Tuesday, February 11, 2014

Taking Full Advantage of RNAi Therapeutics in Lowering Trigylcerides

Today at BIO CEO 2014, Tekmira presented tantalizing preclinical data (slide 11) showing more than 95% reductions in serum triglycerides, the lipids that clog up your arteries (think heart disease and stroke) and in extremely high cases cause severe bouts of pancreatitis.    Such reductions in triglycerides are unprecedented as fiddling around with fish oils, fibrates, and niacins has become a worn, unsatisfactory edge in managing this important lipid.

Enter RNA(i) Therapeutics.  By taking full advantage of the technology in being able to target any gene in the pathways leading up to triglyceride production and accumulation, we are not far away from achieving much more pronounced lowerings than the current standard of medical care.  This was impressively illustrated by the 70-80% lowerings of serum triglyceride in the phase II studies with ISIS-ApoCIIIRx, an RNaseH antisense compound by ISIS Pharmaceuticals.     

If you have been following my blog, however, I believe that despite the ISIS head-start, this lunch will eventually be eaten by RNAi Therapeutics.  In addition to their superior ability to effect gene knockdown in the liver, the Tekmira data went one step further to fully take advantage of the mechanistic opportunities offered by RNAi Therapeutics, in particular those delivered by technologies such as SNALP LNPs: multi-targeting.

As pioneered by SNALP-enabled TKM-EBOLA and ALN-VSP02 (for liver cancer), SNALP LNPs lend themselves to targeting multiple genes in a single drug.  As a consequence, it should be relatively easy to come up with a target combination that can not only lower serum triglycerides more potently than could be achieved by targeting a single gene such as ApoCIIIRx, but also lower liver triglycerides (à fatty liver, fibrosis), improve insulin sensitivity and the lipid profile on other fronts such as LDL-cholesterol.  Such a profile would be highly attractive since a given patient often will suffer from a number of these conditions (metabolic syndrome).

For Tekmira, as for ISIS Pharmaceuticals, the first markets, however, will be the severe orphan diseases related to triglycerides such as those involving severely elevated levels of serum triglycerides (>500) leading to pancreatitis.  Depending on the safety and tolerability profile, the market potential beyond these indications could be considerable and possibly limited by the inconvenience of having to go for monthly infusions.

But seriously, if you are going to take a medicine that costs on the order of $100k a year, you better take what is medically best for you and it would most likely still be a pharmacoeconomic steal if you charged the system for taking a stretch limousine to the infusion center to take care of the inconvenience (I'm particularly keeping an eye here on how the MS market evolves).  At least this primacy of efficacy is where I am hoping the healthcare cost discussion will steer the market in the future.  As such, Tekmira should not by shy in focusing on its competitive strength of achieving maximal target knockdowns.


Anonymous said...

It seems that you have missed the data presented by Alnylam last year with GalNAc targeting ANGPTL3. In that data they showed that they reduced trig by >95% and LDL by >85% by knocking down a single gene ANGPTL3 at a Subq dose of only 3mg/kg.

Anonymous said...

ALNY's ANGPTL3 drug is a couple years away from entering the clinic. Isis's ANGPTL3 drug is entering Phase I trials in the first half of 2014 according to the slides accompanying its JP Morgan presentation.

Xman said...

ALN-PCS using TKMR's LNP works on humans. ALNY's GalNAc sub-Q works on non-humans. Monkeys rejoice.

Dirk Haussecker said...

Good point regarding ANGPTL3. What effect on lipid parameters would combining RNAi triggers for both ANGPTL3 and ApoCIII in a single SNALP have? Superior to any single agent? And 3mg/kg is really borderline for a subQ tech. In the case of TTR with similar borderline monkey data, the efficacy slightly got worse when tested in humans. Now a 2ml injection.

Anonymous said...

Isn't the issue of how much volume you can squeeze into a single subQ injection overblown? If 2ml is considered too large of an injection in terms of discomfort, why not split it into 2 1ml doses? I would think a weekly administration of 2 subQ shots you can perform at home would still be better than having to go in every 3 weeks for a 1-2 hr IV infusion.

Dirk Haussecker said...

It may be overblown, but Alnylam itself keeps stressing it.

I've got little compassion for a person able to go to an infusion center to undergo the medically optimal treatment, but unwilling to do so out of convenience issues. Have the rest of society foot the $150k bill (Aegerion pill $300k?). People (and Big Pharma) need to get their brains checked. Therapeutic profile should be first, deal with the inconvenience yourself.

