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Jul 24, 2014
 |  BC Innovations  |  Cover Story

It is an RNA world

RNA-based molecules have redefined the universe of tractable targets by putting virtually anything that is gene encoded within reach of a disease-modifying agent. This redefinition has launched RNA as the biotech industry's third drug modality.

The emergence of noncoding RNAs presents yet further opportunities for the modality, but a rudimentary understanding of the bioactivities of these molecules, the delivery hurdles and the difficulties of target selection and validation still surround this new therapeutic class.

A think tank convened by SciBX that comprised academic, biotech, pharma and VC stakeholders surveyed the state of the noncoding RNA space. The key opinion leaders laid out a road map for developing and implementing RNA therapeutics and for exploiting the molecules-which include long noncoding RNAs (lncRNAs) and microRNAs-as disease targets.

"With small molecules, there is an undruggable or at least difficult to drug set of targets. A second modality, of course, is biologics-antibodies and so forth. But there are still a lot of targets that we would like to go after that we cannot drug with those approaches. And that is where RNA and oligonucleotides come in. In principle, there is no undruggable target anymore," said panelist Aimee Jackson. She is director of target development at miRagen Therapeutics Inc., which is developing anti-miRNAs.

For the near term, the think tank recommended that drug developers prioritize diseases for which there is solid knowledge of the human genetic underpinning and focus on strategically selecting RNA targets based on how accessible they are in humans. In particular, to avoid clinical setbacks caused by poor target selection, the key opinion leaders emphasized the importance of identifying reliable biomarkers and developing target engagement assays for clinical studies.

For the long term, the panel outlined activities that will be needed to gain a comprehensive understanding of the biology of emerging classes of noncoding RNAs. In addition, it pressed for new delivery agents such as conjugates or particle formulations that expand the repertoire of accessible tissues and improve intracellular release of therapeutics following endocytosis.

Thus, for the second straight year, endocytosis was called out as a black box that impedes drug delivery. The 2012 SciBX Summit, which focused on macrocycles and constrained peptides, also stressed the need for translational studies on endocytosis.1

In addition to Jackson, the think tank consisted of David Corey, Jean-François Formela, Art Krieg, John Maraganore and Laura Sepp-Lorenzino.

Corey is a professor of pharmacology and biochemistry at The University of Texas Southwestern Medical Center and has been exploring oligonucleotide-based therapeutics and RNA targets for more than 20 years. Formela is a partner in the life sciences group at Atlas Venture and a cofounder of RaNA Therapeutics Inc., which is developing molecules to upregulate gene expression by targeting lncRNA. At the time of the meeting, Krieg was CEO of RaNA. Most recently, he was SVP and CSO at Sarepta Therapeutics Inc., which develops RNA-based therapeutics targeting mature or precursor mRNAs to turn gene expression on or off. He departed that position earlier this week.Maraganore is CEO of Alnylam Pharmaceuticals Inc., which develops therapeutics based on RNAi. Sepp-Lorenzino is VP and an entrepreneur in residence at Alnylam. At the time of the summit, she was executive director of RNA therapeutics discovery biology at Merck & Co. Inc.

According to Formela, "The conjunction of the maturation of the modality, the explosion of the biology and the focus of the industry and of the capital market on trying to solve orphan disease has created a perfect opportunity for investors."

Maraganore said that numerous advances have minimized some of the early negatives associated with RNA therapeutics, including undesirable toxicity or immune system activation.

Formela added that in terms of toxicology, therapeutic RNAs are becoming more like small molecules. "If we end up with a platform that is just as good-maybe better in terms of time to development of a candidate because the design on the front end is much more rational than the design of a small molecule-I think it will be a very attractive platform," he said.

RNA buzz

There has been a steady increase in investment in oligonucleotide-based therapeutics over the past three years, including a surge early this year (see "2014 first-quarter industry activity in RNA therapeutics").2

More than $1 billion was invested in the RNA space during 1Q14, headlined by Alnylam receiving a $700 million equity investment from the Genzyme Corp. unit of Sanofi that expanded the strategic alliance between the companies.

Genzyme obtained global rights to commercialize Alnylam's lead compound, patisiran, outside the U.S. and Western Europe. The expansion added three additional molecules from Alnylam's pipeline to the alliance. Until 2020, Genzyme has the option to co-develop and commercialize outside the U.S. and Western Europe all rare genetic disease therapeutics in Alnylam's pipeline.

Other big deals include Alnylam's acquisition of Sirna Therapeutics Inc. from Merck for $75 million up front plus milestones and Moderna Therapeutics Inc.'s $100 million deal with Alexion Pharmaceuticals Inc. to develop messenger RNA-based therapeutics in rare disease.

