RNA Therapeutics Are Here to Stay

6/5/14

Over the past year, we’ve witnessed the biotech bull market expand, deflate and expand again—specifically in relation to RNA-based therapeutic companies. The innovators in the space have increased and decreased their investment levels in the technology, leaving investors, the media, and some in the scientific community wondering which way the pendulum will ultimately swing.

In my view, the answer is clear—RNA therapeutics have proven their clinical utility and will be the next wave of innovative medicines to transform the field of drug development. Last year, I outlined how RNA therapies are coming of age. Over the past year, the successes in the field have established that RNA therapeutics are not only coming of age, but they are here to stay.

In January, Alnylam Pharmaceuticals (NASDAQ: ALNY) entered into a large strategic alliance with Sanofi/Genzyme, which recognized the promise of RNA interference (RNAi) and the progress Alnylam has made in building a meaningful clinical portfolio. We saw Sanofi renew its strategic alliance with Regulus Therapeutics (NASDAQ: RGLS), a San Diego-based microRNA company that I lead with a portfolio of potential therapies focused on the treatment of orphan diseases and oncology. Biogen Idec (NASDAQ: BIIB) has entered into collaborations with RNA-based companies such as Regulus and Isis Pharmaceuticals (NASDAQ: ISIS) geared at using microRNA biomarkers to predict patient responses to multiple sclerosis treatments and developing antisense drug candidates for neurological disorders.

More importantly, significant scientific progress continues to be made across each RNA approach including antisense, RNAi, microRNA, aptamers, messenger RNA technology, and RNA modulation. Companies are also addressing a variety of diseases with significant unmet needs such as hypercholesterolemia, hepatitis C, hepatitis B, kidney fibrosis, brain tumors, liver disease, severe genetic disorders, and rare bleeding disorders through RNA-based therapies with novel delivery options.

• Isis is at the forefront of antisense drug discovery and development and has created a very impressive clinical portfolio in a variety of diseases. Its technology focuses on interrupting the translation phase of protein production by degrading the corresponding mRNA. In 2013, Isis’ mipomersen (Kynamro, partnered with Genzyme) was approved by the FDA for the treatment for homozygous familial hypercholesterolemia. In addition, Isis has reported Phase 2 results of its antisense drug ISIS-ApoC-III in patients with high triglycerides and expects to initiate a Phase 3 trial in 2014 to examine the experimental drug in patients with familial chylomicronemia syndrome (FCS) who have severely high triglyceride levels. Recently, Isis also demonstrated that its antisense-based compound, ISIS-SMNRx, was well tolerated in a Phase 2 multiple-dose study in infants and children with spinal muscular atrophy.

• As the leader in RNAi therapies, Alnylam is developing targeted approaches that harness the power of gene silencing. Alnylam has multiple therapeutics currently in the clinic with its most advanced being a treatment for transthyretin amyloidosis in a Phase 3 clinical trial. Most recently, the company announced positive Phase 1 results of a drug candidate called ALN-AT3, for the treatment of hemophilia. Additionally, Alnylam’s preclinical pipeline continues to advance, including promising data for porphyria and subcutaneous delivery targeting PCSK9 to treat hypercholestrolemia. By the end of 2015, Alnylam has stated that it expects to have six to seven candidates in clinical development, including at least two programs in Phase 3, and five to six that have demonstrated human proof of concept.

• microRNA therapies work even further upstream in biological systems by targeting microRNAs, which control the expression of proteins and entire pathways of disease. Regulus’ anti-miR drug candidates have demonstrated positive preclinical data in hepatitis C and Alport syndrome, an orphan kidney disease driven by genetic mutations with no approved therapy. Regulus plans to establish human proof of concept with RG-101, a compound targeting microRNA-122 for the treatment of hepatitis C, in a Phase 1 study by the end of 2014. If favorable, these results will go a long way toward validating Regulus’ microRNA therapeutic platform and approach to treating disease. Additionally, Regulus is also exploring the utility of identifying microRNAs as biomarkers of human disease.

• Other types of up and coming RNA therapeutics include RNA aptamers, messenger RNA technology, and RNA modulation. RNA aptamers bind with high specificity to a target molecule, and can rival the function and efficacy of therapeutic antibodies. Novartis recently demonstrated its confidence in these next generation ligands by gaining rights to Opthotech’s (NASDAQ: OPHT) aptamer-based treatment for age-related macular degeneration (AMD). RNA-modulating techniques target pre-mRNA processing (alternative splicing) and have significant implications in rare diseases. Both Sarepta Therapeutics (NASDAQ: SRPT) and Prosensa (NASDAQ: RNA) are exploring preclinical and early clinical exon-skipping strategies to treat Duchenne Muscular Dystrophy. Lastly, messenger RNA therapeutics use synthetic mRNAs and have the unique ability to produce intracellular proteins in vivo. Moderna Therapeutics is heading up this research effort, and in January of this year, entered into an agreement with Alexion Pharmaceuticals (NASDAQ: ALXN), collaborating exclusively to develop messenger RNA therapies.

Despite the recent explosion of RNA-based research and positive scientific results, some in the media and investment communities continue to focus on perceived concerns regarding drug delivery and the limited capability of tracking down reliable targets. The recent decisions of Novartis and Merck around their respective RNAi programs are in no way a barometer for the state of the entire platform, but rather reflect internal program priorities. In truth, the science is in a very exciting stage as researchers are quickly getting a better handle on the molecular mechanisms behind RNA technology, allowing companies to identify where RNA-based therapies can work and in which disease areas. New delivery technologies are continuously being developed and mastered with validation being seen in numerous preclinical and clinical studies. For example, in 2013 alone, there were over 7,000 peer review publications on microRNA therapeutic targets, and because the biological knowledge is increasing exponentially, it is projected that there will be approximately 9,000 peer review publications on microRNA therapeutic targets in 2014.

Overall, pharma remains interested and invested, and investors continue to embrace RNA therapies, even through the “expected” fluctuations in the market. Now is an exciting time for the RNA therapeutics space, as biotechs are poised to push treatments through the clinic and to the patient. Antisense, RNAi, microRNA, aptamers, messenger RNA, and RNA-modulation technologies offer a unique opportunity to target a range of human diseases. I believe that we are now experiencing the right combination of technology, intellectual property, leadership, and investment that will further advance RNA therapeutics into powerful medicines to help patients in need.

Kleanthis G. Xanthopoulos, Ph.D. is the president and CEO of Regulus Therapeutics, a company developing drugs based on microRNA technology. Follow @

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