Adhera Therapeutics Inc. · OTC:ATRX
Adhera Therapeutics — Marina Biotech — Nucleic Acid Therapeutics and Rare Diseases Annual Meeting (September 2014)
32 slides from Adhera Therapeutics's conference presentation, Sep 19, 2014
Slide 1: Nucleic Acid Therapeutics and Rare Diseases Annual Meeting
Nucleic Acid Therapeutics and Rare Diseases Annual Meeting San Diego, CA 15 September 2014
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: 2012-2013 Achievements
2012-2013 Achievements » Advanced Clinical Pipeline » Completed Cohort 2 dosing in the dose escalating segment of Phase 1b Study » Validated Technologies Through the Following License Agreements: » SMARTICLES to Mirna Therapeutics for the development of microRNA-based therapeutics » SMARTICLES to Pr
Slide 4: Increase Efforts and Focus on Rare Disease Clinical Pipeline
Increase Efforts and Focus on Rare Disease Clinical Pipeline » Nucleic Acid Therapeutics Have Demonstrated Good Clinical Safety » Numerous constructs (siRNA, antisense, antagomirs, microRNA mimics, etc.) utilizing multiple mechanisms of action (RNAi, mRNA inhibition, exonskipping, steric blocking, m
Slide 5: Capability Comparison (FTO Against Competition)
Capability Comparison (FTO Against Competition) Nucleic Acid Constructs Delivery siRNA ASO MicroRNA mimics Antagomirs Lipid Polymer Peptide Bacterial Marina X X X X X X X Alnylam X X X Arrowhead X X X Dicerna X X Rxi X X Silence X X Tekmira X X Isis X Prosensa X Sarepta X Regulus X X Santaris X Phas
Slide 6: Biochemistry Technologies
Biochemistry Technologies » Unlocked nucleobase monomers (UNA) – non-nucleotide, acyclic monomers 6 » Conformationally restricted nucleotides (CRN) – nucleotide analogs with a “bridge” connecting the C2’ and C4’ carbons of ribose RNA CRN LNA
Slide 7: Delivery Technologies
Delivery Technologies » SMARTICLES – Amphoteric liposomes composed of unique combinations of anionic and cationic lipids which enable cell uptake and pH-triggered endosomal escape » DiLA2 – Liposomes composed of unique combinations of head groups, linkers and alkyl chains where the head group is an
Slide 8: Delivery Capability Is Unparalleled Within the Sector
Delivery Capability Is Unparalleled Within the Sector » Two separate and distinct delivery technologies in clinical development » SMARTICLES (lipid nanoparticle) » tkRNAi (engineered, non-pathogenic bacteria) » Most versatile delivery technology (SMARTICLES) in clinical development » Delivering both
Slide 9: SMARTICLES Clinical Status
SMARTICLES Clinical Status » ProNAi Therapeutics (PNT2258) – Advanced Solid Tumors & Lymphomas » Phase 1 Completed in November 2012 » 30 patients (dose range 1-150 mg/m2); (J Clin Oncol 30, 2012 (suppl; abstr TPS3110)) » Reported interim Phase 2 data at American Society of Hematology in December 201
Slide 10: SMARTICLES Potential Mechanisms of Delivery
SMARTICLES Potential Mechanisms of Delivery » Exosomal repackaging (Cell-to-Cell Communication): » SMARTICLES may promote cellular repackaging of oligonucleotides into exosomes providing sustained functional delivery to certain vascularized tissues » Payload “tells” exosome what tissue to target 10
Slide 11: Broad, Young and Issuing Intellectual Property Estate
Broad, Young and Issuing Intellectual Property Estate Technology US Issued Foreign Issued Worldwide Pending Biochemistry Unlocked Nucleobase Monomers (UNA) 1 5 23 Conformationally Restricted Nucleotides (CRN) 5 -- 10 Delivery Liposome Systems 12 53 43 Liposome Manufacturing Methods -- 2 20 Bacterial
Slide 12: Ability to Utilize Multiple Mechanisms of Action to Achieve Therapeutic Effect
Ability to Utilize Multiple Mechanisms of Action to Achieve Therapeutic Effect Chemistry Delivery UNA CRN SMARTICLES DiLA2 Lipopeptide tkRNAi TrpCage RNAi X X X X X X X mRNA Translational Inhibition X X X X X X Exon Skipping X X X X X Alternative Splicing X X X X Steric Blocking X X microRNA replace
Slide 13: Strategic Alliances
Strategic Alliances » Nitto Denko Avecia – CRN Chemistry » Avecia: » Process development for CRN synthesis » CRN “reagent” sales to academic and research laboratories » CRN GLP manufacturing » Marina: » Dedicated research and manufacturing (i.e. off Marina’s bench) » Rosetta Genomics – microRNA Targ
Slide 14: Rare Disease Drug Development
Rare Disease Drug Development
Slide 15: Familial Adenomatous Polyposis (FAP)
Familial Adenomatous Polyposis (FAP) » Rare hereditary disease » Mutation in Adenomatous Polyposis Coli (APC) gene » Causes dysregulation and accumulation of β-catenin » Results in numerous colon polyps appearing in early adolescence with potential for rapid disease progression » Clinical drug produ
Slide 16: TransKingdom RNAi (tkRNAi)
TransKingdom RNAi (tk RNAi™) Compound is taken orally by the patient Invasin receptor Invasin Receptor-mediated cell entry Bacterial lysis in endosome Endosome lysis and shRNA release into cytoplasm to Dicer for processing shRNA ONLY orally available RNAi clinical candidate
Slide 17: FAP Clinical/Regulatory Strategy
