Myelin water imaging in relapsing multiple sclerosis treated with ocrelizumab and interferon beta-1a.

BACKGROUND: Myelin water imaging is a magnetic resonance imaging (MRI) technique that quantifies myelin damage and repair in multiple sclerosis (MS) via the myelin water fraction (MWF). OBJECTIVE: In this substudy of a phase 3 therapeutic trial, OPERA II, MWF was assessed in relapsing MS participants assigned to interferon beta-1a (IFNb-1a) or ocrelizumab (OCR) during a two-year double-blind period (DBP) followed by a two-year open label extension (OLE) with ocrelizumab treatment. METHODS: MWF in normal appearing white matter (NAWM), including both whole brain NAWM and 5 white matter structures, and chronic lesions, was assessed in 29 OCR and 26 IFNb-1a treated participants at weeks 0, 24, 48 and 96 (DBP), and weeks 144 and 192 (OLE), and in white matter for 23 healthy control participants at weeks 0, 48 and 96. RESULTS: Linear mixed-effects models of data from baseline to week 96 showed a difference in the change in MWF over time favouring ocrelizumab in all NAWM regions. At week 192, lesion MWF was lower for participants originally randomised to IFNb-1a compared to those originally randomised to OCR. Controls showed no change in MWF over 96 weeks in any region. CONCLUSION: Ocrelizumab appears to protect against demyelination in MS NAWM and chronic lesions and may allow for a more permissive micro environment for remyelination to occur in focal and diffusely damaged tissue.

Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomised, double-blind, multicentre, placebo-controlled phase 3 trial.

BACKGROUND: Satralizumab, a humanised monoclonal antibody targeting the interleukin-6 receptor, reduced the risk of relapse in patients with neuromyelitis optica spectrum disorder (NMOSD) when added to immunosuppressant therapy. This study assessed the safety and efficacy of satralizumab monotherapy in patients with the disorder. METHODS: In this phase 3, double-blind, placebo-controlled, parallel-group trial, we enrolled adults aged 18-74 years with aquaporin-4 antibody seropositive or seronegative NMOSD at 44 investigational sites in 13 countries. Eligible participants had experienced at least one documented NMOSD attack or relapse in the past 12 months and had a score of 6·5 or less on the Expanded Disability Status Scale. Exclusion criteria included clinical relapse 30 days or fewer before baseline. Participants were randomly assigned (2:1) to receive satralizumab 120 mg or visually matched placebo subcutaneously at weeks 0, 2, 4, and every 4 weeks thereafter. Taking immunosuppressants concomitantly was prohibited. The primary endpoint was time to the first protocol-defined relapse, based on the intention-to-treat population and analysed with stratification for two randomisation factors (previous therapy for prevention of attacks and nature of the most recent attack). Safety was assessed in all participants who received at least one dose of satralizumab or placebo. The double-blind phase was due to last until 44 protocol-defined relapses occurred or 1·5 years after random assignment of the last patient enrolled, whichever occurred first; participants could enter an open-label phase after the occurrence of a protocol-defined relapse or at the end of the double-blind phase. The study is registered with ClinicalTrials.gov, NCT02073279. FINDINGS: 95 (57%) of 168 screened participants were randomly assigned to treatment (63 to satralizumab; 32 to placebo) between Aug 5, 2014, and April 2, 2017. Protocol-defined relapses occurred in 19 (30%) patients receiving satralizumab and 16 (50%) receiving placebo (hazard ratio 0·45, 95% CI 0·23-0·89; p=0·018). 473·9 adverse events per 100 patient-years occurred in the satralizumab group, as did 495·2 per 100 patient-years in the placebo group; the incidence of serious adverse events and adverse events leading to withdrawal was similar between groups. INTERPRETATION: Satralizumab monotherapy reduced the rate of NMOSD relapse compared with placebo in the overall trial population, with a favourable safety profile. The patient population included a ratio of aquaporin-4 antibody seropositive and seronegative patients that was reflective of clinical practice. Satralizumab has the potential to become a valuable treatment option for patients with NMOSD. FUNDING: Chugai Pharmaceutical (Roche).

Magnetic resonance spectroscopy evidence for declining gliosis in MS patients treated with ocrelizumab versus interferon beta-1a.

