While the top publicly traded RNAi therapeutics developers took great strides this year in getting drug candidates into the clinic, and were rewarded by Wall Street for their efforts, private organizations achieved similar success with their own RNAi compounds, helping round out a successful 12 months for the field.
At the same time, microRNA drug developers have gotten in on the game, moving a handful of drugs based on the small, non-coding RNAs through the clinic or to its doorstep.
One such institute is the MD Anderson Cancer Center, which this year made final preparations for a phase I trial of a cancer drug designed to silence EphA2, a tyrosine kinase receptor in the ephrin family that plays a key role in neuronal development.
EphA2 is highly expressed in many human cancers, particularly ovarian cancer, and it has been shown to function as an oncoprotein in addition to its normal role in neuronal cell migration and development. MD Anderson's compound comprises unmodified siRNAs against the gene that are incorporated in the neutral liposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine, or DOPC.
In 2005, the study's investigators reported published data showing that the drug EphA2 was effective in an orthotopic mouse model of ovarian cancer, reducing tumor growth and "dramatically" enhancing the activity of the chemotherapeutic paclitaxel.
Additional work validating their RNAi approach led the team to seek and secure approval for a phase I trial of the intravenously delivered therapy in up to 40 patients with solid tumors. The trial has not yet officially opened recruitment, however.
Also in 2013, startup CalImmune began a phase I/II trial of an expressed RNAi treatment for HIV.
Called Cal-1, the treatment is based on the work of UCLA AIDS Center's Irvin Chen and the California Institute of Technology's David Baltimore. It involves knocking down CCR5, a chemokine receptor used by HIV as a co-receptor in order to infect cells.
Patients’ T cells and stem cells are isolated from peripheral blood, then treated with the HIV-1 fusion inhibitor C46, as well as a self-inactivating lentiviral vector encoding short hairpin RNAs against CCR5. The cells are then re-infused, with the treated T cells providing immediate protection against the virus and the stem cells offering long-term protection.
The study is designed to enroll 12 patients who will be divided into three treatment cohorts. The first will receive Cal-1 without preconditioning with busulfan, a chemotherapeutic used during bone marrow transplantation procedures and the second and third will receive either one or two initial doses of busulfan prior to Cal-1 treatment.
In addition to RNAi therapeutics, groups working in the microRNA field made significant progress with their own drug candidates including one at Australia's Asbestos Diseases Research Institute, which is set to begin a clinical trial with an miRNA mimic for treatment of the asbestos-related cancer malignant mesothelioma.
Led by former Genesis Research & Development scientist Glen Reid, the ADRI team is focusing on a construct that mimics members of the miR-16 family, which have been shown to inhibit cell growth and induce apoptosis in mesothelioma-derived cells. The payload is delivered using delivery particles, designed by Engeneic, that are based on bacterial minicells and can be targeted to specific tumor cells through the addition of bispecific antibodies on their surfaces.
Unlike most other drug candidates, ADRI's molecule won't initially be tested in phase I. Rather, it's planning a six-patient phase 0 portion — a relatively new stage of clinical testing that is designed to examine the pharmacodynamics and pharmacokinetics of an exploratory therapy. Because these studies involve subtherapeutic doses, they yield no safety or efficacy data.
Should the outcome be positive, the institute hopes to add 24 more patients in a phase I arm of the trial that will examine safety and tolerability.
On the commercial side, Mirna Therapeutics this year became the first to move an miRNA mimic into human testing when it began a phase I trial of MRX34, a synthetic version of miR-34a.
The miRNA is known to play a key role in the p53 tumor-suppressor pathway, and the company has conducted extensive research to establish that it represses the expression of more than 20 oncogenes and inhibits processes required for cancer cell viability, cancer stemness, metastasis, and chemoresistance.
Formulated with Marina Biotech's Smarticle liposomes, MRX34 is being tested in a two-part phase I study will enroll patients with primary liver cancer or advanced metastatic cancer, including lymphoma, with liver involvement.
In the first part of the trial, around 30 patients will receive escalating doses of the drug. Once the maximum tolerated dose is reached, an additional 18 patients with select cancers will be enrolled for a dose-enrichment phase designed to test the drug’s efficacy outside of the liver.
And finally in 2013, privately held Santaris Pharma continued blazing the trail for the miRNA drug space, moving its miRNA inhibitor miravirsen — the most advanced miRNA therapeutic under development — into a phase II study for hepatitis C.
Miravirsen is a locked nucleic acid-modified phosphorothioate antisense oligo that inhibits miR-122, a liver-expressed miRNA shown to play a role in HCV replication. Santaris previously initiated two phase II studies of miravirsen testing multiple doses of the drug.
This year the company kicked off another, examining miravirsen in combination with the antiviral agents telaprevir and ribavirin in up to 20 chronically infected HCV patients who had failed previous treatment.