The tale of Fumagillin-B is a fascinating example of how global forces, which are frequently unseen by us, have a way of altering our daily lives in very unexpected ways. Fumagillin-B is a drug used to treat Nosema apis, one of the most prevalent diseases plaguing adult bees, and now it is no longer on the market.
Nosema apis is a unicellular parasite spread by spores that infect honey bees. Bees develop extreme diarrhea frequently resulting in death and a decrease in a hive’s honey production. The only company producing Fumagillin-B was a Canadian company named Medivet Pharmaceuticals Ltd. Medivet purchased the drug’s active ingredient, fumagilline dicyclohexylamine, formulated it, and sold the formulated drug to beekeepers. In April Medivet issued a letter stating that the supplier of fumagilline dicyclohexylamine was no longer producing the active ingredient, and no alternative suppliers were available. As a result, Medivet was forced to close their operation and go out of business. Medivet was a small company with less than 50 employees, but this small company was the sole supplier of an important medication for beekeepers. Remember that bees are necessary for the production of approximately one-third of the food supply, so medications (or the lack of medications) related to bee health are important. I read several beekeeping blogs that lead me to believe the discontinuation of Fumagillin-B was unexpected. Nosema apis and Fumagillin-B weren’t on my radar. As a first year hobby beekeepers, Doug and I haven’t encountered this disease, and our focus has been on keeping varroa mites and small hive beetles under control.
My first thought after hear the Fumagillin-B news was how did this happen? I spent 15 years working in the field of pharmaceutical contract manufacturing. Supply chain management was a huge issue. We always tried to have multiple suppliers for all critical raw materials in order to ensure continuity of supply and to obtain competitive pricing. We looked several layers deep in the supply chain to see who was supplying the raw materials to our raw material suppliers. The goal was to establish multiple suppliers because all sorts of unexpected things can happen. Manufacturing plants can catch on fire. Extreme weather can cause temporary plant closures. I knew of a small company where many of the employees pooled their money each week to buy lottery tickets. One week they hit the jackpot. The company then had to deal with multiple resignations from employees who were suddenly so rich they didn’t need jobs anymore. Why was there no second source for the active ingredient in Fumagillin-B? I reached out to the owner of Medivet via my contacts on LinkedIn but have not yet obtained a reply. I spent the better part of two days digging through articles on the internet to try to unravel the story of Fumagillin-B, and what I found is an example of how forces in our global economy can unexpectedly impact our lives and our livelihoods.
Note for all my chemistry friends: For the sake of readability, I am going to use the term “fumagillin” for the rest of the post with the understanding that the term encompasses all forms of the molecule including the dch version used by Medivet to make Fumagillin-B.
The compound fumagillin is a natural product that is isolated from the fungus Aspergillus fumigatus. Natural products are chemical compounds isolated from nature (plants, fungi, animals, etc), and they are of interest because they frequently have therapeutic properties. The fungus that produced fumagillin was isolated from soil collected in Kalamazoo County Michigan. Pharmaceutical companies used to send scientists around the globe collecting plant and soil samples to take back to labs where scientists would isolate individual compounds and screen them for their therapeutic activity. One of the most famous natural products is paclitaxel sold as the chemotherapy drug Taxol. This compound is isolated from the bark of the Pacific yew tree. Many people devoted their careers to finding an efficient way to produce paclitaxel in the lab. After decades of research, only a viable semi-synthetic process could be identified. Nature is just better than humans at producing large, complex molecules. In the 80’s and 90’s, pharmaceutical companies started moving away from the needle in the haystack approach of finding drugs in nature and began using techniques such as combinatorial chemistry coupled with high throughput screening. Today pharmaceutical companies place a heavy emphasis on biotechnology and rational drug design, but natural products still have a role to play in pharmaceutical development.
Fumagillin was patented in 1953 by Upjohn, but Upjohn didn’t keep the patent probably because they didn’t think it had any worth. Abbott patented Fumadil-B, a formulated version of fumagillin in 1957. The fumagillin was produced using a fermentation process. Chemists tried to develop ways to synthesize fumagillin in the lab without the use of fermentation, but none of the processes proved to be commercially viable. Abbott used a Hungarian company called Chinoin to produce fumagillin. Chinoin was then sold to the French company Sanofi. Sanofi improved the fermentation process and then transferred the process to a site in India. Chemical companies do this sort of thing all the time and transfer processes to chemical plants better suited to run the process or to plants that are more cost effective. Over the last few decades, the fine chemical and pharmaceutical industries have changed dramatically. China and India now have large numbers of highly educated chemists who are willing to work in their home countries for much smaller salaries than their western counterparts. This makes it much harder for western companies to compete in the production of fine chemicals and pharmaceuticals, and western companies have been forced to innovate in order to remain competitive. A spin off company was created with some of the Sanofi assets, and the French company CEVA Sante Animale was formed. Fumagillin went with the spin off. CEVA was selling fumagillin to Medivet, and presumably the fumagillin was being produced at the same site in India with the process refined during the Sanofi years. Did you follow all that? Here’s a recap of the path of fumagillin: Upjohn to Abbott to Chinoin to Sanofi to CEVA, which sold to Medivet. Welcome to the world of pharmaceuticals where a person can work for a dozen companies over the course of their career without ever changing jobs. Companies merge constantly. Sites spin out of large companies and become smaller companies. Corporate strategies change regularly. Promising drug candidates are discarded, or entire fields of research (e.g. antibiotics) get eliminated along with the staff conducting the research.
I could not find out why CEVA was no longer willing to produce fumagillin, but I will make some educated guesses. Maybe the equipment used to make fumagillin was getting old, and they weren’t making enough money to justify the purchase of new equipment. Maybe they found an alternative product they could make in the same plant for a higher profit margin. Perhaps the site in India had a catastrophe (e.g. plant fire), and CEVA did not wish to transfer the process to another site for economic reasons. Economics always play a role in pharmaceuticals no matter if the drugs are for people or for bees. FDA notes that one of the reasons for shortages of drugs (used in humans) is that companies choose to stop making a drug for economic reasons. The FDA cannot compel companies to produce a drug. The same is true for bee drugs.
Where does all of this leave us? This month’s American Bee Journal has a great article entitled “Life Without Fumagillin” by Alison McAfee. Beekeepers now face even greater pressure to use top notch management techniques to keep their hives strong and healthy. Researchers are trying to find alternative drugs that are safe and effective to fight Nosema apis. The story of fumagillin offers great insight into the trends that shaped the pharmaceutical industry over the last 60 years and how those trends impact humans and honey bees alike.
Author’s note: I am happy to provide references used to prepare this article to anyone interested. Please contact me if you can share any information on the Medivet/Fumagillin-B story to help fill in the gaps. All feedback is welcome. I want to clearly state that I am not criticizing the decision by Medivet to close their business. I am sure this was a difficult decision for all involved. Furthermore, there may have been very legitimate reasons for why a second supplier could not have been brought on line sooner, and this post is not meant to criticize Medivet, its employees, or its owners. For years Medivet provided a valuable service to the beekeeping community, and their closure does not diminish their previous contributions.