<?xml version="1.0" encoding="utf-8"?>
<recommendedContent xmlns="http://api.mspoke.com">
    <recommendedItem id="20100101_19_425"
                     title="AAN: Industrial Cleaner Again Tied to Parkinson Risk (CME/CE)"
                     score="0.015"
                     href="http://www.medpagetoday.com/MeetingCoverage/AAN/tb/18338?impressionId=1265777328521"
                     
      TORONTO  --  The degreasing agent trichloroethylene (TCE) has been linked to increased rates of Parkinson&apos;s disease among industrial workers in yet another study, this time involving a large, well-studied group of World War II veterans.&lt;br&gt;
&lt;br&gt;Parkinson&apos;s disease developed in individuals with occupational exposure to TCE at more than five times the rate seen in those without such exposure (odds ratio 5.5, 95% CI 1.02 to 30), reported Samuel Goldman, MD, of the Parkinson&apos;s Institute in Sunnyvale, Calif.&lt;br&gt;
&lt;br&gt;Goldman described the research in a phone interview with &lt;em&gt;MedPage Today&lt;/em&gt;. It&apos;s scheduled for presentation here in April at the American Academy of Neurology&apos;s annual meeting.&lt;br&gt;
&lt;br&gt;A previous study in 2008 had fingered TCE as the most likely culprit behind a cluster of Parkinson&apos;s disease cases afflicting workers at a single industrial plant. (See &lt;a href=&quot;http://www.medpagetoday.com/Geriatrics/ParkinsonsDisease/7894&quot; mce_href=&quot;http://www.medpagetoday.com/Geriatrics/ParkinsonsDisease/7894&quot; target=&quot;_blank&quot;&gt;Trichloroethylene Implicated as Risk for Parkinsonism&lt;/a&gt;)&lt;p&gt;&lt;/p&gt;
&lt;p&gt;Also, Goldman said, animal studies have found that TCE is selectively toxic to nigral dopaminergic neurons, the same type of nerve cell that progressively dies off in Parkinson&apos;s disease. He said the chemical&apos;s activity in rodent brains is very similar to that of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a dopaminergic neurotoxin commonly used to simulate Parkinson&apos;s disease in preclinical research.&lt;/p&gt;
&lt;p&gt;Goldman said the new study was the first population-based analysis to link TCE to the disease.&lt;/p&gt;
&lt;p&gt;It focused on 198 twin pairs in the National Academy of Sciences-National Research Council&apos;s World War II Twins Cohort, which comprises some 16,000 twin pairs overall.&lt;/p&gt;
&lt;p&gt;Members of the all-male cohort, who were born from 1917 to 1927 and served in the war, have been followed since the 1960s. Occupational histories for participants are available along with medical records from the VA healthcare system.&lt;/p&gt;
&lt;p&gt;In those pairs chosen for the current study, records showed that one twin had developed Parkinson&apos;s disease and the other had not. This design largely eliminates genetics as a confounding factor in the analysis.&lt;/p&gt;
&lt;p&gt;Goldman explained that occupational histories for each participant were reviewed by a blinded industrial hygienist and a preventive medicine physician to identify likely exposures to TCE and four other industrial chemicals: xylene, toluene, carbon tetrachloride, and tetrachloroethylene.&lt;/p&gt;
&lt;p&gt;As a single source of exposure, only TCE was significantly associated with development of Parkinson&apos;s disease, Goldman said.&lt;/p&gt;
&lt;p&gt;People working as aircraft mechanics, machinists, plumbers, and electricians likely had regular exposure to TCE, Goldman said. The chemical was commonly used as a &quot;spot&quot; cleaner to remove grease and oils from metal surfaces. It was also used for a time as a dry cleaning solvent, although tetrachloroethylene was more common for that purpose.&lt;/p&gt;
&lt;p&gt;Goldman said no increased risk was seen with xylene or toluene, but there were near-significant trends toward increased Parkinson&apos;s disease risk from carbon tetrachloride and tetrachloroethylene: &lt;ul&gt; &lt;li&gt;Carbon tetrachloride: OR 2.8 (95% CI 0.97 to 7.8)&lt;/li&gt; &lt;li&gt;Tetrachloroethylene: OR 9.0 (95% CI 0.78 to 103)&lt;/li&gt; &lt;/ul&gt;&lt;/p&gt;
