Welcome to your weekly digest of approaching regulatory and clinical readouts. Interim data are due in the second half of the year from Tocagen’s brain tumour project, comprising Toca 511 delivered directly into resected tumour sites, followed by Toca FC.
And Restorbio is due to report phase IIb data on its mTOR inhibitor RTB101 in the third quarter. Restorbio floated earlier this year, but shares have steadily declined, and RTB101 will have to put in a strong performance to restore investor confidence.
Tocagen’s approach involves infecting glioma cells with an engineered virus called Toca 511 that delivers the gene encoding cytosine deaminase, an enzyme that converts Toca-FC, an inactive precursor, into the chemotherapy 5-fluorouracil.
Toca 511 is injected once into the brain at the time of surgery; oral Toca FC is then given daily over seven-day courses for six weeks after surgery. The aim is to activate the chemotherapy locally to generate high drug levels while reducing systemic exposure and toxicity.
First data should come soon from the open-label phase II/III Toca 5 study in 380 patients with recurrent high-grade glioma – glioblastoma or anaplastic astrocytoma – undergoing resection for first or second recurrence. Overall survival is the primary endpoint, and an interim look once half the patients have died is expected in the second half of the year; a second look at 75% patient deaths is due in 2019.
The study is 85% powered to detect a 31.5% reduction in the risk of death versus standard of care. Assumptions include a median OS of 14.3 months, versus 9.8 months for control.
In a 56-patient phase I study, five of 23 who received Toca FC up to 300mg/kg/day achieved complete responses with a median duration of 36 months. Median OS in all patients in this cohort was 14.4 months, compared with historical rates of 6-9 months.
Toca 511 and Toca FC both have pretty clean safety profiles, with grade three or greater treatment-related severe adverse events of 5.5% and 1.6% respectively. H.C. Wainwright analysts note that standard-of-case lomustine, temozolomide and Avastin have rates of 37%, 57% and 46%, respectively.
Meanwhile, in the third quarter Restorbio will report data from its phase IIb trial of RTB101, an mTOR inhibitor targeting the rapamycin complex 1 pathway and intended to reduce the incidence of respiratory tract infections (RTIs) in elderly subjects – the seventh-biggest cause of death in people aged 65 years and older, according to the company.
The double-blind trial, in 652 patients at an increased risk of RTI-associated morbidity and mortality aged 85 and over, or 65-84 with comorbidities, enrolled elderly subjects enrolled during the winter cold and flu seasons in the southern (part 1) and northern (part 2) hemispheres.
Part 1 involved 179 patients given 10mg or 5mg RTB101 once daily versus placebo. The data-monitoring committee recommended the start of part 2 at the end of last year. This enrolled 473 patients given 10mg RTB101 once or twice daily, or 10mg RTB101 plus 0.1mg Afinitor once-daily, versus placebo. All subjects were treated for 16 weeks, with eight weeks' follow-up.
The primary endpoint is the reduction in the percentage of subjects with RTIs through week 16. The study was 80% powered to show statistical significance for a 40% reduction in RTIs.
In an earlier phase IIa study, run by the project's originator, Novartis, combination of 10mg RTB101 plus 0.1mg Afinitor decreased respiratory tract infections by 58% versus placebo (p=0.038) after six weeks; at one year the reduction was 36%. This trial was initially designed to assess the ability of RTB101 to improve response rates to influenza vaccination, but a noticeable reduction in infections resulted in a focus on RTI prevention.
Novartis licensed RTB101, then known as BEZ235, last year to Restorbio's parent company, Puretech. Novartis has a stake in Restorbio, and the deal calls for future milestones and royalties.
Restorbio raised $98m in a Nasdaq IPO in January, but the shares have since fallen 50%. The company has $135.7m in cash, enough to fund it through 2020, and if the latest data look positive pivotal studies could start next year.