Antiviral Use in Mild-to-Moderate SARS-CoV-2 Infections during the Omicron Wave in Geriatric Patients.

(1) Background: Geriatric patients are at high risk of complications of Coronavirus disease-2019 (COVID-19) and are good candidates for antiviral drugs. (2) Methods: A retrospective study of electronic health records (EHRs) aiming to describe antiviral (nirmatrelvir and ritonavir (nirmatrelvir/r) or remdesivir) use, drug-drug interactions (DDIs) and adverse drug reactions (ADRs) in elderly patients (75 and over), hospitalized with mild-to-moderate COVID-19 between July 2022 and June 2023. (3) Results: Out of 491 patients (mean age: 86.9 years), 180 (36.7%) received nirmatrelvir/r, 78 (15.9%) received remdesivir, and 233 (47.4%) received no antiviral therapy. No association was found between the choice of antiviral and the demographic or medical data. No serious ADR was observed. Nirmatrelvir/r dosage adjustment was inadequate in 65% of patients with renal impairment. In total, 128 patients (71%) on nirmatrelvir/r had potential pharmacokinetic DDIs, with 43 resulting in a possibly related ADR. In the remdesivir group, pharmacodynamic DDIs were more frequent, with QTc prolongation risk in 56 patients (72%). Only 20 patients underwent follow-up ECG, revealing QTc prolongation in 4. (4) Conclusions: There is an underutilization of antivirals despite their justified indications. Nirmatrelvir/r dosage was rarely adjusted to renal function. Dose adjustments and closer monitoring are needed due to the high risk of drug interactions.

Efficacy and safety of temelimab in multiple sclerosis: Results of a randomized phase 2b and extension study.

BACKGROUND: The envelope protein of human endogenous retrovirus W (HERV-W-Env) is expressed by macrophages and microglia, mediating axonal damage in chronic active MS lesions. OBJECTIVE AND METHODS: This phase 2, double-blind, 48-week trial in relapsing-remitting MS with 48-week extension phase assessed the efficacy and safety of temelimab; a monoclonal antibody neutralizing HERV-W-Env. The primary endpoint was the reduction of cumulative gadolinium-enhancing T1-lesions in brain magnetic resonance imaging (MRI) scans at week 24. Additional endpoints included numbers of T2 and T1-hypointense lesions, magnetization transfer ratio, and brain atrophy. In total, 270 participants were randomized to receive monthly intravenous temelimab (6, 12, or 18 mg/kg) or placebo for 24 weeks; at week 24 placebo-treated participants were re-randomized to treatment groups. RESULTS: The primary endpoint was not met. At week 48, participants treated with 18 mg/kg temelimab had fewer new T1-hypointense lesions (p = 0.014) and showed consistent, however statistically non-significant, reductions in brain atrophy and magnetization transfer ratio decrease, as compared with the placebo/comparator group. These latter two trends were sustained over 96 weeks. No safety issues emerged. CONCLUSION: Temelimab failed to show an effect on features of acute inflammation but demonstrated preliminary radiological signs of possible anti-neurodegenerative effects. Current data support the development of temelimab for progressive MS. TRIAL REGISTRATION: CHANGE-MS: ClinicalTrials.gov: NCT02782858, EudraCT: 2015-004059-29; ANGEL-MS: ClinicalTrials.gov: NCT03239860, EudraCT: 2016-004935-18.

Impact of SARS-CoV-2 Infection (COVID-19) on Cytochromes P450 Activity Assessed by the Geneva Cocktail.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is a severe acute respiratory syndrome with an underlying inflammatory state. We have previously demonstrated that acute inflammation modulates cytochromes P450 (CYPs) activity in an isoform-specific manner. We therefore hypothesized that COVID-19 might also impact CYP activity, and thus aimed to evaluate the impact of acute inflammation in the context of SARS-CoV-2 infection on the six main human CYPs activity. This prospective observational study was conducted in 28 patients hospitalized at the Geneva University Hospitals (Switzerland) with a diagnosis of moderate to severe COVID-19. They received the Geneva phenotyping cocktail orally during the first 72 hours of hospitalization and after 3 months. Capillary blood samples were collected 2 hours after cocktail administration to assess the metabolic ratios (MRs) of CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A. C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) levels were also measured in blood. CYP1A2, CYP2C19, and CYP3A MRs decreased by 52.6% (P = 0.0001), 74.7% (P = 0.0006), and 22.8% (P = 0.045), respectively, in patients with COVID-19. CYP2B6 and CYP2C9 MRs increased by 101.1% (P = 0.009) and 55.8% (P = 0.0006), respectively. CYP2D6 MR variation did not reach statistical significance (P = 0.072). As expected, COVID-19 was a good acute inflammation model as mean serum levels of CRP, IL-6, and TNF-α were significantly (P < 0.001) higher during SARS-CoV-2 infection. CYP activity are modulated in an isoform-specific manner by SARS-CoV-2 infection. The pharmacokinetics of CYP substrates, whether used to treat the disease or as the usual treatment of patients, could be therefore clinically impacted.