&lt;p&gt;Twins exposed to either TCE or tetrachloroethylene were at significantly increased risk, with an odds ratio of 8.1 (95% CI 1.43 to 43) relative to individuals with no exposure to either chemical.&lt;/p&gt;
&lt;p&gt;Goldman said the analysis also examined whether duration of exposure was associated with increased risk. He said the results were in the same pattern as for the yes-no exposure analysis, but the findings were very uncertain because of the relatively small sample size.&lt;/p&gt;
&lt;p&gt;Occupational histories were available for only 99 of the 198 discordant twin pairs and some of the information was obtained by proxy rather than from the participant himself.&lt;/p&gt;
&lt;p&gt;Because of the wide confidence intervals even for the yes-no exposure analysis, the findings need confirmation in a larger study, he said, noting that the best approach would be a cohort study involving people with known, long-term exposure to TCE, compared with well-chosen controls.&lt;/p&gt;
&lt;p&gt;&quot;The study wouldn&apos;t have to be large,&quot; Goldman said. He estimated that 1,000 to 2,000 participants would be adequate to determine if the connection to Parkinson&apos;s disease is real.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The study was funded by the National Institute of Neurological Disorders and Stroke, the Valley Foundation, and the James and Sharron Clark Family Fund.&lt;/p&gt;&lt;p&gt;No potential conflicts of interest were reported.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_415"
                     title="AAPM: Drug for Fibromyalgia Boosts Multiple Outcomes (CME/CE)"
                     score="0.013"
                     href="http://www.medpagetoday.com/MeetingCoverage/AAPM/tb/18327?impressionId=1265777328521"
                     
      &lt;p&gt;SAN ANTONIO  --  The fibromyalgia drug milnacipran (Savella) achieved clinically meaningful reductions in pain throughout almost four months of randomized therapy, a post-hoc analysis of daily pain control showed.&lt;/p&gt;
&lt;p&gt;Half of patients treated with the serotonin/norepinephrine reuptake inhibitor had at least a 30% improvement in pain scores at 15 weeks, and 35% to 40% had at least a 50% improvement, according to analyses reported here at the American Academy of Pain Medicine meeting.&lt;/p&gt;
&lt;p&gt;Two different doses of milnacipran led to at least 30% improvement in pain on almost half of the days during the randomized trial. Patients treated with milnacipran had at least 50% improvement during 30% of the days.&lt;/p&gt;
&lt;p&gt;&quot;A 30% improvement in pain is clinically significant, and half the patients treated with milnacipran attained that level of pain relief,&quot; Aroon Datta, MD, of Forest Laboratories in Jersey City, N.J., said in an interview. &quot;Even when the more stringent criteria of 50% improvement were applied, significantly more patients in the milnacipran groups achieved that threshold compared with placebo.&quot;&lt;/p&gt;
&lt;p&gt;&quot;By any measure, it is fair to say that patients treated with milnacipran had significantly better pain control,&quot; he added.&lt;/p&gt;
&lt;p&gt;Milnacipran is chemically similar to the antidepressant venlafaxine (Effexor). However, milnacipran has three times the power to inhibit norepinephrine reuptake. The drug was approved in 2009 for treatment of fibromyalgia.&lt;/p&gt;
&lt;p&gt;Datta reported results of a post-hoc analysis of data from two randomized, placebo-controlled clinical trials. One lasted 27 weeks, and the other had a 15-week follow-up.&lt;/p&gt;
&lt;p&gt;In the 27-week trial, approximately 900 patients were randomized 1:1:2 to placebo, milnacipran 100 mg/d (50 mg BID), or milnacipran 200 mg/d (100 mg BID). In the 15-week trial, 1,200 patients were randomized in equal proportion to placebo and the two doses of milnacipran.&lt;/p&gt;
