Adhera Therapeutics Inc. · OTC:ATRX
Adhera Therapeutics — Marina Biotech — Shareholder Meeting (July 2011)
36 slides from Adhera Therapeutics's shareholder meeting presentation, Jul 18, 2011
Slide 1: Annual Shareholders Meeting Company Update
Exhibit 99.2 Annual Shareholders Meeting Company Update 14 July 2011
Slide 2: Forward Looking Statement
Forward Looking Statement Statements made in this presentation may be forward-looking statements within the meaning of Federal Securities laws that are subject to certain risks and uncertainties and involve factors that may cause actual results to differ materially from those projected or suggested.
Slide 3: Broad Nucleic Acid-Based Platform Provides a Superior Drug Discovery Engine
Broad Nucleic Acid-Based Platform Provides a Superior Drug Discovery Engine Appropriate therapeutic approach to targets not typically suited to small molecule or monoclonal antibody therapeutics Capitalizes on distinct endogenous intracellular processes for protein down-regulation Allows for a scien
Slide 4: Pfizer and Nucleic Acid-based Therapeutics
Pfizer and Nucleic Acid-based Therapeutics Tacere shRNA (TT-033): Three separate, expressed RNAi elements targeting the conserved regions of the Hepatitis C virus entrapped in an AAV protein coat $145 MM deal (upfront and milestone payments have been made through Feb 2010) Quark siRNA (PF-04523655):
Slide 5: Nucleic Acid Therapeutic "Toolbox"
Nucleic Acid Therapeutic “Toolbox” Chemistries Constructs UNA – Non-nucleotide acyclic Dicer length siRNA monomers – greater flexibility RISC length siRNA CRN – nucleotide analogs with a microRNA mimetics linker connecting the C2’ and C4’ microRNA antagonists miniRNAs Single-stranded RNA/DNA Deliver
Slide 6: Critical Needs for a Broad Nucleic Acid-Based Therapeutics Discovery Engine
Critical Needs for a Broad Nucleic Acid- Based Therapeutics Discovery Engine Multiple chemistries to construct single and double-stranded oligonucleotides with suitable affinity, stability and minimization of off- target activity Unlocked Nucleotide Analogs (UNA) Conformationally Restricted Nucleoti
Slide 7: Marina Biotech's Nucleic Acid-based Therapeutic Platform
Marina Biotech’s Nucleic Acid-based Therapeutic Platform “undruggable target” for a specific indication Molecular Target mRNA microRNA dsRNA ssRNA/DNA mimetic antagomir Plasmid + UNA + CRN/RNA UNA/CRN CRN/RNA bacteria delivery CRN/RNA CRN/RNA + delivery + delivery + delivery Oral Local/Systemic tkRN
Slide 8: Selection of a Nucleic Acid-based Therapeutic Approach
Selection of a Nucleic Acid-based Therapeutic Approach Target, indication and patient phenotype determine the most appropriate combination of technologies and thus the specific nucleic acid-based modality(ies) to pursue in preclinical proof-of-concept Determine target and intended biology Specific m
Slide 9: transKingdom RNAi Platform
transKingdom RNAi Platform “undruggable target” for a specific indication Molecular Target mRNA microRNA (protein) dsRNA ssDNA/RNA mimetic antagomir Plasmid + UNA + CRN-RNA UNA/CRN CRN-RNA CRN-RNA CRN/RNA bacteria delivery + delivery + delivery + delivery Oral Local/Systemic tk RNAi 9
Slide 10: About transKingdom RNA interference (tkRNAi)
About transKingdom RNA interference (tkRNAi™) Non-pathogenic bacteria engineered to produce, deliver and release interfering RNA mediators (shRNA) to targeted tissue Efficient delivery to the epithelium of the gastrointestinal tract via oral administration Safe and well tolerated daily dosing of up
Slide 11: Familial Adenomatous Polyposis (FAP)
Familial Adenomatous Polyposis (FAP) Rare hereditary disease Mutation in Adenomatous Polyposis Coli (APC) gene Causes dysregulation and accumulation of -catenin Results in numerous colon polyps appearing in early adolescence with potential for rapid disease progression Clinical drug product, CEQ508,
Slide 12: Actual and Potential Clinical, Regulatory and Commercial Timelines