Genetic Susceptibility Toward Nausea and Vomiting in Surgical Patients.

Postoperative nausea and vomiting (PONV) are frequently occurring adverse effects following surgical procedures. Despite predictive risk scores and a pallet of prophylactic antiemetic treatments, it is still estimated to affect around 30% of the patients, reducing their well-being and increasing the burden of post-operative care. The aim of the current study was to characterize selected genetic risk factors of PONV to improve the identification of at risk patients. We genotyped 601 patients followed during the first 24 h after surgery for PONV symptoms in the absence of any antiemetic prophylaxis. These patients were recruited in the frame of a randomized, placebo controlled clinical study aiming to test the efficacy of dexamethasone as a treatment of established PONV. We examined the impact of selected single nucleotide polymorphisms (SNPs) located around 13 different genes and the predicted activity of 6 liver drug metabolizing enzymes from the cytochromes P450 family (CYP) on the occurrence and recurrence of PONV. Our genetic study confirms the importance of genetic variations in the type 3B serotonin receptor in the occurrence of PONV. Our modelling shows that integration of rs3782025 genotype in preoperative risk assessments may help improve the targeting of antiemetic prophylaxis towards patients at risk of PONV.

Impact of Acute Inflammation on Cytochromes P450 Activity Assessed by the Geneva Cocktail.

Cytochromes P450 (CYP) are subject to important interindividual variability in their activity due to genetic and environmental factors and some diseases. Limited human data support the idea that inflammation downregulates CYP activities. Our study aimed to evaluate the impact of orthopedic surgery (acute inflammation model) on the activity of six human CYP. This prospective observational study was conducted in 30 patients who underwent elective hip surgery at the Geneva University Hospitals in Switzerland. The Geneva phenotyping cocktail containing caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, and midazolam as probe drugs respectively assessing CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A activities was administered orally before surgery, day 1 (D1) and 3 (D3) postsurgery and at discharge. Capillary blood samples were collected 2 hours after cocktail intake to assess metabolic ratios (MRs). Serum inflammatory markers (CRP, IL-6, IL-1ß, TNF-α, and IFN-γ) were also measured in blood. CYP1A2 MRs decreased by 53% (P < 0.0001) between baseline and the nadir at D1. CYP2C19 and CYP3A activities (MRs) decreased by 57% (P = 0.0002) and 61% (P < 0.0001), respectively, with the nadir at D3. CYP2B6 and CYP2C9 MRs increased by 120% (P < 0.0001) and 79% (P = 0.018), respectively, and peaked at D1. Surgery did not have a significant impact on CYP2D6 MR. Hip surgery was a good acute inflammation model as CRP, IL-6, and TNF-α peak levels were reached between D1 and day 2 (D2). Acute inflammation modulated CYP activity in an isoform-specific manner, with different magnitudes and kinetics. Acute inflammation may thus have a clinically relevant impact on the pharmacokinetics of these CYP substrates.

Temelimab, an IgG4 Anti-Human Endogenous Retrovirus Monoclonal Antibody: An Early Development Safety Review.

