Сергей Пузанов – Multiple Sclerosis. Everything you need to know (страница 17)
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