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RXi Pharmaceuticals’ sd-rxRNA: Better delivery than Amazon!



RXi Pharmaceuticals Corporation (NASDAQ:RXII) is a unique player in the RNAi space due to the inherent self-delivery mechanism that efficiently distributes its interference RNA to the cell.  The company was founded by a group of scientists including Nobel Prize Winner Craig Mello and is currently developing a broad range of compounds for indications that leverage its sd-rxRNA technology.  The company has seven compounds in its pipeline, six of which are in the sd-rxRNA class, ranging in development from preclinical to Phase II clinical trials.  

When initially developed, RXi’s flexible sd-rxRNA platform faced a broad menu of indications to pursue.  Given a variety of capital and other constraints, management selected indications primarily based on their phenotypic result so the effectiveness of the technology could be readily observed.  As a result, dermal and retinal scarring indications were selected for development.  Despite initial work launched in cosmetic conditions, the opportunity for the RXi platform can extend into the most pervasive, life threatening and challenging disease states due to the flexibility of RXi’s self-delivering gene silencing technology.  With both the opportunity for sd-rxRNA and capital limitations in mind RXi sublicensed its technology to several partners in order to expand its reach.  These agreements included licensing arrangements with MirImmune, Inc. to develop ex-vivo cell-based cancer immunotherapies and Thera Neuropharma, Inc. to develop therapeutics targeting the SOD1 gene for neurodegenerative diseases.  


Self-delivering interference RNA (sd-rxRNA in the company’s nomenclature) is RXi Pharmaceutical’s key technology platform and it combines the features of interference RNA with RXi’s self-delivery modifications to silence aberrant genes and impact target protein production to cure disease.  

RNA interference (RNAi) (also known as post-transcriptional gene silencing) is a method of disrupting a strand of mRNA that codes for an unwanted protein.  More specifically, the RNAi process evolved to disrupt parasitic and exogenous pathogenic nucleic acids and regulate the expression of protein-coding genes.   The RNAi mechanism can be harnessed to potentially treat viral infection, dominant disorders, neurological disorders, and many types of cancers.  RNAi is triggered by double-stranded RNA (dsRNA) which is divided into fragments that can bind to messenger RNA (mRNA) that is exported from the nucleus in order to code for a protein.  The fragment of dsRNA (also called small interfering RNA, or siRNA) is loaded onto a protein complex called the RNA-induced silencing complex (RISC).  The siRNA is unwound and one strand, the guide strand, is hybridized with the specific mRNA according to base pair rules.  Then, with the help of the Argonaute protein, the mRNA is cleaved and degraded and translation of the mRNA is inhibited.  

The flexibility of the approach provides immense potential to develop therapies for treatment of viral infection, brain disorders, cancer, hepatitis and other diseases including RXi’s clinical portfolio of indications in scarring and pigmentation.  RNAi has many advantages compared to other therapeutic approaches given its high degree of efficiency and specificity.  The approach selectively targets and silences specific genes and is able to perform this function over the long term.

RXi Pharmaceuticals Self-Delivering Technology – sd-rxRNA

Classical siRNAs that are used in therapeutic applications do not readily cross the cellular membrane because of their negative charge and size.  Cellular delivery of chemically synthesized or in vitro transcribed siRNAs is usually achieved via lipids, electroporation or other methods.  The disadvantage of lipid based delivery schemes in vivo is the rapid liver clearance and lack of target tissue specificity and toxicity observed with some formulations.  Electroporation can damage cells and unintentionally allow material in and out of the cell.  Below we list a summary of some key in vitro transfection methods as highlighted in an article by Dharmacon:

To overcome the disadvantages with other delivery mechanisms, RXi developed its sd-rxRNA technology that combines the benefits of conventional RNAi and antisense.  Single stranded antisense compounds have characteristics that allow for favorable tissue distribution and cellular uptake.  When features such as a single-stranded phosphorothioate region, a short duplex region and the addition of nuclease-stabilizing and lipophilic chemical modifications, are incorporated into RNAi compounds they are able to achieve efficient spontaneous cellular uptake and powerful, durable intracellular silencing activity.  Based on data generated by RXi Pharmaceuticals, sd-rxRNA may be efficiently taken up into any tissue that is accessible through local administration.  This hybrid oligonucleotide compound is called sd-rxRNA.

