephalus for infants and young children. At the same time the shunt for treatment of AD was developed.

2001 CSFDynamics entered into a production agreement with Medical Rubber AB in Sweden, a family-owned company established in 1973. The company, which is ISO 9002 and EN 46002 certified and has clean room facilities (class 10,000), currently produces the SinuShunt.

2002 The SinuShunt achieved the CE approval. Pilot testing and clinical studies continued in selected university hospitals in Europe.

Jun. 2003 Dr. Børgesen received the Pudenz Award for 2002 for “Excellence in Cerebrospinal Fluid Physiology”. The award was given to Dr. Børgesen for “his many contributions over the years to the understanding of factors underlying the clinical physiology of hydrocephalus and his recent innovative studies utilizing the ventriculo-cranial venous sinus methodology for treatment of this condition”.

End of 2003 Approx. 200 SinuShunts were implanted in selected hospitals

2007/2009 Development of a new and improved sinus-tube.

CSFDynamics

Introduction

The SinuShunt

CSFDynamics

Introduction

Illustration of the SinuShunt principle

CSFDynamics

Introduction

The SinuShunt vs. traditional shunts

SinuShunt Traditional shunts

CSFDynamics

Hydrocephalus

CSFDynamics

Hydrocephalus occurs when there is an imbalance between the CSF produced and the rate at which it is drained

Hydrocephalus that is present at birth is thought to be caused by a complex interaction of various factors and perhaps generic factors

Acquired hydrocephalus may result from intraventricular hemorrhage, meningitis, head trauma, tumours and cysts

The common clinical presentation in a child is increasing head size, irritability, failure to feed and vomiting

Motor and general developmental delay, failure to make appropriate visual and social contact are among the most common problems found in children with hydrocephalus

In about 40% of the cases there is excessive head growth. The same percentage applies to fullness of anterior fontanelle. Splayed sutures in 20% and scalp vein dilatation in 15%

In adults symptoms are gate disturbances and dementia

Over the past 25 years the mortality of Hydrocephalus has decreased from 54% to 5%. Intellectual disability has decreased from 62% to 30%

Hydrocephalus

Causes and symptoms of Hydrocephalus

Causes Symptoms

CSFDynamics

Hydrocephalus

Diagnosis and treatment of Hydrocephalus

It is very important that Hydrocephalus is diagnosed early to minimise morbidity and mortality

In babies and infants it is sufficient to visualise the intracranial structures and ventricles

In older children a CT scan or MRI could be performed. This would further assist in visualising underlying causes if there are any

Conventional ventriculoperitoneal (VP) shunts are designed for treatment of normal or high pressure Hydrocephalus. They aim at shunting CSF past the partially or fully obstructed outflow pathways

CFS is intended to be drained until a certain, predefined intracranial pressure level is reached

75% of Hydrocephalus patients are treated by shunting

3. ventriculostomy is another way of treating Hydrocephalus patients

As the surgical procedure is more complicated than implanting shunts only 25% of patients are treated by 3rd ventriculostomy

Diagnosis Treatment

CSFDynamics

Hydrocephalus

Two types of Hydrocephalus

Congenital stenosis of the Sylvius Aquaduct

Obstruction of Foramen Magendi

Hypoplasia of the Arachnoidal Granulation

Communicating Communicating (non-

obstructive) hydrocephalus is the situation where there is communication between the ventricular system and the subarachnoid space

The most common cause of this group is post-infective and post-haemorrhagic hydrocephalus

Non-communicating Non-communicating or

obstructive hydrocephalus is where there is no communication between the ventricular system and the subarachnoid space

The most common cause of this category is aqueduct blockage

CSFDynamics

Hydrocephalus

Hydrocephalus market

The market for Hydrocephalus is widely spread across the globe

67% of the sales are to high cost countries indicating that a large share of the market probably will be willing to pay a premium for the enhanced efficacy of the SinuShunt

North America

33%

Europe24%

Japan & Korea10%

RoW33%

PS Medical (Medtronic)

42%

Codman (J&J)20%

Integra24%

Phoenix5%

Radionics9%

The top 3 manufacturers account for 86% of revenues

All current manufacturers capitalise on technology used for more than 50 years

Competitive dynamicsGeographical sales splitGeographical sales split

CSFDynamics

Hydrocephalus

Demand for Hydrocephalus products

The SinuShunt is likely to experience high growth

The SinuShunt is likely to achieve high market shares from the very beginning of the product launch as replacements (probably) will be made to the SinuShunt

