A Phase 1 Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (2R,6R)-Hydroxynorketamine in Healthy Volunteers.

(R,S)-Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)-Hydroxynorketamine (RR-HNK) is a metabolite of ketamine that lacks anesthetic and dissociative activity but maintains antidepressant and analgesic activity in multiple preclinical models. To enable future assessments in selected human indications, we report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RR-HNK in a Phase 1 study in healthy volunteers (NCT04711005). A six-level single-ascending dose (SAD) (0.1-4 mg/kg) and a two-level multiple ascending dose (MAD) (1 and 2 mg/kg) study was performed using a 40-minute IV administration emulating the common practice for ketamine administration for depression. Safety assessments showed RR-HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of dissociation and sedation demonstrated that RR-HNK did not possess anesthetic or dissociative characteristics in the doses examined. RR-HNK PK parameters were measured in both the SAD and MAD studies and exhibited dose-proportional increases in exposure. Quantitative electroencephalography (EEG) measurements collected as a PD parameter based on preclinical findings and ketamine's established effect on gamma-power oscillations demonstrated increases of gamma power in some participants at the lower/mid-range doses examined. Cerebrospinal fluid examination confirmed RR-HNK exposure within the central nervous system (CNS). Collectively, these data demonstrate RR-HNK is well tolerated with an acceptable PK profile and promising PD outcomes to support the progression into Phase 2.

Immune dysregulation in chronic inflammatory demyelinating polyneuropathy.

OBJECTIVE: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disorder of the peripheral nerves with an incompletely understood underlying pathophysiology. This investigation focused on defining B and T cell frequencies, T cell functional capacity and innate immune system analysis in patients with CIDP. METHODS: By using multi-parameter flow cytometry, we examined the phenotype and function of PBMCs in 25 CIDP patients who were relatively clinically stable on treatment who met EFNS/PNS criteria, 21 patients with genetically confirmed hereditary neuropathy and 25 healthy controls. We also evaluated the regulatory T cell (Treg) inhibitory capacity by co-culturing Treg and effector T cells. RESULTS: Proinflammatory CD4 T cells, especially type 1 helper T cell (Th1) and CD8 T cells in patients with CIDP were found to have an enhanced capacity to produce inflammatory cytokines. There was no difference in frequency of Th17 regulatory cells in CIDP patients versus healthy controls, however, Treg function was impaired in CIDP patients. There was no remarkable difference in innate immune system measures. Within B cell subsets, transitional cell frequency was decreased in CIDP patients. INTERPRETATION: Patients with CIDP clinically stable on treatment continued to show evidence of a proinflammatory state with impaired Treg function. This potentially implies an inadequate suppression of ongoing inflammation not addressed by standard of care therapies as well as persistent activity of disease while on treatment. Targeting T cells, especially inhibiting Th1 and polyfunctional CD8 T cells or improving Treg cell function could be potential targets for future therapeutic research.

A chimeric haemagglutinin-based universal influenza virus vaccine boosts human cellular immune responses directed towards the conserved haemagglutinin stalk domain and the viral nucleoprotein.

BACKGROUND: The development of a universal influenza virus vaccine, to protect against both seasonal and pandemic influenza A viruses, is a long-standing public health goal. The conserved stalk domain of haemagglutinin (HA) is a promising vaccine target. However, the stalk is immunosubdominant. As such, innovative approaches are required to elicit robust immunity against this domain. In a previously reported observer-blind, randomised placebo-controlled phase I trial (NCT03300050), immunisation regimens using chimeric HA (cHA)-based immunogens formulated as inactivated influenza vaccines (IIV) -/+ AS03 adjuvant, or live attenuated influenza vaccines (LAIV), elicited durable HA stalk-specific antibodies with broad reactivity. In this study, we sought to determine if these vaccines could also boost T cell responses against HA stalk, and nucleoprotein (NP). METHODS: We measured interferon-γ (IFN-γ) responses by Enzyme-Linked ImmunoSpot (ELISpot) assay at baseline, seven days post-prime, pre-boost and seven days post-boost following heterologous prime:boost regimens of LAIV and/or adjuvanted/unadjuvanted IIV-cHA vaccines. FINDINGS: Our findings demonstrate that immunisation with adjuvanted cHA-based IIVs boost HA stalk-specific and NP-specific T cell responses in humans. To date, it has been unclear if HA stalk-specific T cells can be boosted in humans by HA-stalk focused universal vaccines. Therefore, our study will provide valuable insights for the design of future studies to determine the precise role of HA stalk-specific T cells in broad protection. INTERPRETATION: Considering that cHA-based vaccines also elicit stalk-specific antibodies, these data support the further clinical advancement of cHA-based universal influenza vaccine candidates. FUNDING: This study was funded in part by the Bill and Melinda Gates Foundation (BMGF).

