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.

Merck Double-Knockdown Strategy to Ameliorate Toxicity from Mtp and ApoB Inhibition

The signs are that the next RNAi Therapeutics metabolic/cardiovascular disease candidate will be a dual-targeting one.  While the initial attempts in this area were directed at specifically reducing the well-known cardiovascular risk factor LDL-cholesterol (preferred targets: ApoB and PCSK9), it has become quite tempting to exploit the rare opportunity offered by RNAi Therapeutics to target multiple gene targets with just one formulation to both broaden the therapeutic benefits in patients that typically suffer from a plethora of metabolic dysfunctions (obesity, insulin resistance, and hypercholesterolemia to name a few) and to balance the adverse effects that may result from inhibiting certain targets.

Most notable among the latter is the liver fat accumulation following ApoB knockdown.  Clinical studies with ISIS Pharmaceuticals’ antisense compound mipomersen/KYNAMRO have clearly evidenced such liver fat accumulations which were often accompanied by increases in liver enzymes, general indicators of liver toxicity.  These results further are corroborated by similar clinical observations with the small molecule lomitapide by Aegerion targeting microsomal triglyceride transfer protein (Mtp) which acts essentially at the same stage as ApoB in packaging triglycerides and cholesterol for transport out of liver cells into the circulation.  Aegerion obtained this drug candidate from BMS via UPenn as BMS did not want to further develop this compound due to these safety risks.

Both mipomersen and lomipatide have completed phase III studies and new drug applications for approval in the rare genetic disease homozygous familial hypercholesterolemia (hoFH), and in the case of mipo also for severe heterozygous FH have been submitted to the FDA and EMA.   In terms of therapeutic profile, mipomersen seems to have the edge as, being a phosphorothioate antisense compound, it preferentially accumulates in the liver.  Consequently, it does not cause the side effects resulting from the intestinal inhibition of this pathway that  have been observed with small molecule lomatipe (note: SNALP-delivered RNAi Therapeutics should have similar benefits over small molecules).  Moreover, mipomersen not only lowers LDLc, but also moderately reduces the independent cardiovascular risk factor Lp(a).   Although not a prospective primary goal of mipomersen clinical development, incidental positive findings like this one can go a long way in having regulators take a benevolent look at drug candidates.  This can be seen in the related obesity space where one of the attractive benefits of Arena Pharmaceutical's lorcaserin is that it lowers blood glucose levels.

Obviously, there should be plenty of potential gene targets involved in triglyceride synthesis and utilization/oxidation that could be exploited to concomitantly lower triglyceride content in ApoB/Mtp-inhibited livers while maintaining LDLc-lowering.

Merck Tests ApoB and Mtp Knockdown, Finds Mtp-DGAT Co-Knockdown Promising

Tep and colleagues from Merck published a paper on a study that tested whether an RNAi co-knockdown strategy could be implemented to alleviate the liver fat accumulations due to Mtp and ApoB inhibition.  To be clear, Merck did not state that they have firm intentions of developing such a co-knockdown strategy, but nevertheless noted that such a strategy would have the advantage of  not having to ‘add[ ] a novel compound on top of an approved drug’ and that dual-targeting RNAi Therapeutics candidates are already in clinical development, therefore paving the regulatory path (see ALN-VSP02, and TKM-EBOLA).

In a first step the scientists confirmed the liver fat accumulation following Mtp and ApoB siRNA knockdown.  Not only were they of similar magnitude, the effects of the two knockdowns where essentially the same in almost every other investigated regard.  Notably, there was no reduction in liver fat accumulation following prolonged siRNA treatment as one might have expected based on claims by ISIS Pharmaceuticals of liver fat normalizations with time, but widespread changes in the expression of lipid-related genes were nevertheless observed- this time consistent with claims by ISIS Pharmaceuticals.

