NEW YORK (GenomeWeb) – Australia's Asbestos Diseases Research Institute (ADRI) has recently begun enrolling patients in a Phase I trial of a microRNA-based treatment for malignant pleural mesothelioma (MPM), marking the second time a drug based on the small, non-coding RNAs has moved into human testing.
Meanwhile, ADRI continues to plan for a Phase 0 study of the therapy that was supposed to run prior to the Phase I trial, but was put on hold as the institute addressed concerns about how the drug's pharmacokinetics would be evaluated.
MPM is form of cancer caused by the chronic lung inflammation that results from asbestos exposure. While mesothelioma occurs worldwide, Australia has an especially high incidence because it was mined and widely used in the country. Currently, there are no cures for the disease.
As part of an effort to identify biomarkers for the condition, ADRI researcher Glen Reid and colleagues had been analyzing miRNA signatures in tissue samples from mesothelioma patients and discovered that one miRNA — miR-16 — was significantly downregulated in all tumors examined.
In in vitro testing, Reid discovered that introducing miR-16 mimics into mesothelioma-derived cell lines blocked cell growth and induced apoptosis. In vivo, miR-16 mimics — delivered using bacterial minicell-derived particles targeted to specific tumor cells with bispecific antibodies on their surfaces — slowed tumor growth.
As described in a 2013 publication in the Annals of Oncology, expression of miR-15 family members was decreased between 4- and 22-fold in MPM tumor specimens versus normal pleura samples. Tumor cell growth inhibition stemming from treatment with a miR-16 mimic correlated with the downregulation of target genes and sensitized MPM cells to chemotherapy.
In mouse xenograft models, the paper noted, intravenous administration of the minicell-packaged miR-16 mimics led to consistent and dose-dependent inhibition of MPM tumor growth.
Based on these data, and with the support of a A$1.2 million (US$1.1 million) donation, last year ADRI began laying the groundwork for moving its miRNA therapy into human trials in collaboration with Australian biotech firm Engeneic, which developed the minicell delivery vehicles.
As reported by Gene Silencing News, the institute had originally planned to begin with a Phase 0 study — a stage of clinical testing that is designed to examine the pharmacodynamics and pharmacokinetics of an exploratory therapy using subtherapeutic doses — but ran into difficulties when it came to radiolabeling the miRNA drug.
"There were some concerns … that [the labeling] wasn't a very well controlled process and had the potential to compromise of the vehicle itself," Reid said this week. "In the end, the Phase 0 is now on hold and the Phase I is going ahead."
The single-dose, dose-escalating Phase I study will enroll up to 24 patients with MPM or non-small cell lung cancer (NSCLC) who have failed previous treatment, and is designed to assess safety and help determine optimal dosing.
Reid noted that the study is open to both MPM and NSCLC patients as miR-16 downregulation is implicated in both diseases. The first patient in the study is expected to be treated by mid-September, with the trial wrapping up by the end of 2015.
Currently, there is only one other miRNA drug in the clinic — Mirna Therapeutics' cancer drug MRX34, a mimic of miR-34a currently in Phase I testing.
ADRI's he six-patient Phase 0 study remains on hold, but will move ahead once the labeling issue is worked out, Reid noted.
"Because of the nature of the bacterial source of the [delivery vehicles], there is always the possibility that you have some general immune stimulation that could cause some of the [therapeutic] effects," he explained. "That's probably still the case, but it's also nice to see that there is an accumulation and potential delivery of the cargo to the tumor site."
Although ADRI hopes to eventually find an industry partner for its MPM treatment, Reid said that the institute has secured additional funding for the program. This, he said, should fund a 40- to 50-patient Phase II trial that is expected to start immediately after the Phase I wraps up.
Preparations for that follow-on trial are currently underway, Reid said, adding that ADRI is especially confident that the MPM therapy will prove safe in the ongoing study since the minicell delivery particles, known as EDVs, have already successfully been tested in a Phase I study in which they were loaded with the widely used chemotherapeutic paclitaxel.