Two of medicines most popular and accepted biomarkers, LDL-cholesterol for cardiovascular disease and blood-sugar levels for diabetes, have recently come under scrutiny after high-profile studies showed no benefit or even increased health risk despite the lowering of these biomarkers by drug treatment. Since some of oligonucleotide therapeutics’ most advanced early drug candidates are for metabolic diseases and aimed at lowering these two parameters for an accelerated path into the clinic, the issue deserves some further consideration.
The ENHANCE study used an imaging technique to look at changes in the thickness of plaque deposition in the carotid (large artery running through neck) in patients treated with a combination of a statin (Merck’s “Zocor”) and the dietary cholesterol uptake inhibitor ezetimibe (“Zetia” marketed by Merck and Schering-Plough) versus patients treated with the statin alone. After a year of delay in data reporting, the companies admitted that the combination, called Vytorin, did not lead to improvements in plaque thickness with even a trend towards adverse events, despite the fact that LDL-cholesterol was further decreased by the addition of ezetimibe. Combined with Pfizer’s infamous torcetrabip blunder that despite increasing the level of good cholesterol (HDL) the rate of death was actually increased, this shows that particularly with novel drug targets, biomarkers alone will not suffice and expensive outcome studies instead may be necessary to ensure clinical benefit. A similar lesson may be drawn from the results of a recent diabetes study that aimed to aggressively lower the gold standard biomarker in diabetes care, namely blood sugar levels as measured by glycylated hemoglobin.
It will therefore be interesting whether and how this will affect the view the FDA and other regulatory agencies take on drugs such as ISIS’ ApoB100 targeting antisense compound mipomersen or Alnylam’s PCSK9-targeting ALN-PCS01 siRNA. Although there is little doubt that e.g. in the case of mipomersen, similar to Zetia, there is a marked reduction in LDL-cholesterol in humans, because it is aimed at a novel target in LDL metabolism, the FDA may insist on having its therapeutic utility being proven in large outcome studies, except maybe for some patient populations with familial hypercholesterolemia.
These failed biomarker studies are only going to add to the increasingly conservative stance the FDA takes towards drug approval, at a time when drug approval rates are declining despite ballooning drug development expenses. These expenses are also driven in part by regulatory demands for large late-stage clinical registration studies. Clearly, this trend is not compatible with a drug industry from which we expect new medicines addressing unmet medical needs. This is compounded by popular calls for cheaper generic medicines which, while saving the healthcare system dollars in the short term, undermine long-term productivity and innovation. Drug development overall has become a money-losing game for most, and it is not fair pointing out the huge cash reserves of a few Big Pharma, which we know are about to diminish in the near future anyway, without taking into account the many enterprises that never see the light of profitability.
So what could be the solution? It is difficult to argue that savings should come at the detriment of patient safety. In the difficult act of juggling the demands for patient safety, ensuring innovation, drug access, and profitability for the companies, I see fostering innovation, leading to better medicines and more efficient development paths, as probably THE one solution that may satisfy all four demands.
The RNAi Therapeutics platform e.g. opens the prospect of shortening pre-clinical development times which should lead to faster drug approval times and therefore exponentially longer periods of sales exclusivities. Say conventional drug development takes 12 out of the 15 patent years, resulting in 3 years of sales exclusivity, while an RNAi Therapeutic may take on average 9 years to develop, i.e. doubling the time of sales exclusivity. One could therefore even argue that current trends actually amplify the competitive advantages of the RNAi Therapeutics platform. Nevertheless, in the end even RNAi Therapeutics will suffer when innovation fails to be protected, which is why the current temptation for prematurely approving or tolerating unlawful generics should be resisted and fundamental patents enforced. Given the importance of the US for worldwide drug development, I can only hope the candidates running for President understand all of this.
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