HIV is a hot indication for potential RNAi-based therapeutics and CombiMatrix is getting ready to join the action. The Newport Beach, Calif.-based company said this week that its ongoing collaboration with Spanish non-profit research institute IrsiCaixa has yielded two promising siRNAs with anti-HIV activity, which are now being prepared for in vivo testing.
CombiMatrix began working with IrsiCaixa researcher Bonaventura Clotet in June last year to conduct efficacy screens of various siRNA compounds against HIV-1. This deal “included compounds that we created and compounds they created,” CombiMatrix president and CEO Amit Kumar told RNAi News. “In the end, we felt that the information we were getting was very valuable and we had a real opportunity to develop, downstream, some potential drugs.”
According to Kumar, this information includes in vitro data on an siRNA that targets the gene that codes for HIV-1 reverse transcriptase — the enzyme used by retroviruses to convert RNA into DNA that is incorporated into the genome of host cells — and one that targets the gene encoding HIV-1 Nef — a regulatory protein that modulates a host’s immune system to facilitate HIV replication. Both siRNAs were synthesized by IrsiCaixa.
“We’re finding [that] the two sequences, which we are not prepared to identify yet … appear to inhibit the virus as well, if not better, than anything else that has been seen so far in the literature,” Kumar said.
Kumar said that CombiMatrix and IrsiCaixa researchers have found that the siRNAs, individually or together, were able to inhibit HIV-1 replication in an infected transformed leukemia cell line by between 500- to 1000-fold versus control siRNA. “I can’t comment on anything that’s in people’s laboratories [and] hasn’t been published, but we haven’t seen anything better” than these siRNAs, he said.
Based on these early data, the company is planning to advance the siRNAs into animal testing, Kumar said. “It’s not clear whether we’ll use them in combination or use them individually, but [they] definitely warrant further study.”
Kumar declined to offer a timeline for when animal or human studies might begin — although in March he told RNAi News that an investigational new drug application on one of the compounds could be ready next year — but said that “the next step right now is to focus on developing delivery methods. We’ve started the process and we’re looking at things like standard liposome formulations to some more sophisticated formulations I’d rather not discuss at this time.”
To help move this process along, CombiMatrix has struck a three-year deal under which IrsiCaixa will receive funding totaling less than $500,000 in exchange for conducting research in HIV, hepatitis C, and vector development on behalf of CombiMatrix. Earlier this year, CombiMatrix expanded its research and development relationship with IrsiCaixa to include work on siRNAs targeting hepatitis C (see RNAi News, 3/26/04).
Under the deal, IrsiCaixa will also “support any other thing that we’re going to be doing, including mouse trials and maybe eventually human trials,” Kumar said. Should the siRNA compounds enter human studies, IrsiCaixa stands to receive low six-figure milestone payments — “like $100,000-$150,000,” Kumar noted. If the products reach the market, IrsiCaixa will be entitled to low-single digit royalties, he said.
CombiMatrix holds the exclusive, worldwide rights to the siRNAs.
“It’s a joint development program,” Kumar said. “It’s a way for us to not have to build up a huge infrastructure to do HIV research, when we’ve got our collaborator who has already sunk the capital cost to do that. We’re just providing them some operating costs, while we’ll be moving forward with other types of things like partnership discussions.”
Since speaking with RNAi News in March, Kumar has maintained that CombiMatrix is not likely to bring its siRNA drug candidates through clinical trials on its own, a position he reiterated this week: “The key is, we don’t plan to develop these compounds from start to finish all the way,” he said.
“Long-term, we plan to do a partnership … or multiple partnerships,” Kumar said. “Whether [they’re] delivery partnerships or clinical partnerships, it’s hard to say right now.” He said that heretofore partnering discussions have been limited to potential collaborators on drug delivery, adding that the preliminary stage of the siRNAs’ development makes discussions over a broader partnership — one encompassing clinical development and commercialization, for example — premature.
Despite this, Kumar anticipates that any future wide-scale partnership would likely be with a big pharma rather than a pure-play RNAi company. “We’re focusing more on larger organizations that have significant capital,” he said.
While its HIV program proceeds, CombiMatrix is also continuing work on its hepatitis C program, which has thus far resulted in “some compounds,” but not “any spectacular results to report yet,” Kumar said.
The company is also trying to expand into other diseases areas such as West Nile virus and smallpox, through industry and academic collaborations, but has found the economics of such deals to be significant stumbling blocks. “We’re finding, in some of these cases … that there are certain negotiations we have to undergo regarding ownership and economic interest that have slowed [the process] down,” he said.
CombiMatrix isn’t rushing into any deals for intellectual property either, it seems. Kumar said the company is intent on establishing its own position in the murky RNAi IP landscape, and that patent applications on the HIV siRNAs are to be filed shortly. The company has not, however, taken licenses to the various RNAi IP out there, including the Fire-Mello patent that most players in the sector regard as fundamental.
“It’s not clear who owns what, and until we figure that out, or until we feel we have a pretty good understanding of how things are going fall out, we may not license any broad intellectual property,” Kumar said. “Right now, there are three players that all claim they pretty much own everything. Obviously, all three can’t own everything … and we can’t go out there and do licenses with all three of them.
“At the right time, if necessary, we’ll go out and approach the appropriate group for the appropriate license,” he added.