Safety and efficacy of rozanolixizumab in patients with generalised myasthenia gravis (MycarinG): a randomised, double-blind, placebo-controlled, adaptive phase 3 study.

BACKGROUND: Generalised myasthenia gravis is a chronic, unpredictable, and debilitating autoimmune disease. New treatments for this disease are needed because conventional therapies have limitations, such as side-effects (eg, increased infection risk) or inadequate control of symptoms. Rozanolixizumab is a neonatal Fc receptor blocker that might provide a novel therapeutic option for myasthenia gravis. We aimed to assess the safety and efficacy of rozanolixizumab for generalised myasthenia gravis. METHODS: MycarinG is a randomised, double-blind, placebo-controlled, adaptive phase 3 study done at 81 outpatient centres and hospitals in Asia, Europe, and North America. We enrolled patients (aged ≥18 years) with acetylcholine receptor (AChR) or muscle-specific kinase (MuSK) autoantibody-positive generalised myasthenia gravis (Myasthenia Gravis Foundation of America class II-IVa), a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 3 (non-ocular symptoms), and a quantitative myasthenia gravis score of at least 11. Patients were randomly assigned (1:1:1) to receive subcutaneous infusions once a week for 6 weeks of either rozanolixizumab 7 mg/kg, rozanolixizumab 10 mg/kg, or placebo. Randomisation was stratified by AChR and MuSK autoantibody status. Investigators, patients, and people assessing outcomes were masked to random assignments. The primary efficacy endpoint was change from baseline to day 43 in MG-ADL score, assessed in the intention-to-treat population. Treatment-emergent adverse events (TEAEs) were assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03971422) and EudraCT (2019-000968-18); an open-label extension study has been completed (NCT04124965; EudraCT 2019-000969-21) and another is underway (NCT04650854; EudraCT 2020-003230-20). FINDINGS: Between June 3, 2019, and June 30, 2021, 300 patients were assessed for eligibility, of whom 200 were enrolled. 66 (33%) were randomly assigned to rozanolixizumab 7 mg/kg, 67 (34%) to rozanolixizumab 10 mg/kg, and 67 (34%) to placebo. Reductions in MG-ADL score from baseline to day 43 were greater in the rozanolixizumab 7 mg/kg group (least-squares mean change -3·37 [SE 0·49]) and in the rozanolixizumab 10 mg/kg group (-3·40 [0·49]) than with placebo (-0·78 [0·49]; for 7 mg/kg, least-squares mean difference -2·59 [95% CI -4·09 to -1·25], p<0·0001; for 10 mg/kg, -2·62 [-3·99 to -1·16], p<0·0001). TEAEs were experienced by 52 (81%) of 64 patients treated with rozanolixizumab 7 mg/kg, 57 (83%) of 69 treated with rozanolixizumab 10 mg/kg, and 45 (67%) of 67 treated with placebo. The most frequent TEAEs were headache (29 [45%] patients in the rozanolixizumab 7 mg/kg group, 26 [38%] in the rozanolixizumab 10 mg/kg group, and 13 [19%] in the placebo group), diarrhoea (16 [25%], 11 [16%], and nine [13%]), and pyrexia (eight [13%], 14 [20%], and one [1%]). Five (8%) patients in the rozanolixizumab 7 mg/kg group, seven (10%) in the rozanolixizumab 10 mg/kg group, and six (9%) in the placebo group had a serious TEAE. No deaths occurred. INTERPRETATION: Rozanolixizumab showed clinically meaningful improvements in patient-reported and investigator-assessed outcomes in patients with generalised myasthenia gravis, for both 7 mg/kg and 10 mg/kg doses. Both doses were generally well tolerated. These findings support the mechanism of action of neonatal Fc receptor inhibition in generalised myasthenia gravis. Rozanolixizumab represents a potential additional treatment option for patients with generalised myasthenia gravis. FUNDING: UCB Pharma.

Efficacy and Safety of Rozanolixizumab in Moderate to Severe Generalized Myasthenia Gravis: A Phase 2 Randomized Control Trial.

