Rheopheresis for Dry Age-Related Macular Degeneration (AMD ...

26th Annual Meeting
April 27 - 30, 2005
Chicago, IL
Rheopheresis for Dry
Age-Related
Age Age-Related Related Macular
Degeneration (AMD)- (AMD) (AMD)-
Reference Controlled
RheoNet-Registry
RheoNet RheoNet-Registry Registry
Analysis of Safety and
Efficacy
R. Klingel1 , D. Wong2 , C. Fassbender1 , I. Siegel3 , B. Erdtracht4 R. Klingel ,
for the International Rheopheresis Excellence Centers
1 , D. Wong 2 , C. Fassbender 1 , I. Siegel 3 , B. Erdtracht 4 ,
for the International Rheopheresis Excellence Centers
1 Apheresis Research Institute, Cologne, Germany
2 Dept. Ophthalmol. Ophthalmol
Ophthalmol. . Vis. Sci., Sci Sci., ., Univ. of Toronto, Canada
3 RheoClinic Toronto, Canada
4 Rheopheresis Teaching Center, Cologne, Germany

Definition of Rheopheresis
Rheopheresis from a general methodological point of view is an
application of membrane differential filtration (MDF), synonymous with
double filtration plasmapheresis (DFPP).
However, Rheopheresis was specifically designed to treat
microcirculatory disorders like the microcirculatory impairment of the
macula associated with dry age-related macular degeneration using an
polyethylene membrane plasmaseparator and the Rheofilter in
combination with an appropriate controlled pump technology.
The single Rheopheresis treatment simultaneously eliminates an
exactly defined spectrum of high-molecular weight rheologically
relevant plasma proteins (i.e. α2-macroglobulin, fibrinogen, LDLcholesterol,
Lp(a), von Willebrand factor [vWF], IgM, fibronectin, and
putatively multimeric vitronectin). This results in the immediate pulsed
reduction of plasma viscosity as well whole blood viscosity, which can
lead to sustained microcirculatory recovery.

heopheresis
Blood
Plasmaseparation
Plasma after Rheopheresis
native Plasma
Plasmafiltration
Immediate effect:
pulsed reduction of
plasma viscosity
(blood flow, shear stress,
transmural plasma flux)
Filtration of rheologically active
high-molecular-weight plasmaproteins
-59%
-51%
-50%
-43%
-59%
-55%
LDL-cholesterol 2.500.000 D
21 nm
IgM app. 1.000.000 D
α2-Macroglobulin 725.000 D
Fibronectin 450.000 D
Fibrinogen 340.000 D
von Willebrand factor 250.000 D
(monomer)
-15% - -18%

Rheopheresis Rheopheresis in in Clinical Clinical Practice
Practice
out-patient treatment
app. 3 hrs

Rheopheresis for AMD
Mechanism of Action - Hypothesis
Repetitive pulses of simultaneous plasma protein elimination with
a decrease of blood and plasma viscosity by Rheopheresis result
in a sustained change in the natural course of AMD development
and progression. Rheopheresis treatment seems to restore and
activate or stabilize the functional reserve of the retina at
microcirculatory levels.
Results from clinical trials with patients suffering from AMD and
microcirculatory disorders of other tissue beds (e.g. critical limb
ischemia, ischemic diabetic foot, diabetic retinopathy, and sudden
sensorineural hearing loss, as well as basic research in the field of
AMD pathogenesis, describing structural and functional features of
impaired microcirculation in AMD can be referenced as proof of
principle.

Rheopheresis for AMD
Mechanism of Action
Further Reading
Jose Pulido, Pulido Pulido, , Donald Sanders, Jeffrey Winters, Reinhard Klingel
Clinical Outcomes and Mechanism of Action for
Rheopheresis Treatment of Age-Related Age Age-Related Related Macular
Degeneration
J Clin Apheresis 2005; in press

Rheopheresis for Microcirculatory Disorders
Level of Evidence for Efficacy
Age-Related Macular Degeneration
MAC I: randomized controlled clinical trial at the University of Cologne, Germany
[Brunner et al., Retina 2000]
Utah-Trial: randomized, sham-controlled clinical trial at the University of Salt Lake City, USA
[Swartz et al., Invest Ophthalmol Vis Sci 1999]
MIRA-1: randomized sham-controlled double blinded multicenter trial in the USA
[Pulido et al., Trans Am Ophthalmol Soc 2002 (interim analysis)]
Sudden Deafness (Acute Sensorineural Hearing Loss)
Multicenter randomized controlled clinical trial in Germany (interim analysis [unpublished])
Ischemic Diabetic Foot Syndrome
1 pilot trial [Klingel et al., Ther Apheresis Dial 2003; 7: 444-455]
Critical Limb Ischemia with PAOD
1 pilot trial [Ther Apheresis Dial 2005; in press]

