When Ram Aiyar former CEO of Corvidia (sold for 2,1 B USD to Novo Nordisk in June 20) decided last November 2020 to lead Korro Bio (Cambridge, MA), he did a visionary choice. This RNA therapy company who did a spectacular 91 MM USD Series A in September 2020 (Atlas, NEA, Wu Capital) is one of the last Gold Nugget exploring the potential to modulate disease causing mutation. RNA editing technology has the potential to restore protein function through the precise targeting of RNA sequence…. without entering the nucleotide and touching the DNA. More recently (Dec 2020), the San Diego based RNA platform Locanabio closed a 100 MM $ Series B led by Vida Ventures LLC (with RA Capital, Invus, Acuta, Arch, Lightstones, UCB, GV). While the company already raised 156 MM $ in 18 months, no product is yet in the clinic. Yet this platform is extremely promising and plays on different strategic approaches (RNA destruction, destruction/ replacement, Splicing, RNA editing…) paving the way to a genuine rupture technology able to treat novel diseases. The appetite and expectation from the financial players and industrials are unprecedented and beyond pure RNA drugs, small molecules targeting RNA have raised lots of excitement. A solid sign to validate this approach is nurtured by the presence of corporate Ventures behind all small molecule companies targeting RNA. Pfizer is behind the Advent founder’s leader Arrakis, Novartis behind Expansion therapeutics and Remix… Looking to the Private Equity world, the RNA pioneer Alnylam raised earlier this year 2 billion $ with Blackstone Life Sciences. Funded in 2003 by Abingworth, Atlas Venture, Arch and Cardinal Partners Alnylam has already three FDA approved RNAi products (Patisiran, Givosiram and Lumisiran). As a matter of fact, RNA technologies are able to focus on rare diseases as 80% of them are genetic ones. An extremely appealing field that ultimately allows Market exclusivity, fast track…and price premium as high as 450 K USD/ year/ patient such as for Patisiran (Alnylam) indicated for Polyneuropathy of Hereditary Transthyretin-mediated amyloidosis.
While the use of RNA in Therapeutic/ Prophylactic vaccines will not be covered in this post, scientific and financing activities have positioned RNA as the cornerstone able to dramatically improve the life of patients. Pushing the frontier of uncurable and genetic diseases as well as druggable targets have been the direct consequences of this new R&D field.
CONQUERING A 30 YEARS OLD CONTINENT
Over the 20’000 human proteins 3’000 are druggable and only 667 were approved (as of 2017). The vast majority of proteins can’t be targeted by small molecules nor Monoclonal Antibodies (cell surface protein/ receptor/ secreted protein) as key pocket structures/ cavities are needed in order to inhibit Enzymes, Receptors… Nucleic acid based therapies and more particularly RNA therapies are able to break this issue and are able to interfere with the protein expression itself. Nobel Prize granted in 2006 to Craig Mello and Andrew Fire has been a catalyst converter to the gene silencing technology also called RNA interference. Discovered 60 years ago, RNA has turned out to be investigated as a potential drug in the early 90’s when injection of mRNA in rodents has led to the expression of the targeted protein. Antisense Oligonucleotide (ASO) RNA able to pair with DNA sequence in the nucleus or mRNA in the cytoplasm were the first to be developed. It has been followed by double strained RNAi (more stable, stronger half time) discovered in 1998. When paired with the so called RISC structure (RNA Induced Silencing Complex) the RNA is separated in two strands, the passenger strand is degraded by RISC and the less stable 5’ strand (guide strand) target a complementary mRNA leading to its degradation via the Argonauts protein (slicer part of the RISC complex). The associated gene can’t then be expressed. Up to 50% of the genome are naturally downregulated by the RISC complex. Last, the RNA Aptamer complex is able to target specific protein and could be envisioned as a possible alternative to monoclonal antibodies. RNA Aptamers are then able to stimulate a catalytic activity and disrupt the function of a targeted protein.
ASOs
RNAi
Developing synthetic RNA and adding a delivery carrier was key to decrease immunogenicity and instability. In order to be active, the RNA “drug” need to enter to the targeted cell and cross the bilayer lipid membrane. Alnylam and Dicerna have exploited the fact that Lipid nanoparticules targeted mRNA ends up to the liver to focus on HBV, liver diseases, cardiometabolic disorders….
SMALL MOLECULES: BACK TO THE FUTURE OF THE INDUSTRY
As of today, many small molecules are in development targeting RNA involved in various human diseases, including cancer, genetic disorders and infections. Specific RNA motifs (complexes, loops…) may be recognized with high affinity bound by small molecules leading to their inhibition or activation. RNAs are highly charged macromolecules inducing strong potential affinity but poor selectivity. Computational modeling and chemoinformatics platforms have facilitated the identification of chemically relevant small molecules. Structural optimization is compulsory in order to improve PK and selectivity and improve safety and tolerability. Targeting ribosomal RNA (antibiotics…), Viral RNA (HIV, HCV, SARS-CoV, flue…), Riboswitch with unique ligand binding pocket (in Bacteria), pre-mRNA (genetic diseases such as the neuromuscular disorder SMA), oncogenic micro-RNA (reactivating apoptosis) are the main focus today. To be a target, the RNA should be abundant with structural/ functional sites available and should effectively control the disease. Founded by Advent Life Science and co-funded with Pfizer, Venbio, Canaan, Arrakis Therapeutics was one of the first biotech developing small molecules to bind and modulate RNA. As a consequence, the RNA lifecycle and more specifically the downstream disease related biology is altered leading to Translation and/or Splicing inhibition. Oncology, rare diseases and more remarkably cardio-metabolic diseases (dyslipidemia/ with little innovation since the latest decade) are targeted by this Massachusetts platform. Indeed, altering RNA involved in the formation of cholesterol, plaques or the death of cells after a heart attack should revive this therapeutic franchise. The Florida based company Expansion Therapeutics (Sanofi Ventures, Novartis Ventures, Westlake village) is focusing on designing highly specific compounds that bind diseases causing toxic RNA. Their lead assets are targeting orphan indications such as Myotonic Dystrophy, the most frequent adult muscular dystrophy. More recently, Gotham Therapeutics (NY) founded by Versant (and co-funded with SR One and Forbion) is investigating the deep field of Epitranscriptomics. It mirrors the epigenomics concept but targeting for RNA. Gotham is playing indirectly to RNA by developing small molecule targeting proteins that will ultimately modulate mRNA.
Developing orally bioavailable small molecule targeting RNA drug rise great expectations. As of today, lipid-based nanoparticules or ex-vivo transfection use the IV or intradermal route. Fighting lung diseases with siRNA pulmonary delivered offered great perspectives too. Looking to this 30-year odyssey it appears that RNA therapeutics are reaching a strong inflexion rate. Overcoming key challenges such as delivering RNAi to the targeted cell, scalability or stability, major positive outcomes are expected in the next decade. Silencing RNA has dramatically pushed the frontier of druggability. It is especially true when the expression of one gene is solely responsible of a targeted disease. As the human genome often works in a complex number of post transcriptional activation/ inhibition, finding the key RNA or a couple of RNA specific to the development of one disease will be particularly challenging. Switching off a full mechanism of action involved in certain cancers or cognitive diseases will require the coordinated silencing of a high number of RNA without interfering with the “normal” cell biology. Embracing this complexity is probably the most exciting Future that we may expect from the AI/Biotech couple. Generating platforms that develop leads able to play in multiple post-transcriptional pathways, faster and tailored will be the next ultimate frontier.
Edouard Caram
edouard@vclife.org