15 STUDIES IN FRIDAY'S NEWS

 PLUS: 1590 new Studies we posted from 11/1 to Thursday 2/12 Start at the Bottom!

The NBSS, developed specifically to assess the symptoms and consequences associated with neurogenic bladder dysfunction, has appropriate psychometric properties. Depending on the measurement need, individual domains may be selected, or it can be used as a comprehensive score.

Read Study at Pubmed.gov

The fraction of intrathecally-produced VZV-specific IgG of the total intrathecally produced IgG discriminates between patients with VZV reactivation and MS. Our results provide further evidence that intrathecally-produced VZV antibodies are part of the polyspecific immune response in patients with MS.

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 In addition to autoantigens implicated in thyroid autoimmunity, fibrocytes and derivative fibroblasts express multiple autoantigens associated with T1DM. This expression results from active gene promoters and abundant steady-state mRNA encoding ICA69 and IA-2. These latest findings demonstrate that fibrocytes express antigens relevant to multiple forms of endocrine autoimmunity. They suggest the potential for these cells playing a direct role in immune reactivity directed at the thyroid and pancreatic islets.

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MMPs can also enhance the cleavage of myelin basic protein (MBP) and the demyelination process. Regarding the growing data on the roles of MMPs and their tissue inhibitors (TIMPs) in the pathogenesis of MS, this review discusses the role of different types of MMPs, including MMP-2, -3, -7, -9, -12 and -25, in the immunopathogenesis and treatment of MS.

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In a real-world setting, patients with MS who switched from IFNs to fingolimod were significantly less likely to experience relapses than those who switched to GA.
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Labels: 500 BEST PML STORIES & STUDIES, Aubagio, Avonex, Betaseron, Copaxone, Extavia, Gilenya, Novantrone, PML (Progressive Multifocal Leukoencephalopathy), sativex, TECFIDERA, Tysabri

15 STUDIES IN THURSDAY'S NEWS

 PLUS: 1575 new Studies we posted from 11/1 to Wednesday 2/12 Start at the Bottom!

In patients with SSc, serum levels of ICAM-1 and P-selectin may serve as prognostic indicators of respiratory dysfunction and physical disability, respectively. Further longitudinal studies of larger populations are needed to confirm these findings.

Read Study at Pubmed.gov

Seizures can occur at any stage during the course of MS, but it is more common during the early stages.

Read Study at Pubmed.gov

In a real-world setting, patients with MS who switched from IFNs to fingolimod were significantly less likely to experience relapses than those who switched to GA.

Read Study at Pubmed.gov

In the NARCOMS cohort, functional health literacy is high. However, lower levels of health literacy are associated with adverse health behaviors and greater health care utilization.
Read Study at Pubmed.gov

In the pathogenesis of MS, this review discusses the role of different types of MMPs, including MMP-2, -3, -7, -9, -12 and -25, in the immunopathogenesis and treatment of MS.
Read Study at Pubmed.gov

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Labels: 500 BEST PML STORIES & STUDIES, Aubagio, Avonex, Betaseron, Copaxone, Extavia, Gilenya, Novantrone, PML (Progressive Multifocal Leukoencephalopathy), sativex, TECFIDERA, Tysabri

Natalizumab an Alternative for Those in Whom Other MS Treatments Have Failed

(Posted By: Josi Creek)

 A new study suggests that patients with relapsing-remitting multiple sclerosis (RRMS) in whom previous treatment regimens have failed remain stable or show improvement when switched to treatment with natalizumab (Tysabri, Novartis).


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Labels: 500 BEST PML STORIES & STUDIES, Avonex, Betaseron, Copaxone, PML (Progressive Multifocal Leukoencephalopathy), Tysabri

Biogen added 1500 new Tysabri patients in the 1st quarter compared to 2,600 patients in the 4th quarter last year-This is the 3rd quarter in a row of declining patient growth

Tysabri's label was recently changed to indicate that the longer patients remain on the drug, the greater their risk of a potentially deadly brain infection called progressive multifocal leukoencephalopathy (PML). Even though Tysabri is a more effective drug, patients are comfortable with inferior but safer options such as Teva Pharmaceutical's Copaxone, Novartis'  Extavia, and Rebif from Pfizer.









