Switching to subcutaneous zilucoplan from intravenous complement component 5 inhibitors in generalised myasthenia gravis: a phase IIIb, open-label study

BackgroundZilucoplan, a peptide complement component 5 (C5) inhibitor, is self-administered as a subcutaneous (SC) injection, which offers an alternative to intravenous infusion of antibody-based complement C5 inhibitors.ObjectiveTo evaluate subcutaneous zilucoplan in adults with acetylcholine receptor autoantibody-positive generalised myasthenia gravis (gMG) who switched from intravenous complement C5 inhibitors to zilucoplan.DesignMG0017 (NCT05514873) was a phase IIIb, open-label, single-arm study.MethodsEligible patients had clinically stable gMG on an intravenous complement C5 inhibitor and were willing to switch to zilucoplan. Patients received a 12-week treatment period of daily subcutaneous zilucoplan 0.3 mg/kg. Incidence of treatment-emergent adverse events (TEAEs) was the primary endpoint. Change from baseline in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score at Week 12 was a secondary endpoint. Treatment preference (Week 12) and treatment satisfaction (9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9)) were both exploratory endpoints. Assessments by prior intravenous complement C5 inhibitor were conducted post hoc.ResultsTwenty-six patients enrolled and received zilucoplan; 16 switched from eculizumab and 10 from ravulizumab. TEAEs occurred in 19/26 (73.1%) patients and were mostly mild in severity. At Week 12, least squares (LS) mean (95% confidence interval) MG-ADL scores improved from baseline by -1.15 (-2.11, -0.19), p = 0.0217 and Quantitative MG (QMG) scores by -1.24 (-2.64, 0.16), p = 0.0802. Clinically meaningful improvement from baseline in mean MG-ADL and QMG scores was observed at Week 12 among patients who switched from ravulizumab (-2.41 (-4.52, -0.30; p = 0.0307) and -3.52 (-6.14, -0.90; p = 0.0149), respectively). At Week 12, 76.9% (n = 20) patients preferred subcutaneous injection compared with intravenous infusion. Mean (standard deviation) changes from baseline in the TSQM-9 Global Satisfaction, Effectiveness and Convenience subscores at Week 12 were +19.410 (27.429), +13.889 (21.534) and +21.739 (19.955), respectively. Complement inhibition increased from baseline and was complete (>95%) by Week 2 and maintained to Week 12.ConclusionZilucoplan demonstrated a favourable safety profile. gMG symptoms improved during zilucoplan treatment; this was clinically meaningful for those switching from ravulizumab.Trial registrationClinicalTrials.gov (NCT05514873); 22 August 2022. https://clinicaltrials.gov/study/NCT05514873

Safety, tolerability, and efficacy of subcutaneous efgartigimod in patients with chronic inflammatory demyelinating polyradiculoneuropathy (ADHERE): a multicentre, randomised-withdrawal, double-blind, placebo-controlled, phase 2 trial

