FONT Phase II Clinical Trial

Justification for Novel FSGS TherapyPoor Survival for Resistant FSGS

44

Presler/Gipson, 2005

a. Pediatric FSGS

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

b. Adult FSGS

Troyanov, JASN, 2005

FSGS Clinical Trial: CSA vs. MMF/ Dexamethasone

Primary Outcome

6 months

Secondary Outcome

0

26

52

78

Week

CSA MMF + Dex

ACEi

RandomizePred +ACEi

Gipson et al, 2011

Eligibility CriteriaInclusion• Age 2 – 40 years • eGFR ≥ 40 ml/min/1.73m2

• Up/c > 1.0 • Steroid resistance• Biopsy confirmed primary FSGS

Exclusion• Prior therapy CSA, Tacrolimus, MMF• Obesity• Transplant• Malignancy• Diabetes mellitus

Gipson et al, 2011

Primary Outcome: Week 52 Proteinuria

Remission

Outcome Level

MMF/DEX(n=66)

CSA(n=72)

Odds Ratio

95% CI

1 2 (3.0) 4 (5.6) 0.53 0.09 – 3.03

2 4 (6.1) 10 (13.9) 0.41 0.15 – 1.15

3 16 (24.2) 19 (26.4) 0.59 0.30 – 1.18

CR + PR 22 (33.3) 33 (45.8) 0.59 0.30 – 1.18

OR<1 favor CSAGipson, 2011

FSGS CT: Secondary Outcomes

• 6 months after immunosuppression withdrawal• Proteinuria relapse was common

(CSA 33%; MMF/DEX18%)

• No difference in proteinuria remission status

OR= 1.21 (0.56-2.66)

Gipson et al, 2011

Adverse Events

*

*

* *

*

0

5

10

15

20

25

MMF/Dex

CSA

Gipson et al, 2011

Trachtman et al, 2011 Trachtman 2011

www.fonttrial.org

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

Trachtman et al, 2011

Eligibility criteria

• Age 1-50,

• GFR >40 mL/min/1.73 m2

• FSGS on bx OR genetic mutation

• Steroid resistance

• Resistance to a 2nd immunosuppression

Trachtman et al, 2011

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

Trachtman et al, 2011

Standard Conservative Therapy

Lisinopril

mg/day

Losartan

mg/day

Atorvastatinmg/day

≤40 kg 10 25 10

>40 kg 20 50 20

Trachtman et al, 2011

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

Trachtman et al, 2011

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

Joy, 2009

Adalimumab Safety

• 9 Adverse Events– 1 probably related: injection site reaction– No discontinuation due to adverse event

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

• Treatment Satisfaction Questionnaire for Medicine (effectiveness, side effects, convenience, global satisfaction)

– Scores: 61, 92, 71, 59 out of a possible 100

Phase I: Long-term follow-up

Adalimumab

(n=10)

Rosiglitazone

(n=11)Follow-up (months)

16.1±5.7 18.3±10.2

50% decline in Up/c 4 3

Progression to ESKD1 4

Stabilization in GFRe71% 56%

Trachtman, 2009

Adalimumab: Dosing

• Provided by Abbott– Injectable– 40 mg/0.8 mL – Boxes of 6 vials

• Dose: 24 mg/m2 SC Q 14 days

• Apply EMLA or ice to relieve pain

Galactose Arm Rationale

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., 2008

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

transplantation

0

0.2

0.4

0.6

0.8

1

Norecurrence

of FSGS

Recurrenceof FSGS

Priorrecurrence

or rapidprogression

CollapsingGN,

(McCarthy)

ESRD non-glomerular

disease

Palb

11

1

1. Savin, NEJM, 1996

2. Butcher, ASN, 1998

3. McCarthy, ASN, 1997

2

3

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

Palb < 0.5

Palb 0.5

Time from diagnosis to ESRD, years

Su

rviv

al d

istr

ibu

tio

n F

un

ctio

n

0.0 5 years

.25

.50

.75

1.0

Low activity, about 40% good function after 5 years

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

0.0 2.5 5.0 7.5 10.0 12.5 15.0

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., 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., 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

Serum Urokinase Receptor and FSGS

Wei et al, 2011

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 – same effects as FSGS plasma in vitro

• suPAR

GALACTOSE: Case reports

PatientAge

Gender

Prior

Rx

Bx

ResultDuration ΔPalb Outcome

1 48MPred

CsA, PE

Not

Done18 months

↓Stable GFR

PR

2 3M

Pred, Cytox

MMF, Tac

FSGS7 months

Not Done

Stable GFR

PR

3 16FPred

Tac

C1q

Neph7 months

Not

Done

Stable GFR

PR

Case 1 NDT 2009; Cases 2 and 3 Therapeutic Apheresis Dial 2011

Galactose: Safety

• IND #77,091

• 23 patients

• Duration of therapy: 28 days

• No SAE directly related to drug

• AE: abdominal pain

Galactose: Dosing

• Ferro Pfahnstiel, Inc. (Waukegan, IL)

– 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

FONT Trial Study SummaryVisit Study Visit

Blood and Urine Test

Quality of Life

Pregnancy Screening*

Week -4 x x   x

Week 0 x x x x

Week 2 x x    

Week 8 x x   x

Week 16 x x   x

Week 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 Network16 approved sites

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

Contact Information

FONT2@umich.edu

1-855-4-FONTII (1-855-436-6844)