Marina Biotech Finds Success with Local Bladder Cancer Approach

Marina Biotech this week reported pre-clinical data supporting the use of local, intravesicular siRNA delivery for the treatment of nonmuscle invasive bladder cancer. The publication in Molecular Therapy comes weeks after this early-stage program was partnered with Swiss pharmaceutical Debiopharm which will be responsible for funding the rest of the development.

According to the National Cancer Institute, there are about 70,000 new cases of bladder cancer in the US alone, most of them related to smoking. Because bladder cancer typically starts at the epithelium lining exposed to the urine, simple surgical resection is often sufficient to stop the disease in its tracks. Unfortunately, in some cases the cancer recurs and progresses into a more aggressive, muscle-invasive form of cancer contributing to the 14,700 deaths from bladder cancer annually (US number). Current strategies to prevent recurrence include the instillation of immuno- and chemotherapeutics into the bladder. When this fails, the bladder often has to be removed. Clearly, more treatment options are needed to limit the progression of bladder cancer into the more aggressive forms and maybe also to provide an alternative for bladder removal once more aggressive cancers have developed.

In the present study, Seth and colleagues first screened a range of RNAi triggers against the cancer-related genes polo-like kinase 1 (PLK1) and survivin and were able to demonstrate that Marina’s usiRNA chemistry platform allows for very satisfactory knockdown efficacies with IC50 values in the 10 to 30pM range (bladder cancer cell lines in tissue culture). This triggered widespread apoptosis and, in the case of PLK1, a strong reduction in cell viability. The data therefore add to the notion that PLK1, incidentally also the target in Tekmira’s phase I clinical program TKM-PLK1, may be the single-most promising RNAi cancer target, a view apparently shared by Marina scientists as evidenced in the Discussion part of the paper. Nevertheless, survivin may still be a highly desirable drug target for sensitizing cancer to chemo- and radiation therapies.

The selected siRNAs were then formulated into positively charged multilamellar liposomes of around 100nm. Due to the negatively charged proteoglycan-rich urothelium, a formulation with a lipid containing a guanidinium group was deemed particularly promising in being able to penetrate the 6-7 cell-layered urothelium. Accordingly, these formulations, when instilled into the bladder, were able to very efficiently suppress the growth of nonmuscle invasive bladder cancers in mouse models of the disease. Although equally highly efficient in vivo knockdowns were reported, 90-95% with 1mg/kg (relative to body weight), in my mind there are still some unanswered questions as to how much of that merely reflected the reduction in the size of the tumor.

In terms of safety, no untoward reactions to the formulations were reported. One important reason for this should be the lack of systemic exposure from such treatment. The authors also stated that they were not able to find evidence of innate immune stimulation despite careful investigation. Ideally this analysis would have included a positive control, but then again, also taking into account the 5’ RACE analysis for sequence-specific target cleavage, the overall evidence strongly supports that RNAi knockdown was a main contributor to the in vivo efficacy. Actually, in the case of bladder cancer, having a bit of local immune stimulation may very well be a good thing as I was surprised to learn that bathing the bladder with a solution containing the Calmette-Guerin bacterium (BCG), the famous vaccine against tuberculosis, is part of the current standard of care for superficial bladder cancer and is thought to work by stimulating the immune system. Who knows, Marina may even want to adapt BCG to trans-kingdom RNAi for bladder cancer to combine the RNAi and BCG mechanisms of action into a single agent.

Study Adds yet Another Indication Suitable for Current RNAi technologies

Marina Biotech has made it into an art to select development programs amenable to their current technologies. Given the challenges of systemic RNAi delivery, in a relatively short period of time, the company has already identified and progressed three cancer applications where local approaches can probably be used: familial adenomatous polyposis (FAP; ingested trans-kingdom RNAi), bladder cancer (intravesicular LNP), and most recently malignant ascites (intraperitoneal LNP). Together with developments elsewhere in the field, this clearly shows that the time for RNAi Therapeutics is Now: a range of solid cancers (e.g. liver, lung, FAP, bladder, melanoma), hypercholesterolemia, hemorrhagic fever viruses (Ebola, Marburg), TTR amyloidosis, PHN, AMD, Huntington’s disease etc etc.