OBJECTIVE: To explore the clinical efficacy and safety of subcutaneous (SC) rozanolixizumab, an anti-neonatal Fc receptor humanized monoclonal antibody, in patients with generalized myasthenia gravis (gMG). METHODS: In this phase 2a, randomized, double-blind, placebo-controlled, 2-period, multicenter trial (NCT03052751), patients were randomized (1:1) in period 1 (days 1-29) to 3 once-weekly (Q1W) SC infusions of rozanolixizumab 7 mg/kg or placebo. In period 2 (days 29-43), patients were re-randomized to either rozanolixizumab 7 mg/kg or 4 mg/kg (3 Q1W SC infusions), followed by an observation period (days 44-99). Primary endpoint was change from baseline to day 29 in Quantitative Myasthenia Gravis (QMG) score. Secondary endpoints were change from baseline to day 29 in MG-Activities of Daily Living (MG-ADL) and MG-Composite (MGC) scores and safety. RESULTS: Forty-three patients were randomized (rozanolixizumab 21, placebo 22 [period 1]). Least squares (LS) mean change from baseline to day 29 for rozanolixizumab vs placebo was as follows: QMG (LS mean -1.8 vs -1.2, difference -0.7, 95% upper confidence limit [UCL] 0.8; p = 0.221; not statistically significant), MG-ADL (LS mean -1.8 vs -0.4, difference -1.4, 95% UCL -0.4), and MGC (LS mean -3.1 vs -1.2, difference -1.8, 95% UCL 0.4) scores. Efficacy measures continued to improve with rozanolixizumab 7 mg/kg in period 2. The most common adverse event in period 1 was headache (rozanolixizumab 57%, placebo 14%). CONCLUSION: Whereas change from baseline in QMG was not statistically significant, the data overall suggest rozanolixizumab may provide clinical benefit in patients with gMG and was generally well tolerated. Phase 3 evaluation is ongoing (NCT03971422). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with gMG, rozanolixizumab is well-tolerated, but did not significantly improve QMG score.

Phase 2 multiple-dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia.

Primary immune thrombocytopenia (ITP) is a predominantly immunoglobulin G (IgG)-autoantibody-mediated disease characterized by isolated thrombocytopenia. Rozanolixizumab, a subcutaneously infused humanized monoclonal anti-neonatal Fc receptor (FcRn) antibody, reduced serum IgG in healthy volunteers. In this phase 2, multicenter, open-label study, patients with persistent/chronic primary ITP received 1 to 5 once-weekly subcutaneous infusions of rozanolixizumab (cumulative doses, 15-21 mg/kg). Primary objectives were safety and tolerability, and secondary objectives were clinical efficacy (change in platelet count) and pharmacodynamic effect (change in IgG). In all, 51 (77.3%) of 66 patients reported 1 or more adverse events (AEs), all mild-to-moderate, most commonly headaches (26 [39.4%] of 66), of which 15 were treatment related. Four patients had serious AEs, but none were treatment related. No AEs resulted in discontinuation of the study drug. No serious infections occurred. Platelet counts of ≥50 × 109/L were achieved at least once at any time after multiple infusions (5 × 4, 3 × 7, or 2 × 10 mg/kg: 35.7%, 35.7%, and 45.5% of patients, respectively) or single infusions (15 or 20 mg/kg: 66.7% and 54.5% patients, respectively). Minimum mean IgG levels and maximum mean platelet counts both occurred by day 8 in the higher (15 and 20 mg/kg) single-dose cohorts and maximum platelet count occurred by day 11 onward in the multiple-dose cohorts. No clinically meaningful changes occurred in IgA, IgM, IgE, or albumin levels. In patients with persistent/chronic primary ITP, rozanolixizumab demonstrated a favorable safety profile and rapid, substantial platelet increases concordant with substantial IgG reductions, especially with single doses. By day 8, in the 15 and 20 mg/kg single-dose cohorts, >50% patients achieved clinically relevant platelet responses (≥50 × 109/L), coinciding with the lowest mean IgG levels. These data support phase 3 development of rozanolixizumab in persistent/chronic primary ITP. This trial was registered at www.clinicaltrials.gov as #NCT02718716.

Effect of using a wearable device on clinical decision-making and motor symptoms in patients with Parkinson's disease starting transdermal rotigotine patch: A pilot study.

BACKGROUND: Feedback from wearable biosensors may help assess motor function in Parkinson's disease (PD) patients and titrate medication. Kinesia 360 continuously monitors motor symptoms via wrist and ankle sensors. METHODS: PD0049 was a 12-week pilot study to investigate whether using Kinesia 360 at home could improve motor symptom management in PD patients starting transdermal dopamine agonist rotigotine. Adults with PD and insufficiently controlled motor symptoms (prescribed rotigotine) were randomized 1:1 to Control Group (CG) or Experimental Group (EG) before starting rotigotine. Motor symptoms were assessed in all patients at baseline and Week 12 (W12) using Unified PD Rating Scale (UPDRS) III and Kinesia ONE, which measures standardized motor tasks via a sensor on the index finger. Between baseline and W12, EG used Kinesia 360 at home; clinicians used the data to supplement standard care in adjusting rotigotine dosage. RESULTS: At W12, least squares mean improvements in UPDRS II (-2.1 vs 0.5, p = 0.004) and UPDRS III (-5.3 vs -1.0, p = 0.134) were clinically meaningfully greater, and mean rotigotine dosage higher (4.8 vs 3.9 mg/24 h) in EG (n = 19) vs CG (n = 20). Mean rotigotine dosage increase (+2.8 vs + 1.9 mg/24 h) and mean number of dosage changes (2.8 vs 1.8) during the study were higher in EG vs CG. Tolerability and retention rates were similar. CONCLUSION: Continuous, objective, motor symptom monitoring using a wearable biosensor as an adjunct to standard care may enhance clinical decision-making, and may improve outcomes in PD patients starting rotigotine.