&lt;p&gt;Patients recorded their pain level several times a day by means of an electronic diary. They rated their pain according to a visual analog scale (VAS) with a range of 0 to 100.&lt;/p&gt;
&lt;p&gt;The post-hoc analysis centered on outcomes at 15 weeks in both trials. The primary outcomes were change from baseline in weekly 24-hour VAS pain score, the proportion of patients who achieved &amp;#8805;30% and &amp;#8805;50% improvement in the VAS pain score, and the proportion of days with &amp;#8805;30% and &amp;#8805;50% improvement in pain.&lt;/p&gt;
&lt;p&gt;In the longer trial, the change in the weekly average of 24-hour recall of VAS scores differed significantly in both milnacipran groups within two weeks, and the difference was maintained through 15 weeks (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.05 to &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001).&lt;/p&gt;
&lt;p&gt;Significant differences emerged within the first week in the second trial and persisted through week 15 (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.05 to &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001).&lt;/p&gt;
&lt;p&gt;In both trials, 52% of patients assigned to 100 mg of milnacipran and 56% of those assigned to 200 mg had &amp;#8805;30% improvement in pain scores, compared with 40% to 42% of placebo-treated patients (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.05 to &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001).&lt;/p&gt;
&lt;p&gt;When the more stringent criterion of &amp;#8805;50% improvement was used, 31% to 35% of the 100-mg milnacipran patients achieved that goal, as did 36% to 37% of patients treated with 200 mg.&lt;/p&gt;
&lt;p&gt;About 25% of placebo patients had &amp;#8805;50% improvement. Only the 200-mg dose differed significantly from placebo (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.05 to &lt;em&gt;P&lt;/em&gt;&amp;lt;0.01).&lt;/p&gt;
&lt;p&gt;A similar pattern emerged in evaluation of the proportion of days with threshold pain reductions. Milnacipran-treated patients had &amp;#8805;30% improvement on 44% to 47% of days in the trial and &amp;#8805;50% improvement on 25% to 30% of days.&lt;/p&gt;
&lt;p&gt;For both thresholds, milnacipran was significantly better than placebo, whose patients had &amp;#8805;30% pain improvement on about a third of days and &amp;#8805;50% improvement on fewer than 20% of days (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.01 to &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001).&lt;/p&gt;
&lt;p&gt;Datta also reported findings from a randomized, placebo-controlled clinical trial evaluating the pain relief afforded by the 100-mg daily dose of milnacipran. The study involved 1,025 patients with fibromyalgia randomized to placebo or active therapy.&lt;/p&gt;
&lt;p&gt;The trial had two principal 12-week efficacy outcomes: the composite of &amp;#8805;30% improvement in pain and the Patient Global Impression of Change (PGIC), and the composite of the same two outcomes plus improvement &amp;#8805;6 points on the physical function component of the SF-36 health assessment survey.&lt;/p&gt;
&lt;p&gt;The principal efficacy analysis used baseline observation carried forward (BOCF) for patients with missing data. By that statistical method, 29% of milnacipran patients were responders compared with 18% of the placebo group (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001).&lt;/p&gt;
&lt;p&gt;An analysis that employed last observation carried forward (LOCF) showed response rates of 33% with milnacipran and 19&lt;strong&gt;%&lt;/strong&gt; with placebo (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001).&lt;/p&gt;
&lt;p&gt;An analysis of observed cases resulted in response rates of 42% versus 26% (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001).&lt;/p&gt;
&lt;p&gt;Similar results emerged from analyses of the three-measure outcome. Milnacipran led to significantly higher (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001) response rates by BOCF (20% versus 11%), by LOCF (28% versus 12%), and by observed cases (30% versus 16%).&lt;/p&gt;
