Trying Times: Factoring Risk-Benefit Equations into MS Therapeutics

The temporary withdrawal of natalizumab (Tysabri) from the market in February 2005 in response to 3 cases of progressive multifocal leukoencephalopathy (PML) among clinical trial participants was a wake-up call for the neurology community about the risks of therapies for multiple sclerosis (MS). Although natalizumab returned to the market under a restricted distribution program in June 2006, the impact of the withdrawal remains evident in the more guarded optimism now being expressed by clinicians and researchers about the agent and about other immunosuppressive therapies for relapsing- remitting MS (RRMS) in the absence of longterm safety data.

Such caution was readily apparent at the annual meeting of the American Academy of Neurology (AAN) that took place in Boston from April 28 to May 5. Phase 2 trial results suggesting dramatic reductions in relapse rates and disability associated with the monoclonal antibody alemtuzumab (Campath)^1,2 were offset by presentations on the risks of thyroid abnormalities³ and immune thrombocytopenic purpura (ITP)⁴ for patients taking the drug. Phase 2 trial evidence in support of another monoclonal antibody, rituximab (Rituxan),⁵ seemed somewhat less encouraging in light of the eerily familiar December alert issued by the FDA regarding 2 cases of PML in patients with systemic lupus erythematosus who had been treated with the drug. In several symposia on MS therapy, speakers cited the therapeutic potential of other immunosuppressive agents but cautioned that it is still too soon to know just what types of adverse effects the agents might have.

"We are looking down the barrel of some very exciting times for being able to treat these patients," said Elliot M. Frohman, MD, PhD, director of the Multiple Sclerosis Program and the Multiple Sclerosis Clinical Center at the University of Texas Southwestern Medical Center in Dallas, who spoke during a symposium titled "Hot Topics in Multiple Sclerosis" at the AAN meeting. "But we may be reaching the ceiling of our ability to treat patients without compromising surveillance."

RISKY BUSINESS

Not only must clinicians who treat patients with MS wrestle with the uncertainties about drug-related complications, they must do so on behalf of patients who have a prognosis so daunting that they may be willing to accept a high degree of risk in exchange for therapeutic benefit. In an attempt to quantify patients' risk tolerance, researchers from the Cleveland Clinic surveyed 128 patients who had planned to begin taking natalizumab before its withdrawal. Because 2 of the aforementioned PML cases in natalizumab trials were fatal, the survey focused on what patients considered an acceptable risk of death in exchange for symptom relief, delayed disease progression, or cure.⁶ The survey results, presented at the AAN meeting, confirm what many neurologists have reported anecdotally. Although 18% of patients said that they were unwilling to accept any risk of death, 14% said that they would accept a risk as high as 1-in-2 in exchange for a cure. Patients in the Cleveland Clinic study said they would be willing to accept a risk of death of 1 in 1000 in exchange for a two-thirds reduction in relapse rate and a 42% slowing of disability rate, which were the mean response rates that were reported in the phase 3 AFFIRM (Natalizumab Safety and Efficacy in Relapsing-Remitting MS) trial.⁷ Those who expressed the highest levels of risk tolerance were those with high levels of disability, low self-reported quality of life, and no dependents at home. The Cleveland Clinic study, of course, was focused on a single potential complication of a particular drug in patients who had reason to believe that the drug would help them; other patients with MS may have different levels of risk tolerance for other drugs associated with other adverse effects. But physicians acknowledge that they don't always see eye to eye with patients about what constitutes an acceptable level of risk.

"I think it depends on the patient's perception of how they're doing," said Patricia K. Coyle, MD, professor and acting chair of neurology at Stony Brook University Medical Center and director of the Stony Brook Multiple Sclerosis Comprehensive Care Center in Stony Brook, New York. "A patient with MS who is clearly deteriorating as far as she's concerned and is not responding to treatment is generally willing to take greater risk than someone who is feeling well."

NEW RULES FOR NATALIZUMAB

Since its withdrawal in 2005, natalizumab has come to symbolize the risks associated with immunosuppressive MS therapy—although interestingly, some researchers suspect that the risk of PML associated with natalizumab actually may not be related to diminished immunosurveillance.⁸ The FDA authorized the drug's return to market in June 2006 under specific conditions.

