Urinary excretion of low and high molecular weight Urinary excretion - PowerPoint PPT Presentation

May 6th – 7th 2011 y Mario Negri Institute for Pharmacological Research Clinical Research Centre for Rare Diseases Aldo e Cele Daccò Ald C l D ò Urinary excretion of low and high molecular weight Urinary excretion of low and high molecular weight proteins as predictors of response to rituximab in proteins as predictors of response to rituximab in p p p p p p patients with membranous nephropathy: patients with membranous nephropathy: Fernando C. Fervenza, MD, Ph.D Fernando C. Fervenza, MD, Ph.D Division of Nephrology and Hypertension Division of Nephrology and Hypertension Division of Nephrology and Hypertension Division of Nephrology and Hypertension Mayo Clinic College of Medicine Mayo Clinic College of Medicine Rochester, MN Rochester, MN

Conflict of Interest Conflict of Interest • Studies supported by unrestricted Studies supported by unrestricted research grants from Genentech Inc research grants from Genentech Inc research grants from Genentech Inc, research grants from Genentech Inc, the Fulk Foundation and the Mayo the Fulk Foundation and the Mayo Foundation Foundation Foundation. Foundation.

Rituximab in Membranous Nephropathy Rituximab in Membranous Nephropathy p p p p y y 12 6 10 5 8 8 4 4 Serum Serum * Proteinuria Proteinuria * 6 3 creatinine creatinine * (g (g/24 hr) (g (g/24 hr) ) ) * * (mg/dL) (mg/dL) (mg/dL) (mg/dL) * 4 2 2 2 1 1 0 0 -6 6 0 0 3 3 6 6 9 9 12 12 Months Months * P<0.01 vs months -6 and 0 * P<0.01 vs months -6 and 0 P 0.01 vs months 6 and 0 P 0.01 vs months 6 and 0 Ruggenenti et al: JASN 14:851, 2003 Ruggenenti et al: JASN 14:851, 2003 CP1125840-1

Main Clinical and Laboratory Characteristics Main Clinical and Laboratory Characteristics at Study Entry in Patients with IMN at Study Entry in Patients with IMN Characteristic Characteristic No. No. % % Mean Mean SD SD Min Min Max Max Gender Gender Male Male 17 17 85.0 85.0 Female Female 3 3 15.0 15.0 A Age (years) A Age (years) ( ( ) ) 48.6 48.6 48 6 48 6 12.9 12.9 12 9 12 9 29 29 29 29 80 80 80 80 Disease duration (mo) Disease duration (mo) 29.7 29.7 39.7 39.7 3 3 144 144 Failed prior immunosuppressive therapy Failed prior immunosuppressive therapy 11 11 55.0 55.0 Histology stage Histology stage Histology stage Histology stage I 2 2 10.0 10.0 I- -II II 3 3 15.0 15.0 II II II II 4 4 20.0 20 0 20.0 20 0 II II- -III III 8 8 40.0 40.0 III III 1 1 5.0 5.0 III III IV III-IV III IV IV 2 2 10.0 10.0 10.0 10.0 Urinary protein excretion (g/24 hr) Urinary protein excretion (g/24 hr) 11.9 11.9 4.9 4.9 5.7 5.7 26.5 26.5 Serum creatinine (mg/dL) Serum creatinine (mg/dL) 1.5 1.5 0.5 0.5 0.8 0.8 2.3 2.3 Creatinine clearance (mL/min/1.73 m Creatinine clearance (mL/min/1.73 m 2 ) ( ) 72.4 72.4 33.2 33.2 30 30 156 156 Fervenza, Abraham, …Cattran. CJASN 2010 Fervenza, Abraham, …Cattran. CJASN 2010

100.00 NR NR 4 hr) 4 hr) n=2 n=2 10.00 10.00 in (g/24 in (g/24 LR LR LR LR n=1 n=1 3.50 PR PR 1 00 1.00 n=12 n=12 12 12 e prote e prote 0.30 CR CR n=5 n=5 0 10 0.10 Urine Urine 0.01 0 01 -4 Baseline 28 3 6 9 12 18 24 Months Months Days Days y Months Months Fervenza, Abraham, …Cattran. CJASN 2010 Fervenza, Abraham, …Cattran. CJASN 2010 3030180-5

Can we predict response Can we predict response to therapy? to therapy? 3030180-6

