THE PLAUSIBLE FUTURE OF

THERAPEUTIC PLASMA EXCHANGE

Dobri Kiprov, M.D., H.P. (ASCP)

California Pacific Medical Center, San

Francisco, CA

Fresenius Apheresis Services

Disclosures

• Salary from Fresenius Medical Care

Therapeutic Apheresis in the 21st Century

• Cytapheresis

• Mononuclear cells (MNC) collections

• Therapeutic Plasma Exchange (TPE)

Therapeutic Apheresis in the 21st Century

MNC

Cancer Therapy

Stem Cells

Dendritic Cells

Regenerative Medicine

Orthopedics

Nephrologu

Cardiology

Dermatology

Hematol Dis

Autoimmune Dis

Neurol Dis

Lymphocytes

T-cells, B-cells, NK

Cancer Rx

HIV Rx, vaccine

Genetic Eng

Autoimuune Dis

Current Separation Technology

Plasma

Buffy Coat

RBC

MNC

Lymphocyte

-B-cells

-T-cells

NK cells

Stem Cells

Dendritic cells

Platelets

Lymphocytes

Monocytes

Granulocyte

RBC

(1040)

(1050-1061)

(1065 - 1069)

(1087 - 1092)

Opportunities in Apheresis Stem cells and cancer vaccines

Apheresis for

Cell collection

Lab

manipulation

of the cells

Cell reinfusion

-Very expensive

-Time consuming

-Inefficient

-Infections

-Travel

-Cell viability

New Technology

Current Use of TPE

• A myriad of rare diseases

• Small number of patients in each disease

• Difficulty to perform clinical trials

• Logistical difficulties for running a high quality TA program

• Educational, training, competency difficulties

• Difficulty attracting large number of members to apheresis

societies

Therapeutic Apheresis

TMA (TTP/HUS)

25%

>50 other diseases

Incidence of TMA (TTP/HUS) Per 1 million

0

0.2

0.4

0.6

0.8

1

1.2

1.4

National

National2

Oklahoma

Average

Torok TJ et al. AmJHematol 1995;50:84-90

Miller DP et al. Epidemiology 2004; 15:208-15

Terrel DR et al.Journal of Thrombosis and Hemostasis 2005;3:1432-1436

Focal Segmental Glomerulosclerosis

(FSGS) • The most common primary glomerulopathy

• 20%-30% of patients with nephrotic syndrome

• ESRD due to FSGS increased 11 fold from 1980-2000

• 20%-30% post transplant recurrence (first transplant)

• 80% recurrence after second transplant

• TPE is used in recurrent FSGS

Incidence

0

2

4

6

8

10

12

14

TTP

FSGS

Focal Segmental Glomerulosclerosis

(FSGS)

Focal Segmental Glomerulosclerosis

(FSGS) - pathophysiology

Wei C et al Nat Med 2011;31:17(8):952-60

Circulating urokinase receptor as a cause

of FSGS • “Our findings sugges that the renal disease only develops

when suPAR sufficiently activates podocyte β(3) integrin.

Thus , the disease can be abrogated by lowering serum

suPAR concentration by plasmapheresis, or by interfering

with the suPAR- β(3) integrin by antibodies or other small

molecules.”

• Wei C et al Nat Med 2011;31:17(8):952-60

Angiotensin Antibodies (AT1R) and FSGS

Alachkar N et al. NEJM 2013 368:971-973

IgM contributes to glomerular injury in

FSGS

Srassheim D et al J Am Soc Nephrol 2013;24:393-406

Incidence of Sepsis

0

50

100

150

200

250

300

TTP

Sepsis

Various randomized studies using plasma exchange/plasmapheresis

in the treatment of severe sepsis and in MODS

Study

n

Main mode

of therapy

Surviv

al

(%)

p

Reeves et al.

(26)

Busund et al.

(27)

Nguyen et al.

(28)

14/16c

54/52c

5/5c

PF

PE

PE

57/50

67/44

100/20

ns

0.05

<0.0

5

PE, plasma exchange by centrifugation technique; PF,

plasma exchange by filtration; c, control.

VARIOUS CLINICAL STUDIES USING ADSORPTION

TECHNIQUES IN THE TREATMENT OF SEPSIS, SEVERE

SEPSIS, AND IN MODS

Study/adsorber

n

Main mode

of therapy

Surviv

al

(%)

p

Polymyxin B

Tani et al. (36)

Nemoto et al. (21)

Suzuki et al. (37)

Vincent et al. (23)

Cruz et al. (22)

Albumin as adsorber

Staubach et al.

(19)

37/33c

98

24/24c

17/19c

34/30

67/76c

AdsPmx

AdsPmx

AdsPmx

AdsPmx

AdsPmx

Albumin

adsorber

54/36

41/11c

75/25c

71/72c

68/47c

71/74

<0.05

<0.05

<0.05

ns

<0.05

ns

AdsPmx, adsorption column using polymyxin B; c, control

group;

ns, not significant.