BACKGROUND: Magnetic resonance spectroscopy quantitatively monitors biomarkers of neuron-myelin coupling (N-acetylaspartate (NAA)), and inflammation (total creatine (tCr), total choline (tCho), myo-inositol (mI)) in the brain. OBJECTIVE: This study aims to investigate how ocrelizumab and interferon beta-1a differentially affects imaging biomarkers of neuronal-myelin coupling and inflammation in patients with relapsing multiple sclerosis (MS). METHODS: Forty patients with relapsing MS randomized to either treatment were scanned at 3T at baseline and weeks 24, 48, and 96 follow-up. Twenty-four healthy controls were scanned at weeks 0, 48, and 96. NAA, tCr, tCho, mI, and NAA/tCr were measured in a single large supra-ventricular voxel. RESULTS: There was a time × treatment interaction in NAA/tCr (p = 0.04), primarily driven by opposing tCr trends between treatment groups after 48 weeks of treatment. Patients treated with ocrelizumab showed a possible decline in mI after week 48 week, and stable tCr and tCho levels. Conversely, the interferon beta-1a treated group showed possible increases in mI, tCr, and tCho over 96 weeks. CONCLUSIONS: Results from this exploratory study suggest that over 2 years, ocrelizumab reduces gliosis compared with interferon beta-1a, demonstrated by declining ml, and stable tCr and tCho. Ocrelizumab may improve the physiologic milieu by decreasing neurotoxic factors that are generated by inflammatory processes.

Ocrelizumab efficacy in subgroups of patients with relapsing multiple sclerosis.

OBJECTIVE: The efficacy and safety of ocrelizumab, versus interferon (IFN) ß-1a, for the treatment of relapsing multiple sclerosis (RMS) from the identically designed OPERA I (NCT01247324) and OPERA II (NCT01412333) phase III studies has been reported; here we present subgroup analyses of efficacy endpoints from the pooled OPERA I and OPERA II populations. METHODS: Patients with RMS were randomized to either ocrelizumab 600 mg administered by intravenous infusion every 24 weeks or subcutaneous IFN ß-1a 44 µg three times per week throughout the 96-week treatment period. Relapse, disability, and MRI outcomes were analyzed for predefined and post hoc subgroups based on demographic and disease characteristics along with prior treatment using appropriate statistical tests to determine the treatment effect in subgroups and treatment-by-subgroup interactions. RESULTS: The significant treatment benefit of ocrelizumab, versus IFN ß-1a, observed in the overall OPERA I and OPERA II pooled populations was maintained across most subgroup strata for all endpoints, including annualized relapse rate, disability progression, and MRI outputs. CONCLUSIONS: The treatment effect of ocrelizumab versus IFN ß-1a, measured by clinical and MRI outcomes, was maintained across most of the subgroups and strata of interest, and the pattern of treatment benefit across all subgroups was consistent with that from the pooled OPERA studies.

Advanced imaging findings in progressive solitary sclerosis: a single lesion or a global disease?

BACKGROUND: Progressive solitary sclerosis is a unifocal demyelinating disease recently proposed as a possible multiple sclerosis variant. OBJECTIVE: To compare myelin content and brain metabolite ratio qualitatively in the normal-appearing white matter of progressive solitary sclerosis cases compared to multiple sclerosis and healthy control participants. METHODS: Case report. RESULTS: Progressive solitary sclerosis cases showed abnormal myelin in normal-appearing white matter tracts and global normal-appearing white matter as well as lower N-acetyl-aspartate to total creatine ratio compared to multiple sclerosis and healthy control groups. CONCLUSION: Despite a single demyelinating lesion along the corticospinal tract in progressive solitary sclerosis, we showed evidence of more extensive abnormality within the normal-appearing white matter.

Quantitative neuroimaging measures of myelin in the healthy brain and in multiple sclerosis.