Comparative effectiveness of azathioprine and mycophenolate mofetil for myasthenia gravis (PROMISE-MG): a prospective cohort study.

BACKGROUND: Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. Treatment typically includes symptomatic oral cholinesterase inhibitors, immunosuppression, and immunomodulation. In addition to corticosteroids, azathioprine and mycophenolate mofetil are the most frequently used immunosuppressants in North America. We aimed to evaluate the comparative effectiveness of these two drugs, and to assess the effect of the dose and duration of treatment. METHODS: We did a prospective cohort study at 19 academic centres in Canada and the USA. We included patients (aged ≥18 years) with autoimmune myasthenia gravis, who were never treated with immunosuppressants. Treating clinicians determined the choice of medication, dose, follow-up intervals, and drug monitoring. Outcome measures and adverse events were recorded at each visit. We assessed two co-primary outcomes. The first was the patient-reported Myasthenia Gravis-Quality of Life 15-revised (MGQOL-15r) score, measured as the mean change from treatment initiation to the follow-up visit with the lowest score. A clinically meaningful reduction (CMR) in MGQOL-15r was defined as a 5-point decrease. The second was a composite clinical outcome of disease improvement (Myasthenia Gravis Foundation of America Post-Intervention Status Minimal Manifestations or better) and low adverse event burden (defined as grade ≤1 Common Terminology Criteria for Adverse Events). We also compared these outcomes in patients receiving an adequate dose and duration of azathioprine (≥2 mg/kg per day for at least 12 months) or mycophenolate mofetil (≥2 g per day for at least 8 months) and a lower dose or shorter duration of these agents. We used propensity score weighting with generalised linear regression models. This study is registered with ClinicalTrials.gov (NCT03490539). FINDINGS: Between May 1, 2018, and Aug 31, 2020, 167 patients were enrolled; 85 did not receive azathioprine or mycophenolate mofetil and were excluded. Four were excluded from outcome analyses because they had scores of 0 on an outcome measure at treatment initiation. Of the 78 patients included in analyses, 47 received mycophenolate mofetil (median follow-up 25 months [IQR 13·5-31·5]) and 31 received azathioprine (median follow-up 20 months [IQR 13-30]). The mean change in MG-QOL15r was -10·4 (95% CI -18·9 to -1·3) with mycophenolate mofetil and -6·8 (-17·2 to 3·6) with azathioprine (mean difference -3·3, 95% CI -7·7 to 1·2; p=0·15). 38 (81%) of 47 patients receiving mycophenolate mofetil and 18 (57%) of 31 receiving azathioprine had a CMR in MG-QOL15r (risk difference 24·0%; 95% CI -0·2 to 48·0; p=0·052). The clinical composite outcome was achieved in 22 (47·7%) of 47 patients who received mycophenolate mofetil and nine (28·1%) of 31 who received azathioprine (risk difference 19·6%, 95% CI -4·9 to 44·2; p=0·12). Descriptive analysis did not find a difference in the proportion of patients reaching a CMR in MG-QOL15r between the adequate dose and duration group and the lower dose or shorter duration group. Adverse events occurred in 11 (32%) of 34 patients who received azathioprine and nine (19%) of 48 who received mycophenolate mofetil. The most frequent adverse events were hepatotoxicity with azathioprine (five [15%] of 34) and gastrointestinal disturbances (seven [15%] of 48) with mycophenolate mofetil. There were no study-related deaths. INTERPRETATION: More than half of patients treated with azathioprine and mycophenolate mofetil felt their quality of life improved; no difference in clinical outcomes was noted between the two drugs. Adverse events associated with azathioprine were potentially more serious than those with mycophenolate mofetil, although mycophenolate mofetil is teratogenic. Lower than recommended doses of azathioprine might be effective, with reduced dose-dependent adverse events. More comparative effectiveness studies are required to inform treatment choices in myasthenia gravis. FUNDING: Patient-Centered Outcomes Research Institute, Myasthenia Gravis Foundation of America.