Among the genes that were downregulated following Mtp siRNA treatment, presumably as a result of negative feedback, was DGAT2, a key enzyme in triglyceride synthesis that is also thought to represent an important regulatory node in lipid metabolism (e.g. by promoting fatty acid oxidation).  Reasoning that further reducing DGAT2 with liposomally formulated siRNAs may lead to a measurable reduction in liver fat, they then co-formulated the Mtp siRNA with a DGAT2 siRNA and injected them into mice.  Indeed, this resulted in not only the expected LDL-cholesterol reduction, but liver triglyceride increases were mitigated.  According to data not shown, it was claimed that the same beneficial effect could not be observed with an ApoB-DGAT2 siRNA combination, suggesting that Mtp may be the better target for co-knockdown strategies.

It should be added, however, that the day 14 time-point data these conclusions were based on were somewhat of an outlier as at this time the co-formulation with DGAT2 siRNA reduced the LDLc-lowering potency of Mtp knockdown.  On the other hand, the scientists report (also in data not shown) that they tested the co-inhibition strategy using DNA-directed RNAi and thus validated this conclusion.    Moreover, given the multitude of genes involved in lipid metabolism, the Merck scientists stated that the Mtp-DGAT2 co-knockdown is a proof-of-concept and that other targets besides DGAT2 are also being considered (especially Gpat1).

Given Tekmira’s interest in ApoB as a target and recent LNP work by Alnylam and their PCSK9 collaborators from UT Southwestern (Horton, Goldstein) on SCAP knockdown to alleviate hepatic steatosis and Alnylam's general interest in co-knockdown for metabolic applications, Merck will not be alone in their endeavor of finding an RNAi Therapeutic candidate that can do it all, LDLc lowering, triglyceride lowering, and more.  Given that SNALP technology would likely be used in such a clinical program, this could particularly benefit Tekmira.  

Metabolic Disease Drug Development Anxieties Highlight Benefit of Diversified RNAi Therapeutics Pipeline

Like the commodity bubble, it seems that the regulatory hurdles to drug development are mounting just when we thought we had reached the top. This is the impression one gets from the vote taken by an FDA advisory panel this week that can be essentially boiled down to the presumption that lowering blood sugar increases the risk of heart attack. The prospect of longer and more expensive clinical trials has certainly caused a few mini heart attacks to a number of drug companies developing medicines for diabetes and other metabolic diseases thinking that the obesity epidemic in the prosperous half of the world was bad enough such that regulatory agencies, politicians, and certain clinicians involved in drug development would have a keen interest in new treatment options. Don’t get me wrong here, I see very well the problem of millions of real patients and maybe not-so-needy folks taking drugs from which they do not derive any benefit, but there certainly are other ways of ensuring drug safety and efficacy without rendering drug development, and eventually the cost of drugs just unaffordable to anybody, and often without good reason.

Now that I got this off my chest, what does the broad attack on metabolic disease drug development mean for RNAi Therapeutics?

Metabolic disease, because of the ability of current systemic delivery methods to effectively knock down genes in the liver which is critically involved in regulating blood sugar and lipid levels, is one of the main therapeutic focus areas of current RNAi Therapeutics development. It shares this position with cancer, followed by respiratory, ocular and CNS-related disease. It may therefore be tempting, if you have the ability to target a range of hot metabolic disease targets, to create a development pipeline based on metabolic disease and little else. ISIS Pharmaceuticals from the related field of antisense therapeutics is probably the best example here as it has very much limited their internal drug development activities on metabolic disease, while handing off some of the more challenging targets such as for cancer to one of their many satellite companies.

Of course, if you don’t have the capability to diversify, concentrating on building a franchise around a single, but potentially very lucrative market may be the most efficient way of maximizing shareholder value given the many synergies derived from largely having only to exchange the siRNA inside and comparatively few other changes. However, if you can afford it and you are interested in establishing RNAi Therapeutics as a broadly applicable drug development platform, you probably would want to spread your risk more widely even if all the programs added up individually would yield a higher valuation. The fact that the regulatory environment may change overnight while drug development is a 12-15 year effort being one reason.

Next to insuring from regulatory risk, diversification also means that failure of one drug candidate such as for a given organ does not necessarily have to impact the perceived probability of success for candidates aimed at other organs. In the same vein, it may also be wise not to be too dogmatic about delivery technologies, siRNA modification or DNA-directed RNAi methods and structures. For example, if your entire IP claim depends on just one siRNA modification pattern even without so much as functional validation in a non-human primate, you may have ended up totally reliant on clinically non-viable chemistries. Related technologies have shown that developing chemistries in generations rather than multiple chemistries in parallel may mean that if your chosen chemistry generation turns out to be either inefficient or unsafe, it may take another 7 years to get a shot with the next generation.
Meanwhile, all bets are off what steps the FDA will take next.