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Labels: 500 BEST PML STORIES & STUDIES, Copaxone, Extavia, PML (Progressive Multifocal Leukoencephalopathy), Tysabri

Biogen and marketing partner Elan added 1,500 new Tysabri patients in the first quarter, compared to adding 2,600 patients in the fourth quarter of last year. This marks the third quarter in a row of declining patient growth

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Labels: 500 BEST PML STORIES & STUDIES, Copaxone, Extavia, Gilenya, PML (Progressive Multifocal Leukoencephalopathy), Tysabri

BREAKING NEWS: AAN: Monoclonal Antibodies Shine in Relapsing-Remitting MS but Not All to Same Degree - in Meeting Coverage, AAN from MedPage Today

American Academy of Neurology Meeting: Monoclonal Antibodies Shine in Relapsing-Remitting MS but Not All to Same Degree 

Three monoclonal antibodies in development for relapsing-remitting multiple sclerosis show promise, but alemtuzumab (Campath) appears to be leading the pack, researchers reported here. Once-yearly alemtuzumab reduced relapse risk by 74% and risk of accumulation of disability by 71% compared with standard interferon (both P<0.0001), reported Alasdair Coles, Ph.D., of the University of Cambridge in England, and colleagues, here at the American Academy of Neurology meeting. The benefit continued for two years after the last dose in a subset of patients, according to three-year data from a randomized trial. Other monoclonal antibodies, including daclizumab (Zenapax) and rituximab (Rituxan, MabThera), also looked promising in studies presented here. However, the improvements with alemtuzumab were "probably greater than anything else that's currently on the market or any of the drugs that are being looked at," said Lily Jung, M.D., of the Swedish Neuroscience Institute in Seattle, who commented on the studies. The specific targets of the monoclonal antibodies may account for the differences, Dr. Coles said. Daclizumab is targeted against CD25 on T cells and rituximab is targeted to B cells, but alemtuzumab impacts both types of lymphocytes. "We think one reason why our efficacy is so much better than other more selective monoclonal antibodies is because it has this sort of broad range of action," he said. The phase II CAMMS223 trial included 334 patients with early, active relapsing-remitting disease. Participants were randomized to 44 mcg beta interferon-1a (Rebif) injections three times a week or to once-a-year treatment with either 12 or 24 mg intravenous alemtuzumab delivered every day for five days at baseline and then daily for three days at months 12 and 24. Cumulative relapse rates continued to diverge in favor of alemtuzumab through three years of follow-up for a 74% risk reduction (annualized relapse rate 0.10 versus 0.36, P<0.0001). The load of T2 lesions seen on MRI were reduced to a greater degree with the monoclonal antibody (-16.45 versus -13.3%, P=0.005) and T1 cerebral volume fell less with alemtuzumab as well (-0.5% versus -1.8%, P=0.049). The continued effects were notable because only 46 patients in the alemtuzumab groups received therapy at the 24-month stage. For most participants, dosing was suspended when one patient died of immune thrombocytopenic purpura (ITP) on treatment. ITP was seen in six of 216 patients on alemtuzumab and one of 107 patients on interferon, but all other cases were identified early and treated successfully if needed. Thyroid events were also elevated with the drug but could be monitored and easily treated, Dr. Coles said. Dr. Jung agreed that neither of the more serious adverse events were a deal breaker for the drug, because both can be monitored unlike the progressive multifocal leukoencephalopathy issues seen with natalizumab (Tysabri). Rather, she was impressed by the reversion of disability in the alemtuzumab group. Mean scores on the Expanded Disability Status Scale at three years decreased 0.39 points with the monoclonal antibody compared with an increase of 0.38 for the interferon group (P<0.0001). "We believe this to be unprecedented," Dr. Coles said.Long dosing intervals may be another advantage. Although patients will likely need two cycles of therapy, they may be able to go for three to five years thereafter without treatment, Dr. Coles said. "I think it's a significantly easier treatment for patients," Dr. Coles said. "That's potentially even more acceptable than a daily tablet because you can forget about your illness." For daclizumab, though, treatment will likely have to be given long term because of a rapid loss of efficacy after discontinuation, said Michael D. Kaufman, M.D., of the Carolinas Medical Center in Charlotte, N.C., and colleagues. Their phase II CHOICE study included 230 relapsing-remitting MS patients randomized to 20 weeks of treatment with beta interferon plus placebo, daclizumab 1 mg/kg, or daclizumab 2 mg/kg. For the previously reported primary endpoint findings, new or enlarged gadolinium-enhancing lesions were 25% fewer at 24 weeks with lower dose daclizumab and 72% fewer with the higher dose compared with placebo (3.6 and 1.3 versus 4.8, P=0.514 and P=0.004, respectively). However, these benefits faded within 10 to 20 weeks after stopping treatment. During the 48-week observation phase of the study, the number of new enhancing lesions seen on MRI at week 34 was not significantly different between treatments although there were 56% more with 1 mg/kg and 23% fewer with 2 mg/kg daclizumab compared with placebo (3.56 and 1.77 versus 2.29, P=0.22 and P=0.49, respectively). In another small study, rituximab reduced the frequency of inflammatory brain lesions and relapses through 72 weeks, reported Amit Bar-Or, M.D., of McGill University in Montreal, and colleagues. Their phase I, open-label trial included 26 patients with relapsing-remitting MS given in two courses of two 1,000-mg rituximab infusions six months apart.Patients had rapid, sustained B cell depletion through 48 weeks followed by partial recovery by week 72. Reductions in gadolinium-enhancing lesions and the number and volume of new T2 lesions were rapid, starting at week four, and sustained through week 72. Relapses were also reduced over 72 weeks compared with the year prior to study treatment. Although how these monoclonal antibodies will play out for clinical use remains to be seen, these findings suggest that alemtuzumab would be used as the initial therapy for newly diagnosed patients with the other agents serving as options for patients with a poor response to other therapies, Dr. Jung said. [Note that these studies were published as abstracts and presented orally at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.]

