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Triple A: Arbutus on road to further deals with LNP after $82M Alexion tie-up

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By Randy Osborne
Staff Writer

In what CEO Mark Murray told BioWorld Today may signal "the first of a number of deals," hepatitis B virus (HBV)-focused Arbutus Biopharma Corp. is bringing aboard $7.5 million up front and as much as $75 million in development, regulatory and commercial milestone payments from Alexion Pharmaceuticals Inc. for the lipid nanoparticle (LNP) technology.

Milestones are "spaced out. Some are relatively early and we expect to see them in the next year to two years," Murray said, while others relating to approval and commercialization will take longer, although he pointed out that in rare diseases – where Alexion will be using LNP – "the path to approval is shorter than a lot of conventional products"

Specifically, the "pretty classic" arrangement licenses Arbutus' LNP for exclusive deployment in one of New Haven, Conn.-based Alexion's undisclosed rare-disease programs, and involves directing the platform to delivery of messenger RNA (mRNA) therapy, Murray said. "The field of mRNA and gene editing are becoming quite topical, and in vivo applications of these things will require an LNP agent [for delivery]," he said. "Our experience and clinical validation position us very nicely."

Recent newsmakers in mRNA include Rana Therapeutics Inc., which at the start of the year bought the mRNA replacement therapy platform developed by units of Dublin-based Shire plc, which took an undisclosed equity stake in Rana, of Cambridge, Mass., and is set to receive undisclosed milestones and royalties on products developed. Rana had already identified therapeutic applications for the late preclinical mRNA platform and said it would file its first IND applications over the next 12 to 18 months. (See BioWorld Today, Jan. 5, 2017.)

Arbutus, of Burnaby, British Columbia, has in phase II HBV testing RNA interference (RNAi) candidates ARB-1467 and ARB-1740, the former described as RNAi 1.0 and the latter as RNAi 2.0. "In the last several months" the company has "been able to reduce the HBV surface antigen by about 1 log after three monthly doses," Murray said. "We're continuing to do additional clinical work. I think of [the candidates] together," he added. "With the first agent, we're currently conducting a clinical study in which we are dosing more frequently" and the second, more-potent prospect also is undergoing more work. "Both [trials] are open and enrolling," with data expected in the second half of this year, he said.

More validation for the platform comes from Cambridge, Mass.-based Alnylam Pharmaceuticals Inc.'s RNAi therapeutic patisiran, which targets the transthyretin gene and is in phase III trials for hereditary ATTR amyloidosis with familial amyloid polyneuropathy. A data monitoring committee met in October about the APOLLO trial with the compound and recommended continuation of the trial without modification. Alnylam is developing patisiran in partnership with the Genzyme unit of Sanofi SA, of Paris. Results from a phase II trial in ATTR showed statistically significant (p < 0.001) knockdown of serum TTR protein levels of up to 96 percent. Knockdown of TTR, the protein thought to cause the disease, was rapid, dose-dependent and durable, and similar activity was observed toward both wild-type and mutant protein. Multiple doses of patisiran, also known as ALN-TTR02, were found to be generally safe and well tolerated, with no significant adverse events or discontinuations associated with drug up through a dose of 0.3 mg/kg. The trial was designed to treat up to 30 ATTR polyneuropathy patients with patisiran administered at doses of 0.01 to 0.3 mg/kg, using once-every-four-week or once-every-three-week dosing. Twenty-five patients in eight cohorts were dosed in the global study. According to Alnylam, as little as a 50 percent reduction of TTR can result in disease improvement or stabilization. Randomized, double-blind, placebo-controlled APOLLO will assess efficacy and safety. (See BioWorld Today, Nov. 12, 2013.)

Also, under the terms of the Alexion deal, Arbutus will conduct technology development and provide manufacturing as well as regulatory support to advance the mRNA bid. Given the "features of effective LNP technology, we're primarily talking about delivery to the liver," Murray said. "That's where the real sweet spot is. Without commenting on what Alexion is doing, there are a number of rare-disease applications that are significant in the liver."

In such deals, "there's generally an element of collaboration or technology development where we provide expertise in addition to the economics you see here," Murray said, but the structure is always intended as "accretive [for Arbutus]. We're not using the resources we would otherwise apply to our HBV programs to support these programs. They're fully supported" by the other party, especially in the later stages. Early on, "we're not at their elbow but we are close. We want these partners to be successful, and we're the world leaders in this technology" so Arbutus aims to "get the product configured and developed. In some cases we will actually be carrying out experiments. When [the candidate] evolves further, into the clinic, we can provide consulting on regulatory questions." The Alnylam deal, he said, is "a bit different [from Alexion's] because we're way past the milestone stage. They're pushing toward product approval and we'll get a royalty."