ECTRIMS 2007: Understanding MS: Pathogenesis, Neuroinflammation, and Degeneration CME

The materials presented here were prepared by independent authors under the editorial supervision of Medscape and do not represent a publication of the European Committee for Treatment and Research in Multiple Sclerosis. These materials and the related activity are not sanctioned by the European Committee for Treatment and Research in Multiple Sclerosis or the commercial supporter of the conference and do not constitute an official part of that conference.

Release Date: November 29, 2007;


The Impact and Burden of Multiple Sclerosis
Prevalence, Epidemiology, and Economic Burden

The national and regional prevalence of multiple sclerosis (MS) in France was reported at the 2007 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting, showing the overall prevalence in France and its 22 regions using the same methodology for the first time.[1] The computerized database of the National Health Insurance system (Caisse Nationale d'Assurance Maladie [CNAM]) assessed 80% of the French population or 54,974,101 people. The national and regional prevalence was estimated on October 10, 2004. There were 49,626 cases of MS on the CNAM database on the prevalence date. The national prevalence was 90.3 per 100,000 (2.6 female-to-male ratio). The northern and eastern regions had a higher prevalence (101.1-122.2 per 100,000) compared with the western and southern regions (78.5-84.3), with the central region having an intermediate prevalence (84.3-101.1 per 100,000). The prevalence in Northeast France was 1.5 times that of Southwest France. These observations are consistent with the previously reported data of the heterogeneous distribution of MS in Europe between Northern and Southern European countries.

In Japan there is a geographic phenotype difference in MS. Two distinct subtypes of MS occur in Asians: optic-spinal multiple sclerosis (OCMS or neuromyelitis optica) and conventional multiple sclerosis (CMS). From 4 nationwide surveys in Japan taken in 1972, 1982, 1989, and 2004, 9900 patients with MS were seen with a prevalence of 7.7/100,000.[2] OCMS was more common in southern Japan, whereas CMS was more common in the north. Peak age of onset in patients declined from their early 30s in 1972 to their early 20s in 2004. The proportion of patients with OCMS decreased over the observation period from 1972 to 2004. The frequency of CMS remained predominant in the northern regions.

In another epidemiologic presentation from Japan,[3] an increasing incidence of MS in the Tokachi province of Hokkaido (the northernmost island of Japan) was noted over a 30-year period. Two epidemiologic surveys were conducted to assess the prevalence of MS in 2001 and 2006. The Tokachi province had a population of 350,000 in 2001 and 360,000 in 2006. In 2001 the prevalence of MS that satisfied the Poser criteria was 8.6/100,000 and 13.1/100,000 in 2006. The mean age at the prevalence day was 41.0 years old and the mean age at onset was 28.4. The mean duration of disease was 12.6 years. The rate of primary progressive MS was 4%; relapsing-remitting MS was 70%; and secondary progressive MS was 26%. The prevalence of OCMS was 1.7/100,000 in both 2001 and 2006 showing no change compared with CMS. From prior data, it was known that the mean annual incidence increase of MS was 0.15 from 1975 to 1989 but 0.68 from 1990 to 2004. It appears that the increased prevalence of MS in northern Japan may be due to the increased incidence since 1990.

Since disease-modifying therapies (DMTs) have been available, considerable healthcare resources are used by MS patients. A healthcare utilization survey was carried out from a Health Insurance Portability and Accountability Act (HIPAA)-compliant commercial administrative claims database. The database contained integrated inpatient, outpatient, and pharmacy records on over 12 million persons from all major US regions, with the diagnostic International Classification of Diseases, Ninth Revision (ICD-9) code for MS (340.xx) as the first or second diagnosis.[4] The time span analyzed ranged from June 2005 to June 2006. The results found 12,216 identified MS patients, 77% of whom were women, and 84% aged 30-59 years (mean, 47 years). Fifty-six percent used at least 1 DMT. Interferon (IFN) beta-1a (intramuscular) was most common (19.8%), followed by glatiramer acetate (19.4%), INF IFN beta-1a subcutaneous (10.2%), IFN beta-1b (9.2%), and mitoxantrone (0.9%). Six percent received 2 or more DMTs. Those who used DMT were more likely to use symptomatic treatments: Forty-three percent used medications for depression, 31% for spasticity, 25% for bladder symptoms, 19% for fatigue, and 28% for pain or dysesthesiae. Twelve percent of patients were admitted to a hospital (56% condition-related); 11% had emergency department visits (13% condition-related); 2.4% had intensive care unit stays (44% condition-related); and 1.8% had skilled nursing facility stays (58% condition-related). Even though DMTs are available to the majority of MS patients, only 56% of the MS patients in this particular survey chose to take DMTs, but a significant amount of healthcare resources was still used by this group creating costs beyond the cost of the DMTs. This could be interpreted to suggest that improved treatments are needed to reduce the current healthcare as well as personal burden of MS.

Impact on Patients' Quality of Life and Cognition

Studies examining the impact of stressful life events on MS exacerbations have given conflicting results. However, a study of war stress from the Carmel Medical Center in Haifa, Israel, after the Hezbollah-Israeli war in 2006, showed a significant increase in MS exacerbations compared with similar time periods prior to the war.[5] The influence of psychological coping strategies was also examined.

Participants in the study were 156 MS patients with relapsing-remitting MS, all residents of northern Israel who were followed regularly at the MS clinic. The number of severe relapses treated with steroids during and following the war were compared with similar time periods at the preceding year. Exposure to war events, resulting subjective stress, and psychological coping strategies were evaluated by means of structured interviews. The results of the study indicated that 18 relapses occurred compared with 1-7 relapses in similar time periods over the 13 months prior to the war (P = .001-.02, McNemar's test). The percentage of patients reporting intense stress among wartime relapse patients compared with remission patients was significant (44% vs 20%, P = .03). The percentage of patients reporting high levels of stress from rocket attacks was higher in relapsing patients (67% vs 42%, P = .05). Home evacuation stress was higher in relapsing patients (33% vs 11%, P = .02). Active coping mechanisms, such as planning ahead for home displacement, were used less frequently by patients with relapses (17% vs 47%, P = .01).

Three variables were selected as predictors of wartime relapse by a logistic regression model: subjective sense of stress, distress associated with displacement, and MS relapse in the previous year. Active coping reduced the risk for an exacerbation. The conclusions of the study indicated that the risk for an exacerbation is increased by wartime stress but can be reduced with active coping measures. This suggests a role for preventive measures in dealing with stress-related exacerbations.

Fatigue is the most frequent complaint of MS patients, even those with low Expanded Disability Status Scale (EDSS) scores. Fatigue affects quality of life for many individuals and is the main burden on the health and socioeconomic system. Two studies with longitudinal evaluation over 2 years analyzed variables in regard to fatigue in MS. In the study from the Karolinska Institutet in Stockholm, Sweden,[6] 219 outpatients were assessed every 6 months with the Fatigue Severity Scale (FSS). Personal and environmental factors (sex, age, sense of coherence, living with a partner, living with children, work status, and immunomodulatory treatment) were correlated. The results showed that the FSS varied over the 2 years, with 54% changing FSS category 1 or several times. Twenty-seven percent were persistently fatigued and 19% never fatigued. In those patients who had increased or persistent fatigue, mood and disease-related factors were significantly different: depression (P = .001), weak sense of coherence (P = .02), living with a partner vs not living with a partner (P = .02), not working (P = .05), more than 10 years since the diagnosis of MS and with a moderate EDSS score compared with a mild EDSS (P = .001), more than 10 years since the diagnosis of MS and with a moderate EDSS compared with a severe EDSS score (P = .02), and a moderately progressive course compared with a mild course (P = .001). The conclusions of this study were that fatigue persistently affected at least 27% of the MS population and that those with a moderate course were at greatest risk, especially with an associated depression.

Another longitudinal study of fatigue[7] showed that depression and physical impairment were significantly associated with persistent fatigue in a group of 267 MS patients followed over 2 years. Thirty-seven percent of the patients had persistent fatigue; 38% had sporadic fatigue; and 25% had no fatigue. Persistent and sporadic fatigue were not associated with disease duration, but they were significantly associated with physical impairment, primary progressive MS, insomnia, heat-sensitive fatigue, sudden-onset fatigue, and mood disturbance.

Cognitive Dysfunction

Studies have shown that up to 65% of MS patients have cognitive dysfunction and that cognitive dysfunction is the greatest cause for disability.[8] However, cognitive dysfunction is not well evaluated in the EDSS score nor in the routine office or clinic evaluation. There is a growing awareness that cognitive dysfunction in MS is underappreciated, and the large number of poster and platform presentations concerning cognition in MS at the ECTRIMS 2007 meeting reflects that awareness. It is important that both the practicing neurologist and academic neurologist take into consideration the cognitive function of their MS patients when evaluating the patient for DMT so that prevention of disability can be possibly achieved. Walking with a cane may not be a reason for loss of employment, but inability to follow or carry out directions or inability to formulate a plan of action may be disabling.

A significant percentage of patients with clinically isolated syndromes (CIS) were found to have significant cognitive dysfunction when evaluated with a comprehensive neuropsychological battery.[9] In an evaluation of 15 patients with CIS vs 15 healthy controls, 53.3% of the CIS patients compared with 0% of the controls had cognitive dysfunction. Patients were significantly impaired on tasks evaluating attention (46.6%), long-term verbal and nonverbal memory (33.3%), visuospatial skills (26.6%), executive function (20%), and learning (20%).

In a retrospective review of 71 MS patients with severe cognitive impairment in the first 10 years of their disease, 15 of the patients presented with cognitive impairment as their first and primary symptom.[10] The characteristics of these 15 patients were mean age of onset, 43 years old; 11 women, 4 men; and mean delay from symptom onset to diagnosis, 2.6 years. Oligoclonal bands in the cerebrospinal fluid were present in all but 1 patient. The cognitive dysfunction had a severe impact on daily living activities and remained the predominant feature of the disease for all patients even though physical disability remained mild (mild pyramidal, sensory, cerebellar, brainstem, or bladder signs in 11 of 15) or absent (in 4). Initial MRI pattern showed diffuse and confluent lesions in the periventricular white matter with severe cortical atrophy (n = 7, pattern A). Others showed focal white matter lesions typical of MS with little or no atrophy (n = 8, pattern B). Two patients' MRIs evolved from pattern B to pattern A in 2-5 years. Clinicians need to be aware that MS-related cognitive dysfunction can be disabling even with little or no physical disability.

Available Pharmacologic Therapies

There are 6 US Food and Drug Administration (FDA)-approved DMTs in the United States at this time. These DMTs are IFN beta-1a (intramuscular or subcutaneous), IFN beta-1b, glatiramer acetate, mitoxantrone, and natalizumab. All of these treatments have shown significant reduction of relapse rate and MRI lesions compared with controls. There are some data from pivotal studies to suggest a reduction of disability but long-term prevention of disability needs further evaluation.

Because cognitive dysfunction is the main cause of disability in patients with MS, and brain atrophy is highly associated with cognitive dysfunction, reduction of brain atrophy is a potentially important marker for the prevention of disability -- more important than the EDSS. In the AFFIRM study there was a more rapid brain parenchymal fraction (BPF) reduction in patients receiving natalizumab compared with patients receiving placebo during the first year (0.56 vs 0.24%) than the second year (0.24% vs 0.43%).[11] The question of why this may have occurred includes a time lag between inflammation and subsequent tissue loss (or atrophy in which the decrease in BPF during the first year may be an inevitable consequence of inflammation and tissue damage that occurred prior to initiation of treatment) or "pseudoatrophy" as an initial decrease in BPF from resolution of edema and inflammatory infiltrate rather than actual tissue loss.

To answer these questions, an analysis was conducted on the kinetics of brain atrophy during the first year of treatment with natalizumab from the AFFIRM study. Drs. Fisher and Rudick from the Cleveland Clinic Foundation, Cleveland, Ohio,[12] presented further evaluation of the kinetics of brain atrophy and the relationship between inflammatory lesions and BPF during natalizumab treatment. The study was a randomized, double-blind, placebo-controlled, phase 2 study of 213 patients, of which 148 (100 natalizumab, 48 placebo) had analyzable MRI scans. The scans were performed at 1 month prior to the study, at month 0 (baseline), monthly for 6 months, and at months 9 and 12. The 2 treatment arms of natalizumab (3 mg/kg and 6 mg/kg) were combined for all statistical analyses. The results showed an initial decrease in BPF in the early treatment period, followed by a leveling off after month 4 to the end of the treatment period (month 12). This pattern of BPF change is most suggestive of pseudoatrophy, which is consistent with an anti-inflammatory effect followed by a reduced atrophy rate in the late treatment phase. Therefore, this pattern of decrease in brain volume during the study suggests that natalizumab may have a beneficial effect on brain atrophy, beginning about 4 months after treatment initiation.

