Thursday, January 7, 2016

Daraprim: The 62 Year Old $750 Pill

In September 2015, the CEO of a new company called Turing Pharmaceuticals gained instant notoriety when he jacked up the price of a little known drug called Daraprim from $13.50/pill to $750/pill. Turing is not the first company to raise drug prices to astronomical levels, but the Daraprim situation is unique for a number of reasons. First, Turing inflated the cost of Daraprim over 50-fold overnight, making it one of the largest jumps in a drug’s price ever. Second, the company did not invent or improve upon Daraprim; this drug is 62 years old and all Turing did was pony up $55 million to acquire the rights to it.

Martin Shkreli, who unapologetically increased the cost of Daraprim by 5,500%, has been dubbed “Pharma Bro” and “the most hated man in America” by various media outlets.
Third, the company justified the huge price increase by stating that it will use a portion of the profits to invest in generating better drugs for toxoplasmosis, the neglected disease that Daraprim treats. This reverses the polarity of drug development:  most pharmaceutical companies use money they’ve already raised or earned to develop a new drug. But Turing already has the drug and claims that it will develop a better drug with the profit made from overcharging current patients. Many would argue that Turing should have used the $55 million to develop a new toxoplasmosis drug in the first place, rather than gouge current patients and further strain the US health care system. Moreover, the patients who are forced to pay for this research will not get their money back if Turing fails to deliver, which is often the case in drug research.

The world had Daraprim before Elvis had a song played on the radio!
In addition to highlighting problems with the nation’s policy on drug pricing, the situation has also taken toxoplasmosis from the shadows and into the limelight. This disease is caused by a single-celled parasite called Toxoplasma gondii. The parasite infects nearly anything with a backbone, but animals (including people) that have a healthy immune system keep the parasite in check, locking it into a latent, encysted form. If immunity deteriorates due to disease, such as HIV/AIDS, or chemotherapy, such as that given to fight cancer, the latent Toxoplasma parasites will start replicating again, leaving massive tissue destruction in their wake. If you want to learn more about Toxoplasma parasite, you can do so here.

In the center of this heart tissue is a tissue cyst filled with latent Toxoplasma parasites. These parasites can start growing again if immunity is compromised, causing rapid damage to the heart. The parasite cysts also reside in the brain, creating serious neurological problems if the disease is reactivated.
Toxoplasmosis can be life-threatening if not treated promptly. So how does Daraprim help save lives?

Daraprim is the trade name for pyrimethamine, the chemical structure shown here. $750 will buy you a single pill. A standard round of treatment for toxoplasmosis is usually a month, putting the cost at ~$22,500. Unfortunately, this drug only puts the disease into remission, so the patient typically needs additional courses throughout his or her lifetime.
Daraprim is an antifolate drug; as you may surmise, taking it leads to a depletion of the B-vitamin called folate. Folates are absolutely required by all living cells to make genetic material such as RNA and DNA. Everyone knows we need folate in our diet or else we may suffer from anemia, digestive issues, cognitive defects, or growth problems. But what you may not know is that all living things need folate – bacteria, fungi, and parasites like Toxoplasma.

Pyrimethamine targets an important enzyme in the folate metabolic pathway called DHFR (dihydrofolate reductase). By inhibiting DHFR, pyrimethamine stops the conversion of dihydrofolic acid to tetrahydrofolic acid, the latter of which is needed to make purines and thymidylate, molecules that are required for DNA and RNA synthesis. If germs can’t make DNA or RNA, they simply cannot grow anymore.

Like trimethoprim, pyrimethamine is an inhibitor of the enzyme DHFR. Sulfa drugs (sulfonamides) are also added to the treatment regimen as they serve to block the upstream step of folate metabolism, delivering a one-two punch to the pathogen.
Hopefully you can now see why Daraprim kills parasites like Toxoplasma, but you may be wondering why the drug doesn’t also kill the patient. Truth is, at high enough concentrations for a long enough time, Daraprim can kill a person. But the risk is offset for two main reasons. One, pyrimethamine binds to the parasite form of DHFR much better than to the human form of DHFR. Both Toxoplasma and human DHFR function the same way, but there are subtle differences in the enzyme’s structure between the pathogen and the patient that make it bind to the drug with different affinity. Said another way, if you consider Daraprim to be like a piece of metal, then the parasite DHFR enzyme is like a stronger magnet than the human DHFR enzyme. Two, a patient taking Daraprim is usually given folinic acid (leucovorin), which converts to tetrahydrofolic acid without the need for DHFR.

Pyrimethamine was developed by Nobel-Prize winning scientist Dr. Gertrude Elion in the early 1950s. Dr. Elion was also instrumental in the development of acyclovir for herpes viruses. I wonder what she would say to Mr. Shkreli.
The discovery of pyrimethamine as a potent anti-parasitic agent many years ago marked a great advance in the medical sciences. It is a shame we let the clay from the best minds get molded by the worst hands.

Contributed by:  Bill Sullivan, Ph.D.

Roos DS (1993). Primary structure of the dihydrofolate reductase-thymidylate synthase gene from Toxoplasma gondii. The Journal of biological chemistry, 268 (9), 6269-80 PMID: 8454599

Sullivan WJ Jr, & Jeffers V (2012). Mechanisms of Toxoplasma gondii persistence and latency. FEMS microbiology reviews, 36 (3), 717-33 PMID: 22091606

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