I suffer from episodic migraines: throbbing headaches that might develop a few times a week, will creep outward from behind my eyes and brow and can render me virtually immobile for up to 12 hours, making me think an icy-cold visit from the Lobotomobile wouldn’t be totally unwelcome. Luckily, I finally found one drug that can stop nearly every vicious attack in its neural tracks.
So, every month or so, I head to the pharmacy and pick up a small cardboard crate containing eight doses of dihydroergotamine mesylate (DHE) nasal spray, a derivative of the drug ergotamine. Each dose is individually boxed, bottled and paired with a fresh double-capped nasal insert. I carry one rattling and easily-disturbed package with me at all times and have a memorized explanation to accompany the rigamarole of using it in public—useful for when friends and strangers become curious about the small brown vial of liquid I’ve just un-capped, peeled a protective metal ring from, uncorked, carefully affixed with a now-unwrapped nozzle, sprayed into the air several times so as to ready the spraying mechanism and then shot carefully up each nostril.
My generally well-stocked local pharmacy chain runs out of it and needs to reorder (seemingly just for me) every second month or so, sometimes requiring me to head 30 minutes away on the subway for a refill, and sometimes leaving me stranded—fingers crossed—over a long weekend. For the sake of calling cross-town pharmacies and not holding up the lines once I’m there, I can now teach someone to spell it in under 30 seconds. And after spending up to 48 hours per month over the past decade simply waiting—motionless in the dark, bags of frozen vegetables thawing on my head—for the pain to gratefully pass, the result is well worth the effort.
Very thankfully, too, the managed Medicaid plan I’ve had since being laid off about a year ago covers the drug. But when my income level creeps back above the Medicaid threshold at the end of this year, I may well lose access to it again.
Because each prescription’s worth of eight doses, lasting me about five weeks, costs close to $3,600. An equivalent box of Migranal, the brand-name version—a brand owned by the same parent company that manufactures the generic version I use—costs nearer to $4,000.
Meaning that, during a year of my earning less than the $16,243 threshold for Medicaid in New York State, the healthcare agency will have spent close to $40,000 on my headache treatment.
And, in essence, my miracle spritz is made out of fungus, one we’ve been using for millennia.
I’d been using the drug for a few months before I finally, casually inspected the smaller print on my prescription’s printed label. I was surprised to realize I’d been making the 10-minute walk home from my local pharmacy each month with thousands of dollars of merchandise bouncing lightly in a plastic bag. I wondered how, processing and packaging costs aside, a raw substance with an import price of around $0.97 per milligram could manage an 11,600% markup before reaching consumers as a finished product.
Several months later, it seems the answer to that question has little to do with the drug my medicine contains or the fungus that bore it, and seemingly everything to do with a handoff between two or three multinational pharmaceutical companies, a fed-up FDA, some very cunning patent applications and one very special milliliter of water.
Ergot Fungus: A Long History, in Brief
DHE, the active ingredient in my medication, is an ergot alkaloid (a chemical derived from the fungus) that was first patented for use as an injected treatment in 1946. However, the role of ergot alkaloids in human history began much, much earlier.
For perhaps 4000 years, humans have been medicating, enlightening and accidentally poisoning themselves with ergot fungus (most commonly Claviceps purpurea), which grows on rye, barley and other grasses. Throughout the ages, the effects of ergot poisoning from ingesting contaminated grain products—also called “ergotism”—have varied by individual instance and across regions, resulting in countless deaths but also key scientific discoveries.
Dr. Paul L. Schiff, Jr., professor of Pharmaceutical Sciences at the University of Pittsburg, notes that various ancient Eastern and Western texts make reference to “grain diseases” with a range of serious side effects, and describes two types of reactions that typically result from ergot poisoning. “Gangrenous” ergotism, a condition dubbed “St. Anthony’s Fire” or “holy fire” in the Middle Ages, has been “characterized by pronounced peripheral vasoconstriction of the extremities [...] producing a violent, burning pain that ultimately culminated in the separation of a dry gangrenous limb (usually a foot) at a joint, without pain or loss of blood.”
And while the first documented ergotism epidemic “likely occurred in 944-945 AD, when some 20,000 people of the Aquitaine region of France (about half of the population) died of the effects of ergot poisoning,” smaller outbreaks were still reported throughout the 20th century and even continue today.
