Rozanolixizumab and Zilucoplan Phase 3 Generalised Myasthenia Gravis studies

• MycarinG study publication reports the clinically meaningful and statistically significant effects of rozanolixizumab across key endpoints in adult patients with acetylcholine receptor autoantibody positive (AChR-Ab+) or muscle-specific tyrosine kinase (MuSK-Ab+) autoantibody positive gMG, in the largest study in patients with gMG to date.
• RAISE publication describes clinically meaningful and statistically significant improvements in MG-specific efficacy outcomes, as well as a favorable safety profile, for zilucoplan, the first C5 complement inhibitor to be self-administered at home by adult patients with AChR-Ab+ gMG.  
• Rozanolixizumab and zilucoplan are investigational therapies currently under regulatory review in the U.S., Europe and Japan. 

13 April 2023: UCB, a global biopharmaceutical company, announced that The Lancet Neurology has published data from the Phase 3 MycarinG study evaluating the efficacy and safety of rozanolixizumab in adult patients with acetylcholine receptor autoantibody-positive (AChR-Ab+) or muscle-specific tyrosine kinase autoantibody-positive (MuSK-Ab+) generalised myasthenia gravis (gMG) and the Phase 3 RAISE study evaluating the efficacy and safety of zilucoplan in adult patients with mild to severe AChR-Ab+ gMG.^1,2

UCB is investigating both therapies as part of a broad offering to treat adult patients living with gMG throughout their treatment journey; each has an individual mechanism of action targeting the underlying disease pathology that causes gMG. 

The safety and efficacy of rozanolixizumab and zilucoplan have not been established and neither treatment is approved for use in any indication by any regulatory authority worldwide.

There is an ongoing need for well-tolerated, targeted treatment options to improve the quality of life of people living with gMG. Many of the current treatment options only offer symptomatic relief which results in a treatment burden in addition to the already substantial disease burden. These papers published in The Lancet Neurology further reinforce the potential of rozanolixizumab and zilucoplan – with their different MOAs – to provide targeted treatment options to patients to help them manage fluctuating and unpredictable symptoms both at home and in a healthcare setting.

Iris Loew-Friedrich, Executive Vice-President and Chief Medical Officer at UCB.

In the MycarinG study¹ (n=200) – the largest gMG population Phase 3 study published to date – in adult patients with AChR-Ab+ or MuSK-Ab+ gMG, rozanolixizumab demonstrated statistically significant and clinically meaningful improvements in MG-specific outcomes in patients with MuSK-Ab+ or AChR-Ab+ gMG, that were consistent with prior published results. 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). In the MuSK-Ab+ specific subgroup, improvement in MG-ADL was –7.28 (7mg/kg; n=5), –4.16 (10mg/kg; n=8), and 2.28 (placebo; n=8). In the AChR-Ab+ specific subgroup, improvement in MG-ADL was –3.03 (7mg/kg; n=60), –3.36, (10mg/kg; n=60), and –1.10 (placebo; n=59). 

Both rozanolixizumab doses were generally well tolerated with similar occurrences of TEAEs between both doses. The most frequently reported TEAEs were headache, diarrhea, and pyrexia. A higher incidence of headache was reported in the rozanolixizumab groups versus placebo, with most cases mild to moderate and severe cases generally managed with non-opioid analgesics. Treatment discontinuation rates due to TEAEs were low. 

Importantly, the MycarinG study included Patient-Reported Outcomes (PROs) measures as secondary endpoints. The novel Myasthenia Gravis Symptoms PRO (MGS-PRO) – a measure used to assess symptom severity and impact of MG on patient lives, including physical fatigue which is not covered in other MG clinical outcome assessments – demonstrated statistically significant results vs placebo.

“The findings from the MycarinG study support the mechanism of action of neonatal Fc receptor inhibition and the potential for rozanolixizumab in adult patients with acetylcholine receptor autoantibody positive (AChR-Ab+) or muscle-specific tyrosine kinase (MuSK-Ab+) autoantibody positive generalised myasthenia gravis,” explained  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. “Rozanolixizumab showed clinically meaningful improvements in patient-reported and investigator-assessed outcomes for both 7 mg/kg and 10 mg/kg doses. Both doses were generally well tolerated. If approved in the future, rozanolixizumab represents a potential additional treatment option for adult patients with generalised myasthenia gravis.”

In the RAISE study² (n=174), in adult patients with mild to severe AChR-Ab+ gMG, zilucoplan demonstrated rapid efficacy, with consistent, sustained, clinically meaningful and statistically significant improvements versus placebo from baseline to week 12 in both patient and clinician-reported endpoints, including MG-ADL, which was the primary efficacy endpoint, and QMG, MGC and MGQoL15, which were secondary efficacy endpoints (the threshold for clinically meaningful MG-QoL15r has not yet been established).² At Week 12, more patients receiving zilucoplan, achieved a ≥3-point reduction in MG-ADL score without rescue therapy, compared with those receiving placebo (73% and 46%, respectively; odds ratio [95% CI] = 3·18 [1·66, 6·10]; p=0·0005;). Additionally, more patients receiving zilucoplan, compared with those receiving placebo, (58% and 33%, respectively) achieved a ≥5-point reduction in QMG score without rescue therapy at Week 12 (odds ratio [95% CI] = 2·87 [1·52, 5·40]; p=0·0012;).

