By Kevin Zhao

Endorsed by Professor Richard B. Silverman

Penicillin. Ibuprofen. Aspirin. These are just a few examples of drugs that have benefited our society. It is incredible how far drug discovery has come; we can manipulate biology and use organic molecules as vehicles to treat and cure various diseases. With these advancements, we can selectively target various symptoms and extend the aver- age lifespan. While these treatments have greatly contributed to society, they also are tremendously costly to develop and produce. This applies not only to consumers who purchase these drugs, but also to the researchers and pharmaceutical companies that spend years trying to develop effective medications.

The process of discovering and developing pharmaceuticals is extremely complex. It encompasses fundamental understandings of human biology to recognize how the body’s functions can be modified, utilizes organic chemistry to seek a man-made cure, and requires biochemistry to develop the various properties and mechanisms of a drug. Drug discovery begins by first utilizing a biological model that reflects the properties of the disease or condition of interest. Then, the model’s activity is probed with various chemicals from a large chemical library. This enormous array of compounds is selectively funneled throughout the development process to an end product of one FDA-approved drug. One of the most common models used in this method is a cellular-based drug assay, in which cells that mimic the main conditions of certain diseases are cultured and run through a large chemical assay.

After running this chemical test, scientists are able to select a few com- pounds that show potential in treating the disease. These compounds are the ones that appear to reduce symptoms of disease in the biological mod- el. The compounds are then sent to the organic and medicinal chemists who modify the compounds’ chemical structures in various ways. Many times, this involves making minute structural adjustments, like changing a fluorine atom to a bromine atom. Next, the chemists send the com- pounds back to the biologists who run another assay to see if the new chemical has any effect. This is one of the most time-consuming steps in the entire drug development process because of the many possible changes that can be made. Sometimes, a single carbon can be the difference between a toxin and a cure.

Advancements in technology have had major impacts on drug discovery. Chemists often use computerized modeling programs to predetermine how certain structural changes may affect a compound’s activity. However, many properties of the targeted protein or enzyme must be known to perform such a study. If the necessary data are available, the program is able to visually plot the protein and fit various chemical shapes into a targeted pocket. This will predict chemical interactions with the protein. Although this technology has been extremely helpful for researchers, it is still developing. Sometimes, the pro- gram may predict activity, while in reality the chemical is inactive. The pro- gram might also fail to predict certain chemicals that could effectively treat a disease. Even with this technology, hundreds of chemicals still need to be synthesized before finding the one that has the desired activity in a bio- logical model.

When a drug has shown promise, it is tested in animal studies to further examine the properties of the compound. One important step to- wards achieving a better understanding of the compound’s characteristics is determining the pharmacokinetics of the drug, which means determining what happens to the drug once it enters an animal’s body. To comprehend the pathways a drug follows, researchers must investigate its absorption
rate into the blood-
stream, distribution
to the various tis-
sues, degradation, and
elimination from the
body. It is also important
to note that even if the drug
shows activity in the initial biological model, this does not guarantee that the compound will show activity in the animal model. Each stage brings a new layer of complexity, progressing from a single cell model, to an animal, and eventually to a human being.

If the drug is successful in the animal models and is shown to be nontoxic, it is then moved on to clinical trials. From the hundreds of thousands of chemicals in the initial chemical library, only a handful of compounds actually enter this stage. However, many do not make it through the clinical trial. With each phase, the number of patients tested increases, and the drug has to pass more rigorous tests. While drugs may have shown promising results in the animal studies, they may fail to pro- duce similar results in human trials. For example, some drugs have appeared to “cure” diseases such as ALS in animals, but fail to have the same effect in clinical trials.

The process of drug discovery can be long and tedious, with countless obstacles prior to introduction into the market. Unsurprisingly, such a process requires a great deal of money to fund the work and time it entails. A recent Forbes study has shown that larger pharmaceutical companies spend up to $6.3 billion per drug, while smaller companies spend up to $2.8 billion.2

Due to the extremely high cost in researching and developing medicine, most of the research is per- formed industrially, as opposed to in an academic environment. Large pharmaceutical companies such as Johnson & Johnson and Pfizer, Inc. dominate this industry, as they possess the money to fund this type of research.

 

Developing LyricaTM: Silverman Strikes Gold

Success stories in the realm of academic drug development do exist. Dr. Richard B. Silverman’s discovery of LyricaTM, also known as pregabalin, serves as an example of academic drug research that made the leap into industry. Silverman’s path to successful drug discovery highlights the time, effort, and potential payoff of academic drug research.

Silverman joined the chemistry department at Northwestern University in 1976 and began researching various small molecules that affect the level of gamma-aminobutyric acid (GABA) in the body. It has been shown that “when GABA levels fall too low in some people, it can trigger epileptic seizures.”3 Therefore, Silverman’s lab developed various compounds to increase GABA production in the body.