&lt;p&gt;Milnacipran therapy also led to significantly higher (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001) response rates for each component of the composite outcomes: &amp;#8805;30% improvement in pain (45% versus 31%), PGIC (42% versus 26%), and &amp;#8805;6-point improvement in physical function (40% versus 31%).&lt;/p&gt;
&lt;p&gt;The results indicate that milnacipran 100 mg (50 mg BID) could offer an alternative for patients who cannot tolerate the FDA-approved 200-mg dose, said Datta. If physicians choose to start patients on 100 mg and then titrate up to the approved dose, that also would appear feasible, he said.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The studies were supported by Forest Laboratories and Cypress Bioscience.&lt;/p&gt;&lt;p&gt;All but two of the authors are employees of the study sponsors.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_397"
                     title="AAPM: Nerve Growth Factor Antibody  May Reduce Pain (CME/CE)"
                     score="0.012"
                     href="http://www.medpagetoday.com/MeetingCoverage/AAPM/tb/18300?impressionId=1265777328521"
                     
      &lt;p&gt;SAN ANTONIO  --  A humanized monoclonal antibody against nerve growth factor provided relief in three chronic pain syndromes, according to a summary of small studies reported as an abstract here.&lt;/p&gt;
&lt;p&gt;Treatment with tanezumab led to statistically or clinically significant reductions in pain for patients with osteoarthritis, chronic lower back pain, and interstitial cystitis. The most common adverse events were transient abnormal peripheral sensations, which generally occurred only after the first infusion.&lt;/p&gt;
&lt;p&gt;&quot;Patients with these three different pain syndromes all had significant improvement when treated with tanezumab,&quot; Leslie Tive, PhD, of Pfizer, said in an interview at the American Academy of Pain Medicine meeting. &quot;The pain relief was sustained over time, and patient acceptance was good.&quot;&lt;/p&gt;
&lt;p&gt;&quot;Nerve growth factor is increased in many types of chronic pain and therefore represents an attractive target for therapy,&quot; she added. &quot;Tanezumab is being evaluated in some of these other conditions in ongoing studies.&quot;&lt;/p&gt;
&lt;p&gt;A small phase I study showed that the humanized monoclonal antibody resulted in significant pain improvement in patients with osteoarthritis (&lt;em&gt;Arthritis Rheum&lt;/em&gt; 2005; 52: S461). Tive presented data from a phase II trial involving 400 patients with osteoarthritis of the knee. They were randomized to placebo or to one of five tanezumab doses, administered on day one and day 56.&lt;/p&gt;
&lt;p&gt;All five doses of tanezumab resulted in significant reductions (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.05) versus placebo after one week and were sustained through 16 weeks. As assessed by a visual analog scale, the mean change in pain on walking from baseline to week 16 ranged from 30 to 45 points (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.0001), a two- to threefold difference compared with placebo.&lt;/p&gt;
&lt;p&gt;The trial in chronic low back pain involved 217 adults with Quebec Task Force on Spinal Disorders category 1 or 2 pain for at least three months. The primary location of the pain was between the 12th thoracic vertebra and the lower gluteal folds.&lt;/p&gt;
&lt;p&gt;Eligibility criteria included a score of at least 4 on an 11-point pain scale on at least four occasions in the five days before randomization, as indicated by entries in an electronic pain diary.&lt;/p&gt;
&lt;p&gt;Patients were randomized 2:2:1 to a single infusion of tanezumab, to oral naproxen, or to placebo. The primary endpoint was the change in mean Lower Back Pain Index score from baseline to six weeks, averaged over the last seven days.&lt;/p&gt;
