Targeted Transient Ribosomal Inhibition (TTRI)

Summary: TTRI is a non systemic platform therapeutic that silences expression of every protein involved in the underlying etiology and pathology of a disease condition in a target tissue mass. Topical, Inhalable, or Transdermal delivery is used and the drug is retained where applied. The therapeutic effect is targeted Antiproliferative, Anti-Inflammatory, and Antiviral activity. Normal cells in the target tissue are not harmed when using Non-Ablative regimens, and Ablative regimens (prolonged, uninterrupted, IC100) can be used to achieve disease reversal (e.g. COPD, RA). NexGen believes TTRI will set an unbeatable potency standard versus single protein target technologies such as Antibody and RNAi. For example, topical TTRI will silence all ~100 viral and inflammatory proteins in a Herpes Lesion. Inhalable TTRI will silence all 10 influenza viral proteins and all related inflammatory proteins (cytokines and leukotrienes), preventing mortality from strains such as H5N1. TTRI will also set an unbeatable safety standard, as the targeted therapeutic doses used are thousand of times smaller than the systemic NOEL dose in humans . The technology is covered by 5 issued and 1 pending US patents.

Clinical Data Summary: The data is consistent with the known MOA of binding to the peptidyl transferase site on ribosomes and transiently interfering with translation of RNA into proteins (RNAi / PSR). Antiproliferative activity (not targeted) was characterized in 7 Phase II human clinical trials against cancer. The drug is a cytostatic requiring prolonged administration for ablative effect. Antiviral activity ( ex vivo, human cells, HSV): The drug inhibited de novo synthesis of all viral proteins and inhibited viral DNA synthesis as a secondary effect of protein synthesis inhibition (viral DNA polymerase synthesis inhibition). Anti-inflammatory activity: demonstrated in contact hypersensitive mice. Dermal PK ( topical application, human skin, ex vivo): 97% - 99% retained in the epidermis and dermis. Systemic safety (NOEL from Phase I human trials by IV): Targeted doses are thousands of times smaller than the systemic NOEL (no observable effect level).

Target Markets:

The Competition: TTRI is better suited for disease conditions involving synthesis of a broad spectrum of proteins, whereas traditional RNAi or Antibody technologies are better suited for disease conditions driven by a single protein. A brief background is necessary to understand the difference as well as to understand our IP strategy.

RNA function is summarized below. Drugs that interfere with or inhibit RNA interfere with or inhibit protein synthesis.

Synthesis of a single aberrant protein or overexpression of single normal protein results in certain disease conditions. Disease conditions can also involve hyperactive synthesis of a broad spectrum of proteins, such as happens with inflammation mediated cell hyperproliferation, viral infections with resulting inflammation, etc...

siRNA: siRNA uses Antisense technology to target a specific mRNA sequence and hence inhibit synthesis of a single protein. siRNA requires stabilization and delivery technologies, which are a major impediment to its commercialization.

TTRI: TTRI is better suited for disease conditions that involve synthesis of a large spectrum of proteins and TTRI does not require any stabilization or new delivery technology. TTRI does not require determining which proteins need to be silenced, as it silences them all. Drug concentration defines degree of Protein Synthesis Restriction (e.g. IC50, IC80, IC100). Side chain combinations define intracellular inactivation time, hence biological efficacy period, which can be from hours to days. The compound localizes where applied and its blood insolubility keeps it out of general circulation. It is ideally suited for topical, inhalable, and transdermal administration. Sustained IC100 for up to 3 days does not harm normal cells (non ablative regimens) and beyond that may be used to achieve a desired level of ablation (ablative regimens).

Patent Summary: The availability of 5 side chain sites makes innumerable synthetic variants possible, making composition of matter patents fairly meaningless from a protection standpoint. The issued method of use patents provide protection against the use of any natural or synthetic variant for the following indications:

Business Plan / Roadmap: The plan envisions clinical development of the existing compound (DAS), while simultaneously funding parallel development of synthetic variants to extend patent protection beyond the 2021 - 2029 expiry of the existing patents. The 4 Phase I human trials of DAS remove systemic safety as an issue. The initial focus is to obtain 20+ Phase II type data points per indication in a country that does not require a redo of Phase I for a change in route of administration, in order to eliminate any competitive efficacy risk.

Demonstrable Advantage: Non Ablative regimens (IC100, transient or sustained IC50, IC80 etc...) can be used to silence or attenuate expression of every protein involved in the underlying etiology and pathology of the selected indications, which would set an unbeatable potency standard against single protein target technologies such as RNAi or Antibody. Ablative regimens (prolonged, sustained IC100) would reverse certain disease conditions versus just inhibiting them (e.g. COPD, RA). Delivery of the drug only where needed, retention of the drug in the tissue to which it is applied without going systemic, and total doses used that are hundreds to hundreds of thousands of times smaller than the systemic NOEL dose, should set an exceptional safety standard.

Competitive Landscape: The current lack of fast, decisive efficacy makes many markets easy targets for TTRI. The competitive landscape, by indication, is provided below:




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DISCLAIMER AND IMPORTANT NOTICE: The Compositions and Methods presented on this website are all in preclinical stages. They are based only on our understanding of the proposed underlying mechanisms of action and on any available coincidental corroborative empirical evidence, any of which may in fact turn out not to be correct, or may be prevented from functioning as envisioned because of other factors or mechanisms of action not contemplated or considered, or may even cause harm because of factors or mechanisms of action not anticipated. The process of obtaining FDA approvals has not been started in any of the areas disclosed on this website. The disclosures here are purely for scientific information exchange purposes, representing one scientific point of view, and are not intended to suggest, or be used for, any proposed medical treatments.

© 2010 - 2011 Mark Zamoyski & NexGen Biomedical, Inc.