First experience:
Brunner 1995
Rheopheresis Rheopheresis for for AMD
AMD
Current schedules for the initial treatment series:
MAC I
MAC II/III
Utah
MIRA-1
week 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Target for the single Rheopheresis treatment:
100% of the individual plasma volume (minimum 70%)

Rheopheresis for AMD
www.rheo.com
MIRA-1 Trial
+ LEARN 1 & 2 Trials
MIRA-1:
Dec 2004 185 patients enrolled
Feb 2005 treatments completed
Dec 2005 12 mo follow-up compl.
LEARN 1 & 2:
March 2005 initiation
LEARN 1 booster treatments
LEARN 2 cross-over of sham-pts.
www.amdstudy.com
w.apheresis-research.org
www.rheopherese-zentrum.de
Hamburg
Hannover
Detmold
Münster
Marl
Oberhausen
Essen Lüdenscheid
Wuppertal
DürenKöln
Langenfeld
Bonn Remscheid
Aachen
Bad Hersfeld
Limburg
Koblenz Frankfurt Bad Neustadt
Wiesbaden
Coburg
Ingelheim
Mainz
Mannheim
Homburg/Saar
Neunkirchen
Karlsbad
Tübingen
Friedrichshafen
Gifhorn
Rostock
Greifswald
München
Germering
Neuruppin
Berlin
Potsdam
Plauen
Dresden

Lines of EDTRS BSCVA Change from Baseline
Primary Eyes (Dry AMD/Soft Drusen) Drusen)
Worse than 20/40 @ Baseline
1.5
1.0
0.5
0.0
-0.5 0.5
-1.0 1.0
-1.5 1.5
-2.0 2.0
RHEO
1.0 Lines
Tx
PLACEBO
Mean Line Change Over Time
2.7 Lines
Post-baseline Interval
2.2 Lines 3.0 Line
1.3 1.2 1.1 1.1
-0.1
-1.5
Baseline 3 Month 6 Month 9 Month 12 Month
(n=19/9) (n=19/9) (n=19/7) (n=16/8) (n=19/7)
Lines of EDTRS BSCVA Change from Baseline Primary Eyes (Dry AMD/Soft
p=0.0014
repeated measures
-1.1
-1.9
Pulido et al., Trans Am Ophthalmol Soc 2002 (interim analysis

Rheopheresis for AMD
Regulatory Status
Germany (European Community)
Approved by Medical Device Regulations (CE-mark)
No regular reimbursement by statutory health insurances
Reimbursement by several private health insurances
Canada
USA
Approved by Health Canada medical device regulations
No reimbursement
Investigational device
No FDA approval

Rheopheresis for Dry AMD –
German Practice Guideline
Non-exudative (dry) AMD, soft
drusen, or/and initial atrophy and
pigmentary abnormalities,
visual acuity 20/32-20/200 (0.1-0.63)
Not with exsudation, hemorrhage,
advanced atrophy or fibrosis
Late AMD of the partner eye is no
contraindication
Indication is not defined by levels of
individual plasma parameters
versity of Cologne University of
Frankfurt
.Dr.med. B. Kirchhof, Prof.Dr.med. R. Brunner Prof. Dr.med. F. Koch

Adverse events/side effects:
Adverse events during Rheopheresis:
Defined as any unexpected or symptomatic event, which has a possible, probable or definite causa
relationship with the Rheopheresis treatment. If events are reported after the treatment, specific
time intervals have to be defined for particular events/problems before such events are shown in
the classified RheoNet report. If there is more than one adverse event/side effect at the same time
leading to a discontinuation of the treatment, the discontinuation shall be only accounted to the
adverse event of highest clinical relevance.
Adverse events after Rheopheresis:
- severe hypotension/syncope within 24 hrs after Rheopheresis,
- retinal bleeding withn 14 days after Rheopheresis
Vascular access problem:
Any problem occurring with the vascular access for Rheopheresis, if a treatment is really
performed (e.g. difficult needle insertion, flow problem, dislocation of needle, several attempts of
needle insertion, collapsed vein etc.). Hematoma/bleeding at the needle insertion is accounted as
adverse event/side effect.
Technical problem:
Reporting to RheoNet – SOP
Categories of Adverse Events / Side Effects / Problems
Defined as reports on malfunction of the therapy machine or material (filters, tubes etc.) including
also handling problems of personnel.

