Tuesday, July 3, 2012

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.

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By Dirk Haussecker. All rights reserved.

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