Monday, July 11, 2011

Tekmira Partner to Initiate Phase I Study for the Treatment of Severe Hypercholesterolemia

Tekmira’s partner and licensee Alnylam Pharmaceuticals announced today the submission of files to a European regulatory agency in anticipation of a phase I study with a candidate targeting PCSK9 for the treatment of Severe Hypercholesterolemia. The primary aim of this early-stage study is naturally the safety and tolerability of ALN-PCS. An important secondary aim, not just for Alnylam but also for the entire field of RNAi Therapeutics, will be assessing drug activity as measured by target protein levels in serum. Initial data are expected by year end.

ALN-PCS represents Alnylam’s 4th clinical candidate, three of which are based on Tekmira’s SNALP technology (VSP, TTR, PCS). It also represents the 2nd candidate under its 5x15(TM)program which aims to advance five RNAi Therapeutics candidates into late-stage clinical development by 2015. All disclosed candidates under that program (TTR, PCS, HPN) are based on SNALP technology.

Despite the success of statin in lowering cholesterol, many patients are still considered to be in need of additional treatment options. PCSK9 has emerged as a very attractive target for such uses based on human genetics which suggest PCSK9 knockdown to reduce ‘bad’ LDL cholesterol in addition to being well tolerated. While ALN-PCS is the first RNAi Therapeutics candidate to target PCSK9, other companies have already started clinical development of PCSK9-targeting hypercholesterolemia candidates.

These competitive efforts are based on monoclonal antibodies and antisense approaches and include a recently initiated program by Santaris (LNA antisense) and monoclonal antibody programs by Amgen, Pfizer, and Regeneron amongst others (mostly phase I and II). ISIS with partner BMS together are also developing a PCSK9 antisense candidate. This candidate, however, still appears to be in late preclinical studies following some delays.

The pre-clinical data show that RNAi, antisense, and monoclonal antibodies can all potently down-regulate or bind and inhibit PCSK9. It seems, however, that one advantage of ALN-PCS could turn out to be that it does not simultaneously down-regulate ‘good’ HDL cholesterol as was observed e.g. in a rodent study by ISIS (antisense; significant 50% reductions; Graham et al 2007) or in a non-human primate monoclonal antibody study by Amgen (moderate 20% reductions; Chan et al 2009).

Obviously, it is still early days to speculate on the eventual competitive profile of the various candidates. With regard to safety and tolerability it is notable, however, that the anticipated highest dose with ALN-PCS in the study is 0.25mg/kg. This means that an average Caucasian may receive only about 10-20mg siRNA per week (assuming bi-weekly or monthly administration). While there is still some more uncertainty about the safety profile of non-DLinDMA SNALPs such as ALN-PCS (this candidate uses MC3 while all other SNALP candidates so far made use of DLinDMA), such low doses make me optimistic that the safety profile should be quite competitive.

Adding Tekmira’s efforts, this program is the 5th SNALP candidate in 3 years to enter clinical development. At least two more are anticipated this year. ALN-PCS therefore further illustrates one of the advantages of RNAi Therapeutics development, namely that once there is a suitable delivery technology for a given target organ, in this case SNALP for liver delivery, the indications can be rapidly expanded to multiple drug targets. This also means that the inventor behind and manufacturer of ALN-PCS, Tekmira, should receive a milestone from its partner and licensee upon initiation of dosing, adding to an increasing royalty stream.

14 comments:

Anonymous said...

Lol for the title!

Anonymous said...

I used to be a big fan of your blog. But now I am not. This is because of your bias towards one company. I dont know this comment would make any difference but one thing I can say for sure is that I wont be here to read more of your posts.

Anonymous said...

Some advise, put down the crack pipe before you start writing your blog entries - there's no other explanation for the title of your most recent posting!

Anonymous said...

And they're suing each other;great partnership.

Anonymous said...

These two companies need each other. They need to settle their differences without acrimony so that both can prosper. Extended litigation will be a distraction that may cause both to lose the lead they currently have in RNAi therapeutics. Other companies with exciting RNAi technology are emerging.

Dirk Haussecker said...

