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.

The temporary withdrawal of natalizumab(Tysabri) from the market in February 2005 inresponse to 3 cases of progressive multifocalleukoencephalopathy (PML) among clinical trial participantswas a wake-up call for the neurology communityabout the risks of therapies for multiple sclerosis(MS). Although natalizumab returned to themarket under a restricted distribution program inJune 2006, the impact of the withdrawal remains evidentin the more guarded optimism now being expressedby clinicians and researchers about the agentand about other immunosuppressive therapies for relapsing-remitting MS (RRMS) in the absence of longtermsafety data.

Such caution was readily apparent at the annualmeeting of the American Academy of Neurology(AAN) that took place in Boston from April 28 to May5. Phase 2 trial results suggesting dramatic reductionsin relapse rates and disability associated with themonoclonal antibody alemtuzumab (Campath)1,2were offset by presentations on the risks of thyroidabnormalities3 and immune thrombocytopenic purpura(ITP)4 for patients taking the drug. Phase 2 trialevidence in support of another monoclonal antibody,rituximab (Rituxan),5 seemed somewhat less encouragingin light of the eerily familiar December alert issuedby the FDA regarding 2 cases of PML in patientswith systemic lupus erythematosus who had beentreated with the drug. In several symposia on MS therapy,speakers cited the therapeutic potential of otherimmunosuppressive agents but cautioned that it isstill too soon to know just what types of adverse effectsthe agents might have.

"We are looking . . . [at] some very exciting times forbeing able to treat these patients," said Elliot M. Frohman,MD, PhD, director of the Multiple Sclerosis Programand the Multiple Sclerosis Clinical Center at theUniversity of Texas Southwestern Medical Center inDallas, who spoke during a symposium titled "HotTopics in Multiple Sclerosis" at the AAN meeting."But we may be reaching the ceiling of our ability totreat patients without compromising surveillance," hesaid.

Not only must clinicians who treat patients with MSwrestle with the uncertainties about drug-relatedcomplications, they must do so on behalf of patientswho have a prognosis so daunting that they may bewilling to accept a high degree of risk in exchange fortherapeutic benefit. In an attempt to quantify patients'risk tolerance, researchers from the Cleveland Clinicsurveyed 128 patients who had planned to begin takingnatalizumab before its withdrawal. Because 2 ofthe aforementioned PML cases in natalizumab trialswere fatal, the survey focused on what patients consideredan acceptable risk of death in exchange for symptomrelief, delayed disease progression, or cure.6The survey results, presented at the AAN meeting,confirm what many neurologists have reported anecdotally.Although 18% of patients said that they wereunwilling to accept any risk of death, 14% said thatthey would accept a risk as high as 1-in-2 in exchangefor a cure. Patients in the Cleveland Clinic study saidthey would be willing to accept a risk of death of 1 in1000 in exchange for a two-thirds reduction in relapserate and a 42% slowing of disability rate, which werethe mean response rates that were reported in thephase 3 AFFIRM (Natalizumab Safety and Efficacy inRelapsing-Remitting MS) trial.7 Those who expressedthe highest levels of risk tolerance were those withhigh levels of disability, low self-reported quality oflife, and no dependents at home. The Cleveland Clinicstudy, of course, was focused on a single potentialcomplication of a particular drug in patients who hadreason to believe that the drug would help them;other patients with MS may have different levels ofrisk tolerance for other drugs associated with otheradverse effects. But physicians acknowledge that theydon't always see eye to eye with patients about whatconstitutes an acceptable level of risk.

"I think it depends on the patient's perception ofhow they're doing," said Patricia K. Coyle, MD, professorand acting chair of neurology at Stony BrookUniversity Medical Center and director of the StonyBrook Multiple Sclerosis Comprehensive Care Centerin Stony Brook, New York. "A patient with MS who isclearly deteriorating as far as she's concerned and isnot responding to treatment is generally willing totake greater risk than someone who is feeling well."

