Multiple Sclerosis. Everything you need to know

Yet, for clinical trials and pharmaceutical reporting, the industry chose the EDSS. Why? Because Kurtzke's scale carried the institutional weight of being used in the US military, and because the extreme sensitivity of the SNRS terrified drug manufacturers. Why deploy an instrument that logs every minor glitch when the EDSS allows you to turn a blind eye to them? As a result, the EDSS became the gold standard of the industry, even though the SNRS could have delivered a far more honest picture. The EDSS is streamlined for rapid auditing—thanks to its instant score generation—but it completely ignores an array of symptoms that dictate a patient's quality of life. Take me, for example: during my worst stretches, I couldn't close my eyes while washing my hair in the shower—I would instantly lose balance and crash to the floor. Yet, this total failure of equilibrium didn't shift my EDSS score by a single fraction of a point.

Chapter 3. The Interferon War

«He rainmade you. A guy says if you pay him he can make it rain. You pay him. If and when it rains, he takes the credit. If and when it doesn’t, he finds reasons for you to pay him more».

The Wire, 2002-2008

The Birth of DMTs: Wheelchair Protests and the Big Pharma Lottery

To better understand how the era of interferons began, we need to travel back to the early 1990s. Imagine a world in the middle of a tech boom, where humanity is moving forward in leaps and bounds. Imagine your neighbor just got a car with parking sensors, a navigation system, and an automatic transmission. Televisions are now in every home, and they are talking about biotechnology, genetic engineering, and stem cells. Bill Gates has already created Microsoft and is predicting the explosive development of the Internet—if only anyone understood what that actually meant. More and more people are using cell phones, and the phones are becoming smaller and sleeker. In movie theaters, Terminator 2: Judgment Day was recently released, and the special effects are breathtaking. Everything around you is developing, improving, disappearing, appearing, and changing so fast you can barely keep up! And you suffer from multiple sclerosis, and nobody can offer you a single medication.

In 1980, the WHO declared that mass vaccination had allowed the world to eradicate the smallpox virus. Doctors learned how to cure stomach ulcers in just a couple of weeks with a course of antibiotics—it turned out that Helicobacter pylori was to blame all along. Organ transplants started using cyclosporine: transplantology stopped being an experiment and turned into standard medicine. Patients with diabetes were helped too—using genetic engineering and E. coli, scientists created human insulin. Vaccines protected children from measles, tetanus, and polio. And you have multiple sclerosis. For you, there is not a single medication. Your brain continues to destroy itself, and nobody can do anything about it. Is that fair?

In the early 1990s, everyone was talking about interferons. Time magazine came out with interferon on its cover and an article stating that "this is the cancer killer." People were planning to treat hepatitis B and C with interferons—newspapers wrote that "liver cirrhosis will soon be defeated." Articles appeared claiming that interferon would become a major milestone in oncology and the main weapon for clearing out metastases. Doctors started injecting interferons directly into warts—they said a powerful local strike would force the papillomavirus to retreat, and the tissues would clear without surgical burning. People tried using interferons to treat colds, chronic runny noses, lupus, rheumatoid arthritis, acute respiratory viral infections, and even atypical pneumonias. However, none of this concerns you. You have multiple sclerosis, and medicine has nothing to offer you.

When the trials of Betaseron wrapped up in 1992, patients with multiple sclerosis desperately wanted a miracle. On one side of the scale was the biotechnology company Chiron from California, and on the other was the FDA, the Food and Drug Administration. Chiron's specialists managed to recreate interferon beta-1b using genetic engineering, but they had no money to conduct clinical trials, so they teamed up with the Schering AG corporation, or rather, with their American subsidiary, Berlex. When the results were published, they showed a 30% reduction in the frequency of multiple sclerosis relapses, and Chiron began talking about a victory over multiple sclerosis. However, the boring bureaucrats from the FDA reacted skeptically. The side effects and toxicity levels were deemed horrific, the surrogate markers were ambiguous, and the impact of the number of relapses on disability was unproven. The FDA's position was quite clear: "deny accelerated approval and send it back for years of studies."