Labels: 500 BEST PML STORIES & STUDIES, PML (Progressive Multifocal Leukoencephalopathy), Rituxan, Tysabri

Current Research on Existing and Emerging Therapies for the Treatment of MS

Current Research on Existing and Emerging Therapies for the Treatment of MS

From:

ECTRIMS 2007: 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis

Introduction

The ECTRIMS 2007: 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis, held in Prague, Czech Republic, from October 11 to 14, 2007, discussed the current research and treatment in multiple sclerosis (MS). Scientists and clinicians addressed key issues in the pathogenesis, diagnosis, and treatment of MS. Currently, there are 6 US Food and Drug Administration (FDA)-approved disease-modifying treatments: interferon beta-1a (intramuscular or subcutaneous), interferon beta-1b, glatiramer acetate, mitoxantrone, and natalizumab. This summary discusses the new data presented about these current treatment options and new potential treatments for MS.

New Treatments in Development

Daclizumab, a treatment for renal allograft transplant, is a humanized anti-CD25 monoclonal antibody that blocks the alpha chain of the interleukin-2 receptor. In the CHOICE trial, 230 actively relapsing patients on interferon beta were randomized to treatment with either placebo or 1 mg/kg or 2 mg/kg of daclizumab subcutaneously every 2 weeks for 24 weeks. The mean number of new or enlarging contrast-enhancing lesions at weeks 8-24 were 72% reduced in the 2-mg/kg treated arm compared with placebo (P = .004). A 25% reduction in enhancing lesions was seen on the lower dose, but was not statistically significant. Relapse rate reduction was 33% on the high dose, but was not statistically significant. Serious infections were more common in the patients who were treated with the higher dose, which was reported by Montalban and colleagues.[1]