On the finance side, Dicerna Pharmaceuticals Inc. raised $90 million in a January IPO.

Also that month, the Life Technologies Corp. The goal is to release 65,000 siRNA sequences targeting more than 20,000 human genes. New data generated from the initiative will be added to PubChem on an ongoing basis, making the database a resource for the RNA community.

In fact, investment in basic research and resources for the RNA community has become a high priority for government funding agencies even in the face of shrinking budgets.

The NIH made its first large-scale investment in RNA biology in 2003 when the National Human Genome Research Institute launched a public research consortium called ENCODE (the ENCyclopedia Of DNA Elements) to identify all functional elements in the human genome. The pilot and scale-up phases of ENCODE cost about $185 million. In 2012, the National Human Genome Research Institute announced the third phase of the project and said that it could invest up to $119 million through 2016.

No code

The discovery that the majority of the genome is expressed as noncoding RNA was a major-and unexpected-finding from ENCODE.

"I think that was the big bang," said Formela. "If 80% of the genome is transcribed and biologically active, frankly, it does not take a very smart VC or PhD to figure out that there will be a huge amount of biology that is unprecedented that you can potentially affect."

"Within the last 10 years, it's become clear that most of the genome is transcribed. Most of that transcription is likely to be noise produced at low volumes. And it's not likely to have a biological effect. But what of the transcription, especially around genes' enhancer regions; what kind of effects can that have?" asked Corey.

The panel emphasized that drug developers in the noncoding RNA space can take advantage of existing technologies used for coding RNAs such as those that induce silencing or exon skipping.

"In terms of the platform chemistry, we have a lot of tools at our disposal," said Jackson. "Chemical modifications to the RNA backbone, to the ribose moiety as well as to the base of the RNA enable us to dial in a lot of characteristics for affinity, for stability in the body and for duration of action within the body. We are starting to appreciate just how drug-like we can make these small RNAs by combining the chemical modifications to the various moieties of the RNA structure."

"There is no further generation of chemistry that is going to be needed," said Krieg. "The tools that we have now are the chemistries that have come about from well over 20 years-probably closer to 30 years-of work from chemists. Right now, today, we know that with single-stranded approaches we can get into multiple organs in the body by simple subcutaneous administration. Double-stranded approaches have made huge strides."

Maraganore added that chemical modifications-together with new screening tools-have also addressed toxicology concerns such as activation of toll-like receptors or intracellular RNA sensors.

"There is a huge difference in potency, pharmacology and, you could argue, toxicity, between some of the first-generation chemistry and some of the latest-generation chemistry," added Formela. "In terms of binding specificity and potency pharmacology, a lot of progress has been made. You can now tune those features. Maybe not 100%, but you get a good sense of how quickly you can get to a development candidate, which is a very important first step-and frankly a requirement-to make an investment."

Talking targets

Although the chemistry for noncoding RNA therapeutics is on solid ground, the best way to find good targets is open to debate, and their importance cannot be overstated.

"Target selection is the single most difficult step that an early stage company takes," said Formela. "And I personally feel that it's probably the largest competitive factor or success factor in getting there soon enough that you don't fall out of favor with investors. It's extremely important."

Step one, said Sepp-Lorenzino, is making sure a target is expressed in tissue types amenable to RNA therapeutics. The liver is the clear front-runner here, and additional tissue types include muscle, eye, CNS, lymphocytes, skin, kidney and tumors (see "Accessible human tissues").

Within those tissues, well-validated protein targets that need to be upregulated to achieve a therapeutic effect are particularly attractive. And at RaNA, Krieg said, scientists further home in on the nucleotide regions adjacent to a target's gene to locate potential regulatory noncoding RNA sequences.

Panelists also said that phenotypic approaches should be pursued for identifying therapeutically relevant noncoding RNAs.

At miRagen, Jackson said, scientists "are doing more phenotypic-based approaches in vivo and bypassing in vitro altogether." She added that because expression of both miRNAs and the mRNAs they regulate varies by tissue and cell type, and also varies in the disease setting, phenotypic screening can provide the most physiologically relevant information for target selection.

Ultimately, using biomarkers to assess target engagement in humans will be essential to tie target modulation to impact on disease. Such biomarkers are important tools for predicting success in clinical trials.

At Alnylam, "we have to have a point-of-care marker that we can read out in Phase I, whether it is a secreted protein where you can measure a decrease in the protein levels in the blood or some other indirect but related type of factor," said Maraganore. In the absence of a reliable biomarker, it is difficult if not impossible to distinguish between failure to hit...

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