Since its withdrawal in 2005, natalizumab has come tosymbolize the risks associated with immunosuppressiveMS therapy-although interestingly, some researcherssuspect that the risk of PML associated withnatalizumab actually may not be related to diminishedimmunosurveillance.8 The FDA authorized thedrug's return to market in June 2006 under specificconditions.

Because the clinical trial in which PML developedin 2 patients involved combination natalizumab andinterferon beta 1a (IFN-β-1a, Avonex) therapy,9 natalizumabwas to be used solely as a monotherapy. Itwas approved only for use in patients who had failedor who were ineligible for first-line treatment with interferonsor glatiramer acetate (Copaxone), and it onlymay be used by physicians and patients who enrolledin the Tysabri Outreach: Unified Commitmentto Health (TOUCH) risk-management program,which emphasizes physician training, patient education,and periodic monitoring. Beyond the 3 cases thatled to the drug's withdrawal (1 of which occurred ina patient with Crohn disease rather than with MS),no additional cases of PML have been reported in patientstaking natalizumab.

Meanwhile, evidence of the drug's clinical benefitscontinues to accumulate. The AFFIRM trial investigatorsrecently reported10 on 2-year MRI outcomes forpatients taking natalizumab versus outcomes forthose taking placebo. This report provided more detailthan the initial report on the AFFIRM trial.

Among the more recent findings were a 76% decreasein number of new lesions that were hypointenseon T1-weighted scans relative to the number ofnew lesions in patients taking placebo, a 9.4% decreasein median T2-weighted hyperintense lesion volume(vs an 8.8% increase in the placebo group), and a23.5% decrease in median T1-weighted hypointenselesion volume (vs a 1.5% decrease in the placebogroup).

Researchers from the AFFIRM and SENTINEL(Safety and Efficacy of Natalizumab in Combinationwith Avonex) trials reported that natalizumab was associatedwith significantly reduced levels of visionloss.11 In the AFFIRM patient population, those takingnatalizumab were 35% less likely than those takingplacebo 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 studypopulation, the risk was reduced by 28% for those takingnatalizumab plus IFN-β-1a compared with thosetaking IFN-β-1a alone.

Further analysis of the AFFIRM vision data, presentedat the AAN meeting,12 found that even patientsconsidered treatment failures-those who experienced12 weeks of sustained disability progression asmeasured using the Expanded Disability StatusScale-were significantly less likely to suffer concurrentvision loss if they were treated with natalizumabthan with placebo.

The clinical benefits associated with natalizumab,in turn, improve patients' quality of life, according toanother analysis of both the AFFIRM and SENTINELdata presented at the AAN meeting.13 In the AFFIRMtrial, patients treated with natalizumab were significantlymore likely than those in the placebo group toexperience clinically important improvement (achange of 0.5 SDs) on the physical component summaryof the Short Form-36 (SF-36) health survey after104 weeks. In the SENTINEL trial, those who receivedcombination therapy were more likely to experience asimilar degree of improvement than those treatedwith IFN-β-1a alone. Natalizumab also was associatedwith trends toward significant improvement on themental component summary of the SF-36. Contributingto improvements in quality of life may be issues ofconvenience; natalizumab is administered only onceper month, whereas other drugs require several injectionsor more per week.

Still, despite all of the positives, any professionaldiscussion of natalizumab inevitably returns to therisk of PML-which is of particular concern becausethe differential diagnosis of PML in patients with MSis so difficult.

"PML produces lesions of brain and neurologicalabnormalities that can be very hard to sort out fromMS, at least early on," Coyle said.

Frohman, for one, said he does not consider natalizumabto be the best treatment option for patients whohave 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 treatthem with this drug?"