Reporting to RheoNet – SOP
lasses of adverse events/side effects, vascular access problems, technical problems
Centers only report / only ARI classifies!
Class I All side effects/ problems, which were reported with the single Rheopheresis treatment.
Class II All reported side effects/problems of class I, which were followed by an intervention (e.g. infusion o
saline etc.) and/or temporary break and/or discontinuation of the Rheopheresis treatment.
Class III All reported side effects/problems of class II, which necessitated discontinuation of the
Rheopheresis treatment (no multiple references, discontinuation was assigned to one side
effect/problem).
Discontinuation of Rheopheresis
Discontinuation of Rheopheresis is registered, if the treated plasma volume was 70% or lower of the
100% plasma volume target.
Discontinuation due to side effects is always registered as discontinuation, if the extracorporeal
circuit had started independent of the treated plasma volume.
Discontinuation due to problems with venous access or technical problems is registered as
discontinuation, if the treated plasma volume was already 500 ml or more. If the treated plasma
volume was below 500 ml, the report must be evaluated with the individual case including
discussion with the therapy center.

heopherese-zentrum.de
o
heo.com
he International
pheresis Competence
ers
pheresis-research.org
- Registry Report
Update March, March,
2005
4379 recorded Rheopheresis treatment
717 treated patients (all indications)
mean age 66 years
476 pts. with AMD 66%
mean age 74 years
241 pts. with other indications 34%
mean age 55 years

Number of patients
oNet Registry Update March 2005
Age Distribution of Patients
All indications AMD
240
210
180
150
120
90
60
30
0
n = 714
0-20 21-30 31-40 41-50 51-60 61-70 71-80 81-90 91-100
Years
SSHL, tinnitus
Number of patients
Number of patients
210
180
150
120
90
60
30
45
40
35
30
25
20
15
10
5
0
0
n = 474
0-20 21-30 31-40 41-50 51-60 61-70 71-80 81-90 91-100
Years
n = 172
0-20 21-30 31-40 41-50 51-60 61-70 71-80 81-90 91-100
Years
21% of AMD
patients were
≥ 80 years

oNet Registry Update March 2005
dverse Events / Side Effects (AE) and Vascular Access Problems (VAP
%
50
40
30
20
10
0
Patients with AMD, all age groups
n = 3618 protocols
5,4 6,2
2,0 1,8
0,6
Class I Class II Class III
Adverse events / side effects Vascular access problems
0,9
All class III events
(AE/SE + VAP, 1.49% of treatments)
Dizziness/
lightheaded
0.03%
Chilling
0.08%
Fever
0.03%
Vascular
access
problem
0.88%
Hemolysis/ blood
in plasma circuit
0.14%
Hypotension
0.30%
Nausea/
vomitting
0.03%

oNet Registry Update March 2005
dverse Events / Side Effects (AE) and Vascular Access Problems (VAP
“international international comparison”
comparison
%
50
40
30
20
10
0
All indications, all age groups
Canada Germany
n = 872 protocols
5,3
1,0
2,4
0,5 0,1 0,1
Class I Class II Class III
Adverse events / side effects Vascular access problems
%
50
40
30
20
10
0
n = 3507 protocols
5,7
8,1
2,0
2,5
0,7
Class I Class II Class III
Adverse events / side effects Vascular access problems
1,3

oNet Registry Update March 2005
dverse Events/Side Effects (AE) and Vascular Access Problems (VAP) (VAP)
Stratified by Experience of Rheopheresis Center (international)
E/SE
ll indications
20,0
8,3
2,1
10,4
3,8
1,3
6,4
2,0 0,5
2,4 1,4 0,4
n < 20 n = 20-100 n = 100-1000 n > 1000
20 centers
Ø7
treatments
Class I Class II Class III %
9 centers
Ø 44
treatments
8 centers
Ø 267
treatments
1 center
1579
treatments
50
40
30
20
10
0
VAP
All indications
30,4
17,4
9,4
Class I Class II Class III
17,2
5,8 4,0
7,3
1,9 1,1
1,5 0,3 0,1
n < 20 n = 20-100 n = 100-1000 n > 1000
20 centers
Ø7
treatments
n = number of treatments
9 centers
Ø 44
treatments
8 centers
Ø 267
treatments
1 center
1579
treatments

oNet Registry Update March 2005
dverse Events/Side Effects (AE) and Vascular Access Problems (VAP (VAP
Age Related Frequencies
Class I events
All indications
%
50
40
30
20
10
0
n = 3507 protocols
0-20 21-30 31-40 41-50 51-60 61-70 71-80 81-90 91-100
Years
Adverse events / side effects Vascular access problems
Class II events
All indications
%
50
40
30
20
10
0
n = 3507 protocols
0-20 21-30 31-40 41-50 51-60 61-70 71-80 81-90 91-100
Years
21% of AMD
patients were
≥ 80 years
Adverse events / side effects Vascular access problems