INTRODUCTION: Temelimab (formerly called GNbAC1) is an immunoglobulin (Ig) G4 monoclonal antibody that targets the human endogenous retroviral envelope protein HERV-W-Env, shown to be associated with the pathogenesis of certain autoimmune disorders such as multiple sclerosis (MS) and type 1 diabetes mellitus (T1D). By neutralizing HERV-W-Env, temelimab could act as a disease-modifying therapy for these disorders. It is currently in clinical development for MS and T1D. METHODS: The safety information on temelimab (including potential infusion-related reactions, malignancies, pregnancies and antidrug antibodies) collected during three phase I and four phase II clinical trials was reviewed and is summarized in this article. RESULTS: In the entire development program, 54 healthy volunteers received single doses of temelimab in three phase I studies, and 334 MS or T1D patients received temelimab for a total estimated exposure of 465 patient-years in four phase II trials. No differences were observed between numbers of treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs) between treatment groups (including placebo), and the number of SAEs was limited. Furthermore, no differences were observed in laboratory evaluations, vital signs, electrocardiogram (ECG), or physical examinations between treatment groups. Rare potential infusion-related reactions were reported. Temelimab treatment was not associated with an increased risk of infections or infestations. CONCLUSION: These results suggest that treatment with temelimab was not associated with any particular type of AE. Overall, temelimab was safe and very well tolerated over the tested dose range after repeated monthly administrations.

A High-dose Pharmacokinetic Study of a New IgG4 Monoclonal Antibody Temelimab/GNbAC1 Antagonist of an Endogenous Retroviral Protein pHERV-W Env.

PURPOSE: Temelimab/GNbAC1 is a humanized immunoglobulin G4 monoclonal antibody antagonist of the human endogenous retrovirus W envelope protein, which is associated with multiple sclerosis (MS) pathophysiology and possibly with other autoimmune disorders. Human endogenous retrovirus W envelope protein is expressed in the central nervous system of patients with MS, and sufficient amount of temelimab must reach the target. The safety of very high dosages of temelimab should be tested to support further clinical trials in MS. METHODS: This randomized, placebo-controlled, dose-escalation study evaluated the safety and pharmacokinetic profile of temelimab in 24 healthy volunteers after a single intravenous infusion at doses of 36, 60, 85, and 110 mg/kg administered sequentially. FINDINGS: Temelimab was well tolerated, with no particular adverse drug reactions at any dose. The maximal dose of 110 mg/kg could be administered, and no antidrug antibodies were induced. After administration of 36-110 mg/kg, mean temelimab Cmax increased from 859 to 2450 µg/mL, and AUC values increased from 319,900 to 1,030,000 µg·h/mL. There was an approximate dose-proportional increase in exposure, similar to observations at lower doses. IMPLICATIONS: The favorable data in terms of safety and pharmacokinetic variables support temelimab use at high doses in future MS trials to optimally neutralize the temelimab target in the central nervous system. ClinicalTrials.gov identifier: NCT03574428.

Prevention of clinical and histological signs of MOG-induced experimental allergic encephalomyelitis by prolonged treatment with recombinant human EGF.

Epidermal growth factor (EGF) represents the prototype of the group I EGF family. The pleiotropic effects of the EGF have attracted attention to the possibility that it could be implicated in autoimmune diseases, such as Multiple Sclerosis (MS). We show here that treatment with EGF, as a late prophylactic regime, improved the clinical and histological features of EAE, a preclinical model of MS. In silico analysis further corroborated these findings by demonstrating that EGF receptors are less expressed in CNS from patients with MS as compared to controls. Taken together these data provide clear-cut in vivo proof of concept for a beneficial role of exogenously administered EGF in MS, that may, therefore, represent a novel therapeutic approach.

A new therapeutic approach for type 1 diabetes: Rationale for GNbAC1, an anti-HERV-W-Env monoclonal antibody.

We describe a newly identified therapeutic target for type 1 diabetes (T1D): an envelope protein of endogenous retroviral origin, human endogenous retrovirus W envelope (HERV-W-Env). HERV-W-Env was found to be detected in the blood of ~60% of patients with T1D and is expressed in acinar pancreatic cells of 75% of patients with T1D at post mortem examination. Preclinical experiments showed that this protein displays direct cytotoxicity on human ß-islet cells. In vivo HERV-W-Env impairs the insulin and glucose metabolism in transgenic mice expressing HERV-W-Env. GNbAC1, an IgG4 monoclonal antibody, has been developed to specifically target HERV-W-Env and to neutralize the effect of HERV-W-Env in vitro and in vivo. GNbAC1 is currently in clinical development for multiple sclerosis and > 300 subjects have been administered with GNbAC1 so far. GNbAC1 is now being tested in T1D in the RAINBOW-T1D study, which is a randomized placebo-controlled study with the objective of showing the safety and pharmacodynamic response of GNbAC1 in patients who have had T1D with a maximum of 4 years' duration. GNbAC1 is being tested vs placebo at the dose of 6 mg/kg in 60 patients during six repeated administrations for 6 months; a 6-month open-label extension will follow. The primary endpoint is to assess safety, and secondary endpoints are the pharmacodynamic responses to GNbAC1. GNbAC1 targeting HERV-W-Env is currently in clinical development in T1D, with the first safety and pharmacodynamic study. If the study results are positive, this may open the door to the development of an innovative non-immunomodulatory disease-modifying treatment for T1D.

