The spring of 2002 had just barely sprung when Abbott Laboratories filed the paperwork that would, in just over a decade, pave the way for a root-and-branch restructuring of the blockbuster drug pecking order. The treatment was of course Humira, the first-ever fully human monoclonal antibody to receive Food and Drug Administration (FDA) approval, and regulators granted Abbott’s Biologics License Application (BLA) for its first indication in rheumatoid arthritis at the end of that year.

What followed gave rise to a treatment which, before the COVID-19 pandemic upended the order of all things and necessitated a global vaccination drive that essentially doubled Pfizer’s revenues thanks to its vaccine, the world’s best-selling drug for nearly a decade. The clip at which Humira smashed through pharmaceutical revenue records as it won new indications in inflammatory conditions such as psoriasis, Crohn’s disease, ankylosing spondylitis, and others was head-spinning. It had reached the ever-coveted “blockbuster” status, a treatment with at least $1 billion per year in sales, just over two years following its first approval for arthritis in 2002.

That figure continued to double every two years or so until 2013 (incidentally, the same year Abbott spun off AbbVie as an independent firm with Humira as its lead product), when it officially claimed the mantle of world’s best-selling drug from the previous champion Lipitor, with $10.7 billion in revenues across 60 markets. Yearly revenues for Humira regularly passed the $20 billion mark from the late-2010s and into the 2020s. It raked in $20.7 billion in global 2021 sales, second only to Pfizer’s COVID vaccine.

Humira’s tale is a complex and controversial one. AbbVie’s aggressive approach to IP protection with a brutally effective patent thicket strategy has given it a leg-up over competitors through 2023 in the U.S. market, although it was already under siege from biosimilar competition abroad before 2019. (I wrote extensively about AbbVie’s patent strategy, its effects on would-be competitors and biosimilars, and the downstream costs to patients and the health care system in a Fortune Magazine feature in 2019 for those inclined to peruse the gory details).

But the world’s best-selling therapy didn’t claim that title through IP engineering, questionable price hikes, lawsuits, and licensing arrangements alone (though it no doubt helped): Humira was, truly, a revolutionary treatment built on groundbreaking science that changed and continues to change millions of people’s lives for the better. Its prowess across a range of very common immune and inflammatory disorders underscored the power of the monoclonal antibody, a therapeutic mechanism which dates back to 1986 in the United States, when it was confined to the space of immunosuppressive treatments given to organ transplant patients. Pharma giants quickly picked up on the novelty of this biological approach and competitors such as Remicade and Enbrel followed. Monoclonal antibodies are also at the heart of paradigm-shifting cancer therapies such as Merck’s Keytruda (which placed second in the 2021 best-selling drugs list with $17.9 billion in sales).

If you look to the list of therapies which hold renown for truly revolutionizing the medical landscape, you might harken back all the way to the creation of insulin, aspirin, penicillin, morphine, and oral contraceptives. That’s the level of innovation that makes for a therapy that far outlives its founders and progenitors.

The lesson here is as obvious as the goal of realizing it is difficult: A treatment that’s adaptable enough to meet multiple conditions, unique enough to stand out in the crowd, and constructed for diseases with high unmet need and buttressed by a broad patient base, is the kind of therapy that has sustainable star power.

Just look at this table of 2021’s best-selling treatments compiled by the trade publication Drug Discovery & Development:

Data and chart courtesy of Drug Discovery & Development

The drugs on the 2021 best-seller list encompass inflammatory therapies, cardiovascular drugs, COVID treatments, cancer drugs, drugs for other infectious disease such as HIV cocktails, diabetes treatments, and eye-degeneration therapies which millions of elderly Americans rely on, among others. This shouldn’t be much of a surprise given the level of disease and death linked to heart conditions, cancer, metabolic disorders, and inflammatory conditions.

But now is the time to watch for the blockbusters and paradigm-shifters of the future—and which ones may change the way medicine is practiced and how patients live with their conditions. Not every ingenious production leads to blockbuster sales, of course, and that shouldn’t diminish their critical importance in the marketplace. A revolutionary gene therapy which treats an ultra-rare disorder or is curative with a single administration will never be able to achieve the sorts of eye-popping revenue numbers that a unique, new cancer or psoriasis drug might. That being said, drugs ranging from Bristol-Myers Squibb’s multiple myeloma Rx Revlimid to Roche’s wet AMD leader Lucentis and UCB’s anti-epileptic Vimpat are slated to fall off the patent protection cliff in 2022.

So, which fresh new talent should the medical community be keeping an eye on the coming years? We’ll delve deeper into that in part two of this series, but here’s just one starting point for consideration: IDEA Pharma’s latest Freshness Index, part of our upcoming Pharmaceutical Innovation and Invention Index for 2022:

This portion of the index surveys the top performers in pharmaceutical innovation—defined separately from mere “invention” of a new treatment or class by proven staying power—by the amount of revenue they’ve generated from drugs approved in the past three to five years.

Astute readers may note that several firms derived no revenues at all from treatments approved in the past three years. Moderna and BioNTech are clear outliers bolstered by the COVID-19 pandemic thanks to their vaccine technology. But what may companies like Gilead, Pfizer, Takeda, and others produce as their franchise players? And which drugs that have just received FDA approval in the past two years could make a splash for years to come in the broader service of the public health?

For more on that, including interviews with industry analysts, keep an eye out for part two of this report.