An innovative phase 2 proof-of-concept trial design to evaluate SAR445088, a monoclonal antibody targeting complement C1s in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND AND AIMS: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare immune-mediated disease of the peripheral nerves, with significant unmet treatment needs. Clinical trials in CIDP are challenging; thus, new trial designs are needed. We present design of an open-label phase 2 study (NCT04658472) evaluating efficacy and safety of SAR445088, a monoclonal antibody targeting complement C1s, in CIDP. METHODS: This phase 2, proof-of-concept, multicenter, open-label trial will evaluate the efficacy, and safety of SAR445088 in 90 patients with CIDP across three groups: (1) currently treated with standard-of-care (SOC) therapies, including immunoglobulin or corticosteroids (SOC-Treated); (2) refractory to SOC (SOC-Refractory); and (3) naïve to SOC (SOC-Naïve). Enrolled participants undergo a 24-week treatment period (part A), followed by an optional treatment extension for up to an additional 52 weeks (part B). In part A, the primary endpoint for the SOC-Treated group is the percentage of participants with a relapse after switching from SOC to SAR445088. The primary endpoint for the SOC-Refractory and SOC-Naïve groups is the percentage of participants with a response, compared to baseline. Secondary endpoints include safety, tolerability, immunogenicity, and efficacy of SAR445088 during 12-week overlapping period (SOC-Treated). Part B evaluates long-term safety and durability of efficacy. Data analysis will be performed using Bayesian statistics (predefined efficacy thresholds) and historical data-based placebo assumptions to support program decision-making. INTERPRETATION: This innovative trial design based on patient groups and Bayesian statistics provides an efficient paradigm to evaluate new treatment candidates across the CIDP spectrum and can help accelerate development of new therapies.

Esterase-Mediated Sustained Release of Peptide-Based Therapeutics from a Self-Assembled Injectable Hydrogel.

A synthetic strategy for conjugating small molecules and peptide-based therapeutics, via a cleavable ester bond, to a lipidated ß3-tripeptide is presented. The drug-loaded ß3-peptide was successfully co-assembled with a functionally inert lipidated ß3-tripeptide to form a hydrogel. Quantitative release of lactose from the hydrogel, by the action of serum esterases, is demonstrated over 28 days. The esterase-mediated sustained release of the bioactive brain-derived neurotrophic factor (BDNF) peptide mimics from the hydrogel resulted in increased neuronal survival and normal neuronal function of peripheral neurons. These studies define a versatile strategy for the facile synthesis and co-assembly of self-assembling ß3-peptide-based hydrogels with the ability to control drug release using endogenous esterases with potential in vivo applications for sustained localized drug delivery.

[Evidence based guidelines. Diagnosis and management of Guillain-Barré syndrome in ten steps]. / Guía basada en la evidencia. Diagnóstico y manejo del síndrome de Guillain-Barré en diez pasos.

Guillain-Barré syndrome (GBS) is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections. The incidence of GBS can therefore increase during outbreaks of infectious diseases, as was seen during the Zika virus epidemics in 2013 in French Polynesia and in 2015 in Latin America. Diagnosis and management of GBS can be complicated as its clinical presentation and disease course are heterogeneous, and no international clinical guidelines are currently available. To support clinicians, especially in the context of an outbreak, we have developed a globally applicable guideline for the diagnosis and management of GBS. The guideline is based on current literature and expert consensus, and has a ten-step structure to facilitate its use in clinical practice. We first provide an introduction to the diagnostic criteria, clinical variants and differential diagnoses of GBS. The ten steps then cover early recognition and diagnosis of GBS, admission to the intensive care unit, treatment indication and selection, monitoring and treatment of disease progression, prediction of clinical course and outcome, and management of complications and sequelae.

