11/11/2012
Disclosures Low Doses of Ocaratuzumab, a Fc- and Fab- Engineered Anti-CD20 Antibody, Result in Rapid and • All authors are employees of the company. Sustained Depletion of Circulating B-Cells in • Dr. Vinay Jain, CEO of Mentrik Biotech, is an Rheumatoid Arthritis Patients employee and shareholder of the company.
Presented by Dr. Vinay Jain Mentrik Biotech, LLC Dallas, TX
Abstract authors: A O’Reilly, T Davis, V Jain
Table of Contents
• Ocaratuzumab (AME-133v) engineering and optimization • Phase I/II clinical data in relapsed/refractory follicular lymphoma • Phase I trial of ocaratuzumab in rheumatoid arthritis – trial design • PK and PD data from RA patients receiving a single very low dose of ocaratuzumab • Unmet need in rheumatoid arthitis
Ocaratuzumab (AME-133v) demonstrates 3.5-to 8- Ocaratuzumab triggers ADCC at concentrations Ocaratuzumab (AME-133v) is engineered in Fab and Fc regions for fold higher ADCC than rituximab 2 log orders less than the dose of rituximab superior affinity and ADCC compared to rituximab 110 110
45 F carrier VV 40 90 AME-133v 90 AME-133v 35 rituximab rituximab • Demonstrates 13-20 fold higher 30 70 70 25 rituximab binding affinity for the CD20 antigen, 20 50 50 ocaratuzumab compared to rituximab 15 10 30 30 • Demonstrates 6-fold higher 5
% specific death% specific 10 10 % of maximal of response% 0 maximal of response% antibody-dependent cellular 10 100 1000 10,000 100,000 -10 -10 cytotoxicity (ADCC) than rituximab [Mab] ng/mL -2 -1 0 1 2 3 -2 -1 0 1 2 3 Log10 IgG, ng/ml Log10 IgG, ng/ml • 36 amino acid changes in the heavy Ocaratuzumab depletes healthy B-cells at 2 chain and 28 in the light chain, Ocaratuzumab depletes B-cells in CD16 FF compared to human IgG1 log orders less than the dose of rituximab
Cladogram of Heavy Chain Ocaratuzumab is distinct from rituximab and other antibodies
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Phase I/II US trial and Phase I Japan trial Phase I/II follicular lymphoma patients demonstrate treated 77 relapsed FL patients with 4 weekly CR and prolonged PFS after ocaratuzumab treatment
infusions of ocaratuzumab Outcome Number of Overview of Data Patients Efficacy . 67 patients in Phase I/II CR 12 (16%) • Most patients (75%) US FL trial achieved at least SD PR 12 (16%) ORR = 32% in all . Phase I 10 patient bridging • CR of 16% SD 33 (43%) patients, 36% in 375 • Median PFS of 91 weeks mg/m2 cohort study in Japan PD 15 (19%) Pharmacokinetics . All patients pre-treated • Estimated median terminal Unconfirmed 5 (6%) elimination half-life was 18 with rituximab Total (US & 77 days in NHL patients, similar to rituximab . All patients expressing the Japan) Safety low-affinity FcγRIIIa • ocaratuzumab was safe genotype (FF or FV) US Patients Treated at 375 mg/m2 Dose and well tolerated at the recommended Phase II . 36% ORR and 16% CR 2 Prolonged PFS dose of 375 mg/m Independent review: • AEs Grade 3 or higher . Phase I trial initiated in RA Median PFS: 91 in relapsed included anemia, weeks follicular neutropenia, lymphoma thrombocytopenia, patients treated esophageal achalasia and with aspiration pneumonia Survival ProbabilitySurvival ocaratuzumab
Progression-Free Survival (weeks)
Greater PFS achieved in 5 of the patients, with Retrospective analysis confirmed prolonged benefit and tumor reduction in rituximab-refractory and F/F patients some yet to relapse at time of follow up or study closure Of the 67 US patients enrolled on trial, 8 relapsed within 6 months of prior rituximab-containing treatment and were deemed rituximab-refractory
5 of those patients demonstrated improved PFS following treatment with ocaratuzumab, 4 of which had yet to show disease progression at follow up or at study closure
All 8 of the rituximab refractory patients identified were homozygous for the FcγRIIIa- * Patients who had not progressed at time of follow up or study closure F158 genotype (F/F).
