Tekmira with Multi-Trigger and Parallel Development Plans

As a veteran armchair RNAi Therapeutics strategist, I am frequently frustrated at the inflexibility of companies in the face of rapidly moving competitive and drug development environments.  The worst offenders are those with management and Boards that view their positions as entitlements and could not care less about the science and acknowledge the flaws of their technology.  

Often related to this, another common violation is a failure to cut your losses on an obviously failed development program at the cost of the platform, a strategy though that sometimes works if you can find a greater fool (the ~$700M acquisition of Prosensa by Biomarin yesterday falls into that category).  

Tekmira, too, has been at risk of suffering from such inflexibility in light of an industry-wide shift from nanoparticle-based to small conjugate-based delivery.  This does not mean that nanoparticle-based delivery will not have an important role to play in the future of RNA(i) Therapeutics, but that you have to realize your relative strengths in a highly competitive space.  In addition, Tekmira has been slow to realize the shifting regulatory and payor landscape making biomarker-focused orphan drug development in genetically defined patient populations highly attractive.

Having listened to the Tekmira Analyst Day last Friday, I was therefore quite pleased that not only is Tekmira catching up by beginning to realize that it is running a business and not a scientific think tank, it can even be considered to take on a strategic leadership role in at least two regards:

1)      the adoption of multi-payload candidates thereby addressing the i.v. nanoparticle versus single molecule subQ debate and leveraging key advantages of nanoparticle technology;

2)      running trials in parallel to quickly find out which delivery chemistry platform works best in humans.

1.       Multi-targeting: a key differentiator of nanoparticle-enabled RNA(i) Therapeutics

At the Analyst Day, Tekmira re-iterated that it will put a multivalent HBV formulation into the clinic that will contain three RNAi triggers.  In addition to ensuring that most patients thus become a match for the therapy, just as the two-trigger ARC520 by Arrowhead Research had been geared towards, Tekmira also wants multi-targeting to address viral resistance of the kind it observed in the woodchuck model of HBV.  

From that perspective, the intravenously administered TKM-HBV is preferable to single molecule approaches by Alnylam and ISIS Pharmaceuticals which are both administered subcutaneously.

Tekmira does not limit multivalent RNA Therapeutics to viral applications such as in their HBV and Ebola programs, it will also apply the concept outside that space such as in its hypertriglyceridemia program where it is considering dual-targeting formulations with ApoCIII, ANGPTL3, and DGAT2 as candidate targets.  

Equally or even more intriguing, in the Q&A session it was hinted that other therapeutic strategies that the company is considering may not merely involve multiple payloads of the same type, but even payloads from different categories such as an mRNA and an RNAi trigger.  Obviously, such combinations could open up entirely new therapeutic strategies (e.g. mRNA-RNAi combos for alpha-1 antitrypsin), or maximize potency (e.g. RNAi trigger-RNaseH ASO for HBV).

Scientifically, I see no reason why single molecule technologies such as GalNAc-siRNAs should not be amenable to certain (but not all, e.g. mRNA) multivalent approaches.  Culturally, however, multi-valency takes away from the single molecule simplicity that the pharmaceutical industry apparently loves, ideally in pill form.  From a regulatory point of view, it seems to be the case that nanoparticle-encapsulated RNAi products are seen as just one drug no matter how many RNAi triggers it contains, and it remains to be seen what the regulatory thinking would be when combining multiple single RNAi triggers (I can imagine Alnylam trying to combine their HBV mRNA-targeting GalNAc-siRNA with its PD-L1 GalNAc-siRNA).

In some ways, ARC520 (which is not a nanoparticle) strongly indicates that multi-targeting is not an insurmountable challenge for the non-nanoparticle approaches, so that regulatory advantage may not exist in the future. 

Nevertheless, my prediction is that multi-targeting will be mostly practiced in the nanoparticle and not the conjugate sector of RNAi Therapeutics and nanoparticle-based companies ought to consider multi-targeting almost a Must when there is direct conjugate delivery competition.

Although Tekmira is the most visible RNAi company for multi-targeting, it should be added that multi-targeting has been the motto for US-China-based Sirnaomics from the get-go in 2007.

2.       Testing Multiple Delivery Technologies in Parallel

The RNAi Therapeutics field is both blessed and plagued by the rapid progress in refining particular delivery platforms.  Tekmira has already arrived at the 4th generation of SNALP LNPs while Alnylam is now talking about GalNAcs with standard and enhanced chemistries.  With a multitude of preclinically validated alternatives, it is often difficult to determine which one should be prioritized for human development. 

This can lead to protracted development timelines when a first formulation yields unsatisfactory results in the clinic and the payload has to be re-formulated into a new delivery chemistry.  Especially in competitive environments this can be fatal.  And even if you were somewhat satisfied with the initial results, chances are that you left a lot of money on the table by not finding out about the performance of other formulations in humans.

Needless to say, having multiple candidates for a target is not a unique challenge in the pharmaceutical industry and if money were not an issue, we would see a lot more parallel development programs.  However, RNAi and related delivery is unique as the investment can be amortized across the platform.  

Moreover, in practical terms, RNAi offers a number of opportunities to directly and accurately measure target engagement and thereby assess the impact of changing the formulation.  This is one of the reasons why the early RNAi programs targeting genes in the liver involve targets which can be found in the blood.  For other modalities (e.g. microRNA inhibition in the RNA Therapeutics field), what you measure in your blood sample or other biopsies may differ significantly from what is actually going on in the body.