FAP Clinical/Regulatory Strategy » Accelerated Clinical Development Plan » Approval on single pivotal trial – ~60 patients treated for six months » Based on Pfizer’s Celecoxib accelerated FDA approval » Double-blind, placebo controlled, randomized, multi-center, parallel group study of single daily
Slide 18: FAP Value Drivers
FAP Value Drivers » Near Term » 4Q 2014 – Complete Cohort 1 and 2 sample analysis » 1Q 2015 – Dose Cohort 3 patients » 3Q 2015 – Complete Escalating Dose Phase » Notable Mid- to Long-Term » 1H 2016 – Submit "Breakthrough Therapy“ and complete Stable Dose Phase » 2H 2016 – Initiate Pivotal Phase 2 an
Slide 19: Myotonic Dystrophy Type 1 – A Muscle Disease with Systemic Effects
Myotonic Dystrophy Type 1 (DM1) – A Muscle Disease with Systemic Effects » Myotonia » Skeletal muscle wasting » Cardiac arrythmias » Smooth muscle dysfunction » Radial cataracts » Cognitive dysfunction • Weakness and wasting of voluntary muscles in the face, neck and lower arms and legs • Muscles be
Slide 20: DM1 - Devastating Impact on Entire Families
DM1 - Devastating Impact on Entire Families » Myotonic Dystrophy type 1 (DM1) accounts for >95% cases » Expansion of CTG repeats in 3’ UTR of the DMPK (dystrophia myotonicaprotein kinase) gene » Severity of disease can be progressive within families
Slide 21: Nucleic Acid-based Strategies for Therapeutic Intervention
Nucleic Acid-based Strategies for Therapeutic Intervention Accumulation of altered DMPK mRNA in nucleus sequesters Muscleblind (MBNL1) protein resulting in loss-of-function » Displace/Disrupt the MNBL-CUGn+x interaction » (CAG) oligonucleotide to compete with MNBL1 » Cleave nuclear DMPK mRNA » Initi
Slide 22: Matching the Nucleic Acid Construct to the Most Effective Mechanism of Action
Matching the Nucleic Acid Construct to the Most Effective Mechanism of Action RNAi-dependent Translational Blocker DMPK mRNA to increase degradation and elimination Targeting the CUG-repeat for degradation/elimination or compete with proteins for binding sites Targeting intron-exon splice to bias fo
Slide 23: mRNA Translational Inhibition: Dose-response for CRN- and LNA-Substituted Oligo
mRNA Translational Inhibition: Dose-response for CRN- and LNA-Substituted Oligo1 LNA-substituted Translational Block Oligo CRN-substituted Translational Block Oligo 1Data produced by undisclosed academic laboratory In vitro Myotonic Dystrophy assay measuring CUG repeat blocking (lower % is better)
Slide 24: DM1 Pre-clinical/Clinical Strategy
DM1 Pre-clinical/Clinical Strategy » Efficacy Studies » Tolerability and efficacy in transgenic mouse model of DM1 » mRNA expression/protein conformation and function » Muscle cell histopathology/immunohistochemistry » Physiological signs (muscle strength, gait, etc.) » Safety Studies » Standard in
Slide 25: Duchenne Muscular Dystrophy (DMD)
Duchenne Muscular Dystrophy (DMD) » Muscle weakness can begin as early as age 3 » First affecting the muscles of the hips, pelvic area, thighs and shoulders » Later affecting skeletal (voluntary) muscles in the arms, legs and trunk » By the early teens, heart and respiratory muscles also are affecte
Slide 26: Nucleic Acid-based Strategy – Exon Skipping
Nucleic Acid-based Strategy for Therapeutic Intervention – Exon Skipping 26 » “Exon Skipping” restores a functional form of the dystrophin protein and improves muscle cell survival Modified Full disease Profile disease profile Images adapted from Aartsma-Rus and Van Ommen, RNA (2007), 13:1609–1624.
Slide 27: DMD Competitive Landscape
DMD Competitive Landscape » In Development » Sarepta and Prosensa oligonucleotides » Exon skipping » Sarepta’s eteplirsen: AVI 4658 skipping exon 51 » Prosensa’s drisapersen: PRO 051 skipping exon 51 » Announced that NDAs would be filed prior to end of 2014 » Exon 51 mutation represents ~15% of pati
Slide 28: DMD Strategy
DMD Strategy » Monitor DMD sector progress while conducting research in DM1 » DM1 in vivo POC will demonstrate potential effectiveness of SMARTICLES delivery technology to muscle, etc. » FDA expected to respond to NDA applications by 1Q 2015 » Develop construct targeting Exon 51 skipping » Propriety
Slide 29: DMD Pre-clinical/Clinical Strategy
DMD Pre-clinical/Clinical Strategy » Efficacy Studies » Tolerability and efficacy in transgenic mouse model of DMD » mRNA expression/protein conformation and function » Muscle cell histopathology/immunohistochemistry » Physiological signs (muscle strength, gait, etc.) » Safety Studies » Standard in
Slide 30: DM1 and DMD Value Drivers
DM1 and DMD Value Drivers » Near Term » 4Q 2014 – Demonstrate in vivo proof-of-concept » 2Q 2015 – Lead identification and selection » Notable Mid- to Long-Term » DM1: » 1H 2016 – File IND, submit Orphan Drug application and initiate Phase 1 » 2017 – Submit “Breakthrough Therapy” » 2018 – Initiate P
Slide 31: Partnering Goals
Partnering Goals » Rare Disease “Fast Follower” (i.e. ALS, Cystic Fibrosis, Hemophilia, Spinal Muscular Atrophy) Research Collaboration » Marina: » Identify novel nucleic acid compounds » Conducts in vitro as well as in vivo safety, tolerability and, possibly, efficacy studies » Partner » Conducts i
Slide 32: Thank You
Thank You OT
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