B-cell killing mechanisms of selected anti- CD20 antibodies
Rituximab Ofatumumab Ocaratuzumab Chimeric Fully human Humanized
• Glycoengineered FC region for higher Modifications N/A N/A ADCC • Glycoengineered Fab region for higher binding affinity to CD20 • 36 amino acid changes in the heavy chain, 28 in the light chain, compared to human IgG1 ADCC +++ + +++++ CDC ++ +++ + Apoptosis + + + CD16a FF + N/A +++
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A Randomized, Double-Blind, Placebo-Controlled, Single-Dose, Parallel, Dose-Escalation Study of LY2469298 (Ocaratuzumab), a Study designs of IV ocaratuzumab in rheumatoid arthritis Humanized Antibody to CD20, in Patients with Rheumatoid Arthritis
• Actual dose escalation schema: • Inclusion Criteria: • Initial dose escalation o 5 patients received a single IV dose of 5 mg ▫ Established diagnosis of RA for at least 12 months. schema: ocaratuzumab ▫ Stable doses of regular medication for RA for at least 1 month prior to study enrollment o 4 patients in each cohort. o 1 patient received: Each cohort receives a single - a single IV dose of 5 mg ocaratuzumab • Exclusion criteria: IV dose of ocaratuzumab at: - 650 mg acetaminophen ▫ Prior exposure to these agents in the given timeframes: - 50 mg diphenhydramine Anakinra or Etanercept within 4 weeks of enrollment. 5 mg Adalimumab or Abatacept within 8 weeks of enrollment. 15 mg o 3 patients received: Infliximab within 12 weeks of enrollment. 50 mg - a single IV dose of 7.5 mg ocaratuzumab ▫ Evidence of systemic inflammatory conditions other than RA. - 650 mg acetaminophen ▫ Active vasculitis associated with RA. 150 mg - 50 mg diphenhydramine - 100 methyl prednisolone • Endpoints: 500 mg ▫ To examine safety and tolerability of ocaratuzumab in RA patients 1000 mg Patient demographics: 10 females, 1 male ▫ Secondary endpoints: to evaluate the PD, PK, and potential 8 Caucasians, 2 Hispanics, 1 African immunogenicity effects of ocaratuzumab in RA; to evaluate Mean age 55.6 years (range 49 to 72 years) potential impact of FcγRIIIA genotype on PD effects
Pharmacokinetics of a single dose of ocaratuzumab
5 mg PK 7.5 mg PK
Cmax (ng/mL): 1620 Cmax (ng/mL): 1720
t1/2 (hr): 2.58 t1/2 (hr): 8.21
AUC (ng●hr/mL): 3400 AUC (ng●hr/mL): 24600
Early B-cell depletion following very low doses of ocaratuzumab
Patient Baseline B-cell 3 hours after 12 hours after 1 day after 2 days after Count (cells/μL) infusion infusion infusion infusion 5001 74 6 5 12 5 5002 18 12 15 N/A 6 5004 228 10 5 3 2 1003 199 7 15 52 50 1004 219 21 7 9 15 1005 144 23 9 6 35 2001 243 10 27 N/A 102 4001 477 21 3 2 15 4002 85 77 25 4 79
Sustained B-cell depletion achieved from a B-cell activating factor (BAFF), a key B-cell survival factor, has been shown to increase in single low dose of ocaratuzumab response to rituximab therapy BAFF/BLS
• BAFF, also know as B lymphocyte stimulator BAFF-R Baseline B- 7 Days After (BLyS), is a member of the tumor necrosis Dose cell Count Inf (cells/μL) 3 Months After B-cell recovery over family and acts as a cytokine. Patient (mg) (cells/μL) (% from baseline) Inf time 5001 7.5 74 17 (23%) 16 (22%) 35 at Day 224 (47%) B cell • Previous data has shown that rituximab- TACl 5002 7.5 18 30 (167%) 60 (333%) 56 at Day 205 (311%) induced B-cell depletion is associated with an increase in BAFF levels. 5004 7.5 228 23 (10%) 119 (52%) 160 at Day 172 (70%) BCMA 1003 5 199 93 (47%) 158 (79%) N/A 1004 5 219 33 (15%) 40 (18%) 87 at Day 237 (40%) • In an RA study, BAFF levels increased significantly upon rituximab-induced B-cell 1005 5 144 70 (49%) 88 (61%) 128 at Day 141 (89%) depletion (p<0.01). When B-cells repopulated, 2001 5 243 130 (53%) 20 (8%) N/A BAFF levels decreased. When B-cells 4001 5 477 N/A N/A N/A recovered, BAFF levels decreased further 4002 5 85 139 (164%) 90 (106%) 99 at Day 208 (116%) toward pre-treatment values.
