FONT Phase II Clinical Trial

PI: Howard Trachtman, M.D.Co-PI: Debbie Gipson, M.S., M.D.

Study Coordinator: Suzanne Vento, RN Study Coordinator: Emily Herreshoff

Justification for Novel FSGS TherapyPoor Survial for Resistant FSGS

44

Presler/Gipson, 2005 Cattran, JASN, 2003A

a. Pediatric FSGS b. Adult FSGS

CR 12 12 8 5 5 PR 20 18 13 11 9 NR 28 25 20 10 9

Specific Aims1: To evaluate two novel therapies for resistant FSGS -- anti-TNF-α antibody and galactose against standard therapy

2: To identify one or more novel agents as candidates for future study in a Phase III randomized clinical trial

3: To develop a network of sites to foster the performance of clinical trials for this disease and other glomerular disorders

Eligible Patients with Resistant FSGS

RANDOMIZATION

GalactoseN=17

Standard RxN=17

AdalimumabN=17

Pause for Efficacy Review

YES, Continue recruitment to N=42*

NO, Discontinue study arm

≥2/17 with Up/c<50% baseline and stable GFRe

FONT II REVISED PROJECT

TNF- • Inflammatory cytokine • Produced by circulating or infiltrating mononuclear

cells, macrophages, and kidney mesangial cells • Postulated mechanisms

– recruitment of leukocytes to the site of glomerular injury– induction of cytokines and growth factors– generation of oxygen radicals resulting in increased

glomerular endothelial cell permeability to albumin– direct cytotoxicity to glomerular mesangial and epithelial

cells, and induction of apoptosis • Increases in TNF- α and TNF- α mRNA described

in FSGS

TNF levels from cultured PBMC increased in nephrotic syndrome

Bakr, 2003

TNF-alpha (pg/ml)

P=0.015

P=0.006

P=0.002

2500

2000

1500

1000

500

0 FSGS MCGN DMP-SR MCNS-SR

TNF levels low during remission of nephrotic syndrome

Group N PBMC TNF (pg/ml) Median IQR

FSGS 11 1,955 1,786-2060MCNS-SS 21 19 15-26MCNS-SR 5 34 24-82.5Remission 11 5.5 4.9-6.0Control 10 5.5 4.8-6.0

Bakr, 2003

Phase I Adalimumab

• N=10 (4M:6F)

• Age 16.8±9.0 yr

• GFRe 105±50 ml/min/1.73 m2

• Dose 24 mg/m2 (max: 40 mg) sc q 14 d

• Up/c 15.9±10.4

Adalimumab: PKThe half life, area under the curve, and clearance were increased in proteinuric

FSGS compared with patients with rheumatoid arthritis

FSGS steady state

RA

Tmax (hr) 34.2±9.8* 130±55

Cmax (μg/mL) 12.8±8.3 13.7±2.7

T1/2 (hr) 273±402 389±71

AUC 2019±1693* 3622±587

Cl/F 53.2±43.3* 11.2±2.0

Adalimumab Safety

• 9 AEs– 1 probably related: injection site reaction– No discontinuation due to AE

• Relationship of T1/2 to Up/c and albumin

• TSQM (effectiveness, side effects, convenience, global satisfaction)– Scores: 61, 92, 71, 59

Phase I: Long-term follow-up

Adalimumab(n=10)

Rosiglitazone(n=11)

Follow-up (months)

16.15.7 18.310.2

50% decline in Up/c

4 3

Progression to ESKD

1 4

Stabilization in GFRe (Δ/month)

71% 56%

Galactose Arm Rationale

• Role of FSGS permeability factor

• Effect of galactose on FSGS permeability factor

Circulating permeability factor(s) in FSGS

Permeability activity: In vitro glomerular albumin permeability (Palb) predicts recurrence.

0

0.1

0.2

0.3

0.40.5

0.6

0.7

0.8

0.9

Evidence: Early post-transplant recurrence of proteinuria Proteinuria after injection of FSGS plasma Clinical benefit of plasmapheresis (PP)

1st & 2nd 1 PP rx IV Galactose

Palb of patient specimens

Savin VJ, et al. Transl Res 2008

0

0.2

0.4

0.6

0.8

1

Norecurrence

of FSGS

Recurrenceof FSGS

Priorrecurrence

or rapidprogression

CollapsingGN,

(McCarthy)

ESRD non-glomerular

disease

Permeability is increased most by serum from FSGS patients with severe disease or recurrence

after transplantation

Palb

11

1

1. Savin, NEJM, 1996

2. Butcher, ASN, 1998

3. McCarthy, ASN, 19972

3

More rapid progression to kidney failure is seen in patients with high activity (Pudur)

0

Palb < 0.5

Palb 0.5

Time from diagnosis to ESRD, years

Su

rviv

al d

istr

ibu

tio

n F

un

ctio

n

5 years

10 15

.25

.50

.75

1.0

Low activity, about 40% good function after 5 years

High activity, only about 25% good function after 5 years

Permeability activity is decreased by galactose

• Galactose taken twice daily in water.• Activity decreased at 2 weeks and remained low.

