In the rush to find treatments for COVID-19 patients, one with promise is the anti-inflammatory medication, colchicine. Multiple reports have speculated on how this centuries-old drug might help reduce the long-term effects many COVID patients experience and possibly even aid in speeding recovery for some of the sickest patients.
Colchicine as a treatment for gouty arthritis has a very long history. According to arthritis researchers George Nuki and Peter A. Simkin, colchicine, derived from the autumn crocus (Colchicum autumnale), is thought to have first been used by the Greeks more than 2000 years ago.
It’s not likely that the ancients ever envisioned their simple treatment would stir the kind of war that has been raging over the rights to sell the plant derivative in the U.S., nor the consequences to patients, many of whom don’t even know what gout is.
Early colchicine use
Early use of derivatives of the autumn crocus are well documented around the globe, but in the modern world, it was first written about in the 18th century by Baron Anton Stoerck, who described its uses for “dropsy” (as gout was frequently called at that time) and for pleural effusions. The name “colchicine” was coined by German pharmacist and chemist Philipp Lorenz Geiger when in 1833, he isolated a pure extraction from the plant that was suitable for gout treatment.
Enter the FDA and Colcrys
The Food and Drug Administration started as an offshoot of the agricultural division of the U.S. Patent Office in 1848 but was not officially a consumer protection agency until after the passage of the Pure Food and Drugs Act in 1906. At the time of its formation, numerous drugs, including colchicine, had already been used with relative safety for decades if not centuries. Many of these drugs were simply “grandfathered” and never tested by either the FDA or the drug manufacturers.
In 2006, the FDA began its “Unapproved Drugs Initiative,” urging modern drug manufacturers to put the remaining grandfathered drugs through standard testing in return for lucrative patents. Colchicine was one such drug. The company URL Pharma used randomized testing of 24-hour treatment protocol with colchicine in patients experiencing acute gout flares.
It was deemed unethical to continue the placebo treatment of an acute flare for longer than 24 hours, thus the time constraint. (If you have gout or have ever been around someone experiencing an acute flare, you understand just how unethical it is.)
As a result of the testing, in 2009, the FDA granted URL Pharma a 3-year patent for exclusive sales of colchicine under the brand name Colcrys for the treatment of acute gout flares. They quickly gained an additional 4 years as an orphan drug treatment for the rare disease familial Mediterranean fever (FMF). All other makers and distributors of generic colchicine were required to cease distribution by 2010.
The immediate effect was an increase in price from pennies per pill to more than $5 per pill. And when the drug was used as indicated in the study, at a dose of 2 pills at the onset of symptoms, followed by 1 pill hourly for a maximum of 6 hours, the total cost averaged around $40. Used in that manner, it might seem a bargain if it stopped the flare within the targeted 24 hours.
The problem was that many doctors had traditionally used colchicine as a preventative, with dosing of either one or two pills per day long term. The dramatic increase in the cost of long-term prophylactic treatment often caused doctors and patients to discontinue the use of Colcrys for that purpose, which, of course, resulted in an increase in acute flares which were treated according to the new protocol. That obviously saved gout patients money but left them suffering and treating more flares with short doses. It essentially forced them to choose between monetary pain and physical pain.
The FDA itself approved treatment with Colcrys as a preventative, but that testing was not done by URL Pharma, leaving quite a gap in their patents.
Then along came Mitigare
But first, you need to understand that the FDA hands out exclusive rights to both brand-name and generic drugs and that the initial patent exclusivity time period is subject to extension. Drug companies show a little extra work, an additional test here and there, and boom, the FDA flings new extensions at them like beads at boob flashers at a Mardi Gras parade. Takeda Pharmaceuticals acquired URL Pharma in early 2012 and immediately started flashing boobs.
Takeda eventually ditched URL Pharma after stripping it of its rights to Colcrys. Takeda currently owns multiple patents and exclusivity agreements through at least 2029 for both Colcrys and generic colchicine.
The initial gap in URL Pharma’s patent application caused by their lack of long-term treatment protocol testing allowed Hikma Pharmaceuticals to squeeze into the market in 2014. Combined with their use of a comparable drug other than Colcrys in their application, the FDA first allowed them to produce colchicine capsules marketed exclusively for gout prevention, not for treatment of acute flares.
Greater competition generally leads to lower prices, but the anticipated drop in prices for patients using colchicine long term for a range of diseases was never fully realized. Prices for Colcrys have pushed to near $7 per pill in 2019, while Mitigare and the now available generic colchicine hover near $4.50 per pill, primarily because the generic is still protected under exclusivity agreements by both drug companies and is merely licensed for production. It is not open to manufacturing by other companies.
