TDM to the rescue in biologics boom

Karen Titus

July 2019—In the early, heady days of biologic therapies, use of these drugs resembled a common military tactic of the Civil War: charge and retreat, charge and retreat, charge and retreat. The approach, though modern at the time, often proved disastrous.

Jeffry Katz, MD, recalls the excitement that greeted the arrival of anti-tumor necrosis factor-α agents, starting with infliximab (Remicade) in 1998. “What we used to do is we would give patients a drug, and we would wait for them to get sicker,” says Dr. Katz, medical director, inflammatory bowel diseases, University Hospitals Cleveland Medical Center, and professor of medicine, Case Western Reserve University School of Medicine. “And then we’d give them a stronger drug, and then we’d wait for them to get sicker. And then we’d give them our strongest drugs, or we’d send them to the operating room.” In essence, “We basically didn’t give the strongest, most effective therapies until people got more ill.”

Over time, physicians learned this approach also allowed bowel damage to occur. “And by the time we get to the best drugs, it’s often too late—nothing’s going to work at that time,” says Dr. Katz.

Little wonder that physicians are turning to a new strategy for deploying biologics: using therapeutic drug monitoring, with the aim of aggressively controlling disease and inflammation. Doing so will help prevent downstream complications, says Dr. Katz, including hospitalization, surgery, and strictures.

“For the use of biologics in inflammatory bowel disease, some sort of monitoring is the standard of care at this point,” he says, “whether it’s reactive or proactive or some combination of both.”

The data to support this are far from perfect, and the best approach has yet to be determined. “We still have questions to answer,” Dr. Katz concedes, “but it’s better than flying blind, which is what we did for years with the use of infliximab and, for a while, adalimumab.”

At the very least, physicians are flying in the same direction, guided by assays for therapeutic monitoring and testing for immunogenicity. “This is one of the most rapidly growing areas in clinical immunology testing,” says Eszter Lazar-Molnar, PhD, D(ABMLI), D(ABHI), medical director, Immunology Division, ARUP Laboratories, and director of the Histocompatibility and Immunogenetics Laboratory at the University of Utah. Within the broader biologics category, TNF antagonists—five of the parent drugs and an increasing number of biosimilars have been FDA approved—spur the majority of such testing, she says. The biggest drivers are infliximab and adalimumab (Humira), and the bulk of orders comes from gastroenterologists, though the drug is also used to treat rheumatoid arthritis.

“A huge portion of our health care dollars is being spent in specialty medicine,” says Jane Yang, MD, medical science director at Esoterix specialty lab for biologic TDM of LabCorp. By 2020, she says, an estimated $400 billion could be spent on specialty drugs, accounting for just over nine percent of total national health care spending. Specialty patients represent three percent of the population, but the group accounts for 40 percent of total drug spending, she says. And of the drugs popping out of the FDA approval pipeline every year, Dr. Yang continues, roughly 70 percent are biologics. It is, she says, the fastest growing and highest grossing category of drug.

No surprise there. “These drugs are great,” says Dr. Yang. “They’ve really revolutionized the care of many diseases, especially now in autoimmune disease. But the disconnect is that you have these expensive drugs, and they’re being dosed by standard dose, or dosing by weight. And we can certainly do better than that.”

“These are miracle drugs in patients who respond,” agrees Dr. Lazar-Molnar, who is also assistant professor, Department of Pathology, University of Utah.

Who respond being the key part of that sentence. “Although these are really good treatments,” says Dr. Katz, “they don’t work for everybody.”

Some 30 percent of patients who receive a biologic are primary nonresponders, Dr. Yang says. It could be that they didn’t receive the right dosage, or that they need a drug of a different mechanism. Secondary failure rate is quite high, she continues—some 50 percent of patients on a biologic are not on that drug after one year. And every year thereafter, 10 to 15 percent of patients fall off. “There’s a tremendous problem with persistence,” Dr. Yang says.

Failure is caused primarily by development of antidrug antibodies. “You are giving the protein drug to a patient repeatedly,” says Dr. Lazar-Molnar. “It’s like immunizing someone with that drug, right? So it’s not a surprise that after a while they will develop antidrug antibodies.”

Ten to 15 years ago, physicians who wanted to look for antidrug antibody would have to put the patient on a drug holiday because the only available antibody assays were subject to interference by circulating drug, Dr. Yang says. This may have answered their question, but it compromised treatment and contributed to immunogenicity.