Intravenous Ganaxolone: Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability in Healthy Adults.

Ganaxolone, a neuroactive steroid anticonvulsant that modulates both synaptic and extrasynaptic γ-aminobutyric acid type A (GABAA ) receptors, is in development for treatment of status epilepticus (SE) and rare epileptic disorders, and has been approved in the United States for treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in patients ≥2 years old. This phase 1 study in 36 healthy volunteers evaluated the pharmacokinetics, pharmacodynamics, and safety of intravenous ganaxolone administered as a (i) single bolus, (ii) infusion, and (iii) bolus followed by continuous infusion. After a single bolus over 2 minutes (20 mg) or 5 minutes (10 or 30 mg), ganaxolone was detected in plasma with a median Tmax of 5 minutes, whereas a 60-minute infusion (10 or 30 mg) or a bolus (6 mg over 5 minutes) followed by infusion (20 mg/h) for 4 hours achieved a median Tmax of approximately 1 and 3 hours, respectively. Cmax was dose and administration-time dependent, ranging from 73.8 ng/mL (10 mg over 5 minutes) to 1240 ng/mL (30 mg over 5 minutes). Bolus doses above 10 mg of ganaxolone markedly influenced the bispectral index score with a rapid decline; smaller changes occurred on the Modified Observer's Assessment of Alertness/Sedation scale and in quantitative electroencephalogram. Most adverse events were of mild severity, with 2 events of moderate severity; none were reported as serious. No effects on systemic hemodynamics or respiratory functions were reported. Overall, ganaxolone was generally well tolerated at the doses studied and demonstrated pharmacokinetic and pharmacodynamic properties suitable to treat SE.

Safety and Efficacy of Nipocalimab in Patients With Generalized Myasthenia Gravis: Results From the Randomized Phase 2 Vivacity-MG Study

BACKGROUND AND OBJECTIVES: To evaluate in a phase 2 study the safety and efficacy of IV nipocalimab, a fully human, antineonatal Fc receptor monoclonal antibody, in patients with generalized myasthenia gravis (gMG). METHODS: Patients with gMG with inadequate response to stable standard-of-care (SOC) therapy were randomized 1:1:1:1:1 to receive either IV placebo every 2 weeks (Q2W) or one of 4 IV nipocalimab treatments: 5 mg/kg once every 4 weeks (Q4W), 30 mg/kg Q4W, 60 mg/kg Q2W each for 8 weeks, or a 60 mg/kg single dose, in addition to their background SOC therapy. Infusions (placebo or nipocalimab) were Q2W in all groups to maintain blinding. The primary safety endpoint was incidence of treatment-emergent adverse events (TEAEs), including serious adverse events and adverse events of special interest. The primary efficacy endpoint was change from baseline to day 57 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores. Dose response of change at day 57 was analyzed with a linear trend test over the placebo, nipocalimab 5 mg/kg Q4W, nipocalimab 30 mg/kg Q4W, and nipocalimab 60 mg/kg Q2W groups. RESULTS: Sixty-eight patients (nipocalimab: n = 54; placebo, n = 14) were randomized; 64 patients (94.1%) were positive for antiacetylcholine receptor autoantibodies, and 4 patients (6%) were positive for antimuscle-specific tyrosine kinase autoantibodies. Fifty-seven patients (83.8%) completed treatment through day 57. The combined nipocalimab group compared with the placebo group demonstrated similar incidences of TEAEs (83.3% vs 78.6%, respectively) and infections (33.3% vs 21.4%, respectively). No deaths or discontinuations due to TEAEs and no TEAEs of special interest (grade ≥3 infection or hypoalbuminemia) were observed with nipocalimab treatment. A statistically significant dose response was observed for change from baseline in MG-ADL at day 57 (p = 0.031, test of linear trend). DISCUSSION: Nipocalimab was generally safe, well-tolerated, and showed evidence of dose-dependent reduction in MG-ADL scores at day 57 in this phase 2 study. These results support further evaluation of nipocalimab for the treatment of gMG. TRIAL REGISTRATION INFORMATION: Clinical Trials Registration: NCT03772587; first submitted December 10, 2018; EudraCT Number: 2018-002247-28; first submitted November 30, 2018; date of first patient dosed April 10, 2019. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with gMG, nipocalimab was well-tolerated, and it did not significantly improve MG-ADL at any individual dose but demonstrated a significant dose response for improved MG-ADL across doses.

