Tuesday, June 14, 2011

Tekmira Reports Important Advances in Widening Applications of SNALP RNAi Therapeutics Delivery

We Make RNAi Work.

Tekmira’s slogan may sound a bit cheesy as they all do, but when you consider that it is the only company that has managed to translate the theoretically very powerful unilamellar liposome technology into the clinic and ready for commercialization while essentially everybody else is being frustrated from following up on promising early-stage results with liposomal delivery, it is a very appropriate one.

This leadership position was underlined in a recent presentation by Tekmira Pharmaceuticals at the CC-CRS meeting on May 25 (see related press release here). There, the company presented the advances it has made in widening the applications of SNALP delivery for use in major additional medical and commercial opportunities. Some of these advances were made in collaboration with large pharmaceutical/biotech companies, illustrating that Tekmira views these collaborations not only as a way to simply monetize their assets, but also as a way to grow the potential of SNALP delivery to areas such as respiratory disease (after cancer arguably the highest priority area in drug development) and targeted RNAi delivery by leveraging the partners' capabilities.

However, before reporting on the company’s advances in nebulizing and tagging SNALPs with monoclonal antibodies, the presenter made the point that more potent lipids is not what is holding it, or the field back from applying SNALP technology. Using ApoB as a target in rodents (mouse and rats), the data show that many of Tekmira’s lipids developed without Alnylam, including Alnylam’s Canadian subsidiary Al-Cana, have equal or superior potency to the MC lipids that have become one point of contention in the Tekmira-Alnylam litigation as such lipids, in addition to manufacturing, have been one of the pillars of Tekmira's gate-keeping position in SNALP delivery. For example, in the case of ApoB and the 2111 lipid 10 microgram/kg SNALP-formulated siRNA triggered more than 50% target gene suppression.

The presentation then moved on to demonstrating the progress Tekmira has made in formulating SNALP for respiratory and actively targeted delivery applications. Actually, it is formulating SNALP at commercially relevant scales that is Tekmira’s most valuable competitive asset, and this is why the unbelievable disclosures in the Amended Complaint that Alnylam abused its insights into Tekmira’s technology to misappropriate and represent formulation technology as its own are so grave (I will give it a couple of more days rest before I comment on Tekmira's Amended Complaint).

Data on the Ebola biodefense program show that the US government contract has been successfully commenced and is working just as the program was intended to work: not only is the company on track to developing a treatment for Ebola infection with the goal of filing an IND in the second half of this year, but the process has proven very valuable in maturing and bringing SNALP delivery to the next level, especially in terms of one of the most critical steps in SNALP delivery: high-quality manufacturing at commercial scale. Being able to formulate 1 kilo-gram siRNA instead of just 10 grams at a time without changing critical SNALP parameters such as size, encapsulation efficiency and poly-dispersity is enormous and means that SNALP can not only be used for running clinical trials, but can also be readily commercialized.

Data on targeted SNALP delivery showed that it is possible to decorate SNALPs with antibodies using Genentech’s defined THIOMAB antibody conjugation technology, again without compromising on critical SNALP parameters. Tissue culture data show that highly specific, targeted uptake and gene silencing can be achieved using these antibody-decorated particles. Such liposomes will have particular utility for applications outside the liver where delivery does not rely on ApoE (apparently initially an insight of Tekmira, not Alnylam as that company claims- more on this in that other blog post). I look forward to learning more about the performance of these particles in animal models, especially for cancer applications.

Another area where antibody-targeting could have utility is in the delivery of siRNA to the respiratory epithelium following nebulization. As we know, Alnylam’s ALN-RSV01 has been overshadowed by concerns that some, or even most of the antiviral activity of the nebulized naked and unmodified siRNAs may be due to innate immune stimulation. More generally, while I am convinced by now that high concentrations of naked siRNAs on the epithelial lining of the respiratory tract can achieve some target gene knockdown, to my knowledge, there has been no convincing report of RNAi knockdown through inhaled siRNA delivery robust enough to warrant clinical development.

Tekmira’s success in nebulizing SNALP particles therefore is the first critical step in opening up the respiratory space for inhaled RNAi Therapeutics (there are some strategies such as cationic lipoplexes or PEIs that can deliver to parts of the lung following systemic administration). Again, the key to success will likely come from proper formulation/manufacturing.

Using traditional LNPs, nebulization leads to gross changes in morphology, uniformity, size, and dramatic loss of encapsulation efficiency (from mid 90%s to 10%s). However, with undisclosed changes to Tekmira’s SNALP formulation, it is now possible to nebulize SNALP without changing these parameters. Tissue culture data confirm that these particles retain unchanged knockdown activity.

Altogether the presentation emphasizes that not only has Tekmira/Protiva been leading SNALP technology in the past but is continuing to do so…by a distance. It seems that in order for it and shareholders to capitalize on this leadership, more than getting the technology right, it is preventing Alnylam from using partnership status, money and PR from misappropriating the technology and representing it as its own.

Comment on referring to Tekmira’s delivery technology as SNALP versus LNP

Stable nucleic acid lipid particles (SNALPs) are a form of liposomal nanoparticle (LNP). The reason why I prefer to keep using the narrower term ‘SNALP’ when referring to Tekmira’s liposomal delivery technology instead of adopting the broader term ‘LNP’ as both Tekmira and Alnylam have done, is that the liposomes in clinical development by Tekmira and Alnylam currently and in the foreseeable future are still based on the original formulation (cationic/ionizable lipid+neutral helper lipid+PEG-lipid+siRNA), whether the cationic/ionizable lipid is a different one or whether a ligand is added or not. The term ‘SNALP’ is therefore a reminder of the innovator behind the technology, Protiva (now part of Tekmira), as they coined the term.