El síndrome de Guillain-Barré (SGB) es una enfermedad inmunológica del nervio periférico y las raíces nerviosas, poco frecuente, potencialmente mortal y que suele desencadenarse por infecciones. La incidencia del SGB puede aumentar durante el brote de enfermedades infecciosas, tal como se observó en las epidemias del virus Zika en la Polinesia Francesa en 2013 y en América Latina en 2015. El diagnóstico y el manejo clínico del SGB pueden ser complicados ya que su presentación y el curso de la enfermedad son heterogéneos, y actualmente no se cuenta con guías clínicas internacionales. Para respaldar a los médicos, especialmente en el contexto de un brote de una enfermedad infecciosa, hemos desarrollado una guía clínica aplicable en todo el mundo para el diagnóstico y el tratamiento del SGB. La guía se basa en literatura actualizada y el consenso de expertos, y tiene una estructura de diez pasos para facilitar su uso en la práctica clínica. Inicialmente, brindamos una introducción a los criterios de diagnóstico, variantes clínicas y diagnósticos diferenciales del SGB. Los diez pasos luego abordan el reconocimiento y el diagnóstico temprano del SGB, la admisión a la unidad de cuidados intensivos, indicación y selección de tratamiento, seguimiento y tratamiento de la progresión de la enfermedad, predicción del curso clínico, resultados y tratamiento de complicaciones y secuelas.

Guía basada en la evidencia. Diagnóstico y manejo del síndrome de Guillain-Barré en diez pasos / Evidence based guidelines. Diagnosis and management of Guillain-Barré syndrome in ten steps

Resumen El síndrome de Guillain-Barré (SGB) es una enfermedad inmunológica del nervio periférico y las raíces nerviosas, poco frecuente, potencialmente mortal y que suele desencadenarse por infecciones. La incidencia del SGB puede aumentar durante el brote de enfermedades infecciosas, tal como se observó en las epidemias del virus Zika en la Polinesia Francesa en 2013 y en América Latina en 2015. El diagnóstico y el manejo clínico del SGB pueden ser complicados ya que su presentación y el curso de la enfermedad son heterogéneos, y actualmente no se cuenta con guías clínicas internacionales. Para respaldar a los médicos, especialmente en el contexto de un brote de una enfermedad infecciosa, hemos desarrollado una guía clínica aplicable en todo el mundo para el diagnóstico y el tratamiento del SGB. La guía se basa en literatura actualizada y el consenso de expertos, y tiene una estructura de diez pasos para facilitar su uso en la práctica clínica. Inicialmente, brindamos una introducción a los criterios de diagnóstico, variantes clínicas y diagnósticos diferenciales del SGB. Los diez pasos luego abordan el reconocimiento y el diagnóstico temprano del SGB, la admisión a la unidad de cuidados intensivos, indicación y selección de tratamiento, seguimiento y tratamiento de la progresión de la enfermedad, predicción del curso clínico, resultados y tratamiento de complicaciones y secuelas.

Abstract Guillain-Barré syndrome (GBS) is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections. The incidence of GBS can therefore increase during outbreaks of infectious diseases, as was seen during the Zika virus epidemics in 2013 in French Polynesia and in 2015 in Latin America. Diagnosis and management of GBS can be complicated as its clinical presentation and disease course are heterogeneous, and no international clinical guidelines are currently available. To support clinicians, especially in the context of an outbreak, we have developed a globally applicable guideline for the diagnosis and management of GBS. The guideline is based on current literature and expert consensus, and has a ten-step structure to facilitate its use in clinical practice. We first provide an introduction to the diag nostic criteria, clinical variants and differential diagnoses of GBS. The ten steps then cover early recognition and diagnosis of GBS, admission to the intensive care unit, treatment indication and selection, monitoring and treatment of disease progression, prediction of clinical course and outcome, and management of complications and sequelae.

Intravenous immunoglobulin treatment for mild Guillain-Barré syndrome: an international observational study.

