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Ionis, Biogen leverage RNA-driven drugs to target Alzheimer's disease marker

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Ionis, Biogen leverage RNA-driven drugs to target Alzheimer's disease marker

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This is the third story in an S&P Global Market Intelligence series focusing on Alzheimer's disease. The healthcare news team will examine promising therapies and the failures that have riddled the drug pipeline along the way.

Though recent mentions of Biogen Inc. have primarily revolved around the latest in a line of failures to treat Alzheimer's disease, the company still has a few tricks up its sleeve, including a partnership with Ionis Pharmaceuticals Inc. that takes a different approach to treat the incurable neurodegenerative condition.

Ionis, based in Carlsbad, Calif., primarily leverages a messenger RNA-focused platform, including antisense RNA, for its medicines. Antisense technology was behind the development of Spinraza, which is approved to treat spinal muscular atrophy and was also developed with Cambridge, Mass.-based Biogen. The researchers use antisense RNA to modify the expression of certain genes, interrupting the production of certain disease-causing proteins.

In Alzheimer's disease, abnormal clumps of proteins called tau tangles and beta-amyloid plaques are seen in the brain and are considered one of the hallmarks of the disease. The Biogen-Ionis treatment, IONIS-MAPTrx, rests on the theory that the tau tangles are disease-causing, and that it can eliminate their negative effects by knocking down production of the proteins using antisense RNA.

Targeting tau with ASO

IONIS-MAPTrx's antisense oligonucleotide mechanism, also known as ASO, is the same platform used for Spinraza. ASO works by using short pieces of DNA or RNA, called oligonucleotides, that modify the way proteins are expressed when they bind to them, based on the antisense and messenger RNA technology.

Spinraza, approved by the U.S. Food and Drug Administration in 2016, was one of the first ASO therapies to reach markets. It is administered via spinal cord injection and alters the SMN2 gene to increase production of SMN protein, which is deficient in patients with spinal muscular atrophy. The deficiency of SMN protein results in the degeneration of neurons that characterizes the disease.

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Stifel analyst Paul Matteis said one of the positives of delivering an anti-tau drug with ASO is that Spinraza provides an existing foundation for ASO's distribution of therapy.

IONIS-MAPTrx, targeting all forms of tau in the brain, would similarly be delivered via spinal cord injection once a month. The drug is in phase 1/2a trials in approximately 44 patients with mild Alzheimer's.

Ionis COO Brett Monia said the spinal cord injection would deliver the medicine directly to the central nervous system to block tau, "unlike antibodies which target [the] protein after it's produced and forms amyloid in the [central nervous system], reducing amyloid from the outside."

"We're blocking the production of the protein before it ever gets out into the system where it could do damage," Monia explained, "whereas other approaches are trying to mop up a disease-causing protein after it's produced and is doing damage to the cells already."

Matteis noted that ASO approaches could target tau both within and outside of the neurons, in contrast to something like a tau-targeting antibody, which would bind and clear extracellular tau only.

However, Matteis said, the consequences of inhibiting all forms of tau are unclear.

"This could be a good thing, as it may prevent newly translated tau proteins from being 'seeded' into a misfolded form," Matteis posited in a March 26 white paper, "but it also could be a bad thing if inhibiting the production of 'healthy' tau proteins with an important biological function has a disruptive impact on neurons."

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Editor's note: Please see our first story in the Alzheimer's in Focus series here: Once considered failures, some Alzheimer's drugs get 2nd chance in new trials. The second story is available here: Academic at UK Dementia Research Institute talks Alzheimer's today.