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Biotechnol Healthc. 2010 Summer; 7(2): 12–16.
PMCID: PMC2899797

Managing The Immunomodulators

JOHN CARROLL, Senior Contributing Editor


Dosage and indication “creep” with the new biologics to treat inflammatory diseases have payers enforcing strict utilization policies. Physicians counter that payers can’t dictate treatment. With even more biologics on the horizon, and drug spend spiralling upward, both sides need to seek a middle ground. The question is how?

Lloyd F. Mayer, MD, has spent much of his career honing the cutting edge of medical care in immunology. Co-director of The Immunology Institute at The Mount Sinai Medical Center in New York, Mayer has been a lead player in the field just as the standards of care for inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), Crohn’s disease (CD), and psoriasis have undergone a major treatment shift with the arrival of a new generation of biologics.

Treatment standards once revolved around a few key therapeutics that medical and pharmacy specialists knew well — azathioprine, methotrexate, corticosteroids, and 6-mercaptopurine — all used to suppress the body’s immune system so it won’t attack healthy tissue. Then, in the late ’90s, the first biologics — etanercept (Enbrel) and infliximab (Remicade) for RA — gained U.S. Food and Drug Administration approval for treating inflammatory conditions, followed by a burst of biologic approvals as the new century dawned — adalimumab (Humira) and certolizumab pegol (Cimzia) to treat RA and natalizumab (Tysabri) for MS. CD, psoriasis, and psoriatic arthritis were subsequently added to the approval list for these drugs.

With each passing year, physicians and pharmacy benefit managers have been building up their body of knowledge and experience in the day-to-day use of the newer therapeutics, which often are prescribed in combination with the older therapeutics. “I think there’s a greater comfort level with their use,” says Mayer, who prefers to call the new wave of biologics “immuno-modulators.”

“Evidence is increasing on a yearly basis that the doses we use don’t really suppress the immune system,” Mayer says, who also is chairman of the National Scientific Advisory Committee of the Crohn’s and Colitis Foundation of America (CCFA). “They don’t make patients more susceptible to wide-ranging infections either. They’re like the smart bombs — more targeted.”

And when these immunomodulators work as planned, Mayer adds, patients often tell him that it’s as if they’ve been given their life back.

Like any new, improved — and very expensive — medical weapon added to the armamentarium, though, a number of health insurers say that physicians are too quick to deploy it. Pharmacy benefit specialists at a slate of health plans say that it’s vitally important to clearly illuminate a pathway for the proper clinical use of all biologics. And with more and more immunomodulators either winning approval or in late-stage development, these specialists are intent on using what they’ve learned about biologics to encourage the use of the older and less expensive drugs as they try to control their drug spend.

For payers, that kind of oversight responsibility has spurred them to guard against what they see as dosage and indication “creep” — where physicians step over the payer’s guidelines on dose maximums or prescribe an immunomodulator for an unapproved use.

But what insurers see as common sense can be a daily frustration to physicians like Mayer.


“It’s an interesting category,” says Helen Sherman, PharmD, chief pharmacy officer at RegenceRx, a PBM with nearly 3 million members, about the wave of immunomodulators sweeping the field. “We keep track of all the science and potential uses, but this is a complex category. It is a bit like trying to solve a Rubik’s cube when it comes to drawing evidence-based conclusions, since there are so many new products, indications, and uses.”

For pharmacy benefit specialists like Sherman, several key strategies have emerged to manage the utilization of these therapies. Step therapy programs are in place to point newly diagnosed patients to the therapies that have the longest track record. Health plans also emphasize routine and frequent communication with patients and physicians to help them understand their evidence-based approach to therapy and to help monitor a member’s response to drugs.

“When you look at specialty drugs in terms of the spend, as well as the side effects associated with these drugs, we really want to know that patients are getting the right therapy,” says John Poniatowski, RPh, MS, director of specialty pharmacy clinical programs for CIGNA. “We look at the indication, the dose, and the duration, and monitor for appropriate response to the drugs. Not everybody responds the same way.

“Over time, patients may lose a positive response and need to move to a drug with a different mechanism to control their condition,” Poniatowski adds. “With RA, we ask the doctor to provide us with information that confirms the patient is responding to the prescribed drug.”

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“There’s not a day that goes by that I don’t have to argue to get prior authorization and face delays in getting the medicine I need,”says Lloyd F. Mayer, MD, at The Mount Sinai Medical Center in New York.