OBJECTIVE: To compare the disease course in patients with mild Guillain-Barré syndrome (GBS) who were treated with intravenous immunoglobulin (IVIg) or supportive care only. METHODS: We selected patients from the prospective observational International GBS Outcome Study (IGOS) who were able to walk independently at study entry (mild GBS), treated with one IVIg course or supportive care. The primary endpoint was the GBS disability score four weeks after study entry, assessed by multivariable ordinal regression analysis. RESULTS: Of 188 eligible patients, 148 (79%) were treated with IVIg and 40 (21%) with supportive care. The IVIg group was more disabled at baseline. IVIg treatment was not associated with lower GBS disability scores at 4 weeks (adjusted OR (aOR) 1.62, 95% CI 0.63 to 4.13). Nearly all secondary endpoints showed no benefit from IVIg, although the time to regain full muscle strength was shorter (28 vs 56 days, p=0.03) and reported pain at 26 weeks was lower (n=26/121, 22% vs n=12/30, 40%, p=0.04) in the IVIg treated patients. In the subanalysis with persistent mild GBS in the first 2 weeks, the aOR for a lower GBS disability score at 4 weeks was 2.32 (95% CI 0.76 to 7.13). At 1 year, 40% of all patients had residual symptoms. CONCLUSION: In patients with mild GBS, one course of IVIg did not improve the overall disease course. The certainty of this conclusion is limited by confounding factors, selection bias and wide confidence limits. Residual symptoms were often present after one year, indicating the need for better treatments in mild GBS.

1,3-Dichloroacetone: A Robust Reagent for Preparing Bicyclic Peptides.

The chemical synthesis of cyclic peptides is a well-established area of research. This has been further expanded by development of bio-orthogonal reactions that enable access to peptides of greater structural complexity. One approach utilizes 1,3-dichloroacetone to selectively link free cysteine side-chains with an acetone-like bridge via an SN2 reaction. Here, we have used this reaction to dimerize cyclic peptide monomers to create novel bicyclic dimeric peptides. We investigated a range of reaction parameters to identify the optimal dimerization conditions for our model systems. One of the acetone-linked dimeric peptides was analyzed for proteolytic stability in human serum and was observed to still be fully intact after 48 h. This study provides valuable insights into the application of 1,3-dichloroacetone as a tool in the synthesis of complex, multicyclic peptides.

Original research: Second IVIg course in Guillain-Barré syndrome with poor prognosis: the non-randomised ISID study.

OBJECTIVE: To compare disease course in patients with Guillain-Barré syndrome (GBS) with a poor prognosis who were treated with one or with two intravenous immunoglobulin (IVIg) courses. METHODS: From the International GBS Outcome Study, we selected patients whose modified Erasmus GBS Outcome Score at week 1 predicted a poor prognosis. We compared those treated with one IVIg course to those treated with two IVIg courses. The primary endpoint, the GBS disability scale at 4 weeks, was assessed with multivariable ordinal regression. RESULTS: Of 237 eligible patients, 199 patients received a single IVIg course. Twenty patients received an 'early' second IVIg course (1-2 weeks after start of the first IVIg course) and 18 patients a 'late' second IVIg course (2-4 weeks after start of IVIg). At baseline and 1 week, those receiving two IVIg courses were more disabled than those receiving one course. Compared with the one course group, the adjusted OR for a better GBS disability score at 4 weeks was 0.70 (95%CI 0.16 to 3.04) for the early group and 0.66 (95%CI 0.18 to 2.50) for the late group. The secondary endpoints were not in favour of a second IVIg course. CONCLUSIONS: This observational study did not show better outcomes after a second IVIg course in GBS with poor prognosis. The study was limited by small numbers and baseline imbalances. Lack of improvement was likely an incentive to start a second IVIg course. A prospective randomised trial is needed to evaluate whether a second IVIg course improves outcome in GBS.

Diagnosis and management of Guillain-Barré syndrome in ten steps.

