Dosing Begins in Trial of ION541, Antisense Treatment for Sporadic ALS

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by Sara Guariglia |

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ION541 trial dosing

A Phase 1/2 clinical trial investigating ION541, Ionis Pharmaceuticals‘ third antisense treatment and its first for sporadic, rather than familial, amyotrophic lateral sclerosis (ALS), has started dosing, the company announced.

This ascending dose safety trial (NCT04494256) is recruiting up to 70 patients without a known genetic history of ALS at four U.S. sites. Information on contacts and site locations can be found here.

“Initiation of this clinical trial for ION541 marks an important milestone in Ionis’ ALS program and reaffirms our commitment to the ALS community,” Frank Bennett, PhD, Ionis’ chief scientific officer, said in a press release.

TDP-43 is an essential protein that, under normal circumstances, binds to RNA and regulates how it is processed inside cells. But in people with neurodegenerative diseases, including ALS, TDP-43 forms protein clumps in nerve cells that contribute to disease.

No current therapies target TDP-43, because of its essential roles, to prevent its toxic clumping. But preclinical data  demonstrated that TDP-43 clumps can be markedly decreased by eliminating a different protein, called ataxin-2.

ION541 is an antisense medicine designed to reduce ataxin-2 levels in motor neurons. It binds to ataxin-2’s mRNA — an intermediate molecule generated from DNA that works as a template for protein production — and targets it for elimination, preventing the production of this protein in cells. In mice models of ALS, the therapy helped these animals live longer.

Ionis has two other ALS therapies — tofersen and IONIS-C9Rx — that work in much the same way, but target proteins often associated with familial ALS. In contrast, ION541 is being developed for the 90% of ALS cases with no known genetic cause.

“As our third medicine designed to treat different forms of ALS to enter clinical trials, ION541 represents yet another example of the power of Ionis’ antisense technology to potentially target root causes of devastating neurodegenerative diseases,” Bennett said.

All three treatments are being developed in collaboration with Biogen,  with the aim of advancing antisense therapies for neurological disorders. Biogen supported Ionis’ initiation of the ION541 study with a $10 million payment.

The trial is recruiting patients with and without certain expansions in the ATXN2 gene — an established risk factor for ALS — and the gene that guides ataxin-2 protein production. All enrolled will be randomized to ascending doses of ION541, or to a placebo, given as intrathecal (into the spinal cord) injections.

Its primary goal is to determine ION541’s safety and tolerability. A key secondary objective is to determine how the treatment behaves once inside the body (its pharmacokinetics). The study is due to conclude in February 2023.

Approved treatments that drew on Ionis’ antisense technology include Spinraza (nusinersen), the first approved treatment for spinal muscular atrophy (SMA) and one approved for all disease types, developed by Biogen, and Tegsedi (inotersen), approved to treat adults with familial amyloid polyneuropathy (FAP).