Investigational TORC1 inhibitor observed to reduce respiratory tract infections in elderly with asthma

Joan Mannick

DALLAS — In a phase 2b trial, an investigational TORC1 inhibitor was well tolerated and observed to reduce the incidence of respiratory tract infections in adults aged at least 65 years, including those with asthma, when administered once daily for 16 weeks during winter cold and influenza season, according to data presented at the American Thoracic Society International Conference.

RTB101 (resTORbio) is an oral, small molecule, potent inhibitor of target of rapamycin complex 1, or TORC1, Joan Mannick, MD, chief medical officer of resTORbio, told Healio Pulmonology. TORC1 inhibition has been associated with therapeutic benefit in multiple aging-related conditions in preclinical studies, she said. A prior phase 2a study suggested that TORC1 inhibition may upregulate pan-antiviral immune defenses in the blood of people aged 65 years and older. Upregulation of pan-antiviral immunity has the potential to reduce the incidence of respiratory tract infections which are mainly viral in etiology, she said.

The phase 2b, randomized, double-blind, placebo-controlled trial was conducted to evaluate whether RTB101 alone or in combination with everolimus would enhance immune function and reduce the incidence of respiratory tract infections in an older, high-risk population, including those with asthma.

Researchers enrolled 652 high-risk adults aged at least 85 years, or at least 65 years with asthma, chronic obstructive pulmonary disease, type 2 diabetes or current smokers.

In an analysis of all patient groups combined, RTB101 10 mg once daily for 16 weeks was observed to reduce the percentage of patients who developed laboratory-confirmed respiratory tract infections by 30.6% compared with placebo (P = .025). In a prespecified analysis, patients with asthma were found to be high responders.

Treatment with RTB101 10 mg once daily for 16 weeks was observed to reduce the percentage of patients aged at least 65 years with asthma who developed laboratory-confirmed respiratory tract infections by 68.9% compared with placebo (P = .0001) and also to reduce the percentage of patients with asthma who developed any type of respiratory tract infection, either laboratory confirmed or non-laboratory confirmed, by 58.2% (P = .0002), according to a company press release.

The study also evaluated the impact of treatment on the rate of respiratory tract infections. Compared with placebo, RTB101 treatment was associated with a 78.7% reduction in the rate of laboratory-confirmed respiratory tract infections (P = .001) and a 66.4% reduction in any type of respiratory tract infections (P = .003) in adults aged at least 65 years with asthma, according to the release.

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Treatment was observed to reduce the incidence of respiratory tract infections caused by multiple different viruses in patients with asthma, including rhinovirus, Mannick said during her presentation at the ATS International Conference.

“This is encouraging for asthmatics because the main cause of asthma exacerbations are viral respiratory tract infections,” Mannick told Healio Pulmonology. “The problem is we have nothing to treat or prevent most of these viral infections because there are so many different viruses that cause respiratory tract infections.”

Treatment was well tolerated, with similar adverse events in both the RTB101 10 mg once daily and placebo treatment arms. The rate of severe adverse events was 5.7% with RTB101 vs. 7.8% with placebo and the rate of serious adverse events was 4.5% with RTB101 vs. 7.8% with placebo, according to the results.

“These data presented at ATS show that RTB101 may reduce the incidence of respiratory tract infections caused by multiple viruses, most of which lack current treatments. These findings are particularly encouraging in efforts to prevent not only respiratory infections in high-risk elderly asthma patients, but also the consequences of these illnesses — asthma exacerbations,” William W. Busse, MD, professor of medicine, allergy, pulmonary and critical care medicine at University of Wisconsin, stated in the release. “RTB101 represents a potentially important and novel step forward to improve the treatment of patients 65 years of age and older with asthma, and potentially reduce the risk for asthma exacerbations.”

Research will continue with resTORbio’s PROTECTOR phase 3 clinical trial program with RTB101 in adults aged at least 65 years, including patients with asthma, Mannick said. Patients with chronic obstructive pulmonary disease and current smokers are excluded, based on prior data that suggest RTB101 does not reduce the incidence of respiratory tract infections in these groups, she said. The first phase 3 trial is being enrolled now in the Southern Hemisphere’s winter cold and influenza season and the second phase 3 trial is expected to begin enrollment in November in the Northern Hemisphere during the winter cold and influenza season, she said. – by Katie Kalvaitis

Reference:

Mannick J, et al. Abstract 2623. Presented at: American Thoracic Society International Conference; May 17-22, 2019; Dallas.

Disclosure: Mannick is co-founder and chief medical officer of resTORbio.