Conference Coverage

mTORC1 inhibitor protects elderly asthmatics from viral respiratory tract infections



– A molecule that boosts innate viral immunity may protect elderly people with asthma from the root cause of most exacerbations – viral respiratory tract infections.

Dr. Joan Mannick, chief medical officer of resTORbio, Boston Michele G. Sullivan/MDedge News

Dr. Joan Mannick

Dubbed RTB101, the oral medication is a selective, potent inhibitor of target of rapamycin complex 1 (TORC1). In phase 2b data presented at the American Thoracic Society’s international conference, RTB101 decreased by 52% the number of elderly subjects with severe, lab-confirmed respiratory tract infections (RTI) symptoms.

But the molecule was even more effective in patients with asthma aged 65 years and older, Joan Mannick, MD, said in an interview during the meeting. In this group, it reduced by 69% the percentage of subjects who developed RTIs and reduced the rate of infection by about 79%, compared with placebo.

“The core cause of asthma exacerbations in these patients is viral respiratory tract infection,” said Dr. Mannick, chief medical officer of resTORbio, the Boston company developing RTB101. “About 80% of the viruses detected in these infections are rhinoviruses, and there are 170 rhinovirus serotypes. We have never been able to develop a vaccine against rhinovirus, and we have no treatment other than to treat the inflammation caused by the infection.”

Centers for Disease Control and Prevention mortality records confirm the impact of viral respiratory infections on older people who experience asthma exacerbations: 6 of 10,000 will die, compared with less than 2 per 10,000 for all other age groups. Decreasing the number of these infections in older people with asthma would prevent morbidity and mortality and save considerable health care dollars.

“One of the reasons that asthmatics have such difficulty when they get respiratory infections is that they seem to have deficient antiviral immunity in the airways,” Dr. Mannick said. She pointed to a 2008 study of bronchial epithelial cells from both patients with asthma and healthy controls. When inoculated with rhinovirus, the cells from asthmatic airways were unable to mount a healthy immune response and were particularly deficient in producing interferon-beta.

By inhibiting mammalian TORC1 (mTORC1), RBT101 also inhibits sterol regulatory element binding transcription factor 2, a pathway that influences cholesterol synthesis. Cells perceive cholesterol synthesis attenuation as a threat, Dr. Mannick said, and react by up-regulating a number of immune response genes – including some specifically antiviral genes that up-regulate interferon-alpha and -beta production and immune cytokine signaling pathways.

RTB101 is not a particularly new molecule; Novartis originally investigated it as an anticancer agent. “It failed, because it was too selective for mTORC1,” Dr. Mannick said. After Novartis dropped the molecule, resTORbio, a Novartis spin-off, began to investigate it as an immunotherapy for RTIs, particularly in patients with asthma.

reSTORbio’s phase 2 studies on RTB101 comprised 264 healthy subjects aged 65 years and older, who received placebo or 10 mg RTB101 daily for 6 weeks, during cold and flu season. They were followed for a year, confirming the antiviral gene up-regulation. Treatment was also associated with a 42% reduction in the rate of respiratory tract infections.

Conversations with the Food and Drug Administration and payers collected, Dr. Mannick said. “They said that where this drug could really make a difference was if it could decrease these infections in high-risk elderly, who are expensive to treat. So, we targeted people 65 years and older with asthma, chronic obstructive pulmonary disease, and smokers, and people who are 85 years or older.”

The phase 2b trial comprised 652 of these elderly high-risk subjects randomized to the following treatment arms: RTB101 5 mg once daily (n = 61), RTB101 10 mg once daily (n = 176), RTB101 10 mg b.i.d. (n = 120), RTB101 10 mg plus everolimus 0.1 mg daily (n = 115), or matching placebo (n = 180) over 16 weeks, during the entire cold and flu season. The primary endpoint was laboratory-confirmed RTIs in all groups.

The RTB101 10-mg, once-daily group had the best results with a 30.6% reduction in the percentage of patients with lab-confirmed RTIs, compared with placebo, and a 52% reduction in the percentage with severe symptoms.

A subgroup analysis found even more benefit to those with asthma. Among these patients, RTB101 effected a 58.2% decrease in patients with RTIs, and a 66.4% decrease in the rate of infections, compared with placebo.

RTB101 was most effective against rhinoviruses, but it also prevented RTIs associated with influenza A and coronavirus OC43. It also decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

There were no safety signals, Dr. Mannick noted. Adverse events were similar in both placebo and active groups, and none were deemed related to the study drug. About 5% of each group discontinued the drug because an adverse event.

Plans for a phase 3 trial are underway. A phase 3, placebo-controlled study in the Southern Hemisphere is now ongoing, during the winter cold and flu season. The Northern Hemisphere phase 3 will commence fall and winter of 2019.

Whether RBT101 can help younger people with asthma is an open question. Elderly patients not only have the asthma-related immune deficiency, but also the general age-related immune issues. Younger patients, however, still express the same asthma-related impairment of bronchial immunity.

“We would like to investigate this in younger people and in children, but that will have to wait until our other phase 3 studies are complete,” Dr. Mannick said.

The trial was sponsored by resTORbio.

SOURCE: Mannick J et al. ATS 2019, Abstract A2623.

CORRECTION 5/24/2019 The article was corrected to state a decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

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