Like many technologies that move from hot discoveries on the cover of Nature to the practical ugly sausage-making of drug development, RNA-based therapeutics have been widely derided of late. It seems everyone from Wall Street to Pharma to venture capital has been running from the field, and running fast. Isis and Alnylam have jointly given back almost $1.5B in market capitalization in the past few years. Pfizer, Roche, and Abbott have shut down their RNAi efforts after pouring in $100′s of millions. Novartis, Merck, and others are struggling with how this modality can be turned into drugs. Raising money for new RNA startups is harder than an already tough average.
This widespread bearishness stems from three big perceived challenges for oligo drugs: delivery, delivery, delivery. Getting double-stranded RNAi to work as advertised has been harder than anyone predicted; continued albeit slower-than-hoped-for progress is being made on delivery by Alnylam, Silence, Tekmira, and others on new lipid-based formulations. But this hasn’t convinced the bears.
Rather than try and tackle the RNAi delivery debate, I’d like to draw a distinction overlooked in the field and highlight why this blanket bearish perception is missing one of the most exciting stories within RNA today: short single-stranded RNA therapeutics can effectively target non-coding RNAs
In contrast to their double-stranded cousins, single stranded RNA therapeutics have surprisingly attractive pharmacologic profiles as systemically-delivered agents. ssRNA drugs, typically less than 16 or so nucleotides, can be formulated in saline rather than the lipid-based approaches required for dsRNAs, and can delivered subcutaneously or intravenously with significant cellular uptake across many organs. In vivo IC50′s in the single-digit mg/kg dose range have been shown to work with multiple targets. One of the technologies that has enabled this profile are the bicyclic nucleic acid chemistries such as locked nucleic acids (LNAs). Bicyclic nucleic acid containing oligo’s have much higher binding efficiencies (i.e., melting temperatures), and along with other modifications can provide improved stability and protein binding. Several firms are working on these chemistries, including Santaris Phama A/S and Isis Pharmaceuticals.
These ssRNA drugs can target many types of RNA, but one of the most exciting are the abundant non-coding RNAs like microRNA. These regulatory RNAs create a critical layer of gene regulation by channeling mRNAs for degradation, and their aberrant expression and behavior can lead to disease. Blocking a specific microRNA can lead to the de-repression of a number of downstream pathways, giving it enormous potential to ameliorate disease states that the ‘one-drug-one-target’ classic reductionism struggles to deliver. Its become clear over the past few years that these ssRNA drugs can block these microRNAs very efficiently. Several companies are working on targeting microRNA therapeutics, such as Atlas-backed miRagen Therapeutics, Santaris Pharma A/S, Mirna Therapeutics, and Regulus Therapeutics.
The motivation for writing this post was triggered by two big pieces of great news in the microRNA field in the past few days:
- Human clinical proof-of-concept with a Anti-microRNA oligo therapy has been achieved. miR-122 has been implicated a host factor required for HCV infection and is the first miR targeted in clinical studies by Santaris. Their short LNA-based anti-miR-122 candidate for HCV, miravirsen, just showed a 2.7 log reduction in HCV RNA (the primary endpoint) after once-weekly dosing of 5 mg/kg subcutaneously for a month (to be presented at November’s AASLD 2011). Irrespective of what one may think about HCV as a market today given the competitive dynamic, the achievement of a profound efficacy response via an anti-miR therapeutic in clinical studies is worth celebrating. As the first of its kind, it derisks the concept of miR-targeting and the bicyclic chemistry as well. Kudos to Santaris for scoring this goal for the field.
- miRagen and Servier just announced a major partnership to accelerate cardiovascular microRNA-directed therapeutics. Over the past few years at miRagen, among other discoveries we’ve demonstrated that systemically-administered doses of anti-miRs are taken up by cardiomyocytes where they block cardiac specific miRs, de-repress protein expression in a specific manner, and all this leads to functional cardiac improvements and extended survival in several heart failure animal models. These and other data captured the interest of Servier, a global pharmaceutical company committed to heart failure and cardiovascular disease. Today we announced a major strategic partnership that should facilitate the global development of multiple programs. Servier will fully fund multi-year R&D plans for several programs through Phase II, while MiRagen retains option to co-sponsor or opt-in for Phase III. Most importantly, miRagen retains all U.S. and Japan rights; Servier gains rights to all other global markets. This deal, worth over $350M in payments, direct R&D support, and milestones, is transformative for a company that has raised less than $20M of equity capital to date.
Its worth noting the other players are also pushing the field of ssRNA approaches to miR-based targets. Regulus recently published some very intriguing data with miR-21 in cancer and fibrosis models (the subject of their earlier deal with Sanofi), as well as miR-33 in lipid biology. We’re excited to see the field catching some momentum and anticipate the next few years to be quite exciting as multiple programs enter the clinic.
Another big piece of ssRNA news is right around the corner (hopefully): FDA approval of Isis’ mipomersen as the first systemically delivered single-stranded RNA therapeutic on the market. This should further strengthen the oligo field.
As evidence of our bullishness on ssRNA approaches, Atlas has also recently created another play aimed at targeting long non-coding RNAs: my partner Jean-Francois Formela recently co-founded it with MGH’s Jeannie Lee, Coley/Pfizer’s Art Krieg (now an EIR at Atlas), and Atlas’ Ankit Mahadevia. The company, currently in stealth mode, will be leveraging lots of the emerging insight around the pharmacology of ssRNA approaches. More in the coming months on this one, including its name…
So circling back to beginning, we think the all-encompassing bearishness against RNA therapeutics isn’t justified: there’s been a lot of great progress especially in the field of non-coding RNA targeting. So its worth reflecting on Buffett’s famous quote: “We simply attempt to be fearful when others are greedy and to be greedy only when others are fearful”. Early in the past decade, when RNA Rx was more concept than data, investors and Pharma flooded into the space. Now, when data are looking better than ever (at least in some areas), it seems investors and Pharma are stuck with fear (with the exception of our friends at Servier). With the first anti-miR therapy passed the human safety and efficacy PoC hurdle, now is the time to be bullish on RNA therapeutics and targeting non-coding RNAs in particular.