Drug stuff: Food edition — Larry Rodriguez, PhD

I came across some cool developments at the intersection of diet, drugs, and the brain recently, and wanted share them, including Amarin's drug patent woes, oral semaglutide results, and Adermark et al's paper on how weight gain and neuroadaptations elicited by high fat diet depend on fatty acid composition. Cover art is a meme inspired by the Vascepa saga.

Drug patent woes

I came across Curfman and Shehada’s preprint style write up on on Amarin’s patent issues with Vascepa®® (Icosapent ethyl.) If you take fish oil (or have taken organic chemistry) you might recognize icosapent ethyl as eicosapentaenoic acid (EPA), one of the ingredients in fish oil (the other being docosahexaenoic acid, DHA.) I was finishing my regulatory science degree when the results of the REDUCE-IT trial started making waves, as it should have, since Vascepa® (purified EPA) was shown to significantly reduce the risk of cardiovasculuar events compared to a placebo (mineral oil.)

The clinical trial was successful, so what’s the issue? Many things. For starters, this brings up an important question in intellectual property (the Achilles heel of neutraceuticals): how do you get patent protection for the active ingredient in a dietary supplement? Because no patents = no drug*; simple as that. Early in the discovery process, companies have to make sure they have freedom to operate (FTO), and Amarin took a risk 1) in the method of purification of EPA being patentable and 2) that prior art wouldn’t invalidate its patent. However, ANDAs (abbreviated new drug approvals; drug approvals for generics) were still filed, and as Curfman and Shehada point out, the generics were in fact infringing upon Amarin’s patents. However, because the generic companies questioned the obviousness of Amarin’s patent, things got complicated. An article (i.e. prior art) by Mori et al showed that DHA increased LDL-cholesterol while EPA did not. But there’s a problem: the authors didn’t test for an interaction between the changes in LDL-cholesterol associated with taking pure EPA and pure DHA (there was no difference!) But based on the conclusions Mori et al report, the Judge ruled that Amarin’s patent was invalid due to “an incorrect scientific conclusion in the prior art.” In fact, another [prior art] article included a statistical oversight that cost Amarin a “non-obvious” conclusion on whether EPA lowers Apo B. The wildest part of the story to me is this: “In the case of the invalidation of Amarin’s Vascepa® patents, the district court judge, and the expert witnesses for both the petitioner and defendant all failed to identify a fundamental statistical error in the prior art, and this error was left uncorrected by the Federal Circuit. Indeed, the Federal Circuit has confirmed that district courts are under no obligation to probe the validity of prior art and may presume that the prior art, upon discovery, is true”

The other issue for Amarin are the results of the STRENGTH trial which looked at the benefits of Omega-3 fatty acids (FAs) compared to placebo (corn oil.) While this trial tried to use FAs at doses close to the REDUCE-IT trial, it’s not the best comparison study, since the STRENGTH trial 1) used EPA and DHA (instead of purified EPA) 2) used corn oil instead of mineral oil as a placebo (mineral oil is bad for you?), and 3) used the carboxylic acid forms of EPA and DHA (faster absorption?) All of these factors could have influenced the results of the STRENGTH trial, which found no difference between FAs and placebo. Interestingly, the FDA considered the idea of mineral oil raising biomarkers like LDL and Apo B, but concluded the effects of mineral oil alone didn’t have a major influence on the difference in MACE events.

The academic in me is saying “more studies are needed to blah blah blah” but several clinical trials have already been done. At this point, you have to take each of these results for what they are. Amarin’s Vascepa® probably does reduce cardiovascular events, mineral oil probably impacts cardiovascular biomarkers, and EPA-DHA is probably not the same as EPA. Unfortunately, the courts aren’t required to re-review published results.

So what’s next for Amarin? Well despite the patent ruling shaking up the share price, they reported a strong Q4 a few weeks ago (Vascepa® sales are up >15% YOY; >$150M in revenue), and they’re looking to appeal to the supreme court.

* you might get away with selling a product with your molecule of interest, but it won’t be a drug, you’ll be a dietary supplement with strict limitations (rightfully so!) on what medical claims you can make about your product.

Oral Semaglutide Results

The structure of semaglutide, via pubchem. Molecular weight: over 4000 g/mol

Read the abstract for the recent Semaglutide paper in NEJM: “Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.” Well, the authors confirmed it. Yeah, Trulicity, the injectable form of semaglutide, was approved already, but despite the fact that the long-lasting formulation required only once a week injections, its still an injection. Plus, look at its structure! Its an absolute UNIT of a molecule! Lapinski rules? More like Lapinski suggestions.

Anyway, very impressive results! Maintaining weight loss long-term is notoriously tough. I couldn’t maintain losing 30 lbs for more than a few months before my weight started creeping up again (small update, I’m losing weight again!) Should you be taking Semaglutide for weight loss though? That’s your physician’s call, not mine. I don’t do Pharmacoeconomics, but the economic impact of obesity is not trivial. And sure, weight loss can be done without medicine, but semaglutide is still a great option for people. Think of a chemical reaction with and without a catalyst.

Diet and the brain

I came across a very nice article by Adermark et al and the title says it all: Weight gain and neuroadaptations elicited by high fat diet depend on fatty acid composition. Once I saw the patch-clamp currents in the graphical abstract I immediately started reading. I encourage you to read the paper for yourself, but some of the main findings: mice fed high fat diets (HFD) rich in saturated fats gained weight and showed brain-region specific impairments in synaptic plasticity (long-term depression in dorsomedial striatum), while mice fed HFD rich in polyunsaturated fats didn’t gain weight (despite consuming more food; increased energy expenditure) and saw enhanced AMPA mRNA expression. The results are logical (HFD composition subtly influences brain function), and in this case, more studies are required to figure out what’s going on mechanistically.