Despite Slow Start, RA Specialists See Place for Tofacitinib in the Formulary

Factors ranging from limited perceived advantage to limited geographic availability have prevented the rheumatoid arthritis (RA) treatment tofacitinib (Xeljanz) from becoming the sort of immediate hit that many expected. Even now that analysts have halved their initial forecasts of peak annual revenues around $3 billion,1,2 the drug continues to disappoint Wall Street.

Total sales for the most recent quarter, the fourth quarter of 2013, were just $45 million. But those RA specialists who have accumulated some experience with tofacitinib paint a far brighter picture, a picture of a drug that, while not revolutionary, gives doctors a valuable and versatile new tool that may eventually help a fair number of patients. “Because RA is such a complex and

heterogeneous disease, different treatment regimens work best on individual patients and, quite often, the best treatment regimen combines multiple therapies that attack the disease in different ways,” said Clifton O. Bingham III, MD, associate professor of medicine and director of the Johns Hopkins Arthritis Center in Baltimore, Maryland.“Tofacitinib is a first-in-class therapy that uses a somewhat different mechanism of action than anything else on the market. It gives patients another option, and options are valuable.”

Tofacitinib works primarily by inhibiting Janus kinase enzymes, which are coupled with inflammatory pathways in the joints. The US Food and Drug Administration (FDA) approved a 5-mg, twice-daily dosage late in 2012 for adults with moderate to severely active RA who respond poorly to methotrexate. Tofacitinib’s disappointing sales stem in part from its performance in clinical

trials. Those trials, some of which used nonbiologic disease-modifying antirheumatic drugs for their control arm and some of which used the TNF inhibitor adalimumab, conclusively showed that tofacitinib reduces pain and improves function in most RA patients.1

They did not, however, show that it does so any better—or worse—than nearly a dozen biological competitors. (Tofacitinib tends to get grouped with the biologics even though it’s a small molecule pill rather than an injectable protein, mostly because its mechanisms of action and side effects are similar to those of a biologic.) Performance, in other words, appeared merely comparable to other biological agents currently in use, giving doctors and patients no strong reason to switch from familiar brands.

Still, even without compelling proof that tofacitinib is better than competing medications, specialists like Bingham say the drug deserves consideration, particularly for patients who fare poorly on other biological medications. “The real question, when you’re treating individual patients, isn’t whether one drug performs better on a large cohort than other drugs, but whether it can help the patient in front of you more than another drug,” Bingham said. “Our experience here shows that tofacitinib works for some patients who do not respond well to other medications, so physicians should certainly consider it as an option, either as a replacement for or an addition to other treatments, when those treatments have a less than satisfactory effect.”

The latest data from Pfizer show that more doctors are, indeed, beginning to consider tofacitinib as an option. Sales increased 29% between last year’s third and fourth quarters. Pfizer notes that it has already submitted follow-up material that has allowed it to twice expand tofacitinib’s label, once with additional data on health-related outcomes and once with additional data on the inhibition of the progress of structural damage. Moreover, “Physician feedback has been very positive,” said Victoria Davis, a spokeswoman for the company. “Nearly 3500 healthcare professionals have tried Xeljanz and nearly 80% have repeated prescribing.”

But physicians who do consider prescribing tofacitinib will sometimes find that their patients face obstacles from insurers. Policies vary from state to state, company to company, and plan to plan. Some insurers appear to approve coverage for any prescription. Some mandate, at the very least, that patients try other medications first. The wholesale acquisition cost for tofacitinib totals about $25,000 a year.

That’s about 7% cheaper than the wholesale price of the competing treatments that some insurers prefer,2 but insurers often negotiate discounts that alter relative costs. Another insurance consideration is the nature of the treatment. Tofacitinib is a pill. Some of its competitors are infusions that require a medical facility. Some insurers, such as Medicare, treat them very differently.

Pfizer may be able to remove some of the financial obstacles to tofacitinib’s popularity by negotiating with payers, but the company has struggled to find such an easy way to overcome concerns about safety.

In Europe, regulators have twice recommended against the drug after reviewing data from 5 studies of more than 3300 RA patients and deciding that tofacitinib’s benefits did not outweigh the combination of short-term side effects and uncertain long-term risks.3 Use of the drug in trials was associated with increased risk of serious infections, cancer, elevated cholesterol, decreased blood counts, changes in liver enzyme tests, and a host of more common but less dangerous complaints: upper respiratory tract infections, headache, diarrhea, and inflammation of the nasal passage and the upper part of the pharynx, which are also common for other biological agents.

Davis, the Pfizer spokeswoman, said the company is still evaluating the feedback it received from European regulators to formulate its plan for resubmitting the drug to the European Medicines Agency. In the United States, the FDA approved tofacitinib on the condition that Pfizer conduct a postmarketing study that will evaluate the long-term effects of both 5-mg and 10-mg doses on heart disease, cancer, and serious infections. The FDA approval also requires a boxed warning that briefly highlights the risks to patients and a risk evaluation and mitigation strategy (REMS) that includes a medication guide for patients and a multipronged campaign to inform healthcare providers about the serious risks associated with the drug.4The impact of such warnings, however, is likely muted by the similar warnings and side effects that accompany other RA drugs.