Efficacy of Rotigotine at Different Stages of Parkinson's Disease Symptom Severity and Disability: A Post Hoc Analysis According to Baseline Hoehn and Yahr Stage.

BACKGROUND: The efficacy of rotigotine has been demonstrated in studies of patients with early (i.e. not receiving levodopa) and advanced (i.e. not adequately controlled on levodopa; average 2.5 h/day in 'off' state) Parkinson's disease (PD). OBJECTIVE: To further investigate the efficacy of rotigotine transdermal patch across different stages of PD symptom severity and functional disability, according to baseline Hoehn and Yahr (HY) staging. METHODS: Post hoc analysis of six placebo-controlled studies of rotigotine in patients with early PD (SP506, SP512, SP513; rotigotine ≤8 mg/24 h) or advanced-PD (CLEOPATRA-PD, PREFER, SP921; rotigotine ≤16 mg/24 h). Data were pooled and analyzed according to baseline HY stage (1, 2, 3 or 4) for change from baseline to end of maintenance in Unified Parkinson's Disease Rating Scale (UPDRS) II (activities of daily living), UPDRS III (motor) and UPDRS II+III; statistical tests are exploratory. RESULTS: Data were available for 2057 patients (HY 1 : 262; HY 2 : 1230; HY 3 : 524; HY 4 : 41). Patients at higher HY stages were older, had a longer time since PD diagnosis and higher baseline UPDRS II+III scores vs patients at lower HY stages. Rotigotine improved UPDRS II+III versus placebo for each individual HY stage (p < 0.05 for each HY stage), with treatment differences increasing with increasing HY stages. Similar results were observed for UPDRS II and UPDRS III. CONCLUSIONS: This post hoc analysis suggests that rotigotine may be efficacious across a broad range of progressive stages of PD symptom severity and functional disability (HY stages 1-4).

Impact of 6-month earlier versus postponed initiation of rotigotine on long-term outcome: post hoc analysis of patients with early Parkinson's disease with mild symptom severity.

OBJECTIVE: Investigate impact of 6-month earlier versus postponed initiation of rotigotine in patients with early Parkinson's disease (PD) with mild symptom severity. BACKGROUND: Long-term benefit of rotigotine in early-PD has been demonstrated: SP702 (NCT00594165) and SP716 (NCT00599196) were long-term, open-label extensions of double-blind, placebo-controlled studies of 6-month maintenance; rotigotine was well tolerated for up to 6 years, and demonstrated efficacy (Unified Parkinson's Disease Rating Scale [UPDRS] II + III below baseline) for ∼ 2 years (SP702) and ∼ 4 years (SP716). METHODS: Post hoc analysis of patients at Hoehn and Yahr 1-2; groups defined by treatment received in 6-month double-blind studies: 'Rotigotine-Rotigotine' received rotigotine (n = 221), 'Placebo-Rotigotine' received placebo (n = 125). RESULTS: At the start of open-label rotigotine maintenance, UPDRS II + III mean ± SD change from double-blind baseline was: -8.5 ± 10.6 'Rotigotine-Rotigotine', -7.7 ± 9.0 'Placebo-Rotigotine.' After this initial improvement scores gradually increased: It took ∼ 45 months for mean scores to cross baseline in 'Rotigotine-Rotigotine', and ∼ 21 months in 'Placebo-Rotigotine.' At the time mean UPDRS II + III had crossed baseline in 'Placebo-Rotigotine' (open-label week 84; ∼ 21 months), treatment difference (LS-mean) to 'Rotigotine-Rotigotine' change from baseline was -3.89 (95% CI -6.94, -0.84); p = 0.013. CONCLUSIONS: In this post hoc analysis, 6-month earlier initiation of rotigotine resulted in slower return to baseline mean UPDRS II + III; initiation of rotigotine in patients with minimal/no functional disability or impairment may lead to an extended benefit.