Guillain-Barré syndrome (GBS) is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections. The incidence of GBS can therefore increase during outbreaks of infectious diseases, as was seen during the Zika virus epidemics in 2013 in French Polynesia and 2015 in Latin America. Diagnosis and management of GBS can be complicated as its clinical presentation and disease course are heterogeneous, and no international clinical guidelines are currently available. To support clinicians, especially in the context of an outbreak, we have developed a globally applicable guideline for the diagnosis and management of GBS. The guideline is based on current literature and expert consensus, and has a ten-step structure to facilitate its use in clinical practice. We first provide an introduction to the diagnostic criteria, clinical variants and differential diagnoses of GBS. The ten steps then cover early recognition and diagnosis of GBS, admission to the intensive care unit, treatment indication and selection, monitoring and treatment of disease progression, prediction of clinical course and outcome, and management of complications and sequelae.

Regional variation of Guillain-Barré syndrome.

Guillain-Barré syndrome is a heterogeneous disorder regarding the clinical presentation, electrophysiological subtype and outcome. Previous single country reports indicate that Guillain-Barré syndrome may differ among regions, but no systematic comparative studies have been conducted. Comparative studies are required to identify factors determining disease susceptibility, variation and prognosis, and to improve diagnostic criteria. The International Guillain-Barré Syndrome Outcome Study is a prospective, observational cohort study including all patients within the diagnostic spectrum, aiming to describe the heterogeneity of Guillain-Barré syndrome worldwide. The current study was based on the first 1000 inclusions with a follow-up of at least 1 year and confirmed the variation in clinical presentation, course and outcome between patients. The full clinical spectrum of Guillain-Barré syndrome was observed in patients from all countries participating in the International Guillain-Barré Syndrome Outcome Study, but the frequency of variants differed between regions. We compared three regions based on geography, income and previous reports of Guillain-Barré syndrome subtypes: 'Europe/Americas', 'Asia' (without Bangladesh), and 'Bangladesh'. We excluded 75 (8%) patients because of alternative diagnoses, protocol violations, or missing data. The predominant clinical variant was sensorimotor in Europe/Americas (n = 387/562, 69%) and Asia (n = 27/63, 43%), and pure motor in Bangladesh (n = 74/107, 69%). Miller Fisher syndrome and Miller Fisher-Guillain-Barré overlap syndrome were more common in Asia (n = 14/63, 22%) than in the other two regions (Europe/Americas: n = 64/562, 11%; Bangladesh: n = 1/107, 1%) (P < 0.001). The predominant electrophysiological subtype was demyelinating in all regions (Europe/Americas: n = 312/573, 55%; Asia: n = 29/65, 45%; Bangladesh: n = 38/94, 40%). The axonal subtype occurred more often in Bangladesh (n = 34/94, 36%) than in Europe/Americas (n = 33/573, 6%) and other Asian countries (n = 4/65, 6%) (P < 0.001). In all regions, patients with the axonal subtype were younger, had fewer sensory deficits, and showed a trend towards poorer recovery compared to patients with the demyelinating subtype. The proportion of patients able to walk unaided after 1 year varied between Asia (n = 31/34, 91%), Europe/Americas (n = 334/404, 83%) and Bangladesh (n = 67/97, 69%) (P = 0.003). A similar variation was seen for mortality, being higher in Bangladesh (n = 19/114, 17%) than in Europe/Americas (n = 23/486, 5%) and Asia (n = 1/45, 2%) (P < 0.001). This study showed that factors related to geography have a major influence on clinical phenotype, disease severity, electrophysiological subtype, and outcome of Guillain-Barré syndrome.

Targeting TrkB with a Brain-Derived Neurotrophic Factor Mimetic Promotes Myelin Repair in the Brain.