As of September 21, 2007, a total of 26,200 patients have been exposed to natalizumab,[13] with no new cases of progressive multifocal leukoencephalopathy reported. Seventeen thousand patients remain on natalizumab as of October 2007. The overall rate of serious hypersensitivity reactions is 0.64%, usually at the second infusion. Testing for the presence of persistent antibodies to natalizumab (detected on 2 occasions at least 6 weeks apart) prior to redosing following a prolonged dose interruption is recommended because reduced efficacy and increased risk for hypersensitivity reactions are more common in these patients. Twenty-four women in the United States and Austria with MS and exposure to natalizumab at any time during the first 3 months of pregnancy have enrolled in a pregnancy registry. Twenty-one pregnancies were ongoing as of August 23, 2007 with 1 live birth, 1 spontaneous abortion, and 1 elective abortion.

Nonpharmacologic Intervention

Physical therapy is a mainstay of patients of all types with physical disabilities. Studies of MS patients have shown variable results, probably due to many reasons, such as fatigue, instability of the disease, and small sample size. The type of physical therapy also varies. In a study from Belgium,[14] the benefit between bilateral exercise ("in-phase") and alternating exercise ("antiphase") was evaluated at various speeds of repetition for 10 weeks. Exercise rates of 0.75 Hz, 1.00 Hz, 1.25 Hz, and 1.50 Hz were used. Patients had mild-to-moderate disabilities (EDSS scores from 1.5 to 6.5). Coordination accuracy and stability were measured at baseline and at 10 weeks. The results showed that physical intervention programs with emphasis on strength do not influence motor control of the lower limbs after a 10-week intervention period. Antiphase training is performed with the lowest accuracy at the lowest frequency but improves when frequency increases. This is a particular finding in MS patients and contrasts with the current literature in regard to healthy subjects. This study also found that motor control and the EDSS were not correlated, probably due to the fact that EDSS is a rough picture of the distance that an MS patient can walk, whereas motor control is about stability and accuracy.

A comprehensive rehabilitation program showed improvement of MS patients with primarily pyramidal impairment and mild-to-moderate MS in both activities of daily living and mobility.[15] In a study with 200 patients in an inpatient multidisciplinary program, patients were assessed at the beginning and end of admission with the EDSS. Functional status was evaluated with the Barthel Index and Rivermead Mobility Index. Sixty-five percent were women, with a mean age of 50 and mean duration of disease of 17.3 years. All patients were enrolled in an individualized, goal-oriented, multidisciplinary inpatient program on the basis of practical skills of daily living. Results of rehabilitation were assessed in the whole sample as well as by comparing 3 subgroups: a mild group (EDSS 2-5.5), moderate group (EDSS 6-65), and severe group (EDSS 7-8.5). The results of the program showed greater improvement in patients in the mild and moderate groups, although the severe group did show some improvement. Pyramidal impairment was the greatest predictor of mobility and activities of daily living.

In another rehabilitation study,[16] patients were randomized to 3 treatment groups: outpatient, inpatient, and day hospital. There were 9 patients in each group for a total of 27 patients. The outpatient group (mean EDSS of 6.0) had 1-hour rehabilitation training twice weekly; the inpatient group (mean EDSS of 5.5) had more than 2 hours daily; and the day hospital group (mean EDSS of 6.5) had 2 hours daily. Outcome measures were Berg Scale, Barthel Index, and Hauser Ambulation Scale. The program lasted 5 weeks. The results showed that all patients improved in outcome measures except for ambulation, but there was no difference among the groups. The conclusion was that outpatient rehabilitation is equally effective as inpatient or day hospital therapy, and outpatient rehabilitation saves time and economic resources.

Supported by an independent educational grant from Genentech

References


Moreau R, Kazaz E, Clerc L, et al. Prevalence of multiple sclerosis in France and its 22 regions. Mult Scler. 2007;13(suppl2):S103. Abstract.
Osoegawa M, Fukazawa T, Fujihara K, et al. Temporal and geographical changes of multiple sclerosis phenotype in Japanese: nationwide survey results over 30 years. Mult Scler. 2007;13(suppl2):S101-102. Abstract.
Houzen H, Niino M, Kikuchi S, et al. Increasing risk of multiple sclerosis in Japan. Mult Scler. 2007;13(suppl2):S102. Abstract.
Chin P, Laouri M, Broder M, et al. Healthcare utilization among insured multiple sclerosis patients in the U.S. from 2005-2006. Mult Scler. 2007;13(suppl2):S261. Abstract.
Golan D, Somer E, Dishon S, et al. War stress, psychological coping mechanisms and exacerbations of multiple sclerosis. Mult Scler. 2007;13(suppl2):S238. Abstract.
Johansson S, Ytterberg C, Hillbert J, et al. A longitudinal study of variations in perceived level of energy and predictors of fatigue in multiple sclerosis. Mult Scler. 2007;13(suppl2):S115. Abstract.
Lerdal A, Celius EG, Krupp L, et al. Longitudinal patterns of fatigue in patients with multiple sclerosis. Mult Scler. 2007;13(suppl2):S114-115. Abstract.
Rao SM. Neuropsychology of multiple sclerosis. Curr Opin Neurol. 1995;8:216-220.
Kocer B, Nazliel B, Irkec C. Cognitive dysfunction in patients with clinically isolated syndrome. Mult Scler. 2007;13(suppl2):S114. Abstract.
Assouad R, Tourbah A, Sedel F, et al. Cognitive presentation in multiple sclerosis. Mult Scler. 2007;13(suppl2):S114. Abstract.
Miller DH, Soon D, Fernando KT, et al; AFFIRM Investigators. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology. 2007;68:1390-401.
Fisher E, Rudick R, Dalton CM, et al. The kinetics of brain atrophy during the first year of treatment with natalizumab. Mult Scler. 2007;13(suppl2):S168. Abstract.
Panzara M, Belcher G, Kooijmans M, et al. Use of natalizumab in patients with relapsing multiple sclerosis: updated safety results from TOUCH and TYGRIS. Mult Scler. 2007;13(suppl2):S169. Abstract.
Alders G, Gijbels D, Feys P, et al. The effect of physical intervention programs on coordination quality of the lower limbs in persons with multiple sclerosis. Mult Scler. 2007;13(suppl2):S132. Abstract.
Grasso MG, Triosi E, Tonin A, et al. Effectiveness of multiple sclerosis rehabilitation. Mult Scler. 2007;13(suppl2):S130. Abstract.
Giusti A, Viti B, Pirani G, et al. The effectiveness of neurological rehabilitation in multiple sclerosis: comparison between different rehabilitative settings. Mult Scler. 2007;13(suppl2):S130. Abstract.

Evaluating New Data for the Treatment of MS
New and Emerging Pharmacologic Treatments

Oral Therapies

Several new treatments for multiple sclerosis (MS) are in phase 2 or phase 3 trials. The combined analyses of subcutaneous cladribine were presented by Dr. S. Cook for the Cladribine Clinical Study Group.[1,2] The safety profile of cladribine at parenteral doses of up to 2.1 mg/kg was similar to placebo, with a sustained lymphocytic depleting effect consistent with its therapeutic mechanism. The parenteral trials included MS patients with relapsing remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS). Since parenteral doses of 0.7 to 2.1 mg/kg can be achieved with oral preparations, 2 oral studies are now underway. One study, CLARITY, is a monotherapy, phase 3 trial for patients with RRMS and an Expanded Disability Status Scale (EDSS) score of 0-5.5 for a 2-year period. It has 3 treatment arms; Group 1 receives 10-mg cladribine tablets for 4-5 days on weeks 1, 5, 9, and 13 in the first year. Group 2 receives cladribine for the first 2 treatment periods but placebo for the third and forth treatments. Group 3 receives placebo for all 4 treatments.[3] At this time, enrollment is completed with 1329 patients. The primary efficacy parameter is the relapse rate from baseline to week 96. The other oral cladribine study, ONWARD, is a phase 2b study that combines IFN-beta-1a (subcutaneous 3 times weekly, 44 mcg) with oral cladribine in an otherwise similar design.[4] The primary efficacy parameter is number of new Gd+ T1 lesions from baseline to week 96. A new subcutaneous formulation of IFN-beta-1a is being used in this trial.

Two phase 3 trials are underway with an oral fumaric acid derivation (BG00012) in patients with RRMS.[5] BG00012 has been shown in vitro to inhibit expression of cytokines and adhesion molecules involved in inflammation, with resultant anti-inflammatory and neuroprotective effects. A phase 2b double-blind, placebo-controlled, 24-week study with a 24-week safety extension showed a significant 69% reduction of Gd+ T1 lesions at 720 mg/day of BG00012 compared with placebo. Additionally, patients receiving BG00012 had 48% fewer T2 lesions and 53% fewer T1 lesions compared with placebo (all P = .001). Two phase 3 studies are now underway: DEFINE (a double-blind, placebo-controlled study of 2 doses of BG00012 240 mg 2 or 3 times a day vs placebo) and CONFIRM (same design but with an added comparator of glatiramer acetate). They are 2-year studies of 1000 patients and 1200 patients, respectively, with RRMS and an EDSS score of 0-5.0. The primary efficacy parameter of DEFINE is the proportion of patients relapsing over the 2 years, and the primary efficacy parameter of CONFIRM is the rate of clinical relapse at 2 years.

Monoclonal Antibody Therapies

Alemtuzumab is a humanized monoclonal antibody against the T-cell antigen CD52 on lymphocytes. Two studies evaluating alemtuzumab (ALEM) in patients with RRMS were reported at the ECTRIMS meeting. One trial was in treatment-naive patients comparing 2 doses of ALEM (either 24 mg/day intravenously [IV] for 5 days at month 0 and for 3 days at month 12 or 12 mg/day) and subcutaneous IFN-I-beta 3 times weekly at 44 mcg.[6] At 2 years, 84.4% of low-dose ALEM patients were relapse free, 90.6% of high-dose ALEM patients were relapse free, and 60.4% of IFN patients were relapse free (P = .0002 low-dose and P = .0001 high-dose). ALEM improved disability on the Multiple Sclerosis Functional Composite (MSFC) and EDSS scores. Relapses were reduced and delayed. Safety findings associated with ALEM were immune thrombocytopenic purpura (ITT) and autoimmune disorders of the thyroid gland. The other trial with ALEM included MS patients who had failed prior treatment with any IFN. The patients had to have had the onset of MS in the last 5 years, EDSS scores of 0-6, IFN for at least 6 of the last 24 months, and 2 relapses.[7] Forty-five patients received 2 cycles of ALEM with 1 mg IV methylprednisolone prior to ALEM. Patients received ALEM 24 mg/day for 5 days (cycle 1) and then 24 mg/day for 3 days at month 12 (cycle 2). The result was a 9.3-fold reduction of relapse rate (relapses in 2 years prior to cycle 1 vs relapses in 2 years following; P = .0001). On disability measurements, 70% of patients had stable or improved MSFC. However, 4 cases of autoimmune thyroid disorder and 1 case of ITT developed in the 45 patients.

Daclizumab is a humanized monoclonal antibody that depletes CD25 from the cell surface of T cells and interacts specifically with the interleukin 2 receptor alpha chain (IL2RA). Daclizumab has shown promise as a therapy for both RRMS and SPMS in combination with INF and as monotherapy. The results of a recently completed phase 2 study with 230 patients with RRMS with EDSS scores of 0-5 and breakthrough disease while on any IFN were presented in a platform presentation.[8] There were 230 patients at 51 sites in North America and Europe. There was a 24-week double-blind, placebo-controlled treatment period and a 48-week washout period. There were 3 arms to the study: placebo add-on, 1 mg/kg subcutaneously every 4 weeks, or 2 mg/kg subcutaneously every 2 weeks. Primary endpoint was new Gd+ lesions between weeks 8 and 24. Secondary endpoints were relapse rate and safety issues. The results indicated a 25% reduction of Gd+ lesions with 1 mg/kg add-on of daclizumub (not significant [NS]) and a 72% reduction of Gd+ lesions with 2 mg/kg every 2 weeks (P = .004). Relapse rate reduction was 35% in each dosing group (NS). Daclizumab was safe and well tolerated, with no significant safety issues.

Individually Tailored Therapy for SPMS and PPMS

SPMS without exacerbations is often considered a nonmodifiable disease state. It is a phase of MS considered to consist of neurodegeneration with axonal loss and cortical and spinal cord atrophy. However, there are a few ongoing trials for SPMS. One involves the intravenous administration of a synthetic peptide, MBP8298, for SPMS patients with HLA haplotypes DR2 and/or DR4. MAESTRO-01 is a multicenter, multinational clinical trial in which over 600 patients have been enrolled.[9] An interim safety analysis of the first 508 patients, on a blinded basis, showed no significant safety concerns. An interim analysis of the first 200 patients at 2 years is expected in the third quarter of 2008. MAESTRO-03 is currently enrolling in the United States for SPMS patients without exacerbations to receive 500 mg MBP8298 or sterile water as placebo IV every 6 months.

