Restorbio Inc.'s PROTECTOR 1 phase III study failed to meet its primary endpoint and the company shares tracked deeply downward Friday. The trial was designed to evaluate RTB-101 in preventing clinically symptomatic respiratory illness (CSRI) in adults ages 65 and older. RTB-101, an oral, selective target of rapamycin complex 1 inhibitor, will no longer be developed by Restorbio for the indication.

Not only is that program halting but so is initiation of the PROTECTOR 2 phase III study that was set to start by year-end. Top-line data from its anticipated 1,600 patients in the northern hemisphere were expected in the middle of next year.

PROTECTOR 1 was a randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of RTB-101 10 mg given once daily for 16 weeks during winter cold and flu season to subjects 65 and older. The primary endpoint was the percentage reduction of subjects with clinically symptomatic respiratory illness associated with a respiratory tract infection based on prespecified diagnostic criteria, with or without laboratory confirmation of a pathogen. There were 1,024 patients randomized 1-to-1 to receive RTB-101 or placebo administered once daily for 16 weeks. In an analysis of the primary endpoint, the odds of experiencing a CSRI were 0.44 in the placebo cohort and 0.46 in the RTB-101 cohort (odds ratio 1.07, p=0.65). The company wouldn't comment or speculate on results of the secondary and exploratory endpoints.

Restorbio, an independent affiliate of Puretech Health plc, however, will continue developing RTB-101 in other aging-related diseases, including Parkinson's disease (PD).

The stock (NASDAQ:TORC) dropped dramatically after Friday's opening and stayed there as shares closed down 86.29% at $1.09.

In Friday morning's conference call to investors, Chen Schor, Restorbio's co-founder, president, CEO and director, said despite the phase III failure the company is still has money to continue its work.

"We had $117 million in cash and cash equivalents and marketable securities as of Sept. 30," he said. "We will provide updates on the financial guidance in the near term, but we're well-funded to complete the phase Ib/IIa in Parkinson's disease, and we'll have the data in mid-2020. We're well-funded for additional phase II studies in other indications."

Schor said there might be "some minor modification" of the company but that it was premature to discuss any changes, though he added that most "of our expenses have been on our R&D program."

He also said the PROTECTOR 1 data were "surprisingly inconsistent" with what the company found in its phase IIa and phase IIb studies.

"So, we have to do a full analysis of the data to determine if factors such as differences in the baseline characteristics of the IIb and III population or incidence of specific viral infections or differences in the severity of the seasons explain any of these differences in response that we saw between the phase II and phase III study," Schor said.

A little more than a year after first reporting phase IIb results showing oral TORC1 inhibitor RTB-101 reduced the number of respiratory tract infections in older adults, Restorbio illuminated what may be the mechanism behind its efficacy: the up-regulation of innate antiviral immunity. The data, presented at the Infectious Disease Society of America's IDWeek 2019, had put the company on track to move into the two phase III data readouts next year. (See BioWorld, July 26, 2018.)

The phase Ib/IIa in PD was initiated in April to evaluate the safety and tolerability of RTB-101 alone or in combination with sirolimus. Subjects include 45 patients with mild PD who are already on standard-of-care therapy, including those with and without glucocerebrosidase mutations. Five cohorts are dosed once weekly with RTB-101 300 mg alone or in combination with three dose levels of sirolimus (2 mg, 4 mg and 6 mg). The planned primary endpoint is safety and tolerability, and secondary endpoints include exposure in blood, plasma and cerebrospinal fluid (CSF). The planned exploratory endpoints include biomarkers in plasma and CSF, and various clinical assessments. Data are expected in 2020.

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