&lt;p&gt;Beginning at week one and continuing through week six, patients who were randomized to either dose of tanezumab had significantly greater improvement in pain than those who took the placebo (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.05 to &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001), and compared with the naproxen group beginning at week two (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.05 to &lt;em&gt;P&lt;/em&gt;&amp;lt;0.01).&lt;/p&gt;
&lt;p&gt;The interstitial cystitis study included 64 men and women who had a score &amp;#8805;13 on Pelvic Pain Symptom/Frequency questionnaire, &amp;#8805;7 score on the O&apos;Leary-Sant Interstitial Cystitis index, and micturition frequency &amp;#8805;8 times a day, as recorded in an electronic diary for at least five consecutive days prior to randomization.&lt;/p&gt;
&lt;p&gt;Patients were randomized to intravenous tanezumab or matching placebo. The primary efficacy endpoint was change from baseline to six weeks in the 11-point pain scale. A difference of at least one point from placebo was considered clinically significant. Statistical significance was not evaluated.&lt;/p&gt;
&lt;p&gt;The mean difference between tanezumab and placebo was -0.7 at week two, increasing to -1.1 at week four and -1.4 at week six. The advantage versus placebo was maintained at week 10 (-0.9) and week 16 (-0.5).&lt;/p&gt;
&lt;p&gt;Adverse events were evaluated for all patients combined in the three studies. Adverse events were reported by 66.3% of tanezumab patients, 61.4% of naproxen patients, and 59.3% of placebo patients. Serious and severe adverse events occurred in 1.6% to 3.4% of patients and 4.8% to 5.7%, respectively.&lt;/p&gt;
&lt;p&gt;Tive said 14.4% of tanezumab patients reported abnormal peripheral sensations, the most common being paresthesia (7.1%), hyperesthesia (4.1%), and hypoesthesia (3.9%).&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The studies included in the summary were funded by Pfizer.&lt;/p&gt;&lt;p&gt;Investigators included several Pfizer employees.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_252"
                     title="MS Walking Drug Gets FDA Nod"
                     score="0"
                     href="http://www.medpagetoday.com/Neurology/MultipleSclerosis/tb/18112?impressionId=1265777328521"
                     
      &lt;p&gt;WASHINGTON  --  The FDA has approved the first drug that improves walking in patients with multiple sclerosis, the tablet dalfampridine (Ampyra).&lt;/p&gt;
&lt;p&gt;The approval was based on clinical trial data that found patients could walk better with the drug than those treated with placebo.&lt;/p&gt;
&lt;p&gt;Patients who exceed recommended dosage, 10 mg twice a day, or who have moderate to severe kidney disease, may experience seizures the FDA said.&lt;/p&gt;
&lt;p&gt;Adverse events reported during clinical trials include urinary tract infection, insomnia, dizziness, headache, nausea, weakness, back pain, balance disorder, swelling of the nose or throat, constipation, diarrhea, indigestion, throat pain, and burning, tingling, or itching skin.&lt;/p&gt;
&lt;p&gt;The drug is manufactured by Elan of Dublin, Ireland and distributed by Acorda Therapeutics Inc. of Hawthone, NY.&lt;/p&gt;

    </recommendedItem>
    <recommendedItem id="20100101_19_219"
                     title="Oral MS Drugs Effective in Phase III Trials (CME/CE)"
                     score="-0.002"
                     href="http://www.medpagetoday.com/Neurology/MultipleSclerosis/tb/18069?impressionId=1265777328521"
                     
      Two oral drugs under investigation for multiple sclerosis reduced relapse rates and delayed onset of disability in separate trials reported online this week in the &lt;em&gt;New England Journal of Medicine&lt;/em&gt;.&lt;br&gt;
&lt;br&gt;Fingolimod, a novel agent also known as FTY-720, was more effective than both placebo and the standard of care for MS, interferon-beta-1a (Avonex), in two independent trials.&lt;br&gt;
