RXi Pharmaceuticals Immuno-Oncology World Frontiers Conference January 23, 2018 NASDAQ: RXII
Forward Looking Statements This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as believes, anticipates, plans, expects, indicates, will, intends, potential, suggests and similar expressions are intended to identify forward-looking statements. These statements are based on RXi Pharmaceuticals Corporation s (the Company ) current beliefs and expectations. Such statements include, but are not limited to, statements about the future development of the Company s products (including timing of clinical trials and related matters associated therewith), the expected timing of certain developmental milestones, the reporting of unblinded data, potential partnership opportunities, the Company s competition and market opportunity and pro forma estimates. The inclusion of forward-looking statements should not be regarded as a representation by the Company that any of its plans will be achieved. Actual results may differ from those set forth in this presentation due to risks and uncertainties in the Company s business, including those identified under Risk Factors in the Company s most recently filed Quarterly Report on Form 10-Q and in other filings the Company periodically makes with the U.S. Securities and Exchange Commission. The Company does not undertake to update any of these forward-looking statements to reflect a change in its views or events or circumstances that occur after the date of this presentation. 2
RNAi Mechanism Results in Potent Gene Silencing RNAi is a naturally occurring biological process which can be harnessed to silence the expression of a specific disease protein. For each targeted mrna destroyed, 10s-100s of disease proteins are NOT made. 1 RNAi compound (sd-rxrna) administered 2 sd-rxrna enters cells mrna sd-rxrna RISC 4 Target mrna is cut & destroyed cleaved mrna cell membrane 3 sd-rxrna loads into RNA-induced silencing complex (RISC) Disease protein expression is blocked 3
Novel Self-delivering RNAi (sd-rxrna ) Platform 4 Provides for Broad Pipeline of RNAi Drugs for Unmet Medical Needs Single compound incorporates gene silencing activity & cellular uptake Robust uptake & silencing in multiple preclinical models Demonstration of safety and activity in a clinical setting Delivery is not limited to a specific cell-type Can be used alone or in combination with cell-based therapeutics Best RNAi technology for enhancement of cell-based therapeutics Potential to expand cell therapy beyond its current reach, e.g. CAR-T cells for solid tumors Freedom to operate with broad IP protection 4
RXi Pharmaceuticals Development Pipeline Internal development of Immuno-oncology therapeutics for high unmet medical needs with multi-billion dollar market potential. Aiming to enter the clinic within next 12-18 months. Target Indication Disc. Preclin. P1 P2 P3 *In ACT RXI-762 PD-1* Solid tumors RXI-804 TIGIT* Solid Tumors Undisclosed (3 products) Undisclosed Undisclosed Expanding internal development efforts and external collaborations with various existing cell-based approaches, evaluating hematopoietic stem cells, NK cells, TILs, CAR T, TCR and engineered NK cells to accelerate growth and develop immuno-oncology targets beyond checkpoint inhibition, i.e. cell differentiation. 5
Immunosuppression Major Hurdle for ACT in Solid Tumors Initial clinical trials of CAR T in solid tumors show limited success One of the major issues is immunosuppressive tumor microenvironment Multiple inhibitory receptors - immune checkpoints - are responsible for immunosuppression Clinical and commercial success of monoclonal antibodies targeting PD-1/PD- L1, CTLA-4 validate checkpoint targeting approach Challenging to use antibodies to target multiple checkpoints sd-rxrna proven multitargeting approach in single therapeutic entity 6 Immune Checkpoints: (D. Pardoll, Nature Rev. Cancer, 2012)
sd-rxrna in Adoptive Cell Transfer Modulation of Immune Effector Cells with RNAi Checkpoint Inhibition sd-rxrna pre-treatment of cells can be used to silence one or more immuno-suppressive genes (such as PD-1 and other checkpoints). Results in fewer suppressive receptors on the immune cell surface, which boosts their ability to detect and destroy tumor cells. 7
sd-rxrna: Best RNAi technology for ACT High Transfection Efficiency with High Cell Viability Nearly 100% transfection efficiency combined with high cell viability 98.6% sd-rxrna 8
Efficient uptake of sd-rxrna (red) to Immune Cells Human T Cells Meso CAR T Human NK Cells Dendritic Cells 9
Broad Applicability of sd-rxrna Empower existing clinical treatment paradigms and expand applicability of engineered cells Human T Cells Number one Number two Number three TILs for ovarian cancer or melanoma HSCT for modulation of GvHD γ/δ T cells Human NK Cells Autologous or Allogeneic Natural Killer (NK) cells Cytokine Induced Killer (CIK) cells Engineered NK or CIK Engineered T Cells Number one Number two Number three CAR T TCR Checkpoint inhibition and optimization for persistence and fitness of T cells Dendritic Cells Dendritic cell cancer vaccines 10