RXi’s approach has several benefits compared to existing technologies: 

➢ Combination of antisense and RNAi features allow for efficient cellular uptake without a delivery vehicle; 
➢ Cellular uptake in primary, neuronal and non-adherent cell types; 
➢ Readily manufactured;
➢ Specificity to the target gene;
➢ More reliable at blocking immune side effects than classic siRNA; and 
➢ Ability to target genes of interest individually or in combination 
o For example, in ex-vivo settings, pre-treatment with sd-rxRNA allows for multiple immune checkpoints to be silenced in immune effector cells.

RNAi Clinical Trials

RXi currently has its lead candidate, RXI-109 in two clinical trials for scarring indications.  The most advanced study is in its second Phase II trial for hypertrophic dermal scarring and was launched in July 2014.  The second study is for retinal scarring as a result of “wet” age-related macular degeneration which is in a Phase I/II trial initiated in November 2015.  

RXI-109 is an sd-rxRNA that is designed to reduce the expression of connective tissue growth factor (CTGF), which has important roles in healing, but also may cause fibrotic diseases, including scar formation and cancer.  The compound has undergone several trials for dermal scarring including two Phase I and three Phase II evaluations.  During the progress of the Phase II trials, RXi refined the dose frequency resulting in less noticeable scars following elective scar revision surgery.  A complete read out of the Phase II results are expected in the second half of 2017.  As there are no competing therapies for the prevention of scars in the human skin, FDA approval of RXI-109 would provide a solution for an unmet medical need in dermal scarring and serve a potentially large market.

RXI-109 is also able to target CTGF in retinal tissue.  Based on successful preclinical work, an investigational new drug application was filed with the FDA in July 2015, which was followed several months later by the launch of the Phase I/II trial to examine the impact of the drug on subretinal fibrosis.  The intravitreal injections of RXI-109 are given in one eye in four monthly doses, followed by a 3-month observation period.   Currently, RXi expects that the last patient will complete the study before the end of 2017 and study results will be available by early 2018.


Due to capital limitations, RXi initially sublicensed its sd-rxRNA to partners in order to accelerate the pace of development for this flexible technology.  One of the company’s partners made substantial progress in cancer indications silencing immunosuppressive targets in T-cells.  One of the ways cancer is able to survive and proliferate is by hiding from T-cells through the use of immune checkpoints.  The greater the number of immune checkpoint receptors on a T-cell, the more easily cancer cells can cloak themselves from the immune system.  MirImmune had been successful in identifying sd-rxRNA compounds that target six different checkpoints including PD-1 and CTLA-4.  Using in-vitro and in-vivo murine models of human melanoma and ovarian cancer, MirImmune demonstrated that inhibition of PD-1 with sd-rxRNA in T-cells resulted in improved cytotoxicity against cancer cells.  This approach is particularly amenable to many of the ex-vivo¬ processes used in adoptive cell transfer, including Chimeric Antigen Receptor (CAR)-T therapy where cells are taken from the patient, modified and then returned to the patient, enhanced and primed to fight the tumor.  sd-rxRNA can reduce or eliminate the expression of immunosuppressive receptors on the T-cells, thereby increasing their effectiveness.  

The self-delivering technology also boasts superior transfection as compared to other methods, which is extremely important as there are a finite number of cells that are taken from the patient.  This is shown in efficiency of cellular uptake, where near 100% success is achieved as shown on the left (below).  It is also evident in terms of cell viability, where silencing is observed at concentrations of 0.03 to 1 µM over 90% of cells remain viable.This compares to electroporation, where efficiency is from 70% to 80% and viability is from 50% to 60%.

Based on the strength of this progress, RXi acquired MirImmune and has put in place a plan to further develop their efforts.  The current short-term milestones for the immuno-oncology program include:

1) Targeting cell differentiation genes with sd-rxRNA to optimize the population of immune effector cells with the goal of improving persistence and tumor efficacy for adoptive cell therapy; 
2) Release data on multiple checkpoint inhibiting sd-rxRNA compounds co-transfected in CAR T-cells in mouse models for solid tumors; and
3) Share preclinical results on use of sd-rxRNA with tumor infiltrating lymphocytes in melanoma.


RXi Pharmaceuticals has developed a unique and powerful platform that leverages the power of RNA interference with a self-delivery mechanism that is efficient and effective.  The company has a robust development pipeline with two clinical stage candidates utilizing its sd-rxRNA technology and a pre-clinical portfolio that holds promise to revolutionize CAR-T and other ex-vivo adoptive cell transfer therapies.  The company expects to announce data from its clinical trials later this year and in early 2018, which may provide a catalyst to bring greater attention to the company’s successes and help further develop RXI-109 in scarring and further advance the work the company is doing in cancer indications. 

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