CIGNA also tracks adherence to prescribed dosing. “We focus on providing education, much of it on the telephone,” says Poniatowski. “We’ll get a discussion going between an individual customer and our team of therapy support coordinators, nurses, and pharmacists to educate that individual on drug use and his or her condition, explaining why it’s important to keep taking the drug.” For inflammatory bowel diseases like CD or ulcerative colitis, the disease can be severe, and people are very motivated, Poniatowski says. “Hopefully, the disease goes into remission, but then there’s the risk of less adherence.” Therefore, he says, it’s important to reinforce that the medications have to be taken continually.

“For any of the biologics, the standard is that a patient has tried and failed a first-line immunomodulation agent, such as azathioprine, corticosteroids, or oral methotrexate, before starting a specialty drug. “Unfortunately, over time, some people may stop responding to the oral immunomodulator, and the disease progresses, so a change in therapy is appropriate.”

“We do a full scientific review across all medications regardless of whether they are covered under the prescription or medical benefit,” says Sherman. “All products have either a preferred or nonpreferred status, and we have the same utilization management across the prescription and medical benefit sides to ensure a level playing field.” In terms of better tracking, Sherman says, systems are evolving so all medications, including those covered under the medical benefit, can be identified with an NDC drug code. “With each prior authorization request, we issue a letter to the [plan] member.”

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At Cigna, notes John Poniatowski, RPh, MS, the policy is to engage physicians directly when they want to use doses higher than recommended.

RegenceRx comes down squarely on the side of the older generic medications for initial dosing, particularly when the insurer can go with a scientifically proven standard like methotrexate for RA.


Some troubling side effects have been clearly linked to the new immunomodulating drugs, says Mayer, but with prolonged use among chronically ill patients, physicians have had a chance to observe where the greatest threats lie and how to avoid them.

Some of the biologics, like infliximab and other anti-TNF therapies, may make more patients vulnerable to reactivated tuberculosis (TB), Mayer notes as an example. So specialists have learned to screen for TB to make sure their patients aren’t at a significant risk of contracting the disease. Histoplasmosis, another infection that lives inside cells, also has to be screened for. But, once discovered, these pitfalls usually can be safely navigated. With health plans pushing for compliance with ambitious utilization management programs, physicians and patient advocacy groups in Mayer’s circles often find themselves pushing back against what they see as unnecessarily restrictive policies.

“We make recommendations all the time,” says Mayer, “with the Crohn’s & Colitis Foundation pushing for quality indicators and global statements on therapies that insurance companies will have to pay attention to.”

Sometimes, the argument takes place right in the frontline of medicine.

“There’s not a day that goes by that I don’t have to argue to get prior authorization and face delays in getting the medicine I need,” says the immunologist. “The plan will say, ‘Well, the patient didn’t fail XYZ.’” But if you look at the literature, he says, you know that fistulizing CD is not going to respond well to 6-MP. “That’s a patient who needs to start with a more aggressive therapy to have an impact on the disease course, and the insurance companies won’t approve it. They [patients] may have to wait six months before they start treatment [with a biologic] and can become steroid dependent and have all sorts of prednisone effects.”

CIGNA’s coverage policy for infliximab for fistulizing CD doesn’t require a trial of another agent like 6-MP, notes Poniatowski.

“Don’t tell me how to practice medicine and what drugs to use,” says Mayer. “If a doctor doesn’t get a patient under control, and the patient winds up in a hospital, the financial fallout would be much worse.”


It’s not unusual to find doctors who challenge the guidelines that health plans establish for immunomodulators, say the pharmacy chiefs. But they argue there are strong scientific reasons for having policies in place outlining which therapies and doses should be used.

“All, or a majority, of these medications have a maximum dose that’s covered, based on the scientific evidence,” says Sherman at RegenceRx. “If the medications are not working, there’s a desire to try something that will work. The doctor may want to push the dose, even where there isn’t evidence or experience in doing so.

“We also see indication creep,” adds Sherman. “Doctors are requesting coverage of these medications for conditions without supportive scientific evidence.” An example, says Sherman, is a requests to use infliximab for asthma, Behcet’s disease, or chronic obstructive pulmonary disease, even though there’s no compelling scientific data to back it up.

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“It’s a bit like solving a Rubik’s Cube” when dealing with new immunomodulators, says Helen Sherman, PharmD, with RegenceRX. “We keep track of all the science and potential uses, but this is a complex category.”


“There are some pockets of specialists who are aggressive,” agrees Pete Marshall, PharmD, clinical pharmacy program manager for HealthPartners, based in Minneapolis. “Most rheumatologists, though, are pretty conservative. They prefer to use oral methotrexate first. But they may identify some patients with an aggressive disease” where biologics may be approved more quickly.

