2020-10-15| Technology

Ionis’ Inhaled Antisense Medicine Could Signal Decline for Cystic Fibrosis Medical Devices

by Eduardo Longoria
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By Eduardo Longoria

Ionis Pharmaceuticals, Inc. is a leader in antisense therapeutics. On October 13th, it announced positive clinical trial data of IONIS-ENAC-2.5Rx, an investigational antisense medicine designed to reduce the expression of the epithelial sodium channel (ENaC) in the lung. ENaC is believed to be hyperactive in cystic fibrosis caused by mutations in the cystic fibrosis transmembrane regulator gene.

The study demonstrated a significant decrease in the expression of ENaC in subjects with cystic fibrosis (CF) with a mean 55.6% decrease (p<0.05) in ENaC mRNA expression at the 75 mg dose in the multidose segment of the trial. The study marks the first time an antisense medicine delivered directly to the lung via a nebulizer has shown a significant reduction in ENaC messenger RNA levels. In preclinical studies, ENaC mRNA reductions of 40 percent or more resulted in significant improvement in mouse models of CF lung disease.


Cystic Fibrosis

Cystic fibrosis, a life-threatening disease affecting approximately 70,000 worldwide, is a multisystem disease. Despite this fact, the main cause of morbidity and mortality is a lung disease characterized by small airway obstruction due to mucus accumulation, decreased mucus clearing, and subsequent inflammation, infections, and lung function decline. Data from the Phase 1 study will be presented at the 2020 North American Cystic Fibrosis Conference via e-poster in late October.

“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. The data also confirm our expectations for aerosol delivery of antisense medicines for lung diseases based on a wealth of preclinical data,” said Brett P. Monia, Ph.D., Ionis’ chief executive officer. “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.”

IONIS-ENAC-2.5Rx is one of more than 20 potentially transformative antisense medicines in the company’s growing pipeline. The company also plans to initiate a clinical study to evaluate IONIS-ENAC-2.5Rx in patients with COPD associated with chronic bronchitis starting later this year.


Clinical Trial

The study’s primary endpoint was the evaluation of safety and pharmacokinetics of IONIS-ENAC-2.5Rx delivered via a ParieFlow mesh nebulizer. In the single escalating dose study, 32 subjects in four cohorts received a single dose of 3, 10, 37.5, or 100 mg and were followed for 30 days. In the multiple ascending dose study, 24 subjects in three cohorts received four doses of 10, 37.5, or 75 mg once weekly, with an additional dose administered during the first week. An additional cohort of eight subjects received a 37.5 mg dose given thrice weekly for 10 doses. Subjects were followed for 13 weeks after dosing. Fiberoptic bronchoscopy, including bronchial brushings and bronchoalveolar lavage, was performed during screening and after dosing in the MAD cohorts. Quantitative RT-PCR was performed from the bronchial cell brushings to evaluate ENaC mRNA levels.


Antisense Technology

As the leader in RNA-targeted drug discovery and development, Ionis has created an efficient, broadly applicable drug discovery platform called antisense technology to treat diseases for which no other therapeutic approaches have proven effective. Ionis created the first and only approved treatment for children and adults with spinal muscular atrophy and the world’s first RNA-targeted therapeutic approved for the treatment of polyneuropathy in adults with hereditary transthyretin amyloidosis. Our sights are set on all the patients we have yet to reach with our pipeline of novel medicines designed to potentially treat a broad range of diseases, including neurological, cardio-renal, metabolic, infectious, and pulmonary diseases.

Current treatments for cystic fibrosis include vest therapy and percussive therapy to attempt to clear the excess mucus out of the respiratory tract. In addition to the treatments, the disease can escalate to the point of requiring surgery and lung transplants. With the rise of more advanced medications that focus on the underlying cause of the disease, faulty CFTR protein, or the underlying gene in the case of IONIS-ENAC-2.5Rx, treatment becomes faster, less invasive, and cheaper.

As a result, the medical devices that treat CF and the companies that produce them will likely see a drop in demand as these medications become more common. Given the increased convenience of taking medication instead of coughing up mucus, despite the mechanical assistance, it is likely a good deal of CF sufferers will choose medications like IONIS-ENAC-2.5Rx.

Related Article: An Outlook on the Evolution of Cystic Fibrosis Care



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