By Doug Macron
MDRNA this week released in vivo data from its liver and bladder cancer programs, showing that the same RNAi construct, delivered via two different routes of administration, could reduce tumor size in mouse models of the diseases.
"I'm not sure anybody else has talked about the same compound having effect in two separate cancers via two separate routes of administration," MDRNA President and CEO Michael French told RNAi News. "We think that is … in the very least, encouraging."
French also indicated that while MDRNA's liver cancer program has been its lead drug-development effort since early 2009 (see RNAi News, 3/26/2009), the firm's work in bladder cancer has been so promising that it may jump to the head of the pipeline.
Earlier this year, MDRNA CSO Barry Polisky told investors during a conference call discussing the company's second-quarter financials that a lead liver-cancer candidate was expected to be selected by the end of 2009, with an investigational new drug application filing expected in late 2010.
He also said at the time that the bladder cancer program could potentially yield an IND by late 2011 or early 2012.
This week, French confirmed that the two programs were proceeding apace, but said that the order in which the programs move into the clinic could change.
"We still feel very strongly … that we will have an oncology IND by the end of 2010," he said. "But because of the speed at which [the] bladder cancer [effort] is moving forward," this program could be the first to move into human testing.
The liver and bladder cancer programs "are neck and neck at this point," and a final decision on which moves to the IND stage first will depend on a number of factors including a determination on which has a more straightforward path to the clinic, he added.
"The bottom line is still an IND by the end of [2010] in oncology."
The Data
Although MDRNA had said in March that it would focus on a single drug-development program — liver cancer — in order to conserve cash in a troubled economy, less than five months later the company disclosed that it had added bladder cancer to its formal pipeline based on positive in vivo data generated through a collaboration with researchers at the University of British Columbia (see RNAi News, 8/6/2009).
This week, the company publicly released these data, which showed that its proprietary UsiRNA molecules, targeting the cancer-associated protein survivin and delivered intravesically using its DiLA2 liposomal delivery technology, reduced tumor growth in an orthotopic bladder cancer mouse model.
UsiRNAs are duplex siRNAs modified with non-nucleotide acyclic monomers, called unlocked nucleobase analogs, in which the bond between two adjacent carbon atoms of ribose is removed. The DiLA2 platform, meanwhile, allows for the creation of liposomal delivery vehicles from amino acids, as well as the modification of the lipids’ charge, linker, and acyl chains so that delivery can be optimized for specific target tissues.
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Specifically, the mice received intraurethrally administered doses of either the survivin-directed UsiRNAs or control siRNAs at doses of 0.5 mg/kg on days 2, 4, 7, and 9 following tumor implantation.
Bioluminescence revealed reduced tumor growth in the treated animals, and survivin mRNA was found to be inhibited by around 85 percent at day 10, an effect sustained over a three-week period. 5' RACE analysis confirmed the effect was a result of an RNAi mechanism, and no cytokine induction was observed, according to MDRNA.
These data "really got our attention" and helped lead to the decision to add bladder cancer to the firm's pipeline, French said. Follow-up experiments, also unveiled this week, showed that DiLA2-delivered, survivin-targeting UsiRNAs, at doses of either .5 or 1 mg/kg, could inhibit survivin mRNA in orthotopic bladder tumors up through 21 days following tumor implantation.
With regards to liver cancer, MDRNA also released data from experiments in which the same UsiRNA tested in the bladder cancer model was evaluated in an orthotopic liver cancer model.
Delivered intravenously in a DiLA2 liposome formulation at doses of 2 mg/kg at days 18, 21, 24, 27, 29, and 31 following tumor implantation, the RNAi agent significantly inhibited survivin mRNA levels 24 hours following the second dose, according to MDRNA, while no inhibition was observed with a scrambled control sequence.
Additionally, a roughly 65 percent decrease in liver tumor weights was observed in UsiRNA-treated mice at day 51 compared with controls.
"This decrease was comparable to tumor weight reduction with … mice [treated with the chemotherapeutic Avastin] as a positive control," the company said. "A similar level of survivin mRNA knockdown was noted in subcutaneously implanted liver tumors following intravenous administration of the UsiRNA/DiLA2 liposomes."
In these data, "we're seeing positive and encouraging data through systemic and local administration to two different cancers," French noted. "So we think that that's at least encouraging.
"There is obviously more work to do," he added. "If everyone was rewarded for abating tumor growth in mice, the world would be replete with successful accomplishments. [But] that's not what it's about; we have to be able to continue to study this and understand the implications of moving this to humans."