125,000 new cases of Hydrocephalus every year

Hydrocephalus is believed to occur in about 2 out of 1,000 births

WHO estimates that 125,000 new cases of Hydrocephalus arise each year

An estimated 40,000 operations are completed every year in the US. The cost of an average operation is ~ 1,500 USD. The annual sales to the US market is ~ USD 60 m

Replacement market of 62,500 shunts every year

In addition to the market for new shunts, there is a replacement market

It is estimated that 50% of all traditional shunts will have to be replaced within 5 years

This gives a theoretical replacement market for 62,500 shunts per year

CSFDynamics

Hydrocephalus

Treatment alternatives

Shunting Immediate effect ~ 100% reliability (although 50%

of current shunts are replaced within 5 years)

~75% of patients are treated by this methodology3. Ventriculostomy

(intracranial procedure) Immediate effect When first developed the

procedure had high mortality and morbidity rates. Today it is a very safe procedure

~25% of patients are treated by this methodology

Drug treatment Initially, it was shown that

Acetazolamide reduced CSF production by the choroid plexus

In a series of Hydrocephalus in immature infants the drug was used and success was claimed as shunts was avoided in 50% of the cases

0% of patients are treated by this methodology

Shunting is the preferred treatment

CSFDynamics

Hydrocephalus

The shunting principle

Traditional method of shuntingPressure regulated shunt The shunt will open when the

pressure in the head gets too high

Traditional placement of the shunt

Ventriculo-peritoneal shunt From the ventricular

system to the peritoneal cavity

SinuShunt placement of the shuntPassive shunt There is a continuous flow via the

shunt as the pressure in the Sinus is the same as in the brain

Traditional placement of the shunt

Ventriculo-atrial shunt From the ventricular

system to the right atrium

SinuShuntTraditional shunts

SinuShunt placement of the shunt

From the ventricular system to the transverse sinus

CSFDynamics

Hydrocephalus

Commonly acknowledged shortcomings of traditional shunts*

Late complications

Too many unnecessary technical complications with traditional shunts

Conceptual shortcomings of traditional shunts result in overdrainage

Relatively short lifetime of current shunts

The average lifetime of traditional shunts is unsatisfactory

* FDA conference 8.1.1999 (www.fda.gov/cdrh/stamp)

CSFDynamics

Proximal drain displacement

8%

Distal drain occlusion

31%

Infection16%

Overdrainage11%

Shunt defect or blocked11%

Proximal obstruction

23%

Hydrocephalus

Complications with traditional shunts

Survey at Rigshospitalet on procedures from 1961-1988

The survey was reported in 1998

2,400 surgical procedures in 870 patients

Other studies indicate 48% re-operations in children within 3 years

Overdrainage related complications45%

CSFDynamics

Hydrocephalus

Complications of overdrainage

Accumulation of blood and fluids on the surface of the brain

Low pressure complications

VertigoFatigueHeadache

Obvious complications

Frequent block of ventricular drain and shunt

Other complications

By these criteria ~ 40-50% of complications can be attributed to overdrainage

Result

CSFDynamics

Hydrocephalus

Dependency on posture

Variable pressure The normal pressure inside the head is 10

– 15 cm of water The differing positions complicate the

drainage when using traditional shunts as the pressure in the drain changes substantially

Traditional shunts ShinuShunt

......

0-10 CM

55-75 CM

Supine Standing Supine Standing

Constant differential pressure Withholding the drain in the cranial area

eliminates unnecessary pressure complications

CSFDynamics

Hydrocephalus

Technical details of the shunting principle

Treatment of high pressure hydrocephalus by low resistance valve, high opening pressure

Supine positionICP = -10P(ts) = ICP - 4 = -14Diff. Press.* = -10-(-14) = 4

Standing positionICP = 10P(ts) = ICP - 4 = 6Diff.press.* = 10-6 = 4

+/- intracranial pressure 4 vs. 4 mmHg

Traditional shunts

SinuShunt

Traditional valves have large intervals for the intracranial pressure

The SinuShunt does not have any interval for the intracranial pressure

÷

Treatment of high pressure hydrocephalus by low resistance valve, low opening pressure

Treatment of high pressure hydrocephalus by low resistance valve, high opening pressure

Treatment of normal pressure hydrocephalus by variable resistance valve

Supine position ICP = 0.4*1 + 8 = 8.4 mmHg ICP = 0.4*1+12 = 12.4 mmHg ICP = 0.4*10 = 4 mmHg

