Future Trends In RNAi Drug Delivery

For those interested in RNAi therapeutics, it would be wise to pay attention to every development related to delivery technology. The concept and clinical results behind RNAi are compelling, but perhaps something equally exciting is that there is still room to grow. With human proof of concept demonstrated, RNAi companies can reformulate with new delivery technology and enjoy the benefits. This article will examine next generation LNP delivery the pipeline.

LNP technology for indications involved with the liver is the most mature delivery system within RNAi therapeutics. Current LNP (lipid nanoparticle) technology is in its 2nd generation (such as ALN-PCS, ALN-TTR02) which has ~100-fold increased potency and better safety than 1st generation (such as ALN-VSP, ALN-TTR1) offerings.

One of the issues with the current 2nd generation LNP is that they have long elimination half-lives in plasma and tissues. It is suspected that they might accumulate over time and lead to cytotoxicity in target cells with chronic dosing. Specifically, they end up building up in the liver and spleen.

The idea behind the new 3rd generation LNP technology being researched by Alnylam (ALNY) is to create a rapidly eliminating LNP formulation (reLNP). The idea behind reLNP is to have them be rapidly biodegradable so this accumulation can not occur. Observe these preclinical results of how these rapidly eliminating LNP are eliminated in the plasma, liver and spleen. It looks like 2 reLNP lipids are being evaluated with different elimination half-lives. I assume that 2 reLNPs are being researched so further experimentation can find the sweet spot for therapeutic application.

In addition to this change, Alnylam is investigating subcutaneous (abbreviated SC) administration at smaller (20%), but more frequent intervals as opposed to one bigger dose. This has shown a greater therapeutic index in preclinical animal models. In my opinion, SC administration was always assumed to be better but it is much less convenient for the patient. Never the less, it seems as though Alnylam is warming up to the idea and Tekmira (TKMR) has also chose to do one of their two TKM-PLK1 phase 1 trials subcutaneously also. SC administration may be a trend for RNAi for more serious conditions where it can be justified.

Its interesting to note that Alnylam did the SC reLNP testing with ALN-TTR. They state their plans are to bring this 3rd generation LNP in the clinic in 2013.

Take a look at the comparison between 1st-3rd generation LNP.

The question on my mind is does these rapidly eliminating LNP fall under Tekmira's IP? Tekmira has a patent on all LNP formulations, so reason says that these reLNPs fall under this patent. Upon review of Tekmira's patent and subsequent review of the reLNP information provided by Alnylam, I can find no reason why it does not fall under this patent.

In the context of Tekmira and Alnylam litigation, I can see Alnylam possibly wanting to shift their pipeline offerings from being MC3 dependent to these new generation technologies. MC3 may prove to be toxic (figuratively speaking) as AlCana has been admitted stealing documents from Tekmira then collaborating with Alnylam on the technology. Tekmira has also filed an injunction to prohibit use of MC3 and there is a decent chance it might be granted in my view.

I suspect matters related to delivery expenses may be part of the reason extra funds were needed with their recent capital raise. I cant help but wonder what they intend to do with their pipeline in regards to 3rd generation LNP. Will they redo part (all?) of their Phase I with 3rd generation? Higher doses may be needed with some of their offerings and a formulation with increased safety/efficiency would be desirable.

I have less information about 3rd generation offerings by Tekmira but they are also working on them. In their news reliese for their ALDH2 program, they announced it would be used with next generation LNP formulation that has demonstrated better potency and greater therapeutic index than all previous LNP formulations. I have not seen any specific data on Tekmira's 3rd generation LNP and would love to get my hands on the information. If any readers have any information from Dr. MacLachlan's presentation titled "Progress in the Development of Lipid Nanoparticle siRNA-Based Drugs" from the Asia TIDES Oligonucleotide and Peptide Technology and Product Development Conference, please send me the information.

Much of the information regarding reLNP can be viewed here. I would love for my articles to be more interactive in the comments section, so please feel free to add anything.

Disclosure: I am long TKMR.

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