Because the clinical trial in which PML developed in 2 patients involved combination natalizumab and interferon beta 1a (IFN-ß-1a, Avonex) therapy,⁹ natalizumab was to be used solely as a monotherapy. It was approved only for use in patients who had failed or who were ineligible for first-line treatment with interferons or glatiramer acetate (Copaxone), and it only may be used by physicians and patients who enrolled in the Tysabri Outreach: Unified Commitment to Health (TOUCH) risk-management program, which emphasizes physician training, patient education, and periodic monitoring. Beyond the 3 cases that led to the drug's withdrawal (1 of which occurred in a patient with Crohn disease rather than with MS), no additional cases of PML have been reported in patients taking natalizumab.

Meanwhile, evidence of the drug's clinical benefits continues to accumulate. The AFFIRM trial investigators recently reported¹⁰ on 2-year MRI outcomes for patients taking natalizumab versus outcomes for those taking placebo. Among the more recent findings were a 76% decrease in number of new lesions that were hypointense on T1-weighted scans relative to the number of new lesions in patients taking placebo, a 9.4% decrease in median T2-weighted hyperintense lesion volume (vs an 8.8% increase in the placebo group), and a 23.5% decrease in median T1-weighted hypointense lesion volume (vs a 1.5% decrease in the placebo group).

Researchers from the AFFIRM and SENTINEL (Safety and Efficacy of Natalizumab in Combination with Avonex) trials reported that natalizumab was associated with significantly reduced levels of vision loss.¹¹ In the AFFIRM patient population, those taking natalizumab were 35% less likely than those taking placebo to experience clinically significant vision loss (defined as a 2-line worsening of visual acuity score) at a contrast level of 1.25%. In the SENTINEL study population, the risk was reduced by 28% for those taking natalizumab plus IFN-ß-1a compared with those taking IFN-ß-1a alone.

Further analysis of the AFFIRM vision data, presented at the AAN meeting,¹² found that even patients considered treatment failures—those who experienced 12 weeks of sustained disability progression as measured using the Expanded Disability Status Scale—were significantly less likely to suffer concurrent vision loss if they were treated with natalizumab rather than placebo.

The clinical benefits associated with natalizumab, in turn, improve patients' quality of life, according to another analysis of both the AFFIRM and SENTINEL data presented at the AAN meeting.¹³ In the AFFIRM trial, patients treated with natalizumab were significantly more likely than those in the placebo group to experience clinically important improvement (a change of 0.5 SDs) on the physical component summary of the Short Form-36 (SF-36) health survey after 104 weeks. In the SENTINEL trial, those who received combination therapy were more likely to experience a similar degree of improvement than those treated with IFN-ß-1a alone. Natalizumab also was associated with trends toward significant improvement on the mental component summary of the SF-36. Contributing to improvements in quality of life may be issues of convenience; natalizumab is administered only once per month, whereas other drugs require several injections or more per week.

Still, despite all of the positives, any professional discussion of natalizumab inevitably returns to the risk of PML—which is of particular concern because the differential diagnosis of PML in patients with MS is so difficult.

"PML produces lesions of brain and neurological abnormalities that can be very hard to sort out from MS, at least early on," Coyle said.

Frohman, for one, said he does not consider natalizumab to be the best treatment option for patients who have failed interferons or glatiramer acetate.

"I'm very cautious," he said. "I have to ask myself, if this were my wife or my daughter, would I treat them with this drug?"