Methods to promote myelin regeneration in response to central myelin loss are essential to prevent the progression of clinical disability in demyelinating diseases. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to promote myelination during development via oligodendrocyte expressed TrkB receptors. Here, we use a structural mimetic of BDNF to promote myelin regeneration in a preclinical mouse model of central demyelination. In female mice, we show that selective targeting of TrkB with the BDNF-mimetic enhances remyelination, increasing oligodendrocyte differentiation, the frequency of myelinated axons, and myelin sheath thickness after a demyelinating insult. Treatment with exogenous BDNF exerted an attenuated effect, increasing myelin sheath thickness only. Further, following conditional deletion of TrkB from premyelinating oligodendrocytes, we show the effects of the BDNF-mimetic on oligodendrocyte differentiation and remyelination are lost, indicating these are dependent on oligodendrocyte expression of TrkB. Overall, these studies demonstrate that targeting oligodendrocyte TrkB promotes in vivo remyelination in the brain.SIGNIFICANCE STATEMENT Novel strategies to promote myelin regeneration are required to prevent progressive neurodegeneration and clinical disability in patients with central demyelinating disease. Here, we test whether selectively targeting the TrkB receptor on the myelin-producing oligodendrocytes, can promote remyelination in the brain. Using a structural mimetic of its native ligand, BDNF, we show that stimulation of TrkB enhances remyelination, increasing oligodendrocyte differentiation, the frequency of myelinated axons and thickness of the myelin sheath following a demyelinating insult. Further, we show that these effects are dependent on the phosphorylation of oligodendrocyte expressed TrkB receptors in vivo Overall, we demonstrate that selective targeting of TrkB has therapeutic potential to promote remyelination in the brain.

A Brain-Derived Neurotrophic Factor-Based p75NTR Peptide Mimetic Ameliorates Experimental Autoimmune Neuritis Induced Axonal Pathology and Demyelination.

Axonal damage and demyelination are major determinants of disability in patients with peripheral demyelinating neuropathies. The neurotrophin family of growth factors are essential for the normal development and myelination of the peripheral nervous system (PNS), and as such are potential therapeutic candidates for ameliorating axonal and myelin damage. In particular, BDNF promotes peripheral nerve myelination via p75 neurotrophin receptor (p75NTR) receptors. Here, we investigated the therapeutic efficacy of a small structural mimetic of the region of BDNF that binds to p75NTR (cyclo-dPAKKR) in experimental autoimmune neuritis (EAN), an established animal model of peripheral demyelinating neuropathy. Examination of rodents induced with EAN revealed that p75NTR is abundantly expressed in affected peripheral nerves. We found that systemic administration of cyclo-dPAKKR ameliorates EAN disease severity and accelerates recovery. Animals treated with cyclo-dPAKKR displayed significantly better motor performance compared to control animals. Histological assessment revealed that cyclo-dPAKKR administration limits the extent of inflammatory demyelination and axonal damage, and protects against the disruption of nodal architecture in affected peripheral nerves. In contrast, a structural control peptide of cyclo-dPAKKR exerted no influence. Moreover, all the beneficial effects of cyclo-dPAKKR in EAN are abrogated in p75NTR heterozygous mice, strongly suggesting a p75NTR-dependent effect. Taken together, our data demonstrate that cyclo-dPAKKR ameliorates functional and pathological defects of EAN in a p75NTR-dependant manner, suggesting that p75NTR is a therapeutic target to consider for future treatment of peripheral demyelinating diseases and targeting of p75NTR is a strategy worthy of further investigation.

