AsherAMiller

Asher Miller

=Asleep at the Chiral Switch: the Rules and Results Regarding Racemic Mixtures and Single-Enantiomer, Patent-Protected Pharmaceuticals=

Abstract
Chiral switching is a tactic employed by pharmaceutical companies in order to obtain rights to patent and apply for exclusivity in drug manufacturing. Pharmaceutical companies gain billions when chiral switches are affected successfully. It is not rare for a chiral switch to fail, causing the pharmaceutical industry to lose money. Such losses can increase the cost of healthcare because they decrease the return on investment for developing new drugs through a myriad of business-to-business lawsuits and consumer’s lawsuits. Chiral switches can also introduce perverse incentives to take advantage of the FDA and consumer through withholding better medicines until the timing is right to maximize profit at the expense of the consumers and generic manufacturers. Once again, failures and litigation involved in timing a chiral switch or disputing patents can also leave useful drugs undiscovered or impossible to produce commercially due to no entity clearly having the right to practice. The attitude of the FDA and the consumer seems overly optimistic given the track record for only marginal clinical benefits and pervasive surprises that cause clinical trials to fail. Furthermore, chiral switches are often employed alongside concomitant anticompetitive practices utilized to take money from consumers. With a dearth of new drugs coming to market, chiral switches have no benefit to the consumer despite being profitable to pharmaceutical companies. The future will hopefully see technological advances make it possible to phase out racemic mixtures in place of enantiopure drugs that start that way in the first place. Chiral starting materials and synthesis techniques are changing the next generation of pharmaceuticals, but some to exploit the low-tech racemic mixtures of many legacy pharmaceuticals. Examples include fenfluramine (compound 1), thalidomide (comound 2), omeprazole (compound 3), and modafinil (compound 4).

levofenfluramine (compound 1r) || Inactive[1] || dexfenfluramine (compound 1s) || Anorectic[1] || R (+) Thalidomide (compound 2r) || Sedative, teratogenic [2] || S (-) Thalidomide (compound 2s) || Sedative, teratogenic [2] || R-omeprazole (compound 3r) || Inactive, decreases solubility [3] || esomeprazole (compound 3s) || Proton-Pump Inhibitor [3] || armodafinil (compound 4r) || anti-narcoleptic, reduces sleepiness [4] || S-modafinil (compound 4s) || anti-narcoleptic, reduces sleepiness with short duration of action [4] || Figure 1. The structures, names, and compound id's of each molecule for all the racemic pairs of molecules that will be discussed in this paper.
 * Compound || R enantiomer || R enantiomer's attributes || S enantiomer || S enantiomer's attributes ||
 * Fenfluramine || [[image:dexfenfluramine4010140.jpg width="172" height="185"]]
 * Thalidomide || [[image:rthalidomide101019284.jpg width="196" height="133"]]
 * Omeprazole || [[image:romeprazole2323.jpg width="250" height="127"]]
 * Modafinil || [[image:armodafinil1010929010.jpg width="183" height="201"]]

Patents and FDA-issued exclusivity for pharmaceuticals help developers make back costs. Exclusivity generates billions of dollars in revenue. Strategies to extend exclusivity and patent protection include releasing an improved version of a racemic mixture of compounds with only the biologically active compound (the eutomer). This practice has earned the nom de guerre of "the chiral switch." Relative to the initially released compounds, there can belower costs to investment inresearch and development for chiral switches due to the FDA's relaxed approval process.[5] Chiral derivatives are treated as modifications of existing products and not as new chemicals, granting a period of three years exclusivity.[3]

As outsiders to pharmaceutical corporations, the public's primary source of information about chiral switches relates to commercial successes and failures. A literature survey pertaining to chiral switches reveals differences in metabolism, effectiveness, duration of action, and side-effect profiles for equipotent dosages of enantiopure drugs and racemic products.[6] To be granted a patent for an enantiopure drug subsequent to a patented racemic mixture of said drug, some differences must in fact be surprising in order for the claim of non obviousness to hold up.[7] Therefore it is not surprising that some miscalculations have occurred and resulted in failed clinical trials or products containing enantiopure drugs being taken off the market.[6, 8]