Somewhat differently, “convulsive” ergotism usually presents with such symptoms as sweating, muscle spasms, itching, mania and hallucination—a combination which researchers tend to associate with records suggesting ergot’s cross-cultural involvement in religious ritual and supernatural-seeming behavior. Many suspect “that the [rites of the] Eleusinian Mysteries of ancient Greece were connected with ergot-induced hallucinations,” Schiff points out, while Mesopotamian and Sumerian records c. 1900-1700 BC also hint toward possible religious connections to ergot fungus. Scholars such as Mary Matossian and Nicholas P. Spanos have even vigorously debated the possibility that grain stores contaminated with ergot fungus could’ve led to the hysteria behind the Salem Witch Trials and other supernaturally-tinged moments in history.
About as long as it’s been poisoning and mystifying humankind, ergot has been utilized for its medicinal properties, too. Documentation of its use in obstetrics—namely for stemming post-partum bleeding, thanks to its vasoconstricting properties—have been found and authenticated “in Chinese writings [from] approximately 1100 BC” and among Hippocrates’ 370 BC texts; midwives of the Middle Ages relied on the fungus for difficult childbirths, too, and could acquire it as easily as any wild medicinal herb.
Ergot was duly included in the inaugural United States Pharmacopeia in 1820 and the London version in 1836 as a treatment for postpartum hemorrhage, a method which continued well into the last century (and has even been re-evaluated for this purpose in recent years). In the mid-to-late 1800s, European physicians began proposing the use of ergot in treating migraine headaches—again, thanks to its apparent vasoconstricting effects—but the treatment would resist a wider audience until, several decades later, a stable formulation of the chemical would finally be found.
Ergot Meets the Marketplace, Becoming the “Gold Standard for Migraines”
The 20th century brought a new era for ergot after chemist Arthur Stoll isolated ergotamine tartrate, which his then-employer Sandoz—a giant in the generic drug industry of today (under parent company Novartis, the pharma world’s biggest)—promptly patented, marketed as a powder (one that’s still around today) and began selling to consumers in 1921. This safer, easier-to-process substance revolutionized the role of ergot alkaloids in mainstream medicine. As Schiff explains, Sandoz hence “dominated the world industrial market in ergot alkaloid production up until the 1950s,” a window during which Albert Hofmann semi-accidentally created and "tripped" on lysergic acid diethylamide (LSD) in 1938, a result of his experiments with ergotamine and lysergic acid.
Things begin to pick up speed for ergotamine derivatives mid-century as patent filings for injectable dihydroergotamine, a seemingly safer, semi-synthetic treatment which lowered the impact of side effects and offered new dosage formulations, cropped up from several companies. Arthur Stoll continued exploring the medical applications of ergot alkaloids for Sandoz, and in 1950 Albert Hofmann extended an earlier patent discovery by Stoll concerning the formulation of DHE for the company, with German company E. Merck Aktiengesellschaft filing yet another method for preparing a water-soluble version of the medicine in 1960.
Dr. Robert Krueger, Professor Emeritus of Pharmacognosy at Ferris State University and Treasurer of the American Society of Pharmacognosy, noted during a recent phone interview that ergotamine-based drugs—"still prescribed for aborting migraines” today—were “the gold standard [in migraine treatment] for a long time.”
“This was the one you went to when other things would fail; something you could rely on," Krueger explained. "Ergotamine has been that for a long time, and some patients only respond to this. If they do, they might also respond to dihydroergotamine, which is less potent and has less side effects. If I had a migraine, I’d try other things first, and if nothing else worked, probably where [we’re] gonna end up is with ergotamine, or one of [its] preparations.”
The FDA Starts Cracking Down on Under-Tested “Old Drugs”
In 1962, the Food and Drug Administration passed a set of new amendments building on the 1938 Food, Drug, and Cosmetics Act’s goal to protect consumers from both dangerous and useless products, which was passed after 107 people died from consuming an ingredient that was the “chemical relative of antifreeze.” The new FDA changes would alter the American pharmaceutical industry forever.
The 1962 Kefauver-Harris Amendments represented a "landmark of the modern consumer movement," had a "primary aim of preventing economic loss by regulation of product quality" and sought to tackle the fact that "many new drugs of dubious efficacy were being marketed at unusually high prices." Beginning that year, the FDA began taking an increasingly active role in ensuring that all new drugs seeking FDA approval were safe for consumers, effective, safely prepared and—when possible—reasonably priced.