FTY720 (fingolimod), an important potential oral treatment for MS, is in multiple phase 3 clinical trials. As a potent agonist on sphingosine 1-phosphate (S1P) receptors, FTY720 prevents the egress of activated lymphocytes from peripheral lymphoid tissue. Because S1P receptors are also expressed on astrocytes, oligodendrocytes, microglia, and neurons, other potential mechanisms of action are being explored in new research. FTY720 in cell culture studies has been shown to increase both mature and immature oligodendrocyte lineages, raising the possibility of remyelination.[2] Intraventricular administration of FTY720 reduced the degree of experimental allergic encephalomyelitis (EAE) without decreasing the peripheral lymphocyte count.[3] S1P receptor type 1 knockout mice developed attenuated EAE independent of FTY720 administration.[4]

BHT-3009 is a DNA plasmid vaccine that encodes the full-length myelin basic protein. In a phase 2b trial, 289 patients were randomized to placebo, 0.5 mg of BHT-3009 intramuscular injections, or 1.5 mg of BHT-3009 intramuscular injections. The median rate of contrast-enhancing lesions between weeks 24 and 28 was reduced 50% on the 0.5-mg BHT-3009 dose (P = .07). The 1.5-mg BHT-3009 has no significant effect on contrast-enhancing lesions. In addition, no significant effect was seen either on the relapse rate or T2 lesions, as described in the oral presentation by Garren and colleagues.[5]

MN-166 (ibudilast) is an oral agent with anti-inflammatory and neuroprotectant properties. Two hundred ninety-seven relapsing patients were randomized to placebo, 30 mg/day or 60 mg/day. More patients were relapse-free on 60 mg than on placebo (56.1% vs 41.0%, P = .03). In addition, time to first relapse was greater than 1 year on MN-166 60 mg/day and 244 days on placebo (P = .04). A lower mean cumulative active lesion count was seen on 60 mg/day compared with placebo, but this primary endpoint result was not statistically significant. MN-166 60 mg/day did significantly attenuate the percentage of brain volume loss (P = .04).[6]

Fluoxetine may have beneficial effects in MS because it can reduce lymphocyte proliferation, suppress interferon-gamma, and increase production of neurotrophic factors. Forty relapsing nondepressed patients were randomized to 20 mg of fluoxetine daily or placebo. The mean cumulative number of enhancing lesions during the 24 weeks of treatment was 1.84 on fluoxetine and 5.16 on placebo (P = .15). A significantly lower number of scans had new enhancing lesions on fluoxetine than on placebo (25% vs 41%; P = .04).[7]

Updates on Existing Treatments

The Rebif vs Glatiramer Acetate in Relapsing MS Disease (REGARD) trial examined the efficacy and safety of interferon beta-1a 44 micrograms (mcg) subcutaneously thrice weekly and glatiramer acetate in a randomized assessor-blind trial of 764 patients over 96 weeks. The time to the first relapse for the 30th percentile of patients was 495 days on interferon beta-1a and 432 days on glatiramer acetate. This primary endpoint measure was not statistically significant (P = .643). In the prespecified subgroup analysis of the patients with a score less than or equal to the median Expanded Disability Status Scale (EDSS), a significant difference was seen in the primary outcome measure (P = .022). The overall on-treatment annualized relapse rate was only 0.3, which was much less than planned to demonstrate a 30% difference between the 2 treatments on time to first relapse.

The number of lesions per patient per scan for interferon beta-1a and glatiramer acetate, respectively, was 0.7 vs 0.8 for T2-active lesions (P = .178), 0.2 vs 0.4 for T1-enhancing lesions (P < .001), and 0.9 vs 1.2 for combined unique lesions (P = .010).[8] The effect on T2-active lesions was not statistically significant, but the benefit of interferon beta-1a on T1-enhancing lesions was significant. A similar number of adverse events were seen with both treatments. Discontinuations due to adverse events were 8.1 % on interferon beta-1a (1.6% for flulike symptoms) and 6.4% on glatiramer acetate (1.3% for immediate postinjection reactions). At last assessment at 96 weeks, 27.3% of the patients were neutralizing antibody-positive on interferon therapy.[9]