Rituximab (RTX) is a monoclonal antibody that specifically targets CD20+ B cells. There may be a pathogenic role of B cells in MS, particularly in PPMS. In an ongoing placebo-controlled study, 439 patients with PPMS by the McDonald Criteria with greater than 1 year duration of disease, an EDSS score of 2-6.5, and cerebrospinal fluid (CSF) showing elevated IgG or oligoclonal bands in the past 24 months were randomized in a 2:1 manner to receive 1000 mg RTX twice every 24 weeks over 96 weeks (4 courses) or placebo.[10] The patients are to be followed to 122 weeks with magnetic resonance imaging at -2, 0, 6, 48, 96, and 122 weeks. Primary endpoint is a 1-point increase in the EDSS sustained for at least 12 weeks. Secondary outcomes are change in baseline to week 96, T2 lesion volume, and brain volume. Results of enrollment are that 50.3% of the 439 patients are female with a mean age of 50.4 years; 56% had a baseline EDSS greater than 4 with a mean EDSS of 4.03. Sixty-five percent of patients had never had a disease-modifying treatment. At randomization, there was a mean Gd+ lesion of 0.7 with 75.2% with no new lesions, but 24.8% had greater than 1 Gd+ lesion. These are pooled demographic data from an ongoing blinded study. With nearly 25% of patients with baseline Gd+ lesions and all patients with active CSF due to inclusion criteria, an enrichment for active disease in this trial is suggested. This is consistent with active immunologic activity in this patient population and may increase the possibility for a therapeutic effect of RTX.

Neuromyelitis Optica Treatment Options

Neuromyelitis optica (NMO; called spinal-optical MS in Asia and also called Devic's disease) is a serious, inflammatory, demyelinating disease of the optic nerves and spinal cord. Many patients fail to respond to steroid therapy or other standard treatments, including chemotherapy, for MS. Five-year survival may be less than 80%. Dr. Khatri[11] presented a series of 6 NMO patients who had failed high-dose methylprednisolone and prednisone treatment with plasma exchange (PE). All patients met diagnostic criteria for NMO and were serum NMO-IgG antibody positive. Three patients were white and 3 were African American (age range, 34-53; mean 40). All were female. EDSS ranged from 2 to 8.5 (mean 6.3). Following PE, all patients improved and stabilized (EDSS mean improved from 6.3 to 5.1). Four patients continue to receive PE (1 patient for the past 16 years). The frequency of maintenance PE varied from once a month to every 3 months. Because of insurance problems, 2 of the 4 patients had to stop PE for several months. This resulted in both patients becoming blind and bedridden, despite treatment with high-dose methylprednisolone and cyclophosphamide. When PE was restarted, there was dramatic improvement, although not to the prior functional state before it was stopped. The conclusion is that PE can be effective even on a long-term basis for some NMO patients refractory to other treatments.

Symptomatic Therapy

Fampridine-SR (a sustained-release form of 4-aminopyridine) can be useful in improving central conduction of demyelinated axons in the central nervous system (CNS) by closing potassium channels. Clinically, it has been shown in phase 2 and phase 3 trials to improve pyramidal tract function as measured by the timed 25-foot walk. A meta-analysis of a phase 2 and a phase 3 fampridine trial was presented in a platform presentation discussing the results of the trials, the efficacy assessments, and the clinical validity of outcome measures in the 2 trials. Both were double-blind, placebo-controlled, 14-week studies of MS patients with ambulatory deficits.[12] A total of 501 patients were included in the analysis, with a randomization ratio of 3:1 (drug:placebo). The results showed a significant improvement in ambulation for fampridine-treated patients over placebo (P = .001). The primary efficacy measurement was that of a "timed walk responder," which was a patient whose walking speeds for at least 3 of 4 treatment visits were faster than the fastest speed of any of the 4 pretreatment visits and one follow-up visit. Clinical impact was assessed with the 12-item Multiple Sclerosis Walking Scale, with significant improvement of fampridine over placebo patients (P = .001). Patient satisfaction was also high on both studies, with the Subject Global Impression score significantly better for fampridine treatment vs placebo (P = .001)

Low-dose naltrexone (LDN) has been popular among some MS patients as an alternative therapy. Naltrexone has long been approved by the US Food and Drug Administration as an orally administered treatment for heroin addiction. It is a semisynthetic opiate antagonist approved for use in a 50-mg dose. It has been used for the symptomatic treatment of pain, spasticity, and fatigue. In a study supported by the Italian Federation of Multiple Sclerosis, data supporting some benefit of LDN in PPMS patients were presented.[13] Prior evidence has shown that when naltrexone is given at very low doses (5 mg), an upregulation of endorphins results and no opiate antagonism occurs. In 40 PPMS patients treated with LDN in an open-label manner as a pilot study for safety, LDN has been safe so far. Transient liver function test elevation, mild agitation, and sleep disturbance have occurred as the main side effects. Only 2 dropouts have occurred, 1 for protocol violation and 1 for severely increased hypertonia. Efficacy results are pending, but patients reporting a sense of well-being may have a neurochemical basis for that effect.

Ethics of Placebo-Controlled Clinical Trials

Dr. Chris Polman discussed the ethics of placebo-controlled trials in the treatment of MS in a platform presentation on behalf of the National MS Society International Advisory Committee on Clinical Trials in MS, which met in Washington, DC in March 2007.[14] This committee updated the prior recommendation of the International Advisory Committee that had been published in 2001.[15] The recommendations of the current Committee are in context of the newly available treatment since 2001. The prior recommendations basically said that placebo-controlled trials were allowable "if certain conditions were met." These conditions have been expanded and are more restrictive. The current Committee recommendations for placebo-controlled trials to be ethical are: (1) if there is no existing effective therapy (EET) for their type of MS (such as for PPMS or most SPMS); (2) if the patient refuses treatment (such as with injectable medications); (3) if no EET has been effective for their type of MS (more than 1 adequate trial for each class of medication) or intolerable side-effects have occurred; (4) the patient must be well informed not only through the informed consent (IC) process but there also should be a patient advocate present; (5) there should be a separation between the treating neurologist and research neurologist; (6) the IC process should be repeated throughout the clinical trial to be sure that the patient is aware of all other treatment options; and (7) in areas that are "resource-restricted," the trial drug must be available to the subjects after the trial has been completed.

Supported by an independent educational grant from Genentech

References

Cook S. Combined analysis of the safety and tolerability of cladribine from four randomized, double-blind, parallel-group, placebo-controlled trials in patients with multiple sclerosis. Multiple Sclerosis. 2007;13(suppl 2):S244-245 (abstract).
Cook S. Safety profile of cladribine following repeat treatment: a combined analysis of data from five clinical trials in patients with multiple sclerosis. Multiple Sclerosis. 2007;13(suppl 2):S245 (abstract).
Giovannoni G, Comi G, Cook S, et al. The CLARITY study (CLAdRIbine tablets Treating multiple sclerosis orallY): design of a phase III trial of oral cladribine in relapsing multiple sclerosis. Multiple Sclerosis. 2007;13(suppl 2):S245 (abstract).
Montalban X, Cohen BA, Jeffery DR, et al. Oral cladribine added to interferon beta-1a for active multiple sclerosis: a 96-week, double-blind, placebo-controlled phase IIb study. Multiple Sclerosis. 2007;13(suppl 2):S245-246 (abstract).
Gold R, Fox R, Dawson K, et al. Two phase 3 studies to determine the efficacy and safety of BG00012, a novel, oral fumaric acid derivative, in patients with relapsing multiple sclerosis. Multiple Sclerosis. 2007;13(suppl 2):S173 (abstract).
Coles AJ; on behalf of the CAMMS223 Study Group. Alemtuzumab improved multiple sclerosis functional composite scores and delayed time to first relapse at 2-year interim analysis compared to subcutaneous interferon beta-1a. Multiple Sclerosis. 2007;13(suppl 2):S166 (abstract).
Fox E, Mayer L, Sullivan H, et al. Two-year results with alemtuzumab in patients with active relapsing-remitting multiple sclerosis who have failed licensed beta interferon therapies. Multiple Sclerosis. 2007;13(suppl 2):S166-167 (abstract).
Montalban X, Wynn D, Kaufman et al. Preliminary CHOICE results: a phase 2, randomized, double-blind, placebo-controlled multicentre study of subcutaneous daclizumab in patients with active, relapsing forms of multiple sclerosis on interferon beta. Multiple Sclerosis. 2007;13(suppl 2):S18 (abstract).
Arfors L; on behalf of the MAESTRO-01 Investigators Group. Safety observations from administration of MBP8298 as part of the ongoing phase 3 MAESTRO-01 SPMS clinical trial. Multiple Sclerosis. 2007;13(suppl 2):S171-172 (abstract).
Hawker K, Freedman MS, O'Connor P, et al. Rituximab in patients with primary progressive multiple sclerosis: demographics in a phase II/III randomized, double-blind, placebo-controlled multicentre trial. Multiple Sclerosis. 2007;13(suppl 2):S165 (abstract).
Khatri B, Kramer J, Dukic M, Palencia M. Sustained long-term improvement with plasma exchange in patients with recurrent neuromyelitis optica unresponsive to corticosteroids. Multiple Sclerosis. 2007;13(suppl 2):S173 (abstract).
Goodman AD, Brown TR, Cohen JA, et al. Meta-analysis of phase 2 and 3 fampridine trials in multiple sclerosis: efficacy assessment and validation of clinical meaningfulness of outcome measure. Multiple Sclerosis. 2007;13(suppl 2):S33 (abstract).
Gironi M, Boneschi FM, Solaro C, et al. Pilot multicenter study of low dose naltrexone in primary progressive multiple sclerosis. Multiple Sclerosis. 2007;13(suppl 2):S176 (abstract).
Polman CH; on behalf of the National MS Society International Advisory Committee on Clinical Trials. A reconsideration of the ethics of placebo-controlled clinical trials in MS: outcomes of an international conference. Multiple Sclerosis. 2007;13(suppl 2):S17 (abstract).
Lublin FD, Reingold SC. Placebo-controlled clinical trials in multiple sclerosis: ethical considerations. National Multiple Sclerosis Society (USA) Task Force on Placebo-Controlled Clinical Trials in MS. Ann Neurol. 2001;49:677-681.

Exploring the Pathogenesis of MS and the Rationale for Current Treatments
Discussion of Key Cellular Players and Important Immune Responses

Dr. David Hafler presented a platform discussion reviewing the current and emerging understanding of the genetic basis of multiple sclerosis (MS).[1] Persons with a first-degree relative are known to be at higher risk than the average person. The prevalence of MS is 0.1% in the general population, 2% to 4% in siblings, 5% in dizygotic twins, and 30% in monozygotic twins. MS may be considered a complex genetic disease involving many genomic expressions. It has been known for over 30 years that there is a major histocompatibility complex (MHC) on chromosome 6p21. It is also known that MS is a disease that involves the dysfunction of the CD4+CD25 high regulatory T-cell function.

In order to further elucidate the genetic basis of MS, a collaborative effort of US and UK researchers used a staged approach to identify risk alleles associated with MS. The first stage involved whole genomic association scans using the Affymetrix 500,000 SNP (single nucleotide polymorphisms) GeneChip (Santa Clara, California) to analyze DNA from 931 trio families (an MS patient and both parents). The second stage involved further analysis of the most frequently appearing SNPs. Further analysis identified the 2 most prevalent SNPs, IL2RA and IL7R. Although IL2RA has been identified in both patients with MS and patients with diabetes, it is likely that different variants are associated with each of these diseases because the risk for MS and DM do not coexist. Although there may be different variants of the same gene for IL2RA, this may open up a new area for genetic typing in MS, which could lead to specific therapeutic choices for patients who may be more likely to respond to one type of treatment vs another. Genetic screening is currently being used in the MAESTRO-03 study. Data from the MAESTRO-1 study showed that patients with DR2 or DR4 haplotypes were likely to respond to treatment in secondary progressive MS (SPMS), while MS patients with other markers did not, so one of the inclusion criteria in the MAESTRO-3 study is a blood test on the screening visit. The patient must be DR2 or DR4 positive to be in the study.

In a platform presentation following Dr. Hafler's presentation, Dr. Howard Weiner discussed circulating markers that have been found to differ between relapsing remitting MS (RRMS) and SPMS.[2] The central question regarding MS treatment is whether early and aggressive immunotherapy will prevent the conversion to SPMS in the majority of patients. The specific identification of antibody patterns in MS may help achieve that goal because it is known that inflammatory antibodies are linked to brain pathology. The progression of RRMS to SPMS is likely to be due to neuronal degeneration triggered by inflammation.