One important point of this event is that it highlights the efficiency of RNAi Therapeutics development, an efficiency that depends on the development of robust delivery technologies. Unless Alnylam managed to confuse the world, it is still Tekmira's technology and the title only reflects that.

BTW, have you noticed Alnylam's subtitle and last line in the press release and the omission of Tekmira? These are thinly veiled attacks on Tekmira, which happens to be both the owner of SNALP technology (e.g. regardless of which lipid is used Semple/Wheeler and other Tekmira patents apply) and the manufacturer of ALN-PCS.

Anonymous said...

Dirk,

In my opinion disregard, your ex fans of your blog etc...

You are doing whats right. Standing up for a small company that has been done wrong. Moreover, investors in the company have been embezzled as well.

Whats wrong with taking a stand and letting your opinion be known?

really, should we just sit around and let this highway robbery and bullying go on unchecked.

I beg to differ.

Thank God, for your opinions and perspective Dirk.

I am confident that either there will be reconciliation with benefit to tkmr or straight up legal victory. I dont see why companies such as B.M.S. would continue to extend their research agreements if there was not a slam-dunk otherwise.

Also, I am hoping to a press release announcing an official genentech research collaboration regarding monoclonal antibodies

keep up you good work.

Anonymous said...

I think how Dirk make money for his living is related to his bias,
If this blog is positioned at stock investment of bio-tech, not science discovery discussion. Then, Dirk's management of this blog is OK. Otherwise, it is a fail.

Anonymous said...

The Alnylam group who is so hostile towards Tekmira and Dirk ought to realize that Tekmira has very limited downside in all of this. The second gen lipids (e.g., MC3) are either Joint Collaboration IP or Tekmira Collaboration IP. In either event, Tekmira has rights of ownership under either scenario. Worst case, factually, is the court says it's Joint Collaboration IP, in which case Alnylam has the right to use, sell, keep, license or assign its interest in such IP as if it was a sole owner of the IP, as does Tekmira. Tekmira having controlling rights in the 2d gen lipids is nice and potential revenue generator, but Tekmira's business model is to produce FDA-approved drugs with side revenue from the licensing of its lipid delivery tech to help offset cash burn towards the eventual FDA drug approvals. At current pps, Tekmira is a steal, IF Tekmira can achieve the final FDA-approval milestones, or IF Tekmira prevails in the litigation or realizes a favorable settlement that preserves the IP. Alnylam doesn't lose that badly, either, since Tekmira's advancement of Alnylam licensed siRNAs in the pipeline to eventual FDA approval results in license revenues and royalties to Alnylam. Also, Alnylam has opt-in rights on PLK1 to a certain point in time, by which time it'll be evident whether the TKM-PLK1 is promising. Peace and love among the camps ought to be the mantra, not war.

Anonymous said...

I'm getting tired of this blog. What are you an IR consultant for tekmira?

bion4maticist said...

> ...one advantage of ALN-PCS could turn out to be that it does not simultaneously down-regulate ‘good’ HDL cholesterol...

It seems likely to me that this is a result of differences in the rodent protocols. What makes you think that mRNA knockdown with siRNA rather than with RNAseH will have this difference in pharmacodynamics?

Dirk Haussecker said...

Would you know what these protocol differences could be? Other potential sources for the differences could be a) differences in the pharmacodynamics between RNAi and RNaseH (cholesterol levels are subject to various feedback controls), b) off-targeting (gene-specific or class effects).

bion4maticist said...

A simpler explanation might be that reducing PCSK9 via whatever means lowers HDL in rodents, but not in primates.

Dirk Haussecker said...

I agree, there might be differences in the susceptibility of HLD-c to PCSK9 downregulation in rodents versus primates. Nevertheless, the Amgen non-human primate study did show a slight decrease in HDL-c (20-25%).

I must though say that while Alnylam is making the point of non-HDLc lowering being a major advantage of ALN-PCS compared to the competition, Alnylam has not published much data on HDLc levels in rodents. If, then they were only indirectly expressed in values such as HDLc/(total non-HDLc) ratios or in studies with transgenic rodents that were humanized with regard to cholesterol metabolism and where, as a result, the HLDc levels on the charts are barely visible.

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