Positive Early-Stage Data
Despite pharma’s defection from the space, small companies developing siRNA drug molecules are beginning to see glimmers of success, and business deals continue to go forward. As Pfizer left the space in 2010, Marina Biotech announced a product-specific development deal with Debiopharm.
The agreement covers a preclinical-stage bladder cancer program based on the topical delivery of LNP-siRNs. Marina will perform the early development work, funded by Debiopharm, and has the potential to earn milestone-based fees and royalties.
At the 2011 ASCO meeting, Silence Therapeutics reported positive data from its ongoing Phase I study of Atu027 in patients with advanced solid tumors. It is a liposomal siRNA formulation targeting PKN3, which is reportedly a key regulator of angiogenesis and lymphangiogenesis as well as metastasis and motility during pathological processes.
Data showed that nine of the 24 patients treated with the molecule achieved stable disease after repeated treatment. Six of these cases were confirmed at study end (three months after treatment initiation), and three other patients are continuing to receive treatment.
At the same meeting Alnylam reported results from a Phase I trial with its ALN-VSP, a systemically delivered RNAi therapeutic for the treatment of advanced solid tumors with liver involvement. Data showed that ALN-VSP was generally well tolerated, demonstrated evidence for anti-tumor activity, and was found to mediate RNAi activity in both hepatic and extra-hepatic tumors. The study demonstrated evidence of antitumor activity in heavily pretreated patients at doses of 0.7 mg/kg. Disease stabilization occurred in 64% (7 of 11) of patients who received the recommended Phase II dose of 1 mg/kg.
ALN-VSP comprises two siRNAs designed to target two genes required for the growth and development of cancer cells: vascular endothelial growth factor (VEGF) and kinesin spindle protein (KSP), also known as eglin 5 (Eg5). The siRNA drug is formulated using a first-generation lipid nanoparticle developed by Tekmira Pharmaceuticals, Alnylam’s manufacturing partner for LNPs for RNAi drug delivery.
“At a high level, this was a first-in-human study in refractory cancer patients with metastatic disease, including liver involvement,” Akshay Vaishnaw, M.D., Ph.D., Alnylam’s svp of clinical research, pointed out to GEN. “The drug’s safety profile was very encouraging, but beyond safety, we got a lot of interesting mechanistic information.
“We did a series of DCE-MRI tests on the patients before and after treatment. This type of study allows visualization of blood flow through tumors. Since one of the drug components was an anti-VEGF siRNA, we wanted to monitor its effects. We found that 13 of the 28 study patients had a greater than 40 percent reduction in tumor blood flow, which is very comparable to other anti-angiogenic agents.”
Dr. Vaishnaw explained that the investigators also looked for evidence of specific mRNA cleavage in liver biopsies from patients taken before and after treatment. “We could show target mRNA cleavage in tumor biopsies that was present after but not before treatment,” he noted. “That is a very important molecular proof-of-concept for the field of RNAi therapeutics.”
Dr. Vaishnaw also commented on the lipid nanoparticles used in the drug formulation. “We have shown that LNPs provide a tractable way to achieve siRNA delivery. We think that bodes well for other areas of the platform, where we will use these particles for other siRNA applications.”
Alnylam’s drug candidate for transthyretin mediated amyloidosis, ALN-TTR01, uses the same LNP but has an siRNA directed against transthyretin. The company expects data from its Phase I study with ALN-TTR01 in the third quarter of this year. Finally, Alnylam has a Phase II-stage RNAi therapeutic called ALN-RSV01, which is being tested in lung transplant patients infected with respiratory syncytial virus.