A problem quickly arose, however, with regard to assessing the many “old drugs” on the market. Both the 1938 and 1962 acts contained “grandfather drug” clauses which allowed drugs that were patented and approved before those dates and “generally recognized as safe.” According to the 1938 grandfathered drug clause:
A drug product that was on the market prior to passage of the 1938 Act and which contained in its labeling the same representations concerning the conditions of use as it did prior to passage of that act was not considered a new drug and therefore was exempt from the requirement of having an approved new drug application.
Qualifications for this clause were narrowed with the 1962 amendments, which now emphasized the need to establish a drug’s efficacy and purpose in the market as well as its safety; the revised grandfather clause now allowed:
[Exemption of] a drug from the effectiveness requirements if its composition and labeling has not changed since 1962 and if, on the day before the 1962 Amendments became effective, it was (a) used or sold commercially in the United States, (b) not a new drug as defined by the FD&C Act at that time, and (c) not covered by an effective application.
For decades, many patent holders and generic drug manufacturers quietly continued marketing drugs that had indeed been formulated and approved before these deadlines, but possibly also slightly newer versions of their medicines with tweaks to dosage and formulation that had not been approved by the FDA. So, despite heightened regulation, ergotamine derivatives continued to serve as cost-effective migraine treatments, and new formulations continued to be developed, as in the case of a 1976 Sandoz patent for a more easily absorbed ergot alkaloid preparation. And business continued mostly as usual.
However, in 1983, the FDA got serious about enforcing its narrowed grandfather clause after yet another consumer catastrophe. That year, “it was discovered that one drug that was IRS [“identical, related, or similar”] to a pre-1962 drug, a high-potency Vitamin E intravenous injection named E-Ferol, was associated with adverse reactions in about 100 premature infants, 40 of whom died.” In response, a congressional oversight committee put the FDA in the hot seat with a 1984 report “expressing the committee's concern regarding the thousands of unapproved drug products in the marketplace.”
Thus began the great “Prescription Drug Wrap-Up,” an effort to corral unapproved drugs that were being illegally marketed, once and for all—a mighty task, to be sure. The effort almost immediately began affecting producers of ergotamine derivatives alongside other “old drug”-makers, though the FDA has particularly targeted ergotamine-derived drugs for assessment throughout the decades since its heightened house-cleaning agenda began.
This move for reform caused new headaches for pharmaceutical manufacturers large and small; Sandoz had shipments of Cafergot (or ergotamine sulfate and caffeine) suppositories seized in 1989, and lost its case to exempt the drug under the 1962 grandfather clause the same year. Such instances emphasized the industry’s transition into a new kind of marketplace: one in which drug companies would be required to satisfy the FDA that their products were safe, effective and also unique among the wider market. Further, the FDA placed these burdens directly on manufacturers, requiring them to fund their own clinical studies, even in the case of generic staple drugs—burdens which, for many smaller companies, were simply too much to bear.
Valeant Turns This “Grandfather” Drug Into a Multimillion-Dollar Monopoly
While the FDA was quickly thinning out the generic-drug herd in the '90s, continuing research kept a once-standard migraine treatment from its encroaching obscurity and indicated that DHE could still be a cheap, effective migraine treatment in the contemporary pharmaceutical marketplace. One 1996 study comparing the cost and efficacy of subcutaneous DHE with subcutaneous sumatriptan—the latter drug having become the go-to method for treating migraines in the 21st century—found that DHE was as effective as sumatriptan, which had an “acquisition cost of [over] 3 times that of DHE,” in three of its 11 clinical trial efficacy measures. In a further four efficacy measures, “DHE was the obvious choice because it is more efficacious and less expensive.” The same year, another study reviewing the “many useful medication options available [to today’s physician] for acute migraine treatment” praised “locally compounded dihydroergotamine nasal spray” as being effective and “inexpensive ($0.78/1 mg spray).”
But as clinical research supporting DHE’s role in migraine treatment began to build, the rights to the FDA-approved formulation for the drug and its delivery mechanisms were carefully changing hands several times between a small group of companies. As a result of these exchanges, the cost of DHE was about to soar.