TPE in Sepsis

• Education about the role of TPE in sepsis

• Well designed clinical trial

• Conventional TPE

• With FFP at least patially

• With small dose IVIG post each TPE

One in three elderly have dementia when they die

Janice Lloyd, USA TODAY12:23a.m. EDT March 19, 2013

• The number of people with Alzheimer's disease is

expected to rise from 5.2 million to 13.8 million by 2050

• Payments for health care, long-term care, and hospice

care are expected to increase from $203 billion to $1.2

trillion by 2050 for patients ages 65 and older.

• Medicare costs for an older person with Alzheimer's or

other forms of dementia are nearly three times higher

than for seniors without dementia. Medicaid payments are

19 times higher.

• The stress on caregivers is estimated to result in the more

than $9 billion in increased health care costs.

EM of Amyloid in Brain

Lifelong Management of Amyloid-Beta Metabolism to Prevent Alzheimer's Disease

Sam Gandy, M.D., Ph.D.

N Engl J Med 2012; 367:864-866August 30, 2012DOI: 10.1056/NEJMe1207995

• There is growing interest in Aβ-lowering therapies for

presymptomatic disease.

• What is also clear — regardless of whether, in light of the

protective APP mutation, one considers the “amyloid

hypothesis of Alzheimer's disease” as proven or not — is

that any comprehensive strategy aimed at reduction of

late-life dementia risk will almost certainly include

monitoring and immunopharmacologic or

neuropharmacologic control of Aβ metabolism.

Plasma Exchange as a Novel Approach

for Aβ Mobilization • Pilot study

• 7 patients

• 6 TPE in 3 weeks

• 1 year follow up

• Phase II study

• 29 patients randomized in TPE and control group

• Same treatment schedule

• Boada M et al. Drug News & Perspective 2009; 22:325:339

Mean CSF Levels of Aβ 40 and 42

0

200

400

600

800

1000

1200

1400

1 2 3 4 5 6

Aβ40

0

100

200

300

400

500

600

1 2 3 4 5 6

Aβ42

Months Months

Pg/m

L

Mini-Mental Status Examination (MMSE)

Alzheimer’s Dis. Assessment Scale, Cognitive subscale (ADAS-Cog)

0

0.5

1

1.5

2

2.5

0 3 6 9 12

ADAS-Cog

0

0.5

1

1.5

2

2.5

0 3 6 9 12

MMSE

Months

TPE in Alzheimer’s Disease

• Sham pheresis controlled clinical trial underway

• Trial includes IVIG with TPE

Champagne Improves Memory

• Giulia Corona, David Vauzour, Justine Hercelin, Claire M Williams,

Jeremy P.E. SpencerAntioxidants & Redox Signaling. March 2013,

INTERMITTENT HETEROCHRONIC

PARABIOSIS AS A MODALITY FOR

PREVENTING CELLULAR SENESCENCE

USA is Living Longer but Sicker

• 2012 America’s Health Rankings

(http://americashealthrankings.org)

• JAMA, Mar11, 2013;173:385-386

• “Despite their longer life expectancy over previous generations, US

baby boomers have higher rates of chronic diseases, more

disability and lower self rated health (average age of study

subjects: 54.5 years). With 78 million baby boomers, this situation

is destined to wreak havoc with our already out-of-control

healthcare costs”

• 2030 1 in 5 Americans will be 65 or older

• By 2050 2 billion people on earth will be older than 60-65

• Preventing Chronic Diseases: a vital investment (WHO publication)

Causes of Aging

• Imunosenescence (disordered immune responses)

• Infections

• Poor response to vaccines (1000 higher risk of death from vaccine

preventable diseases)

• Cardiovascular disease

• Stroke

• Dementia

• Increased frequency of cancer

• Increased frequency of autoimmune conditions

• Physical limitations

• >50% of 74 y.o. or older have a disability

Risk of MI and Stroke in The Elderly after Infection

Dysregulated Inflammation

Exhausted

or

Senescent

Phenotypes Associated with Aging

• CD8+CD57+cd28-

• p16

Soluble Factors Associated with Aging

• IL-6

• TNF-α

• CRP

• Fibrinogen

The Circulatory Systemic Environment as a

Modulator of Cellular Senescence

• Decline of intrinsic factors

• Accumulation of inhibitory factors

Heterochronic Parabiosis

Rejuvenation of Aged Progenitor Cells by Exposure to a Young

Systemic Environment

Conboy I et al. 2005, Nature;433:760-764

The Aging Systemic Milieu Negatively Regulates

Neurogenesis and Cognitive Function

Villeda S. 2011 Nature 477:90-96

?

? Adverse reactions

25%

Donor Age 35-45

FFP

Adverse reactions

<3%

Donor Age 18-24

5% Albumin

IVIG

Conclusion

• There are a lot of opportunities for TA to grow

• What is needed are well designed controlled clinical trials

• Funding?