For these reasons, namely to speed up time-to-market in a competitive market and to inform which delivery formulations should be used with other LNP-enabled candidates, Tekmira announced that it is about to put two formulations of TKM-HBV in the clinic that will only differ in their delivery chemistry while using the identical (3) RNAi triggers.

Tekmira investors are not seeing double: the company is becoming a modern drug developer.

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.

Obesity Drug Approval to Unlock Low-Hanging RNAi Therapeutics Opportunities

The FDA approval of weight-loss drug Lorcaserin (to be sold as BELVIQ) a week ago symbolizes a recent shift in the regulatory climate from an extremely conservative, risk-averse one (remember Vioxx and Avandia) to one that tries to better balance the safety concern with providing patients and physicians with new treatment options.  This is also good news for the field of RNAi Therapeutics as the technically lowest-hanging fruits happen to be for targeting genes in the liver, an organ rich in well-validated gene targets related to the metabolic and cardiovascular disease, the two therapeutic fields that arguably suffered the most from the risk-averseness as they had grown heavily reliant on biomarkers in favor of outcomes.  Of course, Tekmira’s SNALP delivery technology, already clinically validated for target gene knockdown in the liver (SNALP Works!), is first in line to benefit from the change, although companies like Merck, Arrowhead Research, and Silence Therapeutics are trying hard to replicate Tekmira’s success with similar and also differentiated approaches.

Lorcaserin Symbolic

The approval path of Lorcaserin has been symbolic for the shift in the regulatory climate.  Despite meeting- in large clinical trials- the FDA’s very own guidelines for weight loss efficacy with what was one of the most benign safety profiles that I have seen, the agency, in briefing documents and Advisory Committee meetings alike seemed about to change the goal-post in the middle of the game by demanding greater degrees of weight loss which it was clear Lorcaserin, as a single agent, could never achieve.  To further justify the negative stance on Lorcaserin, theoretical safety concerns, particularly stemming from clinically irrelevant cases of breast cancer in rats were suddenly picked up on.  If you are a scientist, this scenario might sound familiar to you: if a reviewer of a scientific paper does not like your study or even you personally [on a personal note, the term ‘blogger’ is often used here in a derogative way], he/she will always come up with a reason to reject your study.  In other words, as in publishing, also in drug regulation, no matter how good, anything can be made to look bad if that's the motivation.  

To add insult to injury, Lorcaserin’s two main competitors, Qnexa from Vivus and Contrave from Orexigen, came up ahead of Lorcaserin at least from the AdCom meetings 1-2 years ago, despite these formulations being nothing more than the combination of two established ingredients, the type of life-cycle re-formulation strategy that has pushed the pharmaceutical industry and the healthcare system to the brink of financial viability.  

Thankfully, these events prompted a wide public outcry, including vocal, often ridiculed ‘retail’ shareholders which together with the recognition of the enormous unmet medical need (obesity) caused a remarkable turnaround in the regulatory fortunes of the drug climaxing in a broad label with the main restrictions being that Arena Pharmaceuticals and partner Eisai conduct a number of post-marketing cardiovascular outcome and safety studies- reasonable.  Such a preliminary approval process (witness also the Avastin-breast cancer controversy) that post-pones these studies to a post-marketing setting was also in recognition of the fact that demanding them pre-approval would be financially prohibitive for most small and medium-sized pharmaceutical companies. Moreover, the fact that the only new, single agent among the three weight loss contenders happens to be the first one approved, should be further encouragement for innovative drug developers.

What it means for RNAi Therapeutics

The acceptance of biomarkers such as weight loss, LDL-cholesterol, and glycated hemoglobin, together with postponing hard outcomes studies to the post-marketing setting are the two key ingredients that should greatly increase the attractiveness of harnessing the liver-targeting potential of RNAi Therapeutics to go after metabolic and cardiovascular disease opportunities.  What is more, what in the end may have tilted the agency’s opinion in favor of Lorcaserin (in addition to bowing to political pressure) was the fact that the drug not only promoted weight loss, but also provided clear benefits in terms of other biomarkers such as lowering blood sugar levels in diabetic patients. 

RNAi Therapeutics candidates should be particularly well positioned to take advantage of the regulators valuing the totality of the efficacy data rather than myopically focusing on single end-points that may have been met just marginally.  This is because RNAi Therapeutics have the unique potential to simultaneously go after multiple targets (multi-targeting).  At the risk of repeating myself, an RNAi Therapeutic that could reduce not only atherogenic lipids, but also hepatic fat and increase insulin sensitivity should be very welcome in such an environment.   

The experience with ISIS Pharmaceutical’s mipomersen for which an NDA has been submitted recently, however, also shows that while the emerging approach can speed up drug approval, it can also limit the initial market potential (here, the rare homozygous FH population) and costly outcomes trials may be necessary to address wider patient populations.  It can be argued that ISIS and partner Genzyme simply got unlucky as, unlike the European counterpart, the FDA will only accept LDL-cholesterol lowering as a sufficient end-point for the hoFH population; there should be other cases, however, where the first population in such a staged approval process will justify the investment in the drug development program already.    

In this environment, I look forward to TKM-ApoB and ALN-PCS02 being followed by more metabolic/cardiovascular RNAi Therapeutics candidates, particularly of the multi-targeting type, SNALP-delivered, multi-cassette ddRNAi or otherwise.  With the biomarker-based and staged approval approach, it should be possible again for even small companies like Tekmira to bring such programs into later-stage development on their own.