Human Endogenous Retrovirus and Neuroinflammation in Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

BACKGROUND: Human endogenous retroviruses HERV-W encode a pro-inflammatory protein, named MSRV-Env from its original identification in Multiple Sclerosis. Though not detected in various neurological controls, MSRV-Env was found in patients with chronic inflammatory demyelinating polyradiculoneuropathies (CIDPs). This study investigated the expression of MSRV in CIDP and evaluated relevant MSRV-Env pathogenic effects. METHODS: 50 CIDP patients, 19 other neurological controls (ONDs) and 65 healthy blood donors (HBDs) were recruited from two different countries. MSRV-env and -pol transcripts, IL6 and CXCL10 levels were quantified from blood samples. MSRV-Env immunohistology was performed in distal sensory nerves from CIDP and neurological controls biopsies. MSRV-Env pathogenic effects and mode of action were assayed in cultured primary human Schwann cells (HSCs). FINDINGS: In both cohorts, MSRV-env and -pol transcripts, IL6 positivity prevalence and CXCL10 levels were significantly elevated in CIDP patients when compared to HBDs and ONDs (statistically significant in all comparisons). MSRV-Env protein was detected in Schwann cells in 5/7 CIDP biopsies. HSC exposed to or transfected with MSRV-env presented a strong increase of IL6 and CXCL10 transcripts and protein secretion. These pathogenic effects on HSC were inhibited by GNbAC1, a highly specific and neutralizing humanized monoclonal antibody targeting MSRV-Env. INTERPRETATION: The present study showed that MSRV-Env may trigger the release of critical immune mediators proposed as instrumental factors involved in the pathophysiology of CIDP. Significant MSRV-Env expression was detected in a significant proportion of patients with CIDP, in which it may play a role according to its presently observed effects on Schwann cells along with previously known effects on immune cells. Experimental results also suggest that a biomarker-driven therapeutic strategy targeting this protein with a neutralizing antibody such as GNbAC1 may offer new perspectives for treating CIDP patients with positive detection of MSRV-Env expression. FUNDING: Geneuro-Innovation, France.

MSRV envelope protein is a potent, endogenous and pathogenic agonist of human toll-like receptor 4: Relevance of GNbAC1 in multiple sclerosis treatment.

Multiple sclerosis associated retrovirus envelope protein (MSRV-Env) was repeatedly detected in brain lesions and blood of multiple sclerosis (MS) patients. We performed the first pharmacological characterisation of MSRV-Env on recombinant and native human TLR4. MSRV-Env is a full and highly potent TLR4 agonist of endogenous origin. MSRV-Env induces TLR4-dependent pro-inflammatory stimulation of immune cells in vitro and in vivo, and impairs oligodendrocytes precursor cells differentiation to myelinating oligodendrocytes. MSRV-Env may play a role in chronic inflammation and impaired remyelination in MS. GNbAC1, a selective monoclonal antibody, antagonizes MSRV-Env pathogenic effects and represents an innovative therapeutic approach of MS.

Treatment against human endogenous retrovirus: a possible personalized medicine approach for multiple sclerosis.