“We’ve come a long way in being able to offer physicians better immunogenicity assays that are more sensitive and drug tolerant,” Dr. Yang says. Gastroenterologists should no longer be thinking of immunogenicity as binary, she says; rather, they should use results from high-performing antibody assays the way they would a tumor marker. If a patient starts developing antidrug antibodies, it makes sense to ensure the drug level is optimized and/or to consider adding a second medication, such as methotrexate or azathioprine (Imuran), she says. “There’s some evidence that you can actually reverse antidrug antibodies if they’re low in titer. But if there’s high-titer antidrug antibody, the patient has refractory immunogenicity, and it’s likely time to switch to a different biologic.”

Even more concerning, she says, is that “Once you’ve developed antibodies to one biologic, you need to move on to the next biologic.” And—unlike with marriage—the second or third one is less effective.

“I really think TDM may be the answer to the poor longevity of biologics,” says Dr. Yang. In the best-case scenario, she says, it could allow physicians to consider cotherapies where appropriate and enable patients to successfully remain on a biologic longer, with fewer complications.

Early approaches to biologics involved treating as needed or on demand, until, Dr. Katz says, “We began to see that that wasn’t the best way to go about it. People would lose response or develop antibodies to the treatment. So we developed induction therapies and maintenance therapies.” It has also become clear that there’s a blood level-response curve—generally, the higher the drug level, the better patients tend to do over time. “There’s sort of an optimal therapeutic window—below a certain level, they don’t seem as effective, and above a certain level they don’t seem to gain any additional effectiveness.”

Improving the longevity of these drugs also makes sense in terms of cost, says Dr. Yang, noting treatment can run to more than $30,000 per patient annually. “As great as these medications are, they’re very expensive.”

Several European studies have shown that laboratory-based management of patients on biologics, versus empirical-based management sans lab testing, saves money, Dr. Lazar-Molnar says.

But TDM in this setting poses numerous challenges. While the concept is, obviously, already familiar to laboratories, there are some differences from the traditional approach. With conventional drugs such as digoxin, say, or gentamicin, clinicians are worried about a ceiling, and the proximity of the toxic range to the therapeutic range. That’s not the case with biologics.

“These drugs have their own unique challenges for assay development,” says Dr. Lazar-Molnar. “First, you need an assay to measure drug levels, but perhaps even more importantly, you need an assay to detect antidrug antibodies that arise following treatment with these drugs. You’re measuring antibody against an antibody drug in the serum, which has a lot of antibody, a lot of immunoglobulins, in the background.” And not all antibody will be detectable in the patient who is taking the drug. “It may be bound to the drug, and not available for the assay.”

Dr. Yang advocates for tandem testing, using one assay to measure drug concentration and another to look for antidrug antibodies. “You want to expedite critical clinical decisions, as dictated by the American Gastroenterological

Association’s current guidelines, which necessitate both drug and antibody levels,” she says. Biologics are, of course, proteins, so there’s always the potential for inducing an antibody response. “And those antibodies can negatively impact drug efficacy,” she says.

Some laboratories choose reflex testing, but Dr. Yang is not a fan of this approach. “It flies in the face of what we’ve more recently seen about reversing antidrug antibodies, about adding cotherapies and optimizing drug concentrations in order to treat away lower titers and prevent their progression to high titer refractory immunogenicity.” Reflex testing might seem just as good, and cheaper, but it could mean losing an opportunity to manage early immunogenicity that could be transient and reversible.

It’s critical, she says, to know why a patient is not responding to a biologic. If there are no antibodies and the drug level is good, then the patient may have developed an infection, or they may have another disease. Or, the disease may be driven by a different mechanism, “and then you need to think about a pharmacodynamic mismatch.” On the other hand, if the drug level is low, and there are no antibodies, “then that patient likely just needs more drug.” If there are antidrug antibodies, “then you need to look at the titer.”

As many as 30 percent of patients may be subtherapeutic in the absence of any antidrug antibodies simply because they haven’t been given enough drug based on standard dosing. “We show that in our own clinical database, but it’s also shown in other studies,” Dr. Yang says. It’s true for IBD as well as rheumatoid arthritis. “Your patient may just require more drug on account of being a big male with low serum albumin and really active disease.”

From the laboratory standpoint, she says, “There’s a right way of measuring biologic drug and antidrug antibodies, and then there’s a less-informed way.”

Dr. Katz says there’s solid evidence to support use of reactive monitoring—checking drug levels if the patient is not doing well, which, depending on the result, may prompt higher dosing, use of a different drug, or switching to a different class of drug.