It is worth noting that these were turbulent times for the Food and Drug Administration. In the late 1980s and early 1990s, the FDA offices in Maryland became the arena for fierce protests. Activists from the ACT UP movement, fighting for the rights of patients with HIV, organized massive DIE IN protests: they lay down on the asphalt, brought coffins to the building, and stormed the corridors—demanding an end to bureaucratic red tape and to save human lives. Television reports forced congressmen to put pressure on the FDA, demanding they speed up the approval of life-saving therapy. In public opinion, the agency's employees turned into heartless bureaucrats blocking patients' access to revolutionary medications. Naturally, the manufacturers of interferons did not hesitate to exploit this situation.

Riding this wave of public fury, Berlex and Chiron launched one of the first massive campaigns of hidden corporate lobbying, or "astroturfing," in history. They allocated millions in "educational grants" to the National Multiple Sclerosis Society and other charitable foundations. Through these organizations, patient lists were coordinated, medical databases were collected, and the transportation of people in wheelchairs to rallies outside government buildings was paid for. Using insider information about which stages the documents were stuck at, lobbyists directed the anger of activists at specific officials. FDA employees were making decisions under conditions of extreme pressure—essentially at gunpoint.

Betaseron received registration in the US in the summer of 1993. The official position of the FDA and the statements of the head of the agency, David Kessler, represented a complex political tightrope walk. Publicly, officials categorically denied that they were making decisions under pressure from the streets, but in the corridors, they admitted that it was impossible to ignore the protests. Publicly, they said that the street storms did not force them to lower safety standards; in the corridors, they complained that the pressure was paralyzing. Publicly, they said they heard the voice of terminally ill people; in the corridors, they admitted they heard directives from the White House. This decision changed the FDA. From a closed academic body, the agency transformed into a structure that is forced to account for public opinion.

By the way, the word "lottery" in the headline must be taken literally. At the moment of Betaseron's sudden registration, there were 250,000 patients in the US, and about a third of them had the appropriate relapsing-remitting course. At the start of sales, Berlex, the subsidiary of Schering AG responsible for the distribution of interferon, could only provide the drug to 15,000 patients. Giving the medication away on a first-come, first-served basis meant triggering a bloodbath in pharmacies. Selling it only to the richest meant risking the destruction of the company by angry activists. Management at Berlex hired an independent company—and soon announced the first pharmaceutical lottery in history.

There were 67,000 applicants and only 15,000 doses of the drug. More than 50,000 people did not receive interferons, but a number in a queue, and a number like 48,512 meant the medication would be issued in 2–3 years. This determined the trajectory of the DMT market for many years to come: for a product with a waiting list of 50,000 people, you can set any price—the insurance company won't even dare to squeak. The lottery was conducted right inside neurologists' offices—and doctors accused Berlex of "playing God, shifting the moral responsibility onto heartless software."

The end of 1993 was a time that can be called the peak of global hopes for interferons. FDA employees could not believe their eyes. They knew they were dealing with a medication that did not affect the rate of disability progression, but they could not influence public opinion. The emotions of patients were stronger than numbers and logic. Marketing turned out to be more important than biology, and soon interferons arrived in pharmacies—to the thunderous applause of hundreds of thousands of misled people.

Interferons Beta-1b

Interferons are a family of signaling proteins naturally released by the immune system whenever a virus breaches the body. They were discovered entirely by accident in 1957 by Alick Isaacs and Jean Lindenmann at London’s National Institute for Medical Research. They stumbled upon a fascinating biological anomaly: the presence of one active viral infection blocked a second independent virus from multiplying, both in chicken embryos and lab mice. They termed this "interference"—essentially, a biological obstruction.

The very first drug approved to treat multiple sclerosis was interferon beta-1b. Marketed under the brand name Betaseron, it rammed through US registration in the summer of 1993 following the riots outside the FDA. The annual price tag was set at $9,882—an astronomical, shocking figure that broke the financial baseline of American medicine forever. The drug cost dozens of times more than any standard medication of the era, and the manufacturing deficit—which forced the therapy to be rationed via a randomized computer draw—only fed the hysteria. For comparison, the average annual salary of an American in 1993 sat at $26,362. Insurance companies were forced to engineer a brand-new coverage category called "Specialty Drugs"—prior to 1993, they had never faced a reality where a routine retail medication cost as much as a used car. Betaseron became the most expensive self-injectable drug you could take at home.