Human endogenous retroviruses (HERV) represent about 8 % of the human genome. Some of these genetic elements are expressed in pathological circumstances. A HERV protein, the multiple sclerosis-associated retrovirus (MSRV) envelope protein (MSRV-Env), is expressed in the blood and active brain lesions of multiple sclerosis (MS) patients. It possesses pro-inflammatory and myelinotoxic properties. The patterns of expression and pathogenic properties of MSRV-Env make it a relevant drug target for MS therapeutics-in particular for preventing neurodegeneration, a key component of progressive forms of MS. An immunoglobulin G4 monoclonal antibody (mAb), called GNbAC1, has been developed to neutralize this pathogenic target. After showing neutralizing effects in vitro and in mouse models of MS, GNbAC1 is now in phase II clinical development. MSRV-related biomarkers such as MSRV-Env and MSRV polymerase (MSRV-Pol) gene transcripts are overexpressed in the blood and cerebrospinal fluid of patients with MS. These biomarkers may have prognostic value for long-term MS evolution, and their transcription levels in blood decline during treatments with GNbAC1, which has also been reported in patients administered reference MS drugs such as natalizumab or interferon-ß. GNbAC1 as a new MSRV-Env-antagonist mAb could be a specific and causal treatment for MS, with a particular application for progressive forms of the disease. For possible use in companion diagnostic tests, MSRV-associated biomarkers could open the door to a personalized therapeutic approach for MS.

A phase IIa randomized clinical study testing GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis associated endogenous retrovirus in multiple sclerosis patients - a twelve month follow-up.

GNbAC1 is a humanized monoclonal antibody targeting MSRV-Env, an endogenous retroviral protein, which is expressed in multiple sclerosis (MS) lesions, is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. This paper describes the open-label extension up to 12months of a trial testing GNbAC1 in 10 MS patients at 2 and 6mg/kg. The primary objective was to assess GNbAC1 safety, and other objectives were pharmacokinetic and pharmacodynamic assessments. During the extended study, no safety issues occurred in the 8 remaining patients. No anti-GNbAC1 antibodies were detected. GNbAC1 appears well tolerated.

Preclinical and early clinical development of GNbAC1, a humanized IgG4 monoclonal antibody targeting endogenous retroviral MSRV-Env protein.

Monoclonal antibodies (mAbs) play an increasing important role in the therapeutic armamentarium against multiple sclerosis (MS), an inflammatory and degenerative disorder of the central nervous system. Most of the mAbs currently developed for MS are immunomodulators blocking the inflammatory immune process. In contrast with mAbs targeting immune function, GNbAC1, a humanized IgG4 mAb, targets the multiple sclerosis associated retrovirus envelope (MSRV-Env) protein, an upstream factor in the pathophysiology of MS. MSRV-Env protein is of endogenous retroviral origin, expressed in MS brain lesions, and it is pro-inflammatory and toxic to the remyelination process, by preventing the differentiation of oligodendrocyte precursor cells. We present the preclinical and early clinical development results of GNbAC1. The specificity of GNbAC1 for its endogenous retroviral target is described. Efficacy of different mAb versions of GNbAC1 were assessed in MSRV-Env induced experimental allergic encephalitis (EAE), an animal model of MS. Because the target MSRV-Env is not expressed in animals, no relevant animal model exists for a proper in vivo toxicological program. An off-target 2-week toxicity study in mice was thus performed, and it showed an absence of safety risk. Additional in vitro analyses showed an absence of complement or antibody-dependent cytotoxicity as well as a low level of cross-reactivity to human tissues. The first-in-man clinical study in 33 healthy subjects and a long-term clinical study in 10 MS patients showed that GNbAC1 is well tolerated in humans without induction of immunogenicity and that it induces a pharmacodynamic response on MSRV biomarkers. These initial results suggest that the mAb GNbAC1 could be a safe long-term treatment for patients with MS with a unique therapeutic mechanism of action.

A phase IIa randomised clinical study of GNbAC1, a humanised monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus in multiple sclerosis patients.

BACKGROUND: GNbAC1 is an immunoglobulin (IgG4) humanised monoclonal antibody against multiple sclerosis-associated retrovirus (MSRV)-Env, a protein of endogenous retroviral origin, expressed in multiple sclerosis (MS) lesions, which is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. OBJECTIVE: This is a randomised, double-blind placebo-controlled dose-escalation study followed by a six-month open-label phase to test GNbAC1 in MS patients. The primary objective was to assess GNbAC1 safety in MS patients, and the other objectives were pharmacokinetic and pharmacodynamic assessments. METHODS: Ten MS patients were randomised into two cohorts to receive a single intravenous infusion of GNbAC1/placebo at doses of 2 or 6 mg/kg. Then all patients received five infusions of GNbAC1 at 2 or 6 mg/kg at four-week intervals in an open-label setting. Safety, brain magnetic resonance imaging (MRI), pharmacokinetics, immunogenicity, cytokines and MSRV RNA expression were studied. RESULTS: All patients completed the study. GNbAC1 was well tolerated in all patients. GNbAC1 pharmacokinetics is dose-linear with mean elimination half-life of 27-37 d. Anti-GNbAC1 antibodies were not detected. Cytokine analysis did not indicate an adverse effect. MSRV-transcripts showed a decline after the start of treatment. Nine patients had stable brain lesions at MRI. CONCLUSION: The safety, pharmacokinetic profile, and pharmacodynamic responses to GNbAC1 are favourable in MS patients over a six-month treatment period.

