Perspective

New compound from resTORbio reduces RTI incidence in elderly patients

Positive topline results have been announced from the phase 2b clinical trial that evaluated an appropriate dose range for RTB101 and demonstrated statistically significant reductions in the incidence of respiratory tract infections.

“This phase 2b has successfully defined a dose, RTB101 10 mg once daily, to be evaluated in future pivotal studies,” Joan Mannick, MD, cofounder and chief medical officer of resTORbio, said in a press release. “That dose led to a statistically significant decrease in the incidence of laboratory-confirmed RTIs and was well-tolerated in the high-risk elderly patients enrolled in the phase 2b study.”

According to the release, the randomized, double-blind, placebo-controlled clinical trial enrolled 652 patients at an increased risk for morbidity and mortality from respiratory tract infections (RTI). Patients included in the study were either aged 85 years and older or were aged 65 years or older and had asthma, type 2 diabetes mellitus, chronic obstructive pulmonary disease or were current smokers. The different dosing methods of RTB101 — an oral compound inhibitor of target of rapamycin complex1 (TORC1) — were reviewed in two regions and the study was broken down into two parts with a 16-week treatment period.

Researchers investigated a dose range of 5 mg and 10 mg once-daily dosing during the first part of the trial, which was conducted in the winter cold and flu season in the southern hemisphere. The second part of the clinical trial was conducted in the same season but in the northern hemisphere and investigated a dose range of 10 mg once daily and twice daily, as well as a once daily combination of 10 mg of RTB101 and 0.1 mg of everolimus.

Compared with placebo, the incidence of one or more laboratory-confirmed RTIs was reduced by 20.6% in all patients treated with RTB101 5 mg daily (P = .018). A “statistically significant and clinically meaningful” 30.6% reduction was observed in all patients treated once daily with RTB101 10 mg (P = .026), according to the company. However, the percentage of patients with one or more laboratory-confirmed RTIs was not reduced when treated with RTB101 10 mg twice daily or the combination of 10 mg of RTB101 and 0.1 mg of everolimus once daily. resTORbio suggested that in high-risk elderly patients, less TORC1 inhibition with RTB101 10 mg once daily may be more beneficial.

The study also conducted a prespecified analysis of patient subgroups and compared the RTB101 10 mg once daily cohort with the placebo cohort. In all asthma patients, a 68.4% decline in RTIs was observed. Additionally, all patients aged 85 years and older and all patients with type 2 diabetes had an RTI incidence reduction rate of 66.7% and 26.9%, respectively. No incidence reduction was found in patients with chronic obstructive pulmonary disease or in those who were current smokers, according to the study. However, when patients with chronic obstructive pulmonary disease were excluded, a 42% decrease in RTI incidence was reported (P =.002) for all patients and a 43.9% reduction was observed in all patients when current smokers were excluded (P = .001).

RTB101 with a dosing range of 10 mg once was found to be well-tolerated, and resTORbio looks to further study the compound as a preventive treatment for RTIs in high-risk populations.

“We believe the findings of this trial provide us with a clear path forward for pursuing a pivotal program for RTB101 to reduce the incidence of RTIs in high-risk elderly patients,” Mannick added. “We look forward to working closely with the FDA and other regulatory agencies on this program.”

Disclosure: Mannick founded and currently works for resTORbio.

Positive topline results have been announced from the phase 2b clinical trial that evaluated an appropriate dose range for RTB101 and demonstrated statistically significant reductions in the incidence of respiratory tract infections.

“This phase 2b has successfully defined a dose, RTB101 10 mg once daily, to be evaluated in future pivotal studies,” Joan Mannick, MD, cofounder and chief medical officer of resTORbio, said in a press release. “That dose led to a statistically significant decrease in the incidence of laboratory-confirmed RTIs and was well-tolerated in the high-risk elderly patients enrolled in the phase 2b study.”