The economic burden of individuals living with generalized myasthenia gravis and facing social determinants of health challenges.

Objective: Better understanding the impact of social determinants of health (SDOH) barriers from the patient perspective is crucial to improve holistic patient support in generalized myasthenia gravis (gMG), a rare autoimmune disorder with high disease and treatment burden. The objective of this study was to identify economic challenges experienced by individuals living with gMG and SDOH barriers to better address current unmet needs. Methods: Adults (18-75 years) living with gMG and experiencing SDOH barriers in the United States were recruited to a mixed-methods study including qualitative interviews and a web-based quantitative survey. Quotas were implemented to include a balanced spread of baseline demographic categories including insurance type, living environment, and employment status among the study sample. Direct and indirect economic challenges were identified by degree of concern. Results: The survey was completed by 38 individuals living with gMG, the majority of whom were enrolled in public insurance and not employed. The most commonly reported major economic concerns were managing funds for emergency care (66%), loss of income (61%), and non-medical expenses (58%), highlighting the diversity of economic challenges. Individuals who were using public insurance plans, living in non-urban environments, and unemployed experienced pronounced challenges around managing non-medical costs and accessing government assistance. Conclusion: Both direct and indirect costs were emphasized as major concerns among individuals living with gMG and SDOH barriers. Increasing access to relevant, personalized, and holistic resources, including care management, should be prioritized to improve disease management and outcomes for individuals living with gMG.

Addressing Outcome Measure Variability in Myasthenia Gravis Clinical Trials.

An increasing number of clinical trials are enrolling patients with myasthenia gravis (MG). A lack of standardization in the performance of outcome measures leads to confusion among site research teams and is a source of variability in clinical trial data. MGNet, the NIH-supported Rare Disease Clinical Research Network for MG, views standardization of MG outcome measures as a critical need. To address this issue, a group of experts summarized key outcome measures used in MG clinical trials and a symposium was convened to address issues contributing to outcome measure variability. Consensus recommendations resulted in changes to outcome measure instructions and, in some cases, modifications to specific instruments. Recommended changes were posted for public commentary before finalization. Changes to the MG-Activities of Daily Living, MG-Quality of Life-15r, and MG-Impairment Index were limited to adding details to the administration instructions. Recommendations for proper positioning of participants and how to score items that could not be performed because of non-MG reasons were provided for the MG Composite. The Quantitative MG (QMG) score required the most attention, and changes were made both to the instructions and the performance of certain items resulting in the QMG-Revised. The Postintervention Status was believed to have a limited role in clinical trials, except for the concept of minimal manifestation status. As a next step, training materials and revised source documents, which will be freely available to study teams, will be created and posted on the MGNet website. Further studies are needed to validate changes made to the QMG-Revised.

Clinicoserological insights into patients with immune checkpoint inhibitor-induced myasthenia gravis.