Dendritic cells (DCs) are antigenic cells of the innate immune system that have the unique ability to induce primary immune responses. Circulating myeloid DCs were isolated from blood samples to determine if there were abnormalities in patients with MS and if myeloid DCs were related to disease stage. SPMS patients were found to have a greater percentage of myeloid DCs expressing CD80, IL-12, and TNF-alpha while having a lower percentage of PD-L1 compared with patients with RRMS or controls. A higher percentage of RRMS patients had DCs producing greater amounts of Th1 (IFN-alfa and TNF-alpha) and Th2 (IL-4, IL-13) compared with controls and SPMS patients. These results may be interpreted as showing that there is a loss of an inflammatory component in the immune system when MS patients transition from RRMS to SPMS. This may explain, in part, an immunologic basis for the different stages and clinical patterns of MS.

In a comparison of the treatment effects of FTY720 (a new oral treatment in human trials for MS), IFN-beta, and glatiramer acetate (GA) on experimental autoimmune encephalomyelitis (EAE), each of the 3 compounds were given to Lewis rats in a model of progressive EAE.[3] For decades, EAE has been the experimental model for MS. FTY720 was administered at 3 mg/kg orally. At this dose, the onset of acute EAE was inhibited, and when given after recovery from an acute attack in an untreated animal, FTY720 inhibited further relapses. When FTY720 was given at a dose of 6 mg/kg orally during an acute exacerbation, the progressive phase of EAE was inhibited. GA failed to prevent the progressive phase at doses of 10 mg/kg orally or 5 mg/kg subcutaneously. GA at doses of 15 mg/kg orally or 10 gm/kg subcutaneously failed to prevent the onset or severity of relapses of EAE. IFN-beta given at 10,000 U intraperitoneally 3 times weekly failed to prevent the progressive phase of EAE.

Cerebrospinal Fluid Analysis in Clinically Isolated Syndromes

Clinically isolated syndromes (CIS) have been extensively evaluated by clinical and magnetic resonance imaging (MRI) criteria for risk to develop clinically definite MS (CDMS). The clinical diagnostic value of cerebrospinal fluid (CSF) analysis was presented from 104 patients presenting with a first clinical episode consistent with a demyelinating disease of the central nervous system.[4] A diagnosis of either CIS or possible MS was made. The patients underwent neurologic evaluation, brain MRI, and CSF analysis and were followed from 2 to 6 years as to their course and final diagnosis according to the McDonald criteria. The results of the CSF evaluation showed a significant difference between the possible MS patients and CIS patients, with 82% of the possible MS patients having positive CSF for oligoclonal bands (IgGOB) while 18% of CIS patients had positive CSF for IgGOB. The conclusions of the authors were that "positive CSF" should be considered among the criteria of dissemination in time of lesions in MS.

Rating Scales

Optical coherence tomography (OCT) is a noninvasive and relatively inexpensive way to measure the retinal fiber layer. Dr. Siger and colleagues[5] presented data showing that by measuring the retinal nerve fiber layer (RNFL), the most proximal part of the optic nerve, a measure of axonal degeneration can be obtained. Fifty-one patients underwent OCT with RNFL measurements, 20 with optic neuritis (ON) and MS, 31 with MS and without ON, and 12 healthy controls. T2- and T1-weighted imaging lesion volume, T1/T2 ratio, and brain atrophy were analyzed and correlated with OCT. RNFL was also correlated with disease duration and neurologic status. The results showed that RNFL was significantly reduced compared with controls in the affected eye (ON) but not significantly different when compared with the unaffected eye. Reduction of RFNL was correlated with MRI measures of brain atrophy (P = .01) and increased T1 lesion (black holes) volume (P = .03). RNFL reduction also correlated with clinical data (Expanded Disability Status Scale: P = .004).

Supported by an independent educational grant from Genentech

References

Moreau R, Kazaz E, Clerc L, et al. Prevalence of multiple sclerosis in France and its 22 regions. Multiple Sclerosis. 2007;13(suppl 2):S103 (abstract).
Osoegawa M, Fukazawa T, Fujihara K, et al. Temporal and geographical changes of multiple sclerosis phenotype in Japanese: nationwide survey results over 30 years. Multiple Sclerosis. 2007;13(suppl 2):S101-102 (abstract).
Houzen H, Niino M, Kikuchi S, et al. Increasing risk of multiple sclerosis in Japan. Multiple Sclerosis. 2007;13(suppl 2):S102 (abstract).
Chin P, Laouri M, Broder M, et al. Healthcare utilization among insured multiple sclerosis patients in the U.S. from 2005-2006. Multiple Sclerosis. 2007;13(suppl 2):S261 (abstract).
Siger M, Dziegielewski K, Jasek L, et al. Optical coherence tomography in multiple sclerosis as a measure of brain atrophy. Multiple Sclerosis. 2007;13(suppl 2):S86 (abstract).


Authors and Disclosures

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Author

Keith R. Edwards, MD

Assistant Clinical Professor of Neurology, Harvard Medical School, Boston, Massachusetts; Consulting Neurologist, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts

Disclosure: Keith R. Edwards, MD, has disclosed that he has served as an advisor or consultant to Allergan Pharmaceuticals, GlaxoSmithKline, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, and Serono.
Editor

Iwona Misiuta, PhD, MHA

Scientific Director, Medscape LLC, New York, NY

Disclosure: Iwona Misiuta, PhD, MHA, has disclosed no relevant financial relationships.
Stephanie Kushner, PhD

Scientific Director, Medscape LLC, New York, NY

Disclosure: Stephanie Kushner, PhD, has disclosed no relevant financial relationships.

Resolvyx Pharmaceuticals: Fish-Oil Mystery Solved, Blockbuster Drugs to Follow?

David Stipp 11/30/07

If you haven’t considered eating more fish or taking fish-oil pills by now, you’re probably very young, just in from Mars, or both. The case for the health benefits of omega-3 fatty acids, the compounds of interest in fish oil, rests on thousands of studies over the past two decades, and the list of ills they may ward off or ameliorate includes heart attacks, stroke, diabetes, macular degeneration, rheumatoid arthritis, Alzheimer’s disease, various cancers, osteoporosis—basically every major disease of aging, as well as psoriasis, asthma and others. But there’s a deep mystery here: Why is omega-3 linked to so many different benefits? You could spend weeks immersed in the fish-oil literature trying to answer that. But it would be easier to ask the brain trust at Resolvyx Pharmaceuticals, a two-year-old startup in Bedford, MA. The company not only offers a compelling explanation but is also poised to capitalize on it to develop drugs as versatile as fish oil itself.

Here’s the big idea: One of the main things that goes wrong as we age is the fraying of our inner controls on inflammation, the heated immune reaction, accompanied by pain and swelling, that’s triggered by invading germs or other insults. That allows pockets of low-level inflammation to linger—picture smoldering coal-seam fires across your inner landscape. Just about every degenerative disease of aging, from atherosclerosis to Alzheimer’s, has been found to centrally involve insidious inflammation. Chronic inflammation also does much of the damage in autoimmune diseases, such as rheumatoid arthritis. Thus, if you wanted to come up with a do-all miracle drug, you probably couldn’t do better than to develop a potent anti-inflammatory that could be safely taken for long periods. And if you were smart, you’d probably start, like Resolvyx’s founding scientists, by investigating the safest anti-inflammatory around, fish oil.

Omega-3 fatty acids’ anti-inflammatory effect isn’t new. But the molecular details of the effect—and the ability to explain fish oil’s remarkable diversity of likely benefits—have only come into focus over the past few years. The progress stems largely from the work of Resolvyx cofounder Charles Serhan, an anesthesia professor at Harvard Medical School. Serhan is known for groundbreaking research on natural anti-inflammatory lipids. Since 2000 his group at Boston’s Brigham & Women’s Hospital has elucidated how omega-3 fatty acids are processed in the body to give rise to sets of potent lipids, dubbed resolvins and protectins, that affect the process of inflammation.

One of Serhan’s seminal ideas is that after inflammation has done its thing, it doesn’t just passively fade as its triggering molecules dissipate. Instead, it is actively curtailed during a “resolution phase” by chemical messengers that pacify angry immune cells and halt production of inflammatory signals. Serhan’s research suggests the resolvins are among the most important of these naturally-occurring resolvers of inflammation, hence the name—mere nanograms of them can quell inflammation. The protectins play similar roles, apparently springing forth to help to resolve inflammation in asthma and other diseases, as well as preventing death of stressed, potentially suicidal nerve cells during inflammatory flares caused by strokes and other brain hits.

With the discovery of key lipids that resolve inflammation, says Serhan, “we’ve figured out an old problem that first came up in the 1920s: Why are essential fatty acids essential?” (When discovered in 1923, omega-3 fatty acids were classed as essential because, like vitamins, they were found to be critical for normal growth, and the body can’t make them from scratch—they or their immediate precursors must come from food.) Indeed, adds Resolvyx executive vice president James Nichols, without the lipid peace-makers, “you’d accumulate inflammation over time” as one insult after another triggered unresolved flare-ups.

In 2002, Serhan joined forces with Per Gjorstrup, a native of Sweden who had long worked in the drug industry and was most recently at Biogen, to form Resolvyx. The startup’s goal seemed, literally, a natural: turn the body’s own inflammation regulators into drugs to halt run-amok inflammation. But it took three years to win over venture capitalists,says Gjorstrup, now Resolvyx’s chief scientific officer. They had two main reservations: Natural resolvins and protectins act locally and typically exist only minutes before getting chewed up by enzymes, hence it seemed unlikely that drugs based on them would last long enough in the body to work. And the lipids’ chemical complexity—chains of 20-plus carbon atoms festooned with side groups—suggested it would cost too much to synthesize them in large quantities.

Eventually, Resolvyx advisor Nicos Petasis, a University of Southern California chemist, helped finesse the synthesis issue. Meanwhile, Serhan’s group and Resolvyx scientists demonstrated that the compounds have surprisingly long half-lives when administered as drugs, and that they show efficacy in animals with various inflammatory illnesses. In December 2005, CHL Medical Partners, Atlas Venture, and Flagship Ventures launched Resolvyx with a $17 million first-round financing. A year ago, Resolvyx’s pace quickened when it hired biopharma veteran (Sepracor, GlaxoSmithKline, Abbott) Paul Rubin as CEO.

Now the company faces an enviable problem: an embarrassment of riches when it comes to possible indications for its medicines. “We have an opportunity to campaign our drugs across a really broad range of conditions,” says Nichols—everything from killers such as heart disease to skin inflammation. But its limited resources necessitate a careful choice. Seeking to ward off heart attacks, for example, would require lengthy clinical trials beyond its means. Instead, the startup plans to try oral doses of a resolvin called RvE1 as a treatment for rheumatoid arthritis, inflammatory bowel diseases, and asthma. It’s also plans early trials with resolvins for diseases such as dry eye, a debilitating condition centrally involving inflammation. Nichols adds that the ability to monitor blood levels of inflammatory “markers” in patients on Resolvyx’s drugs should enable it to quickly establish “proof of concept” in early-stage clinical tests, paving the way to raise the large sums needed for bigger trials.

Resolvyx’s drugs promise to be exceptionally safe—an important plus at a time when one high-flying drug after another has crashed due to unexpected toxicity. Existing anti-inflammatories can precipitate gastric bleeding, immune suppression, and other fallout. In contrast, hefty doses of fish oil have been chronically ingested by millions with minimal adverse effects. (Remember the cod liver oil moms used to foist on grimacing kids?) Omega-3’s natural derivatives could be similarly benign. Serhan explains that the derivatives seem to grease many wheels in cells to normalize an out-of-whack process rather than hitting one or two molecular targets very hard, as do most drugs, inviting side effects.

Still, couldn’t the benefits of Resolvyx’s drugs be attained by simply popping fish-oil pills? Probably not, says Nichols. The hot-selling supplements may be good for lowering disease risks in general population, he adds. But to douse the leaping immune flames underlying diseases such as rheumatoid arthritis—and achieve maximal benefits in clinical tests—will probably necessitate the kind of stronger, precision-manufactured medicine Resolvyx is developing. Besides, many if not most patients would likely balk at chronically gulping fistfuls of omega-3 pills. The resulting fishy burps alone could prove fatal—to their social lives.

IMMUNOSYN ANNOUNCES BIOZYME LAB’S RECEIPT OF MHRA MANUFACTURING LICENSE

November 28, 2007

La Jolla, CA … PR Newswire… Immunosyn Corporation (OTC Bulletin Board: IMYN) today announced that Immunosyn Corporationhas received approval from the MHRA to import base material and manufacture SF-1019 for human use in clinical trials: SF-1019 is a biopharmaceutical for which Immunosyn holds the exclusive license for worldwide marketing rights.