Some commercially successful chiral switches have in common that they were not due to monopolistic protection strategies from the start, but rather racemic drugs were initially being produced due to technical challenges and technology became available for the task of synthesizing enantiopure drugs on both small and large scales.[3] Now that technology allows for more rapid screening of both enantiomers and racemic mixtures, the public should be skeptical about chiral switches. By legal necessity, the racemic mixture and the enantiopure drug will have differences.[7] The pharmaceutical company could be aware of these before applying for approval of either compound. The public and the FDA are putting their trust in pharmaceutical companies to release only their best products, intended to help people. Consumers must make well-informed decisions regarding whether to take new blockbuster pharmaceuticals right away and should always be skeptical when told the product of a chiral switch is the same as the previous.

If a patient starts taking a medication right when the medication comes to market and is taking this medication for five years or more, they may encounter the chiral switch.[7] Chiral switching is when a patented racemic mixture is sold until the patent or exclusivity expires and then the enantiopure drug is sold under an extension of the exclusivity.[9] There are always two enantiopure options in this scenario. The molecular formula and skeletal connectivity of the atoms in the drug molecules are the same, but the three-dimensional shapes can be different. Differences between the new drug and the old drug generally are proven as a condition of granting the patent extension.[7] This discourages generic drug development and sale for a period of time. During that time, marketing can be used to switch the patient to the new and improved version of their old medication and away from generics.[10]

Drug companies have been selling drugs that work poorly or have undesirable side effects due to anenantiomer they can eliminate.This incentivizes patients and doctors to make the switch.[6] In at least one example, a pharmaceutical company failed to improve the side effect profile as anticipated, as revealed by injuries and death becoming a clear trend pertaining to exposure to both the old and new version.[1] Dexfenfluramine allegedly replaced the toxic ingredient in Fen-Phen, fenfluramine.Dexfenfluraminewas later discovered to be toxic in the same way as racemic fenfluramine, both were removed from the market in 1997.[6] When pharmaceutical companies perform a chiral switch and claim increased safety, physicians will typically not prescribe the unsafe medicine. Patients will not want the unsafe medicine. Generic companies will usually give up on developing the unsafe medicine.[10] It is impossible to say that the FDA stops caring, but it is likely reprioritized. These assertions are furnished to allude to the premise that the release of a safer medicine, dexfenfluramine, took priority away from studying fenfluramine and extended the total period of time that either dangerous medicine could be sold for, while Interneuron charged very high rates due to exclusivity. If chiral switches were subject to full approval testing by the FDA, this tragedy may not have happened.

Chiral switch strategies do not benefit the consumer and the truth is that the enantiopure drugs bear similarities to the racemic mixtures, but no safety, efficacy, or pharmacologic properties are retained absolutely.[6] Disturbingly, the author asked his pharmacist and doctor about achiral switch from the perspective of a patient and was told the medications were identical except an inactive component had been removed. This is an oversimplification that can be used because it contains a fraction of truth. It also effectively stops further questions. A medication subject to a chiral switch might have an “ar” or “es” appended to the beginning of its name. Examples of this are modafinil and armodafinilor omeprazole and esomerpazole. Medications may also have “dex” or “lev” appended to the beginning of their names.

Drugs often work like keys fitting within locks to trigger certain signaling pathways within the body. Due to this mechanism, changing the different positions in space of a drug’s atoms is similar to making a new drug.[11] In a typical chiral switch, the previous medicine contained two active chemicals with different bioactivity. The new version contains a purified version of only one of them.[6, 9] Clinical trials have shown different side effects between enantiopure and racemic drugs.[6]

Side effects are a common and valid concern regarding drugs. Side effect profiles range from a list of common nuisances that occurred only rarely in the test population to profiles that require warnings similar to: some people have developed a rare type of cancer…This type of cancer often results in death.[12] A patient’s doctor is aware of the side effects of a medication that he or she prescribes. The doctor has prescribed the medication because the medical benefit outweighs the risk and severity of the drug’s side effects.