To compare the immunopathology of immune checkpoint inhibitor-induced myasthenia gravis (ICI-MG) and idiopathic MG, we profiled the respective AChR autoantibody pathogenic properties. Of three ICI-MG patients with AChR autoantibodies, only one showed complement activation and modulation/blocking potency, resembling idiopathic MG. In contrast, AChR autoantibody-mediated effector functions were not detected in the other two patients, questioning the role of their AChR autoantibodies as key mediators of pathology. The contrasting properties of AChR autoantibodies in these cases challenge the accuracy of serological testing in establishing definite ICI-MG diagnoses and underscore the importance of a thorough clinical assessment when evaluating ICI-related adverse events.

The Duke Myasthenia Gravis Clinic Registry: II. Analysis of outcomes.

INTRODUCTION/AIMS: The Duke Myasthenia Gravis (MG) Clinic Registry contains comprehensive physician-derived data on patients with MG seen in the Duke MG Clinic since 1980. The aim of this study was to report outcomes in patients seen in the clinic and treated according to the International Consensus Guidance statements. METHODS: This is a retrospective cohort study of patients initially seen after 2000 and followed for at least 2 years in the clinic. Treatment goal (TG) was defined as achieving MGFA post-intervention status of "minimal manifestations" or better; PIS was determined by the treating neurologist. Time-to-event analysis, including Cox proportional hazards modeling, was performed to assess the effect of sex, acetylcholine receptor antibody (AChR-Ab) status, age at disease onset, distribution (ocular vs generalized), thymectomy, and thymoma on the time to achieve TG. RESULTS: Among the 367 cohort patients, 72% achieved TG (median time less than 2 years). A greater proportion of patients with AChR-Abs and thymectomy achieved TG and they did so sooner than patients without these antibodies or thymectomy. Otherwise, there were no significant differences in these findings within the tested subgroups. The disease duration at the first Duke Clinic visit was shorter in patients who achieved TG than in those who did not. DISCUSSION: These results demonstrate outcomes that can be achieved in patients with MG treated according to the current Consensus Guidance statements. Among other things, they can be used to determine the added value and potential role of new treatment modalities developed since 2018.

Safety of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE) in a Phase I, Open-Label Study in Healthy Adult Volunteers.

This phase I study evaluated the safety of the optimal ceftazidime-avibactam (CZA) with aztreonam (ATM) regimens identified in hollow fiber infection models of MBL-producing Enterobacterales. Eligible healthy subjects aged 18 to 45 years were assigned to one of six cohorts: 2.5 g CZA over 2 h every 8 h (approved dose), CZA continuous infusion (CI) (7.5 g daily), 2 g ATM over 2 h every 6 h, ATM CI (8 g daily), CZA (approved dose) with 1.5 g ATM over 2 h every 6 h, and CZA (approved dose) with 2 g ATM over 2 h every 6 h. Study drug(s) were administered for 7 days. The most frequently observed adverse events (AEs) were hepatic aminotransferase (ALT/AST) elevations (n = 19 subjects). Seventeen of the 19 subjects with ALT/AST elevations received ATM alone or CZA-ATM. The incidence of ALT/AST elevations was comparable between the ATM-alone and CZA-ATM cohorts. Two subjects in the ATM CI cohort experienced severe ALT/AST elevation AEs. All subjects with ALT/AST elevations were asymptomatic with no other findings suggestive of liver injury. Most other AEs were of mild to moderate severity and were similar across cohorts, except for prolonged prothrombin time (more frequent in CZA-ATM cohorts). These results suggest that CZA-ATM administered as 2-h intermittent infusions is safe and that some caution should be exercised with the use of ATM CI at an ATM dose of 8 g daily. If CZA-ATM is prescribed, clinicians are advised to monitor liver function, hematologic, and coagulation parameters. Future controlled studies are required to better define the safety and efficacy of the CZA-ATM regimens evaluated in this phase I study.

Pharmacokinetics of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE) in a Phase 1, Open-Label Study of Healthy Adults.