According to the release, the randomized, double-blind, placebo-controlled clinical trial enrolled 652 patients at an increased risk for morbidity and mortality from respiratory tract infections (RTI). Patients included in the study were either aged 85 years and older or were aged 65 years or older and had asthma, type 2 diabetes mellitus, chronic obstructive pulmonary disease or were current smokers. The different dosing methods of RTB101 — an oral compound inhibitor of target of rapamycin complex1 (TORC1) — were reviewed in two regions and the study was broken down into two parts with a 16-week treatment period.

Researchers investigated a dose range of 5 mg and 10 mg once-daily dosing during the first part of the trial, which was conducted in the winter cold and flu season in the southern hemisphere. The second part of the clinical trial was conducted in the same season but in the northern hemisphere and investigated a dose range of 10 mg once daily and twice daily, as well as a once daily combination of 10 mg of RTB101 and 0.1 mg of everolimus.

Compared with placebo, the incidence of one or more laboratory-confirmed RTIs was reduced by 20.6% in all patients treated with RTB101 5 mg daily (P = .018). A “statistically significant and clinically meaningful” 30.6% reduction was observed in all patients treated once daily with RTB101 10 mg (P = .026), according to the company. However, the percentage of patients with one or more laboratory-confirmed RTIs was not reduced when treated with RTB101 10 mg twice daily or the combination of 10 mg of RTB101 and 0.1 mg of everolimus once daily. resTORbio suggested that in high-risk elderly patients, less TORC1 inhibition with RTB101 10 mg once daily may be more beneficial.

The study also conducted a prespecified analysis of patient subgroups and compared the RTB101 10 mg once daily cohort with the placebo cohort. In all asthma patients, a 68.4% decline in RTIs was observed. Additionally, all patients aged 85 years and older and all patients with type 2 diabetes had an RTI incidence reduction rate of 66.7% and 26.9%, respectively. No incidence reduction was found in patients with chronic obstructive pulmonary disease or in those who were current smokers, according to the study. However, when patients with chronic obstructive pulmonary disease were excluded, a 42% decrease in RTI incidence was reported (P =.002) for all patients and a 43.9% reduction was observed in all patients when current smokers were excluded (P = .001).

RTB101 with a dosing range of 10 mg once was found to be well-tolerated, and resTORbio looks to further study the compound as a preventive treatment for RTIs in high-risk populations.

“We believe the findings of this trial provide us with a clear path forward for pursuing a pivotal program for RTB101 to reduce the incidence of RTIs in high-risk elderly patients,” Mannick added. “We look forward to working closely with the FDA and other regulatory agencies on this program.”

Disclosure: Mannick founded and currently works for resTORbio.

    Perspective
    William Schaffner

    William Schaffner

    I found this to be a provocative study. It’s the first I heard of it. I would like to learn more about the basic biology and how this compound works. Beyond that, there is no doubt that respiratory infections are a major cause of illness — serious illness — in older persons, particularly those with asthma and other underlying illnesses. We know that the vaccines currently available are good but not perfect, and anything that we can do to prevent respiratory infections in this highly vulnerable population would be a good thing. Providing a prophylactic medication through the winter respiratory infection season would be a new way — a novel way — to achieve prevention.

    These are populations for whom we provide influenza and pneumococcal immunization and there are research programs that would provide respiratory syncytial virus vaccines. Down the road, we might, see a combination of several vaccines and, perhaps, a preventive drug such as this that might very substantially reduce the risk of serious respiratory infections in older persons, people with asthma and other vulnerable populations.

    It remains to be seen exactly how well RTB101 is in achieving prevention, which specific viral infections are prevented and how severe they are and the acceptability of the compound on the part of providers — who would have to be educated about this — and patients. Of course, as we move from small to larger studies, the issue of safety will be paramount.

    • William Schaffner, MD
    • Infectious Disease News Editorial Board member
      Professor of preventive medicine at Vanderbilt University

    Disclosures: Schaffner reports that he is a member of Data Safety Monitoring Boards on behalf of Merck and Pfizer. He also is an occasional consultant for Dynavax, Seqirus, SutroVax and Shionogi.