UCB, a global biopharmaceutical company, today announced results from two Phase 3 studies evaluating its investigational treatments, zilucoplan, a self-administered, subcutaneous (SC) peptide inhibitor of complement component 5 (C5 inhibitor) and rozanolixizumab, an SC-infused monoclonal antibody targeting the neonatal Fc receptor (FcRn) in adults with generalized myasthenia gravis (gMG).
Phase 3 RAISE results
Data from the Phase 3 RAISE trial (NCT04115293) (poster 26)1 demonstrated treatment with zilucoplan (0.3 mg/kg daily) resulted in clinically meaningful and statistically significant improvements in key gMG-specific outcomes compared with placebo in patients with acetylcholine receptor autoantibody positive (AChR+) gMG.
The study met its primary endpoint with zilucoplan showing a placebo-corrected mean improvement of 2.12 points in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score at week 12 (p<0.001). Significant improvement in the MG-ADL was observed from Week 1.
All key secondary endpoints were also met, including statistically significant improvements in the Quantitative Myasthenia Gravis (QMG) score, Myasthenia Gravis Composite (MGC) and Myasthenia Gravis Quality of Life 15-Item revised (MG-QoL15r), again with significant improvement observed from Week 1. The proportion of patients on zilucoplan who responded to treatment by at least a 3-point reduction on MG-ADL and at least a 5-point reduction in QMG were also significantly higher than placebo.
A favorable safety profile and good tolerability was observed, consistent with prior data, showing a similar rate of treatment-emergent adverse events (TEAEs) between zilucoplan (76.7%) and placebo (70.5%). The most common TEAEs were injection site bruising, headache, diarrhea, and MG worsening.
In the RAISE study, 174 patients were randomised to Placebo (N=88) and Zilucoplan 0.3 mg/kg (N=86). Patient demographics and baseline disease characteristics were generally balanced between treatment arms.
“The results from the RAISE study are an exciting development in the gMG treatment paradigm and reinforce the critical role that complement inhibition could play for physicians treating patients with this debilitating illness. By targeting the underlying mechanisms of gMG at the neuromuscular junction, complement inhibitors like zilucoplan have the potential to provide rapid, consistent disease control earlier in the disease course. These findings are an encouraging sign that we may be able to meet patients’ needs effectively, with treatments that are minimally invasive and well tolerated,” said James F. Howard, MD, Distinguished Professor of Neuromuscular Disease, Professor of Neurology, Medicine and Allied Health, The University of North Carolina at Chapel Hill School of Medicine and lead investigator in the RAISE trial.
Phase 3 MycarinG results
Results from the Phase 3 MycarinG study (NCT03971422) (poster 25)2 demonstrated that rozanolixizumab significantly reduced MG-ADL from baseline to Day 43 at ~7 mg/kg and ~10 mg/kg doses compared with placebo in patients with AChR or muscle-specific tyrosine kinase (MuSK) autoantibody positive gMG. Rozanolixizumab demonstrated a placebo-corrected mean improvement of 2.586 points at the ~7 mg/kg dose and 2.619 points in the MG-ADL at the ~10 mg/kg dose compared with placebo (both doses at p<0.001).
Rozanolixizumab treatment reduced mean maximum total IgG levels by more than 70% (71 % for 7 mg/kg and 78% for 10 mg/kg) and anti-AChR autoantibody levels decreased over the treatment period in line with the total IgG reduction. Rozanolixizumab was generally well tolerated, with the majority of TEAEs being mild to moderate in intensity. A higher proportion of TEAEs occurred in the active treatment arms versus placebo (81.3% for ~7 mg/kg, 82.6% for ~10 mg/kg and 67.2% for placebo). The most frequently reported TEAE was headache, most of which were mild to moderate, with severe headaches managed with over-the-counter analgesic medications. The other most common TEAEs were diarrhea, pyrexia and nausea.
Due to the fluctuating and unpredictable nature of gMG and the subjectivity of symptoms, patient reported outcomes (PROs) help provide greater insight into disease impact and more granular detail on the effect of treatments than traditional endpoints. Within the MycarinG study, the MG Symptoms PRO measure, which was developed by UCB with patients, was used to assess a series of quality-of-life measures, including muscle weakness fatigability, physical fatigue and bulbar muscle weakness, throughout the treatment and observation periods (poster 64)3. All three MG Symptoms PRO scales or subdomains showed significant improvement from baseline with rozanolixizumab ~7 mg/kg and 10 mg/kg doses compared with placebo at Day 43, indicating treatment with rozanolixizumab improves patients’ symptoms and their ability to undertake daily activities. Further evaluation of the MG Symptoms PRO measure is ongoing.
In the MycarinG study, a total of 66 patients were randomized to rozanolixizumab 7 mg/kg, 67 to rozanolixizumab 10 mg/kg and 67 to placebo. Baseline characteristics were generally balanced between treatment groups.
“The one constant in gMG is unpredictability. People living with this disease experience symptoms that are nebulous, fluctuating, and which vary from one day to the next. For this reason, there is an urgent need for more effective, targeted, and convenient treatments that reduce the burden of disease on patients’ daily lives. The results from the MycarinG study are extremely encouraging, and demonstrate the potential of rozanolixizumab as a new, effective and flexible treatment option to help ease the day-to-day burden of this challenging disease and improve treatment outcomes for patients,” said Professor Vera Bril, Professor of Medicine (Neurology), University of Toronto, Director of the Neuromuscular Section, Division of Neurology, University of Toronto and University Health Network, Toronto, and lead investigator of the MycarinG study.
“Every person living with gMG is unique, so a one-size-fits-all treatment approach will never be appropriate. This is why at UCB we are investigating two medicines with different MOAs. This unique approach means we may be able to offer physicians and patients a range of treatment options to meet the individual needs of many different patients, and therefore leave no one behind in our ambition to improve outcomes in gMG,” said Iris Loew-Friedrich, Executive Vice-President and Chief Medical Officer at UCB.
UCB anticipates filing regulatory submissions for both zilucoplan and rozanolixizumab later this year.
Digital innovation for patients living with myasthenia gravis
Findings from a three-month observational study carried out by UCB in collaboration with digital health company Sharecare, to collect real-world data from gMG patients using smartphones, were also presented at the conference (poster 84)4. Beyond demonstrating that decentralized, smartphone-based methods to collect real-world data from gMG patients are feasible and may provide enhanced visibility into the burden of the disease, the study also identified unique clusters of exacerbation subtypes with specific symptom representation. This requires further validation but suggests that digital phenotyping holds promise for furthering understanding of exacerbations. This analysis forms part of UCB’s holistic approach to delivering differentiated patient experiences, combining patient insights, pioneering research and artificial intelligence to deliver tailored support for individuals living with gMG.
“Our gMG pipeline is supported by a holistic and integrated platform of support services and digital innovation that aims to deliver broad access to seamless and flexible services across the gMG care continuum,” continued Charl van Zyl, Executive Vice President Neurology & Head of Europe/International Markets at UCB “Our ultimate goal is to transform the lives of people living with this challenging disease by putting patients at the center of our world and advancing scientific solutions that meet their complex and varying needs.”