Scant pharmacokinetic (PK) data are available on ceftazidime-avibactam (CZA) and aztreonam (ATM) in combination, and it is unknown if CZA-ATM exacerbates alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations relative to ATM alone. This phase 1 study sought to describe the PK of CZA-ATM and assess the associations between ATM exposures and ALT/AST elevations. Subjects (n = 48) were assigned to one of six cohorts (intermittent infusion [II] CZA, continuous infusion [CI] CZA, II ATM, CI ATM [8 g/daily], II CZA with II ATM [6 g/daily], and II CZA with II ATM [8 g/daily]), and study product(s) were administered for 7 days. A total of 19 subjects (40%) had ALT/AST elevations, and most (89%) occurred in the ATM/CZA-ATM cohorts. Two subjects in the CI ATM cohort experienced severe ALT/AST elevations, which halted the study. All subjects with ALT/AST elevations were asymptomatic with no other signs of liver injury, and all ALT/AST elevations resolved without sequalae after cessation of dosing. In the population PK (PopPK) analyses, CZA-ATM administration reduced total ATM clearance by 16%, had a negligible effect on total ceftazidime clearance, and was not a covariate in the avibactam PopPK model. In the exposure-response analyses, coadministration of CZA-ATM was not found to augment ALT/AST elevations. Modest associations were observed between ATM exposure (maximum concentration of drug in serum [Cmax] and area under the concentration-time curve [AUC]) and ALT/AST elevations in the analysis of subjects in the II ATM/CZA-ATM cohorts. The findings suggest that administration of CZA-ATM reduces ATM clearance but does not exacerbate AST/ALT elevations relative to ATM alone. The results also indicate that CI ATM should be used with caution.

Classical Complement Pathway Inhibition in a "Human-On-A-Chip" Model of Autoimmune Demyelinating Neuropathies.

Chronic autoimmune demyelinating neuropathies are a group of rare neuromuscular disorders with complex, poorly characterized etiology. Here we describe a phenotypic, human-on-a-chip (HoaC) electrical conduction model of two rare autoimmune demyelinating neuropathies, chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN), and explore the efficacy of TNT005, a monoclonal antibody inhibitor of the classical complement pathway. Patient sera was shown to contain anti-GM1 IgM and IgG antibodies capable of binding to human primary Schwann cells and induced pluripotent stem cell derived motoneurons. Patient autoantibody binding was sufficient to activate the classical complement pathway resulting in detection of C3b and C5b-9 deposits. A HoaC model, using a microelectrode array with directed axonal outgrowth over the electrodes treated with patient sera, exhibited reductions in motoneuron action potential frequency and conduction velocity. TNT005 rescued the serum-induced complement deposition and functional deficits while treatment with an isotype control antibody had no rescue effect. These data indicate that complement activation by CIDP and MMN patient serum is sufficient to mimic neurophysiological features of each disease and that complement inhibition with TNT005 was sufficient to rescue these pathological effects and provide efficacy data included in an investigational new drug application, demonstrating the model's translational potential.

Effect of FcRn antagonism on protective antibodies and to vaccines in IgG-mediated autoimmune diseases pemphigus and generalised myasthenia gravis.

Antagonism of the neonatal Fc receptor (FcRn) by efgartigimod has been studied in several autoimmune diseases mediated by immunoglobulin G (IgG) as a therapeutic approach to remove pathogenic IgGs. Whereas reduction of pathogenic titres has demonstrated efficacy in multiple autoimmune diseases, reducing total IgG could potentially increase infection risk in patients receiving FcRn antagonists. The objective of this study was to analyse the effect of FcRn antagonism with efgartigimod on existing protective antibody titres and the ability to mount an immune response after vaccine challenge. Serum levels of total IgG and protective antibodies against tetanus toxoid (TT), varicella zoster virus (VZV), and pneumococcal capsular polysaccharide (PCP) were measured in all patients enrolled in an open-label trial of efgartigimod for the treatment of pemphigus. Vaccine specific-responses were assessed by measuring changes in IgG titres in patients with generalised myasthenia gravis (gMG) who were treated with efgartigimod and who received influenza, pneumococcal, or coronavirus disease 2019 (COVID-19) vaccines during participation in the double-blind trial ADAPT or open-label extension, ADAPT+ (n = 17). FcRn antagonism reduced levels of protective anti-TT, anti-VZV, and anti-PCP antibodies and total IgG to a similar extent; anti-TT and anti-VZV titres remained above minimally protective thresholds for the majority of patients, (10/12) 83% and (14/15) 93% respectively. Protective antibodies returned to baseline values upon treatment cessation. Antigen-specific IgG responses to influenza, pneumococcal, and COVID-19 immunisation were detected in patients with gMG who received these vaccines while undergoing therapy with efgartigimod. In conclusion, FcRn antagonism with efgartigimod did not hamper generation of IgG responses but did transiently reduce IgG titres of all specificities.