CHEMOTHERAPEUTIC CONSIDERATIONS

Of the drugs currently FDA-approved for RRMS, the one that is often included with natalizumab in discussions about risk and benefit is the chemotherapeutic agent mitoxantrone, which was approved in June 1999 for treatment of worsening RRMS and in October 2000 for secondary progressive MS. Because of risks of cardiotoxicity, myelosuppression, and leukemia, dosing with mitoxantrone must be limited to 140 mg/m2, which is the equivalent of 2 to 3 years of therapy.14 Recent therapeutic approaches have involved combining mitoxantrone with glatiramer acetate to, in part, reduce the mitoxantrone dose, thus reducing the risk of complications.^15,16 A multicenter team of researchers from Montreal; Phoenix; and Burlington, Vermont, reported that patients who received 3 monthly infusions of mitoxantrone (36 mg/m2 total) followed by 12.5 months of daily dosing with glatiramer acetate experienced a 70% decrease in gadolinium-enhancing lesions on MRI at 15 months compared with patients who were treated with glatiramer acetate alone. However, researchers and clinicians are somewhat wary of combination therapies for MS because both PML cases in the natalizumab trials occurred in patients receiving combination therapy, and MS in patients treated with atorvastatin (Lipitor) in combination with subcutaneous IFN-ß-1a (Rebif) unexpectedly worsened, which was reported at the AAN meeting.¹⁷

Infertility is another concern when treating patients with chemotherapeutic agents such as mitoxantrone or off-label cyclophosphamide, particularly because patients with MS tend to be relatively young when the diagnosis is made. Interventions such as cryopreservation of sperm or embryos are viable options but need to be part of the overall treatment plan, according to Michael Glantz, MD, associate professor of neurology at the University of Massachusetts in Worcester, who spoke at an AAN symposium on immunosuppressive therapy for demyelinating disease.

"Because fertility intervention delays treatment, it's important to talk about it early on," Glantz said.

CAUTION FROM CAMMS223

Taking at least some of the attention away from natalizumab in the risk-benefit discussion are the recent incidences of adverse events associated with the monoclonal agents alemtuzumab and rituximab. Alemtuzumab was approved by the FDA in May 2001 for treatment of B-cell chronic lymphocytic leukemia. The CAMMS223 phase 2 trial of alemtuzumab in patients with RRMS was suspended in September 2005 after 3 cases of ITP—characterized by low platelet counts and increased risk of hemorrhage—were diagnosed; subsequent screening by the study investigators identified 3 more patients with the disorder. The first patient in whom ITP developed did not seek treatment for 2 weeks despite experiencing symptoms and ultimately died, but the other 5 cases resolved successfully, according to Herman Sullivan, MD, a neurologist with Michigan Medical in Grand Rapids, who described the trial's ITP screening and treatment protocols at the AAN meeting.⁴ Four of the 5 patients were treated with corticosteroids, while the fifth received no treatment; as of early May, all had been stable for 5 to 13 months.

CAMMS223 researchers also found that thyroidrelated adverse events at 2 years occurred in 11.1% of patients treated with alemtuzumab but only in 1.9% of those treated with IFN-ß-1a.³ However, the 2-year rates of thyroid-related complications were much lower than in previous studies, in which antibodies against the thyrotropin receptor and autoimmune hyperthyroidism developed in as many as a third of patients at 18 months.¹⁸

As with natalizumab, the risk of potentially fatal complications associated with alemtuzumab offset what were otherwise extremely encouraging clinical trial results initially presented this past September at the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis in Madrid and presented again at the AAN meeting.¹ In 334 treatment-naive patients with RRMS, those treated with alemtuzumab had a 75% lower risk of relapse and a 65% lower risk of sustained disability at 2 years compared with those treated with IFN-ß-1a.

In an open-label, single-arm study of patients with RRMS in whom interferon treatment had failed, Edward J. Fox, MD, PhD, director of the MS Clinic of Central Texas in Austin, and colleagues found that 71.7% of patients were relapse-free at 2 years, and the annualized relapse rate dropped from 1.6 for the 2 years preceding the study to 0.2 at the 2-year follow-up.²

In terms of convenience, alemtuzumab is even more attractive than natalizumab. Dosing regimens in trials have involved an initial 5-day course of daily injections followed by a 3-day course 1 year later.

"It's given for a couple of days, and then you don't give it again for a year, which is pretty doggone convenient," Coyle said. "The phase 2 trial had good results, with low rates of relapse and disability compared with a very active agent. But there isn't a huge experience with long-term treatment."