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system that can lead to severe disability from muscle weakness and sensory disturbances. Around a third of patients do not respond to currently available treatments, and many patients with a partial response have residual neurological impairment, highlighting the need for effective alternatives. Efgartigimod alfa, a human IgG1 antibody Fc fragment, has demonstrated efficacy and safety in patients with generalised myasthenia gravis. We evaluated the safety, tolerability, and efficacy of subcutaneous efgartigimod PH20 in adults with CIDP. Methods: ADHERE, a multistage, double-blind, placebo-controlled trial, enrolled participants with CIDP from 146 clinical sites from Asia-Pacific, Europe, and North America. Participants with evidence of clinically meaningful deterioration entered an open-label phase of weekly 1000 mg subcutaneous efgartigimod PH20 for no longer than 12 weeks (stage A). Those with confirmed evidence of clinical improvement (ECI; treatment responders) entered a randomised-withdrawal phase of 1000 mg subcutaneous efgartigimod PH20 weekly treatment versus placebo for a maximum of 48 weeks (stage B). Participants were randomised (1:1) through interactive response technology and stratified by their adjusted Inflammatory Neuropathy Cause and Treatment (aINCAT) score change during stage A and their most recent CIDP medication within 6 months before screening. Investigators, the clinical research organisation, and participants were masked to the treatment. The primary endpoint in stage A, evaluated in the stage A safety population, was confirmed ECI (≥1 points aINCAT decrease, ≥4 points [centile metric] Inflammatory Rasch-built Overall Disability Scale increase, or ≥8 kPa grip strength increase after four injections and two consecutive visits). The primary endpoint in stage B, evaluated in the modified intention-to-treat population, was the risk of relapse (time to first aINCAT increase of ≥1 points). ADHERE is registered with ClinicalTrials.gov (NCT04281472) and EudraCT (2019-003076-39) and is completed. Findings: Between April 15, 2020, and May 11, 2023, 629 participants were screened; 322 (114 female, 208 male) entered stage A, of whom 214 (66%, 95% CI 61·0-71·6) had confirmed ECI. In stage B, 221 participants were randomised (79 female, 142 male; 111 to subcutaneous efgartigimod PH20, 110 to placebo). Subcutaneous efgartigimod PH20 significantly reduced the risk of relapse versus placebo (hazard ratio 0·39 [95% CI 0·25-0·61]; p<0·0001). 31 (27·9% [19·6-36·3]) participants given subcutaneous efgartigimod PH20 had a relapse versus 59 (53·6% [44·3-63·0]) given placebo. In stage A, treatment-emergent adverse events (TEAEs) occurred in 204 (63%) participants and serious TEAEs in 21 (7%). In stage B, TEAEs occurred in 71 (64%) participants on subcutaneous efgartigimod PH20 and 62 (56%) participants on placebo, and serious TEAEs in six (5%) on subcutaneous efgartigimod PH20 and six (5%) on placebo. Three deaths occurred: two in stage A (one non-related and one unlikely related to treatment) and one in stage B (placebo group). Interpretation: ADHERE showed the efficacy of subcutaneous efgartigimod PH20 in reducing the risk of relapse versus placebo in people with CIDP who responded to treatment. Further studies are needed to provide data on the longer-term effects of efgartigimod alfa and how it compares with currently available treatment options. Funding: argenx

Late-onset double-seronegative myasthenia gravis syndrome and myasthenic crisis due to nivolumab use for Hodgkin’s lymphoma

Introduction Insofar, use of programmed cell death-1 (PD-1) immune checkpoint inhibitors in oncology has been linked with several immune-mediated neurologic effects. However, grade 3 to 4 adverse events such as myasthenic crisis have been vanishingly rare. Case presentation: We present herein a unique patient with Hodgkin lymphoma who developed late-onset double-seronegative myasthenia gravis syndrome followed by myasthenic crisis after 16 weeks of therapy with nivolumab. One day prior to this event, she developed ptosis, diplopia, bulbar symptoms of dysphagia, dysarthria, orthopnea as well as extremity weakness. She required intubation, mechanical ventilation, plasmapheresis and steroid therapy. Management and outcome: She gradually achieved a near-complete resolution of neurologic symptoms over the next several weeks. On a follow-up visit eight weeks later, she only has some residual diplopia. Restaging scans showed a continued decrease in size of the mediastinal mass, without abnormal uptake. She remains on prednisone 10 mg orally daily. Discussion Prompt recognition of this rare phenomenon, immediate discontinuation of checkpoint inhibitor therapy and subsequent management with immunosuppressive therapy are necessary steps in order to minimize the considerable rates of morbidity and mortality. </jats:sec

CORRELATION OF ESTROGEN RECEPTOR(ER), PROGESTERONE RECEPTOR(PR) AND HER2/NEU EXPRESSION WITH CLINICOPATHOLOGICAL PARAMETERS IN PRIMARY BREAST CARCINOMA -A STUDY OF 175 CASES

Introduction: Breast carcinoma is the most common malignant tumor worldwide and leading cause ofdeath in women .Present study was aimed to study patterns of expression of Hormone receptor (ER PR) andHer-2/neu in invasive breast carcinoma and to correlate ER PR status and Her-2/neu expression with various clinicopathological parameters. Materials and Method: 175 cases of Invasive primary Breast carcinoma were studied from May 2014 to September 2017.Routine H and E staining for histopathological diagnosis and IHC analysis for ER,PR receptor with Her2/neu were carried out in all cases. Results: Mean age at diagnosis was 51.3 years. The predominant histology was Invasive ductal carcinoma 90.9% cases. Most lesions 65.1% were >2 to5 cm in size. Majority of cases were grade II (47.2%) and grade III (47.8%).. Immunohistochemistry revealed 29.8% cases to be ER positive, 32.0% cases PR positive and 29.1% cases Her2/neu positive. 55.7% cases were triple negative. . Conclusion: In our study ER,PR receptor and Her2neu expression revealed significant association with clinicopathological parameters. As the grade of the tumor increased ER and PR positivity gradually decreased. No significant correlation was seen between Her2/neu and tumor grade . ER, PR and Her2/neu expression did not show any significant correlation with age