The clinical need for clustered AChR cell-based assay testing of seronegative MG.

Trial eligibility in myasthenia gravis (MG) remains largely dependent on a positive autoantibody serostatus. This significantly hinders seronegative MG (SNMG) patients from receiving potentially beneficial new treatments. In a subset of SNMG patients, acetylcholine receptor (AChR) autoantibodies are detectable by a clustered AChR cell-based assay (CBA). Of 99 SNMG patients from two academic U.S. centers, 18 (18.2%) tested positive by this assay. Autoantibody positivity was further validated in 17/18 patients. In a complementary experiment, circulating AChR-specific B cells were identified in a CBA-positive SNMG patient. These findings corroborate the clinical need for clustered AChR CBA testing when evaluating SNMG patients.

Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy.

INTRODUCTION/AIMS: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD. METHODS: Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated. RESULTS: Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P < .0001) and 9.5% (3.2%-15.9%) in the TA group (P = .01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection-site reactions. DISCUSSION: Significant increases in TMV with ACE-083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment.

Adverse Reactions in a Phase 1 Trial of the Anti-Malarial DM1157: An Example of Pharmacokinetic Modeling and Simulation Guiding Clinical Trial Decisions.

INTRODUCTION: There is an urgent need to develop new drugs to treat malaria due to increasing resistance to first-line therapeutics targeting the causative organism, Plasmodium falciparum (P. falciparum). One drug candidate is DM1157, a small molecule that inhibits the formation of hemozoin, which protects P. falciparum from heme toxicity. We describe a first-in-human, phase 1 trial of DM1157 in healthy adult volunteers that was halted early because of significant toxicity. METHODS: Adverse events were summarized using descriptive statistics. We used pharmacokinetic modeling to quantitatively assess whether the DM1157 exposure needed for P. falciparum inhibition was achievable at safe doses. RESULTS: We found that there was no dose where both the safety and efficacy target were simultaneously achieved; conversely, the model predicted that 27 mg was the highest dosage at which patients would consistently maintain safe exposure with multiple dosing. By pre-defining dose escalation stopping rules and conducting an interim pharmacokinetic/pharmacodynamic analysis, we determined that the study would be unable to safely achieve a dosage needed to observe an anti-malarial effect, thereby providing strong rationale to halt the study. CONCLUSION: This study provides an important example of the risks and challenges of conducting early phase research as well as the role of modeling and simulation to optimize participant safety (ClinicalTrials.gov, NCT03490162).

Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders.

Autoimmune neuromuscular junction disorders are rare. However, myasthenia gravis is being increasingly recognised in people older than 50 years. In the past 5-10 years, epidemiological studies worldwide suggest an incidence of acetylcholine receptor antibody-positive myasthenia gravis of up to 29 cases per 1 million people per year. Muscle-specific tyrosine kinase antibody-positive myasthenia gravis and Lambert-Eaton myasthenic syndrome are about 20 times less common. Several diagnostic methods are available for autoimmune neuromuscular junction disorders, including serological antibody, electrophysiological, imaging, and pharmacological tests. The course of disease can be followed up with internationally accepted clinical scores or patient-reported outcome measures. For prognostic purposes, determining whether the disease is paraneoplastic is of great importance, as myasthenia gravis can be associated with thymoma and Lambert-Eaton myasthenic syndrome with small-cell lung cancer. However, despite well defined diagnostic parameters to classify patients into subgroups, objective biomarkers for use in the clinic or in clinical trials to predict the course of myasthenia gravis and Lambert-Eaton myasthenic syndrome are needed.