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Palb

Pre-treatment

6 weeks

1 week

2 weeks

4 weeks

4 weeks after stopping galactose

Savin VJ, et al. Transl Res 2008

Galactose and Potential Mechanisms of Action

• Permeability factor may gain access to podocyte by sugar binding.

• Galactose may block the binding between factor and podocyte.

• Factor-galactose complex may be removed by specific receptors in liver or other tissues.

FSPF

galactose galactose

galactose

Galactose receptors

FSPF-galactose complex

FSPF FSPF-galactose complex

galactose galactose

FSPF FSPF

Podocytes Filtration slits

Savin VJ, et al. Transl Res 2008

Cardiotrophin-like cytokine (CLC-1) is present in plasma of a patient with recurrent FSGS

We used galactose to purify active proteins from a patient with FSGS

Proteins were separated on a gel.

A band of low molecular weight protein was present.

CLC-1 was the single cytokine identified in this material by mass spectrometry.

Patient plasma

Proteins of interest

Savin VJ, ASN 2008 (abstract)

• Rat glomeruli were treated with CLC-1 in various concentrations.

• CLC-1 increased permeability as does FSGS serum.

• Synthesis of nephrin, the main protein of the slit-junction, is decreased.

0

0.2

0.4

0.6

0.8

1

Palb, CLC-1

*

***

* P< 0.01 vs C

CLC-1 increases permeability and decreases expression of nephrin, the main junction protein

0

10

20

30

40

50

60

Per

cent

dec

reas

e vs

. con

trol

5 10 CLC [ng/mL]Savin VJ, ASN 2008 (abstract)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Pt 1 Pt 2 Pt 3 Pt 4 CLC-1

Palb Palb + anti CLC-1 mAb

Antibody to CLC-1 prevents permeability caused by patient serum or by CLC-1 itself

Anti-CLC-1 mAb vs. without mAb: Fisher exact test, p < 0.02; paired t-test, p<0.005.

Savin VJ, ASN 2008

Summary of current work about circulating factor in FSGS

• Permeability activity of plasma is highest in patients with severe disease.

• Galactose binds the active protein and can be used for purification or for therapy.

• CLC-1 is a candidate for the FSGS permeability factor due to – presence in FSGS plasma and – same effects of FSGS plasma in vitro

Galactose: NDT 2009;24:2938-40

• 48 year old man, onset of NS 2004

• Resistant to prednisone, cyclophosphamide, cyclosporine, and plasmapheresis

• Elevated Palb

• Galactose 10 g BID started Feb 2007

• After 7 months: – Palb 0.54→0.09– Proteinuria 4.5→0.6 g/24 hours

• Galactose Rx through 1/09, proteinuria 1.1 g/24 h, stable GFR, off cyclosporine

Galactose: Safety

• IND #77,091

• 23 patients

• Duration of therapy: 28 days

• No SAE directly related to drug

• AE: abdominal pain

Galactose: Dosing

• Dispensed by Aptuit– Powder– 500 g in plastic container

• Dose: 0.2 g/kg/dose BID (max: 15 g BID)

• Dissolve in 15-30 ml water

• Administer 15 minutes before breakfast and dinner

Study SummaryVisit

week/yearStudy Visit

Blood and Urine Tests

Quality of LifePregnancy Screening

Week -4 x x   xWeek 0 x x x x

Week 2 x x    Week 8 x x   xWeek 16 x x   xWeek 26 x x x  Month 7 x x    Month 9 x x    Month 12 x x x  Month 18 x x    Year 2 x*    x  

* May be phone follow up

FONT Study Network15 study sites

• Boston Children’s• Carolinas Medical Center• Children’s Mercy Kansas City• Cincinnati Children’s• Cohen Children’s Medical Center• Emory University• Mayo Clinic• Miami Children’s• MUSC• Nationwide Children’s• Oregon• Stollery• Texas Tech El Paso• University of Kansas• University of Michigan

Contact Information

Study Website: www.fonttrial.org

Email: font2@umich.edu

Phone: 1-855-4-FONT II (1-855-

436-6844)