Quantitative magnetic resonance imaging (MRI) techniques have been developed as imaging biomarkers, aiming to improve the specificity of MRI to underlying pathology compared to conventional weighted MRI. For assessing the integrity of white matter (WM), myelin, in particular, several techniques have been proposed and investigated individually. However, comparisons between these methods are lacking. In this study, we compared four established myelin-sensitive MRI techniques in 56 patients with relapsing-remitting multiple sclerosis (MS) and 38 healthy controls. We used T2-relaxation with combined GRadient And Spin Echoes (GRASE) to measure myelin water fraction (MWF-G), multi-component driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) to measure MWF-D, magnetization-transfer imaging to measure magnetization-transfer ratio (MTR), and T1 relaxation to measure quantitative T1 (qT1 ). Using voxelwise Spearman correlations, we tested the correspondence of methods throughout the brain. All four methods showed associations that varied across tissue types; the highest correlations were found between MWF-D and qT1 (median ρ across tissue classes 0.8) and MWF-G and MWF-D (median ρ = 0.59). In eight WM tracts, all measures showed differences (p < 0.05) between MS normal-appearing WM and healthy control WM, with qT1 showing the highest number of different regions (8), followed by MWF-D and MTR (6), and MWF-G (n = 4). Comparing the methods in terms of their statistical sensitivity to MS lesions in WM, MWF-D demonstrated the best accuracy (p < 0.05, after multiple comparison correction). To aid future power analysis, we provide the average and standard deviation volumes of the four techniques, estimated from the healthy control sample.

Evaluation of no evidence of progression or active disease (NEPAD) in patients with primary progressive multiple sclerosis in the ORATORIO trial.

OBJECTIVE: No evidence of progression or active disease (NEPAD) is a novel combined endpoint defined by the absence of both progression and inflammatory disease activity in primary progressive multiple sclerosis (PPMS). In the placebo-controlled phase III ORATORIO study (NCT01194570), we investigated the effect of ocrelizumab on this comprehensive outcome and its components in a post-hoc analysis. METHODS: The proportion of patients with NEPAD (no evidence of progression [NEP; no 12-week confirmed progression of ≥1/≥0.5 points on the Expanded Disability Status Scale if the baseline score was ≤5.5/>5.5 points, respectively; no 12-week confirmed progression of ≥20% on the Timed 25-Foot Walk test and 9-Hole Peg Test], no brain magnetic resonance imaging activity [no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions], and no protocol-defined relapse) from baseline to week 120 was determined in ocrelizumab- (600 mg; n = 465) and placebo-treated (n = 234) patients. RESULTS: The majority of ORATORIO study patients with PPMS experienced clinical progression or evidence of disease activity. From baseline to week 120, 29.9% and 42.7% ocrelizumab-treated compared to 9.4% and 29.1% placebo-treated patients maintained NEPAD (relative risk [95% confidence interval {CI}], 3.15 [2.07-4.79]; p < 0.001) and NEP (relative risk [95% CI], 1.47 [1.17-1.84]; p < 0.001), respectively. Effects on the individual components of both measures were consistent with the compound outcomes. INTERPRETATION: Compared to placebo, ocrelizumab enhanced 3-fold the proportion of PPMS patients with no evidence of either progression or inflammatory disease activity. NEPAD may represent a sensitive and meaningful comprehensive measure of disease control in patients with PPMS. Ann Neurol 2018;84:527-536.

No evidence of disease activity (NEDA) analysis by epochs in patients with relapsing multiple sclerosis treated with ocrelizumab vs interferon beta-1a.

BACKGROUND: No evidence of disease activity (NEDA; defined as no 12-week confirmed disability progression, no protocol-defined relapses, no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions) using a fixed-study entry baseline is commonly used as a treatment outcome in multiple sclerosis (MS). OBJECTIVE: The objective of this paper is to assess the effect of ocrelizumab on NEDA using re-baselining analysis, and the predictive value of NEDA status. METHODS: NEDA was assessed in a modified intent-to-treat population (n = 1520) from the pooled OPERA I and OPERA II studies over various epochs in patients with relapsing MS receiving ocrelizumab (600 mg) or interferon beta-1a (IFN ß-1a; 44 µg). RESULTS: NEDA was increased with ocrelizumab vs IFN ß-1a over 96 weeks by 75% (p < 0.001), from Week 0‒24 by 33% (p < 0.001) and from Week 24‒96 by 72% (p < 0.001). Among patients with disease activity during Weeks 0‒24, 66.4% vs 24.3% achieved NEDA during Weeks 24‒96 in the ocrelizumab and IFN ß-1a groups (relative increase: 177%; p < 0.001). CONCLUSION: Superior efficacy with ocrelizumab compared with IFN ß-1a was consistently seen in maintaining NEDA status in all epochs evaluated. By contrast with IFN ß-1a, the majority of patients with disease activity early in the study subsequently attained NEDA status with ocrelizumab.

Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis.

BACKGROUND: B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. METHODS: In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 µg three times weekly for 96 weeks. The primary end point was the annualized relapse rate. RESULTS: The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a. CONCLUSIONS: Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann-La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333 , respectively.).

Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis.

BACKGROUND: An evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primary progressive form of the disease. METHODS: In this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. RESULTS: The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey. Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections. CONCLUSIONS: Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. Extended observation is required to determine the long-term safety and efficacy of ocrelizumab. (Funded by F. Hoffmann-La Roche; ORATORIO ClinicalTrials.gov number, NCT01194570 .).

Activity of secukinumab, an anti-IL-17A antibody, on brain lesions in RRMS: results from a randomized, proof-of-concept study.

The objective of this study was to assess the effect of secukinumab, a monoclonal antibody that inhibits interleukin (IL)-17A, on number of new active brain magnetic resonance imaging (MRI) lesions in subjects with relapsing-remitting multiple sclerosis (MS). Subjects (N = 73) were randomized 1:1 to secukinumab 10 mg/kg or placebo by intravenous infusion at weeks 0, 2, 4, 8, 12, 16, and 20. MRI scans were obtained within 30 days prior to randomization, on a monthly basis during the treatment period, and at study completion. The primary endpoint was the cumulative number of combined unique active lesions (CUAL) observed on brain MRI scans from week 4 to week 24. Compared with placebo, secukinumab non-significantly reduced the number of CUAL observed on 4-weekly MRI from week 4 to 24 (primary endpoint) by 49 % (95 % CI -10 to 77 %; P = 0.087) and significantly reduced the number of cumulative new gadolinium-enhancing T1 lesions by 67 % (31-84 %, P = 0.003). CUAL reductions were progressively greater from week 4 (1 %) to week 16 (49 %) and persisted until end-study (50 %). There were no serious adverse events; the adverse event rate was comparable to placebo (53 versus 49 %), although mild-to-moderate infection was somewhat more frequent (37 versus 23 %). This proof-of-concept study provides the first evidence that blocking IL-17A with an antibody may reduce MRI lesion activity in MS. Further studies are needed to confirm this finding and determine the magnitude of effect.

Plasmid-encoded proinsulin preserves C-peptide while specifically reducing proinsulin-specific CD8⁺ T cells in type 1 diabetes.

In type 1 diabetes (T1D), there is an intense inflammatory response that destroys the ß cells in the pancreatic islets of Langerhans, the site where insulin is produced and released. A therapy for T1D that targets the specific autoimmune response in this disease while leaving the remainder of the immune system intact, has long been sought. Proinsulin is a major target of the adaptive immune response in T1D. We hypothesized that an engineered DNA plasmid encoding proinsulin (BHT-3021) would preserve ß cell function in T1D patients through reduction of insulin-specific CD8⁺ T cells. We studied 80 subjects over 18 years of age who were diagnosed with T1D within the past 5 years. Subjects were randomized 2:1 to receive intramuscular injections of BHT-3021 or BHT-placebo, weekly for 12 weeks, and then monitored for safety and immune responses in a blinded fashion. Four dose levels of BHT-3021 were evaluated: 0.3, 1.0, 3.0, and 6.0 mg. C-peptide was used both as an exploratory efficacy measure and as a safety measure. Islet-specific CD8⁺ T cell frequencies were assessed with multimers of monomeric human leukocyte antigen class I molecules loaded with peptides from pancreatic and unrelated antigens. No serious adverse events related to BHT-3021 were observed. C-peptide levels improved relative to placebo at all doses, at 1 mg at the 15-week time point (+19.5% BHT-3021 versus -8.8% BHT-placebo, P < 0.026). Proinsulin-reactive CD8⁺ T cells, but not T cells against unrelated islet or foreign molecules, declined in the BHT-3021 arm (P < 0.006). No significant changes were noted in interferon-γ, interleukin-4 (IL-4), or IL-10 production in CD4 T cells. Thus, we demonstrate that a plasmid encoding proinsulin reduces the frequency of CD8⁺ T cells reactive to proinsulin while preserving C-peptide over the course of dosing.