Novel therapeutic options for multiple sclerosis.

Multiple sclerosis (MS) is considered as an autoimmune disorder of the CNS with neuro-inflammatory and neurodegenerative components. We review here the innovative drugs recently registered and those in clinical development for MS. Immunomodulation has been the preferred therapeutic approach for MS since the first IFN-ß was registered in the 1990s. Several immunomodulators are now available, which show a high efficacy in reducing the number of relapses in patients with the relapsing-remitting form of MS (RRMS). The high efficacy of most immunomodulators is, however, associated with substantial safety risks, notably concerning infections or cancers. Recently oral drugs have been approved for RRMS; however, biologics, and notably, monoclonal antibodies are still well represented in the development pipelines. An unmet medical need remains the treatment of the primary and secondary forms of MS or chronic progressive MS (CPMS). Half a dozen immunomodulators with proven efficacy in RRMS are now undergoing evaluation in Phase III trials in the CPMS indication. Neuroprotective drugs that prevent demyelination and/or improve remyelination would be interesting for CPMS, but these drugs are currently in the early development phase and their efficacy has not been demonstrated yet.

GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus: a first-in-humans randomized clinical study.

BACKGROUND: Human endogenous retrovirus (HERV) genes represent about 8% of the human genome. A member of the HERV family W, the Multiple Sclerosis-Associated Retrovirus (MSRV) gene, encodes an envelope protein (Env), which can activate a proinflammatory and autoimmune cascade through its interaction with Toll-like receptor 4. Due to its proinflammatory property and an inhibitory effect on oligodendrocyte precursor cell differentiation, the MSRV-Env protein could play a crucial role in the pathogeny of multiple sclerosis. GNbAC1 is a humanized monoclonal antibody of the immunoglobulin G4 type, which is directed against MSRV-Env. After validation of the MSRV-Env as a therapeutic target in preclinical experimental models, a clinical development program was initiated. OBJECTIVE: This study evaluated the safety profile, pharmacokinetic parameters, and immunogenicity of GNbAC1 in healthy male volunteers. METHODS: In this first-in-humans, Phase I, randomized, double-blind, placebo-controlled, dose-escalation study, each subject received a single dose of IV GNbAC1 0.0025, 0.025, 0.15, 0.6, 2, or 6 mg/kg or inactive vehicle (placebo), infused over 1 hour. Tolerability and other laboratory parameters were observed, and regular blood sampling was performed, to study the pharmacokinetic properties and immunogenicity of this monoclonal antibody. RESULTS: A total of 33 male subjects (mean age, 44 years) completed the study. GNbAC1 was well tolerated after dosing in all subjects and in each dose cohort. Only minor and nonspecific adverse events (AEs) were recorded; no serious AEs were reported. Pharmacokinetic data show a dose-linear pharmacokinetic profile. The mean elimination half-life ranged between 19 and 26 days, with therapeutically efficient concentrations maintained over a 4-week periods at doses of 2 and 6 mg/kg. No emergence of anti-GNbAC1 antibodies were detected after dosing in any subject over the entire observation period of 64 days. CONCLUSIONS: In these healthy male subjects, the safety and pharmacokinetic profiles of GNbAC1 appeared favorable. These findings are expected to allow for the launch of a Phase II development program for this innovative therapeutic approach in patients with multiple sclerosis. ClinicalTrials.gov identifier: NCT01699555.

Psychological distress in fibromyalgia patients: a role for catechol-O-methyl-transferase Val158met polymorphism.