This is exactly how the era of DMTs kicked off—built on magical interferons, genetic breakthroughs, wheelchair riots, a corporate lottery, and mind-boggling prices. Betaseron's registration locked down the rules of the market for decades: from that moment on, FDA officials became terrified of MS patients. Prices continued their upward spiral: today, the annual cost of interferon therapy bounces between $80,000 and $140,000—while the median US salary sits around $62,500. The price inflation of interferons has outpaced standard economic inflation several times over, even though any manufacturing deficits vanished decades ago.

In Europe, interferon beta-1b arrived two years later under the name Betaferon. The lag occurred because on November 1, 1993, the European Union was born, and its unified drug regulator, the EMA, didn’t fire up its engines until January 1995. The application for interferon beta-1b became the first-ever high-tech drug submission managed through the new "centralized procedure." It was a high-stakes exam for the brand-new regulator: the agency desperately wanted to prove it could operate faster and more efficiently than the American FDA. Approval went through in record time—by November 1995, just 10 months after the agency opened its doors, the European Commission granted Betaferon its license. European patients, who numbered around 350,000 in 1995, were ecstatic.

Betaseron was manufactured using recombinant DNA technology—interferon beta-1b is grown inside cultures of E. coli bacteria. It structurally differs from natural human interferon-beta: its amino acid sequence is slightly modified, and the protein is "non-glycosylated." The corporate brochures claimed a brilliant array of mechanisms: immunomodulation, shifting the T-cell response profile, suppressing pro-inflammatory cytokines, switching immune cells to a protective phenotype, and jamming the migration of activated lymphocytes across the blood-brain barrier. The patient had to manually inject this cocktail subcutaneously (under the skin) every other day. In the vast majority of cases, this routine triggered brutal side effects—a heavy flu-like syndrome, spiking fevers, severe chills, and localized skin necrosis at the injection sites.

Back in 1993, Betaseron ran through clinical trials that were packaged as randomized, double-blind, and placebo-controlled—meaning patients were randomly split into groups, and neither the doctors nor the subjects knew who was getting the real drug. But here is a critical detail: the placebo group was injected with a "Sterile Diluent"—a basic saline solution spiked with serum albumin. This additive was included specifically to irritate the skin, causing minor local redness to mimic the injection site reactions of the real drug.

Do you see the structural flaw in this design? Injecting Betaseron caused violent fevers, intense chills, and body aches, while injecting the placebo was entirely painless systemically. In practice, this meant the blinding was instantly shattered—both doctors and patients knew exactly who was on the drug. This setup manufactures the perfect storm for a systematic bias in measuring efficacy, even without any malicious intent and among scientists genuinely trying to "do pure science." A doctor finds it much easier to spot improvements if they know the patient is on the active compound, and a patient finds it much easier to believe their suffering isn't in vain if they are taking the long-awaited miracle drug. Psychology calls this "effort justification"; I prefer to call it the "hard-won health syndrome."

Ultimately, the very first multiple sclerosis medication was born under incredibly messy circumstances—FDA officials signed the registration documents with a metaphorical gun to their heads. Everyone desperately wanted interferons to work—doctors, patients, journalists, politicians, and the public. The regulators had to sacrifice their scientific ideals and close their eyes to a deeply compromised trial design: under unblinded conditions, interferons managed to reduce subjective, self-reported relapses, but failed to show any structural impact on disability progression. As for the patients, the heavy side effects became the master key to their loyalty: the human mind cannot accept that it is enduring such misery for nothing. There’s an old saying: "To make a person happy, make their life miserable first, then return them to where they started." After enduring hours of shaking fevers, patients were simply grateful to return to their baseline well-being.