The “Medicines and Healthcare products Regulatory Agency,” more commonly known as the MHRA, functions in the United Kingdom on behalf of the European Medicines Agency (EMEA) much like the FDA does in the United States. MHRA regulates which drugs are safe and effective for use in humans to treat specific ailments and conditions. The license approvals currently granted by the MHRA include a “Manufacturer’s Authorisation - Investigational Medicinal Products” (MIA(IMP)) as well as “Manufacturer’s / Importer’s Licence” (MIA) for manufacturing investigational medicinal products for use in humans for phase I, II and III clinical trials. If a company successfully completes these trials it can apply for a full license to distribute throughout the European Union.

“The fact that SF-1019 has garnered manufacturing and import approval from the MHRA so rapidly is exciting news,” says Stephen D. Ferrone, CEO and President of Immunosyn, “as every milestone we achieve in this process brings us that much closer to producing revenue for our shareholders.”

“This is another example whereby Immunosyn’s shareholders strongly benefit from our unique relationship with our largest shareholder, Argyll Biotechnologies,” stated David Criner, CFO of Immunosyn. “Under the terms of our exclusive license agreement, Argyll Biotechnologies is responsible for all regulatory approvals and clinical trials including those required by the MHRA and FDA together with their associated costs.”

Under EMEA requirements, in order to obtain approval to manufacture a drug for use in humans, whether for clinical trials or for general use, an approved manufacturer must be able to demonstrate its ability to comply with the rules governing “Good Manufacturing Practice” (GMP) and apply directly to the MHRA for license approval. Following a series of manufacturing “scale-up” studies, Argyll Biotechnologies entered into an agreement with Biozyme Laboratories Limited to manufacture SF-1019. As a result of this agreement, Biozyme applied for and received manufacturing and base materials import approval from MHRA for clinical trials of SF-1019.

About Biozyme Laboratories Limited
Biozyme specializes in the purification of enzymes and related biochemicals (from microbial, animal and
plant tissues), using a variety of sophisticated extraction and filtration techniques. The company has two
high-specification facilities, both located in the United Kingdom. Products manufactured by Biozyme are
currently being distributed worldwide.

About Immunosyn Corporation

La Jolla, CA-headquartered Immunosyn Corporation (IMYN.OTC.BB) plans to market and distribute life enhancing therapeutics. Currently, the company has exclusive worldwide rights from its largest shareholder, Argyll Biotechnologies, LLC, to market, sell and distribute SF-1019, a compound that was developed from extensive research into Biological Response Modifiers (BRMs). Argyll Biotechnologies, LLC has initiated the process for regulatory approval of SF-1019 in several countries and preparations for clinical trials are underway in both the US and Europe. Research suggests that SF-1019 has the potential to affect a number of clinical conditions including complications from Diabetic Mellitus such as Diabetic Neuropathy (DN) and diabetic ulcers (DU), auto-immune disorders such as Multiple Sclerosis (MS) and neurological disorders such as Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) and Reflex Sympathetic Dystrophy Syndrome (RSD or RSDS). (For more information on Immunosyn and SF-1019 go to www.immunosyn.com).
~ ~ ~
The above news release contains forward-looking statements. These statements are based on assumptions that management believes are reasonable based on currently available information, and include statements regarding the intent, belief or current expectations of the Company and its management. Prospective investors are cautioned that any such forward-looking statements are not guarantees of future performance, and are subject to a wide range of business risks, external factors and uncertainties. Actual results may differ materially from those indicated by such forward-looking statements. For additional information, please consult the Company’s most recent public filings and Annual Report on Form 10-K for its most recent fiscal year. The Company assumes no obligation to update the information contained in this press release, whether as a result of new information, future events or otherwise.

Sativex® Commences US Phase II/III Clinical Trial in Cancer Pain

26/11/2007

London, UK; Tokyo, Japan; 26 November 2007: GW Pharmaceuticals plc (AIM: GWP) and Otsuka Pharmaceutical Co., Ltd. today announced that the first US Phase II/III dose-ranging trial has been initiated to evaluate the efficacy and safety of Sativex® in the treatment of pain in patients with advanced cancer, who experience inadequate analgesia during optimized chronic opioid therapy.

The principal investigator of this study is Dr. Russell K. Portenoy, Chairman of the Department of Pain Medicine and Palliative Care at Beth Israel Medical Center in New York City. This five-week, placebo-controlled study will include approximately 40 centers primarily in the US and recruit a total of 336 patients. Patients enrolled in this study must have advanced cancer for which there is no known curative therapy and have a clinical diagnosis of cancer-related pain, which is not wholly alleviated with their current opioid treatment. The primary objective of the study is to evaluate the potential role and dose range of Sativex in these patients as an adjunct to their pre-existing pain medications. The primary endpoint of the study will be the response rate for patients at the end of 5 weeks of therapy, as defined by a 30% or greater reduction in the 11-point, Numeric Rating Scale (NRS).

Commenting on the importance of this study, Dr. Portenoy, said, “Studies suggest that more than one-third of patients with cancer, and more than three-quarters of those with advanced disease, have chronic pain. Large surveys indicate that optimal opioid therapy does not yield sufficient relief in a substantial proportion of these patients. There is a clear need for new treatments to improve these outcomes and it is our hope that cannabinoid formulations may represent an important option in the future. This US-based study is a welcome step in assessing the role of Sativex® as a potential new treatment for cancer pain."

Dr Geoffrey Guy, GW’s Chairman, said, “GW has spent many years preparing for the US development of Sativex® and has established open and positive interactions with relevant federal agencies. The start of the first large scale US clinical trial is a major milestone for the company and for the future prospects for Sativex®. We are delighted to be working in close collaboration with our partner, Otsuka, in advancing Sativex® toward the goal of obtaining US regulatory approval."

Dr. Taro Iwamoto, President of Otsuka Pharmaceutical Development and Commercialization, Inc., likewise noted that “Otsuka is very excited to be working with GW Pharmaceuticals for the development of this potential alternative approach to the treatment of advanced cancer pain. The initiation of this US clinical trial for Sativex is consistent with our mission to develop products for better health.”

Sativex® is an investigational new product composed primarily of two cannabinoids: CBD (cannabidiol,) and THC (delta 9 tetrahydrocannabinol). Sativex® will be administered as a metered dose oro-mucosal spray each 100µL spray contains 2.7mg THC and 2.5mg CBD. The Sativex® formulation is standardized by both composition and dose and is supplied in small spray vials. The components of Sativex have been shown to bind to cannabinoid receptors that are distributed throughout the central nervous system and in immune cells.

This Phase II/III dose ranging study will attempt to replicate and extend data from a previous, two-week clinical trial in 177 patients conducted in Europe. In this European study, Sativex® was administered to patients with terminal cancer and persistent pain that was not fully relieved by current strong opioid therapy. The primary endpoint of this study was the change from baseline to endpoint in the NRS pain score. Sativex, as adjunctive treatment to strong opioid therapy, was associated with a larger decrease in NRS score than was placebo and strong opiods (p=0.014). In addition, 43% of patients who received Sativex®, while remaining on opioids, exhibited at least a 30% decrease in their pain score compared to 21% of patients receiving placebo and opioids (p= 0.024)

Treatment related adverse events in this study were reported by 85% of patients receiving Sativex and by 75% of patients receiving placebo. The most common adverse events (> 10%) reported by patients in this study were somnolence (15% Sativex® vs. 13% placebo); nausea (12% Sativex® vs. 11% placebo) and dizziness (12% Sativex® vs. 5% placebo). Serious adverse events reported by more than one patient receiving Sativex were urinary retention (n=2) and progression of the underlying cancer (n=6).
Enquiries:

For GW:
GW Pharmaceuticals plc Today: +44 20 7831 3113
Dr Geoffrey Guy , Chairman Thereafter: + 44 1980 557000
Justin Gover, Managing Director
Mark Rogerson , Press and PR Tel: + 44 7885 638810

Financial Dynamics Tel: +44 20 7831 3113
David Yates, Ben Atwell

For Otsuka: US Inquiry
Debbie Kaufmann Tel: +1 240 683 3568
Japan Inquiry
Hideki Shirai siraih@otsuka.jp

Notes to Editors

About GW-Otsuka

On 14 February 2007, GW and Otsuka entered into a major long term strategic alliance. The relationship commenced with the signing of an exclusive license agreement to develop and market Sativex® GW’s lead product, in the US. Under this agreement, GW and Otsuka jointly oversee US clinical development and regulatory activities as well as the commercialization strategy. GW is responsible for carrying out the US clinical development program, the costs of which are borne by Otsuka. Otsuka will be responsible for the marketing and sales activities in the US.

On 9 July 2007, GW and Otsuka signed a global research collaboration for the study of cannabinoids in the field of Central Nervous System (CNS) and oncology to research, develop and commercialize a range of candidate cannabinoid products.

About Otsuka Pharmaceutical Co., Ltd

Founded in 1964, Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: 'Otsuka - people creating new products for better health worldwide.' Otsuka researches, develops, manufactures and markets innovative and original products, with a focus on pharmaceutical products for the treatment of diseases and consumer products for the maintenance of everyday health. Otsuka is committed to being a corporation that creates global value, adhering to the high ethical standards required of a company involved in human health and life, maintaining a dynamic corporate culture, and working in harmony with local communities and the natural environment.

The Otsuka Pharmaceutical Group comprises 99 companies and employs approximately 31,000 people in 17 countries and regions worldwide. Otsuka and its consolidated subsidiaries earned US$7.2 billion in annual revenues in fiscal 2006.

Focusing on the central nervous system, the circulatory, respiratory, and digestive systems, ophthalmology and dermatology, Otsuka’s pharmaceutical product business engages in the research and development, manufacture and sale of pharmaceuticals, aiming to maximize the assets of a global network to address unmet medical meets.
For additional information, visit www.otsuka-global.com

About GW

GW was founded in 1998 and listed on the AiM, a market of the London Stock Exchange, in June 2001. Operating under license from the UK Home Office, the company researches and develops cannabinoid pharmaceutical products that alleviate pain and other neurological symptoms in patients who suffer from serious ailments. GW has assembled a team of over 100 scientists with extensive experience in developing both plant-based prescription pharmaceutical products and medicines containing controlled substances. GW occupies a world leading position in cannabinoids and has developed an extensive international network of the most prominent scientists in the field. For further information, please visit www.gwpharm.com

This news release may contain forward-looking statements that reflect GWs current expectations regarding future events, including development and regulatory clearance of the GW’s products. Forward-looking statements involve risks and uncertainties. Actual events could differ materially from those projected herein and depend on a number of factors, including (inter alia), the success of the GW’s research strategies, the applicability of the discoveries made therein, the successful and timely completion of uncertainties related to the regulatory process, and the acceptance of Sativex® and other products by consumer and medical professionals.

New Published Study Shows Sativex® Successfully Treats Neuropathic Pain

12/11/2007

Porton Down, UK, 12 November 2007 - GW Pharmaceuticals plc (AIM: GWP) today announces that The International Association of the Study of Pain has published online the results of a study in its official journal Pain, showing that Sativex® successfully treats peripheral neuropathic pain1.

The trial was a multi centre, double-blind, randomised, placebo-controlled parallel group study, conducted in 125 patients with peripheral neuropathic pain characterised by allodynia. The publication of these data follows the previous announcement of preliminary results of this study.

In the study, Sativex demonstrated significant superiority to placebo in reducing pain, as measured on a 0-10 Numeric Rating Scale (p=0.004), the primary endpoint of the study. Statistically significant improvements were also seen in the Neuropathic Pain Scale composite score (p=0.007), sleep disturbance (p=0.001), dynamic allodynia (p=0.042), punctate allodynia (p=0.021), Pain Disability Index (p=0.003) and Patients Global Impression of Change (p<0.0001).

Sativex was well-tolerated in this study, with the majority of adverse events being mild or moderate. There were no treatment-related serious adverse events.

The five week trial was conducted in patients who were experiencing significant levels of neuropathic pain and who had failed to gain adequate relief from currently available analgesic medications. Patients enrolled in the study continued to take their existing medication throughout the trial. Sixty-nine percent of patients were taking opioid analgesics. Hence, improvements obtained on Sativex were over and above those obtained on currently available treatments.

Professor Turo Nurmikko, Principal Investigator, Professor of Pain Science and Consultant Pain Physician at the Walton Centre for Neurology and Neurosurgery, Liverpool, commented, "Peripheral neuropathic pain can be extremely disabling and is one of the most difficult types of chronic pain to treat. This study demonstrates that Sativex is effective in the relief of peripheral neuropathic pain. In particular, considering the refractory nature of their pain and that patients remained on their existing analgesia, the improvements seen on Sativex are very encouraging."

Dr Stephen Wright, Director of Research & Development at GW, noted "We are pleased that this important study has been published in Pain, a highly regarded and influential journal. This recognition of the high quality of GW clinical research and of the importance of these findings provides further evidence of the utility of Sativex in the relief of neuropathic pain, an area of significant unmet medical need."