Observed Serum Rituxan Concentrations from IMN (Study U4086s) vs. PK Observed Serum Rituxan Concentrations from IMN (Study U4086s) vs. PK profile Simulated* Using model derived from Rituxan RA Study (375mg/m profile Simulated* Using model derived from Rituxan RA Study (375mg/m 2 x 4) x 4) x 4) x 4) 1,000,000 •Red Symbols represent the original observations •Black solid line represents the median of the simulated data (ng/mL) •Black dashed lines represent the lines 5th and 95th percentiles of the simulated data. 100,000 oncentration 10,000 m Rituxan Co 1 000 1,000 Seru *Simulations were based on the estimated PK parameters and inter- and intra- individual variability for RA patients 100 0 28 56 84 112 140 Time (days) Observed serum concentrations (red symbols) from study in IMN are lower than the PK data simulated using PK model from adult RA population .

Do baseline T and B cell Do baseline T and B cell subsets predict response subsets predict response subsets predict response subsets predict response to therapy? to therapy?

B cell subsets B cell subsets • CD19+ B Cells • CD19+ B Cells B Cells B Cells • CD19+CD27+ • CD19+CD27+ Total Memory B Cells Total Memory B Cells • CD19+CD27+IGM+IGD- • CD19+CD27+IGM+IGD- IgM Memory B Cells IgM Memory B Cells • CD19+CD27+IGM+IGD+ • CD19+CD27+IGM+IGD+ Non-Switched Memory B Cells Non-Switched Memory B Cells • CD19+CD27+IGM-IGD- • CD19+CD27+IGM-IGD- CD19+CD27+IGM IGD CD19+CD27+IGM IGD Switched Memory B Cells Switched Memory B Cells Switched Memory B Cells Switched Memory B Cells • CD19+IGM+ B CELLS • CD19+IGM+ B CELLS IgM B Cells IgM B Cells • CD38+IGM+CD19+ • CD38+IGM+CD19+ • CD38+IGM+CD19+ • CD38+IGM+CD19+ T T Transitional B Cells Transitional B Cells iti iti l B C ll l B C ll • CD38+IGM-CD19+ • CD38+IGM-CD19+ Plasmablasts Plasmablasts • CD19+CD21+ • CD19+CD21+ Mature B Cells Mature B Cells • CD19+CD21- • CD19+CD21- Immature B Cells Immature B Cells • CD45+CD20+ • CD45+CD20+ Pan-lymphocyte marker Pan-lymphocyte marker

T cell subsets T cell subsets • CD4+CD45RA+ naïve T-cells • CD4+CD45RA+ naïve T-cells • CD4+CD62L+CD27+ naïve (n) T-cells • CD4+CD62L+CD27+ naïve (n) T-cells CD4 CD62L CD27 naïve (n) T cells CD4 CD62L CD27 naïve (n) T cells • CD8+CD45RA+ naïve T-cells • CD8+CD45RA+ naïve T-cells • CD8+CD62L+CD27+naïve (n) T-cells • CD8+CD62L+CD27+naïve (n) T-cells CD8+CD62L+CD27+naïve (n) T cells CD8+CD62L+CD27+naïve (n) T cells • CD4+CD45RO+ memory T-cells • CD4+CD45RO+ memory T-cells • CD4+CD62L+CD27+CD45RO+ (Tcm) • CD4+CD62L+CD27+CD45RO+ (Tcm) • CD4+CD62L+CD27+CD45RO+ (Tcm) • CD4+CD62L+CD27+CD45RO+ (Tcm) • CD4+CD62L-CD27-CD45RO+ (Tem) • CD4+CD62L-CD27-CD45RO+ (Tem) • CD8+CD45RO+ memory T-cells • CD8+CD45RO+ memory T-cells • CD8+CD45RO+ • CD8+CD45RO+ T T ll ll • CD8+CD62L+CD27+CD45RO+ (Tcm) • CD8+CD62L+CD27+CD45RO+ (Tcm) • CD8+CD62L-CD27- CD45RO+ (Tem) • CD8+CD62L-CD27- CD45RO+ (Tem) • Activated CD4 T-cells (4+CD25+) • Activated CD4 T-cells (4+CD25+) • CD4+HLA DR+CD28+ T-cells • CD4+HLA DR+CD28+ T-cells • CD8+HLA DR+CD28+ T-cells • CD8+HLA DR+CD28+ T-cells

Does urinary excretion of low Does urinary excretion of low Does urinary excretion of low Does urinary excretion of low and high molecular weight and high molecular weight proteins predicts response proteins predicts response to therapy? to therapy? to therapy? to therapy?