Why is double-blinding so vital for a clean clinical trial? Because the scientists who engineer a molecule desperately want it to succeed, and if the study unblinds, they can quietly steer the endpoints in the desired direction. Betaseron lowered the relapse rate by 31%, but what exactly qualified as a relapse? There was no rigid, automatically verified definition of the term, leaving researchers massive room to maneuver. In reality, everything came down to how a specific team interpreted a patient’s complaints and logged them in the charts—either as an active "relapse" or a temporary "fluctuation."

The definitive finding of the Betaseron trials—the one that always gets buried in popular retellings—is that the drug failed to show any impact on slowing down disability progression. Why does this detail disappear? Because slowing down disability wasn't chosen as the primary endpoint of the study. Think about that: a drug reduces self-reported relapses by 31% but leaves the long-term trajectory of disability entirely unchanged, and logging those relapses is left to the discretion of doctors heavily invested in the trial's success. The FDA’s initial refusal to register Betaseron was completely scientifically sound. For a long time, I couldn't comprehend how they managed to rubber-stamp this drug anyway—until I dug into the history of the interferon boom and the wheelchair riots.

Despite the brutal side effects and the total lack of disability modification, Betaseron went on to generate roughly $20 billion for Bayer. This was the turning point for the DMT market: pharmaceutical giants realized that treating multiple sclerosis was a gold mine. Yet, no true generic versions of Betaseron ever emerged in the US. Why did the industry collectively ignore this gold mine? Because by 1996, Biogen stepped onto the field. To bypass Betaseron’s patent blockades, they engineered an upgraded version of the molecule: interferon beta-1a. This time—featuring slowed disability progression!

Intramuscular Interferons Beta-1a

The next drug to hit the MS market after Betaseron was Avonex, registered by Biogen in 1996. Its active ingredient was interferon beta-1a. Instead of growing it in E. coli bacteria, Biogen cultivated it using mammalian cells—specifically, "Chinese hamster ovary cells." This molecular structure was much closer to natural human interferon-beta. Biogen cleverly marketed this as a "natural form," using it to explain why Avonex had milder side effects compared to Betaseron.

There was also a fundamental shift in how the drug was taken: Avonex was injected just once a week, not every other day. Manufacturing it in hamster cells made the molecule far more stable in the body. Furthermore, since subcutaneous injections of Betaseron too frequently caused painful skin reactions, Biogen offered intramuscular injections. To top it all off, they drastically slashed the weekly dosage—from 250 micrograms down to 30 micrograms.

Do you see the pattern? By the time the second interferon arrived, the industry’s focus had already shifted away from maximizing medical efficacy. Instead, they were trying to make the grueling injection routine slightly less miserable for the patient. In any other industry, this is the exact moment you say "the customer service department has arrived."

You have to hand it to Biogen: their entire regulatory launch strategy for Avonex was a masterpiece of marketing and pharmaceutical positioning. They studied Betaseron’s success story inside out, connected the dots, and drew the right financial conclusions. They listened to what patients hated about the first miracle drug and turned those medical complaints into a corporate gold mine.

First of all, they realized that patients desperately wanted to avoid stabbing themselves every other day while enduring a never-ending cycle of fevers. Biogen’s fix was elegant: a vastly reduced dose of interferon injected only once a week. In the eyes of both doctors and patients, this single tweak made the drug look like a quantum leap forward. Once a week is incomparably more convenient than every other day, isn't it? You can easily plan a weekend trip without dragging a cooling kit along or trying to remember when you last did an injection. You only have to endure the flu-like misery once a week, and those symptoms turned out to be noticeably milder anyway. Whichever way you looked, it was a massive win for user experience.

Secondly, Biogen’s strategists realized that their clients (at this stage, calling them "patients" feels a bit naive) weren't idiots. Some scoured the medical journals themselves, while others tracked the scientific pushback against Betaseron. They weren't just demanding fewer relapses anymore; they wanted proof that a drug could actually slow down long-term disability progression. Biogen delivered exactly what the market ordered. Their clinical trials came back with a spectacular claim: the risk of "confirmed disability progression" for patients on Avonex was slashed by 37% compared to the placebo group.