This study is part of a broad programme of clinical trials aimed at securing future regulatory approval for Sativex in neuropathic pain. It is intended to conduct further Phase III clinical trials targeted at neuropathic pain following initial regulatory approval for Sativex in Multiple Sclerosis in Europe.

- ends -

Enquiries:

GW Pharmaceuticals plc Today: +44 (0)20 7831 3113
Dr Geoffrey Guy, Executive Chairman
Justin Gover, Managing Director
Dr Stephen Wright, R&D Director

Financial Dynamics Tel: +44 (0)20 7831 3113
David Yates, Ben Atwell
Notes to Editors

Sativex®
Sativex (THC:CBD), an endocannabinoid system modulator, is derived from whole plant extracts of two specifically bred cannabis plant varieties. The extracts are combined to produce a standardised formulation containing two major components of cannabis, the cannabinoids D9-tetrahydrocannabinol(THC) and cannabidiol(CBD).

Sativex is formulated into a pump action oromucosal (mouth) spray designed for self-administration by the patient. This formulation allows for flexible dosing, ideal for the variable nature of MS. Each spray of Sativex delivers a fixed dose of 2.7mg THC and 2.5mg CBD. Sativex was generally well tolerated in the study.

Allodynia
Allodynia is the occurrence of pain in response to a normally non-painful stimulus (e.g. clothes touching against the skin). It is often intense and can occur in patients suffering from a range of conditions that damage the peripheral nerves (e.g. diabetes, post-herpetic neuralgia) and is a highly reliable marker of neuropathic pain. Neuropathic pain can be difficult to diagnose and may be confused with nociceptive pain (caused by bodily injury - 'visceral' or 'somatic'). The presence of allodynia can confirm that the pain experienced by the patient is truly neuropathic.

Neuropathic Pain
Neuropathic pain is caused by damage to or dysfunction of the nervous system. It is usually chronic and accompanied by unpleasant burning or shooting sensations, or extreme sensitivity to touch. The classification of central or peripheral neuropathic pain is determined by the location of the damage or dysfunction in the nervous system.
It is estimated that at least 1 per cent. of the world's population suffers from neuropathic pain, including over 600,000 patients in UK.
Neuropathic pain can be associated with many conditions including multiple sclerosis, stroke, cancer, spinal cord injury, physical trauma and peripheral neuropathy resulting from diabetes. It can also occur in patients who have previously suffered from shingles, a condition known as post-herpetic neuralgia.
Neuropathic pain is one of the most difficult types of chronic pain to treat. Since treatment options are limited, doctors often prescribe a combination of therapies in an attempt to relieve symptoms.

GW Pharmaceuticals plc
GW was founded in 1998 and listed on the AIM, a market of the London Stock Exchange, in June 2001. Operating under license from the UK Home Office, the company researches and develops cannabinoid pharmaceutical products that alleviate pain and other neurological symptoms in patients who suffer from serious ailments.

GW has assembled a team of over 100 scientists with extensive experience in developing both plant-based prescription pharmaceutical products and medicines containing controlled substances. GW occupies a world leading position in cannabinoids and has developed an extensive international network of the most prominent scientists in the field. For further information, please visit www.gwpharm.com

References

1. Nurmikko T, Serpell M, et al. Sativex Successfully Treats Neuropathic Pain Characterised by Allodynia: a Randomised, Double-Blind, Placebo-Controlled Trial. Pain. 2007: doi:10.1016/j.pain.2007.08.028M

Immune System Reboot Could Treat Autoimmune Disease

By Brandon Keim November 26, 2007

With the help of an ingenious protein hack, scientists have used stem cells to grow new immune systems in mice -- a technique that could someday treat human autoimmune diseases.

In a study published in Science, Stanford University researchers described how blood-forming stem cells generated new immune systems when injected into mouse bone marrow. That wasn't particularly surprising; the real breakthrough took place before the stem cell injections, when the researchers erased the old immune systems.

Traditionally, this is done with radiation and chemicals that also destroy surrounding tissue and sometimes cause brain damage, infertility or cancer. Instead of these scorched-earth therapies, the Stanford scientists gave the mice an antibody designed to neutralize existing blood-forming, or hemapoietic, stem cells. Hematopoietic cells are the building blocks of the immune system; with the old cells out of the way, the researchers added new ones, then sat back and watched fresh immune systems grow.

Duplicating this feat in humans is the holy grail of treatments for for autoimmune diseases, in which bodies are attacked by their own defense systems. But before that happens, more mouse work needs to be finished. The Stanford mice were engineered to possess non-functioning immune systems: they had the necessary components, but the system wasn't on-line.
The researchers must next make their technique work in fully functional mice. Then they need to figure out how to design human-specific antibodies, as the mouse antibodies targeted proteins not present in our own cells.

But if they can do this, the ramifications are enormous: an estimated 20 million Americans suffer from autoimmune diseases, including type 1 diabetes, arthritis and multiple sclerosis. Many other conditions, including chronic fatigue syndrome and obesity, are suspected of having an autoimmune component.

Hollis-Eden Pharmaceuticals Presents Data Demonstrating TRIOLEX(TM) Provides Benefit in Additional Animal Model of Rheumatoid Arthritis

Findings Presented at 36th Annual Autumn Immunology Conference

SAN DIEGO--(BUSINESS WIRE)--Nov. 19, 2007--Hollis-Eden Pharmaceuticals, Inc. (NASDAQ:HEPH), the world leader in the development of a new class of small molecule compounds based on endogenous steroid hormones, is presenting new data this week at the 36th Annual Autumn Immunology Conference, held in Chicago, Illinois, November 16-19, showing that its drug candidate TRIOLEX(TM) (HE3286) provided benefit in an animal model of collagen antibody induced arthritis (CAIA). As previously reported, TRIOLEX, a novel orally bio-available anti-inflammatory cleared by the U.S. Food and Drug Administration for a Phase I/II clinical trial in rheumatoid arthritis (RA), has also demonstrated benefit to date in animal models of collagen induced arthritis (CIA), systemic lupus erythematosus, multiple sclerosis and ulcerative colitis without immune suppressive side effects.

The new data, presented in an oral presentation, are from studies performed by Dr. David Boyle at The University of California, San Diego (UCSD) showing that treatment with TRIOLEX significantly reduced disease in the murine model of CAIA in a dose dependent fashion, with the highest dose completely eliminating disease. In the CAIA model, disease is induced by injecting animals with arthrogenic antibodies, a method that largely bypasses the animal's own cellular immune system. Severe joint inflammation occurs within hours after the injection of antibodies. TRIOLEX was highly effective in this model whether treatment began 1 day or 5 days after injection with antibodies. Benefit at the peak of disease was associated with a significant reduction of interleukin-6 (IL-6) and matrix metalloproteinase-3 (MMP-3) messenger RNA from the joints of TRIOLEX-treated animals when compared to placebo-treated controls. IL-6 and MMP-3 are thought to be among the most important drivers of disease and tissue destruction in human RA. Methotrexate, the current standard of care in RA, is far less effective in the CAIA model than in models of collagen induced arthritis (CIA), where disease is driven by the animal's own cellular immune system.

Methotrexate, a chemotherapy treatment, is focused on treating the cellular infiltration aspect of RA, while other treatments such as corticosteroids and non-steroidal anti-inflammatory agents focus on treating the antibody aspect of the disease. Due to the previously reported activity of TRIOLEX in the CIA animal model and this newly reported activity in the CAIA model, the Company believes that TRIOLEX may be effective at treating both aspects of RA without the immune suppressive side effects associated with some currently prescribed drugs.

Hollis-Eden believes TRIOLEX may act by inhibiting the activation of the NF-kappaB pathway. NF-kappaB is a transcription factor that controls many of the genes involved in the inflammatory signaling pathway, including TNF-alpha, IL-1-beta and IL-6. These cytokines are thought to be key inflammatory mediators that play an important underlying role in many major diseases, including autoimmune disorders. Unlike currently prescribed corticosteroids that can cause immune suppression and bone loss, animal studies to date show that TRIOLEX does not interact with the glucocorticoid receptor and only partially inhibits the NF-kappaB pathway without causing immune suppression or bone loss.

Rheumatoid arthritis is driven by both a cellular and antibody mediated autoimmune response and, as a result, combinations of highly immune suppressive drugs are commonly used to treat both aspects of active disease. Annual sales in the U.S. of drugs to treat RA are expected to reach $14 billion by 2009, driven by the increase in the aging population and use of new expensive biological treatments. Celebrex, a commonly used drug for RA that inhibits the cox-2 enzyme, recorded U.S. annual sales in excess of $2 billion in 2006.

"We are extremely encouraged by these new data in the CAIA model of rheumatoid arthritis," said Dr. James M. Frincke, Chief Scientific Officer at Hollis-Eden Pharmaceuticals. "In our first clear look into the inflamed joint tissue itself, we found that TRIOLEX virtually eliminated messenger RNA to IL-6 and MMP-3 in this animal model, key players thought to drive inflammation and tissue destruction in RA and other autoimmune disorders."

"These findings provide additional, impressive preclinical evidence of the anti-inflammatory activity of TRIOLEX," said Richard Hollis, Chairman and CEO of Hollis-Eden Pharmaceuticals. "The observation that TRIOLEX treats both collagen induced arthritis and collagen antibody induced arthritis in animal models bodes well for the compound's potential efficacy since it appears able to address both cell and antibody mediated elements of RA. Inflammation is increasingly understood to play a role in multiple diseases of aging, including RA and other autoimmune disorders, metabolic disorders, cardiovascular diseases and cancer, and we believe that this work furthers validates the potential of our compounds to possibly provide therapeutic benefit in these major clinical applications. We are currently conducting a Phase I/II clinical trial with TRIOLEX for type 2 diabetes and are evaluating the ability to use safety and dosing data from that trial to accelerate development of the compound for rheumatoid arthritis."

Hollis-Eden Pharmaceuticals

Hollis-Eden Pharmaceuticals, Inc. is a world leader in the development of a proprietary class of adrenal steroid hormones as novel pharmaceuticals for human health. Through its Hormonal Signaling Technology Platform, Hollis-Eden is developing a new series of small molecule compounds that are metabolites or synthetic analogs of endogenous hormones derived by the adrenal glands from the body's most abundant circulating adrenal steroid. These steroid hormones, designed to restore the biological activity of cellular signaling pathways disrupted by disease and aging, have been demonstrated in humans to possess several properties with potential therapeutic benefit -- they regulate innate and adaptive immunity, reduce nonproductive inflammation and stimulate cell proliferation. The Company's clinical drug development candidates include TRIOLEX, a next-generation compound currently in a clinical trial for the treatment of type 2 diabetes and being prepared for clinical trials in rheumatoid arthritis, and HE3235, a next-generation compound selected for cancer. In addition to these clinical development candidates, Hollis-Eden has an active research program that is generating additional new clinical leads that are being further evaluated in preclinical models of a number of different diseases. For more information on Hollis-Eden, visit the Company's website at www.holliseden.com.

This press release contains forward-looking statements within the meaning of the federal securities laws concerning, among other things, the potential and prospects of the Company's drug discovery program and its drug candidates. Any statement included in this press release that are not a description of historical facts are forward-looking statements that involve risks, uncertainties, assumptions and other factors which, if they do not materialize or prove correct, could cause the Company's actual results to differ materially from historical results or those expressed or implied by such forward-looking statements. Such statements are subject to certain risks and uncertainties inherent in the Company's business, including, but not limited to: the ability to complete preclinical and clinical trials successfully and within specified timelines, if at all; the ability to obtain regulatory approval for TRIOLEX (HE3286), APOPTONE (HE3235) or any other investigational drug candidate; the Company's future capital needs; the Company's ability to obtain additional funding; the ability of the Company to protect its intellectual property rights and to not infringe the intellectual property rights of others; the development of competitive products by other companies; and other risks detailed from time to time in the Company's filings with the Securities and Exchange Commission. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this press release. Except as required by law, the Company undertakes no obligation to update or revise the information contained in this press release as a result of new information, future events or circumstances arising after the date of this press release.

CONTACT: Hollis-Eden Pharmaceuticals, Inc.
Scott Rieger, Director, Corporate Communications
858-587-9333

SOURCE: Hollis-Eden Pharmaceuticals, Inc.

New Target For MS Treatment Found Using Old Drug

A drug currently used to treat high blood pressure and heart failure has been found to reduce the symptoms of multiple sclerosis in mice. The discovery that amiloride can reduce the degeneration of nerve tissue in mice suggests it could have a therapeutic potential for people who have MS. However, despite the positive findings, the researchers warn that clinical trials in people, to test the drug's full potential, are crucial before it is given as a treatment for the disease.

The research led by Professor Lars Fugger of the Medical Research Council Human Immunology Unit and Department of Clinical Neurology at Oxford University is published in Nature Medicine. Professor Fugger said:

''This drug [amiloride] is already licensed for another purpose. Looking for new ways to use established drugs is usually cheaper than starting the discovery process from scratch, we've had a really positive result.''

