FDA Acts to Support Development of Ionis Therapy ION582

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by Patricia Inacio, PhD |

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The U.S. Food and Drug Administration (FDA) has granted both orphan drug and rare pediatric disease status to ION582, Ionis Pharmaceutical’s investigational treatment for Angelman syndrome.

The announcement of the new FDA designations — both aimed at encouraging the therapy’s development — follows the launch of the Phase 1/2a HALOS clinical trial (NCT05127226). That open-label study will assess the safety and tolerability of ascending doses of ION582 injected directly into the spinal canal in children and adults with the neurological disorder.

The therapy’s pharmacokinetics and pharmacodynamics also will be assessed as part of the trial. Pharmacokinetics refers to the movement of a medicine into, through, and out of the body, while pharmacodynamics is defined as the effects of a compound on the body

An estimated 44 patients, ages 2 to 50, will be enrolled in the new HALOS trial. Recruitment is ongoing for the two trial sites — Rush University Medical Center, in Chicago, and the University of North Carolina at Chapel Hill School of Medicine, in North Carolina.

“Receiving FDA orphan drug designation for ION582 reflects the important and urgent need for delivering an effective treatment to patients living with Angelman syndrome,” C. Frank Bennett, PhD, executive vice president, chief scientific officer, and franchise leader for neurological programs at Ionis, said in a press release.

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“Ionis is committed to working closely with regulators, clinical investigators, patients and caregivers to advance this novel treatment and make it available to those who need it,” Bennett added.

Orphan drug designation aims to encourage the development of therapies for rare diseases, defined as those affecting fewer than 200,000 patients in the U.S. It carries a series of benefits that include exemption from FDA fees, financial incentives for clinical development and commercialization, and seven years of market exclusivity, if granted approval.

In turn, a rare pediatric disease designation is given to therapies for serious or life-threatening rare diseases that primarily affect individuals from birth to age 18.

The designation includes a voucher program from the FDA which, if ION582 is ultimately approved, allows Ionis to request priority review of a subsequent experimental medication. It may sell the voucher to another company.

In people with Angelman, mutations in the maternal copy of the UBE3A gene prevent a working UBE3A protein from being made. While each person receives two copies of this gene — one from each biological parent — in certain areas of the brain, only the UBE3A copy inherited from the mother is active.

ION582 is designed to “turn on” the paternal copy of the UBE3A gene that is often “silenced” by a molecule called Ubiquitin Protein Ligase E3A-Antisense Transcript (UBE3A-ATS). ION582 blocks UBE3A-ATS, which “unsilences” the UBE3A gene.

In preclinical studies with cells from Angelman patients and a mouse model of the disease, this strategy proved successful with the blocking of UBE3A-ATS effectively “turning on” the silenced paternal gene.