&lt;br&gt;The studies, called FREEDOMS and TRANSFORMS, were reported by Ludwig Kappos, MD, of the University of Basel in Switzerland, and colleagues, and by Jeffrey Cohen, MD, of the Cleveland Clinic, and other researchers, respectively. Some researchers worked on both studies.&lt;br&gt;
&lt;br&gt;Cladribine, an oral drug already marketed for hematologic cancers under the trade name Leustatin, was clearly more effective than placebo in a third trial called CLARITY reported by Gavin Giovannoni, MB, BCh, PhD, of Queen Mary University in London, and colleagues.&lt;p&gt;&lt;/p&gt;
&lt;p&gt;&quot;The studies in this issue of the [&lt;em&gt;NEJM&lt;/em&gt;] provide a new horizon for patients with relapsing-remitting multiple sclerosis and a welcome increase in the range of treatment options,&quot; William M. Carroll, MBBS, MD, of Sir Charles Gairdner Hospital in Perth, Australia, wrote in an accompanying editorial.&lt;/p&gt;
&lt;p&gt;Oral drugs for MS would not only improve patient acceptance of treatment, but also &quot;further support a change in treatment approach to directly prevent immune-mediated injury,&quot; Carroll wrote.&lt;/p&gt;
&lt;p&gt;Existing disease-modifying therapies  --  interferon, glatiramer acetate (Copaxone), and natalizumab (Tysabri)  --  are all injectable drugs.&lt;/p&gt;
&lt;p&gt;&quot;Patients hate the shots and have been waiting 17 years for an oral drug,&quot; John Corboy, MD, a neurologist of the University of Colorado in Denver who was not involved in the study, told &lt;em&gt;MedPage Today&lt;/em&gt; and ABC news when contacted for comment.&quot;&lt;/p&gt;
&lt;p&gt;The National Multiple Sclerosis Society also expressed delight at the reports.&lt;/p&gt;
&lt;p&gt;&quot;The published results ... are wonderful news for people with MS,&quot; wrote John Richert, MD, the group&apos;s executive vice president of research and clinical programs, in a report to local chapters.&lt;/p&gt;
&lt;p&gt;&quot;Having oral therapies in the MS pipeline is real progress, and it should increase the number of people who choose to begin therapy earlier and who stay on therapy, which our experts say is the best way to combat future disease activity.&quot;&lt;/p&gt;
&lt;p&gt;Most of the studies&apos; key results had been presented last spring at the American Academy of Neurology&apos;s annual meeting. (See &lt;a href=&quot;http://www.medpagetoday.com/MeetingCoverage/AAN/14013&quot; mce_href=&quot;http://www.medpagetoday.com/MeetingCoverage/AAN/14013&quot; target=&quot;_blank&quot;&gt;AAN: Oral MS Drug with Novel Mechanism Beats Interferon-Beta1a&lt;/a&gt; and &lt;a href=&quot;http://www.medpagetoday.com/MeetingCoverage/AAN/13996&quot; mce_href=&quot;http://www.medpagetoday.com/MeetingCoverage/AAN/13996&quot; target=&quot;_blank&quot;&gt;AAN: Cancer Drug Shows Promise as Oral MS Therapy&lt;/a&gt;)&lt;/p&gt;
&lt;p&gt;But the journal reports included additional details, especially on adverse effects, as well as peer review.&lt;/p&gt;
&lt;p&gt;The two drugs target different aspects of T-cell biology. These cells are key players in the autoimmune attack on the myelin sheaths surrounding nerve fibers, which, in turn, causes the slow loss of peripheral nerve function.&lt;/p&gt;
&lt;p&gt;Cladribine induces active T cells to undergo apoptosis, which explains its utility in hairy cell leukemia, lymphoma, and certain other hematologic malignancies.&lt;/p&gt;
&lt;p&gt;Fingolimod has a different mechanism. It causes the sphingosine-1-phosphatase receptor, which normally sits on the surface of T and B cells, to withdraw into the cell interior.&lt;/p&gt;
&lt;p&gt;The effect is to leave the cells unresponsive to signals that instruct them to exit lymph nodes and head toward sites of inflammation. Keeping T cells bottled up in lymph nodes prevents them from attacking nerves in MS.&lt;/p&gt;