International Guillain-Barré Syndrome Outcome Study: protocol of a prospective observational cohort study on clinical and biological predictors of disease course and outcome in Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is an acute polyradiculoneuropathy with a highly variable clinical presentation, course, and outcome. The factors that determine the clinical variation of GBS are poorly understood which complicates the care and treatment of individual patients. The protocol of the ongoing International GBS Outcome Study (IGOS), a prospective, observational, multicenter cohort study that aims to identify the clinical and biological determinants and predictors of disease onset, subtype, course and outcome of GBS is presented here. Patients fulfilling the diagnostic criteria for GBS, regardless of age, disease severity, variant forms, or treatment, can participate if included within 2 weeks after onset of weakness. Information about demography, preceding infections, clinical features, diagnostic findings, treatment, course, and outcome is collected. In addition, cerebrospinal fluid and serial blood samples for serum and DNA is collected at standard time points. The original aim was to include at least 1,000 patients with a follow-up of 1-3 years. Data are collected via a web-based data entry system and stored anonymously. IGOS started in May 2012 and by January 2017 included more than 1,400 participants from 143 active centers in 19 countries across 5 continents. The IGOS data/biobank is available for research projects conducted by expertise groups focusing on specific topics including epidemiology, diagnostic criteria, clinimetrics, electrophysiology, antecedent events, antibodies, genetics, prognostic modeling, treatment effects, and long-term outcome of GBS. The IGOS will help to standardize the international collection of data and biosamples for future research of GBS.

Engineering of a Novel Simplified Human Insulin-Like Peptide 5 Agonist.

Insulin-like peptide 5 (INSL5) has recently been discovered as only the second orexigenic gut hormone after ghrelin. As we have previously reported, INSL5 is extremely difficult to assemble and oxidize into its two-chain three-disulfide structure. The focus of this study was to generate structure-activity relationships (SARs) of INSL5 and use it to develop a potent and simpler INSL5 mimetic with RXFP4 agonist activity. A series of human and mouse INSL5 (hINSL5/mINSL5) analogues were designed and chemically synthesized, resulting in a chimeric INSL5 analogue exhibiting more than 10-fold higher potency (0.35 nM) at human RXFP4 compared with native hINSL5 (4.57 nM). The SAR study also identified a key residue (K(A15)) in the A-chain of mINSL5 that contributes to improved RXFP4 affinity and potency of mINSL5 compared with hINSL5. This knowledge ultimately led us to engineer a minimized hINSL5 mimetic agonist that retains native hINSL5-like RXFP4 affinity and potency at human RXFP4. This minimized analogue was synthesized in 17.5-fold higher yield and in less time compared with hINSL5.

The C-terminus of the B-chain of human insulin-like peptide 5 is critical for cognate RXFP4 receptor activity.

Insulin-like peptide 5 (INSL5) is an orexigenic peptide hormone belonging to the relaxin family of peptides. It is expressed primarily in the L-cells of the colon and has a postulated key role in regulating food intake. Its G protein-coupled receptor, RXFP4, is a potential drug target for treating obesity and anorexia. We studied the effect of modification of the C-terminus of the A and B-chains of human INSL5 on RXFP4 binding and activation. Three variants of human INSL5 were prepared using solid phase peptide synthesis and subsequent sequential regioselective disulfide bond formation. The peptides were synthesized as C-terminal acids (both A- and B-chains with free C-termini, i.e., the native form), amides (both chains as the C-terminal amide) and one analog with the C-terminus of its A-chain as the amide and the C-terminus of the B-chain as the acid. The results showed that C-terminus of the B-chain is more important than that of the A-chain for RXFP4 binding and activity. Amidation of the A-chain C-terminus does not have any effect on the INSL5 activity. The difference in RXFP4 binding and activation between the three peptides is believed to be due to electrostatic interaction of the free carboxylate of INSL5 with a positively charged residue (s), either situated within the INSL5 molecule itself or in the receptor extracellular loops.

Progress in inflammatory neuropathy -the legacy of Dr Jack Griffin.

The past quarter of a century has brought incredible advances in our understanding of inflammatory neuropathies, and the insights into Guillain-Barré syndrome (GBS) began in the 1990s with the seminal work of Dr Jack Griffin and his colleagues. In this essay, we provide a tribute to Jack, and review the recent progress in a field that he termed his personal favourite. In particular, we discuss the new developments in our understanding and diagnosis of inflammatory neuropathies, the recent emergence of the node of Ranvier and the paranode as sites of intensive investigation, and the mechanistic evidence that is providing a platform for therapeutic development studies.