However, the drug that brought acclaim to Silverman and his re- search did not actually alter GABA levels. In fact, the discovery of LyricaTM was a surprising one. According to The Chicago Tribune, “Silverman’s experience suggests finding a chemical that turns into a billion-dollar drug takes as much luck as winning the lottery.”4 While it did not affect GABA levels as was initially hypothesized, LyricaTM still showed incredible efficacy in the treatment of epileptic seizures as well as other ill- nesses, such as neuropathic pain and fibromyalgia.

In November 1990, Silverman applied for a patent, which was not approved until March 2001. When Silverman first noticed a few com- pounds that showed great results in affecting GABA levels, he began to look for companies that would be interested in partnering with him to continue the study of these chemicals. Two companies demonstrated interest in this study: Upjohn Pharmaceuticals and Parke-Davis Pharmaceuticals.6 Upjohn
only asked Silverman for the
compound with best activity, whereas Parke-Davis asked for
all of the compounds. The drug
initially thought to be the best
candidate was not effective when
studied further. However, one of
the compounds in the library of
chemicals sent to Parke-Davis
showed high potential. Though
its official mechanism of action
was not yet fully understood, the performance of the compound proved to be so convincing that Parke-Davis and Northwestern proceeded to sign a patent option agreement in December 1991.

Over the next six months, Parke-Davis used the compound to per- form many animal studies such as pharmacokinetics and metabolism experiments. Afterwards, another two years were spent on studying animal toxicology and on synthesizing a specific enantiomer. In December 1995, Parke-Davis filed an investigational new drug application, which allows for clinical studies on a compound before approval by the US Food and Drug Administration (FDA). Phase I of clinical trials started in late 1995 and lasted for two and a half years. A combined Phase II/III trial was then performed from 1999-2003, which involved 100 different clinical trials and tested over 10,000 patients. In 2000, Pfizer bought Warner-Lambert, which had acquired Parke-Davis in 1970, so Pfizer continued studies on the compound. It was also around this time that the compound started being referred to as “LyricaTM”.

When Pfizer took control of the research, they pushed aside Silverman, the initial inventor. As Silverman said, “I became an outsider… There was no longer the possibility to talk with their scientists. No comments. They had a launch party for the drug, and I asked to come. Nope. No party for me. They take your stuff and tell you to go away.”4 This is where academic and industrial research part paths and utilize different ideologies. Large pharmaceutical industries are able to research new medications as long as they have exclusive profit rights, which requires secrecy about what they are doing. In academia, innovative science, which includes collaboration and publication, is the principal driving force.

After continuous success, Pfizer filed a New Drug Application in October 2003 to request approval for LyricaTM to become a commercial product. This was approved by the FDA in 2004. In 2006, during the drug’s first full year on the market, LyricaTM had $1.2 billion in global sales. The next year, Northwestern sold a sizable amount of the royalty interest of LyricaTM to Royalty Pharma for $700 million. With this, Silverman donated part of his royalties to Northwestern to help build a new building for molecular therapeutics and diagnostics. His goals were to broaden the research environment and continue to bring great professors from around the world to the university. Although Silverman hit a scientific jackpot, he continues to perform outstanding research on drug development and hopes to help find treatments for various neurodegenerative diseases such as Parkinson’s, ALS, and Huntington’s. In a competitive research environment dominated by major pharmaceutical companies, Silverman’s development of LyricaTM serves as a source of inspiration to other academic drug researchers.

While few drugs go on to become blockbuster drugs like LyricaTM, advancements in technology and a greater understanding of the human body offer promising developments. Drug development, whether academic or industrial, offers hope for the future of medicine to cure disease and even extend longevity. With creativity, imagination, hard work, diligence, and perhaps a little luck, major drug discoveries can be made in an academic setting. ■ MD

References

  1. Benmohamed, R.; Arvanites, A. C.; Kim, J.; Ferrante, R. J.; Silverman, R. B.; Morimoto, R. I. Kirsch, D. R. Amyotrophic Lateral Sclerosis. 2011 Mar; 12(2): 87-96.
  2. Herper, M. (2013) The Cost of Creating a New Drug Now $5 Billion, Pushing Big Pharma To Change. <http://www.forbes.com/sites/matthewherper/2013/08/11/how-the-staggering-cost-of-inventing-new- drugs-is-shaping-the-future-of-medicine/2/>.
  3. 
Northwestern University Innovation and New Ventures Office. Lyrica. <http://invo.northwestern.edu/ news/2011/lyrica>.
  4. Van, J. (2008) Drug find worth $700 million. March 10, 2008. Chicago Tribune. <http://articles.chi- cagotribune.com/2008-03-10/business/0803090219_1_gaba-richard-silverman-drug-companies>.
  5. World Events Forum. Plenary: The Story of Lyrica-Academic Discovery to Commercial Success. 8th Annual Drug Discovery Neurodegeneration Conference. <http://www.worldeventsforum.com/addf/ drugdiscovery/notes8/oral-presentations/79-2/>.
  6. Silverman, R. B. From Basic Science to Blockbuster Drug: The Discovery of Lyrica. Angew. Chem. Int. Ed. 2008, 47, 3500-3504.

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