Monday, December 14, 2009

RNAi Therapeutics Trends from the International Liposome Society Meeting 2009

Christmas to me means going to London to learn about what liposomes have in store for RNAi Therapeutics. As you know, liposomes have emerged as the leading platform for the systemic delivery of RNAi Therapeutics and offers considerable promise for diseases of the liver, solid cancers, and after that potentially enhanced vaccines, infectious disease and immune cell-related disorders. The fact that liposomal drugs are on the market already should further speed up its development, not least from a regulatory point of view.

The liposome field appears to be split between between cancer and vaccines about 2:1. Especially the success story of doxil (liposomal doxorubicin) has shaped the field and should partly explain why it is attracted so much towards solid cancers for RNAi Therapeutics. The EPR effect, targeted delivery, tumor vascular biology have been recurring topics and research using various advanced imaging modalities nicely informs the application of liposomal siRNAs in oncology. For example, liposomes (not necessarily unique in that regard) are not uniformly distributed within the tumor, but form a concentration gradient around the blood vessels. Strategies to achieve more uniform drug delivery may involve metronomic dosing in which the drug is administered more gradually at lower dosages such that the simultaneous onset of cell killing in proximity to the vessels will relieve intratumoral pressure so that subsequently arriving liposomes are freer to move within the tissue. Hyperthermia or low-dose TNF-alpha were two suggested strategies for increasing the leakiness of tumor vasculature, also to improve liposomal tumor distribution.

Since the highest concentration is achieved around the tumor vasculature and because there are differences between normal and tumor vasculature, targeting genes within the endothelial and supporting cells has become an attractive anti-tumor strategy. This for example is also the strategy that Silence Therapeutics is pursuing and the lipoplex formulation (siRNAs associated with liposome on the outside, not inside as in a SNALP) for some reason might have its application here.

But once within the tumor, mostly the result of the overwhelming EPR effect, the question becomes how to get the liposome into cells and then release the drug cargo into the cytoplasm in the case of siRNAs. Ligand-targeted liposomes are one answer to increase the cellular uptake of the liposomes. Antibodies are an increasingly popular means (immunoliposomes), although they present certain manufacturing challenges. It is still debated how PEG affects cellular attachment. Some claim that you cannot take up a pegylated liposome, some say you can. The answer may be that it depends on the size of the PEG. This is important for example in the context of a targeted liposome and whether to add the ligand to the PEG or directly incorporate it into the lipid bilayer as a lipid-conjugate, and when and how the PEG should leave the liposome. For efficacy and safety, triggerability of membrane lysis is of course important. Too much charge for example can be cytolytic, so you would like to expose membrane lytic activities in a pH-dependent (endosomal acidification), redox or protease-dependent manner. For the liposome field, this typically means pH-sensitive lipids.

Combined chemo-siRNA therapeutics is another trend that will become important for liposomal cancer RNAi Therapeutics. Combining ever more chemotherapeutics appears to be a game of diminishing returns with triple chemo Rx often not any better than double chemo Rx. This is because of limited mechanism of actions of chemotherapeutics and associated resistance mechanisms. RNAi Therapeutics therefore can either target these resistance pathways directly or bring to the table an entirely new anti-tumor mechanism of action.