Take, for example, the biologic response modifiers, drugs such as adalimumab (Humira), that are human proteins designed to inhibit inflammation-causing components of the immune system. Such drugs have become a mainstay of RA treatment despite increasing the risk of serious infection and the risk that dormant chronic diseases will flare up. Indeed, Humira—which is indicated for a wide variety of conditions—generates $10 billion a year in revenues despite the risk of such side effects.

Another mainstay RA treatment, methotrexate, can (rarely) cause serious side effects from bone marrow suppression to liver failure (though hair loss and mouth ulcers are far more common).

Steroids, moreover, cause cataracts, bone thinning, high blood pressure, and increased risk of infection, even at low does.

Still, nearly everyone with RA chooses to take at least 1 of these medications and, quite often, several. Simply put, the disease subjects patients to enough discomfort and disability that they’re willing to endure side effects in exchange for relief.

Tofacitinib, despite similar short-term side effects from other biologicals and unknown long-term safety, actually seems less “scary” to many patients than much of the competition, some doctors report, because it comes from a pill bottle rather than an injection or an infusion. Overall, about 1.5 million Americans have RA, an autoimmune disease that results in chronic, systematic inflammation, particularly around the joints.5 Onset can occur at any age but is more common at middle age. About half the risk for the disease, which afflicts 2 to 3 times as many women as men, is believed to be genetic. Although the biggest nongenetic risk appears to be smoking (RA is up to 3 times as common in smokers), much remains unknown about the cause.

Therapeutic regimes, for many years, centered on non-steroidal anti-inflammatory drugs (NSAIDs) and steroids, both of which reduce pain and increase mobility but do not slow the progression of the disease. Methotrexate, an antifolate approved for RA patients in 1988, became the cornerstone of treatment when studies proved that it slowed progression of the disease. Most treatment regimens for RA combine methotrexate with other agents.

About a decade later came etanercept (Enbrel), the first of the biologics, another major class of medications that treated symptoms and slowed disease progression as well. The sheer number of medications approved to treat RA, combined with the variety of ways in which different patients respond to different medications, has led to an enormous proliferation of treatment regimens.

Most patients, at the very least, take either methotrexate or one of the biologics to slow the progression of the disease. Some take 1 medication as monotherapy. A few patients at the other end of the spectrum may require a combination of methotrexate, a biologic, an NSAID, a steroid, an antidepressant, and an opioid. Nutritional, physical, and occupational therapy are also common components of treatment.

A typical therapeutic regimen includes a handful of these elements, though doctors have been turning away from NSAIDs in recent years due to growing concerns about gastrointestinal bleeding and cardiovascular disease. Opioids, likewise, have become increasingly controversial. There’s no proof that most of them relieve chronic RA pain, they certainly don’t slow the progression of the disease, and agencies from every level of government have stepped up efforts to curb opioid abuse in recent years. When American regulators approved tofacitinib in 2012, they explicitly approved it for use as either monotherapy or for use with methotrexate. Anecdotes report it being used in both ways, often by the same doctor, depending on how individual patients respond.

“The ideal is to find the sweet spot that maximizes function while minimizing disease progression, pain, and side effects,” said Roy Fleischmann, MD, MACR, clinical professor of medicine at University of Texas Southwestern Medical Center, and medical director, Metroplex Clinical Research Center. “When people come to my office, they are generally in a lot of pain, and the first thing we do is control the pain with a comprehensive regimen. Then we start subtracting components. If the pain gets worse, we restore whatever we took out. If not, we leave it out. Some of our patients who respond to tofacitinib do better when they take methotrexate as well. Some do just as well without it.”

Fleischmann, who participated in several tofacitinib trials, said his real world experiences have been exactly what the trials led him to expect. Severe side effects have actually been less common than trial results would predict, but Fleischmann says this is almost certainly explained by the size of his sample population rather than by any tendency of the trials to overestimate adverse events. Among Fleischmann’s patients, tofacitinib has induced responses not only in a majority of patients who failed on methotrexate but also in a majority of patients who failed on other biologics.

For patients who respond, DAS-28 scores have generally dropped 2.5 to 3 points, said Fleischmann, who noted that biologics provide similar levels of relief for patients who respond. Such an improvement constitutes a nearremission for someone who starts with moderate RA (DAS score 4 or 4.5) and about a 50% reduction in pain for someone who begins with a relatively severe case (DAS score 6 or 7). “We haven’t seen any pattern in who responds and who doesn’t, not during the clinical trials and not in normal practice,” Fleischmann said.

How does he choose between biologics and tofacitinib? “I go over all the information and the patient chooses,” he said. “Sometimes it comes down to insurance coverage. Sometimes it comes down to the preference between a twice-daily pill, a weekly self-injection, or a monthly IV. Sometimes it comes down to whether a patient is comfortable with a medication that lacks a long-term safety record. Those are the issues to decide on. The efficacy is comparable.”