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Arcturus Touts Dosing, Specificity of ATTR Drugs as They Move Toward Clinic

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NEW YORK (GenomeWeb) – RNAi startup Arcturus Therapeutics this week released new preclinical data on its lead transthyretin-mediated amyloidosis (ATTR) candidate LUNAR-101, showing that a single dose of the drug could cut levels of its target by more than 90 percent in non-human primates (NHPs) for nearly three weeks.

The findings, the company said, support its plan to pursue a once-monthly dosing regimen for the drug in clinical trials.

Meanwhile, Arcturus also announced data demonstrating that its unlocked nucleobase analog (UNA) chemistry could enable potent, allele-specific gene knockdown in ATTR in vitro. This approach is being used in a second ATTR drug, called LUNAR-102, which is in early-stage development.

Arcturus was founded in early 2013 by two former Nitto Denko researchers, who had played a key role in moving that company's siRNA-based fibrosis drug ND-L02-s0201 into the clinic around a proprietary delivery technology called Lunar that comprises lipid nanoparticles designed to degrade in the body to prevent undesirable accumulation.

Rounding out Arcturus' technology platform are its UNAs, which are essentially acyclic ribonucleoside analogs in which the bond between the C2' and C3' atoms is broken. The resultant change in sugar structure is designed to make the analogs flexible and reduce the binding affinity of siRNA strands.

Arcturus acquired the UNA patent estate from Marina Biotech last year. However, Arcturus' rights do not affect non-exclusive licenses to the technology that had already been granted to Tekmira Pharmaceuticals and Arrowhead Research.

About one year ago, Arcturus announced the closing of a $5 million Series A round, which came just months after the company pulled in $1.5 million in seed financing. Shortly thereafter, the company disclosed that its first therapeutic focus would be on ATTR.

The disease is caused by mutations in the transthyretin (TTR) gene, which leads to the accumulation of abnormal amyloid proteins in the body. One form of the disease, known as familial amyloid cardiomyopathy (FAC), damages heart tissue. Another manifestation, called familial amyloid polyneuropathy (FAP), primarily affects the peripheral nervous system.

The move caught the attention of industry watchers given that Alnylam Pharmaceuticals has its own ATTR program with one drug, patisiran, in Phase III for FAP and another, ALN-TTRsc, in Phase II for FAC. But Arcturus is betting that its technologies give it a competitive advantage over Alnylam in both indications.

According to the newly released NHP data, a single .3-mg/kg dose of LUNAR-101, which is being developed for FAC, can lower TTR levels in the animals by 90 percent 10 days after administration, with a continued reduction of 91 percent at day 20.

Based on these and other data, Arcturus anticipates that it will be able to successfully treat FAC patients with a one-monthly dosing regimen that would coincide with a patient's normal physician visit. Arcturus CSO/COO Pad Chivukula told Gene Silencing News that this compares favorably to the dosing schedule Alnylam is testing with ALN-TTRsc. In the ongoing Phase II study, Alnylam is treating patients once a day for five days with subcutaneous infusions of its drug, followed by once weekly treatments.

Receiving treatment once a month, he added, is expected to be more convenient for FAC patients, who tend to begin experiencing symptoms after the age of 60 and might be less tolerant of frequent drug infusions.

When it comes to LUNAR-102, Arcturus is betting that its specificity will prove to be the key differentiating factor. Both patisiran and ALN-TTRsc are designed to inhibit mutated and wild-type forms TTR. But because FAP patients present much earlier in their lives, they will require treatment much longer than FAC patients and extended knockdown of wild-type TTR may have unexpected adverse effects.

With its UNA chemistry, Arcturus believes it will be able to silence only mutant TTR while leaving the normal form unaffected. In the data released this week, the company noted that it was able to silence the V30M variant of TTR, the mutation most common in FAP, more than 100-fold over the wild-type allele in cell culture with UNA-modified siRNAs.

Chivukula noted that Arcturus opted not to take an allele-specific approach with LUNAR-101 because it believes rapid stabilization of the disease to be more important in this older patient population than avoiding any untoward effects associated with long-term wild-type TTR suppression.

In terms of clinical development, Chivukula said that Arcturus has already had a pre-investigational new drug meeting with US regulators regarding LUNAR-101 and is in the process of manufacturing the drug for toxicology studies that are slated to begin in early 2015. Phase I testing, he added, should begin in the second half of next year.

As for LUNAR-102, Arcturus is still in the process of selecting an siRNA payload, but Chivukula said that he expects human testing to begin in 2016.

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