Big Pharma and RNAi Therapeutics: In-house Platform Development is ‘Out’, External Product-specific Deals are ‘In’

As if to add insult to injury, a few month after Roche exiting RNAi Therapeutics, plans emerged that Pfizer is about to shut down internal oligonucleotide therapeutics development efforts. This is depressing news for sure to me, and I would assume the wider RNAi Therapeutics community. But then again maybe not that surprising, and it would shock me no more to see Last-Man-Standing Merck shut down as well if the Tuschl trial goes against them.

Just as Big Pharma jumped onto the RNAi Therapeutics bandwagon 3-5 years ago, seemingly believing that all you need to do is to inject an siRNA into the blood and all those multi-billion dollar patent expiration woes will go away, the Big Pharma herd is now running for the exits. If you study this quarter’s financial results by Pfizer and Merck, you’ll know that there is little or no room for developing a new technology platform. Rather, it is about rescuing the top-line through Mega-Mergers with the few stilll growing large pharmaceutical companies, phase III, launch, and emerging markets, and managing the bottom-line by cutting in-house R&D. We’ve all heard it, again and again.

In essence, it is an acknowledgment that Big Pharma has failed as an innovation engine and R&D is no more a place to hide from responsibility in Big Pharma. The industry has decided that internal efforts that just serve as evaluation units of external technologies (e.g. delivery) without spearheading cutting-edge R&D themselves are not an efficient use of capital. Instead, if a therapeutic business unit was interested in a specific RNAi Therapeutics candidate, they can deal with the external company directly without the need for an in-house middleman. In fact, Pfizer has already pursued this alternative pathway as they have partnered the ddRNAi program for HCV with Tacere and a synthetic siRNA candidate from Quark for wet AMD. In both cases, there seemed to have been little involvement by Pfizer’s in-house oligonucleotide therapeutics unit.

This is not a criticism of the individuals themselves that have been part of those platform development units, but more one of an organizational nature. The more I learn about Big Pharma, the more I am struck by how little co-ordination there is within these sprawling organizations. For example, a group in one part of the world may utilize RNAi for target discovery and validation, but may not be fully aware of the technologies available from units elsewhere which work on the therapeutic aspects of RNAi.

It is, however, also a criticism of the arrogance of some organizations that innovation will happen if only you throw money at it. More than $500M by Roche, more than $200M by Pfizer, and more than $1.5B by Merck, and little to show in terms of delivery progress compared to a company like Tekmira with much more limited means. What is frustrating is that often money is spent on trying to replicate what already exists, such as LNP delivery, instead of admitting that innovation can’t be manufactured and if you really want to bring it in-house, then it is by buying it where it emerges, wherever in the world.

Almost on cue, the same day that Pfizer’s plans emerged, Marina Biotech announced a product-specific development deal with Swiss drug licensing and development company Debiopharm. This deal covers a pre-clinical stage RNAi Therapeutics program for bladder cancer (via topical LNP-siRNA administration) where much of the early development work will stay with Marina, but which will all be funded by Debiopharm, with potential downstream development milestones and royalties for Marina Biotech. Given the circumstances, severe cash crunch I would think, it is a good deal for Marina given the early stage of the program (pre-clinical). And who knows, maybe some of the work by Marina Biotech and Tekmira with Pfizer will similarly result in product-specific development deals with Pfizer therapeutic area units if results obtained thus far have been promising.

The Pfizer news is definitely not good for building investor confidence in RNAi Therapeutics, but long term it may just mean that companies with already viable clinical technologies will succeed as it will allow them to efficiently churn out and monetize high-quality development candidates, somewhat akin to what Quark’s and ISIS’ business models have been until now. That’s not to say that this is ideal for RNAi therapeutic technology development, but with maybe the exception of Alnylam, most companies won’t have many other choices.

Note: I am currently planning to resume more regular blogging as clinical results come in. Only these will be able to turn around sentiment for RNAi Therapeutics in a lasting manner.