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 • 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 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 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 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/BLS

• 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 () 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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