Identifying a patient-centered outcome measure for a comparative effectiveness treatment trial in myasthenia gravis.

INTRODUCTION/AIMS: Data regarding the comparative effectiveness of myasthenia gravis (MG) treatments is not available. We used patient input to identify a patient-centered outcome measure (PCOM) for PROMISE-MG, a comparative effectiveness trial of MG treatments. METHODS: First, a questionnaire survey was administered to 58 people with MG at the patient meeting of the Myasthenia Gravis Foundation of America (MGFA), evaluating the impact of MG-related symptoms and MG treatments on patients' lives. Second, an online focus group of 13 patients with MG was conducted. Third, a potential outcome measure was selected. Fourth, the selected PCOM was evaluated by patients to assess how completely and accurately it captured their experiences with MG. RESULTS: The patient survey showed that limb weakness had the most impact on patients' lives. Weight gain, mood swings, insomnia, and diarrhea were the most bothersome treatment side effects. Avoiding hospitalization was very important. Focus group participants reported fatigue as one of the most bothersome symptoms and differentiated it from myasthenic weakness. They defined an ideal treatment as having minimal or no side effects and an 80% improvement in symptoms. DISCUSSION: Based on patient input, the 15-item Myasthenia Gravis Quality of Life-Revised (MG-QOL15R) scale, a validated patient-reported outcome measure (PRO), was selected as the primary PCOM for PROMISE-MG. Avoiding hospitalization and having minimal to no treatment adverse effects were selected as additional outcome measures. The patient-centeredness of a PRO depends on the context of a study: PROs should be evaluated for appropriateness as a PCOM for every study.

Perioperative Outcomes of Thymectomy in Myasthenia Gravis: A Thoracic Surgery Database Analysis.

BACKGROUND: There is clinical equipoise regarding the perioperative and long-term outcomes of autoimmune myasthenia gravis (MG) patients undergoing open vs minimally invasive thymectomy, particularly for nonthymomatous MG. This analysis utilizes multicenter, real-world clinical evidence to assess perioperative complications of open and minimally invasive thymectomy techniques in MG patients. METHODS: Thymectomy cases from 2009 to 2019 in MG patients were identified in The Society of Thoracic Surgeons General Thoracic Surgery Database. Thymectomies were grouped by surgical technique: transthoracic (TT), transcervical (TC), video-assisted thoracoscopic surgery (VATS), or robotic VATS (RVATS). Multivariable logistic regression models assessed the association between surgical technique and perioperative complications. RESULTS: Analysis of nonthymomatous cases (n = 1725) revealed VATS (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.23-0.83), RVATS (OR, 0.73; 95% CI, 0.48-1.26), and TC (OR, 0.19; 95% CI, 0.06-0.62) thymectomies had lower odds of perioperative complications than TT thymectomies. VATS (OR, 2.29; 95% CI, 0.63-8.30) and RVATS (OR, 4.08; 95% CI,1.21-3.78) thymectomies had higher odds of perioperative complications than TC thymectomies. Analysis of thymomatous cases (n = 311) found no significant difference in the odds of perioperative complications in TT vs minimally invasive (VATS/RVATS) procedures. The proportion of RVATS procedures increased from 6.43% to 44.27%, while TT (56.43% to 34.35%) and TC (19.29% to 6.87%) thymectomies decreased. CONCLUSIONS: Minimally invasive and TC thymectomies have fewer perioperative complications than TT thymectomies when performed for nonthymomatous MG. Minimally invasive procedures are increasingly performed for both nonthymomatous and thymomatous disease. There is a nationwide shift toward minimally invasive procedures, even for thymoma resections. Long-term neurological outcome data are needed to determine whether a reduced perioperative risk for minimally invasive thymectomies translates to improved MG outcomes.