Takeda sued both the FDA, claiming they should not have allowed Hikma to use an alternative drug for comparison purposes in their application, and competitor Hikma, claiming patent infringement. They lost on all counts and in appeals. Takeda was ordered to pay damages of $31 million to Hikma for losses of profit suffered under an initial restraining order that was later overturned.
Patients who use colchicine
Besides gout and FMF, studies have shown efficacy in treating Behcet’s disease, chronic cutaneous vasculitis, acute and recurrent pericarditis, coronary artery disease, and post-operatively following ablation to treat atrial fibrillation. The majority of these diseases are treated with colchicine for far longer than the 24-hour period Colcrys was initially tested for.
All uses of colchicine for anything other than gout or FMF are considered off-label, leaving yet another gap for both companies or possibly a third company to walk through, gaining additional patent extensions. Hikma’s patents currently stretch out as far as 2033.
The war rages on
Both companies have proven that they intend to defend their colchicine turf with heavy artillery. The latest round of legal battles between the two companies focused on Hikma’s reported heavy-handed marketing tactics. Takeda alleged that Hikma’s exclusivity agreements with U.S. insurance companies, as well as it’s widely-distributed physician samples were an inducement to infringement of their patent for treatment of acute gout flares.
The court ruled that neither of these activities induced doctors or patients to choose Mitigare over Colcrys for acute treatment, particularly in light of the fact that patients prescribed Colcrys for the 24-hour treatment are still not likely to balk at paying the full price for such a limited number of pills, even when insurance coverage is denied.
Meanwhile, Hikma settled a colchicine patent infringement battle with Granules Pharmaceuticals in September 2019, with terms undisclosed.
The reality for patients who need it
Even before the pandemic, for some patients, colchicine treatment is the difference between disability and living a normal life. But those who rely on colchicine for any length of time, especially those who use it long term are left struggling between the two drug giants and often with their insurance companies as well.
Blue Cross of North Carolina now lists Colcrys and generic colchicine as requiring pre-approval, while Mitigare is listed as “the preferred and unrestricted product.” Blue Cross of Texas makes no mention of either Colcrys or colchicine on their 2021 formulary. Mitigare capsules are listed as a tier 3 drug, therefore available, but at a higher cost.
Mitigare offers a co-pay discount card available for patients willing to provide their information and accept emails and/or text messages. The discounts range from $50-$75 per prescription, but even that barely puts a dent in a 30-day supply of 60 pills, which averages near $400. Both programs exclude patients on Medicare, where both brand names appear to be covered as a tier 3 drug, costing $42–47 before the drug coverage gap. Oddly, the Medicare Part D drug finder operated by Express Scripts lists the generic colchicine as “not covered.”
Discount programs like GoodRX and SingleCare help in some locales, but not in others, as they are essentially offering discounts based on negotiated prices with distribution networks and pharmacy chains.
And don’t forget that the strong-arm marketing tactics of the drug makers can include blocking some distribution channels entirely, as each company tries to lay claim to its rights.
The worst-case scenario would be a patient with an insurance plan that no longer contracts with Takeda for Colcrys or its generic colchicine but lives in an area where most of the pharmacies use a distributor that contracts exclusively with Takeda, thereby making Mitigare unavailable to them without lengthy drives.
Obviously, mail order is an option, and one that is pushed harder and harder by insurance companies, but when the cost of a 3-month supply is over $1,000, it becomes a hard pill to not only swallow but to pay for on a high-deductible plan.
Meanwhile, north and south of the border, generic colchicine is still available for pennies per pill for those willing to try that option. Pre-pandemic, it was actually cheaper to take a cruise with stops in Mexico from Los Angeles, Galveston, Mobile, or Miami to buy a year’s supply of generic colchicine in port than it to pay cash for it at many U.S. pharmacies.
The greater problem
The problem here is not that any particular group of patients is struggling to get and afford one medication. The fight over colchicine exposes weaknesses in both the drug approval system and the supply chain of all of our medications. When drug manufacturers are allowed to extend their patents, and thereby their control over drugs almost indefinitely, we are discouraging both innovation and competitive pricing.
And when we allow the system to be manipulated so blatantly with incentives at every step of the approval, manufacturing, prescribing, insuring, and distribution process we have allowed quality patient care to become not the goal of the system, but merely a possible side effect.