Transient B-cell depletion with anti-CD20 in combination with proinsulin DNA vaccine or oral insulin: immunologic effects and efficacy in NOD mice.

A recent type 1 diabetes (T1D) clinical trial of rituximab (a B cell-depleting anti-CD20 antibody) achieved some therapeutic benefit in preserving C-peptide for a period of approximately nine months in patients with recently diagnosed diabetes. Our previous data in the NOD mouse demonstrated that co-administration of antigen (insulin) with anti-CD3 antibody (a T cell-directed immunomodulator) offers better protection than either entity alone, indicating that novel combination therapies that include a T1D-related autoantigen are possible. To accelerate the identification and development of novel combination therapies that can be advanced into the clinic, we have evaluated the combination of a mouse anti-CD20 antibody with either oral insulin or a proinsulin-expressing DNA vaccine. Anti-CD20 alone, given once or on 4 consecutive days, produced transient B cell depletion but did not prevent or reverse T1D in the NOD mouse. Oral insulin alone (twice weekly for 6 weeks) was also ineffective, while proinsulin DNA (weekly for up to 12 weeks) showed a trend toward modest efficacy. Combination of anti-CD20 with oral insulin was ineffective in reversing diabetes in NOD mice whose glycemia was controlled with SC insulin pellets; these experiments were performed in three independent labs. Combination of anti-CD20 with proinsulin DNA was also ineffective in diabetes reversal, but did show modest efficacy in diabetes prevention (p = 0.04). In the prevention studies, anti-CD20 plus proinsulin resulted in modest increases in Tregs in pancreatic lymph nodes and elevated levels of proinsulin-specific CD4+ T-cells that produced IL-4. Thus, combination therapy with anti-CD20 and either oral insulin or proinsulin does not protect hyperglycemic NOD mice, but the combination with proinsulin offers limited efficacy in T1D prevention, potentially by augmentation of proinsulin-specific IL-4 production.

Evolution of MS lesions to black holes under DNA vaccine treatment.

Persistent black holes (PBH) are associated with axonal loss and disability progression in multiple sclerosis (MS). The objective of this work was to determine if BHT-3009, a DNA plasmid-encoding myelin basic protein (MBP), reduces the risk of new lesions becoming PBH, compared to placebo, and to test if pre-treatment serum anti-MBP antibody levels impact on the effect of BHT-3009 treatment. In this retrospective, blinded MRI study, we reviewed MRI scans of 155 MS patients from a double-blind, randomized, phase II trial with three treatment arms (placebo, 0.5 and 1.5 mg BHT-3009). New lesions at weeks 8 and 16 were tracked at week 48 and those appearing as T1-hypointense were classified as PBH. A subset of 46 patients with available pre-treatment serum anti-MBP IgM levels were analyzed separately. Overall, there was no impact of treatment on the risk for PBH. However, there was a significant interaction between anti-MBP antibodies and treatment effect: patients receiving 0.5 mg BHT-3009 showed a reduced risk of PBH with higher antibody levels compared to placebo (p < 0.01). Although we found no overall reduction of the risk for PBH in treated patients, there may be an effect of low-dose BHT-3009, depending on the patients' pre-treatment immune responses.

Biological Therapeutics Research and Development--GTCbio's Fifth Annual Conference. October 20-22, 2010, San Francisco, CA, USA.

The Biological Therapeutics Research and Development--GTCbio's Fifth Annual Conference, held in San Francisco, included topics covering new therapeutic developments in the field of vaccines and peptide therapies. This conference report highlights selected presentations on the development of vaccines for NSCLC, DNA delivery platforms as vaccines, vaccine combination therapy for cancer, DNA vaccines for autoimmune diseases, and improved peptide therapeutics. Investigational drugs discussed include TG-4010 (Transgene), and a series of vaccines targeting autoimmune diseases, including BHT-3021 (Bayhill/Genentech) for type I diabetes, BHT-3009 (Bayhill) for multiple sclerosis and BHT-3034 (Bayhill) for myasthenia gravis.