I have always found it attractive to apply siRNAs for developing more effective vaccines. While I am not familiar with the literature around virosomes, viral ghost shells, a presentation by Swiss company Pevion Biotech caught my attention in this context. Basically, they are using flu viruses, disassemble them to get rid of the viral RNA and associate protein, and then reassemble them. During the reassembly process, they can then variably add their lipid-anchored antigen of choice and use the re-formulated virus as a vaccine. The fact that our bodies have seen flu virus before apparently helps to obtain a more favorable immunological response. By this, they believe to have broken the potency-toxicity linear correlation that seems to plague adjuvant science. While promising and based on a credible scientific presentation, it still does not appear to be among the most potent adjuvants, so I wonder whether an siRNA targeting the right immunomodulatory gene loaded into the virosome, essentially replacing the viral RNA there, could improve this equation even further. A challenge for nanoparticle-formulated siRNAs for enhanced vaccines is that although they are easily taken up by phagocyotic antigen-presenting cells, the phagocytic pathway usually destroys the siRNA and little escapes into the cytoplasm. The virosome could offer a solution since the flu virus is THE paradigm of how membranes fuse with each other and also explains how an extracellular antigen, the vaccine, can produce a favorable cellular immune reponses in this system. What I noted at the conference is the surprising lack of cross-talk between people using liposomes for vaccines versus those using them for oligonucleotide delivery which is unfortunate in cases like virosomes.

Pevion also seems to be producing good-quality liposomes. For liposomal RNAi Therapeutics, it is probably making the jump from rodents to primates and scalable manufacturing that separates the boys from the men. There are many interesting early-stage strategies, but if the goal is translational medicine, it is of utmost importance to take manufacturing issues into account from the very beginning. Of course, if you have such know-how, this challenge also presents an opportunity/entry barrier that can be capitalized on and should also present a significant barrier for generic competition. A scientist from Gilead told the story of the attempt by a fairly large Argentinian generics manufacturer to copy Gilead’s AmbiSome formulation by just mixing the individual components together and that this went quite wrong.

In order to address that gap between basic and applied science, the opening talk advocated the creation of companies whose sole business model is to take promising academic research and transform it into industrially partnerable technologies. Certainly, this concept appears to be gaining traction and it will be important in how the compete with or complement small biotech companies. The Centre for Drug Research and Development in Vancouver is one such entity that can be put into this category, also with a liposome focus (Pieter Culles e.g.). Vancouver in general can be considered the world's capital for liposomal research, which brings us to the Tekmira, UBC/Alcana, Alnylam triangle.

Pieter Cullis, co-founder of a number of liposomal companies including Tekmira, but now apparently more closely associated with Alcana and Alnylam, gave a nice talk about the rational design of lipids for use within SNALPs. Only small changes in the lipids can have large biological and physico-chemical effects. For example, by just modulating the chemical strength of the linkage of the fatty acids with the lipid head-group, SNALPs of very different potencies are obtained. Yet another objective is the investigation of the pKa-potency relationship which again can greatly impact liposomal performance. Through this, Alcana-UBC, largely driven by two ex-Tekmira scientists have come up with around 100 new lipids which further help to refine the design rules in an interative process. Actually, the rational lipid design approach is the approach Tekmira itself has been taking- probably not surprising given this background and may explain why Tekmira is getting access to these lipids for free without having to fund their development. It also differentiates it from the ‘lipidoid’ approach by MIT-Alnylam. Maybe given the varied performances due to even only subtle changes, huge libraries of lipids are not that desperately needed as was thought just 3-5 years ago. It is also the animal model that would become the bottle neck, as the tissue culture system is of only limited utility in predictively characterizing SNALP performance and mice become the system for the screen. Still, ‘lipidoids’ may offer fundamentally new structures which can be further refined using similar rational design approaches. For the liver, at least in terms of potency, this may not be needed according to Cullis’ back-of-the-envelope calculation that predicts single digit microgram(siRNA)/kg potencies that the technology is approaching for this tissue, an area that is approaching certain theoretical limits.

In summary, the conference, has confirmed my view that liposomal delivery is a good place to be in RNAi Therapeutics at the moment. It may even be time to have a conference entirely devoted to liposomal strategies for RNAi Therapeutics. There is a need, however, to focus on those companies that operate on sound scientific principles and ideally have a track record in being able to produce high-quality/consistent liposomes in a manner that is scalable.

8 comments:

Anonymous said...

"Especially the success story of doxil (liposomal doxorubicin) has shaped the field and should partly explain why it is attracted so much towards solid cancers for RNAi Therapeutics."