Standing positionHydrostatic force = -600 mm H2OICP = 0.4*1 - 44 = -43.6

ICP = 0.4*1-44.1+12 = -31.7 mmHgHydrostatic force = -600 mm H2OICP = 0.4*10-44 = -40 mmHg

+/- intracranial pressure 8.4 vs. -43.6 mmHg 12.4 vs. -31.7 mmHg 4 vs. -40 mmHg

CSFDynamics

Hydrocephalus

Dependency on physical activity

At physical activity The pressure in the chest is

increased The blood has problems

entering the chest from the head and the intracranial pressure will rise

The shunt will open and overdrain

Traditional shunts SinuShunt

At physical activity The SinuShunt is

unaffected by the increasing pressure in the chest

Therefore there is no risk of overdrainage

CSFDynamics

Hydrocephalus


On average 50% of all shunts are replaced within 5 years

Patients are operated 2.7 times on average during their lifetime

80% of all shunt patients are re-operated within 8 years

Main part of shunt failures is due to shunt technology

Copenhagen (N=870)

+ Hakim Orbissigma Prudenz

Surv

ival of

shunts

Lund: Codman Medos (N=583)

Surv

ival of

shunts

CSFDynamics

Hydrocephalus

Clinical test of shunting to the sinus

Data on 156 implanted shunts Results

Pilot study111 shunts implanted

Sagittal Sinus 43Transverse Sinus 68

Final study45 intact silicone drains implantedPatients aged 18-1Observation time

Mean observation time 160 daysRange 2 – 846 days

Despite the relatively small test the SinuShunt reflects fewer complications than average

Of the 45 intact silicone drains implanted only 6 patients have had the shunt removed

3 patients had infections which is less than with traditional shunts (16% would imply ~ 7 patients)

There are no complications by draining to the transverse sinus

Event

Drain implant

Total

Drilled

canal

Direct

No complications 26 9 35

Drain occluded 0 6 6

Infection 2 1 3

Intraventr. bleed-not shuntrelated

0 1 1

Total 28 17 45

Effect

Hydrocephalus type

Total

Normal pressure

High pressure

Immediate 15 23 38

None 5 0 5

Transitory 1 1 2

Total 21 24 45

CSFDynamics

Hydrocephalus

Surgical procedure with traditional shunts

General anesthesia is used A small region of the scalp is shaved (cleanness)

and scrubbed with an antiseptic Sterile drapes are placed over the patient Incisions are made in the head and abdominal

areas The shunt tube is placed in the fatty tissue A small hole is made in the scull and the

membranes between the scull and brain are opened

The ventricular end of the shunt is gently passed into the abdominal cavity where the CSF will be absorbed

The incisions are then closed

Surgical procedure

CSFDynamics

Hydrocephalus

Implanting the SinuShunt

1 2 3 4 2 51 2 3 4 2 5

1) Connector2) Valves3) Pre-chamber4) Resistance

tube5) Drain for the

transverse sinus

Incision marks Position of the transverse sinus

CSFDynamics

Hydrocephalus

Surgical procedure with the SinuShunt

A neurosurgeon performs the short and uncomplicated procedure

General anesthesia is used A small region of the scalp is

shaved (cleanness) and scrubbed with an antiseptic

Sterile drapes are placed over the patient

Incisions are made in the head The shunt tube is placed in the

fatty tissue A small hole is made in the scull

and the membranes between the scull and brain are opened

The ventricular end of the shunt is gently passed into the transverse sinus where the CSF will be absorbed

The incisions are then closed

Surgical procedure SinuShunt advantages

Compared with traditional shunts the surgical procedure is very simple

The SinuShunt is easy to implant compared with traditional shunts

The SinuShunt only calls for local anesthesia

The operation area is restricted when implanting the SinuShunt which is not the case for traditional shunts

The SinuShunt implant is much faster than the implant of traditional shunts

Few parts are needed for the surgical procedure when the SinuShunt is used

The SinuShunt imitates physiological drainage close to perfectly which is not the case for traditional shunts

Same procedure as when implanting traditional shunts

Simpler procedure than when implanting traditional shunts

CSFDynamics

Hydrocephalus

The SinuShunt vs. other shunts

General conclusions The SinuShunt is a unique technology

for treatment of AD patients by drainage

The SinuShunt minimises the risk of complications and enhances the quality of the treatment