Gene Based Vaccines: Optimising Development and Delivery - A marcus evans Conference.

The Gene Based Vaccines: Optimising Development and Delivery conference, held in Vienna, included topics covering new therapeutic developments in the field of gene-based vaccines. This conference report highlights selected presentations on gene-based vaccine delivery systems, anti-vector immunity in such vaccines, gene-based influenza vaccines, prime-boost strategies for influenza vaccines, DNA vaccines for the prevention of malaria, considerations in DNA vaccine manufacturing, and the ImmunoBody DNA vaccine technology from Scancell.

Multiple sclerosis therapies: molecular mechanisms and future.

The current treatments for multiple sclerosis (MS) are, by many measures, not satisfactory. The original interferon-ß therapies were not necessarily based on an extensive knowledge of the pathophysiological mechanisms of the disease. As more and more insight has been acquired about the autoimmune mechanisms of MS and, in particular, the molecular targets involved, several treatment approaches have emerged. In this chapter, we highlight both promising preclinical approaches and therapies in late stage clinical trials that have been developed as a result of the improved understanding of the molecular pathophysiology of MS. These clinical stage therapies include oral agents, monoclonal antibodies, and antigen-specific therapies. Particular emphasis is given to the molecular targets when known and any safety concerns that have arisen because, despite the need for improved efficacy, MS remains a disease in which the safety of any agent remains of paramount importance.

DNA vaccines for autoimmune diseases.

Autoimmune diseases represent a group of disorders in which there exists a large unmet medical need for effective treatments, but also where there exists a tremendous responsibility among physicians and drug developers to maintain adequate and acceptable patient safety. Several drugs have been approved and many others are about to be approved for the treatment of autoimmune diseases, but in pushing the envelope of therapeutic efficacy, concerns have been raised about the long-term safety of these new therapies. DNA vaccines provide a method of treating autoimmune diseases in a highly specific manner, and could therefore overcome these safety concerns while still maintaining comparable efficacy. The numerous reports of DNA vaccines in animal models of autoimmune diseases and results from three recent human trials of DNA vaccines in autoimmune diseases are reviewed here.

Improved efficacy of a tolerizing DNA vaccine for reversal of hyperglycemia through enhancement of gene expression and localization to intracellular sites.

Insulin is a major target for the autoimmune-mediated destruction of pancreatic beta cells during the pathogenesis of type I diabetes. A plasmid DNA vaccine encoding mouse proinsulin II reduced the incidence of diabetes in a mouse model of type I diabetes when administered to hyperglycemic (therapeutic mode) or normoglycemic (prophylactic mode) NOD mice. Therapeutic administration of proinsulin DNA was accompanied by a rapid decrease in the number of insulin-specific IFN-gamma-producing T cells, whereas prophylactic treatment was accompanied by enhanced IFN-gamma-secreting cells and a decrease in insulin autoantibodies. Adoptive transfer experiments demonstrated that the protection was not mediated by induction of CD25(+)/CD4(+) T regulatory cells. The efficacy of the DNA vaccine was enhanced by increasing the level of expression of the encoded Ag, more frequent dosing, increasing dose level, and localization of the protein product to the intracellular compartment. The efficacy data presented in this study demonstrate that Ag-specific plasmid DNA therapy is a viable strategy for preventing progression of type I diabetes and defines critical parameters of the dosing regime that influences tolerance induction.

A DNA vaccine for multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a disease in which safety is of paramount importance when developing a potential therapeutic. Antigen-specific treatments provide a method for achieving efficacy while maintaining safety. DNA vaccines are one such form of treatment that have been tested in clinical trials OBJECTIVE: To determine if a DNA vaccine is a viable method of antigen-specific treatment of MS. RESULTS/CONCLUSION: Phase I and II trials of BHT-3009, a DNA vaccine encoding myelin basic protein, demonstrated that it was safe, well-tolerated, and caused antigen-specific immune tolerance. BHT-3009 showed efficacy in reducing brain lesion activity as well as clinical relapses in patients that were immunologically active at baseline. BHT-3009 is a promising therapy in development for MS, and may prove to be one of the first antigen-specific treatments for this disease.