In 1990, Sandoz applied and received FDA and patent approval for Migranal-brand DHE nasal spray, outlining its exclusive claims to what would become the monopolistic nasal spray migraine treatment (and all-around market heavyweight) from 1997 to the present day; among other things, the application outlined the company’s “Need for Action” in producing this medicine for the public, citing its own injectable formulas as “inconvenient for patient home use” and its ergotamine tartrate tablets, Cafergot, as lacking the “reduced instance of nausea” that the new formulation offered.
The application further reserved the company’s exclusive rights to the synthesis of dihydroergotamine mesylate itself, the formulation and packaging of the medicine, and “use of the product designated in this Environmental (EA) as DHE-45 Nasal Spray.” The document also proposes a “propellant-free … hand-pump powered … metered spray delivery system” for use with the product’s “1 ml ampule” containing “4 mg of drug substance per milliliter of of aqueous vehicle”—a vehicle related, perhaps, to the “USP [or U.S. Pharmacopeial Convention-sanctioned] water,” listed as “the only solvent … used in the production of DHE-45 Nasal Spray.”
Thus dihydroergotmine mesylate, USP nasal spray—a.k.a. Migranal, USP—was born, several of its features representing, in effect, the only cost-effective and physiologically feasible way to deliver the superior effects of this intranasal formulation. It was now patented exclusively, and its journey toward high-priced monopoly begun. Dr. Stephen Schondelmeyer, a professor of Pharmaceutical Economics in the College of Pharmacy at the University of Minnesota, explained by phone that Migranal’s patented packaging may be key to its current dominance.
“It is harder and maybe a little more costly to make an inhaled product," said Schondelmeyer, "but it doesn’t justify the high price. It’s hard to make generic versions of inhaled products, [and patented] extensive packaging makes it so another company can’t package their product quite like [the brand does], and so you can’t have an exact generic substitute that is economically feasible to compete with that product.”
In 1997, Novartis took on Sandoz as one of its many subsidiaries in a 1997 merger, and received its own patent and FDA approval for newly-marketed Migranal-brand DHE nasal spray. In 2002, Xcel Pharmaceuticals acquired exclusive licenses to both Migranal and DHE-45, a mere three years before Xcel itself would be absorbed by Valeant Pharmaceuticals in 2005. That year, Valeant launched a redesigned delivery system for the product, which may currently boast up to several dozen related patents internationally.
And while ergotamine derivatives had previously enjoyed several decades as a cost-efficient “gold-standard” migraine treatment, DHE took on a new role under Valeant’s umbrella. As a 2007 Understanding Business Strategy text points out, Valeant seemingly didn’t share the view held by earlier generations of physicians that ergotamine and its derivatives should serve as the go-to, baseline cure for migraine headaches; rather, after Valeant’s 2005 acquisition of Xcel and the rights to Migranal, the drug took on a different role because of the company’s lack of primary-care infrastructure:
Although many primary care physicians treat migraines, Valeant does not have a primary care salesforce, only a neurologist-focused salesforce. Therefore, Migranal is [now] considered a "specialist's drug" [and sales] increased more than 16 percent in 2007 to $13.5 million, representing 10.5 percent market share. It is the number 5 revenue generator within the neurology business segment.
During the same timeframe, however, most generic drugs weren’t receiving the same elite status as previously-generic DHE; a recent Public Policy Institute study by Dr. Schondelmeyer and the AARP’s Leigh Purvis found that “retail prices for widely used generic prescription drugs declined, on average, between 2006 and 2013,” and by an average of 4%.
Valeant Pharmaceuticals did not respond to requests for comment on the price of its DHE offerings, but Dr. Schondelmeyer suggested that the low supply cost of DHE likely isn’t a factor when it comes to the high price of Migranal and its generic version.
“Normally, for most products in the marketplace, [the history of a product] would help you understand the prices that are being charged. In pharmaceuticals, [...] drug prices are not based on what it costs to make them [...]," he said. "They’re really priced more on the degree to which pharmaceutical products and/or companies can get exclusivity to or monopoly control of their product, and then they pretty much price it however they want.”
He added, “I’m not defending or excusing this—this is just an issue we need to deal with as a society.”