Targeting Multiple Immunosuppression Pathways* in a Single Therapeutic Entity Simultaneous Silencing of Multiple Genes is a Major Competitive Advantage of sd-rxrna 140 120 PD-1 *Extracellular TIGIT LAG-3 *Intracellular Undisclosed Target Gene Expression, % of non-targeting control (NTC) 100 80 60 40 20 0 11
Immuno-Oncology Clinical Development with sd-rxrna Two self-delivering RNAi (sd-rxrna ) compounds selected for preclinical development RXI-762, sd-rxrna targeting PD-1 RXI-804, sd-rxrna targeting TIGIT Manufacturing facility selected to initiate production of cgmp grade material, initially for RXI-762 to support moving into clinical development in 12 to 18 months as part of an ACT therapy. 12
Reduction of PD-1 Expression in Human Primary T-cells Expression of PD-1 was Measured by FACS in Intact and Permeabilized Cells Extracellular extracellular PD-1 PD-1 RPMI 8000 ** ** ** Intracellular PD-1 intracellular PD-1 RPMI 20000 * ** 6000 15000 MFI 4000 MFI 10000 2000 5000 0 no beads no beads beads no sd-rxrna sdrna beads no sd-rxrna beads NT C1+2+3fm beads NTC beads PD78fm beads PD-1 beads NT C1+2+3fm beads NTC beads PD78fm beads PD-1 beads NT C1+2+3fm beads NTC beads PD78fm beads PD-1 0 no beads no beads beads no sdrna beads no sd-rxrna beads NT C1+2+3fm beads NTC beads PD78fm beads PD-1 beads NT C1+2+3fm beads NTC beads PD78fm beads PD-1 beads NT C1+2+3fm beads NTC beads PD78fm beads PD-1 0.50 µm u M 1 um µm 2 um µm 0.5 µm 0.5 0 µm u M 1 µm um 2 um µm 13
Meso-CAR T Construct for in vivo Studies Specific Tumor Cell Killing by Meso CAR T in vitro Mesothelin CAR Construct Construct is based on the 28z vector design seen in Carpentio, et. al. (PNAS 2009, 106:9, 3360-3365). Specific Tumor Cell Killing by Meso CAR T Measured by Impedance Assay E:T ratio of 5:1 14
Silencing by sd-rxrna: Long-Term Effect in vivo Reduced in vivo Tumor Growth Using CAR T-cells Treated ex vivo with PD1 targeting sd-rxrna Meso CAR T-cells 1 : T-cells engineered to target mesothelin, overexpressed on many solid tumors Meso CAR T-cells were pretreated with sd-rxrna ex vivo and injected into human ovarian cancer tumors in mice * Pvalue <0.01 (compared to PBS control arm) * Reduction of tumor growth is significantly improved by anti- PD1 sd-rxrna treatment at one month Anti-PD1 sd-rxrna Control 1 CAR T-cells = chimeric antigen receptor T-cells 15
sd-rxrna in Cell Therapy sd-rxrna Induced PD-1 Silencing Present After 1 Month in vivo Mouse xenograft model of ovarian cancer Tumors harvested after one month and human CD45-expressing cells were extracted and analyzed for PD-1 expression by flowcytometry sd-rxrna sd-rxrna 16
PD1 Silencing by sd-rxrna in TILs Enhances Killing of Autologous Tumor Cells In Vitro Tumor Infiltrating Lymphocytes (TILs) Against Melanoma TILs isolated from melanoma patient TILs treated with PD1 sd-rxrna in a clinically used Rapid Expansion Protocol (REP) 17 Tumor cell killing by TILs was measured by chromium release assay in vitro Control PD-1 2uM PD-1 5uM Anti-PD-1 mab 10ug/ml 17
PD-1 Silenced TILs Produce Higher Amount of IFN-γ During Co-Culture with Autologous Melanoma Tumor Cells Anti-PD-1 sd-rxrna Increases IFN-γ+TNF-α+ Tumor-Specific Cytotoxic T- cells During TIL Co-culture with Autologous Tumor Cells PD-1 Silenced TILs Produce More IFN-γ TIL + KADA 24 H Control no sd-rxrna Anti-PD-1 2 µm sd-rxrna 2 µm IFN -γ (p g/m l) 3000 2000 1000 TNF-α 0 no sdrna NTC1+2+3fm 2 um PD78fm 2 um no sdrna NTC1+2+3fm 2 um PD78fm 2 um n o s d R N A NTC1+2+3fm 2 um P D 7 8 fm 2 u M IFN-γ effector:target 20:1 effector:target 10:1 effector:target 5:1 18
Benefits of Using sd-rxrna in ACT sd-rxrna Gene Editing Antibodies No direct off-tumor side effects No persisting rogue cells in the body * Moderate cost of goods Targeting multiple checkpoints *Potentially further complicated by increased evidence of off-target mutations - Schaefer, K. A., Wu, W., Colgan, D.F., Tsang, S.H, Bassuk, A.G., & Mahajan, V.B. (2017). Unexpected mutations after CRISPR Cas9 editing in vivo. Nature Methods, 14, 547-548. doi: 10.1038/nmeth.4293 19
Additional Advantages with sd-rxrna in ACT Single Therapeutic Agent Single therapeutic agent with one or multiple immune checkpoints or differentiation targets attenuated Streamlined Regulatory Path Ex vivo application of sd-rxrna No multiple combination clinical trials required Newly discovered checkpoint targets or differentiation targets can be rapidly tackled Clinically proven safety of sd-rxrna Ease of Manufacturing Only small alterations needed in cell manufacturing process Facilitates adaptation of existing cell technologies 20
Summary of Immuno-oncology Franchise sd-rxrna for Cancer Therapeutics Best RNAi technology for ACT Can target multiple immunosuppression pathways in a single therapeutic entity Demonstrated efficient uptake of sd-rxrna to immune cells Silencing by sd-rxrna - long-term effect in vivo Clinically proven safety of sd-rxrna Ideal technology to affect cell differentiation during manufacturing Numerous ongoing collaborations evaluating hematopoietic stem cells, NK cells, TILS, CAR T, TCR and engineered NK cells RXI-762 and RXI-804 Solid Tumors sd-rxrna compounds targeting PD-1 and TIGIT respectively Established manufacturing of cgmp 21