Gene silencing is firmly back on the R&D radar screen in the fight to combat intractable disease after a hiatus of several years. Promising results from early clinical results have begun to attract investors into the space again with well over $200 million poured into this sector so far in 2013; and public companies developing RNA-based drugs have seen their share prices soar.

However, the delivery of RNAi drugs still continues to be an obstacle that remains to be fully solved before the promise of those exciting therapies currently in development is fully realized.

The delivery problem certainly delayed development of the technology and prompted Roche AG’s headline-grabbing pullout of the space in 2010, leaving some smaller RNAi firms such as Marina Biotech Inc. in a lurch. Unable to raise additional cash, Marina closed up shop and divested its technology. (See BioWorld Today, Nov. 18, 2010, and June 4, 2012.)

However, progress is being made with companies such as Alnylam Pharmaceuticals Inc., of Cambridge, Mass., leading the charge. The company has seen its shares shoot up 178 percent so far this year on the strength of providing investors with a steady diet of positive news, including teaming up with the Medicines Co. for its RNA interference (RNAi) approach to blocking proprotein convertase subtilisin/kexin type 9 (PCSK9), receiving $25 million up front plus a further $180 million in potential milestone payments.

Last week it also received fast track designation for its RNAi therapeutic, patisiran, to accelerate development for the treatment of transthyretin (TTR)-familial amyloid polyneuropathy (FAP). The company recently reported positive Phase II results for the product, and has begun a Phase III program. It is developing patisiran in partnership with Genzyme Corp., a unit of Sanofi SA. (See BioWorld Today, Nov. 12, 2013.)

Its randomized, double-blind, placebo-controlled APOLLO Phase III study will assess efficacy and safety of patisiran in ATTR patients with FAP. The primary endpoint of the study will be the difference in the change in mNIS+7 between patisiran and placebo at 18 months. Secondary endpoints include measures of quality of life, weakness, body mass index, timed 10-meter walk and autonomic symptoms. The trial will enroll up to 200 patients with Stage 1 or Stage 2 disease.

Alnylam’s RNAi therapeutic is enabled by Burnaby, British Columbia-based Tekmira Pharmaceuticals Corp.’s lipid nanoparticle (LNP) technology.

“Today’s most significant RNAi advances within the clinic are driven by our LNP delivery technology,” noted Dr. Mark J. Murray, Tekmira’s president and CEO. “It continues to be validated by positive clinical data.”

Healthy Investments

The company recently completed a public offering of 4.3 million shares inclusive of overallotments at a price of $8 per share for aggregate gross proceeds of $34.5 million.

Shares of Tekmira (NASDAQ:TKMR) have enjoyed a significant 71 percent jump in value since the beginning of the year.

Arrowhead Research Corp., of Pasadena, Calif., also closed a private offering of common and convertible preferred stock for net proceeds of $60 million. The company is developing ARC-520, an RNAi therapeutic targeted at hepatitis B virus infection. It also raised $36 million earlier this year in a private financing. (See BioWorld Today, May 7, 2013.)

The company presented data the American Association for the Study of Liver Diseases (AASLD) meeting in Washington earlier this month on ARC-520, its clinical candidate to treat chronic hepatitis B virus, which demonstrated that intravenous administration of two doses (2 mg/kg, 3 mg/kg) of the compound in a chimpanzee chronically infected with hepatitis B virus resulted in substantial and sustained reductions in HBV DNA, HBeAg and HBsAg, which did not return to baseline until study day 43, 43 and 71, respectively. In addition, an increase in serum alanine transaminase (ALT) occurred four weeks after the last dose, coincident with the nadir of circulating HBsAg. That is suggestive of a therapeutic immunological flare, which is thought to be part of a cascade that under chronic therapy may lead to HBsAg seroconversion and functional cure.

Dicerna Pharmaceuticals Inc. pulled in $60 million in a Series C round, representing one of the largest private financings for biotech so far this year, to move into the clinic with its lead RNAi-based candidates against genetically defined targets in disease areas such as oncology. (See BioWorld Today, Aug 1, 2013.)

Execs from Watertown, Mass.-based Dicerna said the firm is on track to file an investigational new drug application by the end of this year for its lead oncology RNAi therapeutic, with the drug to start clinical testing in the first quarter of 2014. That drug is designed to target Myc, a transcription factor implicated in many different cancer types but one that has proved difficult in terms of drug development. Dicerna describes its DsiRNA molecules as second-generation siRNAs. Engineered with 25 or more base pairs, DsiRNAs are longer than most competing siRNAs, an advantage allowing them to engage the Dicer enzyme, which operates early in the gene silencing cascade. Its Encore platform incorporates lipid-based nanoparticles to deliver the RNAi payload.

Promising Research

In March, Silence Therapeutics plc, of London, said it received formal approval from German regulators for a Phase Ib/IIa combination trial testing Atu027, its antimetastatic RNAi compound, in combination with gemcitabine in pancreatic cancer. The Phase Ib portion is expected to last for three months, with the Phase IIa portion expected to start in July of this year and end in July 2014. The company also reported results from proof-of-concept studies in acute liver injury, showing that its new lipid formulation, DBTC, is effective at delivering RNAi treatments to liver tissues.

Austrian newco, Ugichem GmbH, claims to have come up with a new and broadly applicable gene silencing chemistry that allows delivery to be targeted to specific tissues, cells and intracellular targets.

The company is developing ugimers based on an RNA mimic, peptide nucleic acid (PNA), which is not degraded by proteases and is stable over a wide pH range. Phosphonic ester side chains attached to those synthetic molecules modulate their properties, improving solubility and allowing ugimers to penetrate the cell membrane through passive diffusion.

By varying the side chains, the pharmacokinetics of Ugimers can be modified to alter bioavailability, tissue half-life and the cellular distribution profile. Molecular tags attached to the end of the PNA backbone can be used to control intracellular distribution. It is, for example, possible to deliver ugimers specifically to mitochondria, and Ugichem said they are the first and only gene silencing drugs that are effective in mitochondria through the down-regulation of mitochondrial DNA. (See BioWorld Today, Aug. 21, 2013.)

Interna Technologies BV, of Utrecht, the Netherlands, and VU University Medical Center were granted funding of approximately €1.2 million (US$1.6 million) from the European Union’s FP7 program, together with Quiet Therapeutics Ltd., of Ness Ziona, Israel, which is developing a class of targeted therapeutics for oncology and inflammation. Funding of the consortium is designed to develop the targeted delivery of tumor-selective lethal miRNAs to treat head and neck cancer. The consortium also includes Germany’s Biospring GmbH and Laboratory of Pharmacology and Toxicology LPT and Octoplus NV, of Leiden, the Netherlands.

“The unique tumor-selective lethal miRNAs identified display a very interesting biology and potential therapeutic effect that warrants further development towards the clinic. This FP7 grant exemplifies that with this consortium we have all the expertise in place to bring a tumor killing miRNA in a targeted and safe manner towards registration for first in human testing”, said Roel Schaapveld, CEO of Interna Technologies.