The search for therapeutic potential began with studies of the role of a channel called ASIC1 that creates an opening in the cell membrane. ASIC1 works by sensing acid levels around the cell and lets sodium and calcium molecules into cells. This process is an important part of the process of sensing pain and touch. Using mice with a condition that mimics some aspects of the human form of multiple sclerosis the scientists found that the ASIC1 channel also contributes to degeneration of the axon, the long stem of the nerve. When the channel remains open, sodium and calcium can flood into the cell in higher than normal proportions.

Professor Fugger explained:

''When sodium and calcium levels accumulate in excessive proportions within nerve cells, the axon, the bit that carries messages from one nerve to the next, is damaged. We found that this damage was reduced in mice given amiloride. The drug appears to work by blocking the action of the channel that lets sodium and calcium molecules into the cell.''

The research has shown that not only is the ASIC1 channel a suitable target for drugs that aim to protect against neurodegeneration in research but that amiloride might be beneficial in treatment.

Overall this suggests that drugs targeted at the ASIC1 channel, like amiloride, could help reduce the level of nerve damage caused by multiple sclerosis. The research team are now beginning to plan a clinical trial that will aim to find out if amiloride is beneficial in treating the symptoms of multiple sclerosis in people.

Original research paper: Acid-sensing ion channel 1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system is published in Nature Medicine.

http://www.mrc.ac.uk

MR Imaging Intensity Modeling of Damage and Repair In Multiple Sclerosis: Relationship of Short-Term Lesion Recovery to Progression and Disability

American Journal of Neuroradiology 28:1956-1963, November-December 2007
© 2007 American Society of Neuroradiology

D.S. Meier, Department of Radiology, Center for Neurological Imaging, Multiple Sclerosis Center, Brigham and Women's Hospital, Harvard Medical School, Boston Mass

H.L. Weiner, Department of Neurology, Multiple Sclerosis Center, Brigham and Women's Hospital, Harvard Medical School, Boston Mass

C.R.G. Guttmann, Department of Radiology, Center for Neurological Imaging, Multiple Sclerosis Center, Brigham and Women's Hospital, Harvard Medical School, Boston Mass

Please address correspondence to Dominik Meier, PhD, Center for Neurological Imaging, Brigham and Women's Hospital, 221 Longwood Ave, RF 396, Boston, MA 02115; e-mail: meier@bwh.harvard.edu


BACKGROUND AND PURPOSE: Formation of lesions in multiple sclerosis (MS) shows pronounced short-term fluctuation of MR imaging hyperintensity and size, a qualitatively known but poorly characterized phenomenon. With the use of time-series modeling of MR imaging intensity, our study relates the short-term dynamics of new T2 lesion formation to those of contrast enhancement and markers of long-term progression of disease.

MATERIALS AND METHODS: We analyzed 915 examinations from weekly to monthly MR imaging in 40 patients with MS using a time-series model, emulating 2 opposing processes of T2 prolongation and shortening, respectively. Patterns of activity, duration, and residual hyperintensity within new T2 lesions were measured and evaluated for relationships to disability, atrophy, and clinical phenotype in long-term follow-up.

RESULTS: Significant T2 activity was observed for 8 to 10 weeks beyond contrast enhancement, which suggests that T2 MR imaging is sensitive to noninflammatory processes such as degeneration and repair. Larger lesions showed longer subacute phases but disproportionally more recovery. Patients with smaller average peak lesion size showed trends toward greater disability and proportional residual damage. Higher rates of disability or atrophy were associated with subjects whose lesions showed greater residual hyperintensity.

CONCLUSION: Smaller lesions appeared disproportionally more damaging than larger lesions, with lesions in progressive MS smaller and of shorter activity than in relapsing-remitting MS. Associations of lesion dynamics with rates of atrophy and disability and clinical subtype suggest that changes in lesion dynamics may represent a shift from inflammatory toward degenerative disease activity and greater proximity to a progressive stage, possibly allowing staging of the progression of MS earlier, before atrophy or disability develops.

Initiation Of Enrollment In Pivotal Phase III Clinical Study Of Oral Laquinimod For Relapsing-Remitting Multiple Sclerosis

Jerusalem, Israel and Lund, Sweden, November 7, 2007 - Teva Pharmaceutical Industries Ltd. (NASDAQ: TEVA) and Active Biotech AB (OMX NORDIC: ACTI) announced today the initiation of enrollment in the Allegro trial (assessment of oral laquinimod in preventing progression of multiple sclerosis). Allegro is a global pivotal, 24/30-month, double-blind, Phase III study designed to evaluate the efficacy, safety and tolerability of the oral investigational compound laquinimod versus placebo in the treatment of relapsing-remitting multiple sclerosis (RRMS). The Allegro trial aims to enroll approximately 1,000 patients with RRMS.

"Currently there are several RRMS treatments available; however, they are all administered via injection or infusion. An orally administered therapy brings us one step closer to offering patients and physicians a highly effective, new, convenient and less invasive method of drug delivery," said Doug Jeffery, M.D., Ph.D., Associate Professor, Wake Forest University Baptist Medical Center. "Previous Phase II studies have demonstrated positive results for laquinimod, and we hope that results from this pivotal Phase III trial will further reinforce these findings."

Recently, Teva concluded a 36-week extension of the 36-week Phase IIb core trial, which demonstrated that laquinimod 0.6 mg met its primary endpoint. The data from this extension trial further confirmed and strengthened the results from the initial 36-week Phase IIb trial. The majority of the patients that have participated in the trial are now receiving treatment with laquinimod in a continued open-label extension trial.

"The initiation of Phase III clinical trial is a critical milestone for Teva in our commitment to the MS community," said Moshe Manor, Group Vice President - Global Innovative Resources, of Teva Pharmaceutical Industries Ltd."We are excited about the development of Laquinimod, which together with Copaxone, will broaden our MS platform and position Teva as a leading company in the MS field".

Additional new data, presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) on October 13, 2007 in Prague, demonstrated that laquinimod reduced inflammation, demyelination and axonal damage in an animal model experimental autoimmune encephalomyelitis (EAE), indicating that the compound may have both anti-inflammatory and neuroprotective properties.
Based on encouraging results from various animal models, laquinimod is now being investigated for other autoimmune diseases.

"We are very pleased to see how Teva has successfully advanced the laquinimod clinical trial program in order to bring a novel, first-in-class product to the market for the treatment of MS," said Sven Andr�asson, President and CEO of Active Biotech AB.

The efficacy, safety, and tolerability of laquinimod will also be studied in an additional Phase III pivotal trial in RRMS (BRAVO), which is expected to begin enrollment in the first quarter of 2008. This trial is a multinational, multi-center, randomized, parallel-group, placebo-controlled study which will compare the effects of laquinimod to those of placebo, and provide risk-benefit data comparing once-daily orally administered laquinimod to a product presently used for treatment of RRMS (an active comparator). This study plans to enroll approximately 1,200 participants who will be followed for 24 months.

About Multiple Sclerosis
Multiple Sclerosis (MS) is the leading cause of neurological disability in young adults. It is estimated that 400,000 people in the United States are affected by the disease, and that over one million people are affected worldwide. MS is a progressive, demyelinating disease of the central nervous system, affecting the brain, spinal cord and optic nerves. Demyelination is the destructive breakdown of the fatty tissue that protects nerve endings.

About Allegro
Allegro is a multinational, multi-center, randomized, double-blind, parallel-group, placebo-controlled study, currently enrolling approximately 1,000 patients with RRMS. The globally conducted study will include centers in the United States as well as centers throughout Canada, Europe, and Israel. To learn more about Allegro, visit www.TevaClinicalTrials.com or call 1-866-550-0614.

About Laquinimod
Laquinimod is a novel once-daily, orally administered immunomodulatory compound that is being developed as a disease-modifying treatment for RRMS. Active Biotech developed laquinimod and licensed it to Teva Pharmaceutical Industries, Ltd. in June 2004. A recent Phase IIb study in 306 patients was presented at the 2007 Annual Meeting of the American Academy of Neurology (AAN). The data demonstrated that an oral 0.6 mg dose of laquinimod, administered daily, significantly reduced magnetic resonance imaging (MRI) disease activity by 40 percent versus placebo (p=0.0048) in RRMS patients, and was well tolerated. Looking into the median data of the primary end point laquinimod 0.6mg reduces disease activity (MRI) by 55% compared to placebo. Laquinimod showed consistent and robust effect (statistical significant) on all secondary MRI end points.
In addition, the study showed a favorable trend toward reducing annual relapse rates and the number of relapse-free patients compared with placebo. Treatment with both 0.3 and 0.6 mg doses were well tolerated with only some transient and dose-dependent increases in liver enzymes reported. To date 460 MS patients have received laquinimod in various clinical trials.

Active Biotech AB
Active Biotech AB (OMX NORDIC: ACTI) is a biotechnology company focusing on research and development of pharmaceuticals. Active Biotech has a strong R&D portfolio with pipeline products focused on autoimmune/inflammatory diseases and cancer. Most advanced projects are laquinimod, an orally administered small molecule with unique immunomodulatory properties for the treatment of multiple sclerosis, as well as ANYARA for use in cancer targeted therapy, primarily renal cancer. Further key projects in clinical development comprise the three orally administered compounds TASQ for prostate cancer, 57-57 for SLE and RhuDex® for RA. In addition, the autoimmunity project I-3D is in preclinical development. www.activebiotech.com

About Teva
Teva Pharmaceutical Industries Ltd., headquartered in Israel, is among the top 20 pharmaceutical companies in the world and is the leading generic pharmaceutical company. The company develops, manufactures and markets generic and innovative pharmaceuticals and active pharmaceutical ingredients. Over 80 percent of Teva's sales are in North America and Western Europe.




Safe Harbor Statement under the U. S. Private Securities Litigation Reform Act of 1995: This release contains forward-looking statements, which express the current beliefs and expectations of management. Such statements are based on management�s current beliefs and expectations and involve a number of known and unknown risks and uncertainties that could cause Teva�s future results, performance or achievements to differ significantly from the results, performance or achievements expressed or implied by such forward-looking statements. Important factors that could cause or contribute to such differences include risks relating to: Teva`s ability to successfully develop and commercialize additional pharmaceutical products, the introduction of competing generic equivalents, the extent to which Teva may obtain U.S. market exclusivity for certain of its new generic products and regulatory changes that may prevent Teva from utilizing exclusivity periods, competition from brand-name companies that are under increased pressure to counter generic products, or competitors that seek to delay the introduction of generic products, the impact of consolidation of our distributors and customers, potential liability for sales of generic products prior to a final resolution of outstanding patent litigation, including that relating to the generic versions of Allegra®, Neurontin®, Lotrel®, and Famvir®, the effects of competition on our innovative products, especially Copaxone® sales, the impact of pharmaceutical industry regulation and pending legislation that could affect the pharmaceutical industry, the difficulty of predicting U.S. Food and Drug Administration, European Medicines Agency and other regulatory authority approvals, the regulatory environment and changes in the health policies and structures of various countries, our ability to achieve expected results though our innovative R&D efforts, Teva�s ability to successfully identify, consummate and integrate acquisitions, potential exposure to product liability claims to the extent not covered by insurance, dependence on the effectiveness of our patents and other protections for innovative products, significant operations worldwide that may be adversely affected by terrorism, political or economical instability or major hostilities, supply interruptions or delays that could result from the complex manufacturing of our products and our global supply chain, environmental risks, fluctuations in currency, exchange and interest rates, and other factors that are discussed in Teva�s Annual Report on Form 20-F and its other filings with the U.S. Securities and Exchange Commission. Forward-looking statements speak only as of the date on which they are made and the Company undertakes no obligation to update or revise any forward-looking statement, whether as a result of new information, future events or otherwise.
Company Contacts:
Dan Suesskind, Chief Financial Officer
Teva Pharmaceutical Industries Ltd.
972-2-941-1717

George Barrett,
Corp. E. V.P. - Global pharmaceutical Markets
Chief Executive Officer
Teva Pharmaceutical Industries Ltd.
Teva North America
(215) 591-3030

Liraz Kalif / Kevin Mannix,
Investor Relations
Teva Pharmaceutical Industries Ltd.
Teva North America
972-3-926-7281
(215) 591-8912

Sven Andr�asson President & CEO
Active Biotech
+46 46 19 20 49

Tomas Leanderson Chief Scientific Officer
Active Biotech
+46 46 19 20 95

Cecilia Hofvander Manager Corporate Communication
Active Biotech
+46 46 19 11 22

Apitope vaccine stops MS in its tracks

By Mike Nagle

06/11/2007 - UK biopharmaceutical firm Apitope has developed a vaccine that could halt multiple sclerosis in its relentless march to destroy nerve cells.