&lt;p&gt;The two placebo-controlled studies of fingolimod and cladribine both showed that relapse rates and disease progression were reduced.&lt;/p&gt;
&lt;p&gt;In the 1,272-patient fingolimod study, annualized relapse rates were 0.40 in the placebo group, 0.18 with 0.5 mg of the drug daily, and 0.16 with a 1.25-mg dose over a two-year period (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001 for both doses versus placebo).&lt;/p&gt;
&lt;p&gt;The hazard ratios for disability progression relative to placebo at the two-year evaluation were 0.70 and 0.68 for the low and high doses of fingolimod, respectively (&lt;em&gt;P&lt;/em&gt;=0.02 for both comparisons).&lt;/p&gt;
&lt;p&gt;Cladribine, a more toxic drug, was given in short bursts of treatment over the 96-week study.&lt;/p&gt;
&lt;p&gt;Two dosing regimens were tested, delivering cumulative totals of 3.5 or 5.25 mg/kg, along with placebo. Patients took one or two 10-mg tablets daily for the first four or five days of either two or four monthly periods starting at week zero, followed by two additional monthly courses starting at week 48.&lt;/p&gt;
&lt;p&gt;Results for the primary outcome of annualized relapse rate were 0.33 for placebo, 0.14 for the low cladribine dose, and 0.15 for the higher dose (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001 for both doses versus placebo).&lt;/p&gt;
&lt;p&gt;Hazard ratios for disability progression at week 96 for cladribine versus placebo were 0.67 with the low dose (&lt;em&gt;P&lt;/em&gt;=0.02) and 0.69 with the high dose (&lt;em&gt;P&lt;/em&gt;=0.03).&lt;/p&gt;
&lt;p&gt;Perhaps more striking were the findings in the other fingolimod trial, in which the drug was tested head-to-head against the current standard of care.&lt;/p&gt;
&lt;p&gt;The same two doses of fingolimod were used. Patients assigned to interferon received the drug in weekly intramuscular injections of 30 &amp;#956;g.&lt;/p&gt;
&lt;p&gt;The annualized relapse rate with interferon was 0.33, whereas it was significantly lower with fingolimod: 0.16 with the 0.5-mg dose and 0.20 for the 1.25-mg dose (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001 versus interferon for both).&lt;/p&gt;
&lt;p&gt;But the risk of disease progression did not differ significantly between treatment groups.&lt;/p&gt;
&lt;p&gt;Moreover, two patients receiving the higher fingolimod dose died of herpes zoster infections, disseminated in one case and causing encephalopathy in the other. Increased rates of herpes zoster infections were also seen in the other fingolimod trial and with cladribine. In the cladribine trial, lymphocytopenia was seen in about 14% of patients taking the drug, compared with less than 2% of the placebo group.&lt;/p&gt;
&lt;p&gt;Fingolimod also seemed to be associated with cardiac rhythm disturbances, including bradycardia (2.7% with fingolimod, 0.7% placebo) and atrioventricular conduction block, though the latter was mostly confined to the higher drug dose (five cases versus two each for the low dose and placebo).&lt;/p&gt;
&lt;p&gt;Leukopenia and lymphocytopenia were also seen with fingolimod in the placebo-controlled study, though at lower rates than with cladribine  --  about 3% to 6%, compared with less than 1% in the control group.&lt;/p&gt;
&lt;p&gt;Lymphocytopenia was less frequent overall in the interferon-controlled study, seen in 0.2% of the low-dose group and 1.0% of the high-dose group, compared with no cases in the interferon-treated patients.&lt;/p&gt;
&lt;p&gt;Hillel Panitch, MD, of the University of Vermont in Burlington, Vt., told &lt;em&gt;MedPage Today&lt;/em&gt; and ABC News that the findings were actually reassuring.&lt;/p&gt;
&lt;p&gt;&quot;The adverse events including herpes infections, malignancies, and bradycardia are much less of an issue than expected for these drugs, and with the proper oversight should not delay their use,&quot; Panitch wrote in an e-mail.&lt;/p&gt;
&lt;p&gt;Richert of the National MS Society also indicated that the reported adverse effects were not especially worrisome.&lt;/p&gt;