Characteristics

Codman

Medos

Miethke OSVII Pudenz

DeltaCogni-Shunt

Sinu-Shunt

Type

Pressure regulated X X

Flow/pressure regulated

X X X

Passive X

Opening pressure X X X X X

Antisiphon device X X

Resorption sites

Peritoneum X X X X X

Heart X X X X X

Cranial Venous Sinus X

Susceptible to posture

Posture dependent X X X X X

Posture independent X

Complication possibilities

Prox. drain occl. X X X X X

Shunt house occl. X X X X X

Distal drain occl. X X X X X X

Distal drain disruption

X X X X X

Distal drain displacement

X X X X X

Overdrainage X X X X X

Infection X X X X X X

CogniShunt vs. SinuShunt conclusions The SinuShunt is simpler than the

CogniShunt creating less room for mechanical complications

The SinuShunt is closer to physiological drainage than the CogniShunt

The SinuShunt is simpler due to the natural resorption site

CSFDynamics

Hydrocephalus

General conclusions of shunting to the sinus

Present technology is not acceptable (cit.: FDA conference*)

There are too many re-operations Every new patient can expect 2.7 operations 80% of all shunts are re-operated within 8 years

The frequency of complications is too high Main part of shunt failures are due to shunt technology

Present shunts are un-physiological

Shunting to the sinus is clearly beneficial The differential pressure over the shunt is

Constant Independent of posture

Imitate normal CSF flow dynamics Resistance equal to normal value

Normal drainage in all situations Effective in all cases of hydrocephalus

Overall conclusions Survey of literature

Literature favours shunting to the sinus

155 reported cases ”western literature”

>6 years of observation Good clinical effect No complications from

occlusion of sinus > 400 cases reported in

Russian literature Transverse sinus

standard procedure

* FDA conference 8.1.1999 (www.fda.gov/cdrh/stamp)

CSFDynamics

Alzheimer’s Disease

CSFDynamics


Causes and symptoms of AD

The causes of AD are not fully understood by scientists

One of the key findings is the negative impact of the aggregation of beta-amyloid and tau proteins

Slow onset. At first, the only symptom may be mild forgetfulness

Patients typically start to forget simple everyday tasks

Later the patients loose their ability to speak and write and eventually they require total care

Causes Symptoms

CSFDynamics


Diagnosis and treatment of AD

Diagnosis is difficult Biopsy of cerebral tissue possible

but risky Diagnosis is typically made too

late as patients are not willing to face problem

However, the future promises better diagnosis of AD (e.g. Neurosearch research)

Some drugs are able to slow the onset of AD of up to 12 months

Revenues from current drugs on the market total USD2.1bn (2004e)

A phase II study of the COGNIShunt has shown stabilising effects on patients with mild/moderate AD

Diagnosis Treatment

CSFDynamics

-

5,000,000

10,000,000

15,000,000

20,000,000

25,000,000

30,000,000

2004 2010 2020 2030 2040

US Non US

The world market for AD is ~ 15 million persons of whom 4 million are from the US

It is estimated that 10% of people at the age of 65 and older and 50% of people above 85 suffer from AD

The CAGR of the population older than 65 is 1.8% which is well above the 0.2% representing the total population (incl. people older than 65)


Alzheimer’s patient development

CAGR: 1.8%

Source: OECD demographic report and SG Cowen report (march 2004)

-

500

1,000

1,500

2,000

2,500

3,000

2002 2003 2004 2005 2006 2007 2008

Total US market for Alzheimer's

Indexed development if market were to follow the population dev.

CAGR: 19.7%

The total US sales of AD products was USD1.1bn in 2003

The higher CAGR of the expected sales of Alzheimer’s products compared to the development in Alzheimer’s patients reflects better penetration of Alzheimer’s products due to

More efficient products Increased focus from governments

# o

f p

ers

on

s

US

Dm

Development in population above 65 years

Development in AD products sales

CSFDynamics


Theory behind treating Alzheimer’s disease through shunting of CSF

Aggregation of protein macromolecules in neurons

A Beta proteins Leads to neuronal

damage/cell death

Proteins measurable in CSF

Turnover of CSF too low

Proteins are not removed with the CSF

Treatment of AD by shunting

Artificial and easy outflow of CSF to increase turnover and protein access

MiniShunt can possibly stop and may

even reverse the progression of

Alzheimer’s disease

CSFDynamics


Evidence from the CogniShunt Phase II clinical trial

0

2

4

6

8

10

12

14

16

18

Baseline 3 mds. 6 mds. 9 mds. 12 mds. Total

116117

115114

115

112 112

106

103

98

85

90

95

100

105

110

115

120

Baseline 3 mds. 6 mds. 9 mds. 12 mds.