Of the drugs currently FDA-approved for RRMS, theone that is often included with natalizumab in discussionsabout risk and benefit is the chemotherapeuticagent mitoxantrone, which was approved in June 1999for treatment of worsening RRMS and in October 2000for secondary progressive MS. Because of risks of cardiotoxicity,myelosuppression, and leukemia, dosingwith mitoxantrone must be limited to 140 mg/m2,which is the equivalent of 2 to 3 years of therapy.14Recent therapeutic approaches have involved combiningmitoxantrone with glatiramer acetate to, in part,reduce the mitoxantrone dose, thus reducing the riskof complications.15,16 A multicenter team of researchersfrom Montreal; Phoenix; and Burlington, Vermont, reportedthat patients who received 3 monthly infusionsof mitoxantrone (36 mg/m2 total) followed by 12.5months of daily dosing with glatiramer acetate experienceda 70% decrease in gadolinium-enhancing lesionson MRI at 15 months compared with patients who weretreated with glatiramer acetate alone. However, researchersand clinicians are somewhat wary of combinationtherapies for MS because both PML cases in thenatalizumab trials occurred in patients receiving combinationtherapy, and MS in patients treated withatorvastatin (Lipitor) in combination with subcutaneousIFN-β-1a (Rebif) unexpectedly worsened, whichwas reported at the AAN meeting.17

Infertility is another concern when treating patientswith chemotherapeutic agents such as mitoxantrone oroff-label cyclophosphamide, particularly because patientswith MS tend to be relatively young when thediagnosis is made. Interventions such as cryopreservationof sperm or embryos are viable options but needto be part of the overall treatment plan, according toMichael Glantz, MD, associate professor of neurologyat the University of Massachusetts in Worcester, whospoke at an AAN symposium on immunosuppressivetherapy for demyelinating disease.

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

Taking at least some of the attention away from natalizumabin the risk-benefit discussion are the recent incidencesof adverse events associated with the monoclonalagents alemtuzumab and rituximab. Alemtuzumabwas approved by the FDA in May 2001 fortreatment of B-cell chronic lymphocytic leukemia. TheCAMMS223 phase 2 trial of alemtuzumab in patientswith RRMS was suspended in September 2005 after 3cases of ITP-characterized by low platelet counts andincreased risk of hemorrhage-were diagnosed; subsequentscreening by the study investigators identified3 more patients with the disorder. The first patientin whom ITP developed did not seek treatment for 2weeks despite experiencing symptoms and ultimatelydied, but the other 5 cases resolved successfully, accordingto Herman Sullivan, MD, a neurologist withMichigan Medical in Grand Rapids, who describedthe trial's ITP screening and treatment protocols at theAAN meeting.4 Four of the 5 patients were treatedwith corticosteroids, while the fifth received no treatment;as of early May, all had been stable for 5 to 13months.

CAMMS223 researchers also found that thyroidrelatedadverse events at 2 years occurred in 11.1% ofpatients treated with alemtuzumab but only in 1.9% ofthose treated with IFN-β-1a.3 However, the 2-yearrates of thyroid-related complications were muchlower than in previous studies, in which antibodiesagainst the thyrotropin receptor and autoimmune hyperthyroidismdeveloped in as many as a third of patientsat 18 months.18

As with natalizumab, the risk of potentially fatalcomplications associated with alemtuzumab offsetwhat were otherwise extremely encouraging clinicaltrial results initially presented this past September atthe 22nd Congress of the European Committee forTreatment and Research in Multiple Sclerosis inMadrid and presented again at the AAN meeting.1 In334 treatment-naive patients with RRMS, those treatedwith alemtuzumab had a 75% lower risk of relapseand a 65% lower risk of sustained disability at 2 yearscompared with those treated with IFN-β-1a.

In an open-label, single-arm study of patients withRRMS in whom interferon treatment had failed, EdwardJ. Fox, MD, PhD, director of the MS Clinic of CentralTexas in Austin, and colleagues found that 71.7% ofpatients were relapse-free at 2 years, and the annualizedrelapse rate dropped from 1.6 for the 2 years precedingthe study to 0.2 at the 2-year follow-up.2

In terms of convenience, alemtuzumab is evenmore attractive than natalizumab. Dosing regimens intrials have involved an initial 5-day course of daily injectionsfollowed by a 3-day course 1 year later.