The BECOME trial is a single-center, 2-year study of 75 patients randomized to interferon beta-1b or glatiramer acetate. The confirmed annualized relapse rate was 0.28 on interferon and 0.32 on glatiramer acetate, which was not statistically significant (P = .80). No difference was seen on the EDSS or Multiple Sclerosis Functional Composite (MFSC).[10] The median number of combined active lesions over 24 months was 0.60 on interferon and 0.38 on glatiramer acetate, which was also not statistically significant (P = .24). The median reduction in contrast-enhancing lesions from baseline to on-treatment was 1.19 on interferon beta-1b (P < .001) and 0 on glatiramer acetate (P = .14), which statistically favored interferon beta-1b treatment.[11]

Interferon beta-1a (new formulation) 96-week data revealed a last observation prevalence of neutralizing antibodies of 17%. This preparation of interferon beta-1a lacks human serum albumin. The injection site reactions were only 30.8% compared with 85.8% in the EVIDENCE trial.[12] The COGIMUS trial interim 2-year data demonstrated a significant dose-dependent benefit of interferon beta-1a thrice weekly subcutaneously on neuropsychological testing. Twenty-eight percent of patients on 44 mcg and 39% of patients on 22 mcg had impairment in at least 2 cognitive tests (P = .035).[13]

Further analysis of the BENEFIT trial elucidated the role of interferon beta-1b in patients treated with clinically isolated syndrome. Treatment initiation after the first attack reduced the risk for confirmed EDSS progression by 40% compared with delayed treatment (P = .022). In the early treatment group, 31.8% of patients were neutralizing antibody-positive at any time over 3 years, but 46.6% became antibody-negative by 3 years. Neutralizing antibody positivity did not affect the time to clinically definite MS or time to confirmed disability progression.[14] On the basis of 393 patient MRI studies from the European secondary progressive trial, cerebral brain volume dropped significantly more on interferon beta-1b than placebo on the first year of treatment and less than placebo from years 1 to 3.[15]

Several glatiramer-specific T-cell lines were generated from the cerebrospinal fluid of glatiramer acetate-treated MS patients. Eleven out of 12 of the T-cell lines were of the TH2 phenotype and secreted brain-derived neurotrophic factor.[16]

The STRATA study is examining redosing of natalizumab in patients who participated in the AFFIRM, SENTINEL, and GLANCE trials after voluntary suspension of natalizumab. Of the 1076 patients, 40 (3.7%) developed hypersensitivity reactions. These reactions occurred most frequently in those patients receiving only 1 or 2 doses prior to redosing. No new cases of progressive multifocal leukoencephalopathy have been reported.[17] Khatri and colleagues[18] demonstrated that plasma exchange reduced the serum concentration of natalizumab, which potentially could be a strategy to help restore immunocompetence if progressive multifocal leukoencephalopathy occurs. Interim data of an ongoing trial demonstrated statistically significant improvement on the Fatigue Severity Scale and the Modified Fatigue Impact Scale in 19 patients treated with natalizumab. In addition, improvement was also seen in Beck's Depression Inventory.[19] Oral treatment with a different alpha-4 integrin-blocking agent, AJM300, was effective in reducing the severity of EAE in the Lewis rat.[20]

Combination or Induction Therapy

Mitoxantrone induction therapy followed by interferon beta-1b was compared with interferon beta-1b therapy alone over 3 years in 109 active MS patients. The induction protocol consisted of methylprednisolone 1 g and mitoxantrone 20-mg monthly infusions for 6 months. Nine percent of induction-treated patients and 26% of interferon-only patients had worsening disability of greater than 1 EDSS point (65% benefit). The annualized relapse rate with induction was 0.44 compared with 1.14 on interferon only (56% benefit; P < .007).[21] The risks for mitoxantrone were highlighted in a study in Spain that calculated a leukemia incidence of 2.83% (95% confidence interval 1.2-4.4) in exposed patients.[22] This rate was much higher than previously recorded, including the 0.25% prevalence in a French cohort of 802 patients.[23]