“When some patients don’t respond, providers then try increasing the dose. We see dose creep for CD, psoriasis, and RA. Adalimumab is approved for the standard dosing for RA— 40 mg every two weeks,” adds Marshall by way of an example. “If pharmacy has a claim for a higher dose, it would be rejected as not covered. We see it [dose creep] for etanercept and infliximab, as well. Certolizumab is newer, and I’m less familiar with dose creep on natalizumab,” he adds, which isn’t surprising given its link to a lethal brain infection — a red flag that keeps physicians particularly careful.

At CIGNA, “We would engage one of our medical directors to talk peer-to-peer,” says Poniatowski. “We’d look at the evidence and see what the guidelines say and what makes sense. There may be unique circumstances for that physician’s patient.”

“Some doctors just don’t want to bother with the older medications,” notes Marshall. “They go through the criteria, trying and failing methotrexate and declaring failure faster. It’s an irritant, but we’re allowing variations in practice. If it were more widespread, we’d be more aggressive.

Marshall doesn’t have any specific data on the frequency of off-label use, but he hazards a guess that it accounts for about 1 in 20 requests for biologic approvals. “Rituximab (Rituxan) is one example. It’s also approved for RA, and we see lots of creep for lupus. We would have our medical director review that.”

Drug developers in hot pursuit of oral immunomodulator approvals

The market for multiple sclerosis (MS) is dominated by a group of blockbuster interferon beta injectables like Avonex (Biogen Idec), Rebif (EMD Serono), and Betaseron (Schering/Berlex). But with analysts estimating that the global MS market will grow to $12.5 billion over the next five years, researchers have been in hot pursuit of a new generation of oral immunomodulators that can be just as effective, are easier to stay compliant with, and are possibly safer, as well.

Several new oral immunomodulating therapies are closing in on obtaining marketing approval. Last year, Merck KGaA pushed cladribine (Leustatin) into the lead of a hot race with Novartis’ FTY720 for first approval as an oral MS therapy. But it quickly fell behind its rival after the U.S. Food and Drug Administration unexpectedly handed back its marketing application, saying that it needed more work before the agency could properly consider it. Late last year, researchers for the German drug company unveiled new data showing that oral cladribine was far more effective than placebo in quelling flare-ups of the disease. Close to half the patients in two different dosing arms were symptom free for a two-year period, compared with only 16 percent of the patients taking a placebo. In a market that is now dominated by self-injectables, both of these big pharma companies are acutely aware of the blockbuster revenue that could be garnered from a pill that can swiftly grab a significant chunk of the market.

Cladribine, which has been on the market for hairy cell leukemia for the past decade, works along a clearly defined pathway: executing or blocking lymphocytes, which include specific immune cells that can trigger MS. But while suppressing the immune system can help ease symptoms and prevent relapses of MS, as with any immunomodulator, it also opens the door to various types of infections. Among cladribine patients in the late-stage study, 20 developed shingles, three developed cancer, and one experienced a tuberculosis flare-up that was probably worsened by the therapy.

Novartis FTY720 prevents lymphocytes from being released into the immune system. After testing the drug in 1,200 patients for two years, researchers concluded that a dose of the therapy lowered the rate of relapses by more than half. And, in another study, FTY720 performed better than Avonex. Novartis scientists tested two doses of FTY720 in late-stage clinical trials; at the higher dose, slightly more than one in 20 of all patients developed a herpes infection. There also were more respiratory infections as well as skin and breast cancer cases than the group taking Avonex.

Assessing the late-stage data and mechanisms of cladribine and FTY720, William M. Carroll, MB, BS, MD, concluded in an NEJM editorial1 early this year that the drugs offer “…a new horizon for patients with relapsing–remitting MS and a welcome increase in the range of treatment options. Although current therapies remain very effective, particularly when they are administered early and have well-defined side-effect profiles, oral therapies further support a change in treatment approach to directly prevent immune-mediated injury.”

Further back in the late-stage pipeline, sanofi-aventis hopes to wrap up a phase 3 clinical trial of oral teriflunomide later this year. This immunomodulator, used for treating rheumatoid arthritis, produced promising data last fall in its mid-stage trial of MS. The drug, matched with interferon, helps quell the proliferation of T- and B-cell lymphocytes and prevent flare-ups.

For experts in the field, the arrival of new first-line immunomodulators represents a major shift in the way patients can control the disease.

1Carroll WM. Oral therapy for multiple sclerosis—sea of change or incremental step? NEJM. 2010;362:456–458.

Sherman says RegenceRx has been dedicated to working with physicians in their region, particularly the specialists, to understand where RegenceRx is coming from. The steady attention has paid off. “Most physicians in the region are familiar with the policies. We do quite a bit of educating and getting input. Before we put in place utilization strategies like prior authorization or step therapy, we’ll e-mail them [physicians] the draft policies and get feedback. We get good uptake from that.”

Articles from Biotechnology Healthcare are provided here courtesy of MediMedia, USA