&lt;p&gt;&quot;Herpes infections are likely to occur with many different immune-modulating therapies, including some already approved for MS,&quot; he wrote in an e-mail to &lt;em&gt;MedPage Today&lt;/em&gt; and ABC News, adding that these usually respond to treatment.&lt;/p&gt;
&lt;p&gt;&quot;They should be something patients and doctors keep a lookout for,&quot; he wrote.&lt;/p&gt;
&lt;p&gt;Similarly, he said, the cardiac effects of fingolimod appeared transient and asymptomatic. But he suggested it may be necessary to avoid combining fingolimod with anti-arrhythmic drugs in at least some patients.&lt;/p&gt;
&lt;p&gt;But Colorado&apos;s Corboy was more concerned by the side effect profile. He pointed to the issue of progressive multifocal leukoencephalopathy (PML) seen with natalizumab (Tysabri) in MS patients, which kept the drug off the market for a time.&lt;/p&gt;
&lt;p&gt;&quot;The price you may have to pay for greater efficacy is greater risk,&quot; he wrote in an e-mail. He said some in the MS community would avoid the new oral drugs because of the risks, should they be approved.&lt;/p&gt;
&lt;p&gt;The manufacturers of both drugs have filed for FDA approval. Merck Serono was first to file, for cladribine, but the FDA informed the company in late November that it considered the application incomplete and refused to accept it.&lt;/p&gt;
&lt;p&gt;Company officials promised at the time that they would submit additional information requested by the agency. They did not respond to requests for an update.&lt;/p&gt;
&lt;p&gt;Novartis, maker of fingolimod, announced in mid-December that its FDA filing was imminent and a company representative confirmed that it had been submitted.&lt;/p&gt;
&lt;p&gt;Although the FDA has given both drugs fast-track status, the possibility that the agency will want an advisory committee review may push their final approvals into 2011.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The two fingolimod studies were funded by Novartis. The study of cladribine was funded by Merck Serono.&lt;/p&gt;&lt;p&gt;Authors of the placebo-controlled study of fingolimod reported relationships other than research funding with Novartis and many other firms including Accorda, Actelion, Allergan, Allozyne, Bayer Schering, Biogen Idec, Biogen-Dompe, Boehringer Ingelheim, Genmab, GlaxoSmithKline, Medicinova, Merck Serono, Roche, sanofi aventis, Santhera, Teva, UCB, Wyeth, Helvea, and Mediservice. Several co-authors were employees of Novartis.&lt;/p&gt;&lt;p&gt;Authors of the study of fingolimod versus interferon reported relationships other than research funding with Novartis and other firms including Biogen Idec, EMD Serono, Teva, sanofi aventis, Waterfront Media, Bayer Schering, AstraZeneca, Genentech, Lundbeck, Talecris, Roche, Wyeth, Medicinova, Biogen-Dompe, Medtronic, Accorda, Actelion, Allergan, Allozyne, Boehringer Ingelheim, Genmab, GlaxoSmithKline, Santhera, and UCB. Several co-authors were employees of Novartis.&lt;/p&gt;&lt;p&gt;Authors of the cladribine study reported relationships other than research funding with Merck Serono or EMD Serono and with other firms including Bayer Schering, Biogen Idec, Novartis, Teva-Aventis, UCB, Vertex, sanofi-aventis, Biogen-Dompe, Pfizer, and Genentech. Several co-authors were employees of Merck Serono.&lt;/p&gt;&lt;p&gt;Carroll reported relationships other than research funding with Biogen Idec, Bayer Schering, Merck Serono, and sanofi-a ventis. He also reported agreeing to serve on a Novartis advisory board but did not attend meetings and received no compensation.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;&lt;p&gt;&lt;em&gt;This article was developed in collaboration with ABC News. &lt;/em&gt;&lt;img src=&quot;http://www.medpagetoday.com/upload/2009/10/1/14357_1.jpg&quot; mce_src=&quot;http://www.medpagetoday.com/upload/2009/10/1/14357_1.jpg&quot; alt=&quot;&quot;&gt;&lt;/p&gt;
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