Vallerskog et al, 2006
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BAFF levels following single 5 or 7.5 mg IV dose of ocaratuzumab (AME-133v) Subcutaneous administration of ocaratuzumab provides similar serum levels to IV administration
1003, 5mg, FF 4001, 5mg, VF
L) L) 250 1500
600 8000
200 500 6000 1000 150 400 300 4000 In primate studies, 100 500 200 SC administration achieves 76% the 50 2000
100 BAFF BAFF count (pg/mL)
BAFF count (pg/mL)count BAFF AUC of IV administration 0 0 0 0 0 20 40 60 80 0 20 40 60 80
Time (days) Time (days)
Cell Surface Marker CD19 (cell/ CD19Marker Cell Surface Cell Surface Marker CD19 (cell/ CD19Marker Cell Surface
5002, 7.5mg, VF 5001, 7.5mg, VV
L)
L) 70 2000 80 2500
60 2000 50 1500 60 40 1500 1000 40 30 1000 20 • Effective pharmacokinetics achieved with SC administration 500 20 500
10
BAFF count (pg/mL)count BAFF BAFF count (pg/mL)count BAFF 0 0 0 0 • Sustained B cell depletion seen in primate models 0 20 40 60 80 0 20 40 60 80
Time (days) Time (days)
Cell Surface Marker CD19 (cell/ CD19Marker Cell Surface Cell Surface Marker CD19 (cell/ CD19Marker Cell Surface
Conclusions
• Ocaratuzumab, administered in a single dose less than 1% that of rituximab, results in rapid and sustained B-cell depletion in RA patients, with nonlinear PK obtained. For more information please contact: • At Day 84 in ocaratuzumab’s RA study, 4 out of the 7 patients had B-cells counts less than 50% that of their baseline despite Dr. Vinay Jain the fact by day 8, no detectable levels of antibody were Chief Executive Officer present. Mentrik Biotech,LLC [email protected] • Engineered for optimized binding affinity to both effector (214) 593-0505 cells and the CD20 antigen, ocaratuzumab in being developed subcutaneous administration at very low doses for the treatment of rheumatoid arthritis. Booth 845 at ACR
www.mentrik.com
Rituximab non-depleters have a poorer response in SLE patients
A) SLAM scores in patients with complete versus incomplete B cell depletion.
• In the depleters, differences from baseline were significant at 1, 2, and 3 m post infusion.
B) Geometric mean RTX levels in B-cell depleters and non-depleters. Differences between depleters and non-depleters were significant at 2 months after initial infusion.
Looney et al, 2004
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Opportunity exists to treat RA patients with low-affinity FcγRIIIa genotypes
• Historically, patients with low-affinity FcγRIIIa genotypes (FF or FV at position 158) have a poorer response to rituximab than high affinity patients (VV) FF patients demonstrate the poorest response • Ocaratuzumab demonstrates superior efficacy across genotypes, compared to rituximab 30% FF non responders
Ruyssen-Witrand et al, 2011
Ocaratuzumab has a less infusion reactions compared to rituximab and GA101
In GA101 studies, 18% of patients reported Grade 3/4 infusion related reactions There were no Grade 3/4 infusion reactions reported with ocaratuzumab treatment
Ocaratuzumab1 Rituximab2 GA1013 Pyrexia 14% 53% 23% Nausea 16% 23% 18% Rigors 34% 33% N/A
1AME 06.133v.A Clinical Study Report 2Rituximab Package Insert, Table 1 3ASH 2011 Abstract, “Randomized Phase II trial comparing GA101 (obinutuzumab) with rituximab in patients with relapsed CD20 indolent B-cell non-Hodgkin lymphoma: preliminary analysis of the GAUSS study”; Sehn, L.H., et al.(2011) Blood
Ocaratuzumab has greater ADCC, but low levels of CDC and direct apoptosis, which may explain decreased incidence of fever and other infusion related reactions
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