Actual and Potential Clinical, Regulatory and Commercial Timelines December 2009 – IND granted in U.S. September 2010 – Patent grant in the EP protecting tkRNAi December 2010 – Received FDA Orphan Drug Designation January 2011 – Completed LTT study in Non-Human Primates June 2011 – Completed dosing
Slide 13: tau RNAi Platform
tau RNAi Platform “undruggable target” for a specific indication Molecular Target mRNA microRNA dsRNA ssDNA/RNA mimetic antagomir Plasmid + UNA + CRN/RNA UNA/CRN CRN/RNA CRN/RNA CRN/RNA bacteria delivery + delivery + delivery + delivery Oral Local/Systemic tau RNAi 13
Slide 14: About tauRNA interference (tauRNAi)
About tauRNA interference (tauRNAi) Combination of highly active UsiRNA constructs and liposomal delivery systems UsiRNA – Substitution of unlocked nucleobase analogs (UNA) within siRNA; therapeutic use proprietary to Marina Biotech 2 DiLA - Di-Alkylated Amino Acids for liposomal-based delivery; nov
Slide 15: Publications on UsiRNAs and Systemic and Local Delivery with DiLA2
Publications on UsiRNAs and Systemic and Local Delivery with DiLA2 Nucleic Acids Res. 2011 Mar 1;39(5):1823-32. Improved specificity of gene silencing by siRNAs containing unlocked nucleobase analogs. Vaish N, Chen F, Seth S, Fosnaugh K, Liu Y, Adami R, Brown T, Chen Y, Harvie P, Johns R, Severson G
Slide 16: Marina Biotech/Debiopharm: Bladder Cancer R&D Collaboration
Marina Biotech/Debiopharm: Bladder Cancer R&D Collaboration Exclusive agreement for the research, development and commercialization of Marina Biotech’s pre-clinical program in bladder cancer First agreement to license an RNAi-based therapeutic, delivered with a lipid- or liposomal-based formulation,
Slide 17: ssDNA/RNA Technology
ssDNA/RNA Technology “undruggable target” for a specific indication Molecular Target mRNA microRNA dsRNA ssDNA/RNA mimetic antagomir Plasmid + UNA + CRN/RNA UNA/CRN CRN/RNA CRN/RNA CRN/RNA bacteria delivery + delivery + delivery + delivery Oral Local/Systemic chi RDNA/chi RDNA+ 17
Slide 18: Conformationally Restricted Nucleotides (CRN)
Conformationally Restricted Nucleotides (CRN) CRNs are nucleotide analogs with a linker connecting the C2’ and C4’ carbons of ribose CRN and LNA lock the ribose ring into a stable conformation and increase the hybridization affinity to the mRNA or microRNA target Distinguished from LNA by a longer l
Slide 19: CRN-Substitution Results in Less Ribose Ring Puckering
CRN-Substitution Results in Less Ribose Ring Puckering CRNs are distinguished by a linker whose length results in less ribose ring puckering Conformation of CRN more closely resembles that found in RNA CRN Puckering of the ribose ring at the 2’ carbon LNA 19
Slide 20: Less Ribose Ring Puckering May Result in Lower Structural Distortion
Less Ribose Ring Puckering May Result in Lower Structural Distortion CRN substitution within an oligo may result in lower structural distortion when hybridized to a complementary mRNA Distortion of Duplex Structure The rigid structure imparted by multiple LNA substitutions “stretches” the duplex CRN
Slide 21: Therapeutic Approaches Using CRN Technology
Therapeutic Approaches Using CRN Technology mRNA Translational Blockers Substitute CRN at ends of DNA-RNA hybrid compounds thus preserving DNA in the interior and allowing interaction with RNAse H microRNA Antagonists Substitute CRN throughout strand to maximize hybridization affinity Additional mod
Slide 22: Advantages of CRN Technology
Advantages of CRN Technology Increased affinity with CRN substitution maintains structural orientation thus allowing for variable lengths Standard 19- to 22-mers Greater number of substitutions in 14- to 16-mers Fully substituted 7- to 9-mers targeting microRNA seed region Delivery can be achieved w
Slide 23: CRN-Related Therapeutic Modalities
CRN-Related Therapeutic Modalities Aptamers Therapeutics Diagnostics Delivery/cell surface ligands Exon skipping oligonucleotide Minor/Major Groove Binders/Triplex forming oligonucleotides Ribozymes Splice junction inhibitors Steric blockers tRNA/tRNA suppressors bridge (adapter molecule) between th
Slide 24: Other Uses for CRN technology
