Our Drug Pipeline
The Pharmorage research and development pipeline has two key streams. The synthetic RNA therapeutic platform is exploring oligonucleotides for the improvement of mRNA vaccines, and in the treatment of inflammation for a range of chronic diseases. The small molecule platform is exploring the treatment of auto-immune disease and hyperinflammatory conditions.
Synthetic RNA therapeutic platform - Pharm-RNA
Synthetic RNA therapeutics are a new class of treatments relying on DNA/RNA molecules, also known as oligonucleotides (ON). Synthetic RNA therapeutics are currently approved for the treatment of a range of diseases and can also have applications in mRNA vaccine technology.
The Pharm-RNA platform has the potential to revolutionise the processes of mRNA vaccine production
Our proprietary TLR7 antagonists (Pharm-RNA-7) offer the potential to reduce the inflammatory side-effects of mRNA vaccines and to improve the efficiency of vaccine production. Further detail can be seen here.
Synthetic RNA therapeutics are currently approved for the treatment of a range of diseases, including familial hypercholesterolemia and muscular dystrophy. One of the key advantages of these therapeutics over traditional small molecules or antibody/protein-based therapies is that they can have prolonged efficacy. For example, a single treatment of inclisiran for hypercholesterolemia can last 6 months. As such, oligonucleotide-based therapies are set to revolutionise the long-term management of chronic diseases.
In addition to their capacity to modulate selected disease-causing genes, some oligonucleotides exhibit potent anti-inflammatory effects. Our world-leading expertise in this area has led to the identification of new kinds of oligonucleotides that can block the immune sensors at the root of inflammatory responses. In addition to selective inhibitors, the Pharm-RNA platform enables the creation of molecules inhibiting a range of receptors which is a key asset for the management of diseases where several pathways are aberrantly activated.
One of the key strengths of our Pharm-RNA program is the capacity to develop durable anti-inflammatory molecules with sustained activity over several months.
Our two lead candidates are already well advanced preclinically, ready to undergo in vivo testing
TLR7-suppressive oligonucleotides: in vivo testing stage (Pharm-RNA-7)
Toll-like receptors (TLRs) are one of the key families of immune sensors. TLR7 is a sensor detecting pathogenic RNA, which is essential for clearance of viral and bacterial infections, as recently evidenced in COVID-19 where TLR7 deficiencies have been linked to fatalities. In addition to its protective effects, TLR7 activation can also promote chronic inflammation and is a direct contributing factor in the pathogenesis of rheumatic diseases such as systemic lupus erythematosus (SLE). We have developed novel types of oligonucleotides that directly antagonise TLR7 sensing and are currently testing their therapeutic activity in animal models of TLR7-driven inflammation.I
cGas oligonucleotides: in vivo testing stage (Pharm-RNA-G)
cGAS is a DNA sensor working directly upstream of STING. It is specialised in the detection of cytosolic DNA recognised during infections and nuclear/mitochondrial damages. As such, cGAS acts within the pathway to clear infected and damaged cells, through the production of pro-inflammatory cytokines.
While protective in some contexts, aberrant cGAS signaling has also been identified as a key player in the onset and maintenance of a number of inflammatory, autoimmune and neurodegenerative diseases, and several pharmaceutical companies are developing cGAS inhibitors.
We have recently reported the description of the most potent cGAS inhibiting oligonucleotidesII and are currently investigating their anti-inflammatory effect in animal models driven by cGAS activation.
Small molecule platform - Pharm-ISO
TBK1 Inhibitor lead compound selection (Pharm-ISO-1)
TANK-binding kinase 1 (TBK1) is a kinase best known for its role in the production of type I interferons (IFN-Is), which are critical in antiviral responses. TBK1 is a point of convergence of several pathways that detect pathogens specific RNA, DNA and lipids (such as the MAVS, STING and TRIF pathways).
Nucleic acids sensing is a key driver of inflammation mediated by down-stream signalling proteins including TBK1
Activation of TBK1 leads to the production of pro-inflammatory factors aimed at helping the resolution of infection, including the recruitment of further immune cells. While normally protective, this process can create a positive feedback loop that promotes too much inflammation, which becomes detrimental to the host. This is one of the currently proposed mechanisms that contributes to hyperinflammation seen in COVID-19 patients. III
In addition to its role in infections, TBK1 plays an essential role in the response to endogenous factors produced upon cellular/tissue damage or stress, driven by the STING pathway. Unlike immune pathways such as the Toll Like Receptor (TLR) pathways which are limited to pathogen recognition, STING also detects aberrant cellular function – to facilitate clearance of damaged cells. This extra function of STING means that it is involved in a large number of inflammatory diseases driven by aberrant cellular activities. These diseases range from autoimmune diseases (e.g. SLE), neurological disorders (e.g. Parkinson's disease), metabolic diseases (e.g. liver diseases), cardiovascular diseases (e.g. myocardial infarction) to cancer. Inhibition of the STING/TBK1 axis therefore has great therapeutic potential to help treat a wide range of conditions where there is unmet need for novel and more specific therapeutics.
The Pharmorage drug development program on small molecule inhibitors of TBK1 exploits an entirely novel modality of inhibition of TBK1. This places us in a unique position to deliver a highly potent and specific TBK1 inhibitor, with applications for chronic and acute diseases fuelled by TBK1.
I Rational design of antisense oligonucleotides modulating the activity of TLR7/8 agonists, Arwaf S Alharbi, Aurélie J Garcin, Kim A Lennox, Solène Pradeloux, Christophe Wong, Sarah Straub, Roxane Valentin, Geneviève Pépin, Hong-Mei Li, Marcel F Nold, Claudia A Nold-Petry, Mark A Behlke, Michael P Gantier, Nucleic Acids Research, Volume 48, Issue 13, 27 July 2020, Pages 7052–7065.
II Roxane Valentin, Christophe Wong, Arwaf S Alharbi, Solène Pradeloux, Makala P Morros, Kim A Lennox, Julia I Ellyard, Aurélie J Garcin, Tomalika R Ullah, Gina D Kusuma, Geneviève Pépin, Hong-Mei Li, Jaclyn S Pearson, Jonathan Ferrand, Rebecca Lim, Rakesh N Veedu, Eric F Morand, Carola G Vinuesa, Mark A Behlke, Michael P Gantier, Sequence-dependent inhibition of cGAS and TLR9 DNA sensing by 2′-O-methyl gapmer oligonucleotides, Nucleic Acids Research, Volume 49, Issue 11, 21 June 2021, Pages 6082–6099.
III SARS-CoV-2 sensing by RIG-I and MDA5 links epithelial infection to macrophage inflammation. Lucy G Thorne, Ann-Kathrin Reuschl, Lorena Zuliani-Alvarez, Matthew V X Whelan, Jane Turner, Mahdad Noursadeghi, Clare Jolly, Greg J Towers. The EMBO Journal (2021) 40: e107826.