OBJECTIVE: Fibromyalgia (FM) has been related to biochemical alterations, central pain sensitization and psychological distress. Among genetic and environmental hypotheses, a role was suggested for catechol-O-methyl-transferase (COMT), a modulator in the metabolism of monoaminergic neurotransmitters. METHOD: This study compared the COMT Val158Met enzyme polymorphism (rs4680) of 198 FM patients to 99 pain-free controls. Psychological and functional aspects were assessed through investigating anxiety, depression, catastrophizing, perceived health, and functional status. RESULTS: The distribution of the COMT Val158Met polymorphism was similar in FM and controls. Out of 198 patients, 137 were able to stop medication before evaluation. In these patients, the COMT Val158Met genotype was associated with specific psychological profiles. The Met/Met subgroup scored systematically worse on all psychological and functional variables. All variables displayed a "genotype-trend effect" with the Met/Met and Val/Val subgroups at the two ends of the scores. Genotypes distribution in the 61 patients unable to stop medication was significantly different from that of patients able to stop medication and controls (p = .002 and p = .018, respectively) with an increase in the proportion of the Met/Met genotype associated to the lowest COMT activity. These results suggest a possible role of COMT Val158Met polymorphism in the psychological distress observed in FM. CONCLUSIONS: The association of COMT genotype with psychological distress may be of importance as identifying subgroups is a challenge in the diagnosis and treatment of fibromyalgia patients. This association may contribute to open new perspectives into the understanding of the pathophysiology of fibromyalgia and stress-related genes.

Lithium, antipsychotics, and risk of psoriasis.

BACKGROUND: Observations in controlled trials and case reports have linked lithium exposure to induction or exacerbation of psoriasis. A causal relationship between lithium exposure and incident psoriasis has been questioned, and observational studies are lacking. METHODS: We conducted a case-control analysis using the United Kingdom-based General Practice Research Database to study the association between the use of lithium or antipsychotics and the risk of developing an incident diagnosis of psoriasis. We identified cases with an incident diagnosis of psoriasis between 1994 and 2005, and controls were matched to the cases on age, sex, general practice, calendar time, and years of history in the database. We used conditional logistic regression to estimate the risk of developing a first-time diagnosis of psoriasis in relation to previous exposure to lithium and antipsychotic drugs, stratified by exposure timing and duration. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) adjusted for smoking, body mass index, and additional potential confounders. RESULTS: We identified 36,702 incident cases of psoriasis and the same number of matched controls. Compared with nonuse, current use of 5 or more prescriptions for lithium and atypical antipsychotics yielded adjusted ORs of 1.68 (95% CI, 1.18-2.39; P < 0.01) and 0.76 (95% CI, 0.55-1.06; P = 0.11), respectively. The OR for olanzapine was 0.50 (95% CI, 0.28-0.89, P = 0.02). CONCLUSIONS: Long-term use of lithium was associated with a small increase in risk of incident psoriasis. There was a suggestion of a possible reduced psoriasis risk associated with the use of atypical antipsychotics, mainly olanzapine, a finding that needs further evaluation.

A review of malignancies observed during efalizumab (Raptiva) clinical trials for plaque psoriasis.

BACKGROUND: Psoriasis is a chronic, incurable immune-mediated disease. Most therapies used for moderate to severe psoriasis are immunosuppressive. Agents that depress immune function, including traditional psoriasis therapies, have been associated with an increased incidence of malignancies. Efalizumab is a recombinant monoclonal immunoglobulin G1 (IgG1) antibody approved for use in psoriasis patients. OBJECTIVES: To evaluate the incidence of malignancy in patients receiving efalizumab during clinical trials compared with placebo-treated patients, psoriasis patients from external cohorts and the general US population. METHODS: Patient data were pooled from multiple phase III placebo-controlled, open-label efalizumab clinical trials, and the incidence rate of reported malignancies was calculated as a function of patient years of observation. The results for the efalizumab-treated patients were compared with the data on psoriasis patients from insurance claims databases and a registry of events in the general population. RESULTS: The efalizumab- and placebo-treated patients had similar incidence rates of malignancy, including lymphoproliferative disease, solid tumor, malignant melanoma and nonmelanoma skin cancer. The incidence of nonmelanoma skin cancers, including basal cell carcinoma and squamous cell carcinoma, in patients receiving efalizumab or placebo was elevated relative to the external databases. CONCLUSIONS: These results suggest that efalizumab treatment does not increase a patient's risk for malignancy. The difference observed with nonmelanoma skin cancer may be due to biases introduced by the clinical trial methodology. Additional patient observation is necessary to ascertain whether a link exists between efalizumab therapy and nonmelanoma skin cancer above that normally observed in psoriasis patients.