oNet Registry Update March 2005
Hypotensions
“per patient”
All indications (n = 582 patients) and AMD (n = 355 patients), all age groups
50%
40%
30%
20%
10%
0%
10,8% 12,7%
At least 1
therapy with
class I
hypotension
5,9% 6,6%
At least 1
therapy with
class II
hypotension
All indications AMD
1,9% 2,6%
At least 1
therapy with
class III
hypotension

oNet Registry Update March 2005
Patients
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
n = 2793 protocols
87,3%
Hypotension per Patient
“by by total number occurring with Rheopheresis series” series (AMD)
8,7%
3,2%
0,9% 0,0% 0,0% 0,0%
0,0% 0,0%
93,4%
4,6% 0,3% 0,0% 0,0%
1,7% 0,0% 0,0% 0,0%
97,4%
2,0%
0,0% 0,0% 0,0%
0,6% 0,0% 0,0% 0,0%
Class I Class II Class III
Without hypotension 1 2 3 4 5 6 7 8 therapies with hypotension

oNet Registry Update March 2005
Hypotensions
35%
30%
25%
20%
15%
10%
5%
0%
30,7%
19,4%
8,1%
6,5%
Hypotension per Protocol
“occurring occurring at which treatment of a Rheopheresis series” series (AMD)
n = 2365 protocols
11,3%
6,5%
6,5%
Class I (62
hypotensions)
11,3%
Number of therapy:
17,7%
8,1%
4,8% 4,8% 4,8%
4,8% 3,2%
1,6%
Class II (31
hypotensions)
8,1%
3,2%
1,6% 1,6% 1,6%
1,6%
0,0%
0,0%
Class III (11
hypotensions)
1 2 3 4 5 6 7 8

isual Acuity Before and After Initial Rheopheresis Serie
VA after
eopheresis
of 194 eyes
ETDRS)
1,1
1
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
n= 194 Eyes of 135 Patients with dry AMD
.7 Rheopheresis Treatments within ∅ 16 weeks, ∅ 23 weeks between opthalmological examinatio
110 eyes
(57 %)
21 eyes
(11%)
63 eyes
(32%)
0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1 1,1
VA before Rheopheresis
RheoNet-Registry, April

hange in ETDRS-Lines ETDRS ETDRS-Lines Lines after Initial Rheopheresis Series
ompared to Baseline after Mean Follow-Up Follow Follow-Up Up of 23 Weeks
loss ≥ 3 lines
0%
loss ≥ 2 lines
2%
loss ≥ 1 line
5%
gain ≥ 3 lines
7%
n= 128 Eyes of 91 Patients with dry AMD
gain ≥ 2 lines
12%
no difference
35%
gain ≥ 1 line
39%
RheoNet-Registry, April 200

Mean Change in ETDRS-Lines after Initial Rheopheresis Series
ompared to No Treatment Control and Placebo (Sham-Apheresis
Mean Change in Lines
1,5
1
0,5
0
-0,5
-1
-1,5
Baseline MAC-1 (11 eyes)
MIRA-1 (28 eyes)
RheoNet update (128 of 194 eyes)
MIRA-1 Placebo (15 eyes)
MAC-1 Control (11 eyes)
after Rheopheresis
1,22
1,2
0,82
-0,4
-1,1
MAC-1
(subgroup with soft drusen)
MIRA-1(Interim-Analysis
RheoNet-Analysis
2005
23 wk follow-up period (mean
MIRA-1
(Placebo)
24 wk follow-up interval
MAC-1
(no treatment control)
21 wk follow-up interval
RheoNet-Registry, April 200

RheoNet – Registry
Summary
RheoNet-Registry
RheoNet Registry is an integral part of interdisciplinary quality managemen
of Rheopheresis.
Based on interdisciplinary cooperation Rheopheresis is a safe ambulatory
treatment for elderly patients with AMD.
RheoNet-Registry will be continuously updated and report on data analysis
Dry AMD – Indication for Rheopheresis
Results of the controlled randomised MAC-I Trial from Cologne,
+ the controlled Utah-Trial, + MIRA-1 Interimanalysis, + experience of the
Dept. Ophthalmol. at Cologne University with app. 300 Patienten including
long-term treatment, + RheoNet data justify to offer Rheopheresis to highrisk
patients with dry AMD, who otherwise don‘t have a therapeutic
alternative (in countries with medical device approval, i.e. Europe/Germany
Canada, Japan).