The third season of the American Crime Story focuses on a scandal you likely haven’t forgotten: Bill Clinton and Monica Lewinsky. The season spans 10 full hour-long episodes, and if you think that’s an excessive runtime to cover a straightforward historical event, you underestimate the legal battle of an impeachment trial. I won’t recap the whole drama, but there is one pivotal moment worth highlighting. When Clinton was cornered under oath and asked if he had engaged in sexual relations with Monica Lewinsky, his lawyers said: "Define sexual relations." The prosecutor read the strict, technical definition from the official vocabulary log, and Clinton answered with a completely clear conscience that, under those exact definitions, he had not. If required, he could have passed a polygraph on the spot. The impeachment collapsed, and Clinton remained in the Oval Office until the end of his term.

Why bring this up? When multiple sclerosis patients demanded that interferons slow down their disability, Biogen replied, "Absolutely. But first, let’s define what qualifies as a slowdown." Biogen defined "disability progression" as an increase of 1.0 full point on the EDSS scale, which then had to be verified by a repeat audit six months later. They termed this metric SDP—Sustained Disability Progression. Soon, the industry would rebrand it as CDP, Confirmed Disability Progression, and it remains a core endpoint in DMT trials to this day. But here is the critical catch: if after six months the patient's walking or coordination naturally bounced back to baseline and the deterioration failed to confirm, the "odometer" was entirely wiped clean—the progression was logged as unconfirmed. Furthermore, the calculation completely ignored the patient's starting line, erasing the massive functional difference between shifting from 1.0 to 2.0 versus dropping from 5.0 to 6.0. The non-linear nature of the EDSS manufactures a wall of statistical "noise" spanning dozens of percentage points. Under unblinded conditions, the loose handling of scores below 3.5 leaves researchers massive room to steer the metrics. Once the stage was set for these statistical miracles, all Biogen had to do was navigate the blinding problem.

As their corporate attorneys predicted, the blinding issue resolved itself because the FDA had trapped itself with its 1993 Betaseron ruling. By approving the first interferon despite an entirely compromised trial design, the agency had locked in a legal precedent. Tightening the scientific screws on the very next drug would be an implicit admission that their initial standard was dangerously low. Bureaucratic regulators almost never do this—partly out of sheer institutional inertia, and partly out of fear of nuking public trust in their own past decisions. The FDA officials chose not to rock the boat, likely comforting themselves with thoughts like: "Well, the scientists engineered it, so it must do something useful."

Let’s look at a few numbers to put the scale of this market into perspective:

In its 2007 financial report, Biogen stated that the number of patients on Avonex crossed 135,000, translating to roughly 7 million injections a year.

At launch, a single injection cost about $250. By the early 2000s, that bounced to $400–$500. By the 2010s, it hit $600 per shot.

Over 25 years, anywhere from 600,000 to 700,000 patients cycled through Avonex therapy.

Cumulatively, patients stuck themselves with Avonex between 50 and 70 million times.

Total global sales for Avonex look back on a mountain of roughly $40 billion.

The regulatory compromise the FDA signed under public duress in 1993 did not happen in a vacuum. It forged a precedent that permanently rewrote the rules of the game: clinical trials for DMTs were effectively excused from maintaining strict double-blinding, rigorous efficacy filters, or clinically meaningful endpoints. A drug whose utility was proven purely at the level of loose definitions and statistical assumptions transformed into a multi-billion-dollar corporate juggernaut—and laid down the new baseline framework for how the entire industry would operate for decades. Patients desperately wanted a weapon against multiple sclerosis, and the market gave them exactly what they asked for.

Let's look under the hood of the Avonex trials. The study was exceptionally small, tracking just 301 people: 158 patients injected Avonex, while 143 were given a neutral solution as a placebo. Defining what actually constituted a "relapse" was left entirely to the discretion of the investigators. Because a new interferon molecule was practically pre-ordained for commercial success under the existing rules, Biogen had zero financial incentive to fund a massive, multi-center trial. Nobody wanted to dig into the Pandora's box that Betaseron had opened. In May 1996, Avonex sailed through FDA approval, hit US pharmacies by summer, and locked in the precedent: DMTs could legally claim efficacy without bulletproof double-blinding.