Alnylam Grants Takeda RNAi Therapeutics License for Cancer and Metabolic Disease and Anoints Asian Partner of Choice

As if executing from a script, Alnylam today announced its first major Asian licensing deal giving Japanese pharmaceutical company Takeda access to the US biotech's RNAi Therapeutics IP for cancer and metabolic disease. The deal also provides Takeda with the preferred option of co-developing Alnylam product candidates for the Asian market. In return, Alnylam gets a sizeable $100M in immediate upfront, and another $50M in "near-term technology transfer payments". Adding the typical development and commercialisation milestones, field area expansion payments, and royalties built into these deals, the eventual value may well exceed one billion US dollar.

The agreement is also another validation as to how important SNALP RNAi has become for the current valuation of RNAi Therapeutics, as both metabolic disease and cancer are the two major near-term opportunities for SNALP RNAi. Remember, Roche’s therapeutic areas also included metabolic disease and cancer, as well as certain liver diseases and respiratory disease.

That this deal was announced one day before the close of the Tekmira-Protiva reunion should also be no coincidence and the exact timing may relate to the interests of various Tekmira and Protiva shareholders. Furthermore, my expectation is that the announced $50M in near-term technology transfer payments refers to the final closing of Tekmira-Protiva as well as finalization of an R&D collaboration agreement for SNALP similar to the ones that Tekmira currently has with Alnylam and probably soon with Roche as well. It also reminds us that there are at least another 3 Big Pharma and biotechs that are currently evaluating SNALP RNAi with Protiva-Tekmira. So plenty of more news to come and auction dynamics to set in.

Takeda’s move once more emphasizes the thirst of Big Pharma for innovation. Takeda itself has just propped up its sales numbers and cancer franchise with a headline-grabbing $8.8billion purchase of Millennium Pharmaceuticals and adding to that another $150M for planning more long-term may not be bad for balance. And on the same business trip at that. This is because Millennium is also Alnylam’s Cambridge, MA, neighbor and former employer of Alnylam’s CEO John Maraganore. In fact, it is rather curious that John Maraganore was chosen by the Boston Globe to voice his views on the Millennium deal, to which he responded that “the deal could potentially free Millennium from worries about making every quarter's profit figures, allowing it to invest more money in drug development.” Well, with the $150M in added cash, and ~$400 already stashed in the bank, he has just gotten one step closer to that dream.

Takeda has just had a high-profile failure for an cholesterol-lowering drug candidate, and may now be keen more than ever on exercising its right to partner Alnylam’s PCSK9 program for Asia. ALN-RSV01 interestingly is the only program that Takeda does not have first right of refusal, and may indicate yet another deal in the Alnylam pipeline.

Takeda is also strong in the diabetes area, and it will be interesting as to whether Takeda will pursue such programs with RNAi soon and for which liver-expressed genes may be targeted. This may particularly benefit Alnylam since, unlike in the Roche deal, it now has also the opportunity to opt into Takeda’s RNAi Therapeutics programs in a 50:50 relationship.

Based on statements such as "We believe this alliance will accelerate our initiatives to establish the foundation for RNAi drug discovery" in the presss release by president of Takeda, Yasuchika Hasegawa, it also appears that Takeda has been quite a bit active in RNAi Therapeutics already. Moreover, the deal provides for a cross-licensing of delivery technologies, and it will be exciting to learn what these are.

Novartis, Roche, and now the Takeda deal by yet another major foreign company may illustrate two points. One is that the US currency has fallen so low that foreign companies cannot resist the opportunity to secure their rights to US innovation, in this case to RNAi Therapeutics at bargain exchange rates. The other is that Alnylam may want to keep US rights to itself for the time being.

Finally, the deal is yet another validation that if you have money and are serious about developing RNAi Therapeutics, Alnylam is the company to partner with for access to fundamental IP and, thus far, enablement, too.