Although a relatively high percentage of people are allergic to penicillin, for example, it has fairly benign side effects even when allergic reactions occur.[13] This is the reason why there are still a lot of people living and breathing who report being allergic to penicillin. There is a risk of anaphalactic shock with most drugs, however, and people allergic to penicillin may be prone to anaphalactic shock when they take the medication, so an allergy to penicillin should always be taken very seriously. If not allergic to penicillin, the most common side effect is nausea and vomiting. Considering that a single dose of penicillin treats syphilis, before it progresses to third stage, which can cause deformities that look like those in the picture on the left.14 Clearly, risking nausea and vomiting as well as the other less common side effects is worthwhile to treat horrifying and life-threatening diseases like syphilis.[13]

Figure 2. This is a cast of a person with tertiary syphilis a long time ago.[14]

Another example pertaining to side effects, this time far less innocuous, and which involves chirality is the well-known tale of thalidomide. Thalidomide was used to treat morning sickness in pregnant women, but caused birth defects.[6, 15-17] This is clearly on the other side of the spectrum than penicillin relating to side-effects versus benefits. Morning sickness in comparison to tertiary syphilis is rather bearable. The side effect of causing birth defects is clearly not acceptable to any pregnant woman in exchange for relieving morning sickness.

Thalidomide was sold as a racemic mixture, a 50:50 mixture of thalidomide’s two enantiomers.[16] It is commonly believed that one stereoisomer of thalidomide is teratogenic and one is an effective treatment for morning sickness. An oversimplification lies at the heart of this common example, which will be clearly explained after relating the popular narrative of what happened with thalidomide in the 1950s. Below, a high school chemistry teacher in AMC’s Breaking Bad uses thalidomide as an illustrative example of chirality:[18]

“So the term chiral derives from the greek word hand. Now the concept here being that Just as your left hand and right hand are mirror images of one another, right? Identical and yet opposite. Well, so too organic compounds can exist as mirror image forms of one another all the way down at the molecular level. But although they may look the same, they don’t always behave the same. For instance…..for instance: um um I’m sorry for instance uh thalidomide. The right-handed isomer of the drug thalidomide is a perfectly fine good medicine to give to a pregnant woman to prevent morning sickness, but make the mistake of giving that same pregnant woman the left-handed isomer of the drug thalidomide and her child well be born with horrible birth defects, which is precisely what happened in the 1950’s.” -Walter White in AMC's Breaking Bad

The problem is what Walter White is, and a lot of real high-school chemistry teachers are, telling their classes is not true. A single German paper from 1979, reported that only the S(-) enantiomer was teratogenic in mice and rats. Research in rabbits actually points to the R, S, and racemic mixtures all being teratogenic.[15] Mice, as a species may be fairly resistant to thalidomide’s tendencies to create birth defects.[17] When the R (+) isomer of thalidomide is metabolized by the body, equal proportions of the S (-) isomer are formed in vivo through chiral inversion.[6, 16] And finally, in humans thalidomide does undergo chiral inversion as well. Given time in the body, administration of either enantiomer of thalidomide will equilibrate to an (R/S ratio of 1.7).[2] A finding that will clearly prevent any clinical trial of the R (+) isomer from ever being given to a pregnant woman again. Even if an enantiopure version of thalidomide were sold, a substantial number of birth defects would likely have occurred.6What is known for sure about thalidomide is that the S (-) isomer does cause birth defects.

Hearing about thalidomide from a graduate of Walter White’s high-school chemistry class, one might imagine that the enantiopure drug was the one that was studied and when it became time to mass-produce the drug, the racemic mixture was sold to reduce costs. In light of the fact that both drugs would be teratogenic one can see that this is not the case. Thalidomide was marketed, originally, as a sedative that did not cause nausea and that was not a barbituate.[16] Racemic thalidomide is still used today in research.[2] The unfounded explanation does, however, highlight an important concept about enantiopure drugs and their mass production, enantiopure drugs cost more to make.

In the lab, most organic syntheses produceracemic mixtures of a given organic chemical. In nature, biosynthesis produces chiral products.[19] There are only theories as to why this difference occurs in nature, but it does. Chiral compounds can be separated into their enantiopure racemates by a number of techniques, some simple and some complex or expensive. The purity of a mixture can then be tested by seeing how the chemical rotates plane-polarized light. Which is in and of itself a way to name, define, and keep straight which enantiomer is which.[9] As one can tell, this extra work adds extra cost. The techniques used to make chiral drugs will be discussed.