Guess how many breast cancer patients, often quite old, go to have lymphatic drainage massage after getting lymph nodes removed? Quite a lot and not just once every 3 weeks, but 3 times a week. If they can do it for the rest of their lives because of a simple medical intervention, the average $150k-a-year patient should be able to.

If convenience becomes that much of a factor, the inevitable backlash against drugs for severe orphan diseases will be severe.

What I would agree to, however, is that there may be a need for more infusion centers.

Anonymous said...

Tekmira hasn't proven that its drug is superior to drugs from ISIS/ALNY that knocks down ANGPTL3. In this case convenience does make difference. Add to this the added cost involved in going through infusion and steroid patients have to take with LNP.

Expect 3mg/kg dose to be further optimized as it enters into clinic. For their PCSK9sc, Alnylam is now guiding 2mg/kg dose with a subq dosing frequency of q2w or even q4w. Expect similar profile for ANGPTL3. Also, Alnylam is giving 5mg/kg Subq weekly injection in their p2 trial for TTRsc drug. So volume doesn't seem to be an issue.

Anonymous said...

The sub-q volume can possibly be addressed with formulating the drug with hyaluridonase.


Dirk Haussecker said...

I agree that we have yet to see the relative advantages of Tekmira's drug candidate (targets of which remain undisclosed) and the ANGPTL3s by Alnylam and ISIS. There will be a reason why Tekmira chooses multi-targeting and it's not for lack of relative knockdown efficacy of SNALP vs GalNAc or RNaseH antisense.

With differences in both target genes and technology (delivery, mechanism), expect the drugs to have quite different profiles. Which one will be superior based on therapeutic efficacy, we have to see, but based on knockdown efficacy and multi-targeting, it is likely that Tekmira's approach will prove superior.

PS: I've heard a number of companies trying the hyaluridonase/Halozyme approach for subQ RNAi delivery. Not too much success apparently...

Anonymous said...

Would there be any risk to Tekmira's pole position on this
from a one shot viral delivered RNAi therapy in the future?

There seem to be a number of pre clinical studies on such approaches.

They also have the advantage of multi-targeting, but without the inconvenience. I've not heard of any clinical trials planned however.

Dirk Haussecker said...

ddRNAi for a metabolic disease would probably require the ability to regulate the level of knockdown. Again, the industry (and academia) has been poor in making progress on this. If I had stayed in academia, this would have been one area where I would have worked on.

But again, you need a lab to do this ;) On the delivery front, Voyager, bluebird, Oxford Biomedica, Uniqure are passing by Benitec. OMG, don't they get it?

Anonymous said...

Dirk, I read this blog regularly and greatly appreciate your work and opinions.

Can you please clarify your last comment (OMG, don't they get it?)

Dirk Haussecker said...

'OMG'...the plot of the Benitec movie has been so predictable, yet the company refused to act (and still does- though it's probably too late now anyway).

Anonymous said...

Dirk, I respectfully suggest your Feb 12 comments on the so-called convenience factors of subcu treatment are short-sided. Your question on whether society should foot the rest of the $150K bill doesn’t make sense. Why would subcu administration of a given drug be more expensive than i.v. at an infusion center? If you include the total cost to “society” beyond just the drug, there is no doubt the infusion center is the high end.

Regarding your point that therapeutic profile should come first, then convenience, there is certainly an argument that today’s system has this prioritization upside down. 80% of infusion centers operate only Mon-Fri and do not operate on holidays. For patients facing life-threatening diseases, who exactly benefits from operating hours that are more befitting of an office than a clinic?

Today’s cancer treatment paradigm (i.v. at 5-day/week infusion centers) is a remnant of the days when cytotoxic drugs were usually the only option. With today’s targeted therapies, there certainly is an opportunity to consider more frequent dosing and not allow rapidly-dividing tumor cells to rebound between treatments. Ironically it seems the new targeted drugs coming into the clinic, most of which seem to have i.v. protocols of 1x or 2x per week, are still geared toward a schedule the clinic (and the patient) can deal with, with almost no corresponding discussion on whether more frequent dosages of these drugs would be of therapeutic benefit. When subcu strategies start to become more feasible, this important discussion topic will certainly become more prominent.

Subcu certainly is more convenient, but it's also a lot more than that.

Anonymous said...

what do you think of oxford biomedica. Do you like the co and their pipeline? Thank you

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