You've probably seen the commercials on TV. "This is your wake-up call," a female narrator intones over the sound of a ticking clock while images flash of people rubbing aching joints.
"Humira can help stop the clock," she says, as the ad changes tone and introduces a drug that last year earned its maker, AbbVie, $18 billion in revenues.
AbbVie spends heavily on direct-to-consumer advertising for Humira (adalimumab), filling the airwaves with 60-second spots on the medicine's many uses.
One of most common is for rheumatoid arthritis. The chronic, inflammatory condition affects between 1.3 million and 1.8 million Americans and is most commonly associated with joint swelling and stiffness. Left untreated, however, it can lead to joint damage and deformity.
Over the past 20 years, nearly ten biologic medicines have been approved for rheumatoid arthritis, helping to improve patient outcomes over older medicines like methotrexate. That influx of research and investment is matched by the lucrative returns earned by drugmakers like AbbVie, Amgen and Johnson & Johnson.
Still, pharma sees an opportunity in rheumatoid arthritis — particularly for the hundreds of thousands of patients still not treated with biologic drugs like Humira. New oral therapies are advancing through clinical testing, and Wall Street believes there's room for further market expansion.
It's also a field in which several of the industry's fault lines converge: biosimilars look set to challenge brands in a competition that's playing out elsewhere, while broader scrutiny on drug prices has put a heightened focus on the high cost of arthritis therapies.
Humira, Amgen's Enbrel (etanercept) and J&J's Remicade (infliximab), all so-called TNF inhibitors, have been a go-to option for years in rheumatoid arthritis and are some of the best-selling drugs in the world.
While methotrexate, a multi-purpose drug discovered in the 1940s, is still commonly used, TNF inhibitors are typically the next drug rheumatologists reach for.
Essentially, these drugs work by impeding signaling pathways that trigger the inflammation behind the painful joint swelling characteristic of rheumatoid arthritis. There's strong evidence that TNF inhibitors provide a health benefit compared to older treatments like methotrexate, and use has steadily climbed since their introduction in the late 1990s.
Prices have risen as well, with the annual cost of TNF inhibitor treatment now stretching into the tens of thousands of dollars. Usually the drugs are covered by insurance — government or commercial — but rising costs and high spending make the rheumatoid arthritis market one of several at the heart of pharma pricing scrutiny.
Humira, for example, cost Medicare Part D $1,014 per unit in 2012. Two years ago, that price had risen nearly two-fold to $1,962 per unit, according to a government database. Enbrel's list price per unit, meanwhile, rose by a similarly high 95% over that same period.
Those rising prices have fueled higher and higher spending on the drugs across inflammatory disease conditions, including rheumatoid arthritis. A recent report from Blue Cross Blue Shield Association, a nationwide group of 36 independent insurers, found Humira, Enbrel and Remicade accounted for the greatest per drug spending in 2017. Tellingly, for each medicine the rate of spending growth by Blue Cross plans outstripped the growth rate of prescription volume.
And, while the TNF inhibitor class is considered effective and generally well-tolerated, there are questions on whether the drugs are cost-effective at their current price tags. The Institute for Clinical and Economic Review, a cost watchdog, found all 11 TNF inhibitors and other immuno-modulators it analyzed in an April 2017 report to significantly exceed its cost-effectiveness thresholds.
In the case of the top trio of TNF inhibitors, the drugs are also old. Patents and a 12-year window of regulatory exclusivity have so far shielded them from competition. Yet that's beginning to change, albeit slowly.
Two biosimilars, or cheaper copies of biologic drugs, are already on the market for Remicade. A district court trial now underway between Amgen and Novartis' Sandoz unit, meanwhile, could open the door to earlier entry of copies to Enbrel.
Humira, though, is likely to stay protected until 2023, when as many as six biosimilars could enter per settlement deals between makers of the copycat drugs and AbbVie.
"Especially with biosimilars coming to the market, I think there will be an increasing pressure on price for rheumatoid arthritis treatment," said Marcin Ernst, a vice president of general medicine at Syneos Health, said in an interview with BioPharma Dive.
Room for improvement
Still, a sizable number of patients still aren't treated with the therapies. An analysis by Novartis, for example, estimated about 53% of treated rheumatoid arthritis patients in the U.S. received biologics in 2016 — a substantial share but by no means universal. Not all patients respond well to TNF inhibitors either, leading to treatment "cycling" and a search for other options and combinations.
Both realities underpin the search by other drugmakers for new modes of therapy aimed at reaching those patients still not adequately treated.
"It is important to remember we talk about all these amazing drugs for rheumatoid arthritis that have had a big impact on these patients, but the disease remains very significant, with about 50% of patients who will remain symptomatic after a year of just TNF inhibitor therapy," said Hal Barron, head of R&D at GlaxoSmithKline, which is developing an experimental drug for rheumatoid arthritis, during a July conference call.
"Of course IL-6, and JAK inhibitor molecules have been developed and they are adding value, but almost half of the patients will still experience significant pain," Barron continued.
Barron and GSK have a clear self interest in pointing out the holes in the current treatment armamentarium for rheumatoid arthritis. His comments are revealing, though, signaling the enduring opportunity drugmakers still see despite a crowded market of billion dollar drugs.
French drugmaker Sanofi has made a similar pitch. Last May, the pharma won U.S. approval for Kevzara (sarilumab), an IL-6 inhibitor that's beat out Humira in a head-to-head study.
But it's been another class of drugs, termed JAK inhibitors, that have caught Wall Street's eye and look to pose the most serious clinical competition to the dominance of TNF inhibitors. Most notably, this class of drugs is orally administered rather than injected like the biologics.
Pfizer's Xeljanz (tofactinib) was the first JAK inhibitor to market, earning Food and Drug Administration approval in 2012. Sales totaled $1.2 billion through the first nine months of 2018, although the drug is now OK'd for two other inflammatory diseases.
Eli Lilly's Olumiant (barictinib) was more recently approved, although a restrictive label and safety concerns could weigh on the drug's prospects.
Here, too, AbbVie could end up a leader, with high expectations for its experimental JAK blocker upadacitinib. Gilead and Galapagos are also advancing a drug, dubbed filgotinib, that works similarly.
"JAK inhibitors [are] increasingly likely to move ahead of TNFs in five years," wrote analysts from Cowen, an investment bank, in an October note to investors.
TNF inhibitors won't cede their place overnight, however.
"It's difficult to expect a significant change because we've reached a place where we have a lot to offer to patients," said Syneos' Ernst, while noting that JAK inhibitors had shown good efficacy.
And in five years, biosimilars should be more widely available, including for Humira, adding cheaper competition into the mix.