Chiral synthesis can sometimes use specialized catalysis, often an extensively specialized three-dimensional component. Porous substrates have been used to both catalyze and separate chiral components.[20] A common technique, which can still be very expensive is to simply buy chiral starting materials. For example, if a synthesis strategy can be built around vitamin C this synthesis will have the advantage of one of the most widely produced chemicals being a precursor. Vitamin C production in 2001 was estimated to be near 80,000 metric tons per year.[21] Some chemicals indeed have exactly this precursor for the reason that it is simpler than separating the components at the end of a reaction producing racemates.[22]

What Walter White should have used as an example to teach his students about chirality is the success story of AstraZeneca’s chiral switch from Prilosec to Nexium (omeprazole and esomeprazole). It encompasses all the financial benefits of executing a chiral switch, as well as illustrates how dramatically different chemical properties can be present between enantiomers. Chemically, there are enantiomers with more stark differences. Financially, however, AstraZeneca made enough money from exploiting chirality to grab anyone’s attention. They retained intellectual property rights and sold esomeprazole without competition for years. The drug has better bioavailability and fewer side effects than omeprazole.[3] Furthermore, all signs seem to indicate that the timing of this discovery was not intentionally beneficial, not an attempt to hold out on customers. For a drug company to knowingly sell an inferior drug for five years and then release an expensive, markedly better alternative is not ideal and may expose them to liability.

When a drug’s mechanism is figured out, pharmaceutical companies race to create derivatives of greater merit than the drug. Even the same company will race to replace its own product with an entirely new molecule as long as some benefits can be realized. To reserve the company’s place in the market, the first drug that can effectively treat a conditionwhere there is need will reach the market as soon as possible, under patent of course. Keeping that in mind, realize that omeprazole was one of the first in a class of drugs called proton pump inhibitors. AstraZeneca researched other compounds to try to find one better than racemic omeprazole. What makes this case fascinating, however, is that better than any other molecule they could derive based on omeprazole’s mechanism was esomeprazole, the S-enantiomer of omeprazole.[3]

The problem with omeprazole was that dosing appropriately was difficult to do. The appropriate dosage varied too much from individual to individual. This created less effectiveness in some people and overexposure to omeprazole in other people.[3] In spite of research on completely different drugs consuming resources, AstraZeneca evaluated the enantiomers of omeprazole separately in the rat. In the rat, the R-enantiomer was the effective enantiomer, also known as the eutomer (the inactive, less active, or toxic enantiomer is called the distomer). Amazingly, testing in dogs revealed that both enantiomers were equally effective and testing in humans revealed that the S-enantiomer was the eutomer in human beings. The testing in rats showing a difference in the effectiveness of the enantiomers was enough to qualify the drug for clinical trials.[3] Today, the FDA encourages the patenting of enantiopure drugs. AztraZeneca’s discovery of esomeprazole, ideally would not happen today, but at the time when it did happen it was a great windfall for AstraZeneca.

Nexium, esomeprazole, came out shortly before AstraZeneca’s patent on Prilosec, omeprazole, was about to expire. This enabled AstraZeneca to continue selling the leading proton pump inhibitor with no generic available for years. AstraZeneca’s combined sales of Nexium and Prilosec in 2002 were 6.6 billion dollars. Estimates show that without esomeprazole AstraZeneca would have only made 840 million dollars in 2002 from omeprazole because of loss of market share to the generic.[23, 7] There is some theoretical value to society for AstraZeneca to have all that extra money, presumably they will invest some of it in new drug development; their employees and stockholders will do well. Clearly, however, the consumer has to pay the price when a chiral switch extends the patent protection of a medicine.[5] Another highlight of this chiral switch is that testing the efficacy of these enantiomers can be murkier than it first appears. Considering the tenuous correlation between animal testing and eutomer prediction seen in the case of omeprazole, consider thalidomide again. With thalidomide, it is worth asking how much we really know.