With DHE squared away in its roster of “specialty” drugs, Valeant began nothing short of a meteoric rise to stock-market stardom in the late Oughts and continues its trajectory today; in 2012, the company was praised as “Canada’s hottest stock,” and its leader, J. Michael Pearson—"one of the best-paid CEOs in Canada”—for having having “built Valeant into by far the largest publicly traded Canadian-based drug company … out of nowhere.” In 2013, Valeant subsidiary Oceanside Pharmaceuticals launched a generic version of Migranal, which currently markets for approximately $3600, or $400 less than the brand-name version. Today, Valeant stock is the stuff of “hedge-fund superstars,” Forbes reports, with a May 2015 market capitalization value of over $104 billion.
Less specialized drugs have also benefited the company of late, though not without earning scrutiny over its pricing practices. Sen. Bernie Sanders (D-VT) and Maryland Rep. Elijah E. Cummings (D-MD) recently engaged Valeant on the matter of substantial generic-drug markups—specifically with regard to the company having raised the prices of the heart drugs Isuprel and Nitropress “by 525 percent and 212 percent respectively” after acquiring them from Marathon Pharmaceuticals, which had itself acquired the drugs in 2013 and “quintupled their prices,” the New York Times notes.
Dr. Schondelmeyer, whose work includes tracking the costs of generic drugs in the marketplace, commented that “Valeant is a company that has gone after identifying these products so they can raise the price. They’ve collected a bunch of these, and then they take advantage of the circumstances.”
It was also to Valeant’s good fortune, perhaps, that the FDA rejuvenated its decades-long crackdown by issuing numerous warning letters to remaining manufacturers of ergotamine-based drugs (done with great, industry-trimming effect) in 2007, just two years after Valeant’s overhaul of Migranal and marketing push.
With regard to FDA regulations that have “forced out” generic-drug manufacturers, Dr. Schondelmeyer noted that lawmakers have a responsibility to weigh in.
“I don’t fault the FDA for wanting to have the data to show the effectiveness of [DHE]—although the data is in the literature; it’s not like it doesn’t exist—but I think Congress needs to let the FDA know they shouldn’t be giving exclusivity to a product that’s been on the market for a long time and has multiple players in the market," he said. "It would have been cheaper for the U.S. government to pay for one or two clinical trials on its own rather than give exclusivity and let one company have windfall profits on it.”
Overall, he said, “There are several games going on here that sort of come together in a perfect storm to cost you and/or the government a lot of money.”
What Does the Future Hold for This Old Fungus?
While Migranal, its generic version, and other members of Valeant’s long list of marketed drugs seem to be strengthening the company’s bottom line, the ergotamine-derivative market on the whole doesn’t seem equally healthy; reports of shortages of DHE in its injectable format have surfaced widely in the past two years—something for which its primary U.S. supplier Valeant “could not provide a reason,” the American Society of Health-System Pharmacists noted earlier this year—making Migranal nasal spray and its generic version one of very, very few remaining options for patients whose migraines don’t respond to other kinds of drugs.
This is despite the fact that, of approximately 36 million U.S. migraine sufferers (all of whom are subject to “an immense impact on quality of life and productivity,” according to a 2010 study), “the most difficult patient groups”—including persons plagued “with status migrainosus, migraine recurrence, medication-overuse headache and chronic daily headache”—continue to count DHE as their best treatment option.
On the disappearance of ergotamine-based drugs in the marketplace, Dr. Krueger reflected by phone that “as [a drug] becomes more expensive, the patient is also suffering from that expense.
“The bottom line that people argue—and I argue it myself—is that if there is one patient that can be helped by a drug, it should be available," he observed. "It should be kept on the market. Are we trying to put a price on life?”
Of course, it is possible that other medicines derived from this once-rampant fungus will begin to reemerge in new forms, and under control of new parties, in a future pharmaceutical marketplace. Strategic Science and Technologies LLC, for one (of topical ibuprofen and topical Slidenafil fame), filed a 2013 patent for a patch containing other kinds of ergotamine derivatives, which would allow patients to absorb their medication transdermally. If this next-generation take on an old medicine does start showing up on pharmacy shelves, it’ll help to repopulate what’s become a virtually desolate corner of the pharmaceutical marketplace—and maybe, if others follow suit, even begin to ease the pain of getting migraine relief.
At least, I hope so.