PML REVISITED

The monoclonal agent rituximab, which is FDAapproved for treatment of non-Hodgkin lymphoma and for refractory rheumatoid arthritis, took a hit in the public relations department in December with the release of an FDA warning following 2 deaths from PML in patients with systemic lupus erythematosus who were being treated with the drug. However, perhaps because of physicians' lengthy experience with rituximab for other indications, the warning has done less to distract from the drug's potential benefits for treating MS than might have been expected.

Those potential benefits were described at the AAN meeting by Stephen Hauser, MD, professor and chairman of neurology at the University of California San Francisco. In a phase 2 trial, Hauser and colleagues found that the 69 patients with RRMS treated with rituximab had a 91% reduction in gadolinium-enhancing lesions on MRI and a 58% reduction in relapse rate relative to the 35 patients treated with placebo.⁵ But with a humanized version of the chimeric rituximab projected to be available by 2009, the relative risks and benefits of rituximab may ultimately be less important than those of some other agents currently in trials.

ORAL FIXATIONS

In the next generation of MS drugs, oral formulations are most likely to appeal to patients because of their convenience. Recent studies of 2 oral MS drugs, fingolimod and fumarate, were mixed in relation to both sides of the risk-benefit equation.

A 255-patient, European multicenter proof-of-concept study published last fall in the New England Journal of Medicine¹⁹ reported that the annualized relapse rate for patients with RRMS treated with 1.25 mg/d or 5 mg/d of fingolimod for 6 months was about half that for patients given placebo. The median total number of gadolinium-enhancing lesions on MRI in both dosage groups also was significantly lower than in the placebo group. However, 2 serious infections were reported in the active-treatment groups, and 1 patient in the high-dose group developed posterior reversible encephalopathy syndrome. Fingolimod also was associated with increased alanine aminotransferase levels and a transient decline in heart rate of several hours' duration following the first dose.

The oral fumarate agent BG-12 has relatively few safety concerns, but its phase 2 efficacy data are less remarkable than some other MS agents in development. In a European trial in which 257 patients with RRMS were randomly selected to receive 1 of 3 doses of oral fumarate or placebo, the most common adverse events in the treatment groups were flushing, GI disorders, headache, and nasopharyngitis.²⁰ The 64 patients who received the highest dose (240 mg, 3 times daily) had a 69% reduction in the mean number of new gadolinium-enhancing lesions on MRI and a 48% reduction in new or enlarging T2-weighted hyperintense lesions at 6 months compared with patients who received placebo.²¹ The researchers also reported a 32% reduction in relapse rates for the high-dose group compared with the placebo group, but that difference was not statistically significant.

Two phase 3 trials of BG-12 are currently ongoing: one in which patients will be randomly selected to receive either BG-12 or placebo, and another in which patients also will be randomly selected to receive glatiramer acetate.

NEVER CLOSE THE DOOR

Unfortunately for clinicians already dealing with the challenges of managing this heterogeneous patient population, there appears to be no single right answer to the risk-benefit equation. Fortunately, the most effective means of finding the right answer for each patient involves a skill that also pays dividends in other aspects of MS care: communication.

"I believe in an informed patient," Coyle said. "The more knowledgeable the patient, the better."

Because there is a limit to the frequency with which a patient can realistically be screened for potential adverse events, educating patients about the risks associated with any treatment and maintaining an open line of communication helps maximize the chance that potentially serious symptoms will be reported and addressed early. Including a family member or other caregiver in discussions also can be helpful.

"You definitely need the patient's input," said Anjali Shah, MD, assistant professor of neurology and physical medicine and rehabilitation at the University of Texas Southwestern Medical School and director of multiple sclerosis neurorehabilitation at the Multiple Sclerosis Clinical Center in Dallas. "An office visit is sterile. You're not seeing the patient at home, or at work."

Clinicians who can clearly explain their professional opinions about the risks and benefits of a particular therapy also can help keep patients' expectations in check. But being sensitive to the patient's perspective is important too. "They're the ones who have the disease," Shah said. "I never close the door but instead try to propose a stepwise approach."

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