There are companies who specialize in obtaining patents for enantiopure components of popular racemic medicines.[23] As pharmaceutical companies race to get drugs to the market, a lot of racemic mixtures are released. It is generally rare that both enantiomers are equally bioactive. Instead, the reason why many medicines patented today are racemic mixtures is that competition, strict regulation, and the cost of synthesizing pure enantiomers is enough of a blockade that just getting anything through tends to be a good enough return on investment.[10] One casualty of this environment is that companies specializing in these patents sometimes unintentionally have the effect of blocking anyone from bringing the eutomer of a drug to market.

Sepracor, for example has to take a lot of risk when they invest in filing these patents.[23] Unfortunately, when they fail it hurts everyone. First of all, the types of patents Sepracor files are automatically contentious and will always involve expensive legal discussions and litigation. Companies in their realm may look for blockbuster drugs with patent vulnerabilities. Sepracormight bet that the FDA or EMA(EU’s FDA) will grant them exclusivity on a eutomer. Putting out their own money in the meantime to summon up the bare minimum in clinical evidence to support their claims. They obtain or license a patent for the drug and the patent lasts a lot longer than the exclusivity, typically 20 years. The exclusivity for an enantiomer of a drug in the US, is at best 3 years because it will not qualify as a new chemical (NCE, which lasts 5 years).[5] They will then try to time the release of the eutomer right before the patent or exclusivity of the name brand drug runs out. Giving them 3 years to market and sell their state of the art drug, possibly making billions.[5] The profits get carved up and sent to many different stakeholders; potentiallyeven to generic manufacturersbeing paid not to make the generic of the original version of the drug during their period of generic exclusivity. Similar to Cephalon’s actions when the patent expired on the drug Provigil. The problem is worst when the FDA or EMA does not grant the patent troll exclusivity because they cannot prove substantial differences between the eutomer and the racemic mixture. If there is no clinical benefit, the exclusivity will not be granted. When this situation occurs, nobody will be willing to bring the drug to market due to fear of litigation.

As has been discussed previously, the main objective of the chiral switch is to keep customers from trying generic drugs at all costs. The marketing of modafinil and armodafinil, Provigil and Nuvigil, shows that this can be almost priceless to a pharmaceutical company. When there was going to be a gap in exclusivity between Provigil and Nuvigil, Cephalon preemptively sued every generic company that had applied to manufacture the drug to the FDA in order to utilize their 6-month generic exclusivity. Cephalon’s lawsuit had no grounds; it served as a very pushy way to ensure a deal would be reached. Instead of asking for money, Cephalon paid every generic company the equivalent of 200 million dollars not to manufacture Provigil for 6 months.[4] This allowed Cephalon time to introduce and market Nuvigil while simultaneously raising the price and discrediting Provigil to the public. The only stipulation of the deal with Cephalon that is not anticompetitive is that the agreement begins to allow competition earlier than their patent’s expiration date. The patent in question however is a patent filed after Provigil’s patent had already expired. It was a patent for a different particle size distribution of Modafinil, a very weak patent.[4] Nuvigil’s claim to fame, worth billions of dollars? Not having to take the pill twice per day. Nuvigil is claimed to have effects that last longer than Provigil’s effects.[4] Overall, Cephalon has been a poster child for profitable anticompetitive behaviors, they must be taking their Nuvigil and working 24/7.

As more and more blockbuster drugs are set to come off patent in the next decade or so, chiral switches may be springing up. The consumer and the FDA should really avoid situations wherein drug companies need to be wholly trustworthy. Chiral switches are one of those situations due to the relaxed approval process. If even the particle size distribution of a drug can effect the action of the compound, changes to a compound’s chirality or the resulting changes in excipient molecules could have long-term effects that are disappointing to consumers and may not be realized in the ultra-short clinical trials the FDA requires for a chiral switch. Companies make billions from chiral switches, so there’s bound to be a few more in the future. The fact is: if there is a chiral switch, then the drug is different than the previous version or they lied when they wrote up the study in order to take your money. Either way, there is risk and loss for the consumer. Single-enantiomerdrugs, are on the rise, however, and this is a good thing. They pose advantages and simplify the legal landscape – a notable advantage is that they will reduce the burden on consumers of product hopping vis-à-vis chiral switches.