"It's given for a couple of days, and then you don'tgive 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 comparedwith a very active agent. But there isn't a hugeexperience with long-term treatment."

The monoclonal agent rituximab, which is FDAapprovedfor treatment of non-Hodgkin lymphomaand for refractory rheumatoid arthritis, took a hit inthe public relations department in December with therelease of an FDA warning following 2 deaths fromPML in patients with systemic lupus erythematosuswho were being treated with the drug. However, perhapsbecause of physicians' lengthy experience withrituximab for other indications, the warning has doneless to distract from the drug's potential benefits fortreating MS than might have been expected.

Those potential benefits were described at the AANmeeting by Stephen Hauser, MD, professor and chairmanof neurology at the University of California SanFrancisco. In a phase 2 trial, Hauser and colleaguesfound that the 69 patients with RRMS treated with rituximabhad a 91% reduction in gadolinium-enhancinglesions on MRI and a 58% reduction in relapse raterelative to the 35 patients treated with placebo.5 Butwith a humanized version of the chimeric rituximabprojected to be available by 2009, the relative risks andbenefits of rituximab may ultimately be less importantthan those of some other agents currently in trials.

In the next generation of MS drugs, oral formulationsare most likely to appeal to patients because of theirconvenience. Recent studies of 2 oral MS drugs, fingolimodand fumarate, were mixed in relation to bothsides of the risk-benefit equation.

A 255-patient, European multicenter proof-of-conceptstudy published last fall in the New England Journalof Medicine19 reported that the annualized relapserate for patients with RRMS treated with 1.25 mg/d or5 mg/d of fingolimod for 6 months was about halfthat for patients given placebo. The median total numberof gadolinium-enhancing lesions on MRI in bothdosage groups also was significantly lower than in theplacebo group. However, 2 serious infections were reportedin the active-treatment groups, and 1 patient inthe high-dose group developed posterior reversibleencephalopathy syndrome. Fingolimod also was associatedwith increased alanine aminotransferase levelsand a transient decline in heart rate of several hours'duration following the first dose.

The oral fumarate agent BG-12 has relatively fewsafety concerns, but its phase 2 efficacy data are lessremarkable than some other MS agents in development.In a European trial in which 257 patients withRRMS were randomly selected to receive 1 of 3 dosesof oral fumarate or placebo, the most common adverseevents in the treatment groups were flushing, GI disorders,headache, and nasopharyngitis.20 The 64 patientswho received the highest dose (240 mg, 3 timesdaily) had a 69% reduction in the mean number ofnew gadolinium-enhancing lesions on MRI and a 48%reduction in new or enlarging T2-weighted hyperintenselesions at 6 months compared with patientswho received placebo.21 The researchers also reporteda 32% reduction in relapse rates for the high-dosegroup compared with the placebo group, but that differencewas not statistically significant.

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

Unfortunately for clinicians already dealing with thechallenges of managing this heterogeneous patientpopulation, there appears to be no single right answerto the risk-benefit equation. Fortunately, the most effectivemeans of finding the right answer for each patientinvolves a skill that also pays dividends in otheraspects of MS care: communication.

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

Because there is a limit to the frequency with whicha patient can realistically be screened for potential adverseevents, educating patients about the risks associatedwith any treatment and maintaining an openline of communication helps maximize the chance thatpotentially serious symptoms will be reported and addressedearly. Including a family member or othercaregiver in discussions also can be helpful.

"You definitely need the patient's input," said AnjaliShah, MD, assistant professor of neurology andphysical medicine and rehabilitation at the Universityof Texas Southwestern Medical School and directorof multiple sclerosis neurorehabilitation at the MultipleSclerosis Clinical Center in Dallas. "An office visitis sterile. You're not seeing the patient at home, or atwork," she said.

Clinicians who can clearly explain their professionalopinions about the risks and benefits of a particulartherapy also can help keep patients' expectations incheck. But being sensitive to the patient's perspectiveis important too. "They're the ones who have the disease,"Shah said. "I never close the door but insteadtry to propose a stepwise approach."




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