AD patients seem to maintain their MDRS score when using the CogniShunt, whereas a substantial decrease in the MDRS score was recorded in the control group

Mean

MD

RS

sco

re

Delt

a m

ean

MD

RS

sco

re

Treated Non treated

Note: MDRS is by many considered as the primary efficacy endpoint for Alzheimer’s tests. The clinical study comprised 29 patients

Source: Assessment of low-flow CSF drainage as a treatment for AD, Silverberg et al. (2002)

The difference between the control group and the treated patients is steadily increasing throughout the test period

Phase II study 29 patients

15 treated14 in control

group Clinical studies

performed by Eunoe have shown that shunting of CSF may halt the progression of Alzheimer’s

Eunoe’s results were published 22. Oct. 2002

MDRS scores Delta MDRS scores

CSFDynamics


Shortcomings of traditional shunts in Alzheimer’s

+ As the intracranial

pressure for Alzheimer’s patients is normal, traditional shunts tend to shunt too little CSF

Late complications

Too many unnecessary technical complications with traditional shunts

Conceptual shortcomings of traditional shunts result in overdrainage


The average lifetime of traditional shunts is unsatisfactory

Low CSF turnover

Alzheimer’s disease

Hydrocephalus

CSFDynamics

CSF drainage of AD patients with current shunts is potentially dangerous

Drainage below ICP leads to hyper drainage

Subdural haemorrhage

Hypotensive symptoms

Vertigo Fatigue Headache


Pitfalls of normal csf-drainages

AD patients typically have normal/low ICP

As opposed to Hydrocephalus, AD patients do not have increased pressure

CSF shunting to peritoneal cavity only possible with high resistance shunts to avoid overdrainage

Amount of CSF shunted is limited

CSFDynamics


Principle of the MiniShunt I

CSF compartmentMacromolecules

Low ICP (<6-8 mmHg)

Sinuses of the craniumLow pressure (4 mmHg)

Normal CSF-outflow route• Resistance results in ICP at normal or low levels•

Macromolecules retained at

outflow channels

MiniShunt with low resistance• CSF seeks outflow with least resistance• Macromolecules

being transferred with CSF

Indicates high resistance

Indicates low resistance

CSFDynamics


Physics of the MiniShunt

Traditional shuntsHigh pressure

differential requires much higher resistance

MiniShuntLow pressure differential

enables much larger outflow

with no overdrainage

risk

CSFDynamics


Production of CSF

The production of CSF for Alzheimer patients may be lower than normal

As the CSF is not shunted, the average lifetime of the CSF in the brain is longer compared to the CSF being shunted

Unwanted proteins may be accumulated

CSF production without the MiniShunt

CSF production with the MiniShunt

The production of CSF for Alzheimer patients increases with the MiniShunt

The turnover rate with CSF increases with the MiniShunt

All produced CSF will tend to flow through the shunt instead of via normal channels

CSFDynamics


Benchmarking AD products

Drugs Traditional shunts

MiniShunt

Effect

Cost

Patient convenience

Side effects

Postpones onset for maximum 12 months

USD1,800-2,400 per year

Often low due to side-effects

Potential severe allergic reactions and other less severe (e.g. nausea, diarrhoea, drowsiness, muscle cramps, insomnia)

Data suggest superiority to drugs

USD1,300 per year (incl. operation over an 8 year period with 80% re-operated)

Low due to irritation of the abdomen

Complications lead to re-operations in 80% of cases after 8 years

Theoretically superior to traditional shunts due to high volume shunting

USD870 per year (incl. operation over an 8 year period with e.g. 20% re-operated)

High

Very few side effects expected

Patient compliance

Problem 100% 100%

CSFDynamics


Conclusions regarding the MiniShunt

Treatment benefits It has immediate effect It is easy to implant It has no proven side effects It has much fewer complication

possibilities which is especially important to AD patients due to the typical old age

Surgical benefits: The operation area is restricted The operation is fast Few parts are needed for the

operation Clinical tested design of the

MiniShunt

Treatment downsides: None compared to the

benchmark products

Surgical downsides None compared to the

benchmark products

Benefits of the MiniShunt Drawbacks of the MiniShunt

csf presentation 2009

Health & Medicine