Use of statin medications in MS was reexamined. An earlier pilot trial had demonstrated increased relapses and MRI-enhancing lesions on the combination of atorvastatin (40 or 80 mg) and interferon beta-1a subcutaneously.[24] In a separate randomized trial in Naples, Italy, using only 20 mg of atorvastatin, no significant differences were seen with combination therapy. Twenty-eight percent of patients on interferon beta-1a subcutaneously thrice weekly and 25% of patients on both interferon beta-1a and atorvastatin 20 mg daily had MRI-enhancing lesions.[25] Interim safety analysis of 47 patients in the SIMCOMBIN trial on 80 mg of simvastatin or placebo in addition to interferon beta-1a 30 mcg intramuscularly demonstrated no antagonistic effects of the combination therapy.[26] In a pilot study with MRI imaging, 12 clinically isolated syndrome patients were randomized to placebo or simvastatin 80 mg daily plus interferon beta-1a intramuscularly. The addition of simvastatin was safe and well tolerated.[27]

Labels: 500 BEST PML STORIES & STUDIES, PML (Progressive Multifocal Leukoencephalopathy)

TYSABRI: "Biologic treatment for MS offers hope"

TYSABRI: "Biologic treatment for MS offers hope": Daytona Beach News-Journal

December 18, 2006

Biologic treatment for MS offers hope
By DR. YONG H. TSAI

Susan awoke one day with blurred, obstructed vision along with dizziness and numbness in her legs. A trip to her doctor's office triggered an order for blood tests and an MRI. She was diagnosed with multiple sclerosis (MS), an autoimmune disease involving the central nervous system.

Our brain and spinal cord, that house the main pathway of our body's nerve signals, offer a layer of insulation, called myelin, that surrounds and protects these nerve cells.

Like a plastic cover that surrounds the many wires of an electric cable, myelin covers nerve fibers to ensure that the nerve signals have safe, uninterrupted passage.

With MS, myelin sheaths break down (demyelination), due to inflammation caused by the autoimmune process. Damaged tissue eventually turns into scar tissue (sclerosis), meaning "multiple sclerosis."

Classic symptoms of MS include numbness, visual disturbance, abnormal gait, imbalance, muscle weakness or spasm, urinary incontinence, vertigo, slurred speech and even pain.

There are several forms of MS. Relapsing-remitting MS (RRMS) occurs about 25 percent of the time with intermittent relapses, including worsening of existing symptoms or the development of new ones.

Over the course of 10 to 15 years, more than 50 percent of RRMS will evolve into progressive MS, known for more frequent relapses, incomplete remission bouts and general overall deterioration.

During the past few years, beta interferons such as Avonex, Rebif, Betaseron and Copaxone, by modifying the inflammatory process, have been used to treat MS.

However, all still have side effects and some have poor results. In November 2005, Natalizumab (Tysabri), a biologic agent, was proven to block the function of key molecules. The process could transport immune cells crossing the brain and blood barrier (BBB), and prevent against an attack on one's central nervous system.

Clinical trials have shown Tysabri, administered by monthly intravenous infusion, is a very effective therapy in reducing relapses and decreasing new brain lesions.

However, the shocking news surfaced Feb. 28 that Tysabri was suspended temporarily from commercial distribution due to three serious, adverse events. Multifocal leukoencephalopathy (PML) occurred in clinical trial patients treated with Tysabri plus Avonex.

However, there have been no reports of PML in patients treated with either Tysabri or Avonex alone.

More recently, Tysabri has been permitted for MS treatment. Tysabri is only indicated as a single-agent treatment instead of in combined therapy with Avonex or other agents. It's for patients with the relapsing form of MS and poor response to traditional treatments.

Though there is some concern with rare side effects of Tysabri, this new biologic agent offers new hope.

Labels: 500 BEST PML STORIES & STUDIES, Avonex, Betaseron, Copaxone, PML (Progressive Multifocal Leukoencephalopathy), Tysabri