Zilucoplan was generally well tolerated with a favorable safety profile. The most frequently reported TEAEs in the zilucoplan group were injection site bruising, headache, diarrhea, and (worsening of) MG.² Incidences of serious TEAEs and serious infections were similar in both groups. All patients who completed the 12-week treatment period (n=166) chose to enroll in RAISE-XT, the ongoing open label extension study.² If approved, zilucoplan would be the first C5 complement inhibitor in gMG that patients can self-administer at home.

“In the RAISE study, zilucoplan showed rapid and clinically meaningful improvements in myasthenia gravis-specific efficacy outcomes, had a favorable safety profile, and was generally well tolerated, with no major safety findings,” 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. “These results suggest that, if approved in the future, zilucoplan could present a potential new treatment option for a broad population of adult patients with AChR-Ab+ generalised myasthenia gravis.”

Earlier this year, the US Food and Drug Administration (FDA) accepted UCB’s filing to review a Biologic License Application (BLA) for rozanolixizumab for the treatment of gMG in adult patients. The BLA was designated for Priority Review, with a response from the agency anticipated in Q2 2023. This BLA followed the European Medicines Agency’s (EMA) validation of the Marketing Authorization Application (MAA) for rozanolixizumab, and the FDA’s acceptance of a New Drug Application (NDA) and the EMA’s validation of the MAA for zilucoplan in the same indication. Regulatory applications for rozanolixizumab and zilucoplan for the treatment of gMG have also been filed in Japan. Responses from regulatory agencies to these submissions are expected in H2 2023. 
 
“Our ultimate goal is to provide targeted treatment options that can help reduce the ongoing daily burden of gMG, giving patients additional flexible treatment options that work alongside their daily life,” said Charl van Zyl, Executive Vice President Neurology Solutions & Head of EU/International Markets, UCB. “With measures such as MGS-PRO in the MycarinG study, we have been able to see the positive impact rozanolixizumab has had on patient experience, while results from the RAISE study demonstrated the potential of zilucoplan as an effective and generally well-tolerated treatment that can be self-administered at home, giving people greater independence. These results bring us one step forward towards offering tailored options to meet individual patient needs.”  

gMG is a rare, chronic, heterogeneous (phenotypic and pathogenic), and unpredictable auto-immune disease characterised by dysfunction and damage at the neuromuscular junction.³ Several factors are understood to be drivers of gMG disease pathology, including complement, immune cells and pathogenic IgG autoantibodies.⁴

People living with gMG can experience a variety of symptoms, including drooping eyelids, double vision, and difficulty in swallowing, chewing and talking, as well as severe muscle weakness that can result in life-threatening weakness of the muscles of respiration.^5,6 MG is a rare disease with a global prevalence of 100–350 cases per every 1 million people.⁷

References:

1. Bril V. Efficacy and safety of rozanolixizumab in patients with generalised myasthenia gravis: a randomised, double-blind, placebo-controlled, adaptive Phase 3 study MyCarinG study. The Lancet Neurology. 2023. Published online. Available at: http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(23)00077-7/fulltext 
2. Howard J, Efficacy and safety of zilucoplan in patients with generalised myasthenia gravis: A randomised, double-blind, placebo-controlled, Phase 3 study (RAISE). The Lancet Neurology. 2023. Published online. Available at: http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(23)00080-7/fulltext
3. Juel VC, Massey JM. Myasthenia gravis. Orphanet J Rare Dis. 2007;2:44.
4. Phillips WD, Vincent A. Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms. F1000Res. 2016;5(F1000 Faculty Rev):1513.
5. Myasthenia Gravis Foundation of America. Clinical Overview of MG. https://myasthenia.org/Professionals/Clinical-Overview-of-MG. Accessed February 2023
6. Hansen JS, et al. Mortality in myasthenia gravis: A nationwide population-based follow-up study in Denmark. Muscle Nerve. 2016; 53: 73-77.
7. Punga, Anna Rostedt et al. “Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders.” The Lancet. Neurology vol. 21,2 (2022): 176-188. doi:10.1016/S1474-4422(21)00297-0
8. ClinicalTrials.gov ‘A Study to Test Efficacy and Safety of Rozanolixizumab in Adult Patients With Generalized Myasthenia Gravis’:  https://clinicaltrials.gov/ct2/show/NCT03971422. Accessed February 2023.
9. ClinicalTrials.gov ‘A Study to Evaluate Rozanolixizumab in Study Participants With Generalized Myasthenia Gravis’. https://clinicaltrials.gov/ct2/show/NCT04650854?term=Rozanolixizumab&draw=2&rank=3
10. Kiessling P, et al. The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized Phase 1 study. Sci Transl Med. 2017;9(414:eaan1208).
11. Smith B, et al. Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration. MAbs. 2018;10:1111-1113.
12. US Food and Drug Administration. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=669918. Accessed March 2023
13. European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3202272. Accessed March 2023
14. ClinicalTrials.gov ‘Safety, Tolerability, and Efficacy of Zilucoplan in Subjects With Generalized Myasthenia Gravis (RAISE)’: https://clinicaltrials.gov/ct2/show/NCT04115293. Accessed March 2023.
15. US Food and Drug Administration. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=699319. Accessed March 2023.
16. Data on file, UCB inc