You're kidding, right? FYI from a 25 year indusrty veteran - Doxil (and every other liposomal version of a generic drug for that matter) has been considered a commercial disaster - not a success, period.

All od these second generation generic liposome drugs has bombed as they addressed on minor safety issues, and did not deliver any increases in efficacy.

Hopefully, siRNA can be trule enabled with a liposome-based approach.

Dirk Haussecker said...

I am fundamentally agreeing with you that instead of aiming at an incremental improvement of existing drugs, liposomes can bring much more added value (in a number of regards) in the context RNAi Therapeutics. As a battle-hardened veteran with real-life insights into the commercial aspects of the industry, however, you certainly like to express it in even starker terms than I do. Then there is also the issue of commercial value and clinical value. What's your take on AmbiSome though. Also a commercial failure?

Anonymous said...

Definitely commercial failures. Both Ambisome and Abelcet are essentially generic drugs and/or commodities relegated to competitve bidding wars by hospital pharmacies. Both hold little real clinical value in terms of renal safety.

Pierrot!!! said...

Hi Dirk!!

I was very nice meetig you in London!!

Great blog!!

Keep up the good work!

Pierrot

Anonymous said...

Thanks for the summary, Dirk. Are copies of the slides from this meeting available anywhere?

Dirk Haussecker said...

Some meetings do give participants access to slides and videos, this one, I believe, does not.

Hershberg said...

May I suggest your description of Tekmira’s recent clinical set back overly emphasized the positives and ignored the negatives? While some promising information was gleamed from the trial, much time and money was expended in what turned out to be a dead end. TKM a bit of a one trick pony, delivery, and they failed to deliver. Today they are years away from demonstrating success in the clinic, are a bit short of cash, and vulnerable to alternative technological advances.

Time may be of the essence in developing an ApoB inhibitor. Once mipomersen reaches the market (2012?), Tekmira’s efforts to enroll patients may become quite challenging if they target the same, but limited patient population as mipomersen. Clearly, Tekmira has lost momentum in the race to bring an ApoB inhibitor to market.

This is not a knock on Tekmira’s science. It may ultimately prove quite successful, but I just I sensed too much positive spin for what seems like two steps back before the Company takes its next step forward.

Dirk Haussecker said...

Dear Hershberg,

I agree that the results could have looked better, but they could have been much, much worse and they offer a clear path forward. Bear in mind: this is the first clinical result for SNALP-siRNA delivery and it would have been extraordinary if everything worked like a charm.

For the reasons detailed in the blog, management, now informed by the these results, made the right decision to try and capitalize on the rapid progress in SNALP delivery over the last two years. Combined with good tolerabilty at up to 0.6mg/kg in the present trial and first signs of efficacy, I believe that there is good reason to believe that the much more potent formulations (and probably less immunogenic as well) will push SNALP-ApoB2 into therapeutic territory. In addition, the investments in these early-stage ApoB trials can be amortized over the entire SNALP delivery platform and one should not just focus on the timelines for Tekmira's ApoB drug.

A more potent formulation should also make it more competitive against other ApoB-lowering drugs (8mg/month vs 800mg/month would probably make a difference).
I also don't agree that time is that much of the essence when it comes to mipo. In fact, I'd like mipo to beat the regulatory path for an ApoB inhibitor and built patient-doctor awareness for this class of drugs. The earlier mipo gets approved, the better. Because mipo and SNALP-ApoB should be differentiated in many respects, let the better drug take the lion share. SNALP-ApoB is not a copy of mipomersen and physicians would quickly switch to a better drug. This is very common in the industry.

Also, what makes you think that Tekmira is running out of money soon? Conservative cash guidance until the end of 2011 puts it well ahead of most peers. Investors will have to ask themselves whether they want to fund experiments that are critical for the eventual commercial success of SNALP delivery. Potential partners should understand this.

By Dirk Haussecker. All rights reserved.

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