In a way, you would think that such terms that lack precise scientific definition anyway should not matter that much. However, in Alnylam’s efforts to marginalize Tekmira’s role in liposomal delivery, first changing from ‘SNALP’ to ‘LNP’, and then calling the newer formulations ‘second-gen LNPs’ has been an effective way of hiding ownership of the technology with the goal of eventually not only denying Tekmira contractually owed milestones and royalties, but by-passing Tekmira altogether (incl. manufacturing) also to appease partners such as Novartis and Takeda. ALN-PCS01 looks set to be the first battleground.

24 comments:

Anonymous said...

Dirk,
Thank you for the news. I wonder how long the SNALP will stay in the vein, it is an impoartant factor, isn't it?

Dirk Haussecker said...

About 15 minutes, maybe a bit less with the newer formulations? Obviously, nebulized SNALPs would not involve intravenous infusion.

Anonymous said...

Dirk--You make the point that the Tekmira presenter said more potent lipids are *not* what is holding back the application of SNALP technology, but you fail to mention what is. Can you comment? Thanks.

Dirk Haussecker said...

What is holding the field back from using SNALP to knock down genes in humans? Well, for the liver and some cancer types and viral infections, the field is probably already there. Of course, actual clinical data need to confirm this. Money is probably Tekmira's biggest hindrance.

Anonymous said...

Collaboration with Genentech's monoclonal technology, specific delivery beyond liver may be reachable. Dirk, do you have any insight into the collaboration?

Anonymous said...

Another thoughtful blog post.

Thank you.

Anonymous said...

Dear Dirk,
Is "15 minutes" enough for the efficacy ? How long is enough ? say, one day?

Anonymous said...

BENITEC is on the verge of signing a company making deal we are talking $$$$$. what do you have to say about that Diggler.

Anonymous said...

Any comments on Koblan leaving Alnylam? I mean the guy must have had tons on bargain basement shares. Why throw it all away? Perhaps he had some inside info that RNAi therapeutics are doomed to fail...

Anonymous said...

Very informative, Dirk. Thanks so much for providing such valuable info and insight.

Anonymous said...

"BENITEC is on the verge of signing a company making deal we are talking $$$$$"

Sounds like wishful thinking to me. No way of proving one way or the other. Only time will tell.

Anonymous said...

Dear Dirk,
IF the most advanced SNALP tech can only stay in blood 15 minutes, it is no wonder big pharma is reluctant to put more money into it. It looks more promising that the Oxford Biomedica using lentivector could be better than SNALP tech,

Dirk Haussecker said...

Now I understand what you are getting at. I had misunderstood your question as to the duration of infusion. As to pharmacokinetics, depending on the formulation (especially the length of the PEG-lipid anchor), SNALP blood stability can range from minutes, hours, to days. Also, even if it is only 15min, it can be enough to trigger long-lasting silencing (several weeks). Pharmacokinetics and pharmacodynamics can be 2 very different things in RNAi Rx.

Anonymous said...

Dirk

CAn SNALP be used for other drugs that are not RNAi specific??

Dirk Haussecker said...

I'd think so. Other types of oligotherapeutics payloads, obviously, but also small molecules can be delivered with liposomes.

Anonymous said...

Dirk,

A bit off topic - what mechanism would they be using in the following story

http://www.dailymail.co.uk/health/article-2004033/Genetic-green-light-lead-cure-hundreds-ills.html

Anonymous said...

Infusion time is actually an important factor. Silence uses two hours infusion and has demonstrated build up (loading) of serum concentration of siRNA within the infusion time to increase the pharmacokinetics. Alnylam slowed down the infusion speed (increased infusion time) midway through their study to allow the continuing dose escalation and may finally reached the effective dose of 1 mg/kg. Good thing is both Alnylam and Silence seems to reaching the dose level resulting some stable diseases. More time will tell.

Anonymous said...

Dirk,
I think the readers had enough for the good news from the business reeporter, like Wallstreet Journal, they need the insight,I need the insight, why the LNP is not commerial yet? How long it takes to be proven? What is the short side of SNALP ? Based on your science background,do you think SNALP is better than Lentivector?

Anonymous said...

I will try to help Dirk out a little. Never say never, but integration potential of lentiviral vector makes it much less likely for us to see systemic application in the clinic.

Anonymous said...

Hi Dirk,
If SNALPS is really working as you and TKMR is proclaiming "we make RNAI work", why the market seems to have no positive reaction, and TKMR's pps continues to go south? Isn't there something wrong? Or the data is just not convincing enough?

Dirk Haussecker said...

You seem to put faith into the efficiency of the capital markets. Just as some RNAi technologies got way overvalued 3-4 years ago, we are now dealing with the opposite problem in that pre-commercial RNAi technologies get assigned preciously little value. That's why the current clinical data flow, largely based on SNALP technology, is so important. I also hope that especially with the respiratory applications of SNALP technology, there will be increased urgency by players like Merck, Novartis, and AZ.

Anonymous said...

Dirk is right. It might be a bit of "cry wolf" syndrome here, the market might need "resounding" results for villagers to respond. An intricate game, it will be interesting to see whether Alnylam or its cousins can rise to the level of Genentech or AmGen. $9-10 per share might be a good bet, but many still wonder.

Anonymous said...

Dear Dirk,
First, I want to thank you for the years discussing the RNAi tech.

Some material said lipid has limit in primary cell RNAi transfection.
What is your comment on it?

Dirk Haussecker said...

You are probably referring to the fact that most non-adherent cells are not well transfected by cationic lipids/lipoplexes in tissue culture. It has to do with them not having enough negative charge on their surface. For therapeutic applications, the initial cell contact of such a transfection agent may have to be via other mechanisms than charge. As such, targeted SNALPs should be useful for knocking down genes in cells of the hematopoietic system (blood).

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