Other Uses for CRN technology Primer/Probes for PCR qRT-PCR 5’ and 3’ RACE Single, multiplex and allele specific PCR Capture Probes In situ hybridization/Fluorescence in situ hybridization SNP genotyping Expression analysis Monitor/identify exon skipping Monitor/identify splice variants Research/Dia
Slide 25: microRNA (miRNA) Technology
microRNA (miRNA) Technology “undruggable target” for a specific indication mRNA microRNA dsRNA ssDNA/RNA mimetic antagomir Plasmid + UNA + CRN-RNA UNA/CRN CRN-RNA CRN-RNA CRN/RNA bacteria delivery + Delivery + delivery + delivery Oral Local/Systemic 25
Slide 26: microRNA Mimetic Approach
microRNA Mimetic Approach “undruggable target” for a specific indication Molecular Target mRNA microRNA dsRNA ssDNA/RNA mimetic antagomir Plasmid + UNA + CRN-RNA UNA/CRN CRN-RNA CRN-RNA CRN-RNA bacteria delivery + delivery + delivery + delivery Oral Local/Systemic mu RNA+ 26
Slide 27: microRNA Mimetic using UNA & CRN
microRNA Mimetic using UNA & CRN MicroRNA mimetic - dsRNA Substitute with UNA and CRN = CRN = UNA UNA – increase nuclease resistance and decrease cytokine induction; inhibition of passenger strand activity CRN – increase hybridization affinity; nuclease resistance Additional modifications (e.g., 2’O
Slide 28: Delivery of a miR-34 Mimetic in a Smarticles Formulation Inhibits Tumor Growth
Delivery of a miR-34 Mimetic in a Smarticles Formulation Inhibits Tumor Growth Inhibition of Liver Cancer Biomarker Inhibition of Tumor Growth Alpha Feto Protein Levels Tumor Weight (g) miR-NC miR-34 Untreat. Cont. miR-NC miR-34 Smarticles formulation provided effective delivery to orthotopic liver
Slide 29: mu RNA/ mu RNA+
“undruggable target” for a specific indication Molecular Target mRNA microRNA dsRNA ssDNA/RNA mimetic antagomir Plasmid + UNA + CRN-RNA UNA/CRN CRN-RNA CRN-RNA CRN/RNA bacteria delivery + delivery + delivery + delivery Oral Local/Systemic mu RNA/ mu RNA+ 29
Slide 30: microRNA Antagonist using CRN
microRNA Antagonist using CRN MicroRNA antagonists (Antimir) therapeutics Substitute CRN throughout the strand to maximize the hybridization affinity between antimir and the target microRNA Allows for use of shorter length sequences = CRN Additional modifications (e.g., phosphorothioate and 2’O-meth
Slide 31: CRNs Increase Antimir Activity
CRNs Increase Antimir Activity % Luciferase (Renilla) Activity Remaining Construct 0% 20% 40% 60% 80% 100% 5 nM miR-21 25 nM Antimir-21 5 nM Unmodified 25 nM Antimir-21 5 nM (CRN) 25 nM Antimir-21 5 nM (LNA) 25 nM Dual luciferase assay; Average of triplicate; HeLa cells co-transfected with psiCHECK2
Slide 32: CRNs Increase Antimir Potency
CRNs Increase Antimir Potency CRN-substituted Antimir LNA-substituted Antimir Unmodified Antimir 50% Inhibition Antimir Conc. (nM) Dual luciferase assay; HeLa cells co-transfected with psiCHECK2-miR21plasmid; Unmodified Antimir all RNA; CRN-substituted Antimir has DNA and P=S backbone CRN-substitute
Slide 33: Marina Biotech's Nucleic Acid-based Therapeutic Platform
Marina Biotech’s Nucleic Acid-based Therapeutic Platform “undruggable target” for a specific indication Molecular Target mRNA microRNA dsRNA ssRNA/DNA mimetic antagomir Plasmid + UNA + CRN/RNA UNA/CRN CRN/RNA CRN/RNA CRN/RNA bacteria delivery + delivery + delivery + delivery Oral Local/Systemic tk R
Slide 34: Resourcing a Broad Discovery Engine
Resourcing a Broad Discovery Engine tk RNAi – Funded by Marina Biotech Includes funding CEQ508 Phase 1b/2a Trial tau RNAi – Funded by outside sources siRNA in liposomal delivery for local administration funded by Debiopharm (Marina Biotech UsiRNA and liposomal delivery) chi RDNA/chi RDNA+ – Funded b
Slide 35: 2010-2011 Achievements
2010-2011 Achievements Initiated patient dosing in an FAP Phase 1b/2a Clinical Trial and completed dosing the first cohort Established first ever partnership around a liposomal delivered RNAi compound with Debiopharm for the development and commercialization a bladder cancer therapeutic Established
Slide 36: Thank You
“SS)MARINA BIOTECH