The drug, called ATX-MS-1467, has now been tested in humans for the first time - in six Secondary Progressive Multiple Sclerosis (SPMS) patients in a Phase I/IIa trial - and the results so far are encouraging. No safety issues have been unearthed and one patient also showed good clinical improvement in their symptoms.

The immune system attacks proteins it sees as dangerous and helps protect us from a myriad of pathogens. Occassionally these attacks can be devastating if it mistakenly sees proteins in our own body as dangerous and sets about destroying them. This autoimmune reaction leads to numerous diseases, such as Type I diabetes.

In the case of MS, the immune system wipes out the myelin sheath around nerve cells - an insulating layer that allows the cells to effectively conduct electrical signals. This causes the nerves to die and the symptoms of MS to appear, including visual problems, weakness, difficulties with balance and speech, severe fatigue, pain, impaired mobility and often disability.

According to the MS International Federation, around 2.5 million people suffer from the incurable, progressive disease.

Current therapies aim to reduce the inflammation around the nerve cells to offset further damage or, alternatively, to suppress the immune system. However, these broad approaches also suffer from significant side-effects such as an increased susceptibility to infections and a greater risk of cancer.

Apitope has taken a different approach with their peptide based vaccine that seeks to retune the immune system so it no longer overreacts to proteins in the myelin sheath. One of these proteins in called myelin basic protein (MBP). This protein is chopped up inside a cell into different peptide strips. Some of these strips or epitopes then bind to a protein called major histocompatability complex (MHC) class II and are carried to the surface of the cell where they are presented to the immune system.

Dr Keith Martin, CEO of Apitope, explained to DrugResearcher.com that if certain danger signals are present, then the MBP peptide epitopes can 'switch on' T cells and cause an inflammatory response that damages the myelin.

However, and this is where the Apitope vaccine comes in, if the epitope is presented to the immune system in the absence of these danger signals, a different subset of T cells are switched on (called regulatory T cells) and instead of causing damage, these can suppress the immune system reaction to the epitope in question and thus make it more 'tolerant' to myelin. They do this through producing interleukin-10 (IL-10), an anti-inflammatory cytokine.

One key part of this is to ensure the vaccine is only injected at sites where there are no danger signals. So, the clinicians doing the trial inject the drug in the periphery of the body and the regulatory T cells produced can then travel to the central nervous system (CNS) and begin to retune the immune system there.

One problem remained however. Not all fragments of MBP are capable of causing the immune system to become tolerant to the protein. For example, the MBP peptide made up of amino acids 89 to 101 can induce an immune response both in terms of priming for T cell reactivity and inducing autoimmune encephalomyelitis (EAE) - the commonly used animal model for MS.

However, the same peptide does not induce tolerance. So which peptides do and which don't? After much research, David Wraith, a Professor of Experimental Pathology at the University of Bristol, found the answer. He discovered that only peptide fragments that are the right size and shape to be presented to the immune system without further processing can go on to induce tolerance. The discovery led to the spin out of the company and also gave it its name and the name of this class of potential drug - Antigen Processing Independent epiTOPES or Apitopes. Prof. Wraith became the chief scientific officer at Apitope.

First, the team use bioinformatics to design peptides that will bind to MHC strongly and, crucially, ones that can also adopt the right shape to bind.

"If the peptide isn't the right shape, then it won't trigger a response," said Martin. "If they are in the right conformation, they won't require processing [and therefore will induce immune system tolerance]."

He added that in the case of MS, Apitope identified five different peptide epitopes that looked like they would work and then proceeded to test them in a number of in vitro assays. After that process, four remained and these are what make up ATX-MS-1467. The advantage to having four is that there are different subtypes of MHC class II molecules and these four can bind to different ones, such that the "vast majority" of MS patients will be theoretically responsive to the drug.

The initial signs are that the vaccine is effective. Given that the myelin sheath also contains other proteins that are thought to induce the immune system to attack, such as myelin oligodendrocyte glycoprotein (MOG), and proteolipid protein (PLP), this is perhaps surprising at first. So how does a vaccine based only on MBP peptides also prevent these other proteins from sending the immune system into overdrive? The answer is 'bystander suppression'. The epitopes for a given protein antigen (in this case MBP) can also induce tolerance to other epitopes from the same antigen, and even epitopes from other antigens, such as MOG and PLP.

"Essentially, the activity of the mixture is greater than the sum of its parts," explained Martin.

Indeed, one patient on the trial has shown "remarkable improvement in her eyesight", explained Prof. Wraith.

"Since the optic nerve is acutely sensitive to inflammation and optic neuritis is often one of the first symptoms of MS, this early indication of efficacy is very encouraging. It suggests that treatment with ATX-MS-1467 can suppress the inflammation associated with MS," he continued.

The next step is to continue to monitor the six patients who have completed dosing in the Phase I/IIa trial so that a three month safety follow-up can be conducted. If the drug gets the all clear, Apitope will then continue with a Phase IIb proof-of-concept trial. If that proves successful, the firm will then look to partner the programme with a larger pharma company, although Martin said the company would be willing to partner earlier if the opportunity arose.

Way before this drug makes it anywhere near the market though, Apitope hope to begin generating revenues thanks to a MS diagnostic test they have developed.

Martin said that early diagnosis in MS is crucial as treatments that seek to slow down or halt the progression of the disease are obviously best given before the disease has had the chance to do too much damage. Even with existing treatments, there is evidence to suggest patients would have much better outcomes if they were diagnosed earlier he said.

Unfortunately, the current process of diagnosing the disease can take a while, leaving patients untreated while the disease damages their nerves. Apitope have developed a blood test that can diagnose the disease much more quickly. The test is still undergoing regulatory tests but Martin said that Apitope hopes it will be available to doctors by the end of 2009. The same test also has the potential to be extended as a tool for other autoimmune diseases such as rheumatoid arthritis and lupus.

Apitope's approach is also applicable to other immune hypersensitivity reactions and the firm has a programme to identify apitopes to prevent Factor VIII inhibitor formation, which can cause haemophilia. Martin said that he is confident the company will gain orphan drug status for this programme from the US Food and Drug Administration (FDA), although they haven't applied for it yet. This is important as the faster regulatory process for orphan drugs means that, if necessary, Apitope could bring that drug to market without a partner.

Scientists at Apitope are also conducting preclinical tests on Type I diabetes and allergy peptides.

The MS project remains the most advanced however, and it is this research that will make or break Apitope's approach to peptide induced tolerance. A great number of people with autoimmune diseases will be waiting with baited breath.

Magnetization transfer imaging predicts progression of disability in MS

Author: Will Boggs, MD
Date: Wed, 31 October 2007

Magnetization transfer imaging (MTI) predicts deterioration in patients with primary progressive multiple sclerosis (PPMS), according to a report in the October issue of the Journal of Neurology, Neurosurgery, and Psychiatry.

"Abnormalities in PPMS are diffuse and occur early in the condition," Dr. Alan J. Thompson from the Institute of Neurology, London, UK told Reuters Health.

Dr. Thompson and associates investigated whether the magnetization transfer ratio (MTR), which reflects axonal loss, could predict clinical changes over one year in 31 patients diagnosed with definite or probable PPMS.

Lower MTR at baseline predicted progression of clinical symptoms, as shown by greater increases in Expanded Disability Status Scale (EDSS) and greater decreases in Multiple Sclerosis Functional Composite score (MSFC) over the course of one year, the investigators report.

Lesion MTR was least significantly decreased, followed by normal appearing white matter MTR, and the latter significantly predicted EDSS change. Whole brain MTR was the most complete predictor of the MSFC change.

Predictions of clinical progression persisted after adjustment for intrasegmental volume, the investigators say, "demonstrating that the predictive value of MT imaging is independent of atrophy effects on MTR."

"We have followed this cohort for three years and are about to submit that data for publication; they reinforce these findings," Dr. Thompson added. "We will then go on to a five-year analysis, which will also include cognitive assessment, as MTI of gray matter appears to be particularly susceptible to change."

While MTI is unlikely to have a role in the initial diagnosis of MS, Dr. Thompson noted, it "may be helpful in detecting subtle change which may provide evidence towards establishing early diagnosis."

Acne Medication May Delay Progress Of Multiple Sclerosis, Canada

A common acne medication that has been available for over 30 years has the potential to delay the progress of multiple sclerosis and if proven effective, will offer an inexpensive option for the treatment of early MS, says the MS Society of Canada.

Clinical researchers in Calgary and 13 other Canadian centres will be taking an in-depth look at an oral therapy known as minocycline after initial studies have shown promising results. A new $4 million multi-centre clinical trial involving 200 participants from across Canada is being funded through the MS Society's related MS Scientific Research Foundation.

"The benefits of minocycline are straight forward: it's relatively cheap, has few side effects and can be taken in pill format," says Dr. Luanne Metz, principal investigator for the study and a professor of clinical neurosciences at the University of Calgary Faculty of Medicine. "The aim of our research is to see if this common drug can reduce the occurrence of further disease activity in people who have experienced an initial attack of MS symptoms and who are at high risk of progressing to definite MS. Without treatment, two thirds of people facing this circumstance are expected to be diagnosed with MS within 6 months. We believe minocycline can reduce this number. "

In MS, myelin, which is the protective coating of the nerve fibres of the brain and spinal cord, becomes inflamed. This inflammation can be seen as characteristic lesions by magnetic resonance imaging (MRI). Previous clinical tests of minocycline have shown an 84 per cent reduction of MS lesion activity on MRI.

"There is obvious benefit in delaying the rate of disease progression in MS, from improved quality of life to reduced healthcare expenses," says Dr. William McIlroy, national medical advisor for the MS Society of Canada. "The breadth of the study, the reputation of the researchers involved and the early clinical data supports the view that there is considerable promise for minocycline. We would not be involved if this were not the case."

Minocycline works by inhibiting the activities of an enzyme and immune cells that are keys to initiating MS attacks. It has been used in acne treatment for its anti-bacterial effects but studies have shown its anti-inflammatory properties could be important factors in slowing down MS. These insights were discovered through pioneering research funded by the MS Society of Canada and led by Dr. V. Wee Yong at the University of Calgary (U of C). Drs. Metz and Yong lead the MS program at the Hotchkiss Brain Institute at U of C where many of the early studies on minocycline took place.

In comparing minocycline to current therapies, the cost savings would be substantial. In generic form, minocycline is available for as low as $800 per year. Current MS therapies can cost between $18,000 and $40,000 per year. Researchers note that minocycline would not necessarily replace current therapies, but might delay the timeframe in which they would be required.

The study will be randomized and double-blind by design. Investigators will compare 100 mg of oral minocycline twice daily to placebo over a period of two years.

Enrolment will begin in early 2008 and 14 MS clinics are involved including institutions in Calgary, Vancouver, Burnaby, Edmonton, Red Deer, Saskatoon, London, Toronto, Kingston, Ottawa, Montreal, Quebec City, Sherbrooke and Halifax.

About the MS Society of Canada

Founded in 1948, the MS Society has a membership of 28,000, with seven regional divisions and nearly 120 chapters. The MS Society provides services for people with MS, family members and caregivers. The MS Society also offers a unique support network for children and teenagers with MS and their parents. The MS Society raises funds to support research and services almost entirely through individual and corporate donations and fundraising events across the country. The MS Society is the single largest funder of MS research in Canada.

http://www.mssociety.ca.

Bayer's Betaferon Doesn't Work Better at Higher Dose (Update3)

By Eva von Schaper

Oct. 29 (Bloomberg) -- Bayer AG, Germany's largest drugmaker, will take a 152 million-euro ($219 million) charge after dropping plans to market a higher dose of its Betaferon multiple sclerosis treatment.

A study found the 500-microgram dose wasn't more effective at preventing patients' relapses than the 250-microgram form or Teva Pharmaceutical Industries Ltd.'s Copaxone, Leverkusen, Germany-based Bayer said in an e-mailed statement today.

Betaferon is one of the products Bayer needs for growth as it waits for income from newer medicines such as the cancer treatment Nexavar. Bayer gained Betaferon, also sold as Betaseron, in its 17 billion-euro purchase of German rival Schering AG.

``The standard Betaferon 250-microgram dose is the optimal Betaferon dose,'' Douglas Goodin, a professor of neurology at the University of California, San Francisco, said in the statement.

Bayer today said it expects revenue from Betaferon, which had first-half sales of 500 million euros, to rise between 7 and 9 percent this year and next. Bayer said it won't ask regulators to allow the higher dose version of the drug to go on sale.

The third-quarter charge will cover the writedown of assets from the study, dubbed BEYOND, as part of the Schering purchase, Bayer said.

Bayer shares fell 49 cents, or 0.8 percent, to 57.79 euros in Frankfurt. They've risen 42 percent this year.

To contact the reporter on this story: Eva von Schaper in Munich at evonschaper@bloomberg.net .

Last Updated: October 29, 2007 12:44 EDT