Breaking Good

24-Jan-2018

Senior Master in Academic Extension, Dr Erin Sheridan, details the process of making the drug Daraprim and Grammar’s brush with the ‘Pharma Bro’, Martin Shkreli.

There’s no doubt you’ve heard the news about a group of eight Grammar boys taking on the infamous Martin Shkreli, then-CEO of Turing Pharmaceuticals, having bought the exclusive US marketing rights to a 64-year old drug called Daraprim and immediately increasing the price of a single dose from US$13.50 to $750.

Outraged by Shkreli’s blatant greed, Charles Jameson (VI), Christopher Lai (VI), Brandon Lee (VI), Milan Leonard (VI), Patrick Ngo (VI), Dylan Siow-Lee (VI), James Wood (VI) and Austin Zhang (VI) decided they needed to do something.

Daraprim is used primarily to treat toxoplasmosis, an infection caused by the protozoan parasite Toxoplasma gondii and affects an estimated 22.5 percent of adults in western nations. The infection is asymptomatic in most healthy adults, but for those with an immune system weakened by HIV/AIDS, cancer treatment, pregnancy, or by immunosuppressive drugs used for organ transplantation, the infection can be life threatening.

In most countries around the world, Daraprim can be purchased cheaply. For example in Australia, the cost to the patient is approximately A$13 (US$9.50) for 50 tablets. This is because the drug is off-patent and can be produced generically, which encourages competition and typically results in lower prices. However, in the US, an off-patent drug must go through a specific process of Food and Drug Administration (FDA) approval before it can be produced generically.

But when diseases have a relatively small number of prescriptions per year, other pharmaceutical companies often decide that the potential revenue isn’t worth the cost of the approval process. Toxoplasmosis is one such disease, and in the 44 years it has been off-patent, no generic FDA approval has been granted in the US. This provided the opportunity for Shkreli and Turing to step in and dramatically increase the price.

Approximately two to three thousand Americans are prescribed Daraprim each year, and the Infectious Diseases Society of America and the HIV Medicine Association have estimated that the year-long treatment for toxoplasmosis now costs a prohibitive US$336,000 for those who weigh under 60 kilograms and US$634,500 for those who come in above this weight.

In response to public outrage, Turing lowered the cost of the drug by 50 percent for hospitals in September 2015, but did not change the price for pharmacies, leaving most patients paying the higher price.

But what could a group of high school students do? The boys knew that if they wanted to make a difference, they would need to play to their strength: science.

They predicted that if they were able to synthesise Daraprim cheaply in a high school laboratory, they could expose the price hike as predatory and unjustifiable.

So the boys headed to the lab. The active ingredient in Daraprim is the compound pyrimethamine, and the details of the three step synthetic route from the starting material p-chlorophenylacetonitrile are well known, even detailed on the Wikipedia entry for pyrimethamine. p-Chlorophenylacetonitrile was an ideal choice of starting material as it is readily available and inexpensive, which was essential as the boys wanted to demonstrate that the compound could be prepared cheaply.

Unfortunately, the second step of this standard procedure uses diazomethane, a compound so sensitive that it has been known to explode on contact with scratched glassware. Clearly the challenge would be to develop a new synthetic route that was not only cheap, but also could be safely performed by school students.

Working with Open Source Malaria (OSM) and the University of Sydney, the boys were able to post their questions online and receive help from interested researchers from around the world. With this guidance, the boys successfully performed the first step of the synthesis, and then tried a number of alternative procedures to bypass the potentially explosive second step. After several months of failures the boys found two successful procedures that could be used instead.

The final step of the synthesis also presented challenges, but by changing the reaction solvent and modifying the purification step, the boys were able to produce their first pure sample of pyrimethamine, verified by nuclear magnetic resonance (NMR) spectroscopy at the University of Sydney. This successful reaction sequence used low-cost reagents, removed the need for diazomethane and produced approximately 4 grams of pure pyrimethamine, worth US$130,000 at the current price.

After a year of work before and after school, the boys presented their findings at the Royal Australian Chemical Institute NSW Organic Chemistry Symposium alongside academic researchers and postgraduate students. In addition, since they worked as part of the OSM consortium, all of their experiments (both successes and failures) have been published in an openaccess online notebook
(http://malaria.ourexperiment.org/daraprim_synthesis).

Although the boys’ success was widely reported in the international media, Turing Pharmaceuticals has not caved in to the increased public pressure to drop the price of Daraprim. The US Congressional Committee on Oversight and Government Reform has interrogated Shkreli and the current Chief Commercial Officer of Turing, Nancy Retzlaff, ultimately concluding that although the price hike was legal it was clearly unethical. In August this year, Shkreli was convicted of unrelated securities fraud and currently awaits sentencing in custody.

This year the ‘Breaking Good’ project has continued, building on the success of 2016. Where last year the boys took on Shkreli and Turing Pharmaceuticals, James Arnall (V), Kieran Connor (V), Alexander Crawford (V), Duncan Currie (V), Oliver Hervir (V), Hugo McCahon-Boersma (V) and Harry Thawley (V) are taking on an arguably more menacing foe – the Toxoplasma gondii parasite itself. Although Daraprim remains the drug of choice for toxoplasmosis and the less common parasitic disease isosporiasis, there is worrying evidence of growing resistance. New drugs are needed if we are to keep ahead of the parasite.

Consequently, the boys have turned their attention towards molecular analogues of pyrimethamine. Since a viable synthetic route for the compound has been developed, their aim is to identify similar compounds that could be prepared with only minor changes to this synthetic procedure. The hope is that one or more analogues of pyrimethamine will have advantageous properties over the original compound, including reduced resistance in the parasite.

This approach to drug discovery is known as ‘analogue design’, and is currently responsible for the majority of small molecule drugs that are approved for use around the world. So far the boys have identified a number of promising analogues, and three have been selected for synthesis and further investigation.

And the lesson? No parasite is safe from a group of outraged Grammar boys.

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