New Inhaled Therapy IONIS-ENAC-2.5Rx Shows Promise in Phase 1/2a Trial

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by Teresa Carvalho MSc |

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pneumonia and genetics

Ionis Pharmaceuticals’ investigational inhaled therapy IONIS-ENAC-2.5Rx showed promise in a Phase 1/2a study as a potential new treatment for cystic fibrosis (CF), the company announced, citing trial data.

That clinical data showed that ENAC-2.5Rx led to a reduction in the expression of ENaC, a sodium transport channel that’s highly increased in the lungs of people with CF.

ENaC’s overactivity causes dehydration and a decrease in mucus clearance in the lungs of CF patients, which can lead to persistent infections and damage, and increase lung function decline.

IONIS-ENAC-2.5Rx is an RNA therapy designed to decrease the production of ENaC. It delivers specific antisense oligonucleotides to the lungs, which bind the messenger RNA (mRNA) of ENaC and target it for degradation, preventing the production of ENaC proteins. Of note, mRNA is the intermediate molecule generated from DNA that serves as a template for protein production.

“We are very encouraged by these data, which demonstrate attractive tolerability and safety for IONIS-ENAC-2.5Rx with substantial target reduction and the convenience of once weekly administration,” Brett P. Monia, PhD, CEO of Ionis Pharmaceuticals, said in a press release.

The ongoing, randomized, placebo-controlled Phase 1/2a study (NCT03647228) evaluated the effect of single and multiple ascending doses of IONIS-ENAC-2.5Rx in healthy volunteers and CF patients.

The primary goal of the study was to assess the therapy’s safety and pharmacokinetics — its movement into, through, and out of the body — delivered via a nebulizer (Pari eFlow).

A total of 32 participants in one part of the study, who were randomly divided into four groups, each received a single dose of 3, 10, 37.5, or 100 mg of IONIS-ENAC-2.5Rx and were followed for 30 days. Multiple ascending doses of 10, 37.5, or 75 mg were given to 24 other participants in another part of the study. These individuals received the therapy once a week, with an additional dose administered during the first week.

An additional group of eight participants received a 37.5 mg dose three times a week, up to 10 doses.

Early data from the study showed a mean 55.6% decrease in the amount of ENaC mRNA levels in healthy volunteers, after treatment with the 75 mg dose of IONIS-ENAC-2.5Rx.

Previous studies in mouse models of CF had shown a significant reduction in ENaC mRNA levels with antisense oligonucleotides, resulting in a decrease of mucus accumulation and inflammation — both hallmarks of CF — and improved lung function.

Now, for the first time, a clinical study shows a significant decrease in ENaC mRNA levels through an antisense therapy that is directly delivered to the lung through a nebulizer — aerosol delivery. According to Ionis, the device ensures a broad distribution of the medicine in the lung while minimizing its systemic toxicity.

The findings “confirm our expectations for aerosol delivery of antisense medicines for lung diseases based on a wealth of preclinical data,” Monia said.

IONIS-ENAC-2.5Rx is one of Ionis Pharmaceutical’s investigational antisense therapies. Still this year, the company intends to start a clinical study to evaluate IONIS-ENAC-2.5Rx in patients with chronic obstructive pulmonary disease who have chronic bronchitis — inflammation of the bronchial airways.

“These results point to the exciting potential for aerosol delivery of other Ionis medicines that we plan to advance to the clinic, including treatments for chronic obstructive pulmonary disease, or COPD, and severe asthma,” Monia said.

These findings will be presented in a poster at the virtual sessions of the ongoing 2020 North American Cystic Fibrosis Conference (NACFC), which will have live sessions and discussions taking place Oct. 21–23.


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