Despite advances in adapting its Smarticle delivery technology for use with siRNAs, Novosom has opted to focus its in-house drug-development efforts on antisense therapeutics, a senior company official told RNAi News this week.
While the development of siRNA-based drugs “is something we’d like to do with our partners,” Novosom CEO Elias Papatheodorou told RNAi News this week, “we don’t have any current plans to move ahead with siRNA drugs ourselves.”
Antisense “may be a safer choice for a small biotech right now. If we were a big pharmaceutical or biotechnology company, our strategy might have been different.”
RNAi as a therapeutic modality is promising, he said, but antisense-based drugs have been evaluated in a clinical setting far more than any other type of oligonucleotide drug. Given that Novosom intends to focus its pipeline on chronic diseases, antisense “may be a safer choice for a small biotech right now.
“If we were a big pharmaceutical or biotechnology company, our strategy might have been different,” Papatheodorou added.
To be sure, Novosom continues to collaborate with a number of undisclosed companies using the Smarticle technology to develop siRNA drugs, and the firm remains on the lookout for additional collaborators.
And although Papatheodorou said that therapeutic RNAi would not be something Novosom would pursue on its own, at least in the near term, he left open the option of striking a drug co-development arrangement around the gene-silencing technology — but with the right partner.
“Different partners have different access to RNAi” intellectual property, he said. “I think that a co-development deal would make sense with partners that have wider [freedom to operate in] the RNAi space [beyond just] a product-specific” IP license.
But for now, Novosom is keeping its attention on its first in-house drug program: an antisense inhibitor of CD40, a cell surface receptor and member of the tumor necrosis factor receptor family, as a treatment for autoimmune-based inflammatory diseases.
Earlier this year, Novosom announced that it had acquired from Isis Pharmaceuticals an exclusive, worldwide license to certain antisense inhibitors of CD40 mRNA in “a number of indications,” and a non-exclusive license to “certain aspects” of “core technology” patents, including IP covering 2' MOE oligonucleotides.
In exchange, Isis received an upfront fee and stands to be paid milestones and royalties.
According to Papatheodorou, Novosom has not yet decided what specific indications it will pursue in its CD40 program. However, the company has found that in an animal model of rheumatoid arthritis, CD40-targeting antisense oligos delivered using the Smarticle technology achieved greater and longer-lasting efficacy than Johnson & Johnson’s blockbuster RA drug Remicade. The drug, a monoclonal antibody targeting TNF-alpha, is also approved in the US and Europe for psoriasis and Crohn’s disease.
As a result, “we definitely think the diseases Remicade has been very successful in … are diseases that we should go after,” he said, noting that Novosom has also had some success with using CD40-targeting antisense molecules in an animal model of irritable bowel disease.
RA and IBD “are the two indications that we would like to focus on, at least in the first stage,” Papatheodorou added. “But we are also investigating a couple of niche indications that might provide a faster path to market.” He did not elaborate.
Aside from the market opportunities for inflammatory diseases, Novosom’s decision to go after such conditions is a result of how its core delivery technology works.
Smarticles are fully charge-reversible liposome particles, which Papatheodorou said allows them to be both safe and effective in delivering a therapeutic payload.
In the field of liposomal delivery, “you have anionic constructs or cationic constructs,” he said. Although anionic constructs are safe in the bloodstream, they are difficult to load with an oligo because of a lack of electrostatic interaction. Cationic lipids, meantime, are easily loaded but tend to be toxic.
To address this, Novosom developed so-called “amphoteric” constructs — Smarticles — that are initially cationic to enable oligo loading. Once the particle completely encapsulates the oligo payload, a feature designed to prevent immunostimulation, “we raise the pH so the particle becomes anionic,” Papatheodorou said.
This, according to Novosom, “guarantees stable and aggregate-free travel within the bloodstream” following intravenous administration of the particles. However, after the Smarticles cross the cell membrane, the acidification from endocytosis neutralizes their charge, which activates their fusion machinery to enable escape of the oligo cargo from the endosome.
“The classical biodistribution of an anionic construct would be liver, spleen, site of inflammation, and tumors” because those four places are where the vasculature is permeable enough to allow particles in the bloodstream to escape, Papatheodorou said. “And that kind of biodistribution is very suitable for inflammatory diseases.”
In rodent studies, Smarticles have been shown to have no acute toxicity up to 300 milligrams per kilogram. Papatheodorou added that the particles also appear safe in non-human primate tests conducted by partner ProNAi Therapeutics, which was recently cleared by US regulators to begin testing a nucleic acid-based drug that incorporates the Smarticle technology in humans.
Despite the promise of the Smarticle technology for RNAi, antisense, and other nucleic acid-based drugs, Papatheodorou said that he ultimately sees the technology’s use extending into a variety of therapeutic fields.
“One of the great revolutions will be using the advanced delivery systems people are trying to develop in areas outside of RNAi,” he said. “At the end of the day, what we’re going to be creating, as a delivery industry for RNAi, are systems that have very specific biodistribution, very specific cellular uptake … [and] an escape mechanism into the cytoplasm.
“That triplet, I believe, will have many applications outside of siRNA,” such as with cytotoxic drugs, he said.