Founded less than two years ago, Arcturus Therapeutics Inc. started from ground zero as a Johnson & Johnson Innovation tenant, with no assets, technology or pipeline in hand. That situation changed quickly. In June 2013, the San Diego-based company raised $1.3 million in seed funding from high net worth investors from the U.S. and Canada. Four months later, the company tapped most of those investors again and added interests from Japan in a $5 million series A round.

Now, Arcturus is shooting for the moon with lead compounds LUNAR-101 and LUNAR-102. The RNA therapies are targeting the treatment of rare diseases using the company's lipid-enabled and unlocked nucleic acid modified RNA, or LUNAR, delivery technology platform.

Co-founders Joseph Payne, president and CEO, and Padmanabh Chivukula, chief scientific officer and chief operations officer, came from the Oceanside, Calif., office of Nitto Denko Technical Corp., based in Osaka, Japan, where the veterans of nanoparticle technology helped to deliver an RNA interference (RNAi)-based drug aimed at treating fibrosis in the liver and other organs to the clinic.

"Pad and I thought RNAi medicines would be even better suited for rare diseases, so we decided to jump ship, leverage our expertise and start a new company," Payne told BioWorld Today.

Nanoparticle technology also represents the backbone of Arcturus' platform. LUNAR uses a GMP-ready microfluidic formulation process to yield particles smaller than 80 nm that are biodegradable and biocompatible with a low polydispersity index. The formulation process is scalable, and the resulting particles have demonstrated stability, safety and potency in multiple animal species.

Arcturus elected to buy a second technology, last year acquiring the patented portfolio of unlocked nucleobase analog (UNA) intellectual property from Marina Biotech Inc., of Bothell, Wash., to use in its RNAi work. Terms of the deal were not disclosed, but Payne cited the use of UNAs in RNAi to silence aberrant gene expression as a promising approach to treat disease. The flexible nature of UNA reduces the binding affinity between two strands of an RNAi drug and gives unique characteristics to its gene silencing abilities, he pointed out.

"Unlocked nucleic acids are flexible," Payne explained. "Most nucleic acids are rigid, but by introducing flexibility into a rigid RNA medicine, you capture very important and significant pharmaceutical benefits."

Although the development of RNA therapies is a hot area, having two core technologies – LUNAR and UNA – gives Arcturus a distinct advantage over most RNA companies, many of which rely on solo platforms, he said.

"UNA makes RNA better," Payne pointed out, adding that the combination even attracted two of the company's competitors as licensees. Tekmira Pharmaceuticals Corp., of Vancouver, British Columbia, is using the UNA technology to pursue hepatitis B therapies, while Arrowhead Research Corp., of Pasadena, Calif., is pursuing a rare disease that affects multiple organs.


The allele selectivity of Arcturus' UNA technology offers another advantage: more than 100-fold selectivity, or 99 percent knockdown of a disease allele from one parent with no knockdown of the healthy allele from the other parent, according to Payne.

"Every single one of our competitors knock down both alleles at the same time," he maintained. "We have that capability, too, because some diseases require that profile, but our chemistry unlocks the door to treat autosomal dominant diseases."

Although a group of 117 autosomal dominant diseases comprises the best known therapeutic targets, Arcturus' chemistry profile allows it to pursue a much bigger universe of roughly 3,400 autosomal dominant diseases, Payne said.

In January, at the Biotech Showcase in San Francisco held simultaneously with the J.P. Morgan Healthcare Conference, Arcturus began to strut its stuff, introducing the flagship LUNAR-101 program. The RNAi therapeutic is targeting transthyretin (TTR) to treat familial amyloid cardiomyopathy, or FAC. Preclinical findings in a non-human primate study showed greater than 75 percent knockdown of serum TTR protein levels after 10 days, with the effect sustained over three weeks. No adverse events (AE), including no injection site reactions, were observed using the LUNAR delivery technology.

The company also reported that no AEs were observed at the highest doses (30 mg/kg total; administered three times at 10 mg/kg over 15 days) in a multiple dose rat toxicology study. Serum levels of alanine aminotransferase and aspartate aminotransferase were determined after intravenous administration, and no changes were observed in these liver enzymes.

LUNAR-102 uses the same platform technologies to selectively silence the variant TTR allele V30M to treat familial amyloid polyneuropathy, or FAP.

Arcturus kept up the pace all year, reporting data from preclinical studies in seven of the past nine months. In October, the company presented a poster at the annual meeting of the Oligonucleotide Therapeutics Society in San Diego showing that LUNAR-101 demonstrated a 90 percent reduction in TTR at day 10 and continued reduction of 91 percent at day 20 in non-human primates (n = 3, up to 94 percent) after a single low dose of 0.3 mg/kg.

And last week, Arcturus reported at International mRNA Health Conference in Cambridge, Mass., that LUNAR delivery of synthetic human erythropoietin messenger RNA in non-human primates generated 1000-fold increase of erythropoietin protein with a single low dose (0.3 mg/kg). No safety issues were observed, suggesting LUNAR delivery of messenger RNA was well tolerated.

The company also reported that delivery of chemically modified messenger RNA in LUNAR resulted in rapid expression of protein, within two hours, that persisted for greater than 24 hours.

The next step is to advance LUNAR-101 into a human trial, expected to begin next year and report data in 2016, with the goal of demonstrating safety, tolerability and biological proof of concept. The company completed its pre-investigational new drug application meeting with the FDA "and gained alignment" with the agency on its clinical plan, Payne said.

"As our pipeline progresses, we're going to validate our LUNAR delivery technology and allele selectivity, while our partners are going to further validate UNA in humans," he predicted. "We're in really good shape for a very young company."

Arcturus also is in the midst of raising what Payne described as "a substantial round" that will involve the company's insiders as well as new investors. That financing is expected to close by year-end.

With 13 employees and a recent move into its own space in the former home of Pfizer Labs, Arcturus wants "to establish and build a very prominent and significant company in San Diego," Payne said. Small